Pharmacodynamic and clinical endpoints for functional colonic disorders: statistical considerations.
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).


OBJECTIVE
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
COV(inter) from 87 patients and COV(intra) from 17 patients are reported. Generally, COV(intra) is somewhat greater than COV(inter). 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.


CONCLUSIONS
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.
Division of Biomedical Statistics and Informatics, Department of Health Sciences Research,  College of Medicine, Mayo Clinic, 200 First St. S.W.,  Rochester, MN, USA.
Alan R
AR
Zinsmeister
Duane
D
Burton
Michael
M
Camilleri
D000328:Adult; D001549:Benzamides / Q000493:pharmacokinetics / Q000627:therapeutic use; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000493:pharmacokinetics / Q000627:therapeutic use; D002635:Chenodeoxycholic Acid / Q000493:pharmacokinetics / Q000627:therapeutic use; D017322:Clinical Trials, Phase II as Topic / Q000379:methods; D003108:Colonic Diseases / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000503:physiopathology; D003248:Constipation / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000503:physiopathology; D018849:Controlled Clinical Trials as Topic / Q000379:methods; D018592:Cross-Over Studies; D003967:Diarrhea / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000503:physiopathology; D005260:Female; D005765:Gastrointestinal Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005769:Gastrointestinal Motility / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D010421:Pentanoic Acids / Q000493:pharmacokinetics / Q000627:therapeutic use; D010455:Peptides / Q000493:pharmacokinetics / Q000627:therapeutic use; D011877:Radionuclide Imaging; D012702:Serotonin Antagonists / Q000493:pharmacokinetics / Q000627:therapeutic use
D001549:Benzamides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005765:Gastrointestinal Agents; D010421:Pentanoic Acids; D010455:Peptides; D012702:Serotonin Antagonists; D002635:Chenodeoxycholic Acid; C103490:dexloxiglumide; C053006:renzapride; C523483:linaclotide