Two-stage seamless transition design from open-label single-arm to randomized double-arm clinical trials

Abstract

Conventional phase II clinical trials use either a single- or multi-arm comparison scheme to examine the therapeutic effects of the experimental drug. Both single- and multi-arm evaluations have their own merits; for example, single-arm phase II trials are easy to conduct and often require a smaller sample size, while multiarm trials are randomized and typically lead to a more objective comparison. To bridge the single- and double-arm schemes in one trial, we propose a two-stage design, in which the first stage takes a single-arm comparison of the experimental drug with the standard response rate (no concurrent treatment) and the second stage imposes a two-arm comparison by adding an active control arm. The design is calibrated using a new concept, the detectable treatment difference, to balance the trade-offs between futility termination, power, and sample size. We conduct extensive simulation studies to examine the operating characteristics of the proposed method and provide an illustrative example of our design.