Incorporating baseline measurements into the analysis of crossover trials with time-to-event endpoints.

ABSTRACT

Two-period two-treatment (2×2) crossover designs are commonly used in clinical trials. For continuous endpoints, it has been shown that baseline (pretreatment) measurements collected before the start of each treatment period can be useful in improving the power of the analysis. Methods to achieve a corresponding gain for censored time-to-event endpoints have not been adequately studied. We propose a method in which censored values are treated as missing data and multiply imputed using prespecified parametric event time models. The event times in each imputed data set are then log-transformed and analyzed using a linear model suitable for a 2×2 crossover design with continuous endpoints, with the difference in period-specific baselines included as a covariate. Results obtained from the imputed data sets are synthesized for point and confidence interval estimation of the treatment ratio of geometric mean event times using model averaging in conjunction with Rubin's combination rule. We use simulations to illustrate the favorable operating characteristics of our method relative to two other methods for crossover trials with censored time-to-event data, ie, a hierarchical rank test that ignores the baselines and a stratified Cox model that uses each study subject as a stratum and includes period-specific baselines as a covariate. Application to a real data example is provided.