Summary. Two-arm group sequential designs have been widely used for over 40 years, especially for studies with mortality endpoints. The natural generalization of such designs to trials with multiple treatment arms and a common control (MAMS designs) has, however, been implemented rarely. While the statistical methodology for this extension is clear, the main limitation has been an efficient way to perform the computations. Past efforts were hampered by algorithms that were computationally explosive. With the increasing interest in adaptive designs, platform designs, and other innovative designs that involve multiple comparisons over multiple stages, the importance of MAMS designs is growing rapidly. This article provides break-through algorithms that can compute MAMS boundaries rapidly thereby making such designs practical. For designs with efficacy-only boundaries the computational effort increases linearly with number of arms and number of stages. For designs with both efficacy and futility boundaries the computational effort doubles with successive increases in number of stages.

Two methods for designing adaptive multiarm multistage (MAMS) clinical trials, originating from conceptually different group sequential frameworks are presented, and their operating characteristics are compared. In both methods pairwise comparisons are made, stage‐by‐stage, between each treatment arm and a common control arm with the goal of identifying active treatments and dropping inactive ones. At any stage one may alter the future course of the trial through adaptive changes to the prespecified decision rules for treatment selection and sample size reestimation, and notwithstanding such changes, both methods guarantee strong control of the family‐wise error rate. The stage‐wise MAMS approach was historically the first to be developed and remains the standard method for designing inferentially seamless phase 2‐3 clinical trials. In this approach, at each stage, the data from each treatment comparison are summarized by a single multiplicity adjusted P‐value. These stage‐wise P‐values are combined by a prespecified combination function and the resultant test statistic is monitored with respect to the classical two‐arm group sequential efficacy boundaries. The cumulative MAMS approach is a more recent development in which a separate test statistic is constructed for each treatment comparison from the cumulative data at each stage. These statistics are then monitored with respect to multiplicity adjusted group sequential efficacy boundaries. We compared the powers of the two methods for designs with two and three active treatment arms, under commonly utilized decision rules for treatment selection, sample size reestimation and early stopping. In our investigations, which were carried out over a reasonably exhaustive exploration of the parameter space, the cumulative MAMS designs were more powerful than the stage‐wise MAMS designs, except for the homogeneous case of equal treatment effects, where a small power advantage was discernable for the stage‐wise MAMS designs.

Background Plaque psoriasis (PsO) is an inflammatory skin disease driven, in part, by the activation of Janus kinase (JAK) signalling pathways. Objective To assess the efficacy and safety of multiple doses of topical brepocitinib, a tyrosine kinase 2/JAK1 inhibitor, in participants with mild-to-moderate PsO. Method This phase IIb, multicentre, randomised, double-blind study was conducted in two stages. In stage one, participants received one of eight treatments for 12 weeks: brepocitinib 0·1% once daily (QD), 0·3% QD or twice daily (BID), 1·0% QD or BID, 3·0% QD, or vehicle QD or BID. In stage two, participants received brepocitinib 3·0% BID or vehicle BID. The primary endpoint was the change from baseline in Psoriasis Area and Severity Index (PASI) score at week 12, analysed using analysis of covariance. The key secondary endpoint was the proportion of participants who achieved a Physician Global Assessment (PGA) response (score of clear (0) or almost clear (1) and an improvement of ≥2 points from baseline) at week 12. Additional secondary endpoints included the difference vs. vehicle in change from baseline in PASI, using mixed-model repeated measures (MMRM), and the change from baseline in Peak Pruritus Numerical Rating Scale (PP-NRS) at week 12. Safety was monitored. Results Overall, 344 participants were randomised. Topical brepocitinib did not result in statistically significant changes from respective vehicle controls in the primary or key secondary efficacy endpoints for any dose group. At week 12, least squares mean (LSM) change from baseline in PASI score ranged from -1·4 to -2·4 for brepocitinib QD groups vs. -1·6 for vehicle QD, and from -2·5 to -3·0 for brepocitinib BID groups vs. -2·2 for vehicle BID. From week 8, change from baseline in PASI score separated from vehicle in all brepocitinib BID groups. Brepocitinib was well-tolerated with AEs occurring at similar rates across groups. One participant in the brepocitinib 1·0% QD group developed a treatment-related AE of herpes zoster in the neck area. Conclusion Topical brepocitinib was well-tolerated but did not result in statistically significant changes vs. vehicle when administered at the doses evaluated to treat signs and symptoms of mild-to-moderate PsO. Clinicaltrials.gov identifier NCT03850483

This article has earned an open data badge "Reproducible Research" for making publicly available the code necessary to reproduce the reported results. The results reported in this article could fully be reproduced.