Multiarm, multistage randomized controlled trials with stopping boundaries for efficacy and lack of benefit: An update to nstage

Abstract

Royston et al.’s (2011, Trials 12: 81) multiarm, multistage (MAMS) framework for the design of randomized clinical trials uses intermediate outcomes to drop research arms early for lack of benefit at interim stages, increasing efficiency in multiarm designs. However, additionally permitting interim evaluation of efficacy on the primary outcome measure could increase adoption of the design and result in practical benefits, such as savings in patient numbers and cost, should any efficacious arm be identified early. The nstage command, which aids the design of MAMS trial designs, has been updated to support this methodological extension. Operating characteristics can now be calculated for a design with binding or nonbinding stopping rules for lack of benefit and with efficacy stopping boundaries. An additional option searches for a design that strongly controls the familywise error rate at the desired level. We illustrate how the new features can be used to design a trial with the drop-down menu, using the original comparisons from the MAMS trial STAMPEDE as an example. The new functionality of the command will serve a broader range of trial objectives and increase efficiency of the design and thus increase uptake of the MAMS design in practice.