Optimizing Primary Analyses in Randomized Controlled Trials with Multiple Endpoints: A Simulation Study with Application to Kidney Transplantation

Optimizing Primary Analyses in Randomized Controlled Trials with Multiple Endpoints: A Simulation Study with Application to Kidney Transplantation | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Optimizing Primary Analyses in Randomized Controlled Trials with Multiple Endpoints: A Simulation Study with Application to Kidney Transplantation Felix Herkner, Martin Posch, Gregor Bond, Franz König This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7591828/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 13 Feb, 2026 Read the published version in Scientific Reports → Version 1 posted 11 You are reading this latest preprint version Abstract Relying on a single primary endpoint in randomized controlled trials (RCTs) is often not feasible, e.g. due to low event rates. We explored three approaches to consider multiple endpoints in the primary analysis of RCTs, as stated in the FDA and EMA guidelines on multiplicity issues: (i) a composite endpoint (CE), (ii) multiple testing and multiplicity correction (MTMC), and (iii) a hierarchical non-parametric procedure, called generalized pairwise comparisons (GPC). By means of clinical trial simulations, a broad range of scenarios were investigated to assess the operating characteristics of different strategies to incorporate multiple endpoints into the primary analysis of two-arm RCTs. Both time-to-event and binary endpoints were explored. When testing time-to-event endpoints, we found that the composite approach and GPC were outperforming MTMC in the majority of scenarios. Furthermore, we observed that testing a binary compared to a time-to-event composite endpoint only marginally decreased power. As trials using multiple endpoints are on the rise, understanding how the approaches make use of the limited information available in the analysis of commonly used endpoints will be crucial. Our work supports the choice of endpoint definitions and associated analysis approaches in future trials. Biological sciences/Computational biology and bioinformatics Health sciences/Medical research Full Text Additional Declarations No competing interests reported. Supplementary Files OnlineSupplementHerknerOptimisingMultipleEndpoints.pdf Cite Share Download PDF Status: Published Journal Publication published 13 Feb, 2026 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 06 Oct, 2025 Reviews received at journal 04 Oct, 2025 Reviews received at journal 28 Sep, 2025 Reviewers agreed at journal 26 Sep, 2025 Reviewers agreed at journal 26 Sep, 2025 Reviewers agreed at journal 24 Sep, 2025 Reviewers invited by journal 24 Sep, 2025 Editor assigned by journal 24 Sep, 2025 Editor invited by journal 22 Sep, 2025 Submission checks completed at journal 19 Sep, 2025 First submitted to journal 19 Sep, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7591828","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":525202497,"identity":"99b8446a-d4ac-42a7-b41a-81e27b9a72eb","order_by":0,"name":"Felix Herkner","email":"","orcid":"","institution":"Medical University of Vienna","correspondingAuthor":false,"prefix":"","firstName":"Felix","middleName":"","lastName":"Herkner","suffix":""},{"id":525202498,"identity":"3fdc9cb5-b7ad-41a3-b8c0-5897ce93bdd3","order_by":1,"name":"Martin Posch","email":"","orcid":"","institution":"Medical University of 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