Linaclotide and Improved Abdominal and Bowel Symptoms

Orlando—An analysis of two phase 3 trials found that a higher percentage of patients who received linaclotide to treat abdominal and bowel symptoms had clinically meaningful improvement compared with a group receiving placebo. The clinically meaningful thresholds were based on a patient’s assessment of adequate relief.

Results were presented during a poster session at DDW. The poster was titled Assessing Abdominal and Bowel Symptoms Using Adequate Relief-Based Thresholds: Results From 2 Phase 3 Trials of Linaclotide in Patients with Irritable Bowel Syndrome with Constipation.

The FDA approved linaclotide in August 2012 to treat chronic idiopathic constipation and irritable bowel syndrome (IBS) with constipation. Linaclotide is an oral medication and a minimally absorbed guanylate cyclase-C agonist.

The authors noted that an optimal patient-reported outcome had not been established, although adequate relief has been found to have “excellent qualitative and quantitative properties” as an outcome measure. However, they added that no one has compared adequate relief with the FDA-recommended responder end point.

In the two phase 3 trials, patients with IBS with constipation were randomized to receive linaclotide or placebo once daily. Each day during the studies, patients reported abdominal symptoms (pain, discomfort, bloating, fullness, and cramping) as well as bowel symptoms (spontaneous bowel movement [SBM], complete SBM, stool consistency, and straining). The authors defined a spontaneous bowel movement as a bowel movement occurring without a laxative, an enema, or the use of a suppository on the day of or before the bowel movement. They defined a complete spontaneous bowel movement as having a SBM plus a feeling of complete evacuation. On a weekly basis, patients were also asked if they had adequate relief of their IBS symptoms within the past 7 days.

The weekly responder criteria as defined by the FDA were at least a 30% reduction in the worst abdominal pain and an increase in complete SBMs, both occurring in the same week. The authors used receiver operating characteristic methods to determine the thresholds of clinically meaningful abdominal and bowel symptom relief.

Of the 1602 patients in this analysis, 797 received a placebo pill and 805 were treated with linaclotide. During the 2-week baseline period, the mean SBM rate was 1.8 per week and the mean complete SBM rate was 0.2 per week.

Compared with the placebo group, patients who took linaclotide had significantly higher rates of clinically meaningful improvement for each of the abdominal and bowel symptoms (P≤.0001 for all comparisons).

In addition, the patients in the linaclotide group had significant improvements in the following categories compared with the placebo group (P≤.0001 for all comparisons): average percent of weeks that patients had adequate relief, average percent of weeks that patients were FDA weekly responders, and the average percent of weeks that patients met adequate relief and FDA weekly responder criteria.

The authors noted that the FDA weekly responder criteria were more stringent than the adequate relief criteria. Most patients who were FDA weekly responders also had adequate relief, but 24% of patients in the linaclotide group and 18% of patients in the placebo group had adequate relief, but did not meet the FDA weekly responder criteria.

This study was sponsored by Forest Laboratories, Inc. and Ironwood Pharmaceuticals, Inc.