Design and Analysis of Group Sequential Clinical Trials with Multiple Primary Endpoints
Article first published online: 11 MAR 2004
Volume 60, Issue 1, pages 134–145, March 2004
How to Cite
Kosorok, M. R., Yuanjun, S. and DeMets, D. L. (2004), Design and Analysis of Group Sequential Clinical Trials with Multiple Primary Endpoints. Biometrics, 60: 134–145. doi: 10.1111/j.0006-341X.2004.00146.x
- Issue published online: 11 MAR 2004
- Article first published online: 11 MAR 2004
- Received September 2002. Revised July 2003. Accepted September 2003.
- Alpha-spending function;
- Beta-spending function;
- Multivariate outcomes;
- Sample size;
- Time-to-event data
Summary. In many phase III clinical trials, it is desirable to separately assess the treatment effect on two or more primary endpoints. Consider the MERIT-HF study, where two endpoints of primary interest were time to death and the earliest of time to first hospitalization or death (The International Steering Committee on Behalf of the MERIT-HF Study Group, 1997, American Journal of Cardiology80[9B], 54J–58J). It is possible that treatment has no effect on death but a beneficial effect on first hospitalization time, or it has a detrimental effect on death but no effect on hospitalization. A good clinical trial design should permit early stopping as soon as the treatment effect on both endpoints becomes clear. Previous work in this area has not resolved how to stop the study early when one or more endpoints have no treatment effect or how to assess and control the many possible error rates for concluding wrong hypotheses. In this article, we develop a general methodology for group sequential clinical trials with multiple primary endpoints. This method uses a global alpha-spending function to control the overall type I error and a multiple decision rule to control error rates for concluding wrong alternative hypotheses. The method is demonstrated with two simulated examples based on the MERIT-HF study.