Pilot study on the effect of linaclotide in patients with chronic constipation.
OBJECTIVE
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 microg) 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 microg/day significantly increased spontaneous bowel movement frequency, and linaclotide 1,000 microg/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.
Johnston
Jeffrey M
JM
Ironwood Pharmaceuticals, Inc., 320 Bent Street, Cambridge, MA, USA. jjohnston@ironwoodpharma.com
Kurtz
Caroline B
CB
Drossman
Douglas A
DA
Lembo
Anthony J
AJ
Jeglinski
Brenda I
BI
MacDougall
James E
JE
Antonelli
Stephen M
SM
Currie
Mark G
MG
D000328:Adult; D000368:Aged; D002908:Chronic Disease; D003248:Constipation / Q000188:drug therapy*; D004311:Double-Blind Method; D005260:Female; D005765:Gastrointestinal Agents / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000009:adverse effects / Q000627:therapeutic use*; D050705:Receptors, Guanylate Cyclase-Coupled / Q000037:antagonists & inhibitors; D055815:Young Adult
D005765:Gastrointestinal Agents; D010455:Peptides; D050705:Receptors, Guanylate Cyclase-Coupled; C523483:linaclotide