Linaclotide improves abdominal pain and bowel habits in a phase IIb study of patients with irritable bowel syndrome with constipation.
OBJECTIVE
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.
Johnston
Jeffrey M
JM
Ironwood Pharmaceuticals, Inc, Cambridge, Massachusetts, USA. jjohnston@ironwoodpharma.com
Kurtz
Caroline B
CB
Macdougall
James E
JE
Lavins
Bernard J
BJ
Currie
Mark G
MG
Fitch
Donald A
DA
O'Dea
Chris
C
Baird
Mollie
M
Lembo
Anthony J
AJ
D015746:Abdominal Pain / Q000188:drug therapy*; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D003248:Constipation / Q000188:drug therapy*; D003672:Defecation / Q000187:drug effects*; D003967:Diarrhea / Q000139:chemically induced; D005260:Female; D006162:Guanylate Cyclase / Q000378:metabolism; D006801:Humans; D043183:Irritable Bowel Syndrome / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000008:administration & dosage* / Q000009:adverse effects; D055815:Young Adult
D010455:Peptides; D006162:Guanylate Cyclase; C523483:linaclotide