Seamless Multi-Arm Multi-Stage (MAMS) designs with treatment selection and interim change of outcome: An update to nstage

Session

Multi-Arm Multi-Stage (MAMS) selection designs, as an extension of the standard MAMS designs, offer additional efficiencies that accelerate the evaluation of medical interventions in clinical trials. Standard MAMS designs use stagewise hypothesis testing to compare multiple experimental treatments against a common control at interim analyses, enabling early stopping for overwhelming efficacy or lack-of-benefit. MAMS selection designs further incorporate predefined rules to choose the best-performing treatments. Incorporating intermediate outcomes, introduced to significantly shorten the timing of interim analyses, naturally fits into the seamless trial design framework, which allows for outcome changes at early stages of trial. Our existing "nstage" suite of commands calculates target sample sizes for MAMS designs with binary outcomes such as death or disease progression. The program also projects timelines for trial planning and computes overall operating characteristics (overall pairwise/familywise type I error rates, power, and expected sample sizes). We have enhanced the program to support interim outcome changing and the interim rules for treatment selection, lack of benefit, and overwhelming efficacy. The updated nstage command is now more flexible, enabling changes to trial outcomes at interim stages, making it well-suited for seamless Phase II/III trial designs. It also supports treatment selection based on either Phase II (intermediate) or Phase III (primary clinical) outcomes. We will describe the new MAMS design and the associated Stata command using a miscarriage MAMS platform trial in maternal health.