An adaptive design for optimizing treatment assignment in randomized clinical trials (2509.00429v1)

Abstract: The treatment assignment mechanism in a randomized clinical trial can be optimized for statistical efficiency within a specified class of randomization mechanisms. Optimal designs of this type have been characterized in terms of the variances of potential outcomes conditional on baseline covariates. Approximating these optimal designs requires information about the conditional variance functions, which is often unavailable or unreliable at the design stage. As a practical solution to this dilemma, we propose a multi-stage adaptive design that allows the treatment assignment mechanism to be modified at interim analyses based on accruing information about the conditional variance functions. This adaptation has profound implications on the distribution of trial data, which need to be accounted for in treatment effect estimation. We consider a class of treatment effect estimators that are consistent and asymptotically normal, identify the most efficient estimator within this class, and approximate the most efficient estimator by substituting estimates of unknown quantities. Simulation results indicate that, when there is little or no prior information available, the proposed design can bring substantial efficiency gains over conventional one-stage designs based on the same prior information. The methodology is illustrated with real data from a completed trial in stroke.