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Pharmacodynamic and clinical endpoints for functional colonic disorders: statistical considerations
Alan R Zinsmeister1, Duane Burton, Michael Camilleri
1Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, College of Medicine, Mayo Clinic, 200 First St. S.W., Rochester, MN, USA.
Digestive Diseases and Sciences
|August 25, 2012
Summary
Pharmacodynamic (PD) colonic transit endpoints show lower variability than clinical outcomes in functional gastrointestinal disorder (FGID) studies. This allows for efficient trial design, potentially reducing sample sizes needed to demonstrate treatment efficacy.
Area of Science:
- Gastroenterology
- Clinical Pharmacology
- Biostatistics
Background:
- Scintigraphic colonic transit (SCT) coefficients of variation (COV) are established in lower functional gastrointestinal disorders (FGID).
- SCT response to therapy is a key predictor of clinical efficacy for experimental FGID medications.
Purpose of the Study:
- To compare the variability (COVs) of bowel function endpoints with pharmacodynamic (PD) colonic transit geometric center (GC) endpoints in lower FGID studies.
- To assess the feasibility of Phase IIA studies incorporating both clinical and PD endpoints for FGID.
Main Methods:
- Analysis of data from the placebo arm of 9 Phase IIA clinical trials involving various drugs for constipation and diarrhea-predominant FGID.
- Evaluation of daily patient diary data including stool frequency, consistency (Bristol Stool Form Scale), and ease of passage.
- Calculation of sample sizes required to detect a 30% effect size for colonic transit, stool frequency, consistency, and ease of passage.
Main Results:
- Intra-patient COVs were generally slightly greater than inter-patient COVs.
- Pharmacodynamic (PD) endpoints exhibited lower COVs compared to clinical endpoints.
- Clinically relevant effects can be identified with modest increases in sample size using parallel-group designs.
Conclusions:
- Phase IIA studies integrating clinical and PD endpoints are feasible for FGID patients experiencing constipation or diarrhea.
- Crossover study designs may necessitate smaller sample sizes for most endpoints compared to parallel-group studies.
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