Clinical Trials for Curing Chronic Hepatitis B: A Comprehensive Analysis of Design Principles and Their Impact on Trial Performance

Background/Objectives: The development of novel agents for chronic hepatitis B (CHB) has rapidly evolved, but only with a few candidates progressing to phase III trials. This study aimed to systematically evaluate key design elements of CHB cure trials and their impact on trial performance. Methods: We conducted a systematic review of clinical trial registries (ClinicalTrials.gov, WHO Clinical Trials Registry Platform, and Chinese Clinical Trial Registry) and publications (PubMed, Embase, and the Cochrane Library) for CHB cure trials. The relationship between the design characteristics and the performance of the trials was analyzed with Cox regression and meta-analysis. Results: A total of 244 trials and 23 publications involving 1,798 patients were included. Phase I clinical trials had a completion rate of 65.5%, with 38.7% advancing to phase II. For phase II trials, the completion rate was 48.9%, only with 4.3% advancing to phase III. Novel trial designs were adopted by 30.3% of the CHB clinical trials. Smaller sample size significantly was associated with higher completion rates in both phase I (HR: 0.980, 95% CI: 0.966–0.994) and phase II trials (HR: 0.994, 95% CI: 0.988–0.999). Shorter treatment duration was associated with higher completion rates only in phase I trials (HR: 0.992, 95% CI: 0.986–0.998). Meta-analysis of early-phase trials showed that direct-acting antivirals (SMD: 5.43, 95% CI: 0.22–10.64) were superior to control groups in achieving HBV cure. Conclusions: This study demonstrates that smaller sample sizes and shorter treatment durations are significantly associated with higher completion rates in early-phase trials.