Multi-arm multi-stage trials can improve the efficiency of finding effective treatments for stroke: a case study

Thomas Jaki, James M S Wason, Thomas Jaki, James M S Wason

Abstract

Background: Many recent Stroke trials fail to show a beneficial effect of the intervention late in the development. Currently a large number of new treatment options are being developed. Multi-arm multi-stage (MAMS) designs offer one potential strategy to avoid lengthy studies of treatments without beneficial effects while at the same time allowing evaluation of several novel treatments. In this paper we provide a review of what MAMS designs are and argue that they are of particular value for Stroke trials. We illustrate this benefit through a case study based on previous published trials of endovascular treatment for acute ischemic stroke. We show in this case study that MAMS trials provide additional power for the same sample size compared to alternative trial designs. This level of additional power depends on the recruitment length of the trial, with most efficiency gained when recruitment is relatively slow. We conclude with a discussion of additional considerations required when starting a MAMS trial.

Conclusion: MAMS trial designs are potentially very useful for stroke trials due to their improved statistical power compared to the traditional approach.

Keywords: Adaptive design; Clinical trial design; Multi-arm multi-stage trials; Multi-arm trials.

Conflict of interest statement

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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Figures

Fig. 1
Fig. 1
Illustration of a multi-arm multi-stage design. Crosses represent the test statistic at each analysis for each of the experimental arms against control. The upper dashed line represents the efficacy boundary (with a treatment being recommended as superior to control if the test statistic is above this), and the lower dash-dotted line represents the futility boundary (with the treatment being stopped early for lack of benefit if the test statistic is below this)
Fig. 2
Fig. 2
Plots of a) power and b) expected sample size of separate trials and MAMS trial as the probability of success of one experimental arm changes. Probability of success for the other arms is 0.309. MAMS: multi-arm multi-stage; GS: group-sequential
Fig. 3
Fig. 3
Expected sample size of MAMS design as monthly recruitment rate changes. Constant recruitment is assumed and a 90 day delay is assumed between recruitment and observing the primary endpoint. Vertical dotted line represents recruitment rate of trials described in Ciccone et al. and Broderick et al. combined

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