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Slide 1 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development
Slide 2 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM
Slide 3 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance
Slide 4 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension
Slide 5 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing
Slide 6 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997
Slide 7 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion
Slide 8 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin
Slide 9 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells
Slide 10 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997
Slide 11 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid
Slide 12 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion
Slide 13 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001
Slide 14 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000
Slide 15 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000
Slide 16 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible
Slide 17 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant
Slide 18 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml
Slide 19 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml
Slide 20 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000
Slide 21 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day
Slide 22 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day
Slide 23 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive
Slide 24 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion
Slide 25 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done
Slide 26 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30
Slide 27 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies
Slide 28 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion
Slide 29 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose
Slide 30 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates
Slide 31 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone
Slide 32 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015
Slide 33 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance)
Slide 34 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level
Slide 35 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg
Slide 36 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001)
Slide 37 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen
Slide 38 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure
Slide 39 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001
Slide 40 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997
Slide 41 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997 Study 95-001 Experimental Design *Baseline tympanocentesis
Slide 42 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997 Study 95-001 Experimental Design *Baseline tympanocentesis Study 95-001 Patient Disposition
Slide 43 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997 Study 95-001 Experimental Design *Baseline tympanocentesis Study 95-001 Patient Disposition Study 95-001 Demographics 0% 2% Black 98% 97% White Race: 48% 56% % Male 2.3 (+ 1.4) 2.5 (+ 1.3) Mean Age (Yrs, ±SD) 31 (47%) 40 (61%) 2 Yrs - 12 Yrs 35 (53%) 26 (39%) < 2 Yrs Age: N = 66 Single Dose N = 66 Azithromycin 2% 95% 55% 2.7 (+ 1.5) 40 (61%) 26 (39%) Three Day N = 66 Ceftriaxone 2% 2% Hispanic 3%
Slide 44 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997 Study 95-001 Experimental Design *Baseline tympanocentesis Study 95-001 Patient Disposition Study 95-001 Demographics 0% 2% Black 98% 97% White Race: 48% 56% % Male 2.3 (+ 1.4) 2.5 (+ 1.3) Mean Age (Yrs, ±SD) 31 (47%) 40 (61%) 2 Yrs - 12 Yrs 35 (53%) 26 (39%) < 2 Yrs Age: N = 66 Single Dose N = 66 Azithromycin 2% 95% 55% 2.7 (+ 1.5) 40 (61%) 26 (39%) Three Day N = 66 Ceftriaxone 2% 2% Hispanic 3% Study 95-001 Results
Slide 45 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997 Study 95-001 Experimental Design *Baseline tympanocentesis Study 95-001 Patient Disposition Study 95-001 Demographics 0% 2% Black 98% 97% White Race: 48% 56% % Male 2.3 (+ 1.4) 2.5 (+ 1.3) Mean Age (Yrs, ±SD) 31 (47%) 40 (61%) 2 Yrs - 12 Yrs 35 (53%) 26 (39%) < 2 Yrs Age: N = 66 Single Dose N = 66 Azithromycin 2% 95% 55% 2.7 (+ 1.5) 40 (61%) 26 (39%) Three Day N = 66 Ceftriaxone 2% 2% Hispanic 3% Study 95-001 Results Study 95-001 Clinical Efficacy Population 4 (6) Failure 5 Improvement [- 5, 25] 56 (86) Cure [-12,6] 61 (94) Success 65 Day 28 2 (3) Failure 36 Improvement 26 Cure [-8,5] 62 (97) Success 64 Day 14 66 Randomized Patients 95% CI1 [%] 1 Day (%) 1 95% CI for (single dose azithromycin – comparator) 5 (8) 10 51 (77) 61 (92) 66 3 (5) 42 18 60 (95) 63 66 3 Day (%) 2 (3) 13 49 (77) 62 (97) 64 1 (2) 40 21 61 (98) 62 66 Ceftriaxone (%) Azithromycin
Slide 46 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997 Study 95-001 Experimental Design *Baseline tympanocentesis Study 95-001 Patient Disposition Study 95-001 Demographics 0% 2% Black 98% 97% White Race: 48% 56% % Male 2.3 (+ 1.4) 2.5 (+ 1.3) Mean Age (Yrs, ±SD) 31 (47%) 40 (61%) 2 Yrs - 12 Yrs 35 (53%) 26 (39%) < 2 Yrs Age: N = 66 Single Dose N = 66 Azithromycin 2% 95% 55% 2.7 (+ 1.5) 40 (61%) 26 (39%) Three Day N = 66 Ceftriaxone 2% 2% Hispanic 3% Study 95-001 Results Study 95-001 Clinical Efficacy Population 4 (6) Failure 5 Improvement [- 5, 25] 56 (86) Cure [-12,6] 61 (94) Success 65 Day 28 2 (3) Failure 36 Improvement 26 Cure [-8,5] 62 (97) Success 64 Day 14 66 Randomized Patients 95% CI1 [%] 1 Day (%) 1 95% CI for (single dose azithromycin – comparator) 5 (8) 10 51 (77) 61 (92) 66 3 (5) 42 18 60 (95) 63 66 3 Day (%) 2 (3) 13 49 (77) 62 (97) 64 1 (2) 40 21 61 (98) 62 66 Ceftriaxone (%) Azithromycin Study 95-001 Clinical Outcome at Day 28 by Age 5 (16) 6 (15) 3 (8) Failure 26 (84) 33 (85) 37 (93) Cure 31 39 40 > 2 years of age 10 (30) 9 (33) 6 (24) Failure 23 (70) 18 (67) 19 (76) Cure 33 27 25 < 2 years of age Ceftriaxone (%) 3 Day (%) 1 Day (%) Azithromycin
Slide 47 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997 Study 95-001 Experimental Design *Baseline tympanocentesis Study 95-001 Patient Disposition Study 95-001 Demographics 0% 2% Black 98% 97% White Race: 48% 56% % Male 2.3 (+ 1.4) 2.5 (+ 1.3) Mean Age (Yrs, ±SD) 31 (47%) 40 (61%) 2 Yrs - 12 Yrs 35 (53%) 26 (39%) < 2 Yrs Age: N = 66 Single Dose N = 66 Azithromycin 2% 95% 55% 2.7 (+ 1.5) 40 (61%) 26 (39%) Three Day N = 66 Ceftriaxone 2% 2% Hispanic 3% Study 95-001 Results Study 95-001 Clinical Efficacy Population 4 (6) Failure 5 Improvement [- 5, 25] 56 (86) Cure [-12,6] 61 (94) Success 65 Day 28 2 (3) Failure 36 Improvement 26 Cure [-8,5] 62 (97) Success 64 Day 14 66 Randomized Patients 95% CI1 [%] 1 Day (%) 1 95% CI for (single dose azithromycin – comparator) 5 (8) 10 51 (77) 61 (92) 66 3 (5) 42 18 60 (95) 63 66 3 Day (%) 2 (3) 13 49 (77) 62 (97) 64 1 (2) 40 21 61 (98) 62 66 Ceftriaxone (%) Azithromycin Study 95-001 Clinical Outcome at Day 28 by Age 5 (16) 6 (15) 3 (8) Failure 26 (84) 33 (85) 37 (93) Cure 31 39 40 > 2 years of age 10 (30) 9 (33) 6 (24) Failure 23 (70) 18 (67) 19 (76) Cure 33 27 25 < 2 years of age Ceftriaxone (%) 3 Day (%) 1 Day (%) Azithromycin Study 95-001 Susceptibility S. pneumoniae susceptibility (N=57) Azithromycin 46 susceptible 11 resistant (MIC > 0.5 mg/ml) Ceftriaxone All isolates were susceptible to ceftriaxone All H. influenzae and M. catarrhalis were susceptible to azithromycin and ceftriaxone
Slide 48 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997 Study 95-001 Experimental Design *Baseline tympanocentesis Study 95-001 Patient Disposition Study 95-001 Demographics 0% 2% Black 98% 97% White Race: 48% 56% % Male 2.3 (+ 1.4) 2.5 (+ 1.3) Mean Age (Yrs, ±SD) 31 (47%) 40 (61%) 2 Yrs - 12 Yrs 35 (53%) 26 (39%) < 2 Yrs Age: N = 66 Single Dose N = 66 Azithromycin 2% 95% 55% 2.7 (+ 1.5) 40 (61%) 26 (39%) Three Day N = 66 Ceftriaxone 2% 2% Hispanic 3% Study 95-001 Results Study 95-001 Clinical Efficacy Population 4 (6) Failure 5 Improvement [- 5, 25] 56 (86) Cure [-12,6] 61 (94) Success 65 Day 28 2 (3) Failure 36 Improvement 26 Cure [-8,5] 62 (97) Success 64 Day 14 66 Randomized Patients 95% CI1 [%] 1 Day (%) 1 95% CI for (single dose azithromycin – comparator) 5 (8) 10 51 (77) 61 (92) 66 3 (5) 42 18 60 (95) 63 66 3 Day (%) 2 (3) 13 49 (77) 62 (97) 64 1 (2) 40 21 61 (98) 62 66 Ceftriaxone (%) Azithromycin Study 95-001 Clinical Outcome at Day 28 by Age 5 (16) 6 (15) 3 (8) Failure 26 (84) 33 (85) 37 (93) Cure 31 39 40 > 2 years of age 10 (30) 9 (33) 6 (24) Failure 23 (70) 18 (67) 19 (76) Cure 33 27 25 < 2 years of age Ceftriaxone (%) 3 Day (%) 1 Day (%) Azithromycin Study 95-001 Susceptibility S. pneumoniae susceptibility (N=57) Azithromycin 46 susceptible 11 resistant (MIC > 0.5 mg/ml) Ceftriaxone All isolates were susceptible to ceftriaxone All H. influenzae and M. catarrhalis were susceptible to azithromycin and ceftriaxone Study 95-001 Clinical Cure Per Baseline Pathogen at Day 28
Slide 49 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997 Study 95-001 Experimental Design *Baseline tympanocentesis Study 95-001 Patient Disposition Study 95-001 Demographics 0% 2% Black 98% 97% White Race: 48% 56% % Male 2.3 (+ 1.4) 2.5 (+ 1.3) Mean Age (Yrs, ±SD) 31 (47%) 40 (61%) 2 Yrs - 12 Yrs 35 (53%) 26 (39%) < 2 Yrs Age: N = 66 Single Dose N = 66 Azithromycin 2% 95% 55% 2.7 (+ 1.5) 40 (61%) 26 (39%) Three Day N = 66 Ceftriaxone 2% 2% Hispanic 3% Study 95-001 Results Study 95-001 Clinical Efficacy Population 4 (6) Failure 5 Improvement [- 5, 25] 56 (86) Cure [-12,6] 61 (94) Success 65 Day 28 2 (3) Failure 36 Improvement 26 Cure [-8,5] 62 (97) Success 64 Day 14 66 Randomized Patients 95% CI1 [%] 1 Day (%) 1 95% CI for (single dose azithromycin – comparator) 5 (8) 10 51 (77) 61 (92) 66 3 (5) 42 18 60 (95) 63 66 3 Day (%) 2 (3) 13 49 (77) 62 (97) 64 1 (2) 40 21 61 (98) 62 66 Ceftriaxone (%) Azithromycin Study 95-001 Clinical Outcome at Day 28 by Age 5 (16) 6 (15) 3 (8) Failure 26 (84) 33 (85) 37 (93) Cure 31 39 40 > 2 years of age 10 (30) 9 (33) 6 (24) Failure 23 (70) 18 (67) 19 (76) Cure 33 27 25 < 2 years of age Ceftriaxone (%) 3 Day (%) 1 Day (%) Azithromycin Study 95-001 Susceptibility S. pneumoniae susceptibility (N=57) Azithromycin 46 susceptible 11 resistant (MIC > 0.5 mg/ml) Ceftriaxone All isolates were susceptible to ceftriaxone All H. influenzae and M. catarrhalis were susceptible to azithromycin and ceftriaxone Study 95-001 Clinical Cure Per Baseline Pathogen at Day 28 Study 95-001 Treatment Related Adverse Events* 0 (0) 0 (0) 3 (5) Vomiting 4 (6) 0 (0) 1 (2) Rash 4 (6) 3 (5) 2 (3) Diarrhea 6 (9) 6 (9) 7 (11) Patients w/ AE 66 66 66 Patients Treated Ceftriaxone 3 Day 1 Day 0 (0) 0 (0) 0 (0) Discontinued *2 or more events on any treatment regimen Azithromycin
Slide 50 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997 Study 95-001 Experimental Design *Baseline tympanocentesis Study 95-001 Patient Disposition Study 95-001 Demographics 0% 2% Black 98% 97% White Race: 48% 56% % Male 2.3 (+ 1.4) 2.5 (+ 1.3) Mean Age (Yrs, ±SD) 31 (47%) 40 (61%) 2 Yrs - 12 Yrs 35 (53%) 26 (39%) < 2 Yrs Age: N = 66 Single Dose N = 66 Azithromycin 2% 95% 55% 2.7 (+ 1.5) 40 (61%) 26 (39%) Three Day N = 66 Ceftriaxone 2% 2% Hispanic 3% Study 95-001 Results Study 95-001 Clinical Efficacy Population 4 (6) Failure 5 Improvement [- 5, 25] 56 (86) Cure [-12,6] 61 (94) Success 65 Day 28 2 (3) Failure 36 Improvement 26 Cure [-8,5] 62 (97) Success 64 Day 14 66 Randomized Patients 95% CI1 [%] 1 Day (%) 1 95% CI for (single dose azithromycin – comparator) 5 (8) 10 51 (77) 61 (92) 66 3 (5) 42 18 60 (95) 63 66 3 Day (%) 2 (3) 13 49 (77) 62 (97) 64 1 (2) 40 21 61 (98) 62 66 Ceftriaxone (%) Azithromycin Study 95-001 Clinical Outcome at Day 28 by Age 5 (16) 6 (15) 3 (8) Failure 26 (84) 33 (85) 37 (93) Cure 31 39 40 > 2 years of age 10 (30) 9 (33) 6 (24) Failure 23 (70) 18 (67) 19 (76) Cure 33 27 25 < 2 years of age Ceftriaxone (%) 3 Day (%) 1 Day (%) Azithromycin Study 95-001 Susceptibility S. pneumoniae susceptibility (N=57) Azithromycin 46 susceptible 11 resistant (MIC > 0.5 mg/ml) Ceftriaxone All isolates were susceptible to ceftriaxone All H. influenzae and M. catarrhalis were susceptible to azithromycin and ceftriaxone Study 95-001 Clinical Cure Per Baseline Pathogen at Day 28 Study 95-001 Treatment Related Adverse Events* 0 (0) 0 (0) 3 (5) Vomiting 4 (6) 0 (0) 1 (2) Rash 4 (6) 3 (5) 2 (3) Diarrhea 6 (9) 6 (9) 7 (11) Patients w/ AE 66 66 66 Patients Treated Ceftriaxone 3 Day 1 Day 0 (0) 0 (0) 0 (0) Discontinued *2 or more events on any treatment regimen Azithromycin Study R-0581 Single Dose Therapy
Slide 51 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997 Study 95-001 Experimental Design *Baseline tympanocentesis Study 95-001 Patient Disposition Study 95-001 Demographics 0% 2% Black 98% 97% White Race: 48% 56% % Male 2.3 (+ 1.4) 2.5 (+ 1.3) Mean Age (Yrs, ±SD) 31 (47%) 40 (61%) 2 Yrs - 12 Yrs 35 (53%) 26 (39%) < 2 Yrs Age: N = 66 Single Dose N = 66 Azithromycin 2% 95% 55% 2.7 (+ 1.5) 40 (61%) 26 (39%) Three Day N = 66 Ceftriaxone 2% 2% Hispanic 3% Study 95-001 Results Study 95-001 Clinical Efficacy Population 4 (6) Failure 5 Improvement [- 5, 25] 56 (86) Cure [-12,6] 61 (94) Success 65 Day 28 2 (3) Failure 36 Improvement 26 Cure [-8,5] 62 (97) Success 64 Day 14 66 Randomized Patients 95% CI1 [%] 1 Day (%) 1 95% CI for (single dose azithromycin – comparator) 5 (8) 10 51 (77) 61 (92) 66 3 (5) 42 18 60 (95) 63 66 3 Day (%) 2 (3) 13 49 (77) 62 (97) 64 1 (2) 40 21 61 (98) 62 66 Ceftriaxone (%) Azithromycin Study 95-001 Clinical Outcome at Day 28 by Age 5 (16) 6 (15) 3 (8) Failure 26 (84) 33 (85) 37 (93) Cure 31 39 40 > 2 years of age 10 (30) 9 (33) 6 (24) Failure 23 (70) 18 (67) 19 (76) Cure 33 27 25 < 2 years of age Ceftriaxone (%) 3 Day (%) 1 Day (%) Azithromycin Study 95-001 Susceptibility S. pneumoniae susceptibility (N=57) Azithromycin 46 susceptible 11 resistant (MIC > 0.5 mg/ml) Ceftriaxone All isolates were susceptible to ceftriaxone All H. influenzae and M. catarrhalis were susceptible to azithromycin and ceftriaxone Study 95-001 Clinical Cure Per Baseline Pathogen at Day 28 Study 95-001 Treatment Related Adverse Events* 0 (0) 0 (0) 3 (5) Vomiting 4 (6) 0 (0) 1 (2) Rash 4 (6) 3 (5) 2 (3) Diarrhea 6 (9) 6 (9) 7 (11) Patients w/ AE 66 66 66 Patients Treated Ceftriaxone 3 Day 1 Day 0 (0) 0 (0) 0 (0) Discontinued *2 or more events on any treatment regimen Azithromycin Study R-0581 Single Dose Therapy Study R-0581 Objective Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 30 mg/kg single oral dose Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug
Slide 52 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997 Study 95-001 Experimental Design *Baseline tympanocentesis Study 95-001 Patient Disposition Study 95-001 Demographics 0% 2% Black 98% 97% White Race: 48% 56% % Male 2.3 (+ 1.4) 2.5 (+ 1.3) Mean Age (Yrs, ±SD) 31 (47%) 40 (61%) 2 Yrs - 12 Yrs 35 (53%) 26 (39%) < 2 Yrs Age: N = 66 Single Dose N = 66 Azithromycin 2% 95% 55% 2.7 (+ 1.5) 40 (61%) 26 (39%) Three Day N = 66 Ceftriaxone 2% 2% Hispanic 3% Study 95-001 Results Study 95-001 Clinical Efficacy Population 4 (6) Failure 5 Improvement [- 5, 25] 56 (86) Cure [-12,6] 61 (94) Success 65 Day 28 2 (3) Failure 36 Improvement 26 Cure [-8,5] 62 (97) Success 64 Day 14 66 Randomized Patients 95% CI1 [%] 1 Day (%) 1 95% CI for (single dose azithromycin – comparator) 5 (8) 10 51 (77) 61 (92) 66 3 (5) 42 18 60 (95) 63 66 3 Day (%) 2 (3) 13 49 (77) 62 (97) 64 1 (2) 40 21 61 (98) 62 66 Ceftriaxone (%) Azithromycin Study 95-001 Clinical Outcome at Day 28 by Age 5 (16) 6 (15) 3 (8) Failure 26 (84) 33 (85) 37 (93) Cure 31 39 40 > 2 years of age 10 (30) 9 (33) 6 (24) Failure 23 (70) 18 (67) 19 (76) Cure 33 27 25 < 2 years of age Ceftriaxone (%) 3 Day (%) 1 Day (%) Azithromycin Study 95-001 Susceptibility S. pneumoniae susceptibility (N=57) Azithromycin 46 susceptible 11 resistant (MIC > 0.5 mg/ml) Ceftriaxone All isolates were susceptible to ceftriaxone All H. influenzae and M. catarrhalis were susceptible to azithromycin and ceftriaxone Study 95-001 Clinical Cure Per Baseline Pathogen at Day 28 Study 95-001 Treatment Related Adverse Events* 0 (0) 0 (0) 3 (5) Vomiting 4 (6) 0 (0) 1 (2) Rash 4 (6) 3 (5) 2 (3) Diarrhea 6 (9) 6 (9) 7 (11) Patients w/ AE 66 66 66 Patients Treated Ceftriaxone 3 Day 1 Day 0 (0) 0 (0) 0 (0) Discontinued *2 or more events on any treatment regimen Azithromycin Study R-0581 Single Dose Therapy Study R-0581 Objective Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 30 mg/kg single oral dose Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study R-0581 Visits and Assessments *Patients who vomited within 30 minutes were redosed 1 Including parental questionnaire
Slide 53 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997 Study 95-001 Experimental Design *Baseline tympanocentesis Study 95-001 Patient Disposition Study 95-001 Demographics 0% 2% Black 98% 97% White Race: 48% 56% % Male 2.3 (+ 1.4) 2.5 (+ 1.3) Mean Age (Yrs, ±SD) 31 (47%) 40 (61%) 2 Yrs - 12 Yrs 35 (53%) 26 (39%) < 2 Yrs Age: N = 66 Single Dose N = 66 Azithromycin 2% 95% 55% 2.7 (+ 1.5) 40 (61%) 26 (39%) Three Day N = 66 Ceftriaxone 2% 2% Hispanic 3% Study 95-001 Results Study 95-001 Clinical Efficacy Population 4 (6) Failure 5 Improvement [- 5, 25] 56 (86) Cure [-12,6] 61 (94) Success 65 Day 28 2 (3) Failure 36 Improvement 26 Cure [-8,5] 62 (97) Success 64 Day 14 66 Randomized Patients 95% CI1 [%] 1 Day (%) 1 95% CI for (single dose azithromycin – comparator) 5 (8) 10 51 (77) 61 (92) 66 3 (5) 42 18 60 (95) 63 66 3 Day (%) 2 (3) 13 49 (77) 62 (97) 64 1 (2) 40 21 61 (98) 62 66 Ceftriaxone (%) Azithromycin Study 95-001 Clinical Outcome at Day 28 by Age 5 (16) 6 (15) 3 (8) Failure 26 (84) 33 (85) 37 (93) Cure 31 39 40 > 2 years of age 10 (30) 9 (33) 6 (24) Failure 23 (70) 18 (67) 19 (76) Cure 33 27 25 < 2 years of age Ceftriaxone (%) 3 Day (%) 1 Day (%) Azithromycin Study 95-001 Susceptibility S. pneumoniae susceptibility (N=57) Azithromycin 46 susceptible 11 resistant (MIC > 0.5 mg/ml) Ceftriaxone All isolates were susceptible to ceftriaxone All H. influenzae and M. catarrhalis were susceptible to azithromycin and ceftriaxone Study 95-001 Clinical Cure Per Baseline Pathogen at Day 28 Study 95-001 Treatment Related Adverse Events* 0 (0) 0 (0) 3 (5) Vomiting 4 (6) 0 (0) 1 (2) Rash 4 (6) 3 (5) 2 (3) Diarrhea 6 (9) 6 (9) 7 (11) Patients w/ AE 66 66 66 Patients Treated Ceftriaxone 3 Day 1 Day 0 (0) 0 (0) 0 (0) Discontinued *2 or more events on any treatment regimen Azithromycin Study R-0581 Single Dose Therapy Study R-0581 Objective Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 30 mg/kg single oral dose Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study R-0581 Visits and Assessments *Patients who vomited within 30 minutes were redosed 1 Including parental questionnaire Study R-0581 Patient Disposition
Slide 54 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997 Study 95-001 Experimental Design *Baseline tympanocentesis Study 95-001 Patient Disposition Study 95-001 Demographics 0% 2% Black 98% 97% White Race: 48% 56% % Male 2.3 (+ 1.4) 2.5 (+ 1.3) Mean Age (Yrs, ±SD) 31 (47%) 40 (61%) 2 Yrs - 12 Yrs 35 (53%) 26 (39%) < 2 Yrs Age: N = 66 Single Dose N = 66 Azithromycin 2% 95% 55% 2.7 (+ 1.5) 40 (61%) 26 (39%) Three Day N = 66 Ceftriaxone 2% 2% Hispanic 3% Study 95-001 Results Study 95-001 Clinical Efficacy Population 4 (6) Failure 5 Improvement [- 5, 25] 56 (86) Cure [-12,6] 61 (94) Success 65 Day 28 2 (3) Failure 36 Improvement 26 Cure [-8,5] 62 (97) Success 64 Day 14 66 Randomized Patients 95% CI1 [%] 1 Day (%) 1 95% CI for (single dose azithromycin – comparator) 5 (8) 10 51 (77) 61 (92) 66 3 (5) 42 18 60 (95) 63 66 3 Day (%) 2 (3) 13 49 (77) 62 (97) 64 1 (2) 40 21 61 (98) 62 66 Ceftriaxone (%) Azithromycin Study 95-001 Clinical Outcome at Day 28 by Age 5 (16) 6 (15) 3 (8) Failure 26 (84) 33 (85) 37 (93) Cure 31 39 40 > 2 years of age 10 (30) 9 (33) 6 (24) Failure 23 (70) 18 (67) 19 (76) Cure 33 27 25 < 2 years of age Ceftriaxone (%) 3 Day (%) 1 Day (%) Azithromycin Study 95-001 Susceptibility S. pneumoniae susceptibility (N=57) Azithromycin 46 susceptible 11 resistant (MIC > 0.5 mg/ml) Ceftriaxone All isolates were susceptible to ceftriaxone All H. influenzae and M. catarrhalis were susceptible to azithromycin and ceftriaxone Study 95-001 Clinical Cure Per Baseline Pathogen at Day 28 Study 95-001 Treatment Related Adverse Events* 0 (0) 0 (0) 3 (5) Vomiting 4 (6) 0 (0) 1 (2) Rash 4 (6) 3 (5) 2 (3) Diarrhea 6 (9) 6 (9) 7 (11) Patients w/ AE 66 66 66 Patients Treated Ceftriaxone 3 Day 1 Day 0 (0) 0 (0) 0 (0) Discontinued *2 or more events on any treatment regimen Azithromycin Study R-0581 Single Dose Therapy Study R-0581 Objective Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 30 mg/kg single oral dose Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study R-0581 Visits and Assessments *Patients who vomited within 30 minutes were redosed 1 Including parental questionnaire Study R-0581 Patient Disposition Study R-0581 Demographics
Slide 55 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997 Study 95-001 Experimental Design *Baseline tympanocentesis Study 95-001 Patient Disposition Study 95-001 Demographics 0% 2% Black 98% 97% White Race: 48% 56% % Male 2.3 (+ 1.4) 2.5 (+ 1.3) Mean Age (Yrs, ±SD) 31 (47%) 40 (61%) 2 Yrs - 12 Yrs 35 (53%) 26 (39%) < 2 Yrs Age: N = 66 Single Dose N = 66 Azithromycin 2% 95% 55% 2.7 (+ 1.5) 40 (61%) 26 (39%) Three Day N = 66 Ceftriaxone 2% 2% Hispanic 3% Study 95-001 Results Study 95-001 Clinical Efficacy Population 4 (6) Failure 5 Improvement [- 5, 25] 56 (86) Cure [-12,6] 61 (94) Success 65 Day 28 2 (3) Failure 36 Improvement 26 Cure [-8,5] 62 (97) Success 64 Day 14 66 Randomized Patients 95% CI1 [%] 1 Day (%) 1 95% CI for (single dose azithromycin – comparator) 5 (8) 10 51 (77) 61 (92) 66 3 (5) 42 18 60 (95) 63 66 3 Day (%) 2 (3) 13 49 (77) 62 (97) 64 1 (2) 40 21 61 (98) 62 66 Ceftriaxone (%) Azithromycin Study 95-001 Clinical Outcome at Day 28 by Age 5 (16) 6 (15) 3 (8) Failure 26 (84) 33 (85) 37 (93) Cure 31 39 40 > 2 years of age 10 (30) 9 (33) 6 (24) Failure 23 (70) 18 (67) 19 (76) Cure 33 27 25 < 2 years of age Ceftriaxone (%) 3 Day (%) 1 Day (%) Azithromycin Study 95-001 Susceptibility S. pneumoniae susceptibility (N=57) Azithromycin 46 susceptible 11 resistant (MIC > 0.5 mg/ml) Ceftriaxone All isolates were susceptible to ceftriaxone All H. influenzae and M. catarrhalis were susceptible to azithromycin and ceftriaxone Study 95-001 Clinical Cure Per Baseline Pathogen at Day 28 Study 95-001 Treatment Related Adverse Events* 0 (0) 0 (0) 3 (5) Vomiting 4 (6) 0 (0) 1 (2) Rash 4 (6) 3 (5) 2 (3) Diarrhea 6 (9) 6 (9) 7 (11) Patients w/ AE 66 66 66 Patients Treated Ceftriaxone 3 Day 1 Day 0 (0) 0 (0) 0 (0) Discontinued *2 or more events on any treatment regimen Azithromycin Study R-0581 Single Dose Therapy Study R-0581 Objective Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 30 mg/kg single oral dose Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study R-0581 Visits and Assessments *Patients who vomited within 30 minutes were redosed 1 Including parental questionnaire Study R-0581 Patient Disposition Study R-0581 Demographics Study R-0581 Results
Slide 56 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997 Study 95-001 Experimental Design *Baseline tympanocentesis Study 95-001 Patient Disposition Study 95-001 Demographics 0% 2% Black 98% 97% White Race: 48% 56% % Male 2.3 (+ 1.4) 2.5 (+ 1.3) Mean Age (Yrs, ±SD) 31 (47%) 40 (61%) 2 Yrs - 12 Yrs 35 (53%) 26 (39%) < 2 Yrs Age: N = 66 Single Dose N = 66 Azithromycin 2% 95% 55% 2.7 (+ 1.5) 40 (61%) 26 (39%) Three Day N = 66 Ceftriaxone 2% 2% Hispanic 3% Study 95-001 Results Study 95-001 Clinical Efficacy Population 4 (6) Failure 5 Improvement [- 5, 25] 56 (86) Cure [-12,6] 61 (94) Success 65 Day 28 2 (3) Failure 36 Improvement 26 Cure [-8,5] 62 (97) Success 64 Day 14 66 Randomized Patients 95% CI1 [%] 1 Day (%) 1 95% CI for (single dose azithromycin – comparator) 5 (8) 10 51 (77) 61 (92) 66 3 (5) 42 18 60 (95) 63 66 3 Day (%) 2 (3) 13 49 (77) 62 (97) 64 1 (2) 40 21 61 (98) 62 66 Ceftriaxone (%) Azithromycin Study 95-001 Clinical Outcome at Day 28 by Age 5 (16) 6 (15) 3 (8) Failure 26 (84) 33 (85) 37 (93) Cure 31 39 40 > 2 years of age 10 (30) 9 (33) 6 (24) Failure 23 (70) 18 (67) 19 (76) Cure 33 27 25 < 2 years of age Ceftriaxone (%) 3 Day (%) 1 Day (%) Azithromycin Study 95-001 Susceptibility S. pneumoniae susceptibility (N=57) Azithromycin 46 susceptible 11 resistant (MIC > 0.5 mg/ml) Ceftriaxone All isolates were susceptible to ceftriaxone All H. influenzae and M. catarrhalis were susceptible to azithromycin and ceftriaxone Study 95-001 Clinical Cure Per Baseline Pathogen at Day 28 Study 95-001 Treatment Related Adverse Events* 0 (0) 0 (0) 3 (5) Vomiting 4 (6) 0 (0) 1 (2) Rash 4 (6) 3 (5) 2 (3) Diarrhea 6 (9) 6 (9) 7 (11) Patients w/ AE 66 66 66 Patients Treated Ceftriaxone 3 Day 1 Day 0 (0) 0 (0) 0 (0) Discontinued *2 or more events on any treatment regimen Azithromycin Study R-0581 Single Dose Therapy Study R-0581 Objective Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 30 mg/kg single oral dose Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study R-0581 Visits and Assessments *Patients who vomited within 30 minutes were redosed 1 Including parental questionnaire Study R-0581 Patient Disposition Study R-0581 Demographics Study R-0581 Results Study R-0581 Clinical Outcome 38 (25) 37 (25) Failure 8 2 Improvement [-7, 15] 108 (70) 112 (74) Cure [-10, 11] 116 (75) 114 (75) Success 154 151 Day 28 19 (12) 21 (13) Failure 21 34 Improvement 121 105 Cure [-9, 7] 142 (88) 139 (87) Success 161 160 Day 14 173 173 Number of Patients 95% CI1[%] Amox/Clav (%) Azithromycin (%) 1 95% CI for (azithromycin – comparator)
Slide 57 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997 Study 95-001 Experimental Design *Baseline tympanocentesis Study 95-001 Patient Disposition Study 95-001 Demographics 0% 2% Black 98% 97% White Race: 48% 56% % Male 2.3 (+ 1.4) 2.5 (+ 1.3) Mean Age (Yrs, ±SD) 31 (47%) 40 (61%) 2 Yrs - 12 Yrs 35 (53%) 26 (39%) < 2 Yrs Age: N = 66 Single Dose N = 66 Azithromycin 2% 95% 55% 2.7 (+ 1.5) 40 (61%) 26 (39%) Three Day N = 66 Ceftriaxone 2% 2% Hispanic 3% Study 95-001 Results Study 95-001 Clinical Efficacy Population 4 (6) Failure 5 Improvement [- 5, 25] 56 (86) Cure [-12,6] 61 (94) Success 65 Day 28 2 (3) Failure 36 Improvement 26 Cure [-8,5] 62 (97) Success 64 Day 14 66 Randomized Patients 95% CI1 [%] 1 Day (%) 1 95% CI for (single dose azithromycin – comparator) 5 (8) 10 51 (77) 61 (92) 66 3 (5) 42 18 60 (95) 63 66 3 Day (%) 2 (3) 13 49 (77) 62 (97) 64 1 (2) 40 21 61 (98) 62 66 Ceftriaxone (%) Azithromycin Study 95-001 Clinical Outcome at Day 28 by Age 5 (16) 6 (15) 3 (8) Failure 26 (84) 33 (85) 37 (93) Cure 31 39 40 > 2 years of age 10 (30) 9 (33) 6 (24) Failure 23 (70) 18 (67) 19 (76) Cure 33 27 25 < 2 years of age Ceftriaxone (%) 3 Day (%) 1 Day (%) Azithromycin Study 95-001 Susceptibility S. pneumoniae susceptibility (N=57) Azithromycin 46 susceptible 11 resistant (MIC > 0.5 mg/ml) Ceftriaxone All isolates were susceptible to ceftriaxone All H. influenzae and M. catarrhalis were susceptible to azithromycin and ceftriaxone Study 95-001 Clinical Cure Per Baseline Pathogen at Day 28 Study 95-001 Treatment Related Adverse Events* 0 (0) 0 (0) 3 (5) Vomiting 4 (6) 0 (0) 1 (2) Rash 4 (6) 3 (5) 2 (3) Diarrhea 6 (9) 6 (9) 7 (11) Patients w/ AE 66 66 66 Patients Treated Ceftriaxone 3 Day 1 Day 0 (0) 0 (0) 0 (0) Discontinued *2 or more events on any treatment regimen Azithromycin Study R-0581 Single Dose Therapy Study R-0581 Objective Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 30 mg/kg single oral dose Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study R-0581 Visits and Assessments *Patients who vomited within 30 minutes were redosed 1 Including parental questionnaire Study R-0581 Patient Disposition Study R-0581 Demographics Study R-0581 Results Study R-0581 Clinical Outcome 38 (25) 37 (25) Failure 8 2 Improvement [-7, 15] 108 (70) 112 (74) Cure [-10, 11] 116 (75) 114 (75) Success 154 151 Day 28 19 (12) 21 (13) Failure 21 34 Improvement 121 105 Cure [-9, 7] 142 (88) 139 (87) Success 161 160 Day 14 173 173 Number of Patients 95% CI1[%] Amox/Clav (%) Azithromycin (%) 1 95% CI for (azithromycin – comparator) Study R-0581 Clinical Outcome at Day 28 by Age Cure 26 (49) 24 (38) Failure [-8, 31] 95% CI1[%] Failure < 2 years of age 27 (51) 40 (63) Cure 53 64 > 2 years of age Amox/Clav Azithromycin 1 95% CI for (azithromycin – comparator) N (%) N (%) 72 (83) 15 (17) 87 81 (80) 20 (20) 101 [-10, 15]
Slide 58 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997 Study 95-001 Experimental Design *Baseline tympanocentesis Study 95-001 Patient Disposition Study 95-001 Demographics 0% 2% Black 98% 97% White Race: 48% 56% % Male 2.3 (+ 1.4) 2.5 (+ 1.3) Mean Age (Yrs, ±SD) 31 (47%) 40 (61%) 2 Yrs - 12 Yrs 35 (53%) 26 (39%) < 2 Yrs Age: N = 66 Single Dose N = 66 Azithromycin 2% 95% 55% 2.7 (+ 1.5) 40 (61%) 26 (39%) Three Day N = 66 Ceftriaxone 2% 2% Hispanic 3% Study 95-001 Results Study 95-001 Clinical Efficacy Population 4 (6) Failure 5 Improvement [- 5, 25] 56 (86) Cure [-12,6] 61 (94) Success 65 Day 28 2 (3) Failure 36 Improvement 26 Cure [-8,5] 62 (97) Success 64 Day 14 66 Randomized Patients 95% CI1 [%] 1 Day (%) 1 95% CI for (single dose azithromycin – comparator) 5 (8) 10 51 (77) 61 (92) 66 3 (5) 42 18 60 (95) 63 66 3 Day (%) 2 (3) 13 49 (77) 62 (97) 64 1 (2) 40 21 61 (98) 62 66 Ceftriaxone (%) Azithromycin Study 95-001 Clinical Outcome at Day 28 by Age 5 (16) 6 (15) 3 (8) Failure 26 (84) 33 (85) 37 (93) Cure 31 39 40 > 2 years of age 10 (30) 9 (33) 6 (24) Failure 23 (70) 18 (67) 19 (76) Cure 33 27 25 < 2 years of age Ceftriaxone (%) 3 Day (%) 1 Day (%) Azithromycin Study 95-001 Susceptibility S. pneumoniae susceptibility (N=57) Azithromycin 46 susceptible 11 resistant (MIC > 0.5 mg/ml) Ceftriaxone All isolates were susceptible to ceftriaxone All H. influenzae and M. catarrhalis were susceptible to azithromycin and ceftriaxone Study 95-001 Clinical Cure Per Baseline Pathogen at Day 28 Study 95-001 Treatment Related Adverse Events* 0 (0) 0 (0) 3 (5) Vomiting 4 (6) 0 (0) 1 (2) Rash 4 (6) 3 (5) 2 (3) Diarrhea 6 (9) 6 (9) 7 (11) Patients w/ AE 66 66 66 Patients Treated Ceftriaxone 3 Day 1 Day 0 (0) 0 (0) 0 (0) Discontinued *2 or more events on any treatment regimen Azithromycin Study R-0581 Single Dose Therapy Study R-0581 Objective Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 30 mg/kg single oral dose Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study R-0581 Visits and Assessments *Patients who vomited within 30 minutes were redosed 1 Including parental questionnaire Study R-0581 Patient Disposition Study R-0581 Demographics Study R-0581 Results Study R-0581 Clinical Outcome 38 (25) 37 (25) Failure 8 2 Improvement [-7, 15] 108 (70) 112 (74) Cure [-10, 11] 116 (75) 114 (75) Success 154 151 Day 28 19 (12) 21 (13) Failure 21 34 Improvement 121 105 Cure [-9, 7] 142 (88) 139 (87) Success 161 160 Day 14 173 173 Number of Patients 95% CI1[%] Amox/Clav (%) Azithromycin (%) 1 95% CI for (azithromycin – comparator) Study R-0581 Clinical Outcome at Day 28 by Age Cure 26 (49) 24 (38) Failure [-8, 31] 95% CI1[%] Failure < 2 years of age 27 (51) 40 (63) Cure 53 64 > 2 years of age Amox/Clav Azithromycin 1 95% CI for (azithromycin – comparator) N (%) N (%) 72 (83) 15 (17) 87 81 (80) 20 (20) 101 [-10, 15] Study R-0581 Compliance Based on patients randomized to their study drug regimen
Slide 59 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997 Study 95-001 Experimental Design *Baseline tympanocentesis Study 95-001 Patient Disposition Study 95-001 Demographics 0% 2% Black 98% 97% White Race: 48% 56% % Male 2.3 (+ 1.4) 2.5 (+ 1.3) Mean Age (Yrs, ±SD) 31 (47%) 40 (61%) 2 Yrs - 12 Yrs 35 (53%) 26 (39%) < 2 Yrs Age: N = 66 Single Dose N = 66 Azithromycin 2% 95% 55% 2.7 (+ 1.5) 40 (61%) 26 (39%) Three Day N = 66 Ceftriaxone 2% 2% Hispanic 3% Study 95-001 Results Study 95-001 Clinical Efficacy Population 4 (6) Failure 5 Improvement [- 5, 25] 56 (86) Cure [-12,6] 61 (94) Success 65 Day 28 2 (3) Failure 36 Improvement 26 Cure [-8,5] 62 (97) Success 64 Day 14 66 Randomized Patients 95% CI1 [%] 1 Day (%) 1 95% CI for (single dose azithromycin – comparator) 5 (8) 10 51 (77) 61 (92) 66 3 (5) 42 18 60 (95) 63 66 3 Day (%) 2 (3) 13 49 (77) 62 (97) 64 1 (2) 40 21 61 (98) 62 66 Ceftriaxone (%) Azithromycin Study 95-001 Clinical Outcome at Day 28 by Age 5 (16) 6 (15) 3 (8) Failure 26 (84) 33 (85) 37 (93) Cure 31 39 40 > 2 years of age 10 (30) 9 (33) 6 (24) Failure 23 (70) 18 (67) 19 (76) Cure 33 27 25 < 2 years of age Ceftriaxone (%) 3 Day (%) 1 Day (%) Azithromycin Study 95-001 Susceptibility S. pneumoniae susceptibility (N=57) Azithromycin 46 susceptible 11 resistant (MIC > 0.5 mg/ml) Ceftriaxone All isolates were susceptible to ceftriaxone All H. influenzae and M. catarrhalis were susceptible to azithromycin and ceftriaxone Study 95-001 Clinical Cure Per Baseline Pathogen at Day 28 Study 95-001 Treatment Related Adverse Events* 0 (0) 0 (0) 3 (5) Vomiting 4 (6) 0 (0) 1 (2) Rash 4 (6) 3 (5) 2 (3) Diarrhea 6 (9) 6 (9) 7 (11) Patients w/ AE 66 66 66 Patients Treated Ceftriaxone 3 Day 1 Day 0 (0) 0 (0) 0 (0) Discontinued *2 or more events on any treatment regimen Azithromycin Study R-0581 Single Dose Therapy Study R-0581 Objective Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 30 mg/kg single oral dose Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study R-0581 Visits and Assessments *Patients who vomited within 30 minutes were redosed 1 Including parental questionnaire Study R-0581 Patient Disposition Study R-0581 Demographics Study R-0581 Results Study R-0581 Clinical Outcome 38 (25) 37 (25) Failure 8 2 Improvement [-7, 15] 108 (70) 112 (74) Cure [-10, 11] 116 (75) 114 (75) Success 154 151 Day 28 19 (12) 21 (13) Failure 21 34 Improvement 121 105 Cure [-9, 7] 142 (88) 139 (87) Success 161 160 Day 14 173 173 Number of Patients 95% CI1[%] Amox/Clav (%) Azithromycin (%) 1 95% CI for (azithromycin – comparator) Study R-0581 Clinical Outcome at Day 28 by Age Cure 26 (49) 24 (38) Failure [-8, 31] 95% CI1[%] Failure < 2 years of age 27 (51) 40 (63) Cure 53 64 > 2 years of age Amox/Clav Azithromycin 1 95% CI for (azithromycin – comparator) N (%) N (%) 72 (83) 15 (17) 87 81 (80) 20 (20) 101 [-10, 15] Study R-0581 Compliance Based on patients randomized to their study drug regimen Study R-0581 Treatment Related Adverse Events* 7 (4%) 7 (4%) Vomiting 9 (5%) 3 (2%) 22 (13%) 11 (6%) Diarrhea 39 (23%) 29 (17%) Patients w/ AEs Rash Azithromycin N = 173 Amox/Clav N = 173 7(4%) 4 (2%) Discontinued due to AE * Adverse Events greater than 2 percent in either regimen
Slide 60 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997 Study 95-001 Experimental Design *Baseline tympanocentesis Study 95-001 Patient Disposition Study 95-001 Demographics 0% 2% Black 98% 97% White Race: 48% 56% % Male 2.3 (+ 1.4) 2.5 (+ 1.3) Mean Age (Yrs, ±SD) 31 (47%) 40 (61%) 2 Yrs - 12 Yrs 35 (53%) 26 (39%) < 2 Yrs Age: N = 66 Single Dose N = 66 Azithromycin 2% 95% 55% 2.7 (+ 1.5) 40 (61%) 26 (39%) Three Day N = 66 Ceftriaxone 2% 2% Hispanic 3% Study 95-001 Results Study 95-001 Clinical Efficacy Population 4 (6) Failure 5 Improvement [- 5, 25] 56 (86) Cure [-12,6] 61 (94) Success 65 Day 28 2 (3) Failure 36 Improvement 26 Cure [-8,5] 62 (97) Success 64 Day 14 66 Randomized Patients 95% CI1 [%] 1 Day (%) 1 95% CI for (single dose azithromycin – comparator) 5 (8) 10 51 (77) 61 (92) 66 3 (5) 42 18 60 (95) 63 66 3 Day (%) 2 (3) 13 49 (77) 62 (97) 64 1 (2) 40 21 61 (98) 62 66 Ceftriaxone (%) Azithromycin Study 95-001 Clinical Outcome at Day 28 by Age 5 (16) 6 (15) 3 (8) Failure 26 (84) 33 (85) 37 (93) Cure 31 39 40 > 2 years of age 10 (30) 9 (33) 6 (24) Failure 23 (70) 18 (67) 19 (76) Cure 33 27 25 < 2 years of age Ceftriaxone (%) 3 Day (%) 1 Day (%) Azithromycin Study 95-001 Susceptibility S. pneumoniae susceptibility (N=57) Azithromycin 46 susceptible 11 resistant (MIC > 0.5 mg/ml) Ceftriaxone All isolates were susceptible to ceftriaxone All H. influenzae and M. catarrhalis were susceptible to azithromycin and ceftriaxone Study 95-001 Clinical Cure Per Baseline Pathogen at Day 28 Study 95-001 Treatment Related Adverse Events* 0 (0) 0 (0) 3 (5) Vomiting 4 (6) 0 (0) 1 (2) Rash 4 (6) 3 (5) 2 (3) Diarrhea 6 (9) 6 (9) 7 (11) Patients w/ AE 66 66 66 Patients Treated Ceftriaxone 3 Day 1 Day 0 (0) 0 (0) 0 (0) Discontinued *2 or more events on any treatment regimen Azithromycin Study R-0581 Single Dose Therapy Study R-0581 Objective Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 30 mg/kg single oral dose Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study R-0581 Visits and Assessments *Patients who vomited within 30 minutes were redosed 1 Including parental questionnaire Study R-0581 Patient Disposition Study R-0581 Demographics Study R-0581 Results Study R-0581 Clinical Outcome 38 (25) 37 (25) Failure 8 2 Improvement [-7, 15] 108 (70) 112 (74) Cure [-10, 11] 116 (75) 114 (75) Success 154 151 Day 28 19 (12) 21 (13) Failure 21 34 Improvement 121 105 Cure [-9, 7] 142 (88) 139 (87) Success 161 160 Day 14 173 173 Number of Patients 95% CI1[%] Amox/Clav (%) Azithromycin (%) 1 95% CI for (azithromycin – comparator) Study R-0581 Clinical Outcome at Day 28 by Age Cure 26 (49) 24 (38) Failure [-8, 31] 95% CI1[%] Failure < 2 years of age 27 (51) 40 (63) Cure 53 64 > 2 years of age Amox/Clav Azithromycin 1 95% CI for (azithromycin – comparator) N (%) N (%) 72 (83) 15 (17) 87 81 (80) 20 (20) 101 [-10, 15] Study R-0581 Compliance Based on patients randomized to their study drug regimen Study R-0581 Treatment Related Adverse Events* 7 (4%) 7 (4%) Vomiting 9 (5%) 3 (2%) 22 (13%) 11 (6%) Diarrhea 39 (23%) 29 (17%) Patients w/ AEs Rash Azithromycin N = 173 Amox/Clav N = 173 7(4%) 4 (2%) Discontinued due to AE * Adverse Events greater than 2 percent in either regimen Study 1015 Single Dose Therapy
Slide 61 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997 Study 95-001 Experimental Design *Baseline tympanocentesis Study 95-001 Patient Disposition Study 95-001 Demographics 0% 2% Black 98% 97% White Race: 48% 56% % Male 2.3 (+ 1.4) 2.5 (+ 1.3) Mean Age (Yrs, ±SD) 31 (47%) 40 (61%) 2 Yrs - 12 Yrs 35 (53%) 26 (39%) < 2 Yrs Age: N = 66 Single Dose N = 66 Azithromycin 2% 95% 55% 2.7 (+ 1.5) 40 (61%) 26 (39%) Three Day N = 66 Ceftriaxone 2% 2% Hispanic 3% Study 95-001 Results Study 95-001 Clinical Efficacy Population 4 (6) Failure 5 Improvement [- 5, 25] 56 (86) Cure [-12,6] 61 (94) Success 65 Day 28 2 (3) Failure 36 Improvement 26 Cure [-8,5] 62 (97) Success 64 Day 14 66 Randomized Patients 95% CI1 [%] 1 Day (%) 1 95% CI for (single dose azithromycin – comparator) 5 (8) 10 51 (77) 61 (92) 66 3 (5) 42 18 60 (95) 63 66 3 Day (%) 2 (3) 13 49 (77) 62 (97) 64 1 (2) 40 21 61 (98) 62 66 Ceftriaxone (%) Azithromycin Study 95-001 Clinical Outcome at Day 28 by Age 5 (16) 6 (15) 3 (8) Failure 26 (84) 33 (85) 37 (93) Cure 31 39 40 > 2 years of age 10 (30) 9 (33) 6 (24) Failure 23 (70) 18 (67) 19 (76) Cure 33 27 25 < 2 years of age Ceftriaxone (%) 3 Day (%) 1 Day (%) Azithromycin Study 95-001 Susceptibility S. pneumoniae susceptibility (N=57) Azithromycin 46 susceptible 11 resistant (MIC > 0.5 mg/ml) Ceftriaxone All isolates were susceptible to ceftriaxone All H. influenzae and M. catarrhalis were susceptible to azithromycin and ceftriaxone Study 95-001 Clinical Cure Per Baseline Pathogen at Day 28 Study 95-001 Treatment Related Adverse Events* 0 (0) 0 (0) 3 (5) Vomiting 4 (6) 0 (0) 1 (2) Rash 4 (6) 3 (5) 2 (3) Diarrhea 6 (9) 6 (9) 7 (11) Patients w/ AE 66 66 66 Patients Treated Ceftriaxone 3 Day 1 Day 0 (0) 0 (0) 0 (0) Discontinued *2 or more events on any treatment regimen Azithromycin Study R-0581 Single Dose Therapy Study R-0581 Objective Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 30 mg/kg single oral dose Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study R-0581 Visits and Assessments *Patients who vomited within 30 minutes were redosed 1 Including parental questionnaire Study R-0581 Patient Disposition Study R-0581 Demographics Study R-0581 Results Study R-0581 Clinical Outcome 38 (25) 37 (25) Failure 8 2 Improvement [-7, 15] 108 (70) 112 (74) Cure [-10, 11] 116 (75) 114 (75) Success 154 151 Day 28 19 (12) 21 (13) Failure 21 34 Improvement 121 105 Cure [-9, 7] 142 (88) 139 (87) Success 161 160 Day 14 173 173 Number of Patients 95% CI1[%] Amox/Clav (%) Azithromycin (%) 1 95% CI for (azithromycin – comparator) Study R-0581 Clinical Outcome at Day 28 by Age Cure 26 (49) 24 (38) Failure [-8, 31] 95% CI1[%] Failure < 2 years of age 27 (51) 40 (63) Cure 53 64 > 2 years of age Amox/Clav Azithromycin 1 95% CI for (azithromycin – comparator) N (%) N (%) 72 (83) 15 (17) 87 81 (80) 20 (20) 101 [-10, 15] Study R-0581 Compliance Based on patients randomized to their study drug regimen Study R-0581 Treatment Related Adverse Events* 7 (4%) 7 (4%) Vomiting 9 (5%) 3 (2%) 22 (13%) 11 (6%) Diarrhea 39 (23%) 29 (17%) Patients w/ AEs Rash Azithromycin N = 173 Amox/Clav N = 173 7(4%) 4 (2%) Discontinued due to AE * Adverse Events greater than 2 percent in either regimen Study 1015 Single Dose Therapy Study 1015 Objectives To assess per-pathogen clinical response rates To provide additional data on the safety and toleration of the single dose regimen Design Prospective Open-label Non-comparative Multi-center
Slide 62 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997 Study 95-001 Experimental Design *Baseline tympanocentesis Study 95-001 Patient Disposition Study 95-001 Demographics 0% 2% Black 98% 97% White Race: 48% 56% % Male 2.3 (+ 1.4) 2.5 (+ 1.3) Mean Age (Yrs, ±SD) 31 (47%) 40 (61%) 2 Yrs - 12 Yrs 35 (53%) 26 (39%) < 2 Yrs Age: N = 66 Single Dose N = 66 Azithromycin 2% 95% 55% 2.7 (+ 1.5) 40 (61%) 26 (39%) Three Day N = 66 Ceftriaxone 2% 2% Hispanic 3% Study 95-001 Results Study 95-001 Clinical Efficacy Population 4 (6) Failure 5 Improvement [- 5, 25] 56 (86) Cure [-12,6] 61 (94) Success 65 Day 28 2 (3) Failure 36 Improvement 26 Cure [-8,5] 62 (97) Success 64 Day 14 66 Randomized Patients 95% CI1 [%] 1 Day (%) 1 95% CI for (single dose azithromycin – comparator) 5 (8) 10 51 (77) 61 (92) 66 3 (5) 42 18 60 (95) 63 66 3 Day (%) 2 (3) 13 49 (77) 62 (97) 64 1 (2) 40 21 61 (98) 62 66 Ceftriaxone (%) Azithromycin Study 95-001 Clinical Outcome at Day 28 by Age 5 (16) 6 (15) 3 (8) Failure 26 (84) 33 (85) 37 (93) Cure 31 39 40 > 2 years of age 10 (30) 9 (33) 6 (24) Failure 23 (70) 18 (67) 19 (76) Cure 33 27 25 < 2 years of age Ceftriaxone (%) 3 Day (%) 1 Day (%) Azithromycin Study 95-001 Susceptibility S. pneumoniae susceptibility (N=57) Azithromycin 46 susceptible 11 resistant (MIC > 0.5 mg/ml) Ceftriaxone All isolates were susceptible to ceftriaxone All H. influenzae and M. catarrhalis were susceptible to azithromycin and ceftriaxone Study 95-001 Clinical Cure Per Baseline Pathogen at Day 28 Study 95-001 Treatment Related Adverse Events* 0 (0) 0 (0) 3 (5) Vomiting 4 (6) 0 (0) 1 (2) Rash 4 (6) 3 (5) 2 (3) Diarrhea 6 (9) 6 (9) 7 (11) Patients w/ AE 66 66 66 Patients Treated Ceftriaxone 3 Day 1 Day 0 (0) 0 (0) 0 (0) Discontinued *2 or more events on any treatment regimen Azithromycin Study R-0581 Single Dose Therapy Study R-0581 Objective Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 30 mg/kg single oral dose Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study R-0581 Visits and Assessments *Patients who vomited within 30 minutes were redosed 1 Including parental questionnaire Study R-0581 Patient Disposition Study R-0581 Demographics Study R-0581 Results Study R-0581 Clinical Outcome 38 (25) 37 (25) Failure 8 2 Improvement [-7, 15] 108 (70) 112 (74) Cure [-10, 11] 116 (75) 114 (75) Success 154 151 Day 28 19 (12) 21 (13) Failure 21 34 Improvement 121 105 Cure [-9, 7] 142 (88) 139 (87) Success 161 160 Day 14 173 173 Number of Patients 95% CI1[%] Amox/Clav (%) Azithromycin (%) 1 95% CI for (azithromycin – comparator) Study R-0581 Clinical Outcome at Day 28 by Age Cure 26 (49) 24 (38) Failure [-8, 31] 95% CI1[%] Failure < 2 years of age 27 (51) 40 (63) Cure 53 64 > 2 years of age Amox/Clav Azithromycin 1 95% CI for (azithromycin – comparator) N (%) N (%) 72 (83) 15 (17) 87 81 (80) 20 (20) 101 [-10, 15] Study R-0581 Compliance Based on patients randomized to their study drug regimen Study R-0581 Treatment Related Adverse Events* 7 (4%) 7 (4%) Vomiting 9 (5%) 3 (2%) 22 (13%) 11 (6%) Diarrhea 39 (23%) 29 (17%) Patients w/ AEs Rash Azithromycin N = 173 Amox/Clav N = 173 7(4%) 4 (2%) Discontinued due to AE * Adverse Events greater than 2 percent in either regimen Study 1015 Single Dose Therapy Study 1015 Objectives To assess per-pathogen clinical response rates To provide additional data on the safety and toleration of the single dose regimen Design Prospective Open-label Non-comparative Multi-center Study 1015 Visits and Assessments *Patients who vomited within 30 minutes were redosed
Slide 63 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997 Study 95-001 Experimental Design *Baseline tympanocentesis Study 95-001 Patient Disposition Study 95-001 Demographics 0% 2% Black 98% 97% White Race: 48% 56% % Male 2.3 (+ 1.4) 2.5 (+ 1.3) Mean Age (Yrs, ±SD) 31 (47%) 40 (61%) 2 Yrs - 12 Yrs 35 (53%) 26 (39%) < 2 Yrs Age: N = 66 Single Dose N = 66 Azithromycin 2% 95% 55% 2.7 (+ 1.5) 40 (61%) 26 (39%) Three Day N = 66 Ceftriaxone 2% 2% Hispanic 3% Study 95-001 Results Study 95-001 Clinical Efficacy Population 4 (6) Failure 5 Improvement [- 5, 25] 56 (86) Cure [-12,6] 61 (94) Success 65 Day 28 2 (3) Failure 36 Improvement 26 Cure [-8,5] 62 (97) Success 64 Day 14 66 Randomized Patients 95% CI1 [%] 1 Day (%) 1 95% CI for (single dose azithromycin – comparator) 5 (8) 10 51 (77) 61 (92) 66 3 (5) 42 18 60 (95) 63 66 3 Day (%) 2 (3) 13 49 (77) 62 (97) 64 1 (2) 40 21 61 (98) 62 66 Ceftriaxone (%) Azithromycin Study 95-001 Clinical Outcome at Day 28 by Age 5 (16) 6 (15) 3 (8) Failure 26 (84) 33 (85) 37 (93) Cure 31 39 40 > 2 years of age 10 (30) 9 (33) 6 (24) Failure 23 (70) 18 (67) 19 (76) Cure 33 27 25 < 2 years of age Ceftriaxone (%) 3 Day (%) 1 Day (%) Azithromycin Study 95-001 Susceptibility S. pneumoniae susceptibility (N=57) Azithromycin 46 susceptible 11 resistant (MIC > 0.5 mg/ml) Ceftriaxone All isolates were susceptible to ceftriaxone All H. influenzae and M. catarrhalis were susceptible to azithromycin and ceftriaxone Study 95-001 Clinical Cure Per Baseline Pathogen at Day 28 Study 95-001 Treatment Related Adverse Events* 0 (0) 0 (0) 3 (5) Vomiting 4 (6) 0 (0) 1 (2) Rash 4 (6) 3 (5) 2 (3) Diarrhea 6 (9) 6 (9) 7 (11) Patients w/ AE 66 66 66 Patients Treated Ceftriaxone 3 Day 1 Day 0 (0) 0 (0) 0 (0) Discontinued *2 or more events on any treatment regimen Azithromycin Study R-0581 Single Dose Therapy Study R-0581 Objective Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 30 mg/kg single oral dose Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study R-0581 Visits and Assessments *Patients who vomited within 30 minutes were redosed 1 Including parental questionnaire Study R-0581 Patient Disposition Study R-0581 Demographics Study R-0581 Results Study R-0581 Clinical Outcome 38 (25) 37 (25) Failure 8 2 Improvement [-7, 15] 108 (70) 112 (74) Cure [-10, 11] 116 (75) 114 (75) Success 154 151 Day 28 19 (12) 21 (13) Failure 21 34 Improvement 121 105 Cure [-9, 7] 142 (88) 139 (87) Success 161 160 Day 14 173 173 Number of Patients 95% CI1[%] Amox/Clav (%) Azithromycin (%) 1 95% CI for (azithromycin – comparator) Study R-0581 Clinical Outcome at Day 28 by Age Cure 26 (49) 24 (38) Failure [-8, 31] 95% CI1[%] Failure < 2 years of age 27 (51) 40 (63) Cure 53 64 > 2 years of age Amox/Clav Azithromycin 1 95% CI for (azithromycin – comparator) N (%) N (%) 72 (83) 15 (17) 87 81 (80) 20 (20) 101 [-10, 15] Study R-0581 Compliance Based on patients randomized to their study drug regimen Study R-0581 Treatment Related Adverse Events* 7 (4%) 7 (4%) Vomiting 9 (5%) 3 (2%) 22 (13%) 11 (6%) Diarrhea 39 (23%) 29 (17%) Patients w/ AEs Rash Azithromycin N = 173 Amox/Clav N = 173 7(4%) 4 (2%) Discontinued due to AE * Adverse Events greater than 2 percent in either regimen Study 1015 Single Dose Therapy Study 1015 Objectives To assess per-pathogen clinical response rates To provide additional data on the safety and toleration of the single dose regimen Design Prospective Open-label Non-comparative Multi-center Study 1015 Visits and Assessments *Patients who vomited within 30 minutes were redosed Study 1015 Endpoints Primary Efficacy Endpoint Clinical response by baseline pathogen at day 28 Initial local laboratory isolation of pathogen with confirmation by central laboratory Secondary Efficacy Endpoints Clinical response at day 28 (test of cure) Clinical response at day 10 Safety Evaluation
Slide 64 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997 Study 95-001 Experimental Design *Baseline tympanocentesis Study 95-001 Patient Disposition Study 95-001 Demographics 0% 2% Black 98% 97% White Race: 48% 56% % Male 2.3 (+ 1.4) 2.5 (+ 1.3) Mean Age (Yrs, ±SD) 31 (47%) 40 (61%) 2 Yrs - 12 Yrs 35 (53%) 26 (39%) < 2 Yrs Age: N = 66 Single Dose N = 66 Azithromycin 2% 95% 55% 2.7 (+ 1.5) 40 (61%) 26 (39%) Three Day N = 66 Ceftriaxone 2% 2% Hispanic 3% Study 95-001 Results Study 95-001 Clinical Efficacy Population 4 (6) Failure 5 Improvement [- 5, 25] 56 (86) Cure [-12,6] 61 (94) Success 65 Day 28 2 (3) Failure 36 Improvement 26 Cure [-8,5] 62 (97) Success 64 Day 14 66 Randomized Patients 95% CI1 [%] 1 Day (%) 1 95% CI for (single dose azithromycin – comparator) 5 (8) 10 51 (77) 61 (92) 66 3 (5) 42 18 60 (95) 63 66 3 Day (%) 2 (3) 13 49 (77) 62 (97) 64 1 (2) 40 21 61 (98) 62 66 Ceftriaxone (%) Azithromycin Study 95-001 Clinical Outcome at Day 28 by Age 5 (16) 6 (15) 3 (8) Failure 26 (84) 33 (85) 37 (93) Cure 31 39 40 > 2 years of age 10 (30) 9 (33) 6 (24) Failure 23 (70) 18 (67) 19 (76) Cure 33 27 25 < 2 years of age Ceftriaxone (%) 3 Day (%) 1 Day (%) Azithromycin Study 95-001 Susceptibility S. pneumoniae susceptibility (N=57) Azithromycin 46 susceptible 11 resistant (MIC > 0.5 mg/ml) Ceftriaxone All isolates were susceptible to ceftriaxone All H. influenzae and M. catarrhalis were susceptible to azithromycin and ceftriaxone Study 95-001 Clinical Cure Per Baseline Pathogen at Day 28 Study 95-001 Treatment Related Adverse Events* 0 (0) 0 (0) 3 (5) Vomiting 4 (6) 0 (0) 1 (2) Rash 4 (6) 3 (5) 2 (3) Diarrhea 6 (9) 6 (9) 7 (11) Patients w/ AE 66 66 66 Patients Treated Ceftriaxone 3 Day 1 Day 0 (0) 0 (0) 0 (0) Discontinued *2 or more events on any treatment regimen Azithromycin Study R-0581 Single Dose Therapy Study R-0581 Objective Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 30 mg/kg single oral dose Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study R-0581 Visits and Assessments *Patients who vomited within 30 minutes were redosed 1 Including parental questionnaire Study R-0581 Patient Disposition Study R-0581 Demographics Study R-0581 Results Study R-0581 Clinical Outcome 38 (25) 37 (25) Failure 8 2 Improvement [-7, 15] 108 (70) 112 (74) Cure [-10, 11] 116 (75) 114 (75) Success 154 151 Day 28 19 (12) 21 (13) Failure 21 34 Improvement 121 105 Cure [-9, 7] 142 (88) 139 (87) Success 161 160 Day 14 173 173 Number of Patients 95% CI1[%] Amox/Clav (%) Azithromycin (%) 1 95% CI for (azithromycin – comparator) Study R-0581 Clinical Outcome at Day 28 by Age Cure 26 (49) 24 (38) Failure [-8, 31] 95% CI1[%] Failure < 2 years of age 27 (51) 40 (63) Cure 53 64 > 2 years of age Amox/Clav Azithromycin 1 95% CI for (azithromycin – comparator) N (%) N (%) 72 (83) 15 (17) 87 81 (80) 20 (20) 101 [-10, 15] Study R-0581 Compliance Based on patients randomized to their study drug regimen Study R-0581 Treatment Related Adverse Events* 7 (4%) 7 (4%) Vomiting 9 (5%) 3 (2%) 22 (13%) 11 (6%) Diarrhea 39 (23%) 29 (17%) Patients w/ AEs Rash Azithromycin N = 173 Amox/Clav N = 173 7(4%) 4 (2%) Discontinued due to AE * Adverse Events greater than 2 percent in either regimen Study 1015 Single Dose Therapy Study 1015 Objectives To assess per-pathogen clinical response rates To provide additional data on the safety and toleration of the single dose regimen Design Prospective Open-label Non-comparative Multi-center Study 1015 Visits and Assessments *Patients who vomited within 30 minutes were redosed Study 1015 Endpoints Primary Efficacy Endpoint Clinical response by baseline pathogen at day 28 Initial local laboratory isolation of pathogen with confirmation by central laboratory Secondary Efficacy Endpoints Clinical response at day 28 (test of cure) Clinical response at day 10 Safety Evaluation Study 1015 Patient Disposition 242 Clinical at Day 28 127 Bacteriologic Efficacy Azithromycin 248 Safety 248 Enrolled Evaluation Groups
Slide 65 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997 Study 95-001 Experimental Design *Baseline tympanocentesis Study 95-001 Patient Disposition Study 95-001 Demographics 0% 2% Black 98% 97% White Race: 48% 56% % Male 2.3 (+ 1.4) 2.5 (+ 1.3) Mean Age (Yrs, ±SD) 31 (47%) 40 (61%) 2 Yrs - 12 Yrs 35 (53%) 26 (39%) < 2 Yrs Age: N = 66 Single Dose N = 66 Azithromycin 2% 95% 55% 2.7 (+ 1.5) 40 (61%) 26 (39%) Three Day N = 66 Ceftriaxone 2% 2% Hispanic 3% Study 95-001 Results Study 95-001 Clinical Efficacy Population 4 (6) Failure 5 Improvement [- 5, 25] 56 (86) Cure [-12,6] 61 (94) Success 65 Day 28 2 (3) Failure 36 Improvement 26 Cure [-8,5] 62 (97) Success 64 Day 14 66 Randomized Patients 95% CI1 [%] 1 Day (%) 1 95% CI for (single dose azithromycin – comparator) 5 (8) 10 51 (77) 61 (92) 66 3 (5) 42 18 60 (95) 63 66 3 Day (%) 2 (3) 13 49 (77) 62 (97) 64 1 (2) 40 21 61 (98) 62 66 Ceftriaxone (%) Azithromycin Study 95-001 Clinical Outcome at Day 28 by Age 5 (16) 6 (15) 3 (8) Failure 26 (84) 33 (85) 37 (93) Cure 31 39 40 > 2 years of age 10 (30) 9 (33) 6 (24) Failure 23 (70) 18 (67) 19 (76) Cure 33 27 25 < 2 years of age Ceftriaxone (%) 3 Day (%) 1 Day (%) Azithromycin Study 95-001 Susceptibility S. pneumoniae susceptibility (N=57) Azithromycin 46 susceptible 11 resistant (MIC > 0.5 mg/ml) Ceftriaxone All isolates were susceptible to ceftriaxone All H. influenzae and M. catarrhalis were susceptible to azithromycin and ceftriaxone Study 95-001 Clinical Cure Per Baseline Pathogen at Day 28 Study 95-001 Treatment Related Adverse Events* 0 (0) 0 (0) 3 (5) Vomiting 4 (6) 0 (0) 1 (2) Rash 4 (6) 3 (5) 2 (3) Diarrhea 6 (9) 6 (9) 7 (11) Patients w/ AE 66 66 66 Patients Treated Ceftriaxone 3 Day 1 Day 0 (0) 0 (0) 0 (0) Discontinued *2 or more events on any treatment regimen Azithromycin Study R-0581 Single Dose Therapy Study R-0581 Objective Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 30 mg/kg single oral dose Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study R-0581 Visits and Assessments *Patients who vomited within 30 minutes were redosed 1 Including parental questionnaire Study R-0581 Patient Disposition Study R-0581 Demographics Study R-0581 Results Study R-0581 Clinical Outcome 38 (25) 37 (25) Failure 8 2 Improvement [-7, 15] 108 (70) 112 (74) Cure [-10, 11] 116 (75) 114 (75) Success 154 151 Day 28 19 (12) 21 (13) Failure 21 34 Improvement 121 105 Cure [-9, 7] 142 (88) 139 (87) Success 161 160 Day 14 173 173 Number of Patients 95% CI1[%] Amox/Clav (%) Azithromycin (%) 1 95% CI for (azithromycin – comparator) Study R-0581 Clinical Outcome at Day 28 by Age Cure 26 (49) 24 (38) Failure [-8, 31] 95% CI1[%] Failure < 2 years of age 27 (51) 40 (63) Cure 53 64 > 2 years of age Amox/Clav Azithromycin 1 95% CI for (azithromycin – comparator) N (%) N (%) 72 (83) 15 (17) 87 81 (80) 20 (20) 101 [-10, 15] Study R-0581 Compliance Based on patients randomized to their study drug regimen Study R-0581 Treatment Related Adverse Events* 7 (4%) 7 (4%) Vomiting 9 (5%) 3 (2%) 22 (13%) 11 (6%) Diarrhea 39 (23%) 29 (17%) Patients w/ AEs Rash Azithromycin N = 173 Amox/Clav N = 173 7(4%) 4 (2%) Discontinued due to AE * Adverse Events greater than 2 percent in either regimen Study 1015 Single Dose Therapy Study 1015 Objectives To assess per-pathogen clinical response rates To provide additional data on the safety and toleration of the single dose regimen Design Prospective Open-label Non-comparative Multi-center Study 1015 Visits and Assessments *Patients who vomited within 30 minutes were redosed Study 1015 Endpoints Primary Efficacy Endpoint Clinical response by baseline pathogen at day 28 Initial local laboratory isolation of pathogen with confirmation by central laboratory Secondary Efficacy Endpoints Clinical response at day 28 (test of cure) Clinical response at day 10 Safety Evaluation Study 1015 Patient Disposition 242 Clinical at Day 28 127 Bacteriologic Efficacy Azithromycin 248 Safety 248 Enrolled Evaluation Groups Study 1015 Demographics
Slide 66 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997 Study 95-001 Experimental Design *Baseline tympanocentesis Study 95-001 Patient Disposition Study 95-001 Demographics 0% 2% Black 98% 97% White Race: 48% 56% % Male 2.3 (+ 1.4) 2.5 (+ 1.3) Mean Age (Yrs, ±SD) 31 (47%) 40 (61%) 2 Yrs - 12 Yrs 35 (53%) 26 (39%) < 2 Yrs Age: N = 66 Single Dose N = 66 Azithromycin 2% 95% 55% 2.7 (+ 1.5) 40 (61%) 26 (39%) Three Day N = 66 Ceftriaxone 2% 2% Hispanic 3% Study 95-001 Results Study 95-001 Clinical Efficacy Population 4 (6) Failure 5 Improvement [- 5, 25] 56 (86) Cure [-12,6] 61 (94) Success 65 Day 28 2 (3) Failure 36 Improvement 26 Cure [-8,5] 62 (97) Success 64 Day 14 66 Randomized Patients 95% CI1 [%] 1 Day (%) 1 95% CI for (single dose azithromycin – comparator) 5 (8) 10 51 (77) 61 (92) 66 3 (5) 42 18 60 (95) 63 66 3 Day (%) 2 (3) 13 49 (77) 62 (97) 64 1 (2) 40 21 61 (98) 62 66 Ceftriaxone (%) Azithromycin Study 95-001 Clinical Outcome at Day 28 by Age 5 (16) 6 (15) 3 (8) Failure 26 (84) 33 (85) 37 (93) Cure 31 39 40 > 2 years of age 10 (30) 9 (33) 6 (24) Failure 23 (70) 18 (67) 19 (76) Cure 33 27 25 < 2 years of age Ceftriaxone (%) 3 Day (%) 1 Day (%) Azithromycin Study 95-001 Susceptibility S. pneumoniae susceptibility (N=57) Azithromycin 46 susceptible 11 resistant (MIC > 0.5 mg/ml) Ceftriaxone All isolates were susceptible to ceftriaxone All H. influenzae and M. catarrhalis were susceptible to azithromycin and ceftriaxone Study 95-001 Clinical Cure Per Baseline Pathogen at Day 28 Study 95-001 Treatment Related Adverse Events* 0 (0) 0 (0) 3 (5) Vomiting 4 (6) 0 (0) 1 (2) Rash 4 (6) 3 (5) 2 (3) Diarrhea 6 (9) 6 (9) 7 (11) Patients w/ AE 66 66 66 Patients Treated Ceftriaxone 3 Day 1 Day 0 (0) 0 (0) 0 (0) Discontinued *2 or more events on any treatment regimen Azithromycin Study R-0581 Single Dose Therapy Study R-0581 Objective Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 30 mg/kg single oral dose Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study R-0581 Visits and Assessments *Patients who vomited within 30 minutes were redosed 1 Including parental questionnaire Study R-0581 Patient Disposition Study R-0581 Demographics Study R-0581 Results Study R-0581 Clinical Outcome 38 (25) 37 (25) Failure 8 2 Improvement [-7, 15] 108 (70) 112 (74) Cure [-10, 11] 116 (75) 114 (75) Success 154 151 Day 28 19 (12) 21 (13) Failure 21 34 Improvement 121 105 Cure [-9, 7] 142 (88) 139 (87) Success 161 160 Day 14 173 173 Number of Patients 95% CI1[%] Amox/Clav (%) Azithromycin (%) 1 95% CI for (azithromycin – comparator) Study R-0581 Clinical Outcome at Day 28 by Age Cure 26 (49) 24 (38) Failure [-8, 31] 95% CI1[%] Failure < 2 years of age 27 (51) 40 (63) Cure 53 64 > 2 years of age Amox/Clav Azithromycin 1 95% CI for (azithromycin – comparator) N (%) N (%) 72 (83) 15 (17) 87 81 (80) 20 (20) 101 [-10, 15] Study R-0581 Compliance Based on patients randomized to their study drug regimen Study R-0581 Treatment Related Adverse Events* 7 (4%) 7 (4%) Vomiting 9 (5%) 3 (2%) 22 (13%) 11 (6%) Diarrhea 39 (23%) 29 (17%) Patients w/ AEs Rash Azithromycin N = 173 Amox/Clav N = 173 7(4%) 4 (2%) Discontinued due to AE * Adverse Events greater than 2 percent in either regimen Study 1015 Single Dose Therapy Study 1015 Objectives To assess per-pathogen clinical response rates To provide additional data on the safety and toleration of the single dose regimen Design Prospective Open-label Non-comparative Multi-center Study 1015 Visits and Assessments *Patients who vomited within 30 minutes were redosed Study 1015 Endpoints Primary Efficacy Endpoint Clinical response by baseline pathogen at day 28 Initial local laboratory isolation of pathogen with confirmation by central laboratory Secondary Efficacy Endpoints Clinical response at day 28 (test of cure) Clinical response at day 10 Safety Evaluation Study 1015 Patient Disposition 242 Clinical at Day 28 127 Bacteriologic Efficacy Azithromycin 248 Safety 248 Enrolled Evaluation Groups Study 1015 Demographics Study 1015 Results
Slide 67 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997 Study 95-001 Experimental Design *Baseline tympanocentesis Study 95-001 Patient Disposition Study 95-001 Demographics 0% 2% Black 98% 97% White Race: 48% 56% % Male 2.3 (+ 1.4) 2.5 (+ 1.3) Mean Age (Yrs, ±SD) 31 (47%) 40 (61%) 2 Yrs - 12 Yrs 35 (53%) 26 (39%) < 2 Yrs Age: N = 66 Single Dose N = 66 Azithromycin 2% 95% 55% 2.7 (+ 1.5) 40 (61%) 26 (39%) Three Day N = 66 Ceftriaxone 2% 2% Hispanic 3% Study 95-001 Results Study 95-001 Clinical Efficacy Population 4 (6) Failure 5 Improvement [- 5, 25] 56 (86) Cure [-12,6] 61 (94) Success 65 Day 28 2 (3) Failure 36 Improvement 26 Cure [-8,5] 62 (97) Success 64 Day 14 66 Randomized Patients 95% CI1 [%] 1 Day (%) 1 95% CI for (single dose azithromycin – comparator) 5 (8) 10 51 (77) 61 (92) 66 3 (5) 42 18 60 (95) 63 66 3 Day (%) 2 (3) 13 49 (77) 62 (97) 64 1 (2) 40 21 61 (98) 62 66 Ceftriaxone (%) Azithromycin Study 95-001 Clinical Outcome at Day 28 by Age 5 (16) 6 (15) 3 (8) Failure 26 (84) 33 (85) 37 (93) Cure 31 39 40 > 2 years of age 10 (30) 9 (33) 6 (24) Failure 23 (70) 18 (67) 19 (76) Cure 33 27 25 < 2 years of age Ceftriaxone (%) 3 Day (%) 1 Day (%) Azithromycin Study 95-001 Susceptibility S. pneumoniae susceptibility (N=57) Azithromycin 46 susceptible 11 resistant (MIC > 0.5 mg/ml) Ceftriaxone All isolates were susceptible to ceftriaxone All H. influenzae and M. catarrhalis were susceptible to azithromycin and ceftriaxone Study 95-001 Clinical Cure Per Baseline Pathogen at Day 28 Study 95-001 Treatment Related Adverse Events* 0 (0) 0 (0) 3 (5) Vomiting 4 (6) 0 (0) 1 (2) Rash 4 (6) 3 (5) 2 (3) Diarrhea 6 (9) 6 (9) 7 (11) Patients w/ AE 66 66 66 Patients Treated Ceftriaxone 3 Day 1 Day 0 (0) 0 (0) 0 (0) Discontinued *2 or more events on any treatment regimen Azithromycin Study R-0581 Single Dose Therapy Study R-0581 Objective Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 30 mg/kg single oral dose Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study R-0581 Visits and Assessments *Patients who vomited within 30 minutes were redosed 1 Including parental questionnaire Study R-0581 Patient Disposition Study R-0581 Demographics Study R-0581 Results Study R-0581 Clinical Outcome 38 (25) 37 (25) Failure 8 2 Improvement [-7, 15] 108 (70) 112 (74) Cure [-10, 11] 116 (75) 114 (75) Success 154 151 Day 28 19 (12) 21 (13) Failure 21 34 Improvement 121 105 Cure [-9, 7] 142 (88) 139 (87) Success 161 160 Day 14 173 173 Number of Patients 95% CI1[%] Amox/Clav (%) Azithromycin (%) 1 95% CI for (azithromycin – comparator) Study R-0581 Clinical Outcome at Day 28 by Age Cure 26 (49) 24 (38) Failure [-8, 31] 95% CI1[%] Failure < 2 years of age 27 (51) 40 (63) Cure 53 64 > 2 years of age Amox/Clav Azithromycin 1 95% CI for (azithromycin – comparator) N (%) N (%) 72 (83) 15 (17) 87 81 (80) 20 (20) 101 [-10, 15] Study R-0581 Compliance Based on patients randomized to their study drug regimen Study R-0581 Treatment Related Adverse Events* 7 (4%) 7 (4%) Vomiting 9 (5%) 3 (2%) 22 (13%) 11 (6%) Diarrhea 39 (23%) 29 (17%) Patients w/ AEs Rash Azithromycin N = 173 Amox/Clav N = 173 7(4%) 4 (2%) Discontinued due to AE * Adverse Events greater than 2 percent in either regimen Study 1015 Single Dose Therapy Study 1015 Objectives To assess per-pathogen clinical response rates To provide additional data on the safety and toleration of the single dose regimen Design Prospective Open-label Non-comparative Multi-center Study 1015 Visits and Assessments *Patients who vomited within 30 minutes were redosed Study 1015 Endpoints Primary Efficacy Endpoint Clinical response by baseline pathogen at day 28 Initial local laboratory isolation of pathogen with confirmation by central laboratory Secondary Efficacy Endpoints Clinical response at day 28 (test of cure) Clinical response at day 10 Safety Evaluation Study 1015 Patient Disposition 242 Clinical at Day 28 127 Bacteriologic Efficacy Azithromycin 248 Safety 248 Enrolled Evaluation Groups Study 1015 Demographics Study 1015 Results Study 1015 Clinical Outcome 36 (15%) Failure [80,90] 206 (85%) Cure 242 Day 28 27 (11%) Failure 74 Improvement 139 Cure [85,93] 213 (89%) Success 240 Day 10 247 Number of Patients 95% CI1 [%] Azithromycin (%) 1 95% CI for azithromycin
Slide 68 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997 Study 95-001 Experimental Design *Baseline tympanocentesis Study 95-001 Patient Disposition Study 95-001 Demographics 0% 2% Black 98% 97% White Race: 48% 56% % Male 2.3 (+ 1.4) 2.5 (+ 1.3) Mean Age (Yrs, ±SD) 31 (47%) 40 (61%) 2 Yrs - 12 Yrs 35 (53%) 26 (39%) < 2 Yrs Age: N = 66 Single Dose N = 66 Azithromycin 2% 95% 55% 2.7 (+ 1.5) 40 (61%) 26 (39%) Three Day N = 66 Ceftriaxone 2% 2% Hispanic 3% Study 95-001 Results Study 95-001 Clinical Efficacy Population 4 (6) Failure 5 Improvement [- 5, 25] 56 (86) Cure [-12,6] 61 (94) Success 65 Day 28 2 (3) Failure 36 Improvement 26 Cure [-8,5] 62 (97) Success 64 Day 14 66 Randomized Patients 95% CI1 [%] 1 Day (%) 1 95% CI for (single dose azithromycin – comparator) 5 (8) 10 51 (77) 61 (92) 66 3 (5) 42 18 60 (95) 63 66 3 Day (%) 2 (3) 13 49 (77) 62 (97) 64 1 (2) 40 21 61 (98) 62 66 Ceftriaxone (%) Azithromycin Study 95-001 Clinical Outcome at Day 28 by Age 5 (16) 6 (15) 3 (8) Failure 26 (84) 33 (85) 37 (93) Cure 31 39 40 > 2 years of age 10 (30) 9 (33) 6 (24) Failure 23 (70) 18 (67) 19 (76) Cure 33 27 25 < 2 years of age Ceftriaxone (%) 3 Day (%) 1 Day (%) Azithromycin Study 95-001 Susceptibility S. pneumoniae susceptibility (N=57) Azithromycin 46 susceptible 11 resistant (MIC > 0.5 mg/ml) Ceftriaxone All isolates were susceptible to ceftriaxone All H. influenzae and M. catarrhalis were susceptible to azithromycin and ceftriaxone Study 95-001 Clinical Cure Per Baseline Pathogen at Day 28 Study 95-001 Treatment Related Adverse Events* 0 (0) 0 (0) 3 (5) Vomiting 4 (6) 0 (0) 1 (2) Rash 4 (6) 3 (5) 2 (3) Diarrhea 6 (9) 6 (9) 7 (11) Patients w/ AE 66 66 66 Patients Treated Ceftriaxone 3 Day 1 Day 0 (0) 0 (0) 0 (0) Discontinued *2 or more events on any treatment regimen Azithromycin Study R-0581 Single Dose Therapy Study R-0581 Objective Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 30 mg/kg single oral dose Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study R-0581 Visits and Assessments *Patients who vomited within 30 minutes were redosed 1 Including parental questionnaire Study R-0581 Patient Disposition Study R-0581 Demographics Study R-0581 Results Study R-0581 Clinical Outcome 38 (25) 37 (25) Failure 8 2 Improvement [-7, 15] 108 (70) 112 (74) Cure [-10, 11] 116 (75) 114 (75) Success 154 151 Day 28 19 (12) 21 (13) Failure 21 34 Improvement 121 105 Cure [-9, 7] 142 (88) 139 (87) Success 161 160 Day 14 173 173 Number of Patients 95% CI1[%] Amox/Clav (%) Azithromycin (%) 1 95% CI for (azithromycin – comparator) Study R-0581 Clinical Outcome at Day 28 by Age Cure 26 (49) 24 (38) Failure [-8, 31] 95% CI1[%] Failure < 2 years of age 27 (51) 40 (63) Cure 53 64 > 2 years of age Amox/Clav Azithromycin 1 95% CI for (azithromycin – comparator) N (%) N (%) 72 (83) 15 (17) 87 81 (80) 20 (20) 101 [-10, 15] Study R-0581 Compliance Based on patients randomized to their study drug regimen Study R-0581 Treatment Related Adverse Events* 7 (4%) 7 (4%) Vomiting 9 (5%) 3 (2%) 22 (13%) 11 (6%) Diarrhea 39 (23%) 29 (17%) Patients w/ AEs Rash Azithromycin N = 173 Amox/Clav N = 173 7(4%) 4 (2%) Discontinued due to AE * Adverse Events greater than 2 percent in either regimen Study 1015 Single Dose Therapy Study 1015 Objectives To assess per-pathogen clinical response rates To provide additional data on the safety and toleration of the single dose regimen Design Prospective Open-label Non-comparative Multi-center Study 1015 Visits and Assessments *Patients who vomited within 30 minutes were redosed Study 1015 Endpoints Primary Efficacy Endpoint Clinical response by baseline pathogen at day 28 Initial local laboratory isolation of pathogen with confirmation by central laboratory Secondary Efficacy Endpoints Clinical response at day 28 (test of cure) Clinical response at day 10 Safety Evaluation Study 1015 Patient Disposition 242 Clinical at Day 28 127 Bacteriologic Efficacy Azithromycin 248 Safety 248 Enrolled Evaluation Groups Study 1015 Demographics Study 1015 Results Study 1015 Clinical Outcome 36 (15%) Failure [80,90] 206 (85%) Cure 242 Day 28 27 (11%) Failure 74 Improvement 139 Cure [85,93] 213 (89%) Success 240 Day 10 247 Number of Patients 95% CI1 [%] Azithromycin (%) 1 95% CI for azithromycin Study 1015 Clinical Outcome at Day 28 by Age 11 17 Failure [84, 94] 89 142 Cure 159 > 2 years of age 23 19 Failure [67, 87] 77 64 Cure 83 < 2 years of age 95% CI [%] (%) N Azithromycin
Slide 69 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997 Study 95-001 Experimental Design *Baseline tympanocentesis Study 95-001 Patient Disposition Study 95-001 Demographics 0% 2% Black 98% 97% White Race: 48% 56% % Male 2.3 (+ 1.4) 2.5 (+ 1.3) Mean Age (Yrs, ±SD) 31 (47%) 40 (61%) 2 Yrs - 12 Yrs 35 (53%) 26 (39%) < 2 Yrs Age: N = 66 Single Dose N = 66 Azithromycin 2% 95% 55% 2.7 (+ 1.5) 40 (61%) 26 (39%) Three Day N = 66 Ceftriaxone 2% 2% Hispanic 3% Study 95-001 Results Study 95-001 Clinical Efficacy Population 4 (6) Failure 5 Improvement [- 5, 25] 56 (86) Cure [-12,6] 61 (94) Success 65 Day 28 2 (3) Failure 36 Improvement 26 Cure [-8,5] 62 (97) Success 64 Day 14 66 Randomized Patients 95% CI1 [%] 1 Day (%) 1 95% CI for (single dose azithromycin – comparator) 5 (8) 10 51 (77) 61 (92) 66 3 (5) 42 18 60 (95) 63 66 3 Day (%) 2 (3) 13 49 (77) 62 (97) 64 1 (2) 40 21 61 (98) 62 66 Ceftriaxone (%) Azithromycin Study 95-001 Clinical Outcome at Day 28 by Age 5 (16) 6 (15) 3 (8) Failure 26 (84) 33 (85) 37 (93) Cure 31 39 40 > 2 years of age 10 (30) 9 (33) 6 (24) Failure 23 (70) 18 (67) 19 (76) Cure 33 27 25 < 2 years of age Ceftriaxone (%) 3 Day (%) 1 Day (%) Azithromycin Study 95-001 Susceptibility S. pneumoniae susceptibility (N=57) Azithromycin 46 susceptible 11 resistant (MIC > 0.5 mg/ml) Ceftriaxone All isolates were susceptible to ceftriaxone All H. influenzae and M. catarrhalis were susceptible to azithromycin and ceftriaxone Study 95-001 Clinical Cure Per Baseline Pathogen at Day 28 Study 95-001 Treatment Related Adverse Events* 0 (0) 0 (0) 3 (5) Vomiting 4 (6) 0 (0) 1 (2) Rash 4 (6) 3 (5) 2 (3) Diarrhea 6 (9) 6 (9) 7 (11) Patients w/ AE 66 66 66 Patients Treated Ceftriaxone 3 Day 1 Day 0 (0) 0 (0) 0 (0) Discontinued *2 or more events on any treatment regimen Azithromycin Study R-0581 Single Dose Therapy Study R-0581 Objective Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 30 mg/kg single oral dose Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study R-0581 Visits and Assessments *Patients who vomited within 30 minutes were redosed 1 Including parental questionnaire Study R-0581 Patient Disposition Study R-0581 Demographics Study R-0581 Results Study R-0581 Clinical Outcome 38 (25) 37 (25) Failure 8 2 Improvement [-7, 15] 108 (70) 112 (74) Cure [-10, 11] 116 (75) 114 (75) Success 154 151 Day 28 19 (12) 21 (13) Failure 21 34 Improvement 121 105 Cure [-9, 7] 142 (88) 139 (87) Success 161 160 Day 14 173 173 Number of Patients 95% CI1[%] Amox/Clav (%) Azithromycin (%) 1 95% CI for (azithromycin – comparator) Study R-0581 Clinical Outcome at Day 28 by Age Cure 26 (49) 24 (38) Failure [-8, 31] 95% CI1[%] Failure < 2 years of age 27 (51) 40 (63) Cure 53 64 > 2 years of age Amox/Clav Azithromycin 1 95% CI for (azithromycin – comparator) N (%) N (%) 72 (83) 15 (17) 87 81 (80) 20 (20) 101 [-10, 15] Study R-0581 Compliance Based on patients randomized to their study drug regimen Study R-0581 Treatment Related Adverse Events* 7 (4%) 7 (4%) Vomiting 9 (5%) 3 (2%) 22 (13%) 11 (6%) Diarrhea 39 (23%) 29 (17%) Patients w/ AEs Rash Azithromycin N = 173 Amox/Clav N = 173 7(4%) 4 (2%) Discontinued due to AE * Adverse Events greater than 2 percent in either regimen Study 1015 Single Dose Therapy Study 1015 Objectives To assess per-pathogen clinical response rates To provide additional data on the safety and toleration of the single dose regimen Design Prospective Open-label Non-comparative Multi-center Study 1015 Visits and Assessments *Patients who vomited within 30 minutes were redosed Study 1015 Endpoints Primary Efficacy Endpoint Clinical response by baseline pathogen at day 28 Initial local laboratory isolation of pathogen with confirmation by central laboratory Secondary Efficacy Endpoints Clinical response at day 28 (test of cure) Clinical response at day 10 Safety Evaluation Study 1015 Patient Disposition 242 Clinical at Day 28 127 Bacteriologic Efficacy Azithromycin 248 Safety 248 Enrolled Evaluation Groups Study 1015 Demographics Study 1015 Results Study 1015 Clinical Outcome 36 (15%) Failure [80,90] 206 (85%) Cure 242 Day 28 27 (11%) Failure 74 Improvement 139 Cure [85,93] 213 (89%) Success 240 Day 10 247 Number of Patients 95% CI1 [%] Azithromycin (%) 1 95% CI for azithromycin Study 1015 Clinical Outcome at Day 28 by Age 11 17 Failure [84, 94] 89 142 Cure 159 > 2 years of age 23 19 Failure [67, 87] 77 64 Cure 83 < 2 years of age 95% CI [%] (%) N Azithromycin Study 1015 Clinical Outcome - Per Baseline Pathogen
Slide 70 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997 Study 95-001 Experimental Design *Baseline tympanocentesis Study 95-001 Patient Disposition Study 95-001 Demographics 0% 2% Black 98% 97% White Race: 48% 56% % Male 2.3 (+ 1.4) 2.5 (+ 1.3) Mean Age (Yrs, ±SD) 31 (47%) 40 (61%) 2 Yrs - 12 Yrs 35 (53%) 26 (39%) < 2 Yrs Age: N = 66 Single Dose N = 66 Azithromycin 2% 95% 55% 2.7 (+ 1.5) 40 (61%) 26 (39%) Three Day N = 66 Ceftriaxone 2% 2% Hispanic 3% Study 95-001 Results Study 95-001 Clinical Efficacy Population 4 (6) Failure 5 Improvement [- 5, 25] 56 (86) Cure [-12,6] 61 (94) Success 65 Day 28 2 (3) Failure 36 Improvement 26 Cure [-8,5] 62 (97) Success 64 Day 14 66 Randomized Patients 95% CI1 [%] 1 Day (%) 1 95% CI for (single dose azithromycin – comparator) 5 (8) 10 51 (77) 61 (92) 66 3 (5) 42 18 60 (95) 63 66 3 Day (%) 2 (3) 13 49 (77) 62 (97) 64 1 (2) 40 21 61 (98) 62 66 Ceftriaxone (%) Azithromycin Study 95-001 Clinical Outcome at Day 28 by Age 5 (16) 6 (15) 3 (8) Failure 26 (84) 33 (85) 37 (93) Cure 31 39 40 > 2 years of age 10 (30) 9 (33) 6 (24) Failure 23 (70) 18 (67) 19 (76) Cure 33 27 25 < 2 years of age Ceftriaxone (%) 3 Day (%) 1 Day (%) Azithromycin Study 95-001 Susceptibility S. pneumoniae susceptibility (N=57) Azithromycin 46 susceptible 11 resistant (MIC > 0.5 mg/ml) Ceftriaxone All isolates were susceptible to ceftriaxone All H. influenzae and M. catarrhalis were susceptible to azithromycin and ceftriaxone Study 95-001 Clinical Cure Per Baseline Pathogen at Day 28 Study 95-001 Treatment Related Adverse Events* 0 (0) 0 (0) 3 (5) Vomiting 4 (6) 0 (0) 1 (2) Rash 4 (6) 3 (5) 2 (3) Diarrhea 6 (9) 6 (9) 7 (11) Patients w/ AE 66 66 66 Patients Treated Ceftriaxone 3 Day 1 Day 0 (0) 0 (0) 0 (0) Discontinued *2 or more events on any treatment regimen Azithromycin Study R-0581 Single Dose Therapy Study R-0581 Objective Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 30 mg/kg single oral dose Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study R-0581 Visits and Assessments *Patients who vomited within 30 minutes were redosed 1 Including parental questionnaire Study R-0581 Patient Disposition Study R-0581 Demographics Study R-0581 Results Study R-0581 Clinical Outcome 38 (25) 37 (25) Failure 8 2 Improvement [-7, 15] 108 (70) 112 (74) Cure [-10, 11] 116 (75) 114 (75) Success 154 151 Day 28 19 (12) 21 (13) Failure 21 34 Improvement 121 105 Cure [-9, 7] 142 (88) 139 (87) Success 161 160 Day 14 173 173 Number of Patients 95% CI1[%] Amox/Clav (%) Azithromycin (%) 1 95% CI for (azithromycin – comparator) Study R-0581 Clinical Outcome at Day 28 by Age Cure 26 (49) 24 (38) Failure [-8, 31] 95% CI1[%] Failure < 2 years of age 27 (51) 40 (63) Cure 53 64 > 2 years of age Amox/Clav Azithromycin 1 95% CI for (azithromycin – comparator) N (%) N (%) 72 (83) 15 (17) 87 81 (80) 20 (20) 101 [-10, 15] Study R-0581 Compliance Based on patients randomized to their study drug regimen Study R-0581 Treatment Related Adverse Events* 7 (4%) 7 (4%) Vomiting 9 (5%) 3 (2%) 22 (13%) 11 (6%) Diarrhea 39 (23%) 29 (17%) Patients w/ AEs Rash Azithromycin N = 173 Amox/Clav N = 173 7(4%) 4 (2%) Discontinued due to AE * Adverse Events greater than 2 percent in either regimen Study 1015 Single Dose Therapy Study 1015 Objectives To assess per-pathogen clinical response rates To provide additional data on the safety and toleration of the single dose regimen Design Prospective Open-label Non-comparative Multi-center Study 1015 Visits and Assessments *Patients who vomited within 30 minutes were redosed Study 1015 Endpoints Primary Efficacy Endpoint Clinical response by baseline pathogen at day 28 Initial local laboratory isolation of pathogen with confirmation by central laboratory Secondary Efficacy Endpoints Clinical response at day 28 (test of cure) Clinical response at day 10 Safety Evaluation Study 1015 Patient Disposition 242 Clinical at Day 28 127 Bacteriologic Efficacy Azithromycin 248 Safety 248 Enrolled Evaluation Groups Study 1015 Demographics Study 1015 Results Study 1015 Clinical Outcome 36 (15%) Failure [80,90] 206 (85%) Cure 242 Day 28 27 (11%) Failure 74 Improvement 139 Cure [85,93] 213 (89%) Success 240 Day 10 247 Number of Patients 95% CI1 [%] Azithromycin (%) 1 95% CI for azithromycin Study 1015 Clinical Outcome at Day 28 by Age 11 17 Failure [84, 94] 89 142 Cure 159 > 2 years of age 23 19 Failure [67, 87] 77 64 Cure 83 < 2 years of age 95% CI [%] (%) N Azithromycin Study 1015 Clinical Outcome - Per Baseline Pathogen Study 1015 MIC Distribution for S. pneumoniae (N=67) Percent of Patients Azithromycin MIC (mg/ml)
Slide 71 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997 Study 95-001 Experimental Design *Baseline tympanocentesis Study 95-001 Patient Disposition Study 95-001 Demographics 0% 2% Black 98% 97% White Race: 48% 56% % Male 2.3 (+ 1.4) 2.5 (+ 1.3) Mean Age (Yrs, ±SD) 31 (47%) 40 (61%) 2 Yrs - 12 Yrs 35 (53%) 26 (39%) < 2 Yrs Age: N = 66 Single Dose N = 66 Azithromycin 2% 95% 55% 2.7 (+ 1.5) 40 (61%) 26 (39%) Three Day N = 66 Ceftriaxone 2% 2% Hispanic 3% Study 95-001 Results Study 95-001 Clinical Efficacy Population 4 (6) Failure 5 Improvement [- 5, 25] 56 (86) Cure [-12,6] 61 (94) Success 65 Day 28 2 (3) Failure 36 Improvement 26 Cure [-8,5] 62 (97) Success 64 Day 14 66 Randomized Patients 95% CI1 [%] 1 Day (%) 1 95% CI for (single dose azithromycin – comparator) 5 (8) 10 51 (77) 61 (92) 66 3 (5) 42 18 60 (95) 63 66 3 Day (%) 2 (3) 13 49 (77) 62 (97) 64 1 (2) 40 21 61 (98) 62 66 Ceftriaxone (%) Azithromycin Study 95-001 Clinical Outcome at Day 28 by Age 5 (16) 6 (15) 3 (8) Failure 26 (84) 33 (85) 37 (93) Cure 31 39 40 > 2 years of age 10 (30) 9 (33) 6 (24) Failure 23 (70) 18 (67) 19 (76) Cure 33 27 25 < 2 years of age Ceftriaxone (%) 3 Day (%) 1 Day (%) Azithromycin Study 95-001 Susceptibility S. pneumoniae susceptibility (N=57) Azithromycin 46 susceptible 11 resistant (MIC > 0.5 mg/ml) Ceftriaxone All isolates were susceptible to ceftriaxone All H. influenzae and M. catarrhalis were susceptible to azithromycin and ceftriaxone Study 95-001 Clinical Cure Per Baseline Pathogen at Day 28 Study 95-001 Treatment Related Adverse Events* 0 (0) 0 (0) 3 (5) Vomiting 4 (6) 0 (0) 1 (2) Rash 4 (6) 3 (5) 2 (3) Diarrhea 6 (9) 6 (9) 7 (11) Patients w/ AE 66 66 66 Patients Treated Ceftriaxone 3 Day 1 Day 0 (0) 0 (0) 0 (0) Discontinued *2 or more events on any treatment regimen Azithromycin Study R-0581 Single Dose Therapy Study R-0581 Objective Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 30 mg/kg single oral dose Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study R-0581 Visits and Assessments *Patients who vomited within 30 minutes were redosed 1 Including parental questionnaire Study R-0581 Patient Disposition Study R-0581 Demographics Study R-0581 Results Study R-0581 Clinical Outcome 38 (25) 37 (25) Failure 8 2 Improvement [-7, 15] 108 (70) 112 (74) Cure [-10, 11] 116 (75) 114 (75) Success 154 151 Day 28 19 (12) 21 (13) Failure 21 34 Improvement 121 105 Cure [-9, 7] 142 (88) 139 (87) Success 161 160 Day 14 173 173 Number of Patients 95% CI1[%] Amox/Clav (%) Azithromycin (%) 1 95% CI for (azithromycin – comparator) Study R-0581 Clinical Outcome at Day 28 by Age Cure 26 (49) 24 (38) Failure [-8, 31] 95% CI1[%] Failure < 2 years of age 27 (51) 40 (63) Cure 53 64 > 2 years of age Amox/Clav Azithromycin 1 95% CI for (azithromycin – comparator) N (%) N (%) 72 (83) 15 (17) 87 81 (80) 20 (20) 101 [-10, 15] Study R-0581 Compliance Based on patients randomized to their study drug regimen Study R-0581 Treatment Related Adverse Events* 7 (4%) 7 (4%) Vomiting 9 (5%) 3 (2%) 22 (13%) 11 (6%) Diarrhea 39 (23%) 29 (17%) Patients w/ AEs Rash Azithromycin N = 173 Amox/Clav N = 173 7(4%) 4 (2%) Discontinued due to AE * Adverse Events greater than 2 percent in either regimen Study 1015 Single Dose Therapy Study 1015 Objectives To assess per-pathogen clinical response rates To provide additional data on the safety and toleration of the single dose regimen Design Prospective Open-label Non-comparative Multi-center Study 1015 Visits and Assessments *Patients who vomited within 30 minutes were redosed Study 1015 Endpoints Primary Efficacy Endpoint Clinical response by baseline pathogen at day 28 Initial local laboratory isolation of pathogen with confirmation by central laboratory Secondary Efficacy Endpoints Clinical response at day 28 (test of cure) Clinical response at day 10 Safety Evaluation Study 1015 Patient Disposition 242 Clinical at Day 28 127 Bacteriologic Efficacy Azithromycin 248 Safety 248 Enrolled Evaluation Groups Study 1015 Demographics Study 1015 Results Study 1015 Clinical Outcome 36 (15%) Failure [80,90] 206 (85%) Cure 242 Day 28 27 (11%) Failure 74 Improvement 139 Cure [85,93] 213 (89%) Success 240 Day 10 247 Number of Patients 95% CI1 [%] Azithromycin (%) 1 95% CI for azithromycin Study 1015 Clinical Outcome at Day 28 by Age 11 17 Failure [84, 94] 89 142 Cure 159 > 2 years of age 23 19 Failure [67, 87] 77 64 Cure 83 < 2 years of age 95% CI [%] (%) N Azithromycin Study 1015 Clinical Outcome - Per Baseline Pathogen Study 1015 MIC Distribution for S. pneumoniae (N=67) Percent of Patients Azithromycin MIC (mg/ml) Study 1015 Resistant S. Pneumoniae S. pneumoniae MIC = 8 g/ml 7 baseline isolates All sensitive to clindamycin All with mef A gene by PCR S. pneumoniae MIC >256 g/ml 5 baseline isolates All resistant to clindamycin All with erm B gene by PCR
Slide 72 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997 Study 95-001 Experimental Design *Baseline tympanocentesis Study 95-001 Patient Disposition Study 95-001 Demographics 0% 2% Black 98% 97% White Race: 48% 56% % Male 2.3 (+ 1.4) 2.5 (+ 1.3) Mean Age (Yrs, ±SD) 31 (47%) 40 (61%) 2 Yrs - 12 Yrs 35 (53%) 26 (39%) < 2 Yrs Age: N = 66 Single Dose N = 66 Azithromycin 2% 95% 55% 2.7 (+ 1.5) 40 (61%) 26 (39%) Three Day N = 66 Ceftriaxone 2% 2% Hispanic 3% Study 95-001 Results Study 95-001 Clinical Efficacy Population 4 (6) Failure 5 Improvement [- 5, 25] 56 (86) Cure [-12,6] 61 (94) Success 65 Day 28 2 (3) Failure 36 Improvement 26 Cure [-8,5] 62 (97) Success 64 Day 14 66 Randomized Patients 95% CI1 [%] 1 Day (%) 1 95% CI for (single dose azithromycin – comparator) 5 (8) 10 51 (77) 61 (92) 66 3 (5) 42 18 60 (95) 63 66 3 Day (%) 2 (3) 13 49 (77) 62 (97) 64 1 (2) 40 21 61 (98) 62 66 Ceftriaxone (%) Azithromycin Study 95-001 Clinical Outcome at Day 28 by Age 5 (16) 6 (15) 3 (8) Failure 26 (84) 33 (85) 37 (93) Cure 31 39 40 > 2 years of age 10 (30) 9 (33) 6 (24) Failure 23 (70) 18 (67) 19 (76) Cure 33 27 25 < 2 years of age Ceftriaxone (%) 3 Day (%) 1 Day (%) Azithromycin Study 95-001 Susceptibility S. pneumoniae susceptibility (N=57) Azithromycin 46 susceptible 11 resistant (MIC > 0.5 mg/ml) Ceftriaxone All isolates were susceptible to ceftriaxone All H. influenzae and M. catarrhalis were susceptible to azithromycin and ceftriaxone Study 95-001 Clinical Cure Per Baseline Pathogen at Day 28 Study 95-001 Treatment Related Adverse Events* 0 (0) 0 (0) 3 (5) Vomiting 4 (6) 0 (0) 1 (2) Rash 4 (6) 3 (5) 2 (3) Diarrhea 6 (9) 6 (9) 7 (11) Patients w/ AE 66 66 66 Patients Treated Ceftriaxone 3 Day 1 Day 0 (0) 0 (0) 0 (0) Discontinued *2 or more events on any treatment regimen Azithromycin Study R-0581 Single Dose Therapy Study R-0581 Objective Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 30 mg/kg single oral dose Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study R-0581 Visits and Assessments *Patients who vomited within 30 minutes were redosed 1 Including parental questionnaire Study R-0581 Patient Disposition Study R-0581 Demographics Study R-0581 Results Study R-0581 Clinical Outcome 38 (25) 37 (25) Failure 8 2 Improvement [-7, 15] 108 (70) 112 (74) Cure [-10, 11] 116 (75) 114 (75) Success 154 151 Day 28 19 (12) 21 (13) Failure 21 34 Improvement 121 105 Cure [-9, 7] 142 (88) 139 (87) Success 161 160 Day 14 173 173 Number of Patients 95% CI1[%] Amox/Clav (%) Azithromycin (%) 1 95% CI for (azithromycin – comparator) Study R-0581 Clinical Outcome at Day 28 by Age Cure 26 (49) 24 (38) Failure [-8, 31] 95% CI1[%] Failure < 2 years of age 27 (51) 40 (63) Cure 53 64 > 2 years of age Amox/Clav Azithromycin 1 95% CI for (azithromycin – comparator) N (%) N (%) 72 (83) 15 (17) 87 81 (80) 20 (20) 101 [-10, 15] Study R-0581 Compliance Based on patients randomized to their study drug regimen Study R-0581 Treatment Related Adverse Events* 7 (4%) 7 (4%) Vomiting 9 (5%) 3 (2%) 22 (13%) 11 (6%) Diarrhea 39 (23%) 29 (17%) Patients w/ AEs Rash Azithromycin N = 173 Amox/Clav N = 173 7(4%) 4 (2%) Discontinued due to AE * Adverse Events greater than 2 percent in either regimen Study 1015 Single Dose Therapy Study 1015 Objectives To assess per-pathogen clinical response rates To provide additional data on the safety and toleration of the single dose regimen Design Prospective Open-label Non-comparative Multi-center Study 1015 Visits and Assessments *Patients who vomited within 30 minutes were redosed Study 1015 Endpoints Primary Efficacy Endpoint Clinical response by baseline pathogen at day 28 Initial local laboratory isolation of pathogen with confirmation by central laboratory Secondary Efficacy Endpoints Clinical response at day 28 (test of cure) Clinical response at day 10 Safety Evaluation Study 1015 Patient Disposition 242 Clinical at Day 28 127 Bacteriologic Efficacy Azithromycin 248 Safety 248 Enrolled Evaluation Groups Study 1015 Demographics Study 1015 Results Study 1015 Clinical Outcome 36 (15%) Failure [80,90] 206 (85%) Cure 242 Day 28 27 (11%) Failure 74 Improvement 139 Cure [85,93] 213 (89%) Success 240 Day 10 247 Number of Patients 95% CI1 [%] Azithromycin (%) 1 95% CI for azithromycin Study 1015 Clinical Outcome at Day 28 by Age 11 17 Failure [84, 94] 89 142 Cure 159 > 2 years of age 23 19 Failure [67, 87] 77 64 Cure 83 < 2 years of age 95% CI [%] (%) N Azithromycin Study 1015 Clinical Outcome - Per Baseline Pathogen Study 1015 MIC Distribution for S. pneumoniae (N=67) Percent of Patients Azithromycin MIC (mg/ml) Study 1015 Resistant S. Pneumoniae S. pneumoniae MIC = 8 g/ml 7 baseline isolates All sensitive to clindamycin All with mef A gene by PCR S. pneumoniae MIC >256 g/ml 5 baseline isolates All resistant to clindamycin All with erm B gene by PCR Study 1015 Day 28 Outcome and MIC Distribution for S. pneumoniae (N=66) # of Patients Azithromycin MIC (mg/ml)
Slide 73 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997 Study 95-001 Experimental Design *Baseline tympanocentesis Study 95-001 Patient Disposition Study 95-001 Demographics 0% 2% Black 98% 97% White Race: 48% 56% % Male 2.3 (+ 1.4) 2.5 (+ 1.3) Mean Age (Yrs, ±SD) 31 (47%) 40 (61%) 2 Yrs - 12 Yrs 35 (53%) 26 (39%) < 2 Yrs Age: N = 66 Single Dose N = 66 Azithromycin 2% 95% 55% 2.7 (+ 1.5) 40 (61%) 26 (39%) Three Day N = 66 Ceftriaxone 2% 2% Hispanic 3% Study 95-001 Results Study 95-001 Clinical Efficacy Population 4 (6) Failure 5 Improvement [- 5, 25] 56 (86) Cure [-12,6] 61 (94) Success 65 Day 28 2 (3) Failure 36 Improvement 26 Cure [-8,5] 62 (97) Success 64 Day 14 66 Randomized Patients 95% CI1 [%] 1 Day (%) 1 95% CI for (single dose azithromycin – comparator) 5 (8) 10 51 (77) 61 (92) 66 3 (5) 42 18 60 (95) 63 66 3 Day (%) 2 (3) 13 49 (77) 62 (97) 64 1 (2) 40 21 61 (98) 62 66 Ceftriaxone (%) Azithromycin Study 95-001 Clinical Outcome at Day 28 by Age 5 (16) 6 (15) 3 (8) Failure 26 (84) 33 (85) 37 (93) Cure 31 39 40 > 2 years of age 10 (30) 9 (33) 6 (24) Failure 23 (70) 18 (67) 19 (76) Cure 33 27 25 < 2 years of age Ceftriaxone (%) 3 Day (%) 1 Day (%) Azithromycin Study 95-001 Susceptibility S. pneumoniae susceptibility (N=57) Azithromycin 46 susceptible 11 resistant (MIC > 0.5 mg/ml) Ceftriaxone All isolates were susceptible to ceftriaxone All H. influenzae and M. catarrhalis were susceptible to azithromycin and ceftriaxone Study 95-001 Clinical Cure Per Baseline Pathogen at Day 28 Study 95-001 Treatment Related Adverse Events* 0 (0) 0 (0) 3 (5) Vomiting 4 (6) 0 (0) 1 (2) Rash 4 (6) 3 (5) 2 (3) Diarrhea 6 (9) 6 (9) 7 (11) Patients w/ AE 66 66 66 Patients Treated Ceftriaxone 3 Day 1 Day 0 (0) 0 (0) 0 (0) Discontinued *2 or more events on any treatment regimen Azithromycin Study R-0581 Single Dose Therapy Study R-0581 Objective Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 30 mg/kg single oral dose Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study R-0581 Visits and Assessments *Patients who vomited within 30 minutes were redosed 1 Including parental questionnaire Study R-0581 Patient Disposition Study R-0581 Demographics Study R-0581 Results Study R-0581 Clinical Outcome 38 (25) 37 (25) Failure 8 2 Improvement [-7, 15] 108 (70) 112 (74) Cure [-10, 11] 116 (75) 114 (75) Success 154 151 Day 28 19 (12) 21 (13) Failure 21 34 Improvement 121 105 Cure [-9, 7] 142 (88) 139 (87) Success 161 160 Day 14 173 173 Number of Patients 95% CI1[%] Amox/Clav (%) Azithromycin (%) 1 95% CI for (azithromycin – comparator) Study R-0581 Clinical Outcome at Day 28 by Age Cure 26 (49) 24 (38) Failure [-8, 31] 95% CI1[%] Failure < 2 years of age 27 (51) 40 (63) Cure 53 64 > 2 years of age Amox/Clav Azithromycin 1 95% CI for (azithromycin – comparator) N (%) N (%) 72 (83) 15 (17) 87 81 (80) 20 (20) 101 [-10, 15] Study R-0581 Compliance Based on patients randomized to their study drug regimen Study R-0581 Treatment Related Adverse Events* 7 (4%) 7 (4%) Vomiting 9 (5%) 3 (2%) 22 (13%) 11 (6%) Diarrhea 39 (23%) 29 (17%) Patients w/ AEs Rash Azithromycin N = 173 Amox/Clav N = 173 7(4%) 4 (2%) Discontinued due to AE * Adverse Events greater than 2 percent in either regimen Study 1015 Single Dose Therapy Study 1015 Objectives To assess per-pathogen clinical response rates To provide additional data on the safety and toleration of the single dose regimen Design Prospective Open-label Non-comparative Multi-center Study 1015 Visits and Assessments *Patients who vomited within 30 minutes were redosed Study 1015 Endpoints Primary Efficacy Endpoint Clinical response by baseline pathogen at day 28 Initial local laboratory isolation of pathogen with confirmation by central laboratory Secondary Efficacy Endpoints Clinical response at day 28 (test of cure) Clinical response at day 10 Safety Evaluation Study 1015 Patient Disposition 242 Clinical at Day 28 127 Bacteriologic Efficacy Azithromycin 248 Safety 248 Enrolled Evaluation Groups Study 1015 Demographics Study 1015 Results Study 1015 Clinical Outcome 36 (15%) Failure [80,90] 206 (85%) Cure 242 Day 28 27 (11%) Failure 74 Improvement 139 Cure [85,93] 213 (89%) Success 240 Day 10 247 Number of Patients 95% CI1 [%] Azithromycin (%) 1 95% CI for azithromycin Study 1015 Clinical Outcome at Day 28 by Age 11 17 Failure [84, 94] 89 142 Cure 159 > 2 years of age 23 19 Failure [67, 87] 77 64 Cure 83 < 2 years of age 95% CI [%] (%) N Azithromycin Study 1015 Clinical Outcome - Per Baseline Pathogen Study 1015 MIC Distribution for S. pneumoniae (N=67) Percent of Patients Azithromycin MIC (mg/ml) Study 1015 Resistant S. Pneumoniae S. pneumoniae MIC = 8 g/ml 7 baseline isolates All sensitive to clindamycin All with mef A gene by PCR S. pneumoniae MIC >256 g/ml 5 baseline isolates All resistant to clindamycin All with erm B gene by PCR Study 1015 Day 28 Outcome and MIC Distribution for S. pneumoniae (N=66) # of Patients Azithromycin MIC (mg/ml) Study 1015 Patient 0067 Failed Therapy 1Susceptible to clindamycin; mef A gene identified 2Resistant to clindamycin; erm B gene identified
Slide 74 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997 Study 95-001 Experimental Design *Baseline tympanocentesis Study 95-001 Patient Disposition Study 95-001 Demographics 0% 2% Black 98% 97% White Race: 48% 56% % Male 2.3 (+ 1.4) 2.5 (+ 1.3) Mean Age (Yrs, ±SD) 31 (47%) 40 (61%) 2 Yrs - 12 Yrs 35 (53%) 26 (39%) < 2 Yrs Age: N = 66 Single Dose N = 66 Azithromycin 2% 95% 55% 2.7 (+ 1.5) 40 (61%) 26 (39%) Three Day N = 66 Ceftriaxone 2% 2% Hispanic 3% Study 95-001 Results Study 95-001 Clinical Efficacy Population 4 (6) Failure 5 Improvement [- 5, 25] 56 (86) Cure [-12,6] 61 (94) Success 65 Day 28 2 (3) Failure 36 Improvement 26 Cure [-8,5] 62 (97) Success 64 Day 14 66 Randomized Patients 95% CI1 [%] 1 Day (%) 1 95% CI for (single dose azithromycin – comparator) 5 (8) 10 51 (77) 61 (92) 66 3 (5) 42 18 60 (95) 63 66 3 Day (%) 2 (3) 13 49 (77) 62 (97) 64 1 (2) 40 21 61 (98) 62 66 Ceftriaxone (%) Azithromycin Study 95-001 Clinical Outcome at Day 28 by Age 5 (16) 6 (15) 3 (8) Failure 26 (84) 33 (85) 37 (93) Cure 31 39 40 > 2 years of age 10 (30) 9 (33) 6 (24) Failure 23 (70) 18 (67) 19 (76) Cure 33 27 25 < 2 years of age Ceftriaxone (%) 3 Day (%) 1 Day (%) Azithromycin Study 95-001 Susceptibility S. pneumoniae susceptibility (N=57) Azithromycin 46 susceptible 11 resistant (MIC > 0.5 mg/ml) Ceftriaxone All isolates were susceptible to ceftriaxone All H. influenzae and M. catarrhalis were susceptible to azithromycin and ceftriaxone Study 95-001 Clinical Cure Per Baseline Pathogen at Day 28 Study 95-001 Treatment Related Adverse Events* 0 (0) 0 (0) 3 (5) Vomiting 4 (6) 0 (0) 1 (2) Rash 4 (6) 3 (5) 2 (3) Diarrhea 6 (9) 6 (9) 7 (11) Patients w/ AE 66 66 66 Patients Treated Ceftriaxone 3 Day 1 Day 0 (0) 0 (0) 0 (0) Discontinued *2 or more events on any treatment regimen Azithromycin Study R-0581 Single Dose Therapy Study R-0581 Objective Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 30 mg/kg single oral dose Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study R-0581 Visits and Assessments *Patients who vomited within 30 minutes were redosed 1 Including parental questionnaire Study R-0581 Patient Disposition Study R-0581 Demographics Study R-0581 Results Study R-0581 Clinical Outcome 38 (25) 37 (25) Failure 8 2 Improvement [-7, 15] 108 (70) 112 (74) Cure [-10, 11] 116 (75) 114 (75) Success 154 151 Day 28 19 (12) 21 (13) Failure 21 34 Improvement 121 105 Cure [-9, 7] 142 (88) 139 (87) Success 161 160 Day 14 173 173 Number of Patients 95% CI1[%] Amox/Clav (%) Azithromycin (%) 1 95% CI for (azithromycin – comparator) Study R-0581 Clinical Outcome at Day 28 by Age Cure 26 (49) 24 (38) Failure [-8, 31] 95% CI1[%] Failure < 2 years of age 27 (51) 40 (63) Cure 53 64 > 2 years of age Amox/Clav Azithromycin 1 95% CI for (azithromycin – comparator) N (%) N (%) 72 (83) 15 (17) 87 81 (80) 20 (20) 101 [-10, 15] Study R-0581 Compliance Based on patients randomized to their study drug regimen Study R-0581 Treatment Related Adverse Events* 7 (4%) 7 (4%) Vomiting 9 (5%) 3 (2%) 22 (13%) 11 (6%) Diarrhea 39 (23%) 29 (17%) Patients w/ AEs Rash Azithromycin N = 173 Amox/Clav N = 173 7(4%) 4 (2%) Discontinued due to AE * Adverse Events greater than 2 percent in either regimen Study 1015 Single Dose Therapy Study 1015 Objectives To assess per-pathogen clinical response rates To provide additional data on the safety and toleration of the single dose regimen Design Prospective Open-label Non-comparative Multi-center Study 1015 Visits and Assessments *Patients who vomited within 30 minutes were redosed Study 1015 Endpoints Primary Efficacy Endpoint Clinical response by baseline pathogen at day 28 Initial local laboratory isolation of pathogen with confirmation by central laboratory Secondary Efficacy Endpoints Clinical response at day 28 (test of cure) Clinical response at day 10 Safety Evaluation Study 1015 Patient Disposition 242 Clinical at Day 28 127 Bacteriologic Efficacy Azithromycin 248 Safety 248 Enrolled Evaluation Groups Study 1015 Demographics Study 1015 Results Study 1015 Clinical Outcome 36 (15%) Failure [80,90] 206 (85%) Cure 242 Day 28 27 (11%) Failure 74 Improvement 139 Cure [85,93] 213 (89%) Success 240 Day 10 247 Number of Patients 95% CI1 [%] Azithromycin (%) 1 95% CI for azithromycin Study 1015 Clinical Outcome at Day 28 by Age 11 17 Failure [84, 94] 89 142 Cure 159 > 2 years of age 23 19 Failure [67, 87] 77 64 Cure 83 < 2 years of age 95% CI [%] (%) N Azithromycin Study 1015 Clinical Outcome - Per Baseline Pathogen Study 1015 MIC Distribution for S. pneumoniae (N=67) Percent of Patients Azithromycin MIC (mg/ml) Study 1015 Resistant S. Pneumoniae S. pneumoniae MIC = 8 g/ml 7 baseline isolates All sensitive to clindamycin All with mef A gene by PCR S. pneumoniae MIC >256 g/ml 5 baseline isolates All resistant to clindamycin All with erm B gene by PCR Study 1015 Day 28 Outcome and MIC Distribution for S. pneumoniae (N=66) # of Patients Azithromycin MIC (mg/ml) Study 1015 Patient 0067 Failed Therapy 1Susceptible to clindamycin; mef A gene identified 2Resistant to clindamycin; erm B gene identified Study 1015 Strains From Patient 0067 Are Clonally Distinct 1 2 3 4 MIC = 8 MIC >256
Slide 75 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997 Study 95-001 Experimental Design *Baseline tympanocentesis Study 95-001 Patient Disposition Study 95-001 Demographics 0% 2% Black 98% 97% White Race: 48% 56% % Male 2.3 (+ 1.4) 2.5 (+ 1.3) Mean Age (Yrs, ±SD) 31 (47%) 40 (61%) 2 Yrs - 12 Yrs 35 (53%) 26 (39%) < 2 Yrs Age: N = 66 Single Dose N = 66 Azithromycin 2% 95% 55% 2.7 (+ 1.5) 40 (61%) 26 (39%) Three Day N = 66 Ceftriaxone 2% 2% Hispanic 3% Study 95-001 Results Study 95-001 Clinical Efficacy Population 4 (6) Failure 5 Improvement [- 5, 25] 56 (86) Cure [-12,6] 61 (94) Success 65 Day 28 2 (3) Failure 36 Improvement 26 Cure [-8,5] 62 (97) Success 64 Day 14 66 Randomized Patients 95% CI1 [%] 1 Day (%) 1 95% CI for (single dose azithromycin – comparator) 5 (8) 10 51 (77) 61 (92) 66 3 (5) 42 18 60 (95) 63 66 3 Day (%) 2 (3) 13 49 (77) 62 (97) 64 1 (2) 40 21 61 (98) 62 66 Ceftriaxone (%) Azithromycin Study 95-001 Clinical Outcome at Day 28 by Age 5 (16) 6 (15) 3 (8) Failure 26 (84) 33 (85) 37 (93) Cure 31 39 40 > 2 years of age 10 (30) 9 (33) 6 (24) Failure 23 (70) 18 (67) 19 (76) Cure 33 27 25 < 2 years of age Ceftriaxone (%) 3 Day (%) 1 Day (%) Azithromycin Study 95-001 Susceptibility S. pneumoniae susceptibility (N=57) Azithromycin 46 susceptible 11 resistant (MIC > 0.5 mg/ml) Ceftriaxone All isolates were susceptible to ceftriaxone All H. influenzae and M. catarrhalis were susceptible to azithromycin and ceftriaxone Study 95-001 Clinical Cure Per Baseline Pathogen at Day 28 Study 95-001 Treatment Related Adverse Events* 0 (0) 0 (0) 3 (5) Vomiting 4 (6) 0 (0) 1 (2) Rash 4 (6) 3 (5) 2 (3) Diarrhea 6 (9) 6 (9) 7 (11) Patients w/ AE 66 66 66 Patients Treated Ceftriaxone 3 Day 1 Day 0 (0) 0 (0) 0 (0) Discontinued *2 or more events on any treatment regimen Azithromycin Study R-0581 Single Dose Therapy Study R-0581 Objective Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 30 mg/kg single oral dose Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study R-0581 Visits and Assessments *Patients who vomited within 30 minutes were redosed 1 Including parental questionnaire Study R-0581 Patient Disposition Study R-0581 Demographics Study R-0581 Results Study R-0581 Clinical Outcome 38 (25) 37 (25) Failure 8 2 Improvement [-7, 15] 108 (70) 112 (74) Cure [-10, 11] 116 (75) 114 (75) Success 154 151 Day 28 19 (12) 21 (13) Failure 21 34 Improvement 121 105 Cure [-9, 7] 142 (88) 139 (87) Success 161 160 Day 14 173 173 Number of Patients 95% CI1[%] Amox/Clav (%) Azithromycin (%) 1 95% CI for (azithromycin – comparator) Study R-0581 Clinical Outcome at Day 28 by Age Cure 26 (49) 24 (38) Failure [-8, 31] 95% CI1[%] Failure < 2 years of age 27 (51) 40 (63) Cure 53 64 > 2 years of age Amox/Clav Azithromycin 1 95% CI for (azithromycin – comparator) N (%) N (%) 72 (83) 15 (17) 87 81 (80) 20 (20) 101 [-10, 15] Study R-0581 Compliance Based on patients randomized to their study drug regimen Study R-0581 Treatment Related Adverse Events* 7 (4%) 7 (4%) Vomiting 9 (5%) 3 (2%) 22 (13%) 11 (6%) Diarrhea 39 (23%) 29 (17%) Patients w/ AEs Rash Azithromycin N = 173 Amox/Clav N = 173 7(4%) 4 (2%) Discontinued due to AE * Adverse Events greater than 2 percent in either regimen Study 1015 Single Dose Therapy Study 1015 Objectives To assess per-pathogen clinical response rates To provide additional data on the safety and toleration of the single dose regimen Design Prospective Open-label Non-comparative Multi-center Study 1015 Visits and Assessments *Patients who vomited within 30 minutes were redosed Study 1015 Endpoints Primary Efficacy Endpoint Clinical response by baseline pathogen at day 28 Initial local laboratory isolation of pathogen with confirmation by central laboratory Secondary Efficacy Endpoints Clinical response at day 28 (test of cure) Clinical response at day 10 Safety Evaluation Study 1015 Patient Disposition 242 Clinical at Day 28 127 Bacteriologic Efficacy Azithromycin 248 Safety 248 Enrolled Evaluation Groups Study 1015 Demographics Study 1015 Results Study 1015 Clinical Outcome 36 (15%) Failure [80,90] 206 (85%) Cure 242 Day 28 27 (11%) Failure 74 Improvement 139 Cure [85,93] 213 (89%) Success 240 Day 10 247 Number of Patients 95% CI1 [%] Azithromycin (%) 1 95% CI for azithromycin Study 1015 Clinical Outcome at Day 28 by Age 11 17 Failure [84, 94] 89 142 Cure 159 > 2 years of age 23 19 Failure [67, 87] 77 64 Cure 83 < 2 years of age 95% CI [%] (%) N Azithromycin Study 1015 Clinical Outcome - Per Baseline Pathogen Study 1015 MIC Distribution for S. pneumoniae (N=67) Percent of Patients Azithromycin MIC (mg/ml) Study 1015 Resistant S. Pneumoniae S. pneumoniae MIC = 8 g/ml 7 baseline isolates All sensitive to clindamycin All with mef A gene by PCR S. pneumoniae MIC >256 g/ml 5 baseline isolates All resistant to clindamycin All with erm B gene by PCR Study 1015 Day 28 Outcome and MIC Distribution for S. pneumoniae (N=66) # of Patients Azithromycin MIC (mg/ml) Study 1015 Patient 0067 Failed Therapy 1Susceptible to clindamycin; mef A gene identified 2Resistant to clindamycin; erm B gene identified Study 1015 Strains From Patient 0067 Are Clonally Distinct 1 2 3 4 MIC = 8 MIC >256 Study 1015 Outcome of S. pneumoniae AOM by Penicillin Susceptibility Penicillin Susceptibility *Penicillin MIC > 2 mg/ml **Penicillin MIC > 0.125 - < 2 mg/ml
Slide 76 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997 Study 95-001 Experimental Design *Baseline tympanocentesis Study 95-001 Patient Disposition Study 95-001 Demographics 0% 2% Black 98% 97% White Race: 48% 56% % Male 2.3 (+ 1.4) 2.5 (+ 1.3) Mean Age (Yrs, ±SD) 31 (47%) 40 (61%) 2 Yrs - 12 Yrs 35 (53%) 26 (39%) < 2 Yrs Age: N = 66 Single Dose N = 66 Azithromycin 2% 95% 55% 2.7 (+ 1.5) 40 (61%) 26 (39%) Three Day N = 66 Ceftriaxone 2% 2% Hispanic 3% Study 95-001 Results Study 95-001 Clinical Efficacy Population 4 (6) Failure 5 Improvement [- 5, 25] 56 (86) Cure [-12,6] 61 (94) Success 65 Day 28 2 (3) Failure 36 Improvement 26 Cure [-8,5] 62 (97) Success 64 Day 14 66 Randomized Patients 95% CI1 [%] 1 Day (%) 1 95% CI for (single dose azithromycin – comparator) 5 (8) 10 51 (77) 61 (92) 66 3 (5) 42 18 60 (95) 63 66 3 Day (%) 2 (3) 13 49 (77) 62 (97) 64 1 (2) 40 21 61 (98) 62 66 Ceftriaxone (%) Azithromycin Study 95-001 Clinical Outcome at Day 28 by Age 5 (16) 6 (15) 3 (8) Failure 26 (84) 33 (85) 37 (93) Cure 31 39 40 > 2 years of age 10 (30) 9 (33) 6 (24) Failure 23 (70) 18 (67) 19 (76) Cure 33 27 25 < 2 years of age Ceftriaxone (%) 3 Day (%) 1 Day (%) Azithromycin Study 95-001 Susceptibility S. pneumoniae susceptibility (N=57) Azithromycin 46 susceptible 11 resistant (MIC > 0.5 mg/ml) Ceftriaxone All isolates were susceptible to ceftriaxone All H. influenzae and M. catarrhalis were susceptible to azithromycin and ceftriaxone Study 95-001 Clinical Cure Per Baseline Pathogen at Day 28 Study 95-001 Treatment Related Adverse Events* 0 (0) 0 (0) 3 (5) Vomiting 4 (6) 0 (0) 1 (2) Rash 4 (6) 3 (5) 2 (3) Diarrhea 6 (9) 6 (9) 7 (11) Patients w/ AE 66 66 66 Patients Treated Ceftriaxone 3 Day 1 Day 0 (0) 0 (0) 0 (0) Discontinued *2 or more events on any treatment regimen Azithromycin Study R-0581 Single Dose Therapy Study R-0581 Objective Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 30 mg/kg single oral dose Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study R-0581 Visits and Assessments *Patients who vomited within 30 minutes were redosed 1 Including parental questionnaire Study R-0581 Patient Disposition Study R-0581 Demographics Study R-0581 Results Study R-0581 Clinical Outcome 38 (25) 37 (25) Failure 8 2 Improvement [-7, 15] 108 (70) 112 (74) Cure [-10, 11] 116 (75) 114 (75) Success 154 151 Day 28 19 (12) 21 (13) Failure 21 34 Improvement 121 105 Cure [-9, 7] 142 (88) 139 (87) Success 161 160 Day 14 173 173 Number of Patients 95% CI1[%] Amox/Clav (%) Azithromycin (%) 1 95% CI for (azithromycin – comparator) Study R-0581 Clinical Outcome at Day 28 by Age Cure 26 (49) 24 (38) Failure [-8, 31] 95% CI1[%] Failure < 2 years of age 27 (51) 40 (63) Cure 53 64 > 2 years of age Amox/Clav Azithromycin 1 95% CI for (azithromycin – comparator) N (%) N (%) 72 (83) 15 (17) 87 81 (80) 20 (20) 101 [-10, 15] Study R-0581 Compliance Based on patients randomized to their study drug regimen Study R-0581 Treatment Related Adverse Events* 7 (4%) 7 (4%) Vomiting 9 (5%) 3 (2%) 22 (13%) 11 (6%) Diarrhea 39 (23%) 29 (17%) Patients w/ AEs Rash Azithromycin N = 173 Amox/Clav N = 173 7(4%) 4 (2%) Discontinued due to AE * Adverse Events greater than 2 percent in either regimen Study 1015 Single Dose Therapy Study 1015 Objectives To assess per-pathogen clinical response rates To provide additional data on the safety and toleration of the single dose regimen Design Prospective Open-label Non-comparative Multi-center Study 1015 Visits and Assessments *Patients who vomited within 30 minutes were redosed Study 1015 Endpoints Primary Efficacy Endpoint Clinical response by baseline pathogen at day 28 Initial local laboratory isolation of pathogen with confirmation by central laboratory Secondary Efficacy Endpoints Clinical response at day 28 (test of cure) Clinical response at day 10 Safety Evaluation Study 1015 Patient Disposition 242 Clinical at Day 28 127 Bacteriologic Efficacy Azithromycin 248 Safety 248 Enrolled Evaluation Groups Study 1015 Demographics Study 1015 Results Study 1015 Clinical Outcome 36 (15%) Failure [80,90] 206 (85%) Cure 242 Day 28 27 (11%) Failure 74 Improvement 139 Cure [85,93] 213 (89%) Success 240 Day 10 247 Number of Patients 95% CI1 [%] Azithromycin (%) 1 95% CI for azithromycin Study 1015 Clinical Outcome at Day 28 by Age 11 17 Failure [84, 94] 89 142 Cure 159 > 2 years of age 23 19 Failure [67, 87] 77 64 Cure 83 < 2 years of age 95% CI [%] (%) N Azithromycin Study 1015 Clinical Outcome - Per Baseline Pathogen Study 1015 MIC Distribution for S. pneumoniae (N=67) Percent of Patients Azithromycin MIC (mg/ml) Study 1015 Resistant S. Pneumoniae S. pneumoniae MIC = 8 g/ml 7 baseline isolates All sensitive to clindamycin All with mef A gene by PCR S. pneumoniae MIC >256 g/ml 5 baseline isolates All resistant to clindamycin All with erm B gene by PCR Study 1015 Day 28 Outcome and MIC Distribution for S. pneumoniae (N=66) # of Patients Azithromycin MIC (mg/ml) Study 1015 Patient 0067 Failed Therapy 1Susceptible to clindamycin; mef A gene identified 2Resistant to clindamycin; erm B gene identified Study 1015 Strains From Patient 0067 Are Clonally Distinct 1 2 3 4 MIC = 8 MIC >256 Study 1015 Outcome of S. pneumoniae AOM by Penicillin Susceptibility Penicillin Susceptibility *Penicillin MIC > 2 mg/ml **Penicillin MIC > 0.125 - < 2 mg/ml Study 1015 Outcome of S. pneumoniae AOM by Penicillin Susceptibility Penicillin Susceptibility *Penicillin MIC > 2 mg/ml **Penicillin MIC > 0.125 - < 2 mg/ml
Slide 77 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997 Study 95-001 Experimental Design *Baseline tympanocentesis Study 95-001 Patient Disposition Study 95-001 Demographics 0% 2% Black 98% 97% White Race: 48% 56% % Male 2.3 (+ 1.4) 2.5 (+ 1.3) Mean Age (Yrs, ±SD) 31 (47%) 40 (61%) 2 Yrs - 12 Yrs 35 (53%) 26 (39%) < 2 Yrs Age: N = 66 Single Dose N = 66 Azithromycin 2% 95% 55% 2.7 (+ 1.5) 40 (61%) 26 (39%) Three Day N = 66 Ceftriaxone 2% 2% Hispanic 3% Study 95-001 Results Study 95-001 Clinical Efficacy Population 4 (6) Failure 5 Improvement [- 5, 25] 56 (86) Cure [-12,6] 61 (94) Success 65 Day 28 2 (3) Failure 36 Improvement 26 Cure [-8,5] 62 (97) Success 64 Day 14 66 Randomized Patients 95% CI1 [%] 1 Day (%) 1 95% CI for (single dose azithromycin – comparator) 5 (8) 10 51 (77) 61 (92) 66 3 (5) 42 18 60 (95) 63 66 3 Day (%) 2 (3) 13 49 (77) 62 (97) 64 1 (2) 40 21 61 (98) 62 66 Ceftriaxone (%) Azithromycin Study 95-001 Clinical Outcome at Day 28 by Age 5 (16) 6 (15) 3 (8) Failure 26 (84) 33 (85) 37 (93) Cure 31 39 40 > 2 years of age 10 (30) 9 (33) 6 (24) Failure 23 (70) 18 (67) 19 (76) Cure 33 27 25 < 2 years of age Ceftriaxone (%) 3 Day (%) 1 Day (%) Azithromycin Study 95-001 Susceptibility S. pneumoniae susceptibility (N=57) Azithromycin 46 susceptible 11 resistant (MIC > 0.5 mg/ml) Ceftriaxone All isolates were susceptible to ceftriaxone All H. influenzae and M. catarrhalis were susceptible to azithromycin and ceftriaxone Study 95-001 Clinical Cure Per Baseline Pathogen at Day 28 Study 95-001 Treatment Related Adverse Events* 0 (0) 0 (0) 3 (5) Vomiting 4 (6) 0 (0) 1 (2) Rash 4 (6) 3 (5) 2 (3) Diarrhea 6 (9) 6 (9) 7 (11) Patients w/ AE 66 66 66 Patients Treated Ceftriaxone 3 Day 1 Day 0 (0) 0 (0) 0 (0) Discontinued *2 or more events on any treatment regimen Azithromycin Study R-0581 Single Dose Therapy Study R-0581 Objective Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 30 mg/kg single oral dose Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study R-0581 Visits and Assessments *Patients who vomited within 30 minutes were redosed 1 Including parental questionnaire Study R-0581 Patient Disposition Study R-0581 Demographics Study R-0581 Results Study R-0581 Clinical Outcome 38 (25) 37 (25) Failure 8 2 Improvement [-7, 15] 108 (70) 112 (74) Cure [-10, 11] 116 (75) 114 (75) Success 154 151 Day 28 19 (12) 21 (13) Failure 21 34 Improvement 121 105 Cure [-9, 7] 142 (88) 139 (87) Success 161 160 Day 14 173 173 Number of Patients 95% CI1[%] Amox/Clav (%) Azithromycin (%) 1 95% CI for (azithromycin – comparator) Study R-0581 Clinical Outcome at Day 28 by Age Cure 26 (49) 24 (38) Failure [-8, 31] 95% CI1[%] Failure < 2 years of age 27 (51) 40 (63) Cure 53 64 > 2 years of age Amox/Clav Azithromycin 1 95% CI for (azithromycin – comparator) N (%) N (%) 72 (83) 15 (17) 87 81 (80) 20 (20) 101 [-10, 15] Study R-0581 Compliance Based on patients randomized to their study drug regimen Study R-0581 Treatment Related Adverse Events* 7 (4%) 7 (4%) Vomiting 9 (5%) 3 (2%) 22 (13%) 11 (6%) Diarrhea 39 (23%) 29 (17%) Patients w/ AEs Rash Azithromycin N = 173 Amox/Clav N = 173 7(4%) 4 (2%) Discontinued due to AE * Adverse Events greater than 2 percent in either regimen Study 1015 Single Dose Therapy Study 1015 Objectives To assess per-pathogen clinical response rates To provide additional data on the safety and toleration of the single dose regimen Design Prospective Open-label Non-comparative Multi-center Study 1015 Visits and Assessments *Patients who vomited within 30 minutes were redosed Study 1015 Endpoints Primary Efficacy Endpoint Clinical response by baseline pathogen at day 28 Initial local laboratory isolation of pathogen with confirmation by central laboratory Secondary Efficacy Endpoints Clinical response at day 28 (test of cure) Clinical response at day 10 Safety Evaluation Study 1015 Patient Disposition 242 Clinical at Day 28 127 Bacteriologic Efficacy Azithromycin 248 Safety 248 Enrolled Evaluation Groups Study 1015 Demographics Study 1015 Results Study 1015 Clinical Outcome 36 (15%) Failure [80,90] 206 (85%) Cure 242 Day 28 27 (11%) Failure 74 Improvement 139 Cure [85,93] 213 (89%) Success 240 Day 10 247 Number of Patients 95% CI1 [%] Azithromycin (%) 1 95% CI for azithromycin Study 1015 Clinical Outcome at Day 28 by Age 11 17 Failure [84, 94] 89 142 Cure 159 > 2 years of age 23 19 Failure [67, 87] 77 64 Cure 83 < 2 years of age 95% CI [%] (%) N Azithromycin Study 1015 Clinical Outcome - Per Baseline Pathogen Study 1015 MIC Distribution for S. pneumoniae (N=67) Percent of Patients Azithromycin MIC (mg/ml) Study 1015 Resistant S. Pneumoniae S. pneumoniae MIC = 8 g/ml 7 baseline isolates All sensitive to clindamycin All with mef A gene by PCR S. pneumoniae MIC >256 g/ml 5 baseline isolates All resistant to clindamycin All with erm B gene by PCR Study 1015 Day 28 Outcome and MIC Distribution for S. pneumoniae (N=66) # of Patients Azithromycin MIC (mg/ml) Study 1015 Patient 0067 Failed Therapy 1Susceptible to clindamycin; mef A gene identified 2Resistant to clindamycin; erm B gene identified Study 1015 Strains From Patient 0067 Are Clonally Distinct 1 2 3 4 MIC = 8 MIC >256 Study 1015 Outcome of S. pneumoniae AOM by Penicillin Susceptibility Penicillin Susceptibility *Penicillin MIC > 2 mg/ml **Penicillin MIC > 0.125 - < 2 mg/ml Study 1015 Outcome of S. pneumoniae AOM by Penicillin Susceptibility Penicillin Susceptibility *Penicillin MIC > 2 mg/ml **Penicillin MIC > 0.125 - < 2 mg/ml Study 1015 Treatment Related Adverse Events* (2) 4 Abdominal Pain (6) 14 Vomiting (3) 8 Diarrhea (12) 30 Patients w/ AEs (0) 1 Discontinued due to AEs 248 Patients Treated (%) N * Adverse Events greater than 1%
Slide 78 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997 Study 95-001 Experimental Design *Baseline tympanocentesis Study 95-001 Patient Disposition Study 95-001 Demographics 0% 2% Black 98% 97% White Race: 48% 56% % Male 2.3 (+ 1.4) 2.5 (+ 1.3) Mean Age (Yrs, ±SD) 31 (47%) 40 (61%) 2 Yrs - 12 Yrs 35 (53%) 26 (39%) < 2 Yrs Age: N = 66 Single Dose N = 66 Azithromycin 2% 95% 55% 2.7 (+ 1.5) 40 (61%) 26 (39%) Three Day N = 66 Ceftriaxone 2% 2% Hispanic 3% Study 95-001 Results Study 95-001 Clinical Efficacy Population 4 (6) Failure 5 Improvement [- 5, 25] 56 (86) Cure [-12,6] 61 (94) Success 65 Day 28 2 (3) Failure 36 Improvement 26 Cure [-8,5] 62 (97) Success 64 Day 14 66 Randomized Patients 95% CI1 [%] 1 Day (%) 1 95% CI for (single dose azithromycin – comparator) 5 (8) 10 51 (77) 61 (92) 66 3 (5) 42 18 60 (95) 63 66 3 Day (%) 2 (3) 13 49 (77) 62 (97) 64 1 (2) 40 21 61 (98) 62 66 Ceftriaxone (%) Azithromycin Study 95-001 Clinical Outcome at Day 28 by Age 5 (16) 6 (15) 3 (8) Failure 26 (84) 33 (85) 37 (93) Cure 31 39 40 > 2 years of age 10 (30) 9 (33) 6 (24) Failure 23 (70) 18 (67) 19 (76) Cure 33 27 25 < 2 years of age Ceftriaxone (%) 3 Day (%) 1 Day (%) Azithromycin Study 95-001 Susceptibility S. pneumoniae susceptibility (N=57) Azithromycin 46 susceptible 11 resistant (MIC > 0.5 mg/ml) Ceftriaxone All isolates were susceptible to ceftriaxone All H. influenzae and M. catarrhalis were susceptible to azithromycin and ceftriaxone Study 95-001 Clinical Cure Per Baseline Pathogen at Day 28 Study 95-001 Treatment Related Adverse Events* 0 (0) 0 (0) 3 (5) Vomiting 4 (6) 0 (0) 1 (2) Rash 4 (6) 3 (5) 2 (3) Diarrhea 6 (9) 6 (9) 7 (11) Patients w/ AE 66 66 66 Patients Treated Ceftriaxone 3 Day 1 Day 0 (0) 0 (0) 0 (0) Discontinued *2 or more events on any treatment regimen Azithromycin Study R-0581 Single Dose Therapy Study R-0581 Objective Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 30 mg/kg single oral dose Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study R-0581 Visits and Assessments *Patients who vomited within 30 minutes were redosed 1 Including parental questionnaire Study R-0581 Patient Disposition Study R-0581 Demographics Study R-0581 Results Study R-0581 Clinical Outcome 38 (25) 37 (25) Failure 8 2 Improvement [-7, 15] 108 (70) 112 (74) Cure [-10, 11] 116 (75) 114 (75) Success 154 151 Day 28 19 (12) 21 (13) Failure 21 34 Improvement 121 105 Cure [-9, 7] 142 (88) 139 (87) Success 161 160 Day 14 173 173 Number of Patients 95% CI1[%] Amox/Clav (%) Azithromycin (%) 1 95% CI for (azithromycin – comparator) Study R-0581 Clinical Outcome at Day 28 by Age Cure 26 (49) 24 (38) Failure [-8, 31] 95% CI1[%] Failure < 2 years of age 27 (51) 40 (63) Cure 53 64 > 2 years of age Amox/Clav Azithromycin 1 95% CI for (azithromycin – comparator) N (%) N (%) 72 (83) 15 (17) 87 81 (80) 20 (20) 101 [-10, 15] Study R-0581 Compliance Based on patients randomized to their study drug regimen Study R-0581 Treatment Related Adverse Events* 7 (4%) 7 (4%) Vomiting 9 (5%) 3 (2%) 22 (13%) 11 (6%) Diarrhea 39 (23%) 29 (17%) Patients w/ AEs Rash Azithromycin N = 173 Amox/Clav N = 173 7(4%) 4 (2%) Discontinued due to AE * Adverse Events greater than 2 percent in either regimen Study 1015 Single Dose Therapy Study 1015 Objectives To assess per-pathogen clinical response rates To provide additional data on the safety and toleration of the single dose regimen Design Prospective Open-label Non-comparative Multi-center Study 1015 Visits and Assessments *Patients who vomited within 30 minutes were redosed Study 1015 Endpoints Primary Efficacy Endpoint Clinical response by baseline pathogen at day 28 Initial local laboratory isolation of pathogen with confirmation by central laboratory Secondary Efficacy Endpoints Clinical response at day 28 (test of cure) Clinical response at day 10 Safety Evaluation Study 1015 Patient Disposition 242 Clinical at Day 28 127 Bacteriologic Efficacy Azithromycin 248 Safety 248 Enrolled Evaluation Groups Study 1015 Demographics Study 1015 Results Study 1015 Clinical Outcome 36 (15%) Failure [80,90] 206 (85%) Cure 242 Day 28 27 (11%) Failure 74 Improvement 139 Cure [85,93] 213 (89%) Success 240 Day 10 247 Number of Patients 95% CI1 [%] Azithromycin (%) 1 95% CI for azithromycin Study 1015 Clinical Outcome at Day 28 by Age 11 17 Failure [84, 94] 89 142 Cure 159 > 2 years of age 23 19 Failure [67, 87] 77 64 Cure 83 < 2 years of age 95% CI [%] (%) N Azithromycin Study 1015 Clinical Outcome - Per Baseline Pathogen Study 1015 MIC Distribution for S. pneumoniae (N=67) Percent of Patients Azithromycin MIC (mg/ml) Study 1015 Resistant S. Pneumoniae S. pneumoniae MIC = 8 g/ml 7 baseline isolates All sensitive to clindamycin All with mef A gene by PCR S. pneumoniae MIC >256 g/ml 5 baseline isolates All resistant to clindamycin All with erm B gene by PCR Study 1015 Day 28 Outcome and MIC Distribution for S. pneumoniae (N=66) # of Patients Azithromycin MIC (mg/ml) Study 1015 Patient 0067 Failed Therapy 1Susceptible to clindamycin; mef A gene identified 2Resistant to clindamycin; erm B gene identified Study 1015 Strains From Patient 0067 Are Clonally Distinct 1 2 3 4 MIC = 8 MIC >256 Study 1015 Outcome of S. pneumoniae AOM by Penicillin Susceptibility Penicillin Susceptibility *Penicillin MIC > 2 mg/ml **Penicillin MIC > 0.125 - < 2 mg/ml Study 1015 Outcome of S. pneumoniae AOM by Penicillin Susceptibility Penicillin Susceptibility *Penicillin MIC > 2 mg/ml **Penicillin MIC > 0.125 - < 2 mg/ml Study 1015 Treatment Related Adverse Events* (2) 4 Abdominal Pain (6) 14 Vomiting (3) 8 Diarrhea (12) 30 Patients w/ AEs (0) 1 Discontinued due to AEs 248 Patients Treated (%) N * Adverse Events greater than 1% Study 1014 Three Day Dosing
Slide 79 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997 Study 95-001 Experimental Design *Baseline tympanocentesis Study 95-001 Patient Disposition Study 95-001 Demographics 0% 2% Black 98% 97% White Race: 48% 56% % Male 2.3 (+ 1.4) 2.5 (+ 1.3) Mean Age (Yrs, ±SD) 31 (47%) 40 (61%) 2 Yrs - 12 Yrs 35 (53%) 26 (39%) < 2 Yrs Age: N = 66 Single Dose N = 66 Azithromycin 2% 95% 55% 2.7 (+ 1.5) 40 (61%) 26 (39%) Three Day N = 66 Ceftriaxone 2% 2% Hispanic 3% Study 95-001 Results Study 95-001 Clinical Efficacy Population 4 (6) Failure 5 Improvement [- 5, 25] 56 (86) Cure [-12,6] 61 (94) Success 65 Day 28 2 (3) Failure 36 Improvement 26 Cure [-8,5] 62 (97) Success 64 Day 14 66 Randomized Patients 95% CI1 [%] 1 Day (%) 1 95% CI for (single dose azithromycin – comparator) 5 (8) 10 51 (77) 61 (92) 66 3 (5) 42 18 60 (95) 63 66 3 Day (%) 2 (3) 13 49 (77) 62 (97) 64 1 (2) 40 21 61 (98) 62 66 Ceftriaxone (%) Azithromycin Study 95-001 Clinical Outcome at Day 28 by Age 5 (16) 6 (15) 3 (8) Failure 26 (84) 33 (85) 37 (93) Cure 31 39 40 > 2 years of age 10 (30) 9 (33) 6 (24) Failure 23 (70) 18 (67) 19 (76) Cure 33 27 25 < 2 years of age Ceftriaxone (%) 3 Day (%) 1 Day (%) Azithromycin Study 95-001 Susceptibility S. pneumoniae susceptibility (N=57) Azithromycin 46 susceptible 11 resistant (MIC > 0.5 mg/ml) Ceftriaxone All isolates were susceptible to ceftriaxone All H. influenzae and M. catarrhalis were susceptible to azithromycin and ceftriaxone Study 95-001 Clinical Cure Per Baseline Pathogen at Day 28 Study 95-001 Treatment Related Adverse Events* 0 (0) 0 (0) 3 (5) Vomiting 4 (6) 0 (0) 1 (2) Rash 4 (6) 3 (5) 2 (3) Diarrhea 6 (9) 6 (9) 7 (11) Patients w/ AE 66 66 66 Patients Treated Ceftriaxone 3 Day 1 Day 0 (0) 0 (0) 0 (0) Discontinued *2 or more events on any treatment regimen Azithromycin Study R-0581 Single Dose Therapy Study R-0581 Objective Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 30 mg/kg single oral dose Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study R-0581 Visits and Assessments *Patients who vomited within 30 minutes were redosed 1 Including parental questionnaire Study R-0581 Patient Disposition Study R-0581 Demographics Study R-0581 Results Study R-0581 Clinical Outcome 38 (25) 37 (25) Failure 8 2 Improvement [-7, 15] 108 (70) 112 (74) Cure [-10, 11] 116 (75) 114 (75) Success 154 151 Day 28 19 (12) 21 (13) Failure 21 34 Improvement 121 105 Cure [-9, 7] 142 (88) 139 (87) Success 161 160 Day 14 173 173 Number of Patients 95% CI1[%] Amox/Clav (%) Azithromycin (%) 1 95% CI for (azithromycin – comparator) Study R-0581 Clinical Outcome at Day 28 by Age Cure 26 (49) 24 (38) Failure [-8, 31] 95% CI1[%] Failure < 2 years of age 27 (51) 40 (63) Cure 53 64 > 2 years of age Amox/Clav Azithromycin 1 95% CI for (azithromycin – comparator) N (%) N (%) 72 (83) 15 (17) 87 81 (80) 20 (20) 101 [-10, 15] Study R-0581 Compliance Based on patients randomized to their study drug regimen Study R-0581 Treatment Related Adverse Events* 7 (4%) 7 (4%) Vomiting 9 (5%) 3 (2%) 22 (13%) 11 (6%) Diarrhea 39 (23%) 29 (17%) Patients w/ AEs Rash Azithromycin N = 173 Amox/Clav N = 173 7(4%) 4 (2%) Discontinued due to AE * Adverse Events greater than 2 percent in either regimen Study 1015 Single Dose Therapy Study 1015 Objectives To assess per-pathogen clinical response rates To provide additional data on the safety and toleration of the single dose regimen Design Prospective Open-label Non-comparative Multi-center Study 1015 Visits and Assessments *Patients who vomited within 30 minutes were redosed Study 1015 Endpoints Primary Efficacy Endpoint Clinical response by baseline pathogen at day 28 Initial local laboratory isolation of pathogen with confirmation by central laboratory Secondary Efficacy Endpoints Clinical response at day 28 (test of cure) Clinical response at day 10 Safety Evaluation Study 1015 Patient Disposition 242 Clinical at Day 28 127 Bacteriologic Efficacy Azithromycin 248 Safety 248 Enrolled Evaluation Groups Study 1015 Demographics Study 1015 Results Study 1015 Clinical Outcome 36 (15%) Failure [80,90] 206 (85%) Cure 242 Day 28 27 (11%) Failure 74 Improvement 139 Cure [85,93] 213 (89%) Success 240 Day 10 247 Number of Patients 95% CI1 [%] Azithromycin (%) 1 95% CI for azithromycin Study 1015 Clinical Outcome at Day 28 by Age 11 17 Failure [84, 94] 89 142 Cure 159 > 2 years of age 23 19 Failure [67, 87] 77 64 Cure 83 < 2 years of age 95% CI [%] (%) N Azithromycin Study 1015 Clinical Outcome - Per Baseline Pathogen Study 1015 MIC Distribution for S. pneumoniae (N=67) Percent of Patients Azithromycin MIC (mg/ml) Study 1015 Resistant S. Pneumoniae S. pneumoniae MIC = 8 g/ml 7 baseline isolates All sensitive to clindamycin All with mef A gene by PCR S. pneumoniae MIC >256 g/ml 5 baseline isolates All resistant to clindamycin All with erm B gene by PCR Study 1015 Day 28 Outcome and MIC Distribution for S. pneumoniae (N=66) # of Patients Azithromycin MIC (mg/ml) Study 1015 Patient 0067 Failed Therapy 1Susceptible to clindamycin; mef A gene identified 2Resistant to clindamycin; erm B gene identified Study 1015 Strains From Patient 0067 Are Clonally Distinct 1 2 3 4 MIC = 8 MIC >256 Study 1015 Outcome of S. pneumoniae AOM by Penicillin Susceptibility Penicillin Susceptibility *Penicillin MIC > 2 mg/ml **Penicillin MIC > 0.125 - < 2 mg/ml Study 1015 Outcome of S. pneumoniae AOM by Penicillin Susceptibility Penicillin Susceptibility *Penicillin MIC > 2 mg/ml **Penicillin MIC > 0.125 - < 2 mg/ml Study 1015 Treatment Related Adverse Events* (2) 4 Abdominal Pain (6) 14 Vomiting (3) 8 Diarrhea (12) 30 Patients w/ AEs (0) 1 Discontinued due to AEs 248 Patients Treated (%) N * Adverse Events greater than 1% Study 1014 Three Day Dosing Study 1014 Objectives Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 10 mg/kg/day for 3 days Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug
Slide 80 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997 Study 95-001 Experimental Design *Baseline tympanocentesis Study 95-001 Patient Disposition Study 95-001 Demographics 0% 2% Black 98% 97% White Race: 48% 56% % Male 2.3 (+ 1.4) 2.5 (+ 1.3) Mean Age (Yrs, ±SD) 31 (47%) 40 (61%) 2 Yrs - 12 Yrs 35 (53%) 26 (39%) < 2 Yrs Age: N = 66 Single Dose N = 66 Azithromycin 2% 95% 55% 2.7 (+ 1.5) 40 (61%) 26 (39%) Three Day N = 66 Ceftriaxone 2% 2% Hispanic 3% Study 95-001 Results Study 95-001 Clinical Efficacy Population 4 (6) Failure 5 Improvement [- 5, 25] 56 (86) Cure [-12,6] 61 (94) Success 65 Day 28 2 (3) Failure 36 Improvement 26 Cure [-8,5] 62 (97) Success 64 Day 14 66 Randomized Patients 95% CI1 [%] 1 Day (%) 1 95% CI for (single dose azithromycin – comparator) 5 (8) 10 51 (77) 61 (92) 66 3 (5) 42 18 60 (95) 63 66 3 Day (%) 2 (3) 13 49 (77) 62 (97) 64 1 (2) 40 21 61 (98) 62 66 Ceftriaxone (%) Azithromycin Study 95-001 Clinical Outcome at Day 28 by Age 5 (16) 6 (15) 3 (8) Failure 26 (84) 33 (85) 37 (93) Cure 31 39 40 > 2 years of age 10 (30) 9 (33) 6 (24) Failure 23 (70) 18 (67) 19 (76) Cure 33 27 25 < 2 years of age Ceftriaxone (%) 3 Day (%) 1 Day (%) Azithromycin Study 95-001 Susceptibility S. pneumoniae susceptibility (N=57) Azithromycin 46 susceptible 11 resistant (MIC > 0.5 mg/ml) Ceftriaxone All isolates were susceptible to ceftriaxone All H. influenzae and M. catarrhalis were susceptible to azithromycin and ceftriaxone Study 95-001 Clinical Cure Per Baseline Pathogen at Day 28 Study 95-001 Treatment Related Adverse Events* 0 (0) 0 (0) 3 (5) Vomiting 4 (6) 0 (0) 1 (2) Rash 4 (6) 3 (5) 2 (3) Diarrhea 6 (9) 6 (9) 7 (11) Patients w/ AE 66 66 66 Patients Treated Ceftriaxone 3 Day 1 Day 0 (0) 0 (0) 0 (0) Discontinued *2 or more events on any treatment regimen Azithromycin Study R-0581 Single Dose Therapy Study R-0581 Objective Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 30 mg/kg single oral dose Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study R-0581 Visits and Assessments *Patients who vomited within 30 minutes were redosed 1 Including parental questionnaire Study R-0581 Patient Disposition Study R-0581 Demographics Study R-0581 Results Study R-0581 Clinical Outcome 38 (25) 37 (25) Failure 8 2 Improvement [-7, 15] 108 (70) 112 (74) Cure [-10, 11] 116 (75) 114 (75) Success 154 151 Day 28 19 (12) 21 (13) Failure 21 34 Improvement 121 105 Cure [-9, 7] 142 (88) 139 (87) Success 161 160 Day 14 173 173 Number of Patients 95% CI1[%] Amox/Clav (%) Azithromycin (%) 1 95% CI for (azithromycin – comparator) Study R-0581 Clinical Outcome at Day 28 by Age Cure 26 (49) 24 (38) Failure [-8, 31] 95% CI1[%] Failure < 2 years of age 27 (51) 40 (63) Cure 53 64 > 2 years of age Amox/Clav Azithromycin 1 95% CI for (azithromycin – comparator) N (%) N (%) 72 (83) 15 (17) 87 81 (80) 20 (20) 101 [-10, 15] Study R-0581 Compliance Based on patients randomized to their study drug regimen Study R-0581 Treatment Related Adverse Events* 7 (4%) 7 (4%) Vomiting 9 (5%) 3 (2%) 22 (13%) 11 (6%) Diarrhea 39 (23%) 29 (17%) Patients w/ AEs Rash Azithromycin N = 173 Amox/Clav N = 173 7(4%) 4 (2%) Discontinued due to AE * Adverse Events greater than 2 percent in either regimen Study 1015 Single Dose Therapy Study 1015 Objectives To assess per-pathogen clinical response rates To provide additional data on the safety and toleration of the single dose regimen Design Prospective Open-label Non-comparative Multi-center Study 1015 Visits and Assessments *Patients who vomited within 30 minutes were redosed Study 1015 Endpoints Primary Efficacy Endpoint Clinical response by baseline pathogen at day 28 Initial local laboratory isolation of pathogen with confirmation by central laboratory Secondary Efficacy Endpoints Clinical response at day 28 (test of cure) Clinical response at day 10 Safety Evaluation Study 1015 Patient Disposition 242 Clinical at Day 28 127 Bacteriologic Efficacy Azithromycin 248 Safety 248 Enrolled Evaluation Groups Study 1015 Demographics Study 1015 Results Study 1015 Clinical Outcome 36 (15%) Failure [80,90] 206 (85%) Cure 242 Day 28 27 (11%) Failure 74 Improvement 139 Cure [85,93] 213 (89%) Success 240 Day 10 247 Number of Patients 95% CI1 [%] Azithromycin (%) 1 95% CI for azithromycin Study 1015 Clinical Outcome at Day 28 by Age 11 17 Failure [84, 94] 89 142 Cure 159 > 2 years of age 23 19 Failure [67, 87] 77 64 Cure 83 < 2 years of age 95% CI [%] (%) N Azithromycin Study 1015 Clinical Outcome - Per Baseline Pathogen Study 1015 MIC Distribution for S. pneumoniae (N=67) Percent of Patients Azithromycin MIC (mg/ml) Study 1015 Resistant S. Pneumoniae S. pneumoniae MIC = 8 g/ml 7 baseline isolates All sensitive to clindamycin All with mef A gene by PCR S. pneumoniae MIC >256 g/ml 5 baseline isolates All resistant to clindamycin All with erm B gene by PCR Study 1015 Day 28 Outcome and MIC Distribution for S. pneumoniae (N=66) # of Patients Azithromycin MIC (mg/ml) Study 1015 Patient 0067 Failed Therapy 1Susceptible to clindamycin; mef A gene identified 2Resistant to clindamycin; erm B gene identified Study 1015 Strains From Patient 0067 Are Clonally Distinct 1 2 3 4 MIC = 8 MIC >256 Study 1015 Outcome of S. pneumoniae AOM by Penicillin Susceptibility Penicillin Susceptibility *Penicillin MIC > 2 mg/ml **Penicillin MIC > 0.125 - < 2 mg/ml Study 1015 Outcome of S. pneumoniae AOM by Penicillin Susceptibility Penicillin Susceptibility *Penicillin MIC > 2 mg/ml **Penicillin MIC > 0.125 - < 2 mg/ml Study 1015 Treatment Related Adverse Events* (2) 4 Abdominal Pain (6) 14 Vomiting (3) 8 Diarrhea (12) 30 Patients w/ AEs (0) 1 Discontinued due to AEs 248 Patients Treated (%) N * Adverse Events greater than 1% Study 1014 Three Day Dosing Study 1014 Objectives Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 10 mg/kg/day for 3 days Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study 1014 Inclusion Criteria: Symptoms Symptoms consistent with AOM (but nonspecific) 2 Symptoms which help confirm the diagnosis of AOM (%) Age 261 X Fever 1 Children had one or more of these signs and symptoms 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) X Irritability 251 X Decreased hearing 601 X Ear fullness 921 X Ear pain (tugging or rubbing) 0.5-11yrs X >6 months 1014 1998 FDA Guidance Either Ear pain or fullness 97
Slide 81 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997 Study 95-001 Experimental Design *Baseline tympanocentesis Study 95-001 Patient Disposition Study 95-001 Demographics 0% 2% Black 98% 97% White Race: 48% 56% % Male 2.3 (+ 1.4) 2.5 (+ 1.3) Mean Age (Yrs, ±SD) 31 (47%) 40 (61%) 2 Yrs - 12 Yrs 35 (53%) 26 (39%) < 2 Yrs Age: N = 66 Single Dose N = 66 Azithromycin 2% 95% 55% 2.7 (+ 1.5) 40 (61%) 26 (39%) Three Day N = 66 Ceftriaxone 2% 2% Hispanic 3% Study 95-001 Results Study 95-001 Clinical Efficacy Population 4 (6) Failure 5 Improvement [- 5, 25] 56 (86) Cure [-12,6] 61 (94) Success 65 Day 28 2 (3) Failure 36 Improvement 26 Cure [-8,5] 62 (97) Success 64 Day 14 66 Randomized Patients 95% CI1 [%] 1 Day (%) 1 95% CI for (single dose azithromycin – comparator) 5 (8) 10 51 (77) 61 (92) 66 3 (5) 42 18 60 (95) 63 66 3 Day (%) 2 (3) 13 49 (77) 62 (97) 64 1 (2) 40 21 61 (98) 62 66 Ceftriaxone (%) Azithromycin Study 95-001 Clinical Outcome at Day 28 by Age 5 (16) 6 (15) 3 (8) Failure 26 (84) 33 (85) 37 (93) Cure 31 39 40 > 2 years of age 10 (30) 9 (33) 6 (24) Failure 23 (70) 18 (67) 19 (76) Cure 33 27 25 < 2 years of age Ceftriaxone (%) 3 Day (%) 1 Day (%) Azithromycin Study 95-001 Susceptibility S. pneumoniae susceptibility (N=57) Azithromycin 46 susceptible 11 resistant (MIC > 0.5 mg/ml) Ceftriaxone All isolates were susceptible to ceftriaxone All H. influenzae and M. catarrhalis were susceptible to azithromycin and ceftriaxone Study 95-001 Clinical Cure Per Baseline Pathogen at Day 28 Study 95-001 Treatment Related Adverse Events* 0 (0) 0 (0) 3 (5) Vomiting 4 (6) 0 (0) 1 (2) Rash 4 (6) 3 (5) 2 (3) Diarrhea 6 (9) 6 (9) 7 (11) Patients w/ AE 66 66 66 Patients Treated Ceftriaxone 3 Day 1 Day 0 (0) 0 (0) 0 (0) Discontinued *2 or more events on any treatment regimen Azithromycin Study R-0581 Single Dose Therapy Study R-0581 Objective Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 30 mg/kg single oral dose Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study R-0581 Visits and Assessments *Patients who vomited within 30 minutes were redosed 1 Including parental questionnaire Study R-0581 Patient Disposition Study R-0581 Demographics Study R-0581 Results Study R-0581 Clinical Outcome 38 (25) 37 (25) Failure 8 2 Improvement [-7, 15] 108 (70) 112 (74) Cure [-10, 11] 116 (75) 114 (75) Success 154 151 Day 28 19 (12) 21 (13) Failure 21 34 Improvement 121 105 Cure [-9, 7] 142 (88) 139 (87) Success 161 160 Day 14 173 173 Number of Patients 95% CI1[%] Amox/Clav (%) Azithromycin (%) 1 95% CI for (azithromycin – comparator) Study R-0581 Clinical Outcome at Day 28 by Age Cure 26 (49) 24 (38) Failure [-8, 31] 95% CI1[%] Failure < 2 years of age 27 (51) 40 (63) Cure 53 64 > 2 years of age Amox/Clav Azithromycin 1 95% CI for (azithromycin – comparator) N (%) N (%) 72 (83) 15 (17) 87 81 (80) 20 (20) 101 [-10, 15] Study R-0581 Compliance Based on patients randomized to their study drug regimen Study R-0581 Treatment Related Adverse Events* 7 (4%) 7 (4%) Vomiting 9 (5%) 3 (2%) 22 (13%) 11 (6%) Diarrhea 39 (23%) 29 (17%) Patients w/ AEs Rash Azithromycin N = 173 Amox/Clav N = 173 7(4%) 4 (2%) Discontinued due to AE * Adverse Events greater than 2 percent in either regimen Study 1015 Single Dose Therapy Study 1015 Objectives To assess per-pathogen clinical response rates To provide additional data on the safety and toleration of the single dose regimen Design Prospective Open-label Non-comparative Multi-center Study 1015 Visits and Assessments *Patients who vomited within 30 minutes were redosed Study 1015 Endpoints Primary Efficacy Endpoint Clinical response by baseline pathogen at day 28 Initial local laboratory isolation of pathogen with confirmation by central laboratory Secondary Efficacy Endpoints Clinical response at day 28 (test of cure) Clinical response at day 10 Safety Evaluation Study 1015 Patient Disposition 242 Clinical at Day 28 127 Bacteriologic Efficacy Azithromycin 248 Safety 248 Enrolled Evaluation Groups Study 1015 Demographics Study 1015 Results Study 1015 Clinical Outcome 36 (15%) Failure [80,90] 206 (85%) Cure 242 Day 28 27 (11%) Failure 74 Improvement 139 Cure [85,93] 213 (89%) Success 240 Day 10 247 Number of Patients 95% CI1 [%] Azithromycin (%) 1 95% CI for azithromycin Study 1015 Clinical Outcome at Day 28 by Age 11 17 Failure [84, 94] 89 142 Cure 159 > 2 years of age 23 19 Failure [67, 87] 77 64 Cure 83 < 2 years of age 95% CI [%] (%) N Azithromycin Study 1015 Clinical Outcome - Per Baseline Pathogen Study 1015 MIC Distribution for S. pneumoniae (N=67) Percent of Patients Azithromycin MIC (mg/ml) Study 1015 Resistant S. Pneumoniae S. pneumoniae MIC = 8 g/ml 7 baseline isolates All sensitive to clindamycin All with mef A gene by PCR S. pneumoniae MIC >256 g/ml 5 baseline isolates All resistant to clindamycin All with erm B gene by PCR Study 1015 Day 28 Outcome and MIC Distribution for S. pneumoniae (N=66) # of Patients Azithromycin MIC (mg/ml) Study 1015 Patient 0067 Failed Therapy 1Susceptible to clindamycin; mef A gene identified 2Resistant to clindamycin; erm B gene identified Study 1015 Strains From Patient 0067 Are Clonally Distinct 1 2 3 4 MIC = 8 MIC >256 Study 1015 Outcome of S. pneumoniae AOM by Penicillin Susceptibility Penicillin Susceptibility *Penicillin MIC > 2 mg/ml **Penicillin MIC > 0.125 - < 2 mg/ml Study 1015 Outcome of S. pneumoniae AOM by Penicillin Susceptibility Penicillin Susceptibility *Penicillin MIC > 2 mg/ml **Penicillin MIC > 0.125 - < 2 mg/ml Study 1015 Treatment Related Adverse Events* (2) 4 Abdominal Pain (6) 14 Vomiting (3) 8 Diarrhea (12) 30 Patients w/ AEs (0) 1 Discontinued due to AEs 248 Patients Treated (%) N * Adverse Events greater than 1% Study 1014 Three Day Dosing Study 1014 Objectives Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 10 mg/kg/day for 3 days Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study 1014 Inclusion Criteria: Symptoms Symptoms consistent with AOM (but nonspecific) 2 Symptoms which help confirm the diagnosis of AOM (%) Age 261 X Fever 1 Children had one or more of these signs and symptoms 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) X Irritability 251 X Decreased hearing 601 X Ear fullness 921 X Ear pain (tugging or rubbing) 0.5-11yrs X >6 months 1014 1998 FDA Guidance Either Ear pain or fullness 97 Study 1014 Inclusion Criteria: Signs of Tympanic Membrane Involvement 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level
Slide 82 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997 Study 95-001 Experimental Design *Baseline tympanocentesis Study 95-001 Patient Disposition Study 95-001 Demographics 0% 2% Black 98% 97% White Race: 48% 56% % Male 2.3 (+ 1.4) 2.5 (+ 1.3) Mean Age (Yrs, ±SD) 31 (47%) 40 (61%) 2 Yrs - 12 Yrs 35 (53%) 26 (39%) < 2 Yrs Age: N = 66 Single Dose N = 66 Azithromycin 2% 95% 55% 2.7 (+ 1.5) 40 (61%) 26 (39%) Three Day N = 66 Ceftriaxone 2% 2% Hispanic 3% Study 95-001 Results Study 95-001 Clinical Efficacy Population 4 (6) Failure 5 Improvement [- 5, 25] 56 (86) Cure [-12,6] 61 (94) Success 65 Day 28 2 (3) Failure 36 Improvement 26 Cure [-8,5] 62 (97) Success 64 Day 14 66 Randomized Patients 95% CI1 [%] 1 Day (%) 1 95% CI for (single dose azithromycin – comparator) 5 (8) 10 51 (77) 61 (92) 66 3 (5) 42 18 60 (95) 63 66 3 Day (%) 2 (3) 13 49 (77) 62 (97) 64 1 (2) 40 21 61 (98) 62 66 Ceftriaxone (%) Azithromycin Study 95-001 Clinical Outcome at Day 28 by Age 5 (16) 6 (15) 3 (8) Failure 26 (84) 33 (85) 37 (93) Cure 31 39 40 > 2 years of age 10 (30) 9 (33) 6 (24) Failure 23 (70) 18 (67) 19 (76) Cure 33 27 25 < 2 years of age Ceftriaxone (%) 3 Day (%) 1 Day (%) Azithromycin Study 95-001 Susceptibility S. pneumoniae susceptibility (N=57) Azithromycin 46 susceptible 11 resistant (MIC > 0.5 mg/ml) Ceftriaxone All isolates were susceptible to ceftriaxone All H. influenzae and M. catarrhalis were susceptible to azithromycin and ceftriaxone Study 95-001 Clinical Cure Per Baseline Pathogen at Day 28 Study 95-001 Treatment Related Adverse Events* 0 (0) 0 (0) 3 (5) Vomiting 4 (6) 0 (0) 1 (2) Rash 4 (6) 3 (5) 2 (3) Diarrhea 6 (9) 6 (9) 7 (11) Patients w/ AE 66 66 66 Patients Treated Ceftriaxone 3 Day 1 Day 0 (0) 0 (0) 0 (0) Discontinued *2 or more events on any treatment regimen Azithromycin Study R-0581 Single Dose Therapy Study R-0581 Objective Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 30 mg/kg single oral dose Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study R-0581 Visits and Assessments *Patients who vomited within 30 minutes were redosed 1 Including parental questionnaire Study R-0581 Patient Disposition Study R-0581 Demographics Study R-0581 Results Study R-0581 Clinical Outcome 38 (25) 37 (25) Failure 8 2 Improvement [-7, 15] 108 (70) 112 (74) Cure [-10, 11] 116 (75) 114 (75) Success 154 151 Day 28 19 (12) 21 (13) Failure 21 34 Improvement 121 105 Cure [-9, 7] 142 (88) 139 (87) Success 161 160 Day 14 173 173 Number of Patients 95% CI1[%] Amox/Clav (%) Azithromycin (%) 1 95% CI for (azithromycin – comparator) Study R-0581 Clinical Outcome at Day 28 by Age Cure 26 (49) 24 (38) Failure [-8, 31] 95% CI1[%] Failure < 2 years of age 27 (51) 40 (63) Cure 53 64 > 2 years of age Amox/Clav Azithromycin 1 95% CI for (azithromycin – comparator) N (%) N (%) 72 (83) 15 (17) 87 81 (80) 20 (20) 101 [-10, 15] Study R-0581 Compliance Based on patients randomized to their study drug regimen Study R-0581 Treatment Related Adverse Events* 7 (4%) 7 (4%) Vomiting 9 (5%) 3 (2%) 22 (13%) 11 (6%) Diarrhea 39 (23%) 29 (17%) Patients w/ AEs Rash Azithromycin N = 173 Amox/Clav N = 173 7(4%) 4 (2%) Discontinued due to AE * Adverse Events greater than 2 percent in either regimen Study 1015 Single Dose Therapy Study 1015 Objectives To assess per-pathogen clinical response rates To provide additional data on the safety and toleration of the single dose regimen Design Prospective Open-label Non-comparative Multi-center Study 1015 Visits and Assessments *Patients who vomited within 30 minutes were redosed Study 1015 Endpoints Primary Efficacy Endpoint Clinical response by baseline pathogen at day 28 Initial local laboratory isolation of pathogen with confirmation by central laboratory Secondary Efficacy Endpoints Clinical response at day 28 (test of cure) Clinical response at day 10 Safety Evaluation Study 1015 Patient Disposition 242 Clinical at Day 28 127 Bacteriologic Efficacy Azithromycin 248 Safety 248 Enrolled Evaluation Groups Study 1015 Demographics Study 1015 Results Study 1015 Clinical Outcome 36 (15%) Failure [80,90] 206 (85%) Cure 242 Day 28 27 (11%) Failure 74 Improvement 139 Cure [85,93] 213 (89%) Success 240 Day 10 247 Number of Patients 95% CI1 [%] Azithromycin (%) 1 95% CI for azithromycin Study 1015 Clinical Outcome at Day 28 by Age 11 17 Failure [84, 94] 89 142 Cure 159 > 2 years of age 23 19 Failure [67, 87] 77 64 Cure 83 < 2 years of age 95% CI [%] (%) N Azithromycin Study 1015 Clinical Outcome - Per Baseline Pathogen Study 1015 MIC Distribution for S. pneumoniae (N=67) Percent of Patients Azithromycin MIC (mg/ml) Study 1015 Resistant S. Pneumoniae S. pneumoniae MIC = 8 g/ml 7 baseline isolates All sensitive to clindamycin All with mef A gene by PCR S. pneumoniae MIC >256 g/ml 5 baseline isolates All resistant to clindamycin All with erm B gene by PCR Study 1015 Day 28 Outcome and MIC Distribution for S. pneumoniae (N=66) # of Patients Azithromycin MIC (mg/ml) Study 1015 Patient 0067 Failed Therapy 1Susceptible to clindamycin; mef A gene identified 2Resistant to clindamycin; erm B gene identified Study 1015 Strains From Patient 0067 Are Clonally Distinct 1 2 3 4 MIC = 8 MIC >256 Study 1015 Outcome of S. pneumoniae AOM by Penicillin Susceptibility Penicillin Susceptibility *Penicillin MIC > 2 mg/ml **Penicillin MIC > 0.125 - < 2 mg/ml Study 1015 Outcome of S. pneumoniae AOM by Penicillin Susceptibility Penicillin Susceptibility *Penicillin MIC > 2 mg/ml **Penicillin MIC > 0.125 - < 2 mg/ml Study 1015 Treatment Related Adverse Events* (2) 4 Abdominal Pain (6) 14 Vomiting (3) 8 Diarrhea (12) 30 Patients w/ AEs (0) 1 Discontinued due to AEs 248 Patients Treated (%) N * Adverse Events greater than 1% Study 1014 Three Day Dosing Study 1014 Objectives Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 10 mg/kg/day for 3 days Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study 1014 Inclusion Criteria: Symptoms Symptoms consistent with AOM (but nonspecific) 2 Symptoms which help confirm the diagnosis of AOM (%) Age 261 X Fever 1 Children had one or more of these signs and symptoms 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) X Irritability 251 X Decreased hearing 601 X Ear fullness 921 X Ear pain (tugging or rubbing) 0.5-11yrs X >6 months 1014 1998 FDA Guidance Either Ear pain or fullness 97 Study 1014 Inclusion Criteria: Signs of Tympanic Membrane Involvement 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Study 1014 Key Exclusion Criteria Other exclusions include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, neutropenia, immunosuppressant therapy, cystic fibrosis, retraction pockets, cholesteatoma, phenylketonuria, anticipated use of probenecid or allopurinol
Slide 83 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997 Study 95-001 Experimental Design *Baseline tympanocentesis Study 95-001 Patient Disposition Study 95-001 Demographics 0% 2% Black 98% 97% White Race: 48% 56% % Male 2.3 (+ 1.4) 2.5 (+ 1.3) Mean Age (Yrs, ±SD) 31 (47%) 40 (61%) 2 Yrs - 12 Yrs 35 (53%) 26 (39%) < 2 Yrs Age: N = 66 Single Dose N = 66 Azithromycin 2% 95% 55% 2.7 (+ 1.5) 40 (61%) 26 (39%) Three Day N = 66 Ceftriaxone 2% 2% Hispanic 3% Study 95-001 Results Study 95-001 Clinical Efficacy Population 4 (6) Failure 5 Improvement [- 5, 25] 56 (86) Cure [-12,6] 61 (94) Success 65 Day 28 2 (3) Failure 36 Improvement 26 Cure [-8,5] 62 (97) Success 64 Day 14 66 Randomized Patients 95% CI1 [%] 1 Day (%) 1 95% CI for (single dose azithromycin – comparator) 5 (8) 10 51 (77) 61 (92) 66 3 (5) 42 18 60 (95) 63 66 3 Day (%) 2 (3) 13 49 (77) 62 (97) 64 1 (2) 40 21 61 (98) 62 66 Ceftriaxone (%) Azithromycin Study 95-001 Clinical Outcome at Day 28 by Age 5 (16) 6 (15) 3 (8) Failure 26 (84) 33 (85) 37 (93) Cure 31 39 40 > 2 years of age 10 (30) 9 (33) 6 (24) Failure 23 (70) 18 (67) 19 (76) Cure 33 27 25 < 2 years of age Ceftriaxone (%) 3 Day (%) 1 Day (%) Azithromycin Study 95-001 Susceptibility S. pneumoniae susceptibility (N=57) Azithromycin 46 susceptible 11 resistant (MIC > 0.5 mg/ml) Ceftriaxone All isolates were susceptible to ceftriaxone All H. influenzae and M. catarrhalis were susceptible to azithromycin and ceftriaxone Study 95-001 Clinical Cure Per Baseline Pathogen at Day 28 Study 95-001 Treatment Related Adverse Events* 0 (0) 0 (0) 3 (5) Vomiting 4 (6) 0 (0) 1 (2) Rash 4 (6) 3 (5) 2 (3) Diarrhea 6 (9) 6 (9) 7 (11) Patients w/ AE 66 66 66 Patients Treated Ceftriaxone 3 Day 1 Day 0 (0) 0 (0) 0 (0) Discontinued *2 or more events on any treatment regimen Azithromycin Study R-0581 Single Dose Therapy Study R-0581 Objective Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 30 mg/kg single oral dose Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study R-0581 Visits and Assessments *Patients who vomited within 30 minutes were redosed 1 Including parental questionnaire Study R-0581 Patient Disposition Study R-0581 Demographics Study R-0581 Results Study R-0581 Clinical Outcome 38 (25) 37 (25) Failure 8 2 Improvement [-7, 15] 108 (70) 112 (74) Cure [-10, 11] 116 (75) 114 (75) Success 154 151 Day 28 19 (12) 21 (13) Failure 21 34 Improvement 121 105 Cure [-9, 7] 142 (88) 139 (87) Success 161 160 Day 14 173 173 Number of Patients 95% CI1[%] Amox/Clav (%) Azithromycin (%) 1 95% CI for (azithromycin – comparator) Study R-0581 Clinical Outcome at Day 28 by Age Cure 26 (49) 24 (38) Failure [-8, 31] 95% CI1[%] Failure < 2 years of age 27 (51) 40 (63) Cure 53 64 > 2 years of age Amox/Clav Azithromycin 1 95% CI for (azithromycin – comparator) N (%) N (%) 72 (83) 15 (17) 87 81 (80) 20 (20) 101 [-10, 15] Study R-0581 Compliance Based on patients randomized to their study drug regimen Study R-0581 Treatment Related Adverse Events* 7 (4%) 7 (4%) Vomiting 9 (5%) 3 (2%) 22 (13%) 11 (6%) Diarrhea 39 (23%) 29 (17%) Patients w/ AEs Rash Azithromycin N = 173 Amox/Clav N = 173 7(4%) 4 (2%) Discontinued due to AE * Adverse Events greater than 2 percent in either regimen Study 1015 Single Dose Therapy Study 1015 Objectives To assess per-pathogen clinical response rates To provide additional data on the safety and toleration of the single dose regimen Design Prospective Open-label Non-comparative Multi-center Study 1015 Visits and Assessments *Patients who vomited within 30 minutes were redosed Study 1015 Endpoints Primary Efficacy Endpoint Clinical response by baseline pathogen at day 28 Initial local laboratory isolation of pathogen with confirmation by central laboratory Secondary Efficacy Endpoints Clinical response at day 28 (test of cure) Clinical response at day 10 Safety Evaluation Study 1015 Patient Disposition 242 Clinical at Day 28 127 Bacteriologic Efficacy Azithromycin 248 Safety 248 Enrolled Evaluation Groups Study 1015 Demographics Study 1015 Results Study 1015 Clinical Outcome 36 (15%) Failure [80,90] 206 (85%) Cure 242 Day 28 27 (11%) Failure 74 Improvement 139 Cure [85,93] 213 (89%) Success 240 Day 10 247 Number of Patients 95% CI1 [%] Azithromycin (%) 1 95% CI for azithromycin Study 1015 Clinical Outcome at Day 28 by Age 11 17 Failure [84, 94] 89 142 Cure 159 > 2 years of age 23 19 Failure [67, 87] 77 64 Cure 83 < 2 years of age 95% CI [%] (%) N Azithromycin Study 1015 Clinical Outcome - Per Baseline Pathogen Study 1015 MIC Distribution for S. pneumoniae (N=67) Percent of Patients Azithromycin MIC (mg/ml) Study 1015 Resistant S. Pneumoniae S. pneumoniae MIC = 8 g/ml 7 baseline isolates All sensitive to clindamycin All with mef A gene by PCR S. pneumoniae MIC >256 g/ml 5 baseline isolates All resistant to clindamycin All with erm B gene by PCR Study 1015 Day 28 Outcome and MIC Distribution for S. pneumoniae (N=66) # of Patients Azithromycin MIC (mg/ml) Study 1015 Patient 0067 Failed Therapy 1Susceptible to clindamycin; mef A gene identified 2Resistant to clindamycin; erm B gene identified Study 1015 Strains From Patient 0067 Are Clonally Distinct 1 2 3 4 MIC = 8 MIC >256 Study 1015 Outcome of S. pneumoniae AOM by Penicillin Susceptibility Penicillin Susceptibility *Penicillin MIC > 2 mg/ml **Penicillin MIC > 0.125 - < 2 mg/ml Study 1015 Outcome of S. pneumoniae AOM by Penicillin Susceptibility Penicillin Susceptibility *Penicillin MIC > 2 mg/ml **Penicillin MIC > 0.125 - < 2 mg/ml Study 1015 Treatment Related Adverse Events* (2) 4 Abdominal Pain (6) 14 Vomiting (3) 8 Diarrhea (12) 30 Patients w/ AEs (0) 1 Discontinued due to AEs 248 Patients Treated (%) N * Adverse Events greater than 1% Study 1014 Three Day Dosing Study 1014 Objectives Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 10 mg/kg/day for 3 days Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study 1014 Inclusion Criteria: Symptoms Symptoms consistent with AOM (but nonspecific) 2 Symptoms which help confirm the diagnosis of AOM (%) Age 261 X Fever 1 Children had one or more of these signs and symptoms 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) X Irritability 251 X Decreased hearing 601 X Ear fullness 921 X Ear pain (tugging or rubbing) 0.5-11yrs X >6 months 1014 1998 FDA Guidance Either Ear pain or fullness 97 Study 1014 Inclusion Criteria: Signs of Tympanic Membrane Involvement 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Study 1014 Key Exclusion Criteria Other exclusions include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, neutropenia, immunosuppressant therapy, cystic fibrosis, retraction pockets, cholesteatoma, phenylketonuria, anticipated use of probenecid or allopurinol Study 1014 Visits and Assessments *Patients who vomited within 30 minutes were redosed
Slide 84 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997 Study 95-001 Experimental Design *Baseline tympanocentesis Study 95-001 Patient Disposition Study 95-001 Demographics 0% 2% Black 98% 97% White Race: 48% 56% % Male 2.3 (+ 1.4) 2.5 (+ 1.3) Mean Age (Yrs, ±SD) 31 (47%) 40 (61%) 2 Yrs - 12 Yrs 35 (53%) 26 (39%) < 2 Yrs Age: N = 66 Single Dose N = 66 Azithromycin 2% 95% 55% 2.7 (+ 1.5) 40 (61%) 26 (39%) Three Day N = 66 Ceftriaxone 2% 2% Hispanic 3% Study 95-001 Results Study 95-001 Clinical Efficacy Population 4 (6) Failure 5 Improvement [- 5, 25] 56 (86) Cure [-12,6] 61 (94) Success 65 Day 28 2 (3) Failure 36 Improvement 26 Cure [-8,5] 62 (97) Success 64 Day 14 66 Randomized Patients 95% CI1 [%] 1 Day (%) 1 95% CI for (single dose azithromycin – comparator) 5 (8) 10 51 (77) 61 (92) 66 3 (5) 42 18 60 (95) 63 66 3 Day (%) 2 (3) 13 49 (77) 62 (97) 64 1 (2) 40 21 61 (98) 62 66 Ceftriaxone (%) Azithromycin Study 95-001 Clinical Outcome at Day 28 by Age 5 (16) 6 (15) 3 (8) Failure 26 (84) 33 (85) 37 (93) Cure 31 39 40 > 2 years of age 10 (30) 9 (33) 6 (24) Failure 23 (70) 18 (67) 19 (76) Cure 33 27 25 < 2 years of age Ceftriaxone (%) 3 Day (%) 1 Day (%) Azithromycin Study 95-001 Susceptibility S. pneumoniae susceptibility (N=57) Azithromycin 46 susceptible 11 resistant (MIC > 0.5 mg/ml) Ceftriaxone All isolates were susceptible to ceftriaxone All H. influenzae and M. catarrhalis were susceptible to azithromycin and ceftriaxone Study 95-001 Clinical Cure Per Baseline Pathogen at Day 28 Study 95-001 Treatment Related Adverse Events* 0 (0) 0 (0) 3 (5) Vomiting 4 (6) 0 (0) 1 (2) Rash 4 (6) 3 (5) 2 (3) Diarrhea 6 (9) 6 (9) 7 (11) Patients w/ AE 66 66 66 Patients Treated Ceftriaxone 3 Day 1 Day 0 (0) 0 (0) 0 (0) Discontinued *2 or more events on any treatment regimen Azithromycin Study R-0581 Single Dose Therapy Study R-0581 Objective Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 30 mg/kg single oral dose Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study R-0581 Visits and Assessments *Patients who vomited within 30 minutes were redosed 1 Including parental questionnaire Study R-0581 Patient Disposition Study R-0581 Demographics Study R-0581 Results Study R-0581 Clinical Outcome 38 (25) 37 (25) Failure 8 2 Improvement [-7, 15] 108 (70) 112 (74) Cure [-10, 11] 116 (75) 114 (75) Success 154 151 Day 28 19 (12) 21 (13) Failure 21 34 Improvement 121 105 Cure [-9, 7] 142 (88) 139 (87) Success 161 160 Day 14 173 173 Number of Patients 95% CI1[%] Amox/Clav (%) Azithromycin (%) 1 95% CI for (azithromycin – comparator) Study R-0581 Clinical Outcome at Day 28 by Age Cure 26 (49) 24 (38) Failure [-8, 31] 95% CI1[%] Failure < 2 years of age 27 (51) 40 (63) Cure 53 64 > 2 years of age Amox/Clav Azithromycin 1 95% CI for (azithromycin – comparator) N (%) N (%) 72 (83) 15 (17) 87 81 (80) 20 (20) 101 [-10, 15] Study R-0581 Compliance Based on patients randomized to their study drug regimen Study R-0581 Treatment Related Adverse Events* 7 (4%) 7 (4%) Vomiting 9 (5%) 3 (2%) 22 (13%) 11 (6%) Diarrhea 39 (23%) 29 (17%) Patients w/ AEs Rash Azithromycin N = 173 Amox/Clav N = 173 7(4%) 4 (2%) Discontinued due to AE * Adverse Events greater than 2 percent in either regimen Study 1015 Single Dose Therapy Study 1015 Objectives To assess per-pathogen clinical response rates To provide additional data on the safety and toleration of the single dose regimen Design Prospective Open-label Non-comparative Multi-center Study 1015 Visits and Assessments *Patients who vomited within 30 minutes were redosed Study 1015 Endpoints Primary Efficacy Endpoint Clinical response by baseline pathogen at day 28 Initial local laboratory isolation of pathogen with confirmation by central laboratory Secondary Efficacy Endpoints Clinical response at day 28 (test of cure) Clinical response at day 10 Safety Evaluation Study 1015 Patient Disposition 242 Clinical at Day 28 127 Bacteriologic Efficacy Azithromycin 248 Safety 248 Enrolled Evaluation Groups Study 1015 Demographics Study 1015 Results Study 1015 Clinical Outcome 36 (15%) Failure [80,90] 206 (85%) Cure 242 Day 28 27 (11%) Failure 74 Improvement 139 Cure [85,93] 213 (89%) Success 240 Day 10 247 Number of Patients 95% CI1 [%] Azithromycin (%) 1 95% CI for azithromycin Study 1015 Clinical Outcome at Day 28 by Age 11 17 Failure [84, 94] 89 142 Cure 159 > 2 years of age 23 19 Failure [67, 87] 77 64 Cure 83 < 2 years of age 95% CI [%] (%) N Azithromycin Study 1015 Clinical Outcome - Per Baseline Pathogen Study 1015 MIC Distribution for S. pneumoniae (N=67) Percent of Patients Azithromycin MIC (mg/ml) Study 1015 Resistant S. Pneumoniae S. pneumoniae MIC = 8 g/ml 7 baseline isolates All sensitive to clindamycin All with mef A gene by PCR S. pneumoniae MIC >256 g/ml 5 baseline isolates All resistant to clindamycin All with erm B gene by PCR Study 1015 Day 28 Outcome and MIC Distribution for S. pneumoniae (N=66) # of Patients Azithromycin MIC (mg/ml) Study 1015 Patient 0067 Failed Therapy 1Susceptible to clindamycin; mef A gene identified 2Resistant to clindamycin; erm B gene identified Study 1015 Strains From Patient 0067 Are Clonally Distinct 1 2 3 4 MIC = 8 MIC >256 Study 1015 Outcome of S. pneumoniae AOM by Penicillin Susceptibility Penicillin Susceptibility *Penicillin MIC > 2 mg/ml **Penicillin MIC > 0.125 - < 2 mg/ml Study 1015 Outcome of S. pneumoniae AOM by Penicillin Susceptibility Penicillin Susceptibility *Penicillin MIC > 2 mg/ml **Penicillin MIC > 0.125 - < 2 mg/ml Study 1015 Treatment Related Adverse Events* (2) 4 Abdominal Pain (6) 14 Vomiting (3) 8 Diarrhea (12) 30 Patients w/ AEs (0) 1 Discontinued due to AEs 248 Patients Treated (%) N * Adverse Events greater than 1% Study 1014 Three Day Dosing Study 1014 Objectives Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 10 mg/kg/day for 3 days Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study 1014 Inclusion Criteria: Symptoms Symptoms consistent with AOM (but nonspecific) 2 Symptoms which help confirm the diagnosis of AOM (%) Age 261 X Fever 1 Children had one or more of these signs and symptoms 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) X Irritability 251 X Decreased hearing 601 X Ear fullness 921 X Ear pain (tugging or rubbing) 0.5-11yrs X >6 months 1014 1998 FDA Guidance Either Ear pain or fullness 97 Study 1014 Inclusion Criteria: Signs of Tympanic Membrane Involvement 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Study 1014 Key Exclusion Criteria Other exclusions include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, neutropenia, immunosuppressant therapy, cystic fibrosis, retraction pockets, cholesteatoma, phenylketonuria, anticipated use of probenecid or allopurinol Study 1014 Visits and Assessments *Patients who vomited within 30 minutes were redosed Study 1014 Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint: Day 28 Cure Failure
Slide 85 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997 Study 95-001 Experimental Design *Baseline tympanocentesis Study 95-001 Patient Disposition Study 95-001 Demographics 0% 2% Black 98% 97% White Race: 48% 56% % Male 2.3 (+ 1.4) 2.5 (+ 1.3) Mean Age (Yrs, ±SD) 31 (47%) 40 (61%) 2 Yrs - 12 Yrs 35 (53%) 26 (39%) < 2 Yrs Age: N = 66 Single Dose N = 66 Azithromycin 2% 95% 55% 2.7 (+ 1.5) 40 (61%) 26 (39%) Three Day N = 66 Ceftriaxone 2% 2% Hispanic 3% Study 95-001 Results Study 95-001 Clinical Efficacy Population 4 (6) Failure 5 Improvement [- 5, 25] 56 (86) Cure [-12,6] 61 (94) Success 65 Day 28 2 (3) Failure 36 Improvement 26 Cure [-8,5] 62 (97) Success 64 Day 14 66 Randomized Patients 95% CI1 [%] 1 Day (%) 1 95% CI for (single dose azithromycin – comparator) 5 (8) 10 51 (77) 61 (92) 66 3 (5) 42 18 60 (95) 63 66 3 Day (%) 2 (3) 13 49 (77) 62 (97) 64 1 (2) 40 21 61 (98) 62 66 Ceftriaxone (%) Azithromycin Study 95-001 Clinical Outcome at Day 28 by Age 5 (16) 6 (15) 3 (8) Failure 26 (84) 33 (85) 37 (93) Cure 31 39 40 > 2 years of age 10 (30) 9 (33) 6 (24) Failure 23 (70) 18 (67) 19 (76) Cure 33 27 25 < 2 years of age Ceftriaxone (%) 3 Day (%) 1 Day (%) Azithromycin Study 95-001 Susceptibility S. pneumoniae susceptibility (N=57) Azithromycin 46 susceptible 11 resistant (MIC > 0.5 mg/ml) Ceftriaxone All isolates were susceptible to ceftriaxone All H. influenzae and M. catarrhalis were susceptible to azithromycin and ceftriaxone Study 95-001 Clinical Cure Per Baseline Pathogen at Day 28 Study 95-001 Treatment Related Adverse Events* 0 (0) 0 (0) 3 (5) Vomiting 4 (6) 0 (0) 1 (2) Rash 4 (6) 3 (5) 2 (3) Diarrhea 6 (9) 6 (9) 7 (11) Patients w/ AE 66 66 66 Patients Treated Ceftriaxone 3 Day 1 Day 0 (0) 0 (0) 0 (0) Discontinued *2 or more events on any treatment regimen Azithromycin Study R-0581 Single Dose Therapy Study R-0581 Objective Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 30 mg/kg single oral dose Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study R-0581 Visits and Assessments *Patients who vomited within 30 minutes were redosed 1 Including parental questionnaire Study R-0581 Patient Disposition Study R-0581 Demographics Study R-0581 Results Study R-0581 Clinical Outcome 38 (25) 37 (25) Failure 8 2 Improvement [-7, 15] 108 (70) 112 (74) Cure [-10, 11] 116 (75) 114 (75) Success 154 151 Day 28 19 (12) 21 (13) Failure 21 34 Improvement 121 105 Cure [-9, 7] 142 (88) 139 (87) Success 161 160 Day 14 173 173 Number of Patients 95% CI1[%] Amox/Clav (%) Azithromycin (%) 1 95% CI for (azithromycin – comparator) Study R-0581 Clinical Outcome at Day 28 by Age Cure 26 (49) 24 (38) Failure [-8, 31] 95% CI1[%] Failure < 2 years of age 27 (51) 40 (63) Cure 53 64 > 2 years of age Amox/Clav Azithromycin 1 95% CI for (azithromycin – comparator) N (%) N (%) 72 (83) 15 (17) 87 81 (80) 20 (20) 101 [-10, 15] Study R-0581 Compliance Based on patients randomized to their study drug regimen Study R-0581 Treatment Related Adverse Events* 7 (4%) 7 (4%) Vomiting 9 (5%) 3 (2%) 22 (13%) 11 (6%) Diarrhea 39 (23%) 29 (17%) Patients w/ AEs Rash Azithromycin N = 173 Amox/Clav N = 173 7(4%) 4 (2%) Discontinued due to AE * Adverse Events greater than 2 percent in either regimen Study 1015 Single Dose Therapy Study 1015 Objectives To assess per-pathogen clinical response rates To provide additional data on the safety and toleration of the single dose regimen Design Prospective Open-label Non-comparative Multi-center Study 1015 Visits and Assessments *Patients who vomited within 30 minutes were redosed Study 1015 Endpoints Primary Efficacy Endpoint Clinical response by baseline pathogen at day 28 Initial local laboratory isolation of pathogen with confirmation by central laboratory Secondary Efficacy Endpoints Clinical response at day 28 (test of cure) Clinical response at day 10 Safety Evaluation Study 1015 Patient Disposition 242 Clinical at Day 28 127 Bacteriologic Efficacy Azithromycin 248 Safety 248 Enrolled Evaluation Groups Study 1015 Demographics Study 1015 Results Study 1015 Clinical Outcome 36 (15%) Failure [80,90] 206 (85%) Cure 242 Day 28 27 (11%) Failure 74 Improvement 139 Cure [85,93] 213 (89%) Success 240 Day 10 247 Number of Patients 95% CI1 [%] Azithromycin (%) 1 95% CI for azithromycin Study 1015 Clinical Outcome at Day 28 by Age 11 17 Failure [84, 94] 89 142 Cure 159 > 2 years of age 23 19 Failure [67, 87] 77 64 Cure 83 < 2 years of age 95% CI [%] (%) N Azithromycin Study 1015 Clinical Outcome - Per Baseline Pathogen Study 1015 MIC Distribution for S. pneumoniae (N=67) Percent of Patients Azithromycin MIC (mg/ml) Study 1015 Resistant S. Pneumoniae S. pneumoniae MIC = 8 g/ml 7 baseline isolates All sensitive to clindamycin All with mef A gene by PCR S. pneumoniae MIC >256 g/ml 5 baseline isolates All resistant to clindamycin All with erm B gene by PCR Study 1015 Day 28 Outcome and MIC Distribution for S. pneumoniae (N=66) # of Patients Azithromycin MIC (mg/ml) Study 1015 Patient 0067 Failed Therapy 1Susceptible to clindamycin; mef A gene identified 2Resistant to clindamycin; erm B gene identified Study 1015 Strains From Patient 0067 Are Clonally Distinct 1 2 3 4 MIC = 8 MIC >256 Study 1015 Outcome of S. pneumoniae AOM by Penicillin Susceptibility Penicillin Susceptibility *Penicillin MIC > 2 mg/ml **Penicillin MIC > 0.125 - < 2 mg/ml Study 1015 Outcome of S. pneumoniae AOM by Penicillin Susceptibility Penicillin Susceptibility *Penicillin MIC > 2 mg/ml **Penicillin MIC > 0.125 - < 2 mg/ml Study 1015 Treatment Related Adverse Events* (2) 4 Abdominal Pain (6) 14 Vomiting (3) 8 Diarrhea (12) 30 Patients w/ AEs (0) 1 Discontinued due to AEs 248 Patients Treated (%) N * Adverse Events greater than 1% Study 1014 Three Day Dosing Study 1014 Objectives Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 10 mg/kg/day for 3 days Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study 1014 Inclusion Criteria: Symptoms Symptoms consistent with AOM (but nonspecific) 2 Symptoms which help confirm the diagnosis of AOM (%) Age 261 X Fever 1 Children had one or more of these signs and symptoms 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) X Irritability 251 X Decreased hearing 601 X Ear fullness 921 X Ear pain (tugging or rubbing) 0.5-11yrs X >6 months 1014 1998 FDA Guidance Either Ear pain or fullness 97 Study 1014 Inclusion Criteria: Signs of Tympanic Membrane Involvement 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Study 1014 Key Exclusion Criteria Other exclusions include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, neutropenia, immunosuppressant therapy, cystic fibrosis, retraction pockets, cholesteatoma, phenylketonuria, anticipated use of probenecid or allopurinol Study 1014 Visits and Assessments *Patients who vomited within 30 minutes were redosed Study 1014 Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint: Day 28 Cure Failure Study 1014 Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure
Slide 86 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997 Study 95-001 Experimental Design *Baseline tympanocentesis Study 95-001 Patient Disposition Study 95-001 Demographics 0% 2% Black 98% 97% White Race: 48% 56% % Male 2.3 (+ 1.4) 2.5 (+ 1.3) Mean Age (Yrs, ±SD) 31 (47%) 40 (61%) 2 Yrs - 12 Yrs 35 (53%) 26 (39%) < 2 Yrs Age: N = 66 Single Dose N = 66 Azithromycin 2% 95% 55% 2.7 (+ 1.5) 40 (61%) 26 (39%) Three Day N = 66 Ceftriaxone 2% 2% Hispanic 3% Study 95-001 Results Study 95-001 Clinical Efficacy Population 4 (6) Failure 5 Improvement [- 5, 25] 56 (86) Cure [-12,6] 61 (94) Success 65 Day 28 2 (3) Failure 36 Improvement 26 Cure [-8,5] 62 (97) Success 64 Day 14 66 Randomized Patients 95% CI1 [%] 1 Day (%) 1 95% CI for (single dose azithromycin – comparator) 5 (8) 10 51 (77) 61 (92) 66 3 (5) 42 18 60 (95) 63 66 3 Day (%) 2 (3) 13 49 (77) 62 (97) 64 1 (2) 40 21 61 (98) 62 66 Ceftriaxone (%) Azithromycin Study 95-001 Clinical Outcome at Day 28 by Age 5 (16) 6 (15) 3 (8) Failure 26 (84) 33 (85) 37 (93) Cure 31 39 40 > 2 years of age 10 (30) 9 (33) 6 (24) Failure 23 (70) 18 (67) 19 (76) Cure 33 27 25 < 2 years of age Ceftriaxone (%) 3 Day (%) 1 Day (%) Azithromycin Study 95-001 Susceptibility S. pneumoniae susceptibility (N=57) Azithromycin 46 susceptible 11 resistant (MIC > 0.5 mg/ml) Ceftriaxone All isolates were susceptible to ceftriaxone All H. influenzae and M. catarrhalis were susceptible to azithromycin and ceftriaxone Study 95-001 Clinical Cure Per Baseline Pathogen at Day 28 Study 95-001 Treatment Related Adverse Events* 0 (0) 0 (0) 3 (5) Vomiting 4 (6) 0 (0) 1 (2) Rash 4 (6) 3 (5) 2 (3) Diarrhea 6 (9) 6 (9) 7 (11) Patients w/ AE 66 66 66 Patients Treated Ceftriaxone 3 Day 1 Day 0 (0) 0 (0) 0 (0) Discontinued *2 or more events on any treatment regimen Azithromycin Study R-0581 Single Dose Therapy Study R-0581 Objective Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 30 mg/kg single oral dose Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study R-0581 Visits and Assessments *Patients who vomited within 30 minutes were redosed 1 Including parental questionnaire Study R-0581 Patient Disposition Study R-0581 Demographics Study R-0581 Results Study R-0581 Clinical Outcome 38 (25) 37 (25) Failure 8 2 Improvement [-7, 15] 108 (70) 112 (74) Cure [-10, 11] 116 (75) 114 (75) Success 154 151 Day 28 19 (12) 21 (13) Failure 21 34 Improvement 121 105 Cure [-9, 7] 142 (88) 139 (87) Success 161 160 Day 14 173 173 Number of Patients 95% CI1[%] Amox/Clav (%) Azithromycin (%) 1 95% CI for (azithromycin – comparator) Study R-0581 Clinical Outcome at Day 28 by Age Cure 26 (49) 24 (38) Failure [-8, 31] 95% CI1[%] Failure < 2 years of age 27 (51) 40 (63) Cure 53 64 > 2 years of age Amox/Clav Azithromycin 1 95% CI for (azithromycin – comparator) N (%) N (%) 72 (83) 15 (17) 87 81 (80) 20 (20) 101 [-10, 15] Study R-0581 Compliance Based on patients randomized to their study drug regimen Study R-0581 Treatment Related Adverse Events* 7 (4%) 7 (4%) Vomiting 9 (5%) 3 (2%) 22 (13%) 11 (6%) Diarrhea 39 (23%) 29 (17%) Patients w/ AEs Rash Azithromycin N = 173 Amox/Clav N = 173 7(4%) 4 (2%) Discontinued due to AE * Adverse Events greater than 2 percent in either regimen Study 1015 Single Dose Therapy Study 1015 Objectives To assess per-pathogen clinical response rates To provide additional data on the safety and toleration of the single dose regimen Design Prospective Open-label Non-comparative Multi-center Study 1015 Visits and Assessments *Patients who vomited within 30 minutes were redosed Study 1015 Endpoints Primary Efficacy Endpoint Clinical response by baseline pathogen at day 28 Initial local laboratory isolation of pathogen with confirmation by central laboratory Secondary Efficacy Endpoints Clinical response at day 28 (test of cure) Clinical response at day 10 Safety Evaluation Study 1015 Patient Disposition 242 Clinical at Day 28 127 Bacteriologic Efficacy Azithromycin 248 Safety 248 Enrolled Evaluation Groups Study 1015 Demographics Study 1015 Results Study 1015 Clinical Outcome 36 (15%) Failure [80,90] 206 (85%) Cure 242 Day 28 27 (11%) Failure 74 Improvement 139 Cure [85,93] 213 (89%) Success 240 Day 10 247 Number of Patients 95% CI1 [%] Azithromycin (%) 1 95% CI for azithromycin Study 1015 Clinical Outcome at Day 28 by Age 11 17 Failure [84, 94] 89 142 Cure 159 > 2 years of age 23 19 Failure [67, 87] 77 64 Cure 83 < 2 years of age 95% CI [%] (%) N Azithromycin Study 1015 Clinical Outcome - Per Baseline Pathogen Study 1015 MIC Distribution for S. pneumoniae (N=67) Percent of Patients Azithromycin MIC (mg/ml) Study 1015 Resistant S. Pneumoniae S. pneumoniae MIC = 8 g/ml 7 baseline isolates All sensitive to clindamycin All with mef A gene by PCR S. pneumoniae MIC >256 g/ml 5 baseline isolates All resistant to clindamycin All with erm B gene by PCR Study 1015 Day 28 Outcome and MIC Distribution for S. pneumoniae (N=66) # of Patients Azithromycin MIC (mg/ml) Study 1015 Patient 0067 Failed Therapy 1Susceptible to clindamycin; mef A gene identified 2Resistant to clindamycin; erm B gene identified Study 1015 Strains From Patient 0067 Are Clonally Distinct 1 2 3 4 MIC = 8 MIC >256 Study 1015 Outcome of S. pneumoniae AOM by Penicillin Susceptibility Penicillin Susceptibility *Penicillin MIC > 2 mg/ml **Penicillin MIC > 0.125 - < 2 mg/ml Study 1015 Outcome of S. pneumoniae AOM by Penicillin Susceptibility Penicillin Susceptibility *Penicillin MIC > 2 mg/ml **Penicillin MIC > 0.125 - < 2 mg/ml Study 1015 Treatment Related Adverse Events* (2) 4 Abdominal Pain (6) 14 Vomiting (3) 8 Diarrhea (12) 30 Patients w/ AEs (0) 1 Discontinued due to AEs 248 Patients Treated (%) N * Adverse Events greater than 1% Study 1014 Three Day Dosing Study 1014 Objectives Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 10 mg/kg/day for 3 days Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study 1014 Inclusion Criteria: Symptoms Symptoms consistent with AOM (but nonspecific) 2 Symptoms which help confirm the diagnosis of AOM (%) Age 261 X Fever 1 Children had one or more of these signs and symptoms 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) X Irritability 251 X Decreased hearing 601 X Ear fullness 921 X Ear pain (tugging or rubbing) 0.5-11yrs X >6 months 1014 1998 FDA Guidance Either Ear pain or fullness 97 Study 1014 Inclusion Criteria: Signs of Tympanic Membrane Involvement 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Study 1014 Key Exclusion Criteria Other exclusions include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, neutropenia, immunosuppressant therapy, cystic fibrosis, retraction pockets, cholesteatoma, phenylketonuria, anticipated use of probenecid or allopurinol Study 1014 Visits and Assessments *Patients who vomited within 30 minutes were redosed Study 1014 Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint: Day 28 Cure Failure Study 1014 Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Study 1014 Definition of Cure
Slide 87 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997 Study 95-001 Experimental Design *Baseline tympanocentesis Study 95-001 Patient Disposition Study 95-001 Demographics 0% 2% Black 98% 97% White Race: 48% 56% % Male 2.3 (+ 1.4) 2.5 (+ 1.3) Mean Age (Yrs, ±SD) 31 (47%) 40 (61%) 2 Yrs - 12 Yrs 35 (53%) 26 (39%) < 2 Yrs Age: N = 66 Single Dose N = 66 Azithromycin 2% 95% 55% 2.7 (+ 1.5) 40 (61%) 26 (39%) Three Day N = 66 Ceftriaxone 2% 2% Hispanic 3% Study 95-001 Results Study 95-001 Clinical Efficacy Population 4 (6) Failure 5 Improvement [- 5, 25] 56 (86) Cure [-12,6] 61 (94) Success 65 Day 28 2 (3) Failure 36 Improvement 26 Cure [-8,5] 62 (97) Success 64 Day 14 66 Randomized Patients 95% CI1 [%] 1 Day (%) 1 95% CI for (single dose azithromycin – comparator) 5 (8) 10 51 (77) 61 (92) 66 3 (5) 42 18 60 (95) 63 66 3 Day (%) 2 (3) 13 49 (77) 62 (97) 64 1 (2) 40 21 61 (98) 62 66 Ceftriaxone (%) Azithromycin Study 95-001 Clinical Outcome at Day 28 by Age 5 (16) 6 (15) 3 (8) Failure 26 (84) 33 (85) 37 (93) Cure 31 39 40 > 2 years of age 10 (30) 9 (33) 6 (24) Failure 23 (70) 18 (67) 19 (76) Cure 33 27 25 < 2 years of age Ceftriaxone (%) 3 Day (%) 1 Day (%) Azithromycin Study 95-001 Susceptibility S. pneumoniae susceptibility (N=57) Azithromycin 46 susceptible 11 resistant (MIC > 0.5 mg/ml) Ceftriaxone All isolates were susceptible to ceftriaxone All H. influenzae and M. catarrhalis were susceptible to azithromycin and ceftriaxone Study 95-001 Clinical Cure Per Baseline Pathogen at Day 28 Study 95-001 Treatment Related Adverse Events* 0 (0) 0 (0) 3 (5) Vomiting 4 (6) 0 (0) 1 (2) Rash 4 (6) 3 (5) 2 (3) Diarrhea 6 (9) 6 (9) 7 (11) Patients w/ AE 66 66 66 Patients Treated Ceftriaxone 3 Day 1 Day 0 (0) 0 (0) 0 (0) Discontinued *2 or more events on any treatment regimen Azithromycin Study R-0581 Single Dose Therapy Study R-0581 Objective Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 30 mg/kg single oral dose Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study R-0581 Visits and Assessments *Patients who vomited within 30 minutes were redosed 1 Including parental questionnaire Study R-0581 Patient Disposition Study R-0581 Demographics Study R-0581 Results Study R-0581 Clinical Outcome 38 (25) 37 (25) Failure 8 2 Improvement [-7, 15] 108 (70) 112 (74) Cure [-10, 11] 116 (75) 114 (75) Success 154 151 Day 28 19 (12) 21 (13) Failure 21 34 Improvement 121 105 Cure [-9, 7] 142 (88) 139 (87) Success 161 160 Day 14 173 173 Number of Patients 95% CI1[%] Amox/Clav (%) Azithromycin (%) 1 95% CI for (azithromycin – comparator) Study R-0581 Clinical Outcome at Day 28 by Age Cure 26 (49) 24 (38) Failure [-8, 31] 95% CI1[%] Failure < 2 years of age 27 (51) 40 (63) Cure 53 64 > 2 years of age Amox/Clav Azithromycin 1 95% CI for (azithromycin – comparator) N (%) N (%) 72 (83) 15 (17) 87 81 (80) 20 (20) 101 [-10, 15] Study R-0581 Compliance Based on patients randomized to their study drug regimen Study R-0581 Treatment Related Adverse Events* 7 (4%) 7 (4%) Vomiting 9 (5%) 3 (2%) 22 (13%) 11 (6%) Diarrhea 39 (23%) 29 (17%) Patients w/ AEs Rash Azithromycin N = 173 Amox/Clav N = 173 7(4%) 4 (2%) Discontinued due to AE * Adverse Events greater than 2 percent in either regimen Study 1015 Single Dose Therapy Study 1015 Objectives To assess per-pathogen clinical response rates To provide additional data on the safety and toleration of the single dose regimen Design Prospective Open-label Non-comparative Multi-center Study 1015 Visits and Assessments *Patients who vomited within 30 minutes were redosed Study 1015 Endpoints Primary Efficacy Endpoint Clinical response by baseline pathogen at day 28 Initial local laboratory isolation of pathogen with confirmation by central laboratory Secondary Efficacy Endpoints Clinical response at day 28 (test of cure) Clinical response at day 10 Safety Evaluation Study 1015 Patient Disposition 242 Clinical at Day 28 127 Bacteriologic Efficacy Azithromycin 248 Safety 248 Enrolled Evaluation Groups Study 1015 Demographics Study 1015 Results Study 1015 Clinical Outcome 36 (15%) Failure [80,90] 206 (85%) Cure 242 Day 28 27 (11%) Failure 74 Improvement 139 Cure [85,93] 213 (89%) Success 240 Day 10 247 Number of Patients 95% CI1 [%] Azithromycin (%) 1 95% CI for azithromycin Study 1015 Clinical Outcome at Day 28 by Age 11 17 Failure [84, 94] 89 142 Cure 159 > 2 years of age 23 19 Failure [67, 87] 77 64 Cure 83 < 2 years of age 95% CI [%] (%) N Azithromycin Study 1015 Clinical Outcome - Per Baseline Pathogen Study 1015 MIC Distribution for S. pneumoniae (N=67) Percent of Patients Azithromycin MIC (mg/ml) Study 1015 Resistant S. Pneumoniae S. pneumoniae MIC = 8 g/ml 7 baseline isolates All sensitive to clindamycin All with mef A gene by PCR S. pneumoniae MIC >256 g/ml 5 baseline isolates All resistant to clindamycin All with erm B gene by PCR Study 1015 Day 28 Outcome and MIC Distribution for S. pneumoniae (N=66) # of Patients Azithromycin MIC (mg/ml) Study 1015 Patient 0067 Failed Therapy 1Susceptible to clindamycin; mef A gene identified 2Resistant to clindamycin; erm B gene identified Study 1015 Strains From Patient 0067 Are Clonally Distinct 1 2 3 4 MIC = 8 MIC >256 Study 1015 Outcome of S. pneumoniae AOM by Penicillin Susceptibility Penicillin Susceptibility *Penicillin MIC > 2 mg/ml **Penicillin MIC > 0.125 - < 2 mg/ml Study 1015 Outcome of S. pneumoniae AOM by Penicillin Susceptibility Penicillin Susceptibility *Penicillin MIC > 2 mg/ml **Penicillin MIC > 0.125 - < 2 mg/ml Study 1015 Treatment Related Adverse Events* (2) 4 Abdominal Pain (6) 14 Vomiting (3) 8 Diarrhea (12) 30 Patients w/ AEs (0) 1 Discontinued due to AEs 248 Patients Treated (%) N * Adverse Events greater than 1% Study 1014 Three Day Dosing Study 1014 Objectives Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 10 mg/kg/day for 3 days Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study 1014 Inclusion Criteria: Symptoms Symptoms consistent with AOM (but nonspecific) 2 Symptoms which help confirm the diagnosis of AOM (%) Age 261 X Fever 1 Children had one or more of these signs and symptoms 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) X Irritability 251 X Decreased hearing 601 X Ear fullness 921 X Ear pain (tugging or rubbing) 0.5-11yrs X >6 months 1014 1998 FDA Guidance Either Ear pain or fullness 97 Study 1014 Inclusion Criteria: Signs of Tympanic Membrane Involvement 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Study 1014 Key Exclusion Criteria Other exclusions include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, neutropenia, immunosuppressant therapy, cystic fibrosis, retraction pockets, cholesteatoma, phenylketonuria, anticipated use of probenecid or allopurinol Study 1014 Visits and Assessments *Patients who vomited within 30 minutes were redosed Study 1014 Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint: Day 28 Cure Failure Study 1014 Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Study 1014 Definition of Cure Study 1014 Patient Disposition
Slide 88 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997 Study 95-001 Experimental Design *Baseline tympanocentesis Study 95-001 Patient Disposition Study 95-001 Demographics 0% 2% Black 98% 97% White Race: 48% 56% % Male 2.3 (+ 1.4) 2.5 (+ 1.3) Mean Age (Yrs, ±SD) 31 (47%) 40 (61%) 2 Yrs - 12 Yrs 35 (53%) 26 (39%) < 2 Yrs Age: N = 66 Single Dose N = 66 Azithromycin 2% 95% 55% 2.7 (+ 1.5) 40 (61%) 26 (39%) Three Day N = 66 Ceftriaxone 2% 2% Hispanic 3% Study 95-001 Results Study 95-001 Clinical Efficacy Population 4 (6) Failure 5 Improvement [- 5, 25] 56 (86) Cure [-12,6] 61 (94) Success 65 Day 28 2 (3) Failure 36 Improvement 26 Cure [-8,5] 62 (97) Success 64 Day 14 66 Randomized Patients 95% CI1 [%] 1 Day (%) 1 95% CI for (single dose azithromycin – comparator) 5 (8) 10 51 (77) 61 (92) 66 3 (5) 42 18 60 (95) 63 66 3 Day (%) 2 (3) 13 49 (77) 62 (97) 64 1 (2) 40 21 61 (98) 62 66 Ceftriaxone (%) Azithromycin Study 95-001 Clinical Outcome at Day 28 by Age 5 (16) 6 (15) 3 (8) Failure 26 (84) 33 (85) 37 (93) Cure 31 39 40 > 2 years of age 10 (30) 9 (33) 6 (24) Failure 23 (70) 18 (67) 19 (76) Cure 33 27 25 < 2 years of age Ceftriaxone (%) 3 Day (%) 1 Day (%) Azithromycin Study 95-001 Susceptibility S. pneumoniae susceptibility (N=57) Azithromycin 46 susceptible 11 resistant (MIC > 0.5 mg/ml) Ceftriaxone All isolates were susceptible to ceftriaxone All H. influenzae and M. catarrhalis were susceptible to azithromycin and ceftriaxone Study 95-001 Clinical Cure Per Baseline Pathogen at Day 28 Study 95-001 Treatment Related Adverse Events* 0 (0) 0 (0) 3 (5) Vomiting 4 (6) 0 (0) 1 (2) Rash 4 (6) 3 (5) 2 (3) Diarrhea 6 (9) 6 (9) 7 (11) Patients w/ AE 66 66 66 Patients Treated Ceftriaxone 3 Day 1 Day 0 (0) 0 (0) 0 (0) Discontinued *2 or more events on any treatment regimen Azithromycin Study R-0581 Single Dose Therapy Study R-0581 Objective Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 30 mg/kg single oral dose Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study R-0581 Visits and Assessments *Patients who vomited within 30 minutes were redosed 1 Including parental questionnaire Study R-0581 Patient Disposition Study R-0581 Demographics Study R-0581 Results Study R-0581 Clinical Outcome 38 (25) 37 (25) Failure 8 2 Improvement [-7, 15] 108 (70) 112 (74) Cure [-10, 11] 116 (75) 114 (75) Success 154 151 Day 28 19 (12) 21 (13) Failure 21 34 Improvement 121 105 Cure [-9, 7] 142 (88) 139 (87) Success 161 160 Day 14 173 173 Number of Patients 95% CI1[%] Amox/Clav (%) Azithromycin (%) 1 95% CI for (azithromycin – comparator) Study R-0581 Clinical Outcome at Day 28 by Age Cure 26 (49) 24 (38) Failure [-8, 31] 95% CI1[%] Failure < 2 years of age 27 (51) 40 (63) Cure 53 64 > 2 years of age Amox/Clav Azithromycin 1 95% CI for (azithromycin – comparator) N (%) N (%) 72 (83) 15 (17) 87 81 (80) 20 (20) 101 [-10, 15] Study R-0581 Compliance Based on patients randomized to their study drug regimen Study R-0581 Treatment Related Adverse Events* 7 (4%) 7 (4%) Vomiting 9 (5%) 3 (2%) 22 (13%) 11 (6%) Diarrhea 39 (23%) 29 (17%) Patients w/ AEs Rash Azithromycin N = 173 Amox/Clav N = 173 7(4%) 4 (2%) Discontinued due to AE * Adverse Events greater than 2 percent in either regimen Study 1015 Single Dose Therapy Study 1015 Objectives To assess per-pathogen clinical response rates To provide additional data on the safety and toleration of the single dose regimen Design Prospective Open-label Non-comparative Multi-center Study 1015 Visits and Assessments *Patients who vomited within 30 minutes were redosed Study 1015 Endpoints Primary Efficacy Endpoint Clinical response by baseline pathogen at day 28 Initial local laboratory isolation of pathogen with confirmation by central laboratory Secondary Efficacy Endpoints Clinical response at day 28 (test of cure) Clinical response at day 10 Safety Evaluation Study 1015 Patient Disposition 242 Clinical at Day 28 127 Bacteriologic Efficacy Azithromycin 248 Safety 248 Enrolled Evaluation Groups Study 1015 Demographics Study 1015 Results Study 1015 Clinical Outcome 36 (15%) Failure [80,90] 206 (85%) Cure 242 Day 28 27 (11%) Failure 74 Improvement 139 Cure [85,93] 213 (89%) Success 240 Day 10 247 Number of Patients 95% CI1 [%] Azithromycin (%) 1 95% CI for azithromycin Study 1015 Clinical Outcome at Day 28 by Age 11 17 Failure [84, 94] 89 142 Cure 159 > 2 years of age 23 19 Failure [67, 87] 77 64 Cure 83 < 2 years of age 95% CI [%] (%) N Azithromycin Study 1015 Clinical Outcome - Per Baseline Pathogen Study 1015 MIC Distribution for S. pneumoniae (N=67) Percent of Patients Azithromycin MIC (mg/ml) Study 1015 Resistant S. Pneumoniae S. pneumoniae MIC = 8 g/ml 7 baseline isolates All sensitive to clindamycin All with mef A gene by PCR S. pneumoniae MIC >256 g/ml 5 baseline isolates All resistant to clindamycin All with erm B gene by PCR Study 1015 Day 28 Outcome and MIC Distribution for S. pneumoniae (N=66) # of Patients Azithromycin MIC (mg/ml) Study 1015 Patient 0067 Failed Therapy 1Susceptible to clindamycin; mef A gene identified 2Resistant to clindamycin; erm B gene identified Study 1015 Strains From Patient 0067 Are Clonally Distinct 1 2 3 4 MIC = 8 MIC >256 Study 1015 Outcome of S. pneumoniae AOM by Penicillin Susceptibility Penicillin Susceptibility *Penicillin MIC > 2 mg/ml **Penicillin MIC > 0.125 - < 2 mg/ml Study 1015 Outcome of S. pneumoniae AOM by Penicillin Susceptibility Penicillin Susceptibility *Penicillin MIC > 2 mg/ml **Penicillin MIC > 0.125 - < 2 mg/ml Study 1015 Treatment Related Adverse Events* (2) 4 Abdominal Pain (6) 14 Vomiting (3) 8 Diarrhea (12) 30 Patients w/ AEs (0) 1 Discontinued due to AEs 248 Patients Treated (%) N * Adverse Events greater than 1% Study 1014 Three Day Dosing Study 1014 Objectives Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 10 mg/kg/day for 3 days Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study 1014 Inclusion Criteria: Symptoms Symptoms consistent with AOM (but nonspecific) 2 Symptoms which help confirm the diagnosis of AOM (%) Age 261 X Fever 1 Children had one or more of these signs and symptoms 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) X Irritability 251 X Decreased hearing 601 X Ear fullness 921 X Ear pain (tugging or rubbing) 0.5-11yrs X >6 months 1014 1998 FDA Guidance Either Ear pain or fullness 97 Study 1014 Inclusion Criteria: Signs of Tympanic Membrane Involvement 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Study 1014 Key Exclusion Criteria Other exclusions include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, neutropenia, immunosuppressant therapy, cystic fibrosis, retraction pockets, cholesteatoma, phenylketonuria, anticipated use of probenecid or allopurinol Study 1014 Visits and Assessments *Patients who vomited within 30 minutes were redosed Study 1014 Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint: Day 28 Cure Failure Study 1014 Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Study 1014 Definition of Cure Study 1014 Patient Disposition Study 1014 Demographics
Slide 89 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997 Study 95-001 Experimental Design *Baseline tympanocentesis Study 95-001 Patient Disposition Study 95-001 Demographics 0% 2% Black 98% 97% White Race: 48% 56% % Male 2.3 (+ 1.4) 2.5 (+ 1.3) Mean Age (Yrs, ±SD) 31 (47%) 40 (61%) 2 Yrs - 12 Yrs 35 (53%) 26 (39%) < 2 Yrs Age: N = 66 Single Dose N = 66 Azithromycin 2% 95% 55% 2.7 (+ 1.5) 40 (61%) 26 (39%) Three Day N = 66 Ceftriaxone 2% 2% Hispanic 3% Study 95-001 Results Study 95-001 Clinical Efficacy Population 4 (6) Failure 5 Improvement [- 5, 25] 56 (86) Cure [-12,6] 61 (94) Success 65 Day 28 2 (3) Failure 36 Improvement 26 Cure [-8,5] 62 (97) Success 64 Day 14 66 Randomized Patients 95% CI1 [%] 1 Day (%) 1 95% CI for (single dose azithromycin – comparator) 5 (8) 10 51 (77) 61 (92) 66 3 (5) 42 18 60 (95) 63 66 3 Day (%) 2 (3) 13 49 (77) 62 (97) 64 1 (2) 40 21 61 (98) 62 66 Ceftriaxone (%) Azithromycin Study 95-001 Clinical Outcome at Day 28 by Age 5 (16) 6 (15) 3 (8) Failure 26 (84) 33 (85) 37 (93) Cure 31 39 40 > 2 years of age 10 (30) 9 (33) 6 (24) Failure 23 (70) 18 (67) 19 (76) Cure 33 27 25 < 2 years of age Ceftriaxone (%) 3 Day (%) 1 Day (%) Azithromycin Study 95-001 Susceptibility S. pneumoniae susceptibility (N=57) Azithromycin 46 susceptible 11 resistant (MIC > 0.5 mg/ml) Ceftriaxone All isolates were susceptible to ceftriaxone All H. influenzae and M. catarrhalis were susceptible to azithromycin and ceftriaxone Study 95-001 Clinical Cure Per Baseline Pathogen at Day 28 Study 95-001 Treatment Related Adverse Events* 0 (0) 0 (0) 3 (5) Vomiting 4 (6) 0 (0) 1 (2) Rash 4 (6) 3 (5) 2 (3) Diarrhea 6 (9) 6 (9) 7 (11) Patients w/ AE 66 66 66 Patients Treated Ceftriaxone 3 Day 1 Day 0 (0) 0 (0) 0 (0) Discontinued *2 or more events on any treatment regimen Azithromycin Study R-0581 Single Dose Therapy Study R-0581 Objective Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 30 mg/kg single oral dose Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study R-0581 Visits and Assessments *Patients who vomited within 30 minutes were redosed 1 Including parental questionnaire Study R-0581 Patient Disposition Study R-0581 Demographics Study R-0581 Results Study R-0581 Clinical Outcome 38 (25) 37 (25) Failure 8 2 Improvement [-7, 15] 108 (70) 112 (74) Cure [-10, 11] 116 (75) 114 (75) Success 154 151 Day 28 19 (12) 21 (13) Failure 21 34 Improvement 121 105 Cure [-9, 7] 142 (88) 139 (87) Success 161 160 Day 14 173 173 Number of Patients 95% CI1[%] Amox/Clav (%) Azithromycin (%) 1 95% CI for (azithromycin – comparator) Study R-0581 Clinical Outcome at Day 28 by Age Cure 26 (49) 24 (38) Failure [-8, 31] 95% CI1[%] Failure < 2 years of age 27 (51) 40 (63) Cure 53 64 > 2 years of age Amox/Clav Azithromycin 1 95% CI for (azithromycin – comparator) N (%) N (%) 72 (83) 15 (17) 87 81 (80) 20 (20) 101 [-10, 15] Study R-0581 Compliance Based on patients randomized to their study drug regimen Study R-0581 Treatment Related Adverse Events* 7 (4%) 7 (4%) Vomiting 9 (5%) 3 (2%) 22 (13%) 11 (6%) Diarrhea 39 (23%) 29 (17%) Patients w/ AEs Rash Azithromycin N = 173 Amox/Clav N = 173 7(4%) 4 (2%) Discontinued due to AE * Adverse Events greater than 2 percent in either regimen Study 1015 Single Dose Therapy Study 1015 Objectives To assess per-pathogen clinical response rates To provide additional data on the safety and toleration of the single dose regimen Design Prospective Open-label Non-comparative Multi-center Study 1015 Visits and Assessments *Patients who vomited within 30 minutes were redosed Study 1015 Endpoints Primary Efficacy Endpoint Clinical response by baseline pathogen at day 28 Initial local laboratory isolation of pathogen with confirmation by central laboratory Secondary Efficacy Endpoints Clinical response at day 28 (test of cure) Clinical response at day 10 Safety Evaluation Study 1015 Patient Disposition 242 Clinical at Day 28 127 Bacteriologic Efficacy Azithromycin 248 Safety 248 Enrolled Evaluation Groups Study 1015 Demographics Study 1015 Results Study 1015 Clinical Outcome 36 (15%) Failure [80,90] 206 (85%) Cure 242 Day 28 27 (11%) Failure 74 Improvement 139 Cure [85,93] 213 (89%) Success 240 Day 10 247 Number of Patients 95% CI1 [%] Azithromycin (%) 1 95% CI for azithromycin Study 1015 Clinical Outcome at Day 28 by Age 11 17 Failure [84, 94] 89 142 Cure 159 > 2 years of age 23 19 Failure [67, 87] 77 64 Cure 83 < 2 years of age 95% CI [%] (%) N Azithromycin Study 1015 Clinical Outcome - Per Baseline Pathogen Study 1015 MIC Distribution for S. pneumoniae (N=67) Percent of Patients Azithromycin MIC (mg/ml) Study 1015 Resistant S. Pneumoniae S. pneumoniae MIC = 8 g/ml 7 baseline isolates All sensitive to clindamycin All with mef A gene by PCR S. pneumoniae MIC >256 g/ml 5 baseline isolates All resistant to clindamycin All with erm B gene by PCR Study 1015 Day 28 Outcome and MIC Distribution for S. pneumoniae (N=66) # of Patients Azithromycin MIC (mg/ml) Study 1015 Patient 0067 Failed Therapy 1Susceptible to clindamycin; mef A gene identified 2Resistant to clindamycin; erm B gene identified Study 1015 Strains From Patient 0067 Are Clonally Distinct 1 2 3 4 MIC = 8 MIC >256 Study 1015 Outcome of S. pneumoniae AOM by Penicillin Susceptibility Penicillin Susceptibility *Penicillin MIC > 2 mg/ml **Penicillin MIC > 0.125 - < 2 mg/ml Study 1015 Outcome of S. pneumoniae AOM by Penicillin Susceptibility Penicillin Susceptibility *Penicillin MIC > 2 mg/ml **Penicillin MIC > 0.125 - < 2 mg/ml Study 1015 Treatment Related Adverse Events* (2) 4 Abdominal Pain (6) 14 Vomiting (3) 8 Diarrhea (12) 30 Patients w/ AEs (0) 1 Discontinued due to AEs 248 Patients Treated (%) N * Adverse Events greater than 1% Study 1014 Three Day Dosing Study 1014 Objectives Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 10 mg/kg/day for 3 days Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study 1014 Inclusion Criteria: Symptoms Symptoms consistent with AOM (but nonspecific) 2 Symptoms which help confirm the diagnosis of AOM (%) Age 261 X Fever 1 Children had one or more of these signs and symptoms 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) X Irritability 251 X Decreased hearing 601 X Ear fullness 921 X Ear pain (tugging or rubbing) 0.5-11yrs X >6 months 1014 1998 FDA Guidance Either Ear pain or fullness 97 Study 1014 Inclusion Criteria: Signs of Tympanic Membrane Involvement 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Study 1014 Key Exclusion Criteria Other exclusions include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, neutropenia, immunosuppressant therapy, cystic fibrosis, retraction pockets, cholesteatoma, phenylketonuria, anticipated use of probenecid or allopurinol Study 1014 Visits and Assessments *Patients who vomited within 30 minutes were redosed Study 1014 Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint: Day 28 Cure Failure Study 1014 Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Study 1014 Definition of Cure Study 1014 Patient Disposition Study 1014 Demographics Study 1014 Results
Slide 90 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997 Study 95-001 Experimental Design *Baseline tympanocentesis Study 95-001 Patient Disposition Study 95-001 Demographics 0% 2% Black 98% 97% White Race: 48% 56% % Male 2.3 (+ 1.4) 2.5 (+ 1.3) Mean Age (Yrs, ±SD) 31 (47%) 40 (61%) 2 Yrs - 12 Yrs 35 (53%) 26 (39%) < 2 Yrs Age: N = 66 Single Dose N = 66 Azithromycin 2% 95% 55% 2.7 (+ 1.5) 40 (61%) 26 (39%) Three Day N = 66 Ceftriaxone 2% 2% Hispanic 3% Study 95-001 Results Study 95-001 Clinical Efficacy Population 4 (6) Failure 5 Improvement [- 5, 25] 56 (86) Cure [-12,6] 61 (94) Success 65 Day 28 2 (3) Failure 36 Improvement 26 Cure [-8,5] 62 (97) Success 64 Day 14 66 Randomized Patients 95% CI1 [%] 1 Day (%) 1 95% CI for (single dose azithromycin – comparator) 5 (8) 10 51 (77) 61 (92) 66 3 (5) 42 18 60 (95) 63 66 3 Day (%) 2 (3) 13 49 (77) 62 (97) 64 1 (2) 40 21 61 (98) 62 66 Ceftriaxone (%) Azithromycin Study 95-001 Clinical Outcome at Day 28 by Age 5 (16) 6 (15) 3 (8) Failure 26 (84) 33 (85) 37 (93) Cure 31 39 40 > 2 years of age 10 (30) 9 (33) 6 (24) Failure 23 (70) 18 (67) 19 (76) Cure 33 27 25 < 2 years of age Ceftriaxone (%) 3 Day (%) 1 Day (%) Azithromycin Study 95-001 Susceptibility S. pneumoniae susceptibility (N=57) Azithromycin 46 susceptible 11 resistant (MIC > 0.5 mg/ml) Ceftriaxone All isolates were susceptible to ceftriaxone All H. influenzae and M. catarrhalis were susceptible to azithromycin and ceftriaxone Study 95-001 Clinical Cure Per Baseline Pathogen at Day 28 Study 95-001 Treatment Related Adverse Events* 0 (0) 0 (0) 3 (5) Vomiting 4 (6) 0 (0) 1 (2) Rash 4 (6) 3 (5) 2 (3) Diarrhea 6 (9) 6 (9) 7 (11) Patients w/ AE 66 66 66 Patients Treated Ceftriaxone 3 Day 1 Day 0 (0) 0 (0) 0 (0) Discontinued *2 or more events on any treatment regimen Azithromycin Study R-0581 Single Dose Therapy Study R-0581 Objective Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 30 mg/kg single oral dose Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study R-0581 Visits and Assessments *Patients who vomited within 30 minutes were redosed 1 Including parental questionnaire Study R-0581 Patient Disposition Study R-0581 Demographics Study R-0581 Results Study R-0581 Clinical Outcome 38 (25) 37 (25) Failure 8 2 Improvement [-7, 15] 108 (70) 112 (74) Cure [-10, 11] 116 (75) 114 (75) Success 154 151 Day 28 19 (12) 21 (13) Failure 21 34 Improvement 121 105 Cure [-9, 7] 142 (88) 139 (87) Success 161 160 Day 14 173 173 Number of Patients 95% CI1[%] Amox/Clav (%) Azithromycin (%) 1 95% CI for (azithromycin – comparator) Study R-0581 Clinical Outcome at Day 28 by Age Cure 26 (49) 24 (38) Failure [-8, 31] 95% CI1[%] Failure < 2 years of age 27 (51) 40 (63) Cure 53 64 > 2 years of age Amox/Clav Azithromycin 1 95% CI for (azithromycin – comparator) N (%) N (%) 72 (83) 15 (17) 87 81 (80) 20 (20) 101 [-10, 15] Study R-0581 Compliance Based on patients randomized to their study drug regimen Study R-0581 Treatment Related Adverse Events* 7 (4%) 7 (4%) Vomiting 9 (5%) 3 (2%) 22 (13%) 11 (6%) Diarrhea 39 (23%) 29 (17%) Patients w/ AEs Rash Azithromycin N = 173 Amox/Clav N = 173 7(4%) 4 (2%) Discontinued due to AE * Adverse Events greater than 2 percent in either regimen Study 1015 Single Dose Therapy Study 1015 Objectives To assess per-pathogen clinical response rates To provide additional data on the safety and toleration of the single dose regimen Design Prospective Open-label Non-comparative Multi-center Study 1015 Visits and Assessments *Patients who vomited within 30 minutes were redosed Study 1015 Endpoints Primary Efficacy Endpoint Clinical response by baseline pathogen at day 28 Initial local laboratory isolation of pathogen with confirmation by central laboratory Secondary Efficacy Endpoints Clinical response at day 28 (test of cure) Clinical response at day 10 Safety Evaluation Study 1015 Patient Disposition 242 Clinical at Day 28 127 Bacteriologic Efficacy Azithromycin 248 Safety 248 Enrolled Evaluation Groups Study 1015 Demographics Study 1015 Results Study 1015 Clinical Outcome 36 (15%) Failure [80,90] 206 (85%) Cure 242 Day 28 27 (11%) Failure 74 Improvement 139 Cure [85,93] 213 (89%) Success 240 Day 10 247 Number of Patients 95% CI1 [%] Azithromycin (%) 1 95% CI for azithromycin Study 1015 Clinical Outcome at Day 28 by Age 11 17 Failure [84, 94] 89 142 Cure 159 > 2 years of age 23 19 Failure [67, 87] 77 64 Cure 83 < 2 years of age 95% CI [%] (%) N Azithromycin Study 1015 Clinical Outcome - Per Baseline Pathogen Study 1015 MIC Distribution for S. pneumoniae (N=67) Percent of Patients Azithromycin MIC (mg/ml) Study 1015 Resistant S. Pneumoniae S. pneumoniae MIC = 8 g/ml 7 baseline isolates All sensitive to clindamycin All with mef A gene by PCR S. pneumoniae MIC >256 g/ml 5 baseline isolates All resistant to clindamycin All with erm B gene by PCR Study 1015 Day 28 Outcome and MIC Distribution for S. pneumoniae (N=66) # of Patients Azithromycin MIC (mg/ml) Study 1015 Patient 0067 Failed Therapy 1Susceptible to clindamycin; mef A gene identified 2Resistant to clindamycin; erm B gene identified Study 1015 Strains From Patient 0067 Are Clonally Distinct 1 2 3 4 MIC = 8 MIC >256 Study 1015 Outcome of S. pneumoniae AOM by Penicillin Susceptibility Penicillin Susceptibility *Penicillin MIC > 2 mg/ml **Penicillin MIC > 0.125 - < 2 mg/ml Study 1015 Outcome of S. pneumoniae AOM by Penicillin Susceptibility Penicillin Susceptibility *Penicillin MIC > 2 mg/ml **Penicillin MIC > 0.125 - < 2 mg/ml Study 1015 Treatment Related Adverse Events* (2) 4 Abdominal Pain (6) 14 Vomiting (3) 8 Diarrhea (12) 30 Patients w/ AEs (0) 1 Discontinued due to AEs 248 Patients Treated (%) N * Adverse Events greater than 1% Study 1014 Three Day Dosing Study 1014 Objectives Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 10 mg/kg/day for 3 days Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study 1014 Inclusion Criteria: Symptoms Symptoms consistent with AOM (but nonspecific) 2 Symptoms which help confirm the diagnosis of AOM (%) Age 261 X Fever 1 Children had one or more of these signs and symptoms 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) X Irritability 251 X Decreased hearing 601 X Ear fullness 921 X Ear pain (tugging or rubbing) 0.5-11yrs X >6 months 1014 1998 FDA Guidance Either Ear pain or fullness 97 Study 1014 Inclusion Criteria: Signs of Tympanic Membrane Involvement 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Study 1014 Key Exclusion Criteria Other exclusions include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, neutropenia, immunosuppressant therapy, cystic fibrosis, retraction pockets, cholesteatoma, phenylketonuria, anticipated use of probenecid or allopurinol Study 1014 Visits and Assessments *Patients who vomited within 30 minutes were redosed Study 1014 Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint: Day 28 Cure Failure Study 1014 Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Study 1014 Definition of Cure Study 1014 Patient Disposition Study 1014 Demographics Study 1014 Results Study 1014 Clinical Outcome 56 (31) 48 (26) Failure [-5, 15] 124 (69) 134 (74) Cure 180 182 Day 28 22 (12) 32 (17) Failure 45 53 Improvement 114 100 Cure [-13,3] 159 (88) 153 (83) Success 181 185 Day 10 185 188 Number of Patients 95% CI1 [%] Amox/Clav (%) Azithromycin (%) 1 95% CI for (azithromycin – comparator)
Slide 91 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997 Study 95-001 Experimental Design *Baseline tympanocentesis Study 95-001 Patient Disposition Study 95-001 Demographics 0% 2% Black 98% 97% White Race: 48% 56% % Male 2.3 (+ 1.4) 2.5 (+ 1.3) Mean Age (Yrs, ±SD) 31 (47%) 40 (61%) 2 Yrs - 12 Yrs 35 (53%) 26 (39%) < 2 Yrs Age: N = 66 Single Dose N = 66 Azithromycin 2% 95% 55% 2.7 (+ 1.5) 40 (61%) 26 (39%) Three Day N = 66 Ceftriaxone 2% 2% Hispanic 3% Study 95-001 Results Study 95-001 Clinical Efficacy Population 4 (6) Failure 5 Improvement [- 5, 25] 56 (86) Cure [-12,6] 61 (94) Success 65 Day 28 2 (3) Failure 36 Improvement 26 Cure [-8,5] 62 (97) Success 64 Day 14 66 Randomized Patients 95% CI1 [%] 1 Day (%) 1 95% CI for (single dose azithromycin – comparator) 5 (8) 10 51 (77) 61 (92) 66 3 (5) 42 18 60 (95) 63 66 3 Day (%) 2 (3) 13 49 (77) 62 (97) 64 1 (2) 40 21 61 (98) 62 66 Ceftriaxone (%) Azithromycin Study 95-001 Clinical Outcome at Day 28 by Age 5 (16) 6 (15) 3 (8) Failure 26 (84) 33 (85) 37 (93) Cure 31 39 40 > 2 years of age 10 (30) 9 (33) 6 (24) Failure 23 (70) 18 (67) 19 (76) Cure 33 27 25 < 2 years of age Ceftriaxone (%) 3 Day (%) 1 Day (%) Azithromycin Study 95-001 Susceptibility S. pneumoniae susceptibility (N=57) Azithromycin 46 susceptible 11 resistant (MIC > 0.5 mg/ml) Ceftriaxone All isolates were susceptible to ceftriaxone All H. influenzae and M. catarrhalis were susceptible to azithromycin and ceftriaxone Study 95-001 Clinical Cure Per Baseline Pathogen at Day 28 Study 95-001 Treatment Related Adverse Events* 0 (0) 0 (0) 3 (5) Vomiting 4 (6) 0 (0) 1 (2) Rash 4 (6) 3 (5) 2 (3) Diarrhea 6 (9) 6 (9) 7 (11) Patients w/ AE 66 66 66 Patients Treated Ceftriaxone 3 Day 1 Day 0 (0) 0 (0) 0 (0) Discontinued *2 or more events on any treatment regimen Azithromycin Study R-0581 Single Dose Therapy Study R-0581 Objective Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 30 mg/kg single oral dose Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study R-0581 Visits and Assessments *Patients who vomited within 30 minutes were redosed 1 Including parental questionnaire Study R-0581 Patient Disposition Study R-0581 Demographics Study R-0581 Results Study R-0581 Clinical Outcome 38 (25) 37 (25) Failure 8 2 Improvement [-7, 15] 108 (70) 112 (74) Cure [-10, 11] 116 (75) 114 (75) Success 154 151 Day 28 19 (12) 21 (13) Failure 21 34 Improvement 121 105 Cure [-9, 7] 142 (88) 139 (87) Success 161 160 Day 14 173 173 Number of Patients 95% CI1[%] Amox/Clav (%) Azithromycin (%) 1 95% CI for (azithromycin – comparator) Study R-0581 Clinical Outcome at Day 28 by Age Cure 26 (49) 24 (38) Failure [-8, 31] 95% CI1[%] Failure < 2 years of age 27 (51) 40 (63) Cure 53 64 > 2 years of age Amox/Clav Azithromycin 1 95% CI for (azithromycin – comparator) N (%) N (%) 72 (83) 15 (17) 87 81 (80) 20 (20) 101 [-10, 15] Study R-0581 Compliance Based on patients randomized to their study drug regimen Study R-0581 Treatment Related Adverse Events* 7 (4%) 7 (4%) Vomiting 9 (5%) 3 (2%) 22 (13%) 11 (6%) Diarrhea 39 (23%) 29 (17%) Patients w/ AEs Rash Azithromycin N = 173 Amox/Clav N = 173 7(4%) 4 (2%) Discontinued due to AE * Adverse Events greater than 2 percent in either regimen Study 1015 Single Dose Therapy Study 1015 Objectives To assess per-pathogen clinical response rates To provide additional data on the safety and toleration of the single dose regimen Design Prospective Open-label Non-comparative Multi-center Study 1015 Visits and Assessments *Patients who vomited within 30 minutes were redosed Study 1015 Endpoints Primary Efficacy Endpoint Clinical response by baseline pathogen at day 28 Initial local laboratory isolation of pathogen with confirmation by central laboratory Secondary Efficacy Endpoints Clinical response at day 28 (test of cure) Clinical response at day 10 Safety Evaluation Study 1015 Patient Disposition 242 Clinical at Day 28 127 Bacteriologic Efficacy Azithromycin 248 Safety 248 Enrolled Evaluation Groups Study 1015 Demographics Study 1015 Results Study 1015 Clinical Outcome 36 (15%) Failure [80,90] 206 (85%) Cure 242 Day 28 27 (11%) Failure 74 Improvement 139 Cure [85,93] 213 (89%) Success 240 Day 10 247 Number of Patients 95% CI1 [%] Azithromycin (%) 1 95% CI for azithromycin Study 1015 Clinical Outcome at Day 28 by Age 11 17 Failure [84, 94] 89 142 Cure 159 > 2 years of age 23 19 Failure [67, 87] 77 64 Cure 83 < 2 years of age 95% CI [%] (%) N Azithromycin Study 1015 Clinical Outcome - Per Baseline Pathogen Study 1015 MIC Distribution for S. pneumoniae (N=67) Percent of Patients Azithromycin MIC (mg/ml) Study 1015 Resistant S. Pneumoniae S. pneumoniae MIC = 8 g/ml 7 baseline isolates All sensitive to clindamycin All with mef A gene by PCR S. pneumoniae MIC >256 g/ml 5 baseline isolates All resistant to clindamycin All with erm B gene by PCR Study 1015 Day 28 Outcome and MIC Distribution for S. pneumoniae (N=66) # of Patients Azithromycin MIC (mg/ml) Study 1015 Patient 0067 Failed Therapy 1Susceptible to clindamycin; mef A gene identified 2Resistant to clindamycin; erm B gene identified Study 1015 Strains From Patient 0067 Are Clonally Distinct 1 2 3 4 MIC = 8 MIC >256 Study 1015 Outcome of S. pneumoniae AOM by Penicillin Susceptibility Penicillin Susceptibility *Penicillin MIC > 2 mg/ml **Penicillin MIC > 0.125 - < 2 mg/ml Study 1015 Outcome of S. pneumoniae AOM by Penicillin Susceptibility Penicillin Susceptibility *Penicillin MIC > 2 mg/ml **Penicillin MIC > 0.125 - < 2 mg/ml Study 1015 Treatment Related Adverse Events* (2) 4 Abdominal Pain (6) 14 Vomiting (3) 8 Diarrhea (12) 30 Patients w/ AEs (0) 1 Discontinued due to AEs 248 Patients Treated (%) N * Adverse Events greater than 1% Study 1014 Three Day Dosing Study 1014 Objectives Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 10 mg/kg/day for 3 days Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study 1014 Inclusion Criteria: Symptoms Symptoms consistent with AOM (but nonspecific) 2 Symptoms which help confirm the diagnosis of AOM (%) Age 261 X Fever 1 Children had one or more of these signs and symptoms 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) X Irritability 251 X Decreased hearing 601 X Ear fullness 921 X Ear pain (tugging or rubbing) 0.5-11yrs X >6 months 1014 1998 FDA Guidance Either Ear pain or fullness 97 Study 1014 Inclusion Criteria: Signs of Tympanic Membrane Involvement 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Study 1014 Key Exclusion Criteria Other exclusions include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, neutropenia, immunosuppressant therapy, cystic fibrosis, retraction pockets, cholesteatoma, phenylketonuria, anticipated use of probenecid or allopurinol Study 1014 Visits and Assessments *Patients who vomited within 30 minutes were redosed Study 1014 Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint: Day 28 Cure Failure Study 1014 Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Study 1014 Definition of Cure Study 1014 Patient Disposition Study 1014 Demographics Study 1014 Results Study 1014 Clinical Outcome 56 (31) 48 (26) Failure [-5, 15] 124 (69) 134 (74) Cure 180 182 Day 28 22 (12) 32 (17) Failure 45 53 Improvement 114 100 Cure [-13,3] 159 (88) 153 (83) Success 181 185 Day 10 185 188 Number of Patients 95% CI1 [%] Amox/Clav (%) Azithromycin (%) 1 95% CI for (azithromycin – comparator) Study 1014 Clinical Outcome at Day 28 by Age [-5, 18] (73) 94 (80) 99 Cure 128 124 > 2 years of age [-18, 23] (58) 30 (60) 35 Cure 52 58 < 2 years of age (%) N (%) N Amox/Clav Azithromycin 1 95% CI for (azithromycin – comparator) Failure Failure (27) 34 (20) 25 (42) 22 (40) 23 95% CI1 [%]
Slide 92 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997 Study 95-001 Experimental Design *Baseline tympanocentesis Study 95-001 Patient Disposition Study 95-001 Demographics 0% 2% Black 98% 97% White Race: 48% 56% % Male 2.3 (+ 1.4) 2.5 (+ 1.3) Mean Age (Yrs, ±SD) 31 (47%) 40 (61%) 2 Yrs - 12 Yrs 35 (53%) 26 (39%) < 2 Yrs Age: N = 66 Single Dose N = 66 Azithromycin 2% 95% 55% 2.7 (+ 1.5) 40 (61%) 26 (39%) Three Day N = 66 Ceftriaxone 2% 2% Hispanic 3% Study 95-001 Results Study 95-001 Clinical Efficacy Population 4 (6) Failure 5 Improvement [- 5, 25] 56 (86) Cure [-12,6] 61 (94) Success 65 Day 28 2 (3) Failure 36 Improvement 26 Cure [-8,5] 62 (97) Success 64 Day 14 66 Randomized Patients 95% CI1 [%] 1 Day (%) 1 95% CI for (single dose azithromycin – comparator) 5 (8) 10 51 (77) 61 (92) 66 3 (5) 42 18 60 (95) 63 66 3 Day (%) 2 (3) 13 49 (77) 62 (97) 64 1 (2) 40 21 61 (98) 62 66 Ceftriaxone (%) Azithromycin Study 95-001 Clinical Outcome at Day 28 by Age 5 (16) 6 (15) 3 (8) Failure 26 (84) 33 (85) 37 (93) Cure 31 39 40 > 2 years of age 10 (30) 9 (33) 6 (24) Failure 23 (70) 18 (67) 19 (76) Cure 33 27 25 < 2 years of age Ceftriaxone (%) 3 Day (%) 1 Day (%) Azithromycin Study 95-001 Susceptibility S. pneumoniae susceptibility (N=57) Azithromycin 46 susceptible 11 resistant (MIC > 0.5 mg/ml) Ceftriaxone All isolates were susceptible to ceftriaxone All H. influenzae and M. catarrhalis were susceptible to azithromycin and ceftriaxone Study 95-001 Clinical Cure Per Baseline Pathogen at Day 28 Study 95-001 Treatment Related Adverse Events* 0 (0) 0 (0) 3 (5) Vomiting 4 (6) 0 (0) 1 (2) Rash 4 (6) 3 (5) 2 (3) Diarrhea 6 (9) 6 (9) 7 (11) Patients w/ AE 66 66 66 Patients Treated Ceftriaxone 3 Day 1 Day 0 (0) 0 (0) 0 (0) Discontinued *2 or more events on any treatment regimen Azithromycin Study R-0581 Single Dose Therapy Study R-0581 Objective Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 30 mg/kg single oral dose Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study R-0581 Visits and Assessments *Patients who vomited within 30 minutes were redosed 1 Including parental questionnaire Study R-0581 Patient Disposition Study R-0581 Demographics Study R-0581 Results Study R-0581 Clinical Outcome 38 (25) 37 (25) Failure 8 2 Improvement [-7, 15] 108 (70) 112 (74) Cure [-10, 11] 116 (75) 114 (75) Success 154 151 Day 28 19 (12) 21 (13) Failure 21 34 Improvement 121 105 Cure [-9, 7] 142 (88) 139 (87) Success 161 160 Day 14 173 173 Number of Patients 95% CI1[%] Amox/Clav (%) Azithromycin (%) 1 95% CI for (azithromycin – comparator) Study R-0581 Clinical Outcome at Day 28 by Age Cure 26 (49) 24 (38) Failure [-8, 31] 95% CI1[%] Failure < 2 years of age 27 (51) 40 (63) Cure 53 64 > 2 years of age Amox/Clav Azithromycin 1 95% CI for (azithromycin – comparator) N (%) N (%) 72 (83) 15 (17) 87 81 (80) 20 (20) 101 [-10, 15] Study R-0581 Compliance Based on patients randomized to their study drug regimen Study R-0581 Treatment Related Adverse Events* 7 (4%) 7 (4%) Vomiting 9 (5%) 3 (2%) 22 (13%) 11 (6%) Diarrhea 39 (23%) 29 (17%) Patients w/ AEs Rash Azithromycin N = 173 Amox/Clav N = 173 7(4%) 4 (2%) Discontinued due to AE * Adverse Events greater than 2 percent in either regimen Study 1015 Single Dose Therapy Study 1015 Objectives To assess per-pathogen clinical response rates To provide additional data on the safety and toleration of the single dose regimen Design Prospective Open-label Non-comparative Multi-center Study 1015 Visits and Assessments *Patients who vomited within 30 minutes were redosed Study 1015 Endpoints Primary Efficacy Endpoint Clinical response by baseline pathogen at day 28 Initial local laboratory isolation of pathogen with confirmation by central laboratory Secondary Efficacy Endpoints Clinical response at day 28 (test of cure) Clinical response at day 10 Safety Evaluation Study 1015 Patient Disposition 242 Clinical at Day 28 127 Bacteriologic Efficacy Azithromycin 248 Safety 248 Enrolled Evaluation Groups Study 1015 Demographics Study 1015 Results Study 1015 Clinical Outcome 36 (15%) Failure [80,90] 206 (85%) Cure 242 Day 28 27 (11%) Failure 74 Improvement 139 Cure [85,93] 213 (89%) Success 240 Day 10 247 Number of Patients 95% CI1 [%] Azithromycin (%) 1 95% CI for azithromycin Study 1015 Clinical Outcome at Day 28 by Age 11 17 Failure [84, 94] 89 142 Cure 159 > 2 years of age 23 19 Failure [67, 87] 77 64 Cure 83 < 2 years of age 95% CI [%] (%) N Azithromycin Study 1015 Clinical Outcome - Per Baseline Pathogen Study 1015 MIC Distribution for S. pneumoniae (N=67) Percent of Patients Azithromycin MIC (mg/ml) Study 1015 Resistant S. Pneumoniae S. pneumoniae MIC = 8 g/ml 7 baseline isolates All sensitive to clindamycin All with mef A gene by PCR S. pneumoniae MIC >256 g/ml 5 baseline isolates All resistant to clindamycin All with erm B gene by PCR Study 1015 Day 28 Outcome and MIC Distribution for S. pneumoniae (N=66) # of Patients Azithromycin MIC (mg/ml) Study 1015 Patient 0067 Failed Therapy 1Susceptible to clindamycin; mef A gene identified 2Resistant to clindamycin; erm B gene identified Study 1015 Strains From Patient 0067 Are Clonally Distinct 1 2 3 4 MIC = 8 MIC >256 Study 1015 Outcome of S. pneumoniae AOM by Penicillin Susceptibility Penicillin Susceptibility *Penicillin MIC > 2 mg/ml **Penicillin MIC > 0.125 - < 2 mg/ml Study 1015 Outcome of S. pneumoniae AOM by Penicillin Susceptibility Penicillin Susceptibility *Penicillin MIC > 2 mg/ml **Penicillin MIC > 0.125 - < 2 mg/ml Study 1015 Treatment Related Adverse Events* (2) 4 Abdominal Pain (6) 14 Vomiting (3) 8 Diarrhea (12) 30 Patients w/ AEs (0) 1 Discontinued due to AEs 248 Patients Treated (%) N * Adverse Events greater than 1% Study 1014 Three Day Dosing Study 1014 Objectives Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 10 mg/kg/day for 3 days Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study 1014 Inclusion Criteria: Symptoms Symptoms consistent with AOM (but nonspecific) 2 Symptoms which help confirm the diagnosis of AOM (%) Age 261 X Fever 1 Children had one or more of these signs and symptoms 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) X Irritability 251 X Decreased hearing 601 X Ear fullness 921 X Ear pain (tugging or rubbing) 0.5-11yrs X >6 months 1014 1998 FDA Guidance Either Ear pain or fullness 97 Study 1014 Inclusion Criteria: Signs of Tympanic Membrane Involvement 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Study 1014 Key Exclusion Criteria Other exclusions include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, neutropenia, immunosuppressant therapy, cystic fibrosis, retraction pockets, cholesteatoma, phenylketonuria, anticipated use of probenecid or allopurinol Study 1014 Visits and Assessments *Patients who vomited within 30 minutes were redosed Study 1014 Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint: Day 28 Cure Failure Study 1014 Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Study 1014 Definition of Cure Study 1014 Patient Disposition Study 1014 Demographics Study 1014 Results Study 1014 Clinical Outcome 56 (31) 48 (26) Failure [-5, 15] 124 (69) 134 (74) Cure 180 182 Day 28 22 (12) 32 (17) Failure 45 53 Improvement 114 100 Cure [-13,3] 159 (88) 153 (83) Success 181 185 Day 10 185 188 Number of Patients 95% CI1 [%] Amox/Clav (%) Azithromycin (%) 1 95% CI for (azithromycin – comparator) Study 1014 Clinical Outcome at Day 28 by Age [-5, 18] (73) 94 (80) 99 Cure 128 124 > 2 years of age [-18, 23] (58) 30 (60) 35 Cure 52 58 < 2 years of age (%) N (%) N Amox/Clav Azithromycin 1 95% CI for (azithromycin – comparator) Failure Failure (27) 34 (20) 25 (42) 22 (40) 23 95% CI1 [%] Study 1014 Compliance Based on patients randomized to their study drug regimen
Slide 93 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997 Study 95-001 Experimental Design *Baseline tympanocentesis Study 95-001 Patient Disposition Study 95-001 Demographics 0% 2% Black 98% 97% White Race: 48% 56% % Male 2.3 (+ 1.4) 2.5 (+ 1.3) Mean Age (Yrs, ±SD) 31 (47%) 40 (61%) 2 Yrs - 12 Yrs 35 (53%) 26 (39%) < 2 Yrs Age: N = 66 Single Dose N = 66 Azithromycin 2% 95% 55% 2.7 (+ 1.5) 40 (61%) 26 (39%) Three Day N = 66 Ceftriaxone 2% 2% Hispanic 3% Study 95-001 Results Study 95-001 Clinical Efficacy Population 4 (6) Failure 5 Improvement [- 5, 25] 56 (86) Cure [-12,6] 61 (94) Success 65 Day 28 2 (3) Failure 36 Improvement 26 Cure [-8,5] 62 (97) Success 64 Day 14 66 Randomized Patients 95% CI1 [%] 1 Day (%) 1 95% CI for (single dose azithromycin – comparator) 5 (8) 10 51 (77) 61 (92) 66 3 (5) 42 18 60 (95) 63 66 3 Day (%) 2 (3) 13 49 (77) 62 (97) 64 1 (2) 40 21 61 (98) 62 66 Ceftriaxone (%) Azithromycin Study 95-001 Clinical Outcome at Day 28 by Age 5 (16) 6 (15) 3 (8) Failure 26 (84) 33 (85) 37 (93) Cure 31 39 40 > 2 years of age 10 (30) 9 (33) 6 (24) Failure 23 (70) 18 (67) 19 (76) Cure 33 27 25 < 2 years of age Ceftriaxone (%) 3 Day (%) 1 Day (%) Azithromycin Study 95-001 Susceptibility S. pneumoniae susceptibility (N=57) Azithromycin 46 susceptible 11 resistant (MIC > 0.5 mg/ml) Ceftriaxone All isolates were susceptible to ceftriaxone All H. influenzae and M. catarrhalis were susceptible to azithromycin and ceftriaxone Study 95-001 Clinical Cure Per Baseline Pathogen at Day 28 Study 95-001 Treatment Related Adverse Events* 0 (0) 0 (0) 3 (5) Vomiting 4 (6) 0 (0) 1 (2) Rash 4 (6) 3 (5) 2 (3) Diarrhea 6 (9) 6 (9) 7 (11) Patients w/ AE 66 66 66 Patients Treated Ceftriaxone 3 Day 1 Day 0 (0) 0 (0) 0 (0) Discontinued *2 or more events on any treatment regimen Azithromycin Study R-0581 Single Dose Therapy Study R-0581 Objective Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 30 mg/kg single oral dose Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study R-0581 Visits and Assessments *Patients who vomited within 30 minutes were redosed 1 Including parental questionnaire Study R-0581 Patient Disposition Study R-0581 Demographics Study R-0581 Results Study R-0581 Clinical Outcome 38 (25) 37 (25) Failure 8 2 Improvement [-7, 15] 108 (70) 112 (74) Cure [-10, 11] 116 (75) 114 (75) Success 154 151 Day 28 19 (12) 21 (13) Failure 21 34 Improvement 121 105 Cure [-9, 7] 142 (88) 139 (87) Success 161 160 Day 14 173 173 Number of Patients 95% CI1[%] Amox/Clav (%) Azithromycin (%) 1 95% CI for (azithromycin – comparator) Study R-0581 Clinical Outcome at Day 28 by Age Cure 26 (49) 24 (38) Failure [-8, 31] 95% CI1[%] Failure < 2 years of age 27 (51) 40 (63) Cure 53 64 > 2 years of age Amox/Clav Azithromycin 1 95% CI for (azithromycin – comparator) N (%) N (%) 72 (83) 15 (17) 87 81 (80) 20 (20) 101 [-10, 15] Study R-0581 Compliance Based on patients randomized to their study drug regimen Study R-0581 Treatment Related Adverse Events* 7 (4%) 7 (4%) Vomiting 9 (5%) 3 (2%) 22 (13%) 11 (6%) Diarrhea 39 (23%) 29 (17%) Patients w/ AEs Rash Azithromycin N = 173 Amox/Clav N = 173 7(4%) 4 (2%) Discontinued due to AE * Adverse Events greater than 2 percent in either regimen Study 1015 Single Dose Therapy Study 1015 Objectives To assess per-pathogen clinical response rates To provide additional data on the safety and toleration of the single dose regimen Design Prospective Open-label Non-comparative Multi-center Study 1015 Visits and Assessments *Patients who vomited within 30 minutes were redosed Study 1015 Endpoints Primary Efficacy Endpoint Clinical response by baseline pathogen at day 28 Initial local laboratory isolation of pathogen with confirmation by central laboratory Secondary Efficacy Endpoints Clinical response at day 28 (test of cure) Clinical response at day 10 Safety Evaluation Study 1015 Patient Disposition 242 Clinical at Day 28 127 Bacteriologic Efficacy Azithromycin 248 Safety 248 Enrolled Evaluation Groups Study 1015 Demographics Study 1015 Results Study 1015 Clinical Outcome 36 (15%) Failure [80,90] 206 (85%) Cure 242 Day 28 27 (11%) Failure 74 Improvement 139 Cure [85,93] 213 (89%) Success 240 Day 10 247 Number of Patients 95% CI1 [%] Azithromycin (%) 1 95% CI for azithromycin Study 1015 Clinical Outcome at Day 28 by Age 11 17 Failure [84, 94] 89 142 Cure 159 > 2 years of age 23 19 Failure [67, 87] 77 64 Cure 83 < 2 years of age 95% CI [%] (%) N Azithromycin Study 1015 Clinical Outcome - Per Baseline Pathogen Study 1015 MIC Distribution for S. pneumoniae (N=67) Percent of Patients Azithromycin MIC (mg/ml) Study 1015 Resistant S. Pneumoniae S. pneumoniae MIC = 8 g/ml 7 baseline isolates All sensitive to clindamycin All with mef A gene by PCR S. pneumoniae MIC >256 g/ml 5 baseline isolates All resistant to clindamycin All with erm B gene by PCR Study 1015 Day 28 Outcome and MIC Distribution for S. pneumoniae (N=66) # of Patients Azithromycin MIC (mg/ml) Study 1015 Patient 0067 Failed Therapy 1Susceptible to clindamycin; mef A gene identified 2Resistant to clindamycin; erm B gene identified Study 1015 Strains From Patient 0067 Are Clonally Distinct 1 2 3 4 MIC = 8 MIC >256 Study 1015 Outcome of S. pneumoniae AOM by Penicillin Susceptibility Penicillin Susceptibility *Penicillin MIC > 2 mg/ml **Penicillin MIC > 0.125 - < 2 mg/ml Study 1015 Outcome of S. pneumoniae AOM by Penicillin Susceptibility Penicillin Susceptibility *Penicillin MIC > 2 mg/ml **Penicillin MIC > 0.125 - < 2 mg/ml Study 1015 Treatment Related Adverse Events* (2) 4 Abdominal Pain (6) 14 Vomiting (3) 8 Diarrhea (12) 30 Patients w/ AEs (0) 1 Discontinued due to AEs 248 Patients Treated (%) N * Adverse Events greater than 1% Study 1014 Three Day Dosing Study 1014 Objectives Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 10 mg/kg/day for 3 days Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study 1014 Inclusion Criteria: Symptoms Symptoms consistent with AOM (but nonspecific) 2 Symptoms which help confirm the diagnosis of AOM (%) Age 261 X Fever 1 Children had one or more of these signs and symptoms 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) X Irritability 251 X Decreased hearing 601 X Ear fullness 921 X Ear pain (tugging or rubbing) 0.5-11yrs X >6 months 1014 1998 FDA Guidance Either Ear pain or fullness 97 Study 1014 Inclusion Criteria: Signs of Tympanic Membrane Involvement 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Study 1014 Key Exclusion Criteria Other exclusions include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, neutropenia, immunosuppressant therapy, cystic fibrosis, retraction pockets, cholesteatoma, phenylketonuria, anticipated use of probenecid or allopurinol Study 1014 Visits and Assessments *Patients who vomited within 30 minutes were redosed Study 1014 Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint: Day 28 Cure Failure Study 1014 Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Study 1014 Definition of Cure Study 1014 Patient Disposition Study 1014 Demographics Study 1014 Results Study 1014 Clinical Outcome 56 (31) 48 (26) Failure [-5, 15] 124 (69) 134 (74) Cure 180 182 Day 28 22 (12) 32 (17) Failure 45 53 Improvement 114 100 Cure [-13,3] 159 (88) 153 (83) Success 181 185 Day 10 185 188 Number of Patients 95% CI1 [%] Amox/Clav (%) Azithromycin (%) 1 95% CI for (azithromycin – comparator) Study 1014 Clinical Outcome at Day 28 by Age [-5, 18] (73) 94 (80) 99 Cure 128 124 > 2 years of age [-18, 23] (58) 30 (60) 35 Cure 52 58 < 2 years of age (%) N (%) N Amox/Clav Azithromycin 1 95% CI for (azithromycin – comparator) Failure Failure (27) 34 (20) 25 (42) 22 (40) 23 95% CI1 [%] Study 1014 Compliance Based on patients randomized to their study drug regimen Study 1014 Treatment Related Adverse Events* (15) (20) Azithromycin Amox/Clav Patients Treated Discontinued due to AE Patients with AE Diarrhea Vomiting Rash 1 20 11 4 0 2 37 27 2 8 N N (1) (11) (6) (2) (0) (4) (1) (1) % % 188 185 * Adverse events greater than 2% in either treatment regimen
Slide 94 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997 Study 95-001 Experimental Design *Baseline tympanocentesis Study 95-001 Patient Disposition Study 95-001 Demographics 0% 2% Black 98% 97% White Race: 48% 56% % Male 2.3 (+ 1.4) 2.5 (+ 1.3) Mean Age (Yrs, ±SD) 31 (47%) 40 (61%) 2 Yrs - 12 Yrs 35 (53%) 26 (39%) < 2 Yrs Age: N = 66 Single Dose N = 66 Azithromycin 2% 95% 55% 2.7 (+ 1.5) 40 (61%) 26 (39%) Three Day N = 66 Ceftriaxone 2% 2% Hispanic 3% Study 95-001 Results Study 95-001 Clinical Efficacy Population 4 (6) Failure 5 Improvement [- 5, 25] 56 (86) Cure [-12,6] 61 (94) Success 65 Day 28 2 (3) Failure 36 Improvement 26 Cure [-8,5] 62 (97) Success 64 Day 14 66 Randomized Patients 95% CI1 [%] 1 Day (%) 1 95% CI for (single dose azithromycin – comparator) 5 (8) 10 51 (77) 61 (92) 66 3 (5) 42 18 60 (95) 63 66 3 Day (%) 2 (3) 13 49 (77) 62 (97) 64 1 (2) 40 21 61 (98) 62 66 Ceftriaxone (%) Azithromycin Study 95-001 Clinical Outcome at Day 28 by Age 5 (16) 6 (15) 3 (8) Failure 26 (84) 33 (85) 37 (93) Cure 31 39 40 > 2 years of age 10 (30) 9 (33) 6 (24) Failure 23 (70) 18 (67) 19 (76) Cure 33 27 25 < 2 years of age Ceftriaxone (%) 3 Day (%) 1 Day (%) Azithromycin Study 95-001 Susceptibility S. pneumoniae susceptibility (N=57) Azithromycin 46 susceptible 11 resistant (MIC > 0.5 mg/ml) Ceftriaxone All isolates were susceptible to ceftriaxone All H. influenzae and M. catarrhalis were susceptible to azithromycin and ceftriaxone Study 95-001 Clinical Cure Per Baseline Pathogen at Day 28 Study 95-001 Treatment Related Adverse Events* 0 (0) 0 (0) 3 (5) Vomiting 4 (6) 0 (0) 1 (2) Rash 4 (6) 3 (5) 2 (3) Diarrhea 6 (9) 6 (9) 7 (11) Patients w/ AE 66 66 66 Patients Treated Ceftriaxone 3 Day 1 Day 0 (0) 0 (0) 0 (0) Discontinued *2 or more events on any treatment regimen Azithromycin Study R-0581 Single Dose Therapy Study R-0581 Objective Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 30 mg/kg single oral dose Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study R-0581 Visits and Assessments *Patients who vomited within 30 minutes were redosed 1 Including parental questionnaire Study R-0581 Patient Disposition Study R-0581 Demographics Study R-0581 Results Study R-0581 Clinical Outcome 38 (25) 37 (25) Failure 8 2 Improvement [-7, 15] 108 (70) 112 (74) Cure [-10, 11] 116 (75) 114 (75) Success 154 151 Day 28 19 (12) 21 (13) Failure 21 34 Improvement 121 105 Cure [-9, 7] 142 (88) 139 (87) Success 161 160 Day 14 173 173 Number of Patients 95% CI1[%] Amox/Clav (%) Azithromycin (%) 1 95% CI for (azithromycin – comparator) Study R-0581 Clinical Outcome at Day 28 by Age Cure 26 (49) 24 (38) Failure [-8, 31] 95% CI1[%] Failure < 2 years of age 27 (51) 40 (63) Cure 53 64 > 2 years of age Amox/Clav Azithromycin 1 95% CI for (azithromycin – comparator) N (%) N (%) 72 (83) 15 (17) 87 81 (80) 20 (20) 101 [-10, 15] Study R-0581 Compliance Based on patients randomized to their study drug regimen Study R-0581 Treatment Related Adverse Events* 7 (4%) 7 (4%) Vomiting 9 (5%) 3 (2%) 22 (13%) 11 (6%) Diarrhea 39 (23%) 29 (17%) Patients w/ AEs Rash Azithromycin N = 173 Amox/Clav N = 173 7(4%) 4 (2%) Discontinued due to AE * Adverse Events greater than 2 percent in either regimen Study 1015 Single Dose Therapy Study 1015 Objectives To assess per-pathogen clinical response rates To provide additional data on the safety and toleration of the single dose regimen Design Prospective Open-label Non-comparative Multi-center Study 1015 Visits and Assessments *Patients who vomited within 30 minutes were redosed Study 1015 Endpoints Primary Efficacy Endpoint Clinical response by baseline pathogen at day 28 Initial local laboratory isolation of pathogen with confirmation by central laboratory Secondary Efficacy Endpoints Clinical response at day 28 (test of cure) Clinical response at day 10 Safety Evaluation Study 1015 Patient Disposition 242 Clinical at Day 28 127 Bacteriologic Efficacy Azithromycin 248 Safety 248 Enrolled Evaluation Groups Study 1015 Demographics Study 1015 Results Study 1015 Clinical Outcome 36 (15%) Failure [80,90] 206 (85%) Cure 242 Day 28 27 (11%) Failure 74 Improvement 139 Cure [85,93] 213 (89%) Success 240 Day 10 247 Number of Patients 95% CI1 [%] Azithromycin (%) 1 95% CI for azithromycin Study 1015 Clinical Outcome at Day 28 by Age 11 17 Failure [84, 94] 89 142 Cure 159 > 2 years of age 23 19 Failure [67, 87] 77 64 Cure 83 < 2 years of age 95% CI [%] (%) N Azithromycin Study 1015 Clinical Outcome - Per Baseline Pathogen Study 1015 MIC Distribution for S. pneumoniae (N=67) Percent of Patients Azithromycin MIC (mg/ml) Study 1015 Resistant S. Pneumoniae S. pneumoniae MIC = 8 g/ml 7 baseline isolates All sensitive to clindamycin All with mef A gene by PCR S. pneumoniae MIC >256 g/ml 5 baseline isolates All resistant to clindamycin All with erm B gene by PCR Study 1015 Day 28 Outcome and MIC Distribution for S. pneumoniae (N=66) # of Patients Azithromycin MIC (mg/ml) Study 1015 Patient 0067 Failed Therapy 1Susceptible to clindamycin; mef A gene identified 2Resistant to clindamycin; erm B gene identified Study 1015 Strains From Patient 0067 Are Clonally Distinct 1 2 3 4 MIC = 8 MIC >256 Study 1015 Outcome of S. pneumoniae AOM by Penicillin Susceptibility Penicillin Susceptibility *Penicillin MIC > 2 mg/ml **Penicillin MIC > 0.125 - < 2 mg/ml Study 1015 Outcome of S. pneumoniae AOM by Penicillin Susceptibility Penicillin Susceptibility *Penicillin MIC > 2 mg/ml **Penicillin MIC > 0.125 - < 2 mg/ml Study 1015 Treatment Related Adverse Events* (2) 4 Abdominal Pain (6) 14 Vomiting (3) 8 Diarrhea (12) 30 Patients w/ AEs (0) 1 Discontinued due to AEs 248 Patients Treated (%) N * Adverse Events greater than 1% Study 1014 Three Day Dosing Study 1014 Objectives Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 10 mg/kg/day for 3 days Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study 1014 Inclusion Criteria: Symptoms Symptoms consistent with AOM (but nonspecific) 2 Symptoms which help confirm the diagnosis of AOM (%) Age 261 X Fever 1 Children had one or more of these signs and symptoms 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) X Irritability 251 X Decreased hearing 601 X Ear fullness 921 X Ear pain (tugging or rubbing) 0.5-11yrs X >6 months 1014 1998 FDA Guidance Either Ear pain or fullness 97 Study 1014 Inclusion Criteria: Signs of Tympanic Membrane Involvement 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Study 1014 Key Exclusion Criteria Other exclusions include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, neutropenia, immunosuppressant therapy, cystic fibrosis, retraction pockets, cholesteatoma, phenylketonuria, anticipated use of probenecid or allopurinol Study 1014 Visits and Assessments *Patients who vomited within 30 minutes were redosed Study 1014 Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint: Day 28 Cure Failure Study 1014 Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Study 1014 Definition of Cure Study 1014 Patient Disposition Study 1014 Demographics Study 1014 Results Study 1014 Clinical Outcome 56 (31) 48 (26) Failure [-5, 15] 124 (69) 134 (74) Cure 180 182 Day 28 22 (12) 32 (17) Failure 45 53 Improvement 114 100 Cure [-13,3] 159 (88) 153 (83) Success 181 185 Day 10 185 188 Number of Patients 95% CI1 [%] Amox/Clav (%) Azithromycin (%) 1 95% CI for (azithromycin – comparator) Study 1014 Clinical Outcome at Day 28 by Age [-5, 18] (73) 94 (80) 99 Cure 128 124 > 2 years of age [-18, 23] (58) 30 (60) 35 Cure 52 58 < 2 years of age (%) N (%) N Amox/Clav Azithromycin 1 95% CI for (azithromycin – comparator) Failure Failure (27) 34 (20) 25 (42) 22 (40) 23 95% CI1 [%] Study 1014 Compliance Based on patients randomized to their study drug regimen Study 1014 Treatment Related Adverse Events* (15) (20) Azithromycin Amox/Clav Patients Treated Discontinued due to AE Patients with AE Diarrhea Vomiting Rash 1 20 11 4 0 2 37 27 2 8 N N (1) (11) (6) (2) (0) (4) (1) (1) % % 188 185 * Adverse events greater than 2% in either treatment regimen Summary of Clinical Data
Slide 95 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997 Study 95-001 Experimental Design *Baseline tympanocentesis Study 95-001 Patient Disposition Study 95-001 Demographics 0% 2% Black 98% 97% White Race: 48% 56% % Male 2.3 (+ 1.4) 2.5 (+ 1.3) Mean Age (Yrs, ±SD) 31 (47%) 40 (61%) 2 Yrs - 12 Yrs 35 (53%) 26 (39%) < 2 Yrs Age: N = 66 Single Dose N = 66 Azithromycin 2% 95% 55% 2.7 (+ 1.5) 40 (61%) 26 (39%) Three Day N = 66 Ceftriaxone 2% 2% Hispanic 3% Study 95-001 Results Study 95-001 Clinical Efficacy Population 4 (6) Failure 5 Improvement [- 5, 25] 56 (86) Cure [-12,6] 61 (94) Success 65 Day 28 2 (3) Failure 36 Improvement 26 Cure [-8,5] 62 (97) Success 64 Day 14 66 Randomized Patients 95% CI1 [%] 1 Day (%) 1 95% CI for (single dose azithromycin – comparator) 5 (8) 10 51 (77) 61 (92) 66 3 (5) 42 18 60 (95) 63 66 3 Day (%) 2 (3) 13 49 (77) 62 (97) 64 1 (2) 40 21 61 (98) 62 66 Ceftriaxone (%) Azithromycin Study 95-001 Clinical Outcome at Day 28 by Age 5 (16) 6 (15) 3 (8) Failure 26 (84) 33 (85) 37 (93) Cure 31 39 40 > 2 years of age 10 (30) 9 (33) 6 (24) Failure 23 (70) 18 (67) 19 (76) Cure 33 27 25 < 2 years of age Ceftriaxone (%) 3 Day (%) 1 Day (%) Azithromycin Study 95-001 Susceptibility S. pneumoniae susceptibility (N=57) Azithromycin 46 susceptible 11 resistant (MIC > 0.5 mg/ml) Ceftriaxone All isolates were susceptible to ceftriaxone All H. influenzae and M. catarrhalis were susceptible to azithromycin and ceftriaxone Study 95-001 Clinical Cure Per Baseline Pathogen at Day 28 Study 95-001 Treatment Related Adverse Events* 0 (0) 0 (0) 3 (5) Vomiting 4 (6) 0 (0) 1 (2) Rash 4 (6) 3 (5) 2 (3) Diarrhea 6 (9) 6 (9) 7 (11) Patients w/ AE 66 66 66 Patients Treated Ceftriaxone 3 Day 1 Day 0 (0) 0 (0) 0 (0) Discontinued *2 or more events on any treatment regimen Azithromycin Study R-0581 Single Dose Therapy Study R-0581 Objective Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 30 mg/kg single oral dose Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study R-0581 Visits and Assessments *Patients who vomited within 30 minutes were redosed 1 Including parental questionnaire Study R-0581 Patient Disposition Study R-0581 Demographics Study R-0581 Results Study R-0581 Clinical Outcome 38 (25) 37 (25) Failure 8 2 Improvement [-7, 15] 108 (70) 112 (74) Cure [-10, 11] 116 (75) 114 (75) Success 154 151 Day 28 19 (12) 21 (13) Failure 21 34 Improvement 121 105 Cure [-9, 7] 142 (88) 139 (87) Success 161 160 Day 14 173 173 Number of Patients 95% CI1[%] Amox/Clav (%) Azithromycin (%) 1 95% CI for (azithromycin – comparator) Study R-0581 Clinical Outcome at Day 28 by Age Cure 26 (49) 24 (38) Failure [-8, 31] 95% CI1[%] Failure < 2 years of age 27 (51) 40 (63) Cure 53 64 > 2 years of age Amox/Clav Azithromycin 1 95% CI for (azithromycin – comparator) N (%) N (%) 72 (83) 15 (17) 87 81 (80) 20 (20) 101 [-10, 15] Study R-0581 Compliance Based on patients randomized to their study drug regimen Study R-0581 Treatment Related Adverse Events* 7 (4%) 7 (4%) Vomiting 9 (5%) 3 (2%) 22 (13%) 11 (6%) Diarrhea 39 (23%) 29 (17%) Patients w/ AEs Rash Azithromycin N = 173 Amox/Clav N = 173 7(4%) 4 (2%) Discontinued due to AE * Adverse Events greater than 2 percent in either regimen Study 1015 Single Dose Therapy Study 1015 Objectives To assess per-pathogen clinical response rates To provide additional data on the safety and toleration of the single dose regimen Design Prospective Open-label Non-comparative Multi-center Study 1015 Visits and Assessments *Patients who vomited within 30 minutes were redosed Study 1015 Endpoints Primary Efficacy Endpoint Clinical response by baseline pathogen at day 28 Initial local laboratory isolation of pathogen with confirmation by central laboratory Secondary Efficacy Endpoints Clinical response at day 28 (test of cure) Clinical response at day 10 Safety Evaluation Study 1015 Patient Disposition 242 Clinical at Day 28 127 Bacteriologic Efficacy Azithromycin 248 Safety 248 Enrolled Evaluation Groups Study 1015 Demographics Study 1015 Results Study 1015 Clinical Outcome 36 (15%) Failure [80,90] 206 (85%) Cure 242 Day 28 27 (11%) Failure 74 Improvement 139 Cure [85,93] 213 (89%) Success 240 Day 10 247 Number of Patients 95% CI1 [%] Azithromycin (%) 1 95% CI for azithromycin Study 1015 Clinical Outcome at Day 28 by Age 11 17 Failure [84, 94] 89 142 Cure 159 > 2 years of age 23 19 Failure [67, 87] 77 64 Cure 83 < 2 years of age 95% CI [%] (%) N Azithromycin Study 1015 Clinical Outcome - Per Baseline Pathogen Study 1015 MIC Distribution for S. pneumoniae (N=67) Percent of Patients Azithromycin MIC (mg/ml) Study 1015 Resistant S. Pneumoniae S. pneumoniae MIC = 8 g/ml 7 baseline isolates All sensitive to clindamycin All with mef A gene by PCR S. pneumoniae MIC >256 g/ml 5 baseline isolates All resistant to clindamycin All with erm B gene by PCR Study 1015 Day 28 Outcome and MIC Distribution for S. pneumoniae (N=66) # of Patients Azithromycin MIC (mg/ml) Study 1015 Patient 0067 Failed Therapy 1Susceptible to clindamycin; mef A gene identified 2Resistant to clindamycin; erm B gene identified Study 1015 Strains From Patient 0067 Are Clonally Distinct 1 2 3 4 MIC = 8 MIC >256 Study 1015 Outcome of S. pneumoniae AOM by Penicillin Susceptibility Penicillin Susceptibility *Penicillin MIC > 2 mg/ml **Penicillin MIC > 0.125 - < 2 mg/ml Study 1015 Outcome of S. pneumoniae AOM by Penicillin Susceptibility Penicillin Susceptibility *Penicillin MIC > 2 mg/ml **Penicillin MIC > 0.125 - < 2 mg/ml Study 1015 Treatment Related Adverse Events* (2) 4 Abdominal Pain (6) 14 Vomiting (3) 8 Diarrhea (12) 30 Patients w/ AEs (0) 1 Discontinued due to AEs 248 Patients Treated (%) N * Adverse Events greater than 1% Study 1014 Three Day Dosing Study 1014 Objectives Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 10 mg/kg/day for 3 days Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study 1014 Inclusion Criteria: Symptoms Symptoms consistent with AOM (but nonspecific) 2 Symptoms which help confirm the diagnosis of AOM (%) Age 261 X Fever 1 Children had one or more of these signs and symptoms 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) X Irritability 251 X Decreased hearing 601 X Ear fullness 921 X Ear pain (tugging or rubbing) 0.5-11yrs X >6 months 1014 1998 FDA Guidance Either Ear pain or fullness 97 Study 1014 Inclusion Criteria: Signs of Tympanic Membrane Involvement 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Study 1014 Key Exclusion Criteria Other exclusions include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, neutropenia, immunosuppressant therapy, cystic fibrosis, retraction pockets, cholesteatoma, phenylketonuria, anticipated use of probenecid or allopurinol Study 1014 Visits and Assessments *Patients who vomited within 30 minutes were redosed Study 1014 Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint: Day 28 Cure Failure Study 1014 Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Study 1014 Definition of Cure Study 1014 Patient Disposition Study 1014 Demographics Study 1014 Results Study 1014 Clinical Outcome 56 (31) 48 (26) Failure [-5, 15] 124 (69) 134 (74) Cure 180 182 Day 28 22 (12) 32 (17) Failure 45 53 Improvement 114 100 Cure [-13,3] 159 (88) 153 (83) Success 181 185 Day 10 185 188 Number of Patients 95% CI1 [%] Amox/Clav (%) Azithromycin (%) 1 95% CI for (azithromycin – comparator) Study 1014 Clinical Outcome at Day 28 by Age [-5, 18] (73) 94 (80) 99 Cure 128 124 > 2 years of age [-18, 23] (58) 30 (60) 35 Cure 52 58 < 2 years of age (%) N (%) N Amox/Clav Azithromycin 1 95% CI for (azithromycin – comparator) Failure Failure (27) 34 (20) 25 (42) 22 (40) 23 95% CI1 [%] Study 1014 Compliance Based on patients randomized to their study drug regimen Study 1014 Treatment Related Adverse Events* (15) (20) Azithromycin Amox/Clav Patients Treated Discontinued due to AE Patients with AE Diarrhea Vomiting Rash 1 20 11 4 0 2 37 27 2 8 N N (1) (11) (6) (2) (0) (4) (1) (1) % % 188 185 * Adverse events greater than 2% in either treatment regimen Summary of Clinical Data Acute Otitis Media Summary Clinical Cure at Day 28 [-5, 25] [-15, 17] 49/64 (77%) 56/65 (86%) 51/66 (77%) 95-001 AzSD-CTX Az3D-CTX [-5, 15] 124/180 (69%) 134/182 (74%) 1014 Az-Amox/Clav 206/242 (85%) 1015 [-7, 15] 108/154 (70%) 112/151 (74%) R-0581 Az-Amox/Clav 95% CI Comparator Azithromycin Single Dose Azithromycin 3 Day Study
Slide 96 - Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM Pharmacokinetic profile suited for treatment of infection Reaches effective concentrations in middle ear Sustained concentrations in white blood cells Complete course of therapy in single dose Optimizes compliance Well tolerated, safe antibiotic Recommended in penicillin allergic patients Over 40 million prescriptions for oral suspension Clinical efficacy equivalent to approved therapies Originally established in five day regimen Extended to shorter regimens of three day and single dosing Advantages of Single Dose Azithromycin Provides best drug levels early in course of infection Takes advantage of important host defenses Maximal neutrophil recruitment optimizes azithromycin delivery Febrile response increases azithromycin uptake1 Maximizes rate of compliance Minimizes burden on caregiver 1Fietta, et al., J. Chemotherapy 1997 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: The First Azalide Antibiotic H3C H3 C H3 C H3C H3 C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Data Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics Microbiology Clinical Program Overview of Five Day Program Single Dose Three Day Dosing Focus on Selected Topics Conclusion Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media Five Day Dosing 30 mg/kg: 10 mg/kg then 5,5,5,5 Approved in United States in 1995 Three Day Dosing 30 mg/kg: 10 mg/kg qd X 3 Approved in Europe in 1990 Single Dose Therapy 30 mg/kg: given as single dose 1998 FDA Guidance Acute Otitis Media “Clinical-only” Trial One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study Baseline tympanocentesis performed Compares three day dosing with single dose therapy with ceftriaxone Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) Single Dose Program Inclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Single Dose Program Key Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint (Test of Cure): Day 28 Cure Failure Improvement (R-0581 and 95-001) Single Dose Program Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Bacteriological Efficacy Population Positive baseline culture for at least one relevant pathogen Single Dose Program Definition of Cure Study 95-001 Study 95-001 Methods Objectives Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media Design Prospective Single-center in Costa Rica Performed in 1995-1997 Study 95-001 Experimental Design *Baseline tympanocentesis Study 95-001 Patient Disposition Study 95-001 Demographics 0% 2% Black 98% 97% White Race: 48% 56% % Male 2.3 (+ 1.4) 2.5 (+ 1.3) Mean Age (Yrs, ±SD) 31 (47%) 40 (61%) 2 Yrs - 12 Yrs 35 (53%) 26 (39%) < 2 Yrs Age: N = 66 Single Dose N = 66 Azithromycin 2% 95% 55% 2.7 (+ 1.5) 40 (61%) 26 (39%) Three Day N = 66 Ceftriaxone 2% 2% Hispanic 3% Study 95-001 Results Study 95-001 Clinical Efficacy Population 4 (6) Failure 5 Improvement [- 5, 25] 56 (86) Cure [-12,6] 61 (94) Success 65 Day 28 2 (3) Failure 36 Improvement 26 Cure [-8,5] 62 (97) Success 64 Day 14 66 Randomized Patients 95% CI1 [%] 1 Day (%) 1 95% CI for (single dose azithromycin – comparator) 5 (8) 10 51 (77) 61 (92) 66 3 (5) 42 18 60 (95) 63 66 3 Day (%) 2 (3) 13 49 (77) 62 (97) 64 1 (2) 40 21 61 (98) 62 66 Ceftriaxone (%) Azithromycin Study 95-001 Clinical Outcome at Day 28 by Age 5 (16) 6 (15) 3 (8) Failure 26 (84) 33 (85) 37 (93) Cure 31 39 40 > 2 years of age 10 (30) 9 (33) 6 (24) Failure 23 (70) 18 (67) 19 (76) Cure 33 27 25 < 2 years of age Ceftriaxone (%) 3 Day (%) 1 Day (%) Azithromycin Study 95-001 Susceptibility S. pneumoniae susceptibility (N=57) Azithromycin 46 susceptible 11 resistant (MIC > 0.5 mg/ml) Ceftriaxone All isolates were susceptible to ceftriaxone All H. influenzae and M. catarrhalis were susceptible to azithromycin and ceftriaxone Study 95-001 Clinical Cure Per Baseline Pathogen at Day 28 Study 95-001 Treatment Related Adverse Events* 0 (0) 0 (0) 3 (5) Vomiting 4 (6) 0 (0) 1 (2) Rash 4 (6) 3 (5) 2 (3) Diarrhea 6 (9) 6 (9) 7 (11) Patients w/ AE 66 66 66 Patients Treated Ceftriaxone 3 Day 1 Day 0 (0) 0 (0) 0 (0) Discontinued *2 or more events on any treatment regimen Azithromycin Study R-0581 Single Dose Therapy Study R-0581 Objective Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 30 mg/kg single oral dose Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study R-0581 Visits and Assessments *Patients who vomited within 30 minutes were redosed 1 Including parental questionnaire Study R-0581 Patient Disposition Study R-0581 Demographics Study R-0581 Results Study R-0581 Clinical Outcome 38 (25) 37 (25) Failure 8 2 Improvement [-7, 15] 108 (70) 112 (74) Cure [-10, 11] 116 (75) 114 (75) Success 154 151 Day 28 19 (12) 21 (13) Failure 21 34 Improvement 121 105 Cure [-9, 7] 142 (88) 139 (87) Success 161 160 Day 14 173 173 Number of Patients 95% CI1[%] Amox/Clav (%) Azithromycin (%) 1 95% CI for (azithromycin – comparator) Study R-0581 Clinical Outcome at Day 28 by Age Cure 26 (49) 24 (38) Failure [-8, 31] 95% CI1[%] Failure < 2 years of age 27 (51) 40 (63) Cure 53 64 > 2 years of age Amox/Clav Azithromycin 1 95% CI for (azithromycin – comparator) N (%) N (%) 72 (83) 15 (17) 87 81 (80) 20 (20) 101 [-10, 15] Study R-0581 Compliance Based on patients randomized to their study drug regimen Study R-0581 Treatment Related Adverse Events* 7 (4%) 7 (4%) Vomiting 9 (5%) 3 (2%) 22 (13%) 11 (6%) Diarrhea 39 (23%) 29 (17%) Patients w/ AEs Rash Azithromycin N = 173 Amox/Clav N = 173 7(4%) 4 (2%) Discontinued due to AE * Adverse Events greater than 2 percent in either regimen Study 1015 Single Dose Therapy Study 1015 Objectives To assess per-pathogen clinical response rates To provide additional data on the safety and toleration of the single dose regimen Design Prospective Open-label Non-comparative Multi-center Study 1015 Visits and Assessments *Patients who vomited within 30 minutes were redosed Study 1015 Endpoints Primary Efficacy Endpoint Clinical response by baseline pathogen at day 28 Initial local laboratory isolation of pathogen with confirmation by central laboratory Secondary Efficacy Endpoints Clinical response at day 28 (test of cure) Clinical response at day 10 Safety Evaluation Study 1015 Patient Disposition 242 Clinical at Day 28 127 Bacteriologic Efficacy Azithromycin 248 Safety 248 Enrolled Evaluation Groups Study 1015 Demographics Study 1015 Results Study 1015 Clinical Outcome 36 (15%) Failure [80,90] 206 (85%) Cure 242 Day 28 27 (11%) Failure 74 Improvement 139 Cure [85,93] 213 (89%) Success 240 Day 10 247 Number of Patients 95% CI1 [%] Azithromycin (%) 1 95% CI for azithromycin Study 1015 Clinical Outcome at Day 28 by Age 11 17 Failure [84, 94] 89 142 Cure 159 > 2 years of age 23 19 Failure [67, 87] 77 64 Cure 83 < 2 years of age 95% CI [%] (%) N Azithromycin Study 1015 Clinical Outcome - Per Baseline Pathogen Study 1015 MIC Distribution for S. pneumoniae (N=67) Percent of Patients Azithromycin MIC (mg/ml) Study 1015 Resistant S. Pneumoniae S. pneumoniae MIC = 8 g/ml 7 baseline isolates All sensitive to clindamycin All with mef A gene by PCR S. pneumoniae MIC >256 g/ml 5 baseline isolates All resistant to clindamycin All with erm B gene by PCR Study 1015 Day 28 Outcome and MIC Distribution for S. pneumoniae (N=66) # of Patients Azithromycin MIC (mg/ml) Study 1015 Patient 0067 Failed Therapy 1Susceptible to clindamycin; mef A gene identified 2Resistant to clindamycin; erm B gene identified Study 1015 Strains From Patient 0067 Are Clonally Distinct 1 2 3 4 MIC = 8 MIC >256 Study 1015 Outcome of S. pneumoniae AOM by Penicillin Susceptibility Penicillin Susceptibility *Penicillin MIC > 2 mg/ml **Penicillin MIC > 0.125 - < 2 mg/ml Study 1015 Outcome of S. pneumoniae AOM by Penicillin Susceptibility Penicillin Susceptibility *Penicillin MIC > 2 mg/ml **Penicillin MIC > 0.125 - < 2 mg/ml Study 1015 Treatment Related Adverse Events* (2) 4 Abdominal Pain (6) 14 Vomiting (3) 8 Diarrhea (12) 30 Patients w/ AEs (0) 1 Discontinued due to AEs 248 Patients Treated (%) N * Adverse Events greater than 1% Study 1014 Three Day Dosing Study 1014 Objectives Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM Design Multicenter, randomized All sites in the United States Double blind, double dummy Azithromycin: 10 mg/kg/day for 3 days Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days Matching placebo for each active study drug Study 1014 Inclusion Criteria: Symptoms Symptoms consistent with AOM (but nonspecific) 2 Symptoms which help confirm the diagnosis of AOM (%) Age 261 X Fever 1 Children had one or more of these signs and symptoms 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) X Irritability 251 X Decreased hearing 601 X Ear fullness 921 X Ear pain (tugging or rubbing) 0.5-11yrs X >6 months 1014 1998 FDA Guidance Either Ear pain or fullness 97 Study 1014 Inclusion Criteria: Signs of Tympanic Membrane Involvement 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Study 1014 Key Exclusion Criteria Other exclusions include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, neutropenia, immunosuppressant therapy, cystic fibrosis, retraction pockets, cholesteatoma, phenylketonuria, anticipated use of probenecid or allopurinol Study 1014 Visits and Assessments *Patients who vomited within 30 minutes were redosed Study 1014 Statistical Methods Primary Endpoint: Clinical Cure Primary Timepoint: Day 28 Cure Failure Study 1014 Statistical Methods Clinical Efficacy Population At least one dose of study medication Diagnosis of AOM at baseline Analyzed at Day 28 Return for visit at Day 28 Concomitant antibiotic for failure counts as failure Study 1014 Definition of Cure Study 1014 Patient Disposition Study 1014 Demographics Study 1014 Results Study 1014 Clinical Outcome 56 (31) 48 (26) Failure [-5, 15] 124 (69) 134 (74) Cure 180 182 Day 28 22 (12) 32 (17) Failure 45 53 Improvement 114 100 Cure [-13,3] 159 (88) 153 (83) Success 181 185 Day 10 185 188 Number of Patients 95% CI1 [%] Amox/Clav (%) Azithromycin (%) 1 95% CI for (azithromycin – comparator) Study 1014 Clinical Outcome at Day 28 by Age [-5, 18] (73) 94 (80) 99 Cure 128 124 > 2 years of age [-18, 23] (58) 30 (60) 35 Cure 52 58 < 2 years of age (%) N (%) N Amox/Clav Azithromycin 1 95% CI for (azithromycin – comparator) Failure Failure (27) 34 (20) 25 (42) 22 (40) 23 95% CI1 [%] Study 1014 Compliance Based on patients randomized to their study drug regimen Study 1014 Treatment Related Adverse Events* (15) (20) Azithromycin Amox/Clav Patients Treated Discontinued due to AE Patients with AE Diarrhea Vomiting Rash 1 20 11 4 0 2 37 27 2 8 N N (1) (11) (6) (2) (0) (4) (1) (1) % % 188 185 * Adverse events greater than 2% in either treatment regimen Summary of Clinical Data Acute Otitis Media Summary Clinical Cure at Day 28 [-5, 25] [-15, 17] 49/64 (77%) 56/65 (86%) 51/66 (77%) 95-001 AzSD-CTX Az3D-CTX [-5, 15] 124/180 (69%) 134/182 (74%) 1014 Az-Amox/Clav 206/242 (85%)