Faculty Collaboration Database

Group sequential clinical trial designs for composite endpoints incorporating recurrent and terminal events. Biometrics 2026 Jul 01;82(3)

Date

07/24/2026

Pubmed ID

42496177

Pubmed Central ID

PMC13397504

DOI

10.1093/biomtc/ujag135

Scopus ID

2-s2.0-105045424465 (requires institutional sign-in at Scopus site)

Abstract

Composite endpoints, which combine multiple events of interest, are commonly used in medical research. Compared to evaluating a single outcome, a composite endpoint analysis captures the full clinical impact of treatment and leverages a greater number of events, potentially reducing the required sample size for the study. While composite endpoints have gained much attention in clinical trials, studying them in group sequential designs remains challenging due to the correlated nature of event data collected from the same individual, as the sequence of test statistics may not possess an independent increments structure. In this paper, we propose both one-sample and two-sample group sequential designs grounded in the mean frequency function, defined as the cumulative count of all recurrent and terminal events over time. Recognizing the lack of independent increments, our proposed method leverages the asymptotic covariance structure of the test statistics to construct group sequential boundaries that control the Type I error rate. Extensive simulation studies show the proposed design controls Type I error well and achieves the desired power. We illustrate the utility of our method through a reanalysis of BMT CTN 1703, a phase III randomized controlled trial that evaluated an experimental therapy for the prevention of adverse outcomes after allogeneic stem cell transplant.

Author List

Lian Q, Ahn KW, Kim S, Logan BR, Solh M, Martens MJ

Author

Michael Martens PhD Associate Professor in the Data Science Institute department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Biometry
Bone Marrow Transplantation
Clinical Trials, Phase III as Topic
Computer Simulation
Data Interpretation, Statistical
Endpoint Determination
Humans
Models, Statistical
Randomized Controlled Trials as Topic
Recurrence
Research Design
Sample Size