Original article
Alimentary tract
Effect of Linaclotide on Severe Abdominal Symptoms in Patients With Irritable Bowel Syndrome With Constipation

https://doi.org/10.1016/j.cgh.2013.09.022Get rights and content
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open access

Background & Aims

Patients with irritable bowel syndrome with constipation (IBS-C) have abdominal symptoms that vary in severity. Linaclotide, a guanylate cyclase-C agonist, improves abdominal and bowel symptoms in these patients. We examined the prevalence of severe abdominal symptoms in patients with IBS-C and assessed the effects of linaclotide on abdominal symptoms, global measures, and quality of life (QOL).

Methods

In two phase 3 trials, patients who met modified Rome II criteria for IBS-C were randomly assigned to groups given oral, once-daily linaclotide (290 μg) or placebo for 12 weeks. During the baseline (2 weeks prior to treatment) and treatment periods, patients rated abdominal pain, discomfort, bloating, fullness, and cramping daily (from 0 = none to 10 = very severe). Linaclotide's effects on abdominal symptoms, global measures, and IBS-related QOL were assessed in subpopulations of patients who rated specific individual abdominal symptoms as severe (≥7.0) at baseline.

Results

In the intent-to-treat population (1602 patients; 797 receiving placebo and 805 receiving linaclotide), baseline prevalence values for severe abdominal symptoms were 44% for bloating, 44% for fullness, 32% for discomfort, 23% for pain, and 22% for cramping, with considerable overlap among symptoms. In patients with severe symptoms, linaclotide reduced all abdominal symptoms; mean changes from baseline severity scores ranged from –2.7 to –3.4 for linaclotide vs –1.4 to –1.9 for placebo (P < .0001). Linaclotide improved global measures (P < .0001) and IBS-QOL scores (P < .01) compared with placebo. Diarrhea was the most common adverse event of linaclotide in patients with severe abdominal symptoms (18.8%–21.0%).

Conclusions

Of 5 severe abdominal symptoms assessed, bloating and fullness were most prevalent in patients with IBS-C. Linaclotide significantly improved all abdominal symptoms, global measures, and IBS-QOL in subpopulations of IBS-C patients with severe abdominal symptoms. Clinicaltrials.gov Numbers: NCT00938717, NCT00948818.

Keywords

Guanylate Cyclase-C
IBS-C
Abdominal Pain
Bloating

Abbreviations used in this paper

AE
adverse event
ANCOVA
analysis of covariance
BM
bowel movement
cGMP
cyclic guanosine monophosphate
CMH
Cochran–Mantel-Haenszel
GC-C
guanylate cyclase-C
IBS
irritable bowel syndrome
IBS-C
irritable bowel syndrome with constipation
ITT
intent to treat
IVRS
interactive voice response system
LOCF
last observation carried forward
NNT
number needed to treat
NRS
numerical rating scale
QOL
quality of life

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Conflicts of interest The authors disclose the following: Jeffrey Johnston, Caroline Kurtz, James MacDougall, Bernard Lavins, and Mark Currie are employees of Ironwood Pharmaceuticals and own stock/stock options in Ironwood Pharmaceuticals. Steven Shiff is an employee of Forest Laboratories and owns stock/stock options in Forest Laboratories. Satish S. C. Rao participated as a principal investigator and has served on the advisory boards and received honoraria from Ironwood Pharmaceuticals and Forest Research Institute. Eamonn M. M. Quigley has served on the advisory boards for Ironwood Pharmaceuticals and Forest Research Institute.

Funding Supported by Forest Research Institute and Ironwood Pharmaceuticals, Inc.