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Group sequential designs for stepped-wedge cluster randomised trials.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Grayling, Michael J 
Wason, James Ms 
Mander, Adrian P 

Abstract

BACKGROUND/AIMS: The stepped-wedge cluster randomised trial design has received substantial attention in recent years. Although various extensions to the original design have been proposed, no guidance is available on the design of stepped-wedge cluster randomised trials with interim analyses. In an individually randomised trial setting, group sequential methods can provide notable efficiency gains and ethical benefits. We address this by discussing how established group sequential methodology can be adapted for stepped-wedge designs. METHODS: Utilising the error spending approach to group sequential trial design, we detail the assumptions required for the determination of stepped-wedge cluster randomised trials with interim analyses. We consider early stopping for efficacy, futility, or efficacy and futility. We describe first how this can be done for any specified linear mixed model for data analysis. We then focus on one particular commonly utilised model and, using a recently completed stepped-wedge cluster randomised trial, compare the performance of several designs with interim analyses to the classical stepped-wedge design. Finally, the performance of a quantile substitution procedure for dealing with the case of unknown variance is explored. RESULTS: We demonstrate that the incorporation of early stopping in stepped-wedge cluster randomised trial designs could reduce the expected sample size under the null and alternative hypotheses by up to 31% and 22%, respectively, with no cost to the trial's type-I and type-II error rates. The use of restricted error maximum likelihood estimation was found to be more important than quantile substitution for controlling the type-I error rate. CONCLUSION: The addition of interim analyses into stepped-wedge cluster randomised trials could help guard against time-consuming trials conducted on poor performing treatments and also help expedite the implementation of efficacious treatments. In future, trialists should consider incorporating early stopping of some kind into stepped-wedge cluster randomised trials according to the needs of the particular trial.

Description

Keywords

Stepped wedge, cluster randomised trial, error spending, group sequential, interim analyses, Endpoint Determination, Humans, Linear Models, Medical Futility, Patient Selection, Randomized Controlled Trials as Topic, Research Design, Sample Size, Treatment Outcome

Journal Title

Clin Trials

Conference Name

Journal ISSN

1740-7745
1740-7753

Volume Title

14

Publisher

SAGE Publications
Sponsorship
Medical Research Council (MR/N028171/1)
MRC (unknown)
Wellcome Trust (099770/Z/12/Z)