Sample size re-estimation in crossover trials: application to the AIM HY-INFORM study

Julie Wych,Adrian P Mander,Michael J Grayling

doi:10.1186/s13063-019-3724-6

Abstract

BackgroundCrossover 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 sample size 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.MethodsThe 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 reassess the assumptions of the planned sample size for the study. The aims of this paper are: (1) to provide a formula for sample size re-estimation in both crossover trials; and (2) to present a simulation study of the planned interim analysis to investigate alternative within-person SDs to that assumed.ResultsThe AIM HY-INFORM protocol sample size calculation fixes the within-person SD to be 8 mmHg, giving > 90% power for a primary treatment effect of 4 mmHg. Using the method developed here and simulating the interim sample size reassessment, 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.ConclusionsThe 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.Trial registrationClinicalTrials.gov, NCT02847338. Registered on 28 July 2016.

Highlights

Crossover designs are commonly utilised in randomised controlled trials investigating treatments for long-term chronic illnesses
A 2 mmHg increase in within-person standard deviation (SD) from that assumed in the protocol means that 75% of the time with a sample size of 979 participants would give us 80% power detect a treatment effect of 3 mmHg (Fig. 3)
A 2 mmHg increase in within-person SD from that assumed in the protocol means that 75% of trials with a sample size of 966 participants would give us 80% power detect a planned treatment effect of 3 mmHg; again, in both scenarios, fewer participants are required than in the monotherapy trial, as a result of having more measurements overall in the dual-therapy trial

Summary

Introduction

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. The UK hypertension NICE guidance (CG127) stratifies hypertension treatment by age and self-defined ethnicity (SDE), with guidelines adopting a ‘black versus white’ approach [2] The problems with this stratification include a lack of data from UK populations supporting the current SDE stratification and no reference to South Asians – the largest ethnic minority group in the UK [2]. With the absence of reliable prior estimates of the within-person SD available for the AIMHY INFORM study, in particular for South Asian ethnicities, the calculation of the required sample size to ensure the desired power to detect a single treatmentby-ethnic interaction is challenging

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