Gastroenterology

Gastroenterology

Volume 139, Issue 6, December 2010, Pages 1877-1886.e2
Gastroenterology

Clinical—Alimentary Tract
Linaclotide Improves Abdominal Pain and Bowel Habits in a Phase IIb Study of Patients With Irritable Bowel Syndrome With Constipation

https://doi.org/10.1053/j.gastro.2010.08.041Get rights and content

Background & Aims

Linaclotide, a minimally absorbed, 14-amino acid peptide agonist of guanylate cyclase-C, has shown benefit in a proof-of-concept study for the treatment of patients with irritable bowel syndrome (IBS) with constipation (IBS-C). We assessed the efficacy and safety of linaclotide at a daily dose range of 75–600 μg in IBS-C.

Methods

We performed a randomized, double-blind, multicenter, placebo-controlled study of 420 patients with IBS-C given oral linaclotide at doses of 75, 150, 300, or 600 μg or placebo once daily for 12 weeks. End points included change from baseline in daily bowel habits, daily abdominal symptoms, and weekly global assessments, in addition to responder criteria.

Results

All doses of linaclotide significantly improved bowel habits, including frequency of spontaneous bowel movements and complete spontaneous bowel movements (primary end point), severity of straining, and stool consistency. Abdominal pain was significantly reduced from baseline, compared with placebo; mean changes in abdominal pain (assessed on a 5-point scale) from baseline were −0.71, −0.71, −0.90, and −0.86 for linaclotide doses of 75, 150, 300, and 600 μg, respectively, compared with −0.49 for placebo. Likewise, most doses of linaclotide significantly improved other abdominal symptoms, including discomfort and bloating, and global measures of IBS-C compared with placebo. Effects were observed within the first week and were sustained throughout 12 weeks of treatment. Except for diarrhea, the incidence of adverse events was similar between placebo and linaclotide groups.

Conclusions

Linaclotide, across a wide range of doses, significantly improved symptoms of IBS-C, including abdominal pain and bowel symptoms. Diarrhea was the only dose-dependent adverse event and was usually of mild or moderate severity.

Section snippets

Study Design

A randomized, double-blind, parallel-group, placebo-controlled, phase IIb study was conducted at 92 clinical centers in the United States and Canada between March 2007 (first patient randomized) and February 2008 (last patient completed). The study was performed in accordance with the Declaration of Helsinki and US21 Code of Federal Regulations and registered on clinicaltrials.gov (NCT00460811). Written informed consent was obtained from each patient prior to participation in the study. The

Patient Disposition, Demographics, and Baseline Characteristics

Nine hundred ninety-six (996) patients signed consent forms, of whom 254 were screen failures and 322 were pretreatment failures. Four hundred twenty patients were randomized to 1 of the 5 treatment arms of the study and received study medication (safety population, N = 420). All but 1 of these patients had at least 1 assessment of the primary efficacy end point (intent-to-treat population, n = 419). A total of 83 (19.8%) patients did not complete the study: 25 (6.0%) because of AEs, 4 (1.0%)

Discussion

The results of this large, 12-week, placebo-controlled trial show that across a wide range of doses linaclotide statistically significantly improved multiple symptoms of IBS-C, including abdominal pain, bloating, and constipation. Linaclotide also resulted in statistically significant improvements in several global measurements. Linaclotide's effects occurred within the first week of therapy and were sustained for the entire 3-month duration of this study. Thus, linaclotide resulted in

Acknowledgments

The authors thank the investigators for their participation in this study and Nicole LaVallee, PhD, who independently reviewed the data set and confirmed the analyses.

Clinicaltrials.gov ID: NCT00460811.

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 Nicole LaVallee, PhD, a biostatistician

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    Conflicts of interest The authors disclose the following: Jeffrey Johnston, Caroline Kurtz, James MacDougall, B. J. Lavins, Mark Currie, Donald Fitch, Chris O'Dea, and Mollie Baird are employees of Ironwood Pharmaceuticals. Anthony Lembo is a paid consultant to Ironwood Pharmaceuticals.

    Funding Supported by Ironwood Pharmaceuticals.

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