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FDA Advisory Meeting Clinical Trial Design – Hepatitis B Treatment

FDA Advisory Meeting Clinical Trial Design – Hepatitis B Treatment. Anna S.F. Lok, M.D. University of Michigan Ann Arbor, M I. TREATMENT OF CHRONIC HEPATITIS B. Review of sentinel trials and meta-analysis of randomized controlled trials of Interferon (IFN) and Lamivudine (LAM)

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FDA Advisory Meeting Clinical Trial Design – Hepatitis B Treatment

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  1. FDA Advisory MeetingClinical Trial Design – Hepatitis B Treatment Anna S.F. Lok, M.D. University of Michigan Ann Arbor, M I

  2. TREATMENT OF CHRONIC HEPATITIS B • Review of sentinel trials and meta-analysis of randomized controlled trials of Interferon (IFN) and Lamivudine (LAM) • Clinical Practice Guidelines • Issues for future clinical trials

  3. Goals of Antiviral Treatment of Chronic Hepatitis B 1. Sustained suppression of HBV replication Decrease in serum HBV DNA to <105 copies/ml HBeAg to anti-HBe seroconversion HBsAg to anti-HBs seroconversion 2. Remission of liver disease Normalization of serum ALT levels Decreased necroinflammation in liver 3. Improvement in clinical outcome Decreased risks of developing cirrhosis, liver failure and HCC Increased survival

  4. Review of Clinical Trials ofIFN and Lamivudine • Study population • HBeAg+ CHB • HBeAg- CHB • Decompensated cirrhosis • Inclusion/exclusion criteria • Treatment regimen • Sample size • End-points, response rates • Ability of measurements of response to predict outcome

  5. Sentinel Clinical Trials of IFN and LAM in HBeAg + CHB HBV DNA Assay ------ dot-blot/liquid hybridization * liquid hybridization #

  6. ‘Sentinel’ Clinical Trials of IFN and LAMin HBeAg- CHB

  7. Meta-analysis of 24 RCTs of IFNin HBeAg+ CHB 855 IFN Rx, 444 no Rx Craxi et al., J Hepatol (in press)

  8. Meta-analysis of 12 Studies of IFN Rx on Long-Term Outcome of HBeAg+ Adults# 765 IFN Rx, 1210 no Rx* Mean FU 6·1 yr (2.1 – 8.9 yr) # Significant heterogeneity of results * Includes non-concurrent controls Craxi et al., J Hepatol (In press)

  9. IFN Rx of HBeAg+ CHB Perrillo et al., NEJM 1990;323:295

  10. IFN Treatment of HBeAg - CHB Type of Study # Studies # Treated # Untreated Randomized 4 86 84 (IFN vs. no treatment) Randomized 2 110  (comparing different IFN schedule) Randomized 3 45  (IFN vs. other active compound) Not Randomized 9 702  ALL 18 943 84

  11. IFN Treatment of HBeAg - CHBCumulative results of published studies Alberti, NIH, HBV 2000 Meeting 44 - 69 38 - 59 7 - 38 7 - 38 * HBV DNA by non-PCR assays

  12. IFN Rx of HBeAg - CHB: Histologic Response Author, Mean HAI Score Mean Fibrosis Score Year IFN Control IFN Control Lampertico, 1997 Baseline 10.3 9.3 2.1 2.2 } p=.001 End of Rx 5.3 9.3 1.8 2.0 Fattovich, 1992 Baseline 8.1 9.0 N/A N/A } p=.004 12 mon post-Rx 5.5 7.5 N/A N/A

  13. IFN Rx of HBeAg- CHB 216 patients, FU median 7 yr 78 patients - median 5 months Rx 138 patients - median 12 months Rx 3 MU tiw Response End of Rx 54% FU Yr. 1 44% of initial responders, 24% of all patients End of FU 33% of initial responders, 18% of all patients Predictors of Response Duration of Rx > 6 months Early response, within 4 months Manesis & Hadziyannis, Gastroenterology 2001;121:101

  14. Lamivudine Rx of HBeAg+ CHB HBeAg seroconversion at week 52 Placebo Lam x 52 wk IFN x 16 wk Lam x 24 wk +IFN x 16 wk Lai et al., NEJM 1998 Dienstag et al., NEJM 1999 Schalm et al., Gut 2000 13

  15. Lamivudine Rx of HBeAg+ CHB Histologic response at week 52 Placebo Lam x 52 wk IFN x 16 wk Lam x 24 wk . +IFN x 16 wk Lai et al., NEJM 1998 Dienstag et al., NEJM 1999 Schalm et al., Gut 2000 14

  16. LAM PLA LAM & IFN IFN Lamivudine Rx of HBeAg+ CHB Normal ALT at Week 52

  17. Lamivudine Rx of HBeAg+ CHB % of Patients Multi-center Asian Study

  18. Lamivudine Rx of HBeAg- CHB Lamivudine Placebo 0 24 52 At wk 24 At wk 52 HBV DNA - (bDNA) ALT Normal HBV DNA - (bDNA) ALT Normal HBV DNA - (PCR)  HAI  2 points Tassopoulos et al., Hepatology 1999; 29:889

  19. Lamivudine Rx of HBeAg- CHB ALT (xULN) HBV DNA (pg/mL) Lamivudine Treatment (0-52 Weeks) Normal ALT Tassopoulos et al., Hepatology 1999; 29:889

  20. Treatment of HBeAg - CHB

  21. Treatment of Decompensated Cirrhosis Measurements of Response • Viral suppression  • Biochemical improvement  • Decrease in CTP score  (Alb, bil, PT, ascites, encephalopathy) • Decrease clinical complications + • Decrease need for transplant + • Decrease HCC ? • Improve survival +

  22. Lamivudine Rx of Decompensated Cirrhosis 35 patients decomp cirrhosis 5 deaths 7 OLT 23 patients RX 6 months 1 no improvement  OLT 22 patients  CTP score  2 points 2 deaths; 1 SBP, 1 HCC 20 patients alive at 19  2 months 3 with resistant mutants Villeneuve et al., Hepatology 2000;31:207

  23. Clinical Practice Guidelines • Who to treat • What treatment • When to stop treatment

  24. AASLD Practice Guidelines • Current therapy has limited long-term efficacy • Careful balance of benefits and risks before treatment is initiated • patients’ age • severity of liver disease • likelihood of response • potential adverse events Lok and McMahon, Hepatology 2001;34:1225

  25. AASLD Practice Guidelines: Rx Strategies HBeAg HBV DNA* ALT Treatment + + <2x ULN Both IFN and Lam low efficacy Observe + + >2x ULN IFN or Lam IFN NR or contraindications  Lam – + >2x ULN IFN or Lam Long-term Rx required – – normal No Rx required +/ – + cirrhosis Compensated: IFN low dose or Lam Decompensated: Lam, optimal timing unknown Transplant +/ – – cirrhosis Compensated: observe Decompensated: Transplant *HBV DNA in serum >105 copies/ml Lok and McMahon, Hepatology 2001;34:1225

  26. Treatment of Chronic Hepatitis B Interferon Lamivudine Pros • Finite duration of Rx • More durable response • Resistant mutants not • reported • Oral administration • Negligible side effects • Lower costs? Cons • Expensive • Frequent side effects • Long/indefinite duration of Rx • Resistant mutants

  27. AASLD Practice GuidelinesTreatment Regimen - IFN Dose 5 MU QD or 10 MU tiw SC Duration e + CHB - 16 wk e – CHB - 12 months Lok and McMahon, Hepatology 2001;34:1225

  28. AASLD Practice GuidelinesTreatment Regimen - Lamivudine Dose 100mg daily po HIV Coinfection – 150mg bid + other HIV Rx Duration e+ CHB – 1yr... HBeAg seroconversion – Stop Rx? DNA suppression, HBeAg+ - Continue Rx? Breakthrough infection – continue Rx if clinically stable? Stop Rx if clinical deterioration e- CHB > 1yr, optimal duration? Lok and McMahon, Hepatology 2001;34:1225

  29. Issues for Future Clinical Trials • Study population • Entry criteria • Treatment regimens • Indications for assessing treatment response • End-points for stopping treatment • Durability of response after treatment withdrawal • Short and long term safety and efficacy

  30. Issues for Future Clinical Trials Study population • Adults with • e+ CHB (normal vs. elevated ALT) • e- CHB • decompensated cirrhosis • Coinfection (HIV, HCV) • Extrahepatic disease • Patients on immunosuppressive/chemo Rx • Children

  31. Issues for Future Clinical Trials Entry Criteria

  32. Issues for Future Clinical Trials Treatment Regimens Study Design • Monotherapy – placebo vs. active control • Monotherapy vs. combination therapy Duration of Rx • Finite duration – 1 or 2 years • Built in follow-up/follow-on • durability of response • long-term safety • drug resistance • additional response with extended Rx

  33. Issues for Future Clinical Trials End-points for Treatment Response - Liver Histology Pros Direct assessment of liver disease – inflammation and fibrosis Cons Requires 2 biopsies Risks of complications Expensive Sampling error Intra and Inter observer variability Scores not linear Not applicable outside clinical trials Clinical significance of a 2-point decrease in HAI uncertain

  34. Issues for Future Clinical Trials End-points for treatment response HBeAg+ CHB HBeAg loss, + anti-HBe + Decreased HBV DNA level, <105 copies/ml + ALT normal HBeAg- CHB Decreased HBV DNA level, <103 copies/ml + ALT normal range Decompensated Cirrhosis Decreased HBV DNA level + CTP score decrease > 2 points and/or MELD score (INR, bil, Cr) decrease

  35. Issues for Future Clinical Trials Do proposed composite (virologic, serologic biochemical) end-points correlate with • Histologic response • Improved clinical outcome?

  36. Ability of Surrogate Markersto Predict Clinical Outcome Limited data Problems: • Prolonged natural course • Limited follow-up in prospective studies • Few RCTs, small sample size • Disease heterogeneity between treated and untreated controls (historical/non-concurrent) in retrospective studies

  37. IFN Rx of HBeAg+ CHB Perrillo et al., NEJM 1990;323:295

  38. Impact of HBeAg Clearanceon Long-Term Clinical Outcome 1.0 0.8 0.6 0.4 0.2 0.0 Clearance of HBeAg IFN No Rx Proportion with complication free survival No Clearance of HBeAg 0 12 24 36 48 60 72 84 96 Month Niederau et al., NEJM 1996;334:1422-7

  39. 100 80 IFN-SR (n=57) 60 Percent Un-Rx (n=195) 40 IFN-NR (n=152) 20 0 0 2 4 6 8 10 12 14 Years Cumulative Transplant-Free Survival of Patients with HBeAg- Chronic Hepatitis IFN-SR vs IFN-NR p=0.03 IFN-SR vs Un-Rx p=0.05 Papatheodoridis et al., J Hepatol 2001; 34:306-313

  40. PLA (n=120) LAM 100 (n=169) e-Sero e-Sero Correlation Between Week 52 HBV DNA Levels and HBeAg Seroconversion in Lamivudine TrialsNUCB 3009/NUCA 3010 Log10 HBV DNA Levels Dienstag et al., NEJM 1999, Lai et al., NEJM 1998 Courtesy of GSK – L Condreay and S Gardner

  41. PLA (n=97) LAM 100 (n=124) ALT Normal ALT Normal Correlation between Week 52 HBV DNA Levelsand ALT NormalizationLamivudine Trials NUCB 3009/NUCA 3010 Log10 HBV DNA Levels Dienstag et al., NEJM 1999, Lai et al., NEJM 1998 Courtesy of GSK – L Condreay and S Gardner

  42. PLA (n=104) LAM 100 (n=150) Histologic Response Histologic Response Correlation Between Week 52 HBV DNA Levelsand Histologic ResponseLamivudine Trials NUCB 3009/NUCA 3010 Log10 HBV DNA Levels Dienstag et al., NEJM 1999, Lai et al., NEJM 1998 Courtesy of GSK – L Condreay and S Gardner

  43. Correlation Between Week 48 HBeAg Seroconversion,HBV DNA, ALT and Histologic ResponseAdefovir Trial GS-437 (e+ CHB) ADV 10mg HBeAg Seroconversion Log10 HBV DNA Levels No HBeAg Seroconversion Log10 HBV DNA Levels Courtesy of J Fry, C Brosgart, Gillead

  44. Correlation Between Week 48 HBV DNA, ALT and Histologic Response Adefovir Trial GS-438 (e-CHB) ADV Log10 HBV DNA Levels PLA Log10 HBV DNA Levels Courtesy of J Fry, C. Brosgart, Gilead

  45. Issues for Future Clinical Trials Indications for stopping treatment • Achievement of on-treatment response • Maintenance of on-treatment response for defined duration • Indications may vary depending on severity of underlying liver disease and immune status of host

  46. Correlation between Week 48HBeAg loss, HBV DNA,ALT and Histologic Response ADV 10 mg HBeAg Loss Log10 HBV DNA Levels No HBeAg Loss Log10 HBV DNA Levels

  47. Treatment of Chronic Hepatitis B Role of IFN in Patients with Cirrhosis • IFN vs Pred + IFN in CHB - US multi-center trial • 98/150 (65%) had cirrhosis • 1 treated and 1 control patient died of liver failure • Perrillo et al., NEJM 1990 Low dose IFN in clinical cirrhosis Child’s class n Response Rx withdrawal A 5 5 0 B 15 5 3 C 6 0 4 Perrillo et al., Gastro 1995

  48. Treated group 100 P=0.018 75 Control group Cumulative Incidence (%) 50 25 Control group P=0.013 Treated group 0 0 2 4 6 8 10 12 Year of Follow-up Effect of IFN on Survival and HCC Development Survival HCC Lin et al., Hepatology 1999;29:971

  49. RCTs of IFN Treatment of HBeAg - CHB Author, IFN Dose, Number Number Follow Year Duration Treated Untreated Up Hadziyannis, 5 MU/m2, 25 25 12 mo. 1990 14-16 wks Fattovich, 5 MU/m2, 30 30 12 mo. 1992 6 mo. Pastore, 5 MU/m2, 10 8 24 mo. 1992 6 mo. Lampertico, 6 MU/m2, 21 21 22 mo. 1997 24 mo.

  50. IFN Treatment of HBeAg- Patients Hadziyannis S, et al., J Hepatology 1990; 11(Suppl 1):513 Fattovich G, Hepatology 1992; 15:584 Pastore G, J Hepatology 1992; 14;221 Lampertico p, Hepatology 1997; 26:1621

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