Mo1856 Linaclotide Significantly Improved Abdominal Pain Compared With Placebo in Patients With Irritable Bowel Syndrome Regardless of Baseline Pain Severity in Two Phase 3 Trials

Abstract

Introduction: Linaclotide (LIN) is a minimally absorbed, 14-amino-acid peptide that significantly improved abdominal and bowel symptoms in two Phase 3 irritable bowel syndrome with constipation (IBS-C) trials. Previous IBS trials with other therapies have shown conflicting effects of baseline abdominal pain severity on measures of efficacy. Aim: To determine the effect of LIN treatment on abdominal pain stratified by patients' self-reported baseline abdominal pain severity.Methods: Patients meeting Rome II criteria for IBS-C were randomized to oral once-daily 290-μg LIN or placebo (PBO). Patients rated abdominal pain at its worst during the previous 24 hours daily on a 0-10 point scale (0=none to 10=very severe) during the Baseline and Treatment Periods using an interactive voice response system (IVRS). In this post hoc analysis, which used pooled data from the two Phase 3 trials, patients were stratified based on mean baseline abdominal pain (<5, ≥5 to <7, and ≥7). In addition, at each trial visit following randomization, patients rated their relief of abdominal pain over the past week compared to baseline on a 1-7 point balanced scale (1=completely relieved to 7=as bad as I can imagine). The least squares (LS) mean change (improvement) from the 2-week Baseline Period to 12-week Treatment Period, percent improvement, difference estimates, and p-values were obtained from an analysis of covariance (ANCOVA) model. Results: Overall, LIN led to statistically significant improvement in 12-week abdominal pain vs PBO. When results were stratified by baseline abdominal pain severity, LIN led to significant benefit in all three baseline abdominal pain subgroups, achieving decreases in pain score of 29-36% vs 18-20% for PBO (p<0.0001, Table 1), although improvement was numerically less in those with milder baseline severity (NRS <5). Baseline abdominal pain scores were significantly correlated with the absolute magnitude of change-from-baseline improvement in abdominal pain (r=0.26, p<0.0001) but not with percent improvement (r= 0.00, p=0.9184). Patient ratings of relief were significantly improved with LIN vs PBO (2.9 vs 3.5 overall; p<0.0001); improvement was also observed for all three baseline abdominal pain subgroups (p<0.0001, Table 2). Conclusions: LIN led to significant absolute and percent improvement in abdominal pain vs PBO, both overall and in an analysis stratified by baseline abdominal pain severity. The absolute magnitude of improvement in abdominal pain significantly correlated with baseline abdominal pain severity; however, all groups experienced similar percent improvement in abdominal pain. Patient rating of relief of abdominal pain was consistent across baseline pain severity groups. Table 1. Change-from-baseline and Percent Change-from-baseline Improvement in Abdominal Pain