Effect of Linaclotide on Quality of Life in Adults With Chronic Constipation: Results From 2 Randomized, Double-Blind, Placebo-Controlled Phase III Trials

Abstract

Linaclotide is a first-in-class, minimally absorbed guanylate cyclase type C receptor agonist that significantly improved bowel and abdominal symptoms and constipation severity in 2 phase III chronic constipation (CC) trials. CC is a common functional GI disorder that significantly affects patients' quality of life. Patients meeting modified Rome II criteria for CC were randomized to oral once-daily 133 μg or 266 μg linaclotide or placebo for 12 weeks in 2 phase III trials (trials 01 and 303). The Patient Assessment of Constipation Quality of Life (PAC-QOL) questionnaire, consisting of 28 items, was completed at baseline and end of treatment. The PAC-QOL consists of an overall and 4 subscale scores (physical discomfort, satisfaction, worries/concern, and psychosocial discomfort). The change from baseline to week 12 was analyzed using an analysis of covariance model with fixed effect terms for treatment group and geographical region and the corresponding baseline PAC-QOL score as a covariate. The percentage of responders (ie, patients with ≥1 point decrease) was calculated by treatment group. In both trials, the change from baseline in the PAC-QOL overall and physical discomfort, worries/concern, and satisfaction subscale scores was significant for both linaclotide dosage groups vs placebo. The psychosocial discomfort score was significant for both linaclotide dosage groups vs placebo in trial 01. A greater percentage of patients treated with linaclotide were responders at week 12 for the PAC-QOL overall score (42.2% and 44.9% at 133 μg; 46.8% and 35.5% at 266 μg; 27.8% and 18.7% with placebo in trials 01 and 303, respectively). Compared with placebo, once-daily linaclotide treatment significantly improved overall QOL and important QOL domains of physical discomfort, worries/concern, and satisfaction, as measured by the PAC-QOL, in adults with CC in 2 phase III trials.Table 1.Table 1Mean Change From Baseline to Week 12 in ITT PopulationTrial 01 (n = 630)Trial 303 (n = 642)BaselineaBaseline mean for all patients; range = 0 (best) to 4 (worse).Placebo (n = 215)133 μg (n = 213)266 μg (n = 202)BaselineaBaseline mean for all patients; range = 0 (best) to 4 (worse).Placebo (n = 209)133 μg (n = 217)266 μg (n = 216)Overall (P value)2.13−0.6−0.89 (<.0001)−0.98 (<.0001)2.04−0.46−0.94 (<.0001)−0.87 (<.0001)Physical discomfort2.28−0.63−0.99 (<.0001)−1.06 (<.0001)2.28−0.47−1.07 (<.0001)−.92 (<.0001)Psychosocial discomfort1.25−0.49−0.52 (.0185)−0.64 (.0010)1.10−0.44−0.53 (.0497)−0.55 (.1472)Worries/concerns2.1−0.62−0.94 (<.0001)−1.02 (<.0001)2.02−0.510.51–1.01 (<.0001)−0.96 (<.0001)Satisfaction3.47−0.71−1.26 (<.0001)−1.36 (<.0001)3.41−0.36−1.34 (<.0001)−1.13 (<.0001)a Baseline mean for all patients; range = 0 (best) to 4 (worse). Open table in a new tab