The design of a Bayesian platform trial to prevent and eradicate inhibitors in patients with hemophilia

Abstract

Abstract Among individuals with the rare congenital bleeding disorder hemophilia A, the major challenge is inhibitor formation, which is associated with significant morbidity and cost. Yet, as the optimal approach to prevent and eradicate inhibitors is not known, we are at equipoise. Because classic trial design is not practical in a rare disease setting, we designed 2 48-week randomized trials comparing ELOCTATE and emicizumab to prevent and eradicate inhibitors. To achieve statistical efficiency, we incorporated historic data (Bayesian priors) on inhibitor formation to allow preferential randomization to emicizumab, piecewise exponential survival models to determine mean and 95% confidence interval for inhibitor formation in each arm, and simulations to determine the best model design to optimize power. To achieve administrative efficiency, the trials will be performed with the same sites, staff, visit frequency, blood sampling, laboratories, and laboratory assays, with streamlined enrollment so patients developing inhibitors in the first trial may be enrolled on the second trial. The primary end point is the probability of inhibitor formation or inhibitor eradication, respectively. The design indicates early stopping rules for overwhelming evidence of superiority of the emicizumab arms. Simulations indicate that, with 66 subjects, the Prevention Trial will have 84% power to detect noninferiority of emicizumab to ELOCTATE with a margin of 10% if emicizumab is truly 10% superior to ELOCTATE; with 90 subjects, the Eradication Trial will have 80% power to detect 15% superiority of ELOCTATE immune tolerance induction with vs without emicizumab. Thus, a platform design provides statistical and administrative efficiency to conduct INHIBIT trials.