Effect of Diarrhea Adverse Events on Health-Related Quality of Life and Treatment Satisfaction in Patients With Irritable Bowel Syndrome With Constipation

Abstract

Introduction: To evaluate the effect of diarrhea adverse events (AEs) on health-related quality of life (HRQOL) and treatment satisfaction (TS) in patients with irritable bowel syndrome with constipation (IBS-C). Methods: Data were pooled from 2 similarly designed phase 3 trials in IBS-C patients of linaclotide, the first-in-class guanylate cyclase-C agonist FDA-approved treatment for adults with IBS-C or chronic idiopathic constipation. Presence and severity (i.e., mild, moderate, severe) of diarrhea episodes were recorded by trial investigators as AEs at any time during the 12-week treatment period in both trials. HRQOL was assessed at baseline and week 12 using the irritable bowel syndrome quality of life (IBSQOL) questionnaire overall score (range: 0-100, higher scores indicate better HRQOL); TS was evaluated at weeks 2, 4, 8, and 12 with a 5-point scale (1=not at all satisfied, 5=very satisfied). Data were evaluated longitudinally by pairing the most severe diarrhea episode with the nearest HRQOL/TS assessment following the episode. Change-from-baseline to week 12 in IBS-QOL overall score and mean TS at week 12 were evaluated by treatment (linaclotide 290 mcg vs. placebo) stratified by diarrhea presence/severity. Patients with no recorded diarrhea episodes were the reference group. Longitudinal multivariate models examined adjusted associations between diarrhea episodes and HRQOL/TS, controlling for patient characteristics and change in abdominal (e.g., pain, bloating, discomfort) and bowel symptoms (stool frequency, stool consistency, straining). Results: Of 1,602 patients randomized, 1,336 completed HRQOL and TS assessments (linaclotide 290 mcg n=654, placebo n=682); of these, 129 diarrhea episodes were reported in 122 patients (n=69 mild, n=53 moderate, n=7 severe). Mean TS and change in IBS-QOL did not significantly differ in linaclotide patients with diarrhea AEs vs. those with no recorded diarrhea AEs (TS=3.54 vs. 3.40; p=0.433; change in IBS-QOL=18.47 vs. 19.06; p=0.408, respectively). Change in IBS-QOL also did not significantly differ for placebo patients with diarrhea AEs vs those with no recorded diarrhea AEs (8.54 vs. 13.58; p=0.931, respectively). For both linaclotide and placebo, the presence of diarrhea (any severity) had no statistically significant impact on HRQOL, even after controlling for confounders. A statistically significant impact on TS was found among linaclotide patients with a recorded episode of severe diarrhea (-0.80, p=0.001); among placebo patients, mild (-0.40, p=0.042) and severe (-1.55, p=0.046) diarrhea AEs had a significant impact. Conclusion: Presence of mild/moderate diarrhea AEs did not negatively affect HRQOL or TS among IBS-C patients receiving linaclotide 290 mcg. Disclosure - Michael Munsell and Robert Griffiths are employees of Boston Health Economics, Inc, which is a consultancy whose activities related to the project are funded by Forest Research Institute, and Ironwood Pharmaceuticals; Huan Huang is a consultant to Ironwood Pharmaceuticals, Inc., and Forest Research Institute; Jessica Buono and Robyn Carson are employees of Forest Research Institute and own stock and/or stock options in Forest Laboratories, Inc.; William Spalding and Douglas Taylor are employees of Ironwood Pharmaceuticals, Inc., and own stock and/or stock options in Ironwood Pharmaceuticals. This research was supported by an industry grant from Forest Research Institute and Ironwood Pharmaceuticals.