Functional GI Disorders
Subject Category: Functional GI Disorders
Am J Gastroenterol 2009; 104:125–132; doi:10.1038/ajg.2008.59
Pilot Study on the Effect of Linaclotide in Patients With Chronic Constipation
Jeffrey M Johnston MD1, Caroline B Kurtz PhD1, Douglas A Drossman MD2, Anthony J Lembo MD3, Brenda I Jeglinski1, James E MacDougall PhD1, Stephen M Antonelli PhD1 and Mark G Currie PhD1
- 1Ironwood Pharmaceuticals, Inc., Cambridge, Massachusetts, USA
- 2Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
- 3Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
Correspondence: Jeffrey M. Johnston, MD, Ironwood Pharmaceuticals, Inc., 320 Bent Street, Cambridge, MA, USA. E-mail: jjohnston@ironwoodpharma.com
Received 9 January 2008; Accepted 26 August 2008.
Abstract
OBJECTIVES:
Chronic constipation is a common gastrointestinal disorder with limited treatment options. Oral administration of linaclotide, a novel peptide agonist of guanylate cyclase-C receptors, has been shown in animal studies to stimulate intestinal fluid secretion and transit. In Phase 1 studies in healthy human volunteers, linaclotide was well-tolerated, increased bowel movement frequency, and loosened stool consistency.
METHODS:
This randomized, double-blind, placebo-controlled pilot study evaluated the safety, tolerability, and exploratory efficacy of oral linaclotide in 42 patients with chronic constipation. Patients were randomized to linaclotide (100, 300, or 1,000 
g) or placebo once daily for 2 weeks. Bowel habits (stool frequency, consistency, straining, completeness of evacuation) and degree of abdominal discomfort were monitored daily using an interactive voice response system. Patient-reported outcomes of severity of constipation and overall relief were evaluated weekly.
RESULTS:
Linaclotide treatment produced dose-dependent increases from the pretreatment baseline values in weekly complete spontaneous bowel movement frequency (range: 2.2–3.2), stool consistency scores (range: 1.1–2.6, 7-point scale), and straining scores (range: 0.4–1.5, 7-point scale); corresponding placebo increases were 1.3, 0.4, 0.4, respectively. Clinical improvements were also demonstrated in abdominal discomfort, severity of constipation, and overall relief. Compared to placebo, linaclotide 100 g/day significantly increased spontaneous bowel movement frequency, and linaclotide 1,000 g/day significantly improved stool consistency (P<0.05). Adverse events were primarily gastrointestinal, with diarrhea being the most common.
CONCLUSIONS:
In this pilot study, linaclotide treatment improved bowel habits and symptoms of patients with chronic constipation. Further randomized controlled trials are warranted.
