A 12-week, randomized, controlled trial with a 4-week randomized withdrawal period to evaluate the efficacy and safety of linaclotide in irritable bowel syndrome with constipation

Objectives: Linaclotide is a minimally absorbed guanylate cyclase-C agonist. The objective of this trial was to determine the efficacy and safety of linaclotide in patients with irritable bowel syndrome with constipation (IBS-C). Methods: This phase 3, double-blind, parallel-group, placebo-controlled trial randomized IBS-C patients to placebo or 290 μg oral linaclotide once daily in a 12-week treatment period, followed by a 4-week randomized withdrawal (RW) period. There were four primary end points, the Food and Drug Administration's (FDA's) primary end point for IBS-C (responder: improvement of 30% in average daily worst abdominal pain score and increase by 1 complete spontaneous bowel movement (CSBM) from baseline (same week) for at least 50% of weeks assessed) and three other primary end points, based on improvements in abdominal pain and CSBMs for 9/12 weeks. Adverse events (AEs) were monitored. Results: The trial evaluated 800 patients (mean age43.5 years, female90.5%, white76.9%). The FDA end point was met by 136/405 linaclotide-treated patients (33.6%), compared with 83/395 placebo-treated patients (21.0%) (P0.0001) (number needed to treat: 8.0, 95% confidence interval: 5.4, 15.5). A greater percentage of linaclotide patients, compared with placebo patients, reported for at least 6/12 treatment period weeks, a reduction of 30% in abdominal pain (50.1 vs. 37.5%, P0.0003) and an increase of 1 CSBM from baseline (48.6 vs. 29.6%, P0.0001). A greater percentage of linaclotide patients vs. placebo patients were also responders for the other three primary end points (P0.05). Significantly greater improvements were seen in linaclotide vs. placebo patients for all secondary end points (P0.001). During the RW period, patients remaining on linaclotide showed sustained improvement; patients re-randomized from linaclotide to placebo showed return of symptoms, but without worsening of symptoms relative to baseline. Diarrhea, the most common AE, resulted in discontinuation of 5.7% of linaclotide and 0.3% of placebo patients. Conclusions: Linaclotide significantly improved abdominal pain and bowel symptoms associated with IBS-C for at least 12 weeks; there was no worsening of symptoms compared with baseline following cessation of linaclotide during the RW period.