Innovative Adaptive Study Design in Transfusion-Dependent Beta-Thalassemia: Bayesian Design with Concurrent Randomization and Borrowing from Historical Data
Authors: Muehlemann Natalia , Mukherjee Rajat , Taher Ali T. , Gudmundsdottir Thordis , Morin Isabelle , Richard Frank 
Published: November 2021

Abstract
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 dose arms while using a robustified informative prior for the control arm. Historical control data will be "borrowed" in an informative prior for the control arm rate from the Phase 3 trial - BELIEVE. The robustification is required in order to control the level of borrowing depending on the level of prior-data conflict.
Prior-data conflict can arise from multiple sources like population heterogeneity between the historical and current study. Therefore, the selection of historical data (BELIEVE trial) addresses similarity in inclusion / exclusion criteria, standard of care etc. The robustification of the informative prior does not take into account prior-data conflict in terms of population or study characteristics but directly focuses on the informative prior of the parameter of interest and the corresponding likelihood of the current data. For example, in the BELIEVE study, out of 112 patients randomized to the control arm, 5 patients (4.5%) had a ≥33% reduction in transfusion burden over 24 weeks. A prior-data conflict may arise if the Phase-2b trial of interest here, suggests that the proportion is substantially different that 4.5% and this can inflate the frequentist Type-I or Type-II error rates examined via simulations.
We evaluated Type-I error rates of the proposed design with 5000 Monte-Carlo runs for each scenario of the response rates. Using informative prior with no prior-data conflict the type-I error with no robustification is ≈ 2.4%. As the prior-data conflict increases, without robustification, the type-I error cannot be controlled. However, with a robustification weight of 0.5 the type-I errors can be controlled in line with regulatory requirements.
Discussion
A proposed Bayesian design with robustified informative prior for the control arm helps reduce patients' burden of randomization to control arm and reduce overall sample size for a rare disease trial when recruitment and trial duration are challenging.

Disclosures
Muehlemann: Vifor Pharma AG: Consultancy. Mukherjee: Vifor Pharma AG: Consultancy. Taher: Bristol Myers Squibb: Consultancy, Research Funding; Vifor Pharma: Consultancy, Research Funding; Agios Pharmaceuticals: Consultancy; Ionis Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Gudmundsdottir: Vifor Pharma AG: Current Employment. Morin: Vifor Pharma AG: Current Employment. Richard: Vifor Pharma AG: Current Employment.