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

Abstract

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.

Keywords:

• Attributes of estimands
• Composite variable strategy
• Hypothetical strategy
• Prioritized composite outcome

Supplementary Materials

The supplementary materials contain the correlation structure for data generation in the simulation (Supplementary table 1), and the simulation results in the weak correlation structure (Supplementary tables 2-5).

Acknowledgments

We would like to thank Udo-Michael Göhring, Peter Szecsödy, Jia Ma, Takayuki Ishii and Shun Shiota for their reviews.

Disclosure Statement

No potential competing interest was reported by the authors.

Additional information

Funding

This study was partly supported by a Grant-in-Aid for Early-Career Scientists (JSPS KAKENHI grant number 19K19383).