Time to Relief of Key Abdominal and Bowel Symptoms of Irritable Bowel Syndrome with Constipation: A Post-Hoc Analysis of Randomized Controlled Trials of Linaclotide

Introduction: Linaclotide (LIN) is a guanylate cyclase-C agonist approved for irritable bowel syndrome with constipation (IBS-C) in adults. Phase 2 and 3 trials demonstrated LIN’s efficacy for relieving abdominal and bowel symptoms associated with IBS-C. However, time to treatment response is not fully understood. This post-hoc analysis aimed to examine this for abdominal pain, discomfort, and bloating, and the temporal relationship between abdominal symptom and stool frequency responses. Methods: Patient data were pooled from one Phase 2b and three Phase 3 randomized controlled trials comparing LIN 290 µg with placebo (PBO) in IBS-C (2009–2019; NCT00460811, NCT00948818, NCT00938717, and NCT03573908). Inclusion criteria were similar across studies; patients met Rome II or III criteria for IBS-C and had a baseline abdominal pain severity score ≥3. Patients assessed daily worst abdominal pain, discomfort, and bloating using a 0–10 scale. Response for individual abdominal symptoms was defined as a ≥30% improvement from baseline in weekly average. Complete spontaneous bowel movement (CSBM) response was defined as an increase of ≥1 CSBMs/week from baseline or achieving ≥3 CSBMs/week. Time to response was assessed using the Kaplan-Meier method. Results: 2350 patients (1172 PBO (mean age 44.7 years, 86.8% female) and 1178 LIN 290 µg (mean age 44.56 years, 86.8% female)) were included. For LIN-treated patients, median time to achieve responder definition was 3 weeks for abdominal pain and discomfort, and 4 weeks for bloating (vs. 6, 7, and 8 weeks, respectively for PBO). Time to response curves showed a clear and significant separation between LIN and PBO (p< 0.0001; Figure 1). Median time to an increase of ≥1 CSBMs/week was 2 weeks for LIN vs 4 weeks for PBO (curve separation, p< 0.0001). Median time to achieving ≥3 CSBMs/week was 4 weeks for LIN; this endpoint was not reached by PBO-treated patients during the 12-week treatment period (curve separation, p< 0.0001). Conclusion: These results suggest >50% of patients with IBS-C treated with LIN will experience ≥30% decrease in the severity of abdominal pain and discomfort within 3 weeks, and bloating within 4 weeks after initiating treatment. Median time to improved CSBM frequency preceded abdominal responses, although achievement of a “normal” CSBM frequency lagged slightly behind abdominal pain and discomfort responses. LIN significantly improves both abdominal and bowel symptoms compared to PBO with most responding within the first 4 weeks of treatment.Figure 1.: Time to response for abdominal symptoms. The number of patients per treatment group who are included in the analysis and have not yet met the definition of response is presented for each week. Data were truncated to Week 12 and include patients who had at least one post-baseline assessment. Response for abdominal pain (A), discomfort (B), and bloating (C) was defined as the weekly average improvement of ≥30% from baseline average (11-point numerical rating scale).