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Hierarchical endpoints and win statistics for geromedicine trials
Mahmoud Abdellatif1,2,3, Yevgeniy Kim4, Guido Kroemer5,6,7
1Department of Cardiology, Medical University of Graz, Graz, Austria. Mahmoud.abdellatif@medunigraz.at.
Nature Aging
|June 24, 2026
Summary
Developing new clinical trial endpoints for geroscience is crucial. Hierarchical composite endpoints prioritize severe events while incorporating healthspan measures, improving trial efficiency and capturing treatment effects.
Area of Science:
- Geromedicine and Geroscience
- Clinical Trial Design
- Biomarker Research
Background:
- Geroscience has advanced, but clinical translation is limited by outcome measures.
- Existing trial endpoints (mortality, healthspan surrogates) have limitations in capturing multidimensional effects and meeting regulatory standards.
- Geroprotective interventions require novel outcome measures for effective clinical trial evaluation.
Purpose of the Study:
- To propose a pragmatic and scientifically sound compromise for clinical trial endpoints in geroscience.
- To introduce hierarchical composite endpoints using time-to-worst-event analysis.
- To enhance the efficiency and comprehensiveness of geromedicine trials.
Main Methods:
- Utilizing hierarchical composite endpoints with time-to-worst-event analysis.
- Comparing participant pairs using win statistics based on a prespecified clinical hierarchy.
- Prioritizing severe, objective clinical events while integrating health surrogates and biomarkers at lower tiers.
Main Results:
- The proposed method offers a compromise between objective mortality measures and feasible healthspan surrogates.
- Hierarchical endpoints can improve geromedicine trial efficiency.
- This approach allows for the capture of overall treatment effects without compromising clinical priorities when aligned with regulatory standards.
Conclusions:
- Hierarchical composite endpoints represent a pragmatic approach to evaluating geroprotective interventions.
- This methodology enhances clinical trial design in geroscience by balancing clinical significance and feasibility.
- Successful implementation requires clinical justification, mechanistic rationale, and regulatory agreement for outcome selection and ordering.
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