Digestive Diseases and Sciences

, Volume 58, Issue 2, pp 509–518

Pharmacodynamic and Clinical Endpoints for Functional Colonic Disorders: Statistical Considerations

  • Alan R. Zinsmeister
  • Duane Burton
  • Michael Camilleri
Original Article

DOI: 10.1007/s10620-012-2369-z

Cite this article as:
Zinsmeister, A.R., Burton, D. & Camilleri, M. Dig Dis Sci (2013) 58: 509. doi:10.1007/s10620-012-2369-z
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Abstract

Background

Intra- and inter-subject coefficients of variation (COV) of scintigraphic colonic transit (SCT) are well characterized. SCT response to therapy predicts clinical efficacy of experimental medications in lower functional gastrointestinal disorders (FGID).

Aim

To compare COVs for bowel function with pharmacodynamic (PD) colonic transit geometric center (GC) as endpoints in lower FGID studies.

Methods

We evaluated data from placebo arm of 9 phase IIA, parallel-group, clinical trials of PD effects of linaclotide, dexloxiglumide, renzapride, elobixibat, ROSE 010, and chenodeoxycholate in lower FGID with constipation, and pexacerafont, VSL#3, and colesevelam in lower FGID with diarrhea. Patients completed daily diaries for at least 7 days of stool frequency, consistency (7-point Bristol Stool Form Scale), and ease of passage (7-point scale from manual disimpaction to incontinence). Seventeen patients received placebo in 2 separate studies allowing assessment of intra-patient COVs. We calculated sample sizes required to demonstrate a 30 % effect size for colonic transit, stool frequency, consistency and ease of passage for patients with lower FGID with constipation and, separately, diarrhea.

Results

COVinter from 87 patients and COVintra from 17 patients are reported. Generally, COVintra is somewhat greater than COVinter. The COVs for PD endpoints are lower than for clinical endpoints; however, clinically relevant effects can be identified with modest (~50 %) increases in the sample size using parallel-group design studies.

Conclusion

Phase IIA studies that incorporate clinical and PD endpoints are feasible in lower FGID associated with constipation or diarrhea. Crossover design would require lower sample size for most endpoints compared to parallel-group studies.

Keywords

TransitConstipationDiarrheaParallelCrossover

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Alan R. Zinsmeister
    • 2
  • Duane Burton
    • 1
  • Michael Camilleri
    • 1
  1. 1.Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), College of MedicineMayo ClinicRochesterUSA
  2. 2.Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, College of MedicineMayo Clinic RochesterUSA