Responsiveness of a Tri-Component Endpoint in Non-Constipation Irritable Bowel Syndrome: Pooled Results from Two Phase 3 Trials, TARGET 1 and TARGET 2

Abstract

Purpose: Current FDA guidance suggests the use of a composite endpoint that includes two primary symptoms of IBS with diarrhea (IBS-D): abdominal pain and stool consistency. Because this endpoint may not capture otherwise unmeasured GI symptoms such as urgency and bloating, which may be important to patients with IBS-D, we sought to evaluate the responsiveness of a tri-component endpoint that includes daily assessment of abdominal pain and stool consistency as recommended by the FDA guidance as well as daily assessment of global IBS symptoms. Methods: Patients with mild-to-moderate non-constipation IBS (N=1260) were randomized to rifaximin 550 mg three times daily (TID) or placebo for two weeks and evaluated for 10 weeks post treatment. The primary results of these trials have been previously published. Patients rated daily IBS symptom severity for global IBS symptoms and IBS-related abdominal pain using a 7-point scale (0=not at all - 6=a very great deal). Stool consistency was rated using a 5-point scale (1=very hard-5=watery). The proposed tri-component endpoint defines the weekly responders as patients who reported ≥30% improvement from baseline in abdominal pain, had ≥50% improvement in the number of days in a week with stool consistency of loose or watery compared with baseline, and had ≥1 point improvement in weekly average score of daily global IBS symptoms. Responsiveness (ability to detect change) was assessed (Wilcoxon rank-sum test) by comparing the change from baseline in each daily question between weekly responder and non-responder. Spearman rank correlation coefficients were calculated to assess the correlations among weekly responders and daily measures of efficacy. Results: For each study and the combined data, the responders defined by the tri-component endpoint had significantly greater improvements in all daily IBS symptom severity measures than non-responders at each week during the course of the study, demonstrating it was a responsive endpoint. The tricomponent endpoint also demonstrated evidence for convergent validity as it consistently correlated with all daily IBS symptom severity measures at each week during the course of the study based on a Spearman's correlation of 0.40 or greater with other daily symptom severity measures. Conclusion: The tri-component endpoint, which adds a global assessment of IBS symptoms to the FDA's guidance endpoint, is a responsive endpoint that correlates with all daily IBS symptoms. Further study with this endpoint is warranted in patients with IBS-D. Disclosure: Salix Pharmaceuticals, Inc. provided all study drug and research funding for these studies. Dr. Lembo - Consultant and Speaker: Salix Pharmaceuticals, Inc.; Dr. Pimentel - Consultant, Speaker, and Investigator: Salix Pharmaceuticals, Inc.; Dr. Yu - Employee and Stockholder: Salix Pharmaceuticals, Inc.; Dr. Paterson - Employee and Stockholder: Salix Pharmaceuticals, Inc.; Dr. Bortey - Employee and Stockholder: Salix Pharmaceuticals, Inc.; and Dr. Forbes - Employee and Stockholder: Salix Pharmaceuticals, Inc. This research was supported by an industry grant from Salix Pharmaceuticals, Inc.