Response-adaptive treatment allocation for clinical studies with recurrent event and terminal event data.

Abstract

In long-term clinical studies, recurrent event data are frequently collected to contrast the efficacy of two different treatments. However, the recurrent event process can be stopped by a terminal event, such as death. For analyzing recurrent event and terminal event data, joint frailty modeling has recently received considerable attention because it makes it possible to study the joint evolution over time of both recurrent and terminal event processes and gives consistent and efficient parameters. For a two-arm clinical trial design based on these data sets, there has been limited research on investigating the balanced design, let alone adaptive treatment allocation. Although equal sample size allocation obtained for both treatments is intuitively first adopted in a trial design, if one treatment is expected to be superior, it may be desirable to allocate more subjects to the effective treatment. In this article, we calculate the required sample size based on restricted randomization and then propose a target response-adaptive randomization procedure for recurrent and terminal event outcomes based on the joint frailty model. A randomization procedure, the doubly adaptive biased coin design that targets some optimal allocations, is implemented. The proposed adaptive treatment allocation schemes have been shown to be capable of reducing the number of trial participants who receive inferior treatment while simultaneously reaching an optimal target, as well as retaining a comparable test power as compared to a restricted randomization design. Finally, two clinical studies, the COAPT trial and the A-HeFT trial, are used to illustrate the advantages of adopting the proposed procedure.