Effect of 5 Days Linaclotide on Transit and Bowel Function in Females With Constipation-Predominant Irritable Bowel Syndrome

doi:10.1053/j.gastro.2007.06.067

Gastroenterology

Volume 133, Issue 3, September 2007, Pages 761-768

https://doi.org/10.1053/j.gastro.2007.06.067 Get rights and content

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 μg 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 μg vs placebo (P = .004 and P = .01, respectively) but no significant effect of linaclotide 100-μg 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 μg once daily significantly accelerated ascending colonic transit and altered bowel function. Further randomized controlled trials of clinical efficacy of linaclotide are warranted.

Section snippets

Study Design, Participants, and Medication

This study was a single-site, double-blind, placebo-controlled, randomized, multiple repeat-dose study evaluating the pharmacodynamic effects of linaclotide, 100 and 1000 μg, and placebo administered orally once daily for 5 days in patients with IBS-C. We enrolled 36 female, nonpregnant, nonbreastfeeding participants aged 18–65 years with IBS-C, based on Rome II criteria.¹⁴ The study was approved by the Mayo Clinic Institutional Review Board, and all participants signed informed consent.

Participants, Study Conduct, and Completion

Forty-seven patients were recruited for the study, as shown in Figure 2. Six were ineligible because of concomitant medication or evidence of rectal evacuation disorder. Five were not randomized to treatment because their colonic transit at baseline was too fast, relative to the preset criteria. Demographic and baseline colonic transit data of all randomized patients are shown in Table 1. The linaclotide and placebo groups were similar regarding baseline values of colonic transit. All 36

Discussion

This study demonstrates that the novel, first-in-class GC-C agonist linaclotide accelerates ascending colon emptying and dose dependently improves bowel functions in female patients with IBS-C. There was also acceleration of overall colonic transit at 48 hours, but this was not significant at 24 hours. These results are consistent with prior findings of the pharmacodynamic effects of linaclotide in animals and observed changes in bowel function noted in both healthy volunteers during phase I

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: Description of trial analysis and access to data: This is a phase IIa trial. The statistical analysis of the entire data sets pertaining to efficacy (specifically primary and major secondary efficacy end points) and safety (specifically, serious adverse events as defined in federal guidelines) have been independently confirmed by a biostatistician (Dr. Zinsmeister) who is not employed by Microbia. The corresponding author, Dr. Camilleri, had full access to all of the data and takes full responsibility for the veracity of the data and analysis.

: Supported by Microbia, Inc. and grants RO1-DK54681 and K24-DK02638 from the National Institutes of Health (to M.C.) for research on irritable bowel syndrome.

: The authors thank Cindy Stanislav for excellent secretarial support.

: Employment and Disclosures: The authors, Drs. Kurtz, Sharma, Johnston, and Currie, are employees of Microbia. Dr. Kurtz facilitated planning and operational aspects as well as direct scientific guidance to this study. Dr. Sharma contributed to the scientific aspects and data management of the study. Dr. Johnston provided medical input to the design and interpretation of the data analysis from the study. Dr. Currie is the inventor of linaclotide and provided scientific direction to the development of the clinical studies.

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Clinical–alimentary tractEffect of 5 Days Linaclotide on Transit and Bowel Function in Females With Constipation-Predominant Irritable Bowel Syndrome

Section snippets

Study Design, Participants, and Medication

Participants, Study Conduct, and Completion

Discussion

Gastroenterology

Gastroenterology

Regul Pept

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Clin Gastroenterol Hepatol

Gastroenterology

Regul Pept

Eur J Pharm

Gastroenterology

Gastroenterology

Mechanisms in IBS: something old, something new, something borrowed

Neurogastroenterol Motil

Irritable bowel syndrome: recent and novel therapeutic approaches

Drugs

Clinical–alimentary tract
Effect of 5 Days Linaclotide on Transit and Bowel Function in Females With Constipation-Predominant Irritable Bowel Syndrome