Innovative Adaptive Study Design in Transfusion-Dependent Beta-Thalassemia: Bayesian Design with Concurrent Randomization and Borrowing from Historical Data

Background Clinical development of new therapies in transfusion-dependent beta-thalassemia has several challenges. Patient enrollment in rare diseases requires multi-center multi-country studies, and the lack of reliable surrogate endpoint for dose selection requires powering for clinical endpoints usually used in Phase 3 trials. An acceptable endpoint from a regulatory perspective which is based on responders analysis, such as proportion of patients experiencing ≥50% reduction in Red Blood Cell (RBC) transfusion burden and a reduction of ≥2 units, requires 12 weeks screening period to establish baseline transfusion burden for reliable comparison. Importantly, higher randomization ratio of treatment:placebo can improve patients' motivation to enroll into a trial, but it is less statistically efficient and requires higher sample size. We designed a Phase-2b, double-blind, randomized, placebo controlled, multi-center study with Vamifeport (NCT04938635) to assess the efficacy and safety of multiple doses of a new therapy in adults with transfusion-dependent beta-thalassemia. The proposed design follows the Bayesian framework with borrowing from published historical control data. The historical control data is used to construct an informative prior for the control arm to reduce the burden of patients randomized to a control arm and improve the trial's efficiency in performing dose selection. Study Design and Methods Adults (18 to 65 y.o.) with documented diagnosis of β-thalassemia or hemoglobin E / β-thalassemia will be randomized to three doses of the investigational drug or placebo plus best supportive care. RBC transfusion dependence is defined as at least 6 RBC Units in the 24 weeks prior to randomization and no transfusion-free period for ≥35 days during that period. The primary endpoint is the proportion of patients experiencing ≥33% reduction of RBC units from baseline and a reduction of ≥2 units assessed from week 13 to week 24. The key secondary endpoints include proportion of patients experiencing ≥33% reduction from week 37 to week 48; proportion of patients experiencing ≥50% reduction over any consecutive 12-week interval from week 1 to week 48 and the mean change from baseline in RBC transfusions (units) from week 13 to week 24. The primary and key-secondary analysis will be conducted in a hierarchical fashion to account for multiplicity. We proposed a Bayesian design with the use of noninformative, or weakly informative, priors for the active dos