Effect of Diarrhea Adverse Events on Health-Related Quality of Life and Treatment Satisfaction in Patients With Chronic Idiopathic 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 chronic idiopathic constipation (CIC). Methods: Data were pooled from 2 similarly designed phase 3 trials in CIC patients of linaclotide, the first-in-class guanylate cyclase-C agonist FDA-approved treatment for adults with CIC and irritable bowel syndrome with constipation. Presence and severity (ie, 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 patient assessment of constipation quality of life questionnaire (PAC-QOL) overall score (range: 0-4, lower 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 PAC-QOL overall score and mean TS score at week 12 were evaluated by treatment (linaclotide 145 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 (pain, bloating, discomfort) and bowel symptoms (stool frequency, stool consistency, straining). Results: Of 1,276 patients randomized, 854 received a treatment of interest for these analyses (linaclotide 145 mcg n=430, placebo n=424), of which 746 completed HRQOL and TS assessments (linaclotide 145 mcg n=369, placebo n=377). Of these, 105 diarrhea episodes were reported in 98 patients (n=51 mild, n=46 moderate, n=8 severe). Mean TS and change in PAC-QOL overall scores did not significantly differ in linaclotide or placebo patients with diarrhea AEs vs. those with no recorded diarrhea AEs (TS=3.52 vs. 3.28; p=0.269 for linaclotide and 2.80 vs. 2.21; p=0.185 for placebo; change in PAC-QOL=-0.96 vs. -0.95; p=0.340 for linaclotide and -0.98 vs. -0.57; p=0.207 for placebo). For both linaclotide and placebo, the presence of diarrhea (any severity) had no statistically significant impact on TS or HRQOL, even after controlling for confounders. Conclusion: Presence of diarrhea AEs did not negatively affect HRQOL or TS among CIC patients receiving linaclotide 145 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.