S524 Predictors of Placebo Response in Patients With Irritable Bowel Syndrome and Constipation: A Post-Hoc Analysis From Pooled Phase 2b/3 Studies Assessing the Safety and Efficacy of Linaclotide

Abstract

Introduction: In clinical studies of irritable bowel syndrome (IBS), the placebo response rate is variable, with a pooled placebo response rate of 34% for the US Food and Drug Administration (FDA) abdominal pain responder endpoint.1 Further understanding of the factors that drive the placebo response can improve clinical study design. We aim to identify potential factors associated with a high placebo response via a post-hoc analysis of clinical studies in IBS patients with constipation (IBS-C). Methods: Patient data from placebo-controlled studies that assessed the efficacy and safety of linaclotide for IBS-C were pooled from 1 phase 2b (NCT02559206) and 3 phase 3 (NCT00948818, NCT00938717, NCT03573908) studies. Inclusion criteria were similar across studies, and all patients had a baseline abdominal pain severity score ≥3 (0–10 scale). The primary endpoint of interest was abdominal pain responder, defined as ≥30% improvement from a 2-week baseline in average daily worst abdominal pain score for ≥50% of the first 12 weeks on treatment. Predictors of placebo response were identified using backwards selection via a regression analysis from a list of demographics and baseline disease characteristics. Additionally, standardized coefficients were calculated to rank the magnitude of association of each selected predictor with the response. Results: The 4 studies included 2073 patients (1027 placebo and 1046 linaclotide 290 μg). Two predictors of placebo response were identified as having the largest impact on the FDA abdominal pain responder endpoint. Higher baseline variation in abdominal pain was associated with higher placebo response (coefficient, standard error [SE]: 0.20, 0.068; P = .0032), and higher mean baseline abdominal pain was associated with lower placebo response (coefficient, SE: −0.15, 0.019; P < .0001) [Table]. Age, sex, baseline spontaneous bowel movement frequency, baseline Bristol Stool Form Scale score, anxiety, depression, and prior gastrointestinal drugs taken were not found to impact the placebo response for the abdominal pain responder endpoint. Conclusion: In this pooled analysis of IBS-C clinical studies, higher baseline variation in abdominal pain was a positive predictor of placebo response, while higher mean baseline abdominal pain score was a negative predictor of placebo response. These findings may have implications towards future clinical study design. Table 1. - Factors that predict placebo response for abdominal pain improvement, pooled data from phase 2b/3 studies Predictor Placebo (n = 1046) Estimated coefficient (SE) P value SC SD of baseline abdominal pain 0.20 (0.068) .0032 0.08 Mean baseline pain −0.15 (0.019) < .0001 −0.14 A responder was defined as ≥30% improvement in average daily worst abdominal pain score from baseline for 50% of weeks on treatment. Predictors assessed were age, sex, baseline spontaneous bowel movement, mean baseline abdominal pain score, SD of baseline abdominal pain score, pre-US Food and Drug Administration approval, baseline Bristol Stool Form Scale score, anxiety, depression, baseline pain conditions, prior gastrointestinal drug taken. SC, standardized coefficient; SD, standard deviation; SE, standard error.