A Nonparametric Global Win Probability Approach to the Analysis and Sizing of Randomized Controlled Trials With Multiple Endpoints of Different Scales and Missing Data: Beyond O'Brien-Wei-Lachin.

Abstract

Multiple primary endpoints are commonly used in randomized controlled trials to assess treatment effects. When the endpoints are measured on different scales, the O'Brien rank-sum test or the Wei-Lachin test for stochastic ordering may be used for hypothesis testing. However, the O'Brien-Wei-Lachin (OWL) approach is unable to handle missing data and adjust for baseline measurements. We present a nonparametric approach for data analysis that encompasses the OWL approach as a special case. Our approach is based on quantifying an endpoint-specific treatment effect using the probability that a participant in the treatment group has a better score than (or a win over) a participant in the control group. The average of the endpoint-specific win probabilities (WinPs), termed the global win probability (gWinP), is used to quantify the global treatment effect, with the null hypothesis gWinP = 0.50. Our approach involves converting the data for each endpoint to endpoint-specific win fractions, and modeling the win fractions using multivariate linear mixed models to obtain estimates of the endpoint-specific WinPs and the associated variance-covariance matrix. Focusing on confidence interval estimation for the gWinP, we derive sample size formulas for clinical trial design. Simulation results demonstrate that our approach performed well in terms of bias, interval coverage percentage, and assurance of achieving a pre-specified precision for the gWinP. Illustrative code for implementing the methods using SAS PROC RANK and PROC MIXED is provided.