Sample size re-estimation in crossover trials: application to the AIM HY-INFORM study.
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Wych, J., Grayling, M. J., & Mander, A. (2019). Sample size re-estimation in crossover trials: application to the AIM HY-INFORM study.. Trials, 20 (1), 665. https://doi.org/10.1186/s13063-019-3724-6
Background: Crossover designs are commonly utilised in randomised controlled trials investigating treatments for long-term chronic illnesses. One problem with this design is its inherent repeated measures necessitate the availability of an estimate of the within-person standard deviation (SD) to perform a sample size calculation, which may be rarely available at the design stage of a trial. Interim samplesize re-estimation designs can be used to help alleviate this issue by adapting the sample size mid-way through the trial, using accrued information in a statistically robust way. Methods: AIM HY-INFORM study is part of the Informative Markers in Hypertension (AIM HY) Programme and comprises two crossover trials, each with a planned recruitment of 600 participants. The objective of the study is to test whether blood pressure response to first line antihypertensive treatment depends on ethnicity. An interim analysis is planned to re-assess the assumptions of the planned sample size for the study. The aims of this paper are: (i) to provide a formula for sample size re-estimation in both crossover trials and (ii) to present a simulation study of the planned interim analysis to investigate alternative within-person SDs to that assumed. Results: The AIM HY-INFORM protocol sample size calculation fixes the within person SD to be 8 mmHg, giving over 90% power for a primary treatment effect of 4 mmHg. Using the method developed here and simulating the interim sample size re-assessment, if we were to see a larger within person SD of 9 mmHg at interim, 640 participants for 90% power 90% of the time in the three-period three-treatment design would be required. Similarly, in the four-period four-treatment crossover design, 602 participants would be required. Conclusions: The formulas presented here provide a method for re-estimating the sample size in crossover trials. In the context of the AIM HY-INFORM study, simulating the interim analysis allows us to explore the results of a possible increase in the within-person SD from that assumed. Simulations show that without increasing the planned sample size of 600 participants, we can reasonably still expect to achieve 80% power with a small increase in the within person SD from that assumed.
Humans, Hypertension, Antihypertensive Agents, Prospective Studies, Cross-Over Studies, Sample Size, Clinical Trials as Topic
Medical Research Council and British Heart Foundation (Medical Research Council Reference: MR/M016560/1; EUDRACT number 2016-000165-23).
MRC (via King's College London) (unknown)
External DOI: https://doi.org/10.1186/s13063-019-3724-6
This record's URL: https://www.repository.cam.ac.uk/handle/1810/297889
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