Valid test for multi-arm trials with generalized linear models under covariate-adaptive randomization

Abstract

Modern medical research, such as dose-finding studies, seamless trials, and shared control designs, often involves comparing multiple treatments simultaneously. Despite its wide applications, most research focuses on continuous endpoints, leaving the inference for general outcome types in high demand. In this article, we propose a new inference method for conducting multiple-treatment comparisons involving endpoints within the generalized linear model (GLM) framework under covariate-adaptive randomization (CAR). First, we investigate the asymptotic properties of the standard Wald z-statistics (z-scores) in multi-arm trials, highlighting issues when the working model is misspecified, particularly through omitted covariates. Our theoretical findings reveal that these \textcolor{black}{z-scores} do not consistently converge to a standard multivariate normal distribution, leading to either conservative or inflated Type I error rates, depending on the specific GLM endpoint. Second, based on these theoretical results, we develop adjusted test statistics to correct the distributional problems. To appropriately control the family-wise Type I error rate inherent in multi-arm comparisons, we incorporate our adjusted statistics with Simes-type multiple-testing procedures. This robust inference method can effectively control Type I error while potentially improving power. Extensive simulation studies and a real-world application to a metastatic breast cancer trial confirm the effectiveness and practicality of our approach.