Methodological study demonstrates how inconsistent covariate adjustment biases group sequential trials, suggesting new boundary corrections prevent type I error inflation.
Group sequential designs in clinical trials allow for interim efficacy and futility monitoring. Adjustment for baseline covariates can increase power and precision of estimated effects. However, inconsistently applying covariate adjustment throughout the stages of a group sequential trial can result in inflation of type I error, biased point estimates, and anticonservative confidence intervals. We propose methods for performing correct interim monitoring, estimation, and inference in this setting that avoid these issues. We focus on two-arm trials with simple, balanced randomization and continuous outcomes. We study the performance of our boundary, estimation, and inference adjustments in simulation studies. We end with recommendations about the application of covariate adjustment in group sequential designs.
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Bannick et al. (2025) studied this question.
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