S. aureus Bacteremia and Endocarditis Study Efficacy Results - PowerPoint PPT Presentation

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S. aureus Bacteremia and Endocarditis Study Efficacy Results

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  1. S. aureus Bacteremia and Endocarditis Study Efficacy Results Helen Whamond Boucher, MD Assistant Professor of Medicine Director, Infectious Diseases Fellowship Program Division of Infectious Diseases and Geographic Medicine Tufts University - New England Medical Center Boston, Massachusetts

  2. Study Objective and Statistical Considerations • Hypothesis tested • Daptomycin is not inferior to standard therapy in the treatment of S. aureus bacteremia and infective endocarditis as assessed by Adjudication Committee outcome at Test of Cure (TOC) • Non-inferiority design • Sample size calculation • 80% power • Delta 20% • Assumed 65% success rates in both groups • ITT required 90 per arm

  3. Key Inclusion and Exclusion Criteria • Inclusion criteria • Written informed consent •  18 years of age • Documented S. aureus bacteremia • Exclusion criteria • Intravascular foreign material • Prosthetic heart valve • Creatinine clearance < 30 mL/minute • Known pneumonia, osteomyelitis • Polymicrobial bacteremia • Moribund

  4. Blood Culture+ S. aureus Work-up includes TEE within 5 days End of Therapy (EOT) Test of Cure (TOC) 6 weeks -2 Daptomycin 6 mg/kg IV q24h Outcome Outcome PrimaryEndpoint • Comparator • Vancomycin 1 g IV q12h+ Gentamicin 1 mg/kg IV q8h x 4 days • Anti-staphylococcal penicillin 2 g IV q4h+ Gentamicin 1 mg/kg IV q8h x 4 days Study Design

  5. Entry Diagnosis using Modified Duke Criteria • Definite Endocarditis • Possible Endocarditis • Not Endocarditis • Final Diagnosis • Uncomplicated Bacteremia • Complicated Bacteremia • Right-sided Endocarditis • Left-sided Endocarditis End of Therapy (EOT) Test of Cure (TOC) 6 weeks -2 Outcome Outcome PrimaryEndpoint Blinded Independent External Adjudication Committee

  6. Outcome Definitions Success (all of the following required) • Clinically cured or improved • Negative blood culture • Did not receive a potentially effective non-study antibiotic • Received minimum amount of study medication per Investigator Failure (any of the following) • Persisting or relapsing S. aureus • Death • Clinical failure • Received a potentially effective non-study antibiotic • Discontinued study medication prematurely due to either: • Adverse event • Microbiological failure • Clinical failure • No blood culture at Test of Cure

  7. S. aureus Bacteremia and Endocarditis Study Results

  8. Study Conduct • 44 sites treated patients; 4 countries • August 2002 - February 2005 • 236 treated • 200 US • 36 EU • Resource intensive for investigators and patients • Amendment to allow LIE April 2004

  9. 246Randomized Daptomycin Comparator 122 124 Did not receive study drug 116 120 Safety population LIE prior to amendment to allow LIE 115 120 Intent-To-Treat population Protocol adherence criteria 60 79 Per-Protocol population Patient Disposition

  10. Study Compliance (ITT) 235 Patients in ITT 157 Completed therapy 78 Withdrawn from therapy 148 Met TOC visit requirements 9 No contact or culture at TOC 69 Completed studyrequirements 9 W/D consent or lost to follow-up 217/235 (92.3%) completed study requirements

  11. Demographics (ITT)

  12. Infecting Pathogen and Risk Factors (ITT)

  13. Pre-specified Efficacy Analyses • Primary efficacy endpoint • Success at Test of Cure • Success in subgroups • MRSA/MSSA • Entry diagnosis • Final diagnosis • Success at End of Therapy

  14. Difference in Success Rates (95% CI): 2.4% (-10.2, 15.1) Difference in Success Rates (95% CI): 1.1% (-15.6, 17.8) 70 Daptomycin 60 Comparator 54.4 53.3 50 44.2 41.7 40 % Success 3260 43 79 30 53 120 48 115 20 10 0 ITT PP Primary Endpoint: Success at Test of Cure per Adjudication Committee (ITT/PP)

  15. Difference in Success Rates (95% CI): 11.9% (-8.3, 32.1) Difference in Success Rates (95% CI): -2.1% (-19.0, 14.9) Daptomycin Vancomycin SSP 46.7 32.6 20 45 14 43 33 74 2860 MRSA and MSSA Success at Test of Cure:Pathogen Specific Therapy per Adjudication Committee (ITT) 70 60 50 44.6 44.4 40 % Success 30 20 10 0 MRSA MSSA

  16. Daptomycin GroupN = 120 Comparator GroupN = 115 Definite IE14% Definite IE17% Not IE 25% Not IE 21% Possible IE61% Possible IE62% Entry Diagnosis per Adjudication Committee (ITT)

  17. 70 60 Daptomycin Comparator 45.6 45.8 50 40.7 40.0 40 % Success 30 20 10 4190 3791 1230 1124 0 Definite or PossibleEndocarditis Not Endocarditis Entry Diagnosis: Success at Test of Cure per Adjudication Committee (ITT)

  18. Daptomycin GroupN = 120 Comparator GroupN = 115 LIE8% LIE8% RIE16% RIE14% uBAC27% uBAC25% cBAC50% cBAC53% Final Diagnosis per Adjudication Committee (ITT)

  19. Daptomycin Comparator 19 29 26 60 23 61 8 19 716 18 32 16 29 Final Diagnosis: Success at Test of Cure per Adjudication Committee (ITT) 70 56.3 60 55.2 50 43.8 43.3 42.1 37.7 40 % Success 30 22.2 20 11.1 10 0 uBAC cBAC RIE LIE

  20. Daptomycin Comparator 819 716 914 816 Right Sided Endocarditis: Success at Test of Cure (ITT) 70 64.3 60 50.0 50 43.8 42.1 40 % Success 30 20 10 0 Adjudication Committee Investigator

  21. Left Sided Endocarditis (ITT) Comparator patient 001 entered study with LIE prior to LIE amendment Success at EOT, failed at TOC due to sepsis and death (no valve replacement surgery)

  22. 70 61.7 60.9 60 Daptomycin Comparator 50 44.2 41.7 40 % Success 30 70 115 53 120 48 115 74 120 20 10 0 End of Therapy Test of Cure End of Therapy and Test of Cure: Success per Adjudication Committee (ITT)

  23. Secondary Endpoint: Time to Clearance of S. aureus Bacteremia (ITT) Daptomycin (N = 62) Comparator (N = 65) 1.0 0.9 0.8 Wilcoxon p = 0.165 0.7 0.6 0.5 Probability of Clearance 0.4 0.3 0.2 0.1 0.0 0 10 20 30 40 50 60 70 Time (Days)

  24. All Reasons for Failure at Test of Cure (ITT)

  25. Failure Due to Persisting/Relapsing S. aureusEmergence of Reduced Susceptibility to Daptomycin

  26. Vancomycin Failures With MIC  2 • 1 vancomycin patient failed with vancomycin MIC 2 µg/mL at Central Lab • Failed due to persisting or relapsing S. aureus • 5 additional vancomycin patients failed with vancomycin MIC  2 µg/mL at Local Lab • 3 failed due to persisting or relapsing S. aureus Sakoulas et al. JCM 2004.

  27. Sensitivity Analysis: Treatment-limiting Adverse Events Not Considered Failure (ITT TOC)

  28. Sensitivity Analyses (ITT TOC) Success considering failure based only on Daptomycin N = 120 n (%) Comparator N = 115 n (%) Differences In Success Rates (95% CI) Non-evaluable 111 (92.5) 101 (87.8) N/A

  29. Sensitivity Analyses (ITT TOC) Success considering failure based only on Daptomycin N = 120 n (%) Comparator N = 115 n (%) Differences In Success Rates (95% CI) Non-evaluable 111 (92.5) 101 (87.8) N/A Persisting/relapsing S. aureus (PRSA) 92 (76.7) 90 (78.3) -1.6% (-12.3, 9.1)

  30. Sensitivity Analyses (ITT TOC) Success considering failure based only on Daptomycin N = 120 n (%) Comparator N = 115 n (%) Differences In Success Rates (95% CI) Non-evaluable 111 (92.5) 101 (87.8) N/A Persisting/relapsing S. aureus (PRSA) 92 (76.7) 90 (78.3) -1.6% (-12.3, 9.1) +Death 86 (71.7) 81 (70.4) 1.2% (-10.4, 12.8)

  31. Sensitivity Analyses (ITT TOC) Success considering failure based only on Daptomycin N = 120 n (%) Comparator N = 115 n (%) Differences In Success Rates (95% CI) Non-evaluable 111 (92.5) 101 (87.8) N/A Persisting/relapsing S. aureus (PRSA) 92 (76.7) 90 (78.3) -1.6% (-12.3, 9.1) +Death 86 (71.7) 81 (70.4) 1.2% (-10.4, 12.8) +Clinical failure 84 (70.0) 79 (68.7) 1.3% (-10.5, 13.1)

  32. Sensitivity Analyses (ITT TOC) Success considering failure based only on Daptomycin N = 120 n (%) Comparator N = 115 n (%) Differences In Success Rates (95% CI) Non-evaluable 111 (92.5) 101 (87.8) N/A Persisting/relapsing S. aureus (PRSA) 92 (76.7) 90 (78.3) -1.6% (-12.3, 9.1) +Death 86 (71.7) 81 (70.4) 1.2% (-10.4, 12.8) +Clinical failure 84 (70.0) 79 (68.7) 1.3% (-10.5, 13.1) +Treatment-limiting adverse event 77 (64.2) 67 (58.3) 5.9% (-6.5, 18.3)

  33. Sensitivity Analyses (ITT TOC) Success considering failure based only on Daptomycin N = 120 n (%) Comparator N = 115 n (%) Differences In Success Rates (95% CI) Non-evaluable 111 (92.5) 101 (87.8) N/A Persisting/relapsing S. aureus (PRSA) 92 (76.7) 90 (78.3) -1.6% (-12.3, 9.1) +Death 86 (71.7) 81 (70.4) 1.2% (-10.4, 12.8) +Clinical failure 84 (70.0) 79 (68.7) 1.3% (-10.5, 13.1) +Treatment-limiting adverse event 77 (64.2) 67 (58.3) 5.9% (-6.5, 18.3) +PENS 62 (51.7) 58 (50.4) 1.2% (-11.6, 14.0)

  34. Sensitivity Analyses (ITT TOC) Success considering failure based only on Daptomycin N = 120 n (%) Comparator N = 115 n (%) Differences In Success Rates (95% CI) Non-evaluable 111 (92.5) 101 (87.8) N/A Persisting/relapsing S. aureus (PRSA) 92 (76.7) 90 (78.3) -1.6% (-12.3, 9.1) +Death 86 (71.7) 81 (70.4) 1.2% (-10.4, 12.8) +Clinical failure 84 (70.0) 79 (68.7) 1.3% (-10.5, 13.1) +Treatment-limiting adverse event 77 (64.2) 67 (58.3) 5.9% (-6.5, 18.3) +PENS 62 (51.7) 58 (50.4) 1.2% (-11.6, 14.0) +No blood culture 55 (45.8) 49 (42.6) 3.2% (-9.5, 15.9)

  35. Sensitivity Analyses (ITT TOC) Success considering failure based only on Daptomycin N = 120 n (%) Comparator N = 115 n (%) Differences In Success Rates (95% CI) Non-evaluable 111 (92.5) 101 (87.8) N/A Persisting/relapsing S. aureus (PRSA) 92 (76.7) 90 (78.3) -1.6% (-12.3, 9.1) +Death 86 (71.7) 81 (70.4) 1.2% (-10.4, 12.8) +Clinical failure 84 (70.0) 79 (68.7) 1.3% (-10.5, 13.1) +Treatment-limiting adverse event 77 (64.2) 67 (58.3) 5.9% (-6.5, 18.3) +PENS 62 (51.7) 58 (50.4) 1.2% (-11.6, 14.0) +No blood culture 55 (45.8) 49 (42.6) 3.2% (-9.5, 15.9) +D/C for reason other than AE 53 (44.2) 48 (41.7) 2.4% (-10.2, 15.1)

  36. Comparator Daptomycin Kaplan-Meier Survival Curve (ITT) 100 75 50 % Survival 25 Wilcoxon p=0.823; Log-rank p=0.976 0 0 25 50 75 100 125 150 175 Days

  37. Deaths in Patients With Endocarditis and Persisting or Relapsing S. aureus Safety Population

  38. 70 60 53.9 Daptomycin 50.5 Comparator 45.6 50 40.7 40 % Success 30 20 4190 3791 4889 4793 10 0 Definite or Possible IEAdjudication Committee Definite or Possible IEInvestigator Known or Suspected Endocarditis: Success at Test of Cure (ITT)

  39. Efficacy Conclusions • Primary efficacy endpoint met in ITT and PP populations • Daptomycin response higher than vancomycin response in MRSA • Efficacy results robust and consistent • Across pre-specified subgroups • Per Adjudication Committee and Investigator

  40. Efficacy Conclusions • Daptomycin 6 mg/kg IV once daily was efficacious in the treatment of patients with S. aureus bacteremia including those with known or suspected endocarditis