Gastroenterology

Gastroenterology

Volume 138, Issue 3, March 2010, Pages 886-895.e1
Gastroenterology

Clinical—Alimentary Tract
Efficacy of Linaclotide for Patients With Chronic Constipation

https://doi.org/10.1053/j.gastro.2009.12.050Get rights and content

Background & Aims

Linaclotide is a minimally absorbed peptide agonist of the guanylate cyclase-C receptor that stimulates intestinal fluid secretion and transit and reduces pain in animal models. We assessed the safety and efficacy of a range of linaclotide doses in patients with chronic constipation.

Methods

We performed a multicenter, double-blind, placebo-controlled, parallel-group study of 310 patients with chronic constipation. Patients were randomly assigned to groups given 75, 150, 300, or 600 μg oral linaclotide or placebo once daily for 4 weeks. Symptom assessments included spontaneous bowel movements (SBMs), complete SBMs, stool consistency, straining, abdominal discomfort, and bloating. Severity of constipation, adequate relief of constipation, global relief of constipation, treatment satisfaction, quality of life, adverse events, clinical laboratory data, and electrocardiogram results were assessed.

Results

All doses of linaclotide improved the weekly rate of SBM (primary end point) compared with placebo; the increases in overall weekly number of SBMs from baseline were 2.6, 3.3, 3.6, and 4.3 for linaclotide doses of 75, 150, 300, and 600 μg, respectively, compared with 1.5 for placebo (P ≤ .05 for each pair-wise comparison of a linaclotide dose to placebo). Likewise, linaclotide significantly improved the weekly rate of complete SBM, stool consistency, straining, abdominal discomfort, bloating, global assessments, and quality of life. The most common and only dose-related adverse event was diarrhea (only 6 patients discontinued treatment because of diarrhea).

Conclusions

Linaclotide therapy was associated with few adverse events and produced rapid and sustained improvement of bowel habits, abdominal symptoms, global relief, and quality of life in patients with chronic constipation.

Section snippets

Study Design

A randomized, double-blind, parallel-group, placebo-controlled, dose-range−finding study was conducted at 57 clinical centers in the United States between November 2006 (first signed informed consent) and December 2007 (last patient visit). The study was performed in accordance with the Declaration of Helsinki and US21 Code of Federal Regulations. Written informed consent was obtained from all patients prior to their participating in the study. Each participating center's Institutional Review

Participant Flow and Demographics

Of the 639 patients who signed consent, 120 were screen failures, 209 were pretreatment failures, and 310 patients were randomized to 1 of the 5 arms of the study. One patient randomized to 150 μg linaclotide withdrew prior to receiving the study medication (safety population, n = 309), 2 additional patients withdrew prior to any postdose evaluation of the primary efficacy assessment (Intent-to-Treat population, n = 307) and 32 additional patients discontinued while receiving study medication

Discussion

In this dose-range−finding study in patients with CC, linaclotide, a minimally absorbed GC-C receptor agonist, significantly improved bowel habits and abdominal symptoms associated with constipation. Linaclotide's effects on bowel habits were observed within 24 hours after the start of the medication and maintained throughout the 4 weeks of treatment, with no evidence of rebound constipation after discontinuation of the medication during the 14-day follow-up period. There was evidence of a

Acknowledgments

The authors thank the investigators for their participation in this study.

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 not employed by the corporate entity.

Clinicaltrials.gov ID NCT00402337.

References (27)

  • A. Wald et al.

    The burden of constipation on quality of life: results of a multinational survey

    Aliment Pharmacol Ther

    (2007)
  • J.F. Johanson et al.

    Chronic constipation: a survey of the patient perspective

    Aliment Pharmacol Ther

    (2007)
  • N.J. Talley

    Functional gastrointestinal disorders as a public health problem

    Neurogastroenterol Motil

    (2008)
  • Cited by (199)

    • Pediatric and adolescent GI motility disorders and management

      2023, Handbook of Gastrointestinal Motility and Disorders of Gut-Brain Interactions, Second Edition
    View all citing articles on Scopus

    Conflicts of interest The authors disclose the following: Jeffrey Johnston, Caroline Kurtz, James MacDougall, Bernard Lavins, Donald Fitch, Brenda Jeglinski, and Mark Currie are employees of Ironwood Pharmaceuticals. Anthony Lembo is a consultant to Ironwood Pharmaceuticals.

    Funding This study was funded by Ironwood Pharmaceuticals.

    View full text