Comparison of adequate relief with symptom, global, and responder endpoints in linaclotide phase 3 trials in IBS-C. Issue 1 (February 2015)

• Record Type: Journal Article
• Authors: Camilleri, Michael; Lembo, Anthony J; Lavins, Bernard J; MacDougall, James E; Carson, Robyn T; Williams, Valerie SL; Nelson, Lauren M; Shiff, Steven J; Currie, Mark G; Kurtz, Caroline B; Johnston, Jeffrey M
• Is Part Of: United European Gastroenterology journal. Volume 3:Issue 1(2015:Feb.)
• Page Start: 53
• Page End: 62
• Publication Date: 2015-02
• Subjects: Linaclotide -- adequate relief -- clinically meaningful change -- responder endpoints -- GC-C -- IBS-C; Gastroenterology -- Periodicals; Periodicals; 616.33005
• DOI: 10.1177/2050640614555946
• Languages: English
• ISSNs: 2050-6406

Abstract

Background: Optimal clinical trial endpoints for irritable bowel syndrome with constipation (IBS-C) are uncertain. Objective: The objective of this article is to compare adequate relief (AR) to abdominal/bowel symptoms, global endpoints, and FDA and EMA responder criteria; and to use AR as an anchor to assess clinically meaningful change (CMC) in IBS-C symptoms. Methods: Using pooled 12-week data from two phase 3 linaclotide clinical trials, daily abdominal/bowel symptoms and weekly global assessments were correlated with AR. Symptom CMC thresholds were estimated using AR as an anchor. Agreement between AR and FDA/EMA responder criteria was assessed. Results: Correlations of AR with percentage change in abdominal symptoms, bowel symptoms, and global endpoints ranged from 0.48–0.54, 0.32–0.39, and 0.61–0.71, respectively. Using AR as an anchor, CMC thresholds were 29% improvement in abdominal pain, 29% improvement in abdominal discomfort, and 0.7/week increase in CSBMs, similar to thresholds for IBS-C responder endpoints recommended by the FDA and EMA. There was considerable agreement of weekly responder rates between AR and the FDA and EMA endpoints (on average, 70%–76% and 71%–82% of weeks with agreement, respectively). Conclusions: AR bridges IBS-C clinical trials, putting into perspective the disparate primary endpoints recommended by professional societies and regulatory authorities, and allowing researchers, practitioners, and regulators to compare trial results.