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Surrogate Endpoints for Hepatitis B Trials

Surrogate Endpoints for Hepatitis B Trials

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Surrogate Endpoints for Hepatitis B Trials

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  1. Surrogate Endpoints for Hepatitis B Trials Greg Soon, Ph.D Rafia Bhore, Ph.D. Division of Biometrics III/Antiviral 8/7/2002 AC

  2. Potential Surrogate Endpoints • Knodell Score (Biopsy, Histology) • ALT, HBV DNA • Proportion < threshold • Change from Baseline • End of treatment • Time to suppression • Duration of suppression • Time to virologic failure • DAVG or Average change over time • Others • HBeAg, HBeAb, HBsAg, HBsAb • Composition of the above

  3. Data Source: EpivirHBV Submission

  4. Data Source: Adefovir Submission

  5. HBV DNA Assays • Lamivudine trials used Abbott Hybridization assay, which has a lower limit of approximately 500,000 copies/mL • Limiting ability to differentiate patient responses on viral load • Converted to copies/mL for this presentation • Adefovir Trials used PCR assay that has a lower limit of 400 copies/mL

  6. Overview • Summary of Efficacy • Patient-level Correlation • Trial-level Correlation • Proportion of Treatment Effect Explained (PTE) • Summary

  7. Overview • Summary of Efficacy • Patient-level Correlation • Trial-level Correlation • Proportion of Treatment Effect Explained (PTE) • Summary

  8. Change of Knodell Score vs Baseline

  9. Convention • White for placebo arms • Yellow for LAM 100mg or ADV 10mg • Orange for LAM 25mg or ADV 30mg • Red for IFN + LAM 100mg • Green for IFN alone

  10. Log10 ALT/ULN Over Time

  11. Study 438

  12. Study 437

  13. LAM Studies

  14. Study 437

  15. Log10 HBV DNA Over Time

  16. Study 438

  17. Study 437

  18. LAM Studies

  19. Study 437

  20. HBeAg Loss Over Time

  21. Study 437

  22. LAM Studies

  23. Transition of HBeAg Status

  24. Overview • Summary of Efficacy • Patient-level Correlation • Trial-level Correlation • Proportion of Treatment Effect Explained (PTE) • Summary

  25. Lamivudine: HBV DNA vs. Knodell Change of Knodell Score Year 1 LOG10 HBV DNA

  26. Lamivudine: HBV DNA vs. Knodell Change of Knodell Score Year 1 LOG10 HBV DNA

  27. Lamivudine: CorrelationYear 1 HBV DNA vs. Knodell Score Change *: p-value<0.05 **: p-value<0.001

  28. Adefovir: HBV DNA vs. Knodell Change of Knodell Score Year 1 LOG10 HBV DNA

  29. Adefovir: CorrelationYear 1 HBV DNA vs. Knodell Score Change *: p-value<0.05 **: p-value<0.001

  30. Lamivudine: ALT vs. Knodell Change of Knodell Score Change of LOG10 ALT

  31. Lamivudine: ALT vs. Knodell Change of Knodell Score Change of LOG10 ALT

  32. Lamivudine: CorrelationALT Change vs. Knodell Score Change *: p-value<0.05 **: p-value<0.001

  33. Adefovir: ALT vs. Knodell Change of Knodell Score Change of LOG10 ALT