Increasing the efficiency of clinical trials in neurodegenerative disorders using group sequential trial designs

Objectives: Clinical trials in neurodegenerative disorders are facing high futility rates and rising development costs. We aim to review and exemplify the value of group sequential trial designs (i.e., designs with one or more prospectively planned interim analyses) within the field of amyotrophic lateral sclerosis. Study Design and Setting: We reviewed the literature to identify sequentially conducted trials. Subsequently, we reanalyzed the dexpramipexole trial (EMPOWER), a classically designed and conducted trial involving 942 participants, by sequentially monitoring the functional questionnaire and survival endpoint. Finally, we simulated the performance of the sequential methodology under different treatment effects. Results: Only six (12%) randomized, placebo-controlled trials incorporated stopping rules for both futility and superiority. Despite its high enrollment rate, sequential reanalysis of the EMPOWER study reduced the total trial duration with 140 days (23.4%, 95% confidence interval [CI] 13.2–34.4%), the number of follow-ups with 2,688 visits (23.6%, 95% CI 11.3–38.6%), and the total drug exposure time with 73,377 days (20.6%, 95% CI 9.8–35.9%). The functional questionnaire considerably increased the heterogeneity in the test statistics, which may negatively affect sequential monitoring. Conclusion: Group sequential trials can result in important reductions in the trial duration, which could make clinical trials more ethical by reducing the patients’ exposure to noneffective treatments or by limiting their time on placebo.