Paper detail

Combining Covariate Adjustment with Group Sequential, Information Adaptive Designs to Improve Randomized Trial Efficiency

In clinical trials, there is potential to improve precision and reduce the required sample size by appropriately adjusting for baseline variables in the statistical analysis. This is called covariate adjustment. Despite recommendations by regulatory agencies in favor of covariate adjustment, it remains underutilized leading to inefficient trials. We address two obstacles that make it challenging to use covariate adjustment. A first obstacle is the incompatibility of many covariate adjusted estimators with commonly used boundaries in group sequential designs (GSDs). A second obstacle is the uncertainty at the design stage about how much precision gain will result from covariate adjustment. We propose a method that modifies the original estimator so that it becomes compatible with GSDs, while increasing or leaving unchanged the estimator's precision. Our approach allows the use of any asymptotically linear estimator, which covers many estimators used in randomized trials. Building on this, we propose using an information adaptive design, that is, continuing the trial until the required information level is achieved. Such a design adapts to the amount of precision gain and can lead to faster, more efficient trials, without sacrificing validity or power. We evaluate estimator performance in simulations that mimic features of a completed stroke trial.