Surrogate Endpoints for Hepatitis B Trials

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Surrogate Endpoints for Hepatitis B Trials

• Greg Soon, Ph.D
• Rafia Bhore, Ph.D.
• Division of Biometrics III/Antiviral

8/7/2002 AC
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Potential Surrogate Endpoints

• Knodell Score (Biopsy, Histology)
• ALT, HBV DNA
• Proportion
• 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

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Data Source EpivirHBV Submission
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Data Source Adefovir Submission
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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

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Overview

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

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Overview

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

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Change of Knodell Score vs Baseline
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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

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Log10 ALT/ULN Over Time
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Study 438
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Study 437
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LAM Studies
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Study 437
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Log10 HBV DNA Over Time
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Study 438
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Study 437
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LAM Studies
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Study 437
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HBeAg Loss Over Time
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Study 437
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LAM Studies
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Transition of HBeAg Status
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Overview

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

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Lamivudine HBV DNA vs. Knodell
Change of Knodell Score
Year 1 LOG10 HBV DNA
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Lamivudine HBV DNA vs. Knodell
Change of Knodell Score
Year 1 LOG10 HBV DNA
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Lamivudine CorrelationYear 1 HBV DNA vs.
Knodell Score Change
p-value 45
Adefovir HBV DNA vs. Knodell
Change of Knodell Score
Year 1 LOG10 HBV DNA
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Adefovir CorrelationYear 1 HBV DNA vs. Knodell
Score Change
p-value 47
Lamivudine ALT vs. Knodell
Change of Knodell Score
Change of LOG10 ALT
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Lamivudine ALT vs. Knodell
Change of Knodell Score
Change of LOG10 ALT
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Lamivudine CorrelationALT Change vs. Knodell
Score Change
p-value 50
Adefovir ALT vs. Knodell
Change of Knodell Score
Change of LOG10 ALT
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Adefovir CorrelationALT Change vs. Knodell
Score Change
p-value 52
DNA, HBeAg Knodell
438
437 Yr 1 eAg
437 Yr 1 eAg Neg
38 68 62
34 13 21
13 6 17
41 10 16
215 10 53
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Joint Prediction
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Predicting Change of Knodell
Excluding adefovir HBeAg negative
study stratified by study and treatment
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Summary

• With near certainty, better response on change of
  log10 ALT and Year 1 log10 HBV DNA are associated
  with better Knodell improvement
• The associations are weak to moderate
• Multiple predictors do not improve much on top of
  ALT

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Overview

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

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Methods

• Studies were divided into smaller trials
  according to region and ethnic background to
  increase data points for analysis
• Size of trials range from 20 to 70.

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HBV DNA vs. Knodell By Trial and Treatment
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ALT vs. Knodell By Trial and Treatment
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HBV DNA vs Knodell Treatment effects by Trial
R225 (0, 60)
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HBV DNA vs Knodell Treatment effects by Trial
R26 (0, 30)
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ALT vs Knodell Treatment effects by Trial
R224 (0, 49)
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ALT vs Knodell Treatment effects by Trial
R233 (8, 57)
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Variability and Correlation
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Variability and Correlation
Assume overall SD for Knodell is 3
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Impact on relationship among treatment effects
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Replication of a Single Trial
r10.74 r00.31 R0.56
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Replication of a Single Trial
r10.50 r00.47 R0.44
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Other considerations

• Variations in trial results are desirable for the
  trial-level correlation validation method. Two
  trials of different effect sizes are more useful
  than two trials of similar effect size

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Overview

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

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Proportion of Treatment Effect Explained

• Attempts to determine, of the total effect size
  observed for the Knodell score in each trial, how
  much can be attributed to the effect on the
  potential surrogate?
• Linear regression model to determine how much
  effect remain when there is no effects on
  surrogate
• The remainder portion of the treatment effect is
  considered mediated through surrogate
• Long used but also widely debated

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PTE HBV DNA vs Knodell
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PTE ALT vs Knodell
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Overview

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

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Summary

• Treatment effects and variability for HBV DNA,
  ALT, HBeAg and Knodell score.
• Baseline Knodell correlates with change
• Effects over time for HBV DNA, ALT, and HBeAg
• Both ALT and HBV DNA are variable over time

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Summary

• Weak individual level correlation with Change of
  Knodell score
• Year 1 HBV DNA, r 0.3
• Change of ALT, r 0.45
• Not much improvement with multiple predictors

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Summary

• Weak Trial-level correlation
• Biopsy variability may reduce individual
  correlation
• Trial level correlation will be similar to
  individual level correlation if trials are
  similar
• Adefovir and Epivir trial results are somewhat
  similar in effect sizes

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Summary

• PTE for Year 1 HBV DNA and Change of ALT
• For baseline HBeAg negative study, both HBV DNA
  and ALT have low PTE
• For baseline HBeAg Study, PTE are somewhat
  consistent in adefovir or lamivudine vs placebo
  comparisons
• Interferon-containing comparisons are not
  informative

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