FDAAdvisoryMeetingClinicalTrialDesign–HepatitisB.pptVIP

FDA Advisory MeetingClinical 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) Clinical Practice Guidelines Issues for future clinical trials 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 Sentinel Clinical Trials of IFN and LAM in HBeAg + CHB ‘Sentinel’ Clinical Trials of IFN and LAMin HBeAg- CHB Meta-analysis of 24 RCTs of IFNin HBeAg+ CHB 855 IFN Rx, 444 no Rx Meta-analysis of 12 Studies of IFN Rx on Long-Term Outcome of HBeAg+ Adults# IFN Rx of HBeAg+ CHB 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 IFN Treatment of HBeAg - CHBCumulative results of published studies 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 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 Y