The benefits of covariate adjustment for adaptive multi-arm designs

Covariate adjustment via a regression approach is known to increase the precision of statistical inference when fixed trial designs are employed in randomized controlled studies. When an adaptive multi-arm design is employed with the ability to select treatments, it is unclear how covariate adjustment affects various aspects of the study. Consider the design framework that relies on pre-specified treatment selection rule(s) and a combination test approach for hypothesis testing. It is our primary goal to evaluate the impact of covariate adjustment on adaptive multi-arm designs with treatment selection. Our secondary goal is to show how the Uniformly Minimum Variance Conditionally Unbiased Estimator can be extended to account for covariate adjustment analytically. We find that adjustment with different sets of covariates can lead to different treatment selection outcomes and hence probabilities of rejecting hypotheses. Nevertheless, we do not see any negative impact on the control of the familywise error rate when covariates are included in the analysis model. When adjusting for covariates that are moderately or highly correlated with the outcome, we see various benefits to the analysis of the design. Conversely, there is negligible impact when including covariates that are uncorrelated with the outcome. Overall, pre-specification of covariate adjustment is recommended for the analysis of adaptive multi-arm design with treatment selection. Having the statistical analysis plan in place prior to the interim and final analyses is crucial, especially when a non-collapsible measure of treatment effect is considered in the trial.