Study design for restricted mean time analysis of recurrent events and death

Lu Mao

Biometrics, 2023, vol. 79, issue 4, 3701-3714

Abstract: The restricted mean time in favor (RMT‐IF) of treatment has just been added to the analytic toolbox for composite endpoints of recurrent events and death. To help practitioners design new trials based on this method, we develop tools to calculate the sample size and power. Specifically, we formulate the outcomes as a multistate Markov process with a sequence of transient states for recurrent events and an absorbing state for death. The transition intensities, in this case the instantaneous risks of another nonfatal event or death, are assumed to be time‐homogeneous but nonetheless allowed to depend on the number of past events. Using the properties of Coxian distributions, we derive the RMT‐IF effect size under the alternative hypothesis as a function of the treatment‐to‐control intensity ratios along with the baseline intensities, the latter of which can be easily estimated from historical data. We also reduce the variance of the nonparametric RMT‐IF estimator to calculable terms under a standard set‐up for censoring. Simulation studies show that the resulting formulas provide accurate approximation to the sample size and power in realistic settings. For illustration, a past cardiovascular trial with recurrent‐hospitalization and mortality outcomes is analyzed to generate the parameters needed to design a future trial. The procedures are incorporated into the rmt package along with the original methodology on the Comprehensive R Archive Network (CRAN).

Date: 2023
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