Estimands for Continuous Longitudinal Outcomes in the Presence of Treatment Discontinuation—A Simulation Study in Hyperkalemia Treatments

The ICH-E9 (R1) addendum guideline requires a precise description of the treatment effect of interest, named “estimand,” reflecting the clinical question posed by the trial objective, in each specific therapeutic setting. In clinical trials evaluating maintenance treatments, such as hyperkalemia treatments, one of the intercurrent events is planned treatment discontinuation due to abnormal laboratory values (outside the acceptable range). When using longitudinal data for evaluation, the mixed model for repeated measures, responder analysis, and survival analysis are often used to deal with intercurrent events. Under composite variable or hypothetical strategies, prioritized composite outcome or the last rank carried forward can also be considered. In this study, we propose a prioritized composite outcome in clinical trials evaluating maintenance treatments with treatment discontinuation. In addition, the estimand for each analysis was defined, and operating characteristics were evaluated. Simulation studies indicate the usefulness of the prioritized composite outcome using the composite variable strategy and the mixed model for repeated measures using the hypothetical strategy.