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. 2025 May;44(10-12):e70082.
doi: 10.1002/sim.70082.

Accounting for Inconsistent Use of Covariate Adjustment in Group Sequential Trials

Marlena S Bannick  1 , Sonya L Heltshe  2 , Noah Simon  1   3
Affiliations

Accounting for Inconsistent Use of Covariate Adjustment in Group Sequential Trials

Marlena S Bannick et al. Stat Med. 2025 May.

Abstract

Group sequential designs in clinical trials allow for interim efficacy and futility monitoring. Adjustment for baseline covariates can increase power and precision of estimated effects. However, inconsistently applying covariate adjustment throughout the stages of a group sequential trial can result in inflation of type I error, biased point estimates, and anticonservative confidence intervals. We propose methods for performing correct interim monitoring, estimation, and inference in this setting that avoid these issues. We focus on two-arm trials with simple, balanced randomization and continuous outcomes. We study the performance of our boundary, estimation, and inference adjustments in simulation studies. We end with recommendations about the application of covariate adjustment in group sequential designs.

Keywords: clinical trials; covariate adjustment; group sequential trials.

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References

    1. L. Yang and A. A. Tsiatis, “Efficiency Study of Estimators for a Treatment Effect in a Pretest‐Posttest Trial,” American Statistician 55, no. 4 (2001): 314–321.
    1. E. Colantuoni and M. Rosenblum, “Leveraging Prognostic Baseline Variables to Gain Precision in Randomized Trials,” Statistics in Medicine 34, no. 18 (2015): 2602–2617, https://doi.org/10.1002/sim.6507.
    1. K. Van Lancker, A. Vandebosch, and S. Vansteelandt, “Improving Interim Decisions in Randomized Trials by Exploiting Information on Short‐Term Outcomes and Prognostic Baseline Covariates,” print, (2019).
    1. B. Wang, E. L. Ogburn, and M. Rosenblum, “Analysis of Covariance in Randomized Trials: More Precision and Valid Confidence Intervals, Without Model Assumptions,” Biometrics 75, no. 4 (2019): 1391–1400, https://doi.org/10.1111/biom.13062.
    1. B. Wang, R. Susukida, R. Mojtabai, M. Amin‐Esmaeili, and M. Rosenblum, “Model‐Robust Inference for Clinical Trials That Improve Precision by Stratified Randomization and Covariate Adjustment,” Journal of the American Statistical Association 118, no. 542 (2021): 1–12, https://doi.org/10.1080/01621459.2021.1981338.

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