Efficacy, Safety of 12-Week Regimen of Once-Daily Oral Linaclotide in Patients With Chronic Constipation
Linaclotide is an orally administered, minimally absorbed, guanylate cyclase type-C receptor agonist. Two double-blind phase III trials (01 and 303) evaluated the efficacy and safety of linaclotide in 1,272 patients with chronic constipation. Patients had met the modified Rome II standardized criteria for chronic constipation, with fewer than 3 complete spontaneous bowel movements (CSBM) per week and no more than 6 SBMs per week during a 2-week baseline period. Patients were randomly assigned to linaclotide administered at 133 ug or 266 ug or placebo once daily for 12 weeks. The primary endpoint, the proportion of CSBM overall responders (>3 CSBM, with an increase of >1 CSBM from baseline, for at least 9 weeks of the 12-week treatment phase), was met at both dose levels of lina-clotide in both trials. In Trial 01, CSBM overall response rates were 16.0%, 21.3%, and 6.0%, respectively, for linaclotide 133 ug, 266 ug, and placebo (P=.0012 for low-dose linaclotide vs placebo; P<.0001 for high-dose linaclotide vs placebo). In Trial 303, CSBM response rates were 21.2%, 19.4%, and 3.3%, respectively (P<.0001 for both linaclotide doses vs placebo). Secondary end-points (change from baseline in CSBMs, SBMs, stool consistency, straining, constipation severity, abdominal discomfort, and bloating) also improved with linaclotide versus placebo. Treatment responses first occurred during Week 1 and were sustained over the 12-week treatment period. The most common adverse event, diarrhea, was more frequent with linaclotide versus placebo in both trials (Trial 01, 17% vs 3%; Trial 303, 13% vs 7%). A few linaclotide and placebo patients discontinued treatment due to diarrhea (Trial 01, 5% and 1%, respectively; Trial 303, 3% and 1%, respectively).