Randomized controlled trials with time-to-event outcomes:: How much does prespecified covariate adjustment increase power?

PURPOSE: We evaluated the effects of various strategies of covariate adjustment on type I error, power, and potential reduction in sample size in randomized controlled trials (RCTs) with time-to-event outcomes. METHODS: We used Cox models in simulated data sets with different treatment effects (hazard ratios [HRs] = 1, 1.4, and 1.7), covariate effects (HRs = 1, 2, and 5), covariate prevalences (10% and 50%), and censoring levels (no, low, and high). Treatment and a single covariate were dichotomous. We examined the sample size that gives the same power as an unadjusted analysis for three strategies: prespecified, significant predictive, and significant imbalance. RESULTS: Type I error generally was at the nominal level, The power to detect a true treatment effect was greater with adjusted than unadjusted analyses, especially with prespecified and significant-predictive strategies. Potential reductions in sample size with a covariate HR between 2 and 5 were between 15% and 44% (covariate prevalence 50%) and between 4% and 12% (covariate prevalence 10%). The significant imbalance strategy yielded small reductions. The reduction was greater with stronger covariate effects, but was independent of treatment effect, sample size, and censoring level. CONCLUSIONS: Adjustment for one predictive baseline characteristic yields greater power to detect a true treatment effect than unadjusted analysis, without inflation of type I error and with potentially moderate reductions in sample size. Analysis of RCTs with time-to-event outcomes should adjust for predictive covariates.