Guidelines for calculating sample size in 2 x 2 crossover trials : a simulation study

In crossover trials, patients receive two or more treatments in a random order in different periods. The sample size determination is often an important step in planning a crossover study. This paper concerns sample size calculations in 2x2 crossover trials, with random patient effects and no interaction between the treatment and the patient under two scenarios, namely the exact and the large sample size approaches. Simulation was carried out for determining the sample size for both scenarios. For varying parameter values, simulation was used for generating samples of the required size and examining whether the significance level and power of the tests are maintained. The results indicate that when the sample size was ≤ 5, neither method maintained error rates and when the sample size was >5 and < 12 only the exact approach maintained error rates. However, when the sample size is approximately > 12 both methods maintained error rates. In addition it was found that a saving in sample size can be achieved depending on the extent of the correlation between the observations on the same patient. The simulation results indicate that crossover studies should not be conducted when the anticipated sample size is ≤ 5 and when a sample size of >5 and < 12 is anticipated, the exact method of determining sample size should be used. When larger sample sizes are anticipated either method can be used but the method based on large sample size approximation is simpler.