Multi-arm, multi-stage randomised controlled trials with stopping boundaries for efficacy and lack-of-benefit: An update to nstage

Multi-arm multi-stage (MAMS) adaptive clinical trials offer several practical advantages over traditional two-arm designs. The framework proposed by Royston et al. (2011) uses intermediate outcomes at interim analyses to drop research arms demonstrating insufficient benefit prior to the final analysis on the primary outcome. To our knowledge, the nstage program developed for Stata (Barthel, Royston and Parmar, 2009) is the only sample size software for MAMS trials with time-to-event outcomes, a common outcome measure in modern trials in cancer, cardiovascular disease and other disease areas. We present an update to nstage to increase the efficiency and uptake of MAMS designs. nstage can accommodate efficacy stopping boundaries at interim analyses with a new option. Users choose a stopping rule and the program estimates the operating characteristics for a design which can assess for early evidence of overwhelming efficacy on the primary outcome when interim analyses for lack-of-benefit occur on an intermediate outcome. The user specifies whether the trial is expected to terminate, or continue with the remaining arms, should an efficacious research arm be identified before the final analysis of the trial. Since the probability of a type I error is increased through such a design, the updated program offers an option to search for a design which strongly controls the maximum familywise error rate at the desired level, if it is required. The program estimates the operating characteristics of the chosen design within a reasonable time-frame, allowing users to compare trial designs for different input parameters easily. We illustrate how the updates can be used to design a trial with the drop-down menu, using the MAMS trial STAMPEDE as an example. We hope the new functionality of the program will serve a broader range of trial objectives and, as such, increase adoption of the design in practice.