Background & aims: Oral linaclotide, a novel agonist of guanylate cylase-C, stimulates intestinal fluid secretion and transit, and decreases visceral hypersensitivity in animal studies. In healthy volunteers, linaclotide was safe, well tolerated, increased stool frequency, and decreased stool consistency and time to first bowel movement. This randomized, double-blind, placebo-controlled study evaluated the effects of oral linaclotide, 100 and 1000 microg once daily, in 36 women with constipation-predominant irritable bowel syndrome; colonic transit was normal in >50% patients.
Methods: Participants underwent 5-day baseline and 5-day treatment periods; gastrointestinal transit (by validated scintigraphy) and bowel function (by daily diaries) were assessed. Treatment effects were compared using analysis of covariance (baseline colonic transit as covariate) with pairwise comparisons of each dose vs placebo.
Results: There was a significant overall treatment effect on ascending colon emptying half-time (P = .015) and overall colonic transit at 48 hours (P = .02) but not overall transit at 24 hours (P = ns), with a significant acceleration by linaclotide 1000 microg vs placebo (P = .004 and P = .01, respectively) but no significant effect of linaclotide 100-microg dose. There were significant overall treatment effects on stool frequency, stool consistency, ease of passage, and time to first bowel movement with a strong dose response for stool consistency (overall, P < .001). No safety issues were identified.
Conclusions: In women with constipation-predominant irritable bowel syndrome, linaclotide 1000 microg once daily significantly accelerated ascending colonic transit and altered bowel function. Further randomized controlled trials of clinical efficacy of linaclotide are warranted.