Use of Mediation in Designing Clinical Trials with Two Primary Endpoints

Clinical Trials are the gold standard for assessing the efficacy of newtreatments in the medical sciences. Efficacy is assessed by the effect oftreatment on a clinically relevant endpoint (e.g. death, time to cancerrecurrence etc). However, often times the assessment of efficacy is bestmeasured by the effect of treatment on multiple endpoints. For example, a drug may be assessed by it's effect on both a clinical endpoint and a intermediateendpoint that is a mechanistically related to the clinical endpoint. The current trend is to design studies to detect treatment effects on the clinical endpoint, and treat the intermediate endpoint as a secondary endpoint. However, pre-planned stopping criteria based on the primary clinical endpoint are often modified ad-hoc by considering the joint results on both endpoints. This can distort the operating characteristics of the trial and lead to erroneous conclusions. We propose methodology for specifying bivariate decision criteria at the design stage based on information from both endpoints. We incorporate the mechanistic relationship between the endpoints using concepts of statistical mediation. We illustrate the use of this method in both Fixed Sample and Group Sequential Designs using an example from a clinical trial in Pulmonary Arterial Hypertension.

Author

• Tripputi, Mark Thomas

Language

• en

Keyword

• Statistical Mediation
• Clinical Trial
• Bivariate Design
• Group Sequential

Date created

• 2009

Type of Work

• Dissertation

License

• All rights reserved

Rights statement

• In Copyright

GW Unit

• Biostatistics

Degree

• Ph.D.

Advisor

• Li, Zhaohai
• Kittelson, John

Committee Member(s)

• Liu, Aiyi
• Verme, Dante
• Lai, Yinglei
• Stroud, Jonathon
• Hoffman, Heather

Persistent URL

•  https://scholarspace.library.gwu.edu/etd/br86b362v