Linaclotide in Chronic Idiopathic Constipation Patients with Moderate to Severe Abdominal Bloating: A Randomized, Controlled Trial

Abstract

Background: Abdominal bloating is a common and bothersome symptom of chronic idiopathic constipation. The objective of this trial was to evaluate the efficacy and safety of linaclotide in patients with chronic idiopathic constipation and concomitant moderate-to-severe abdominal bloating.

Methods: This Phase 3b, randomized, double-blind, placebo-controlled clinical trial randomized patients to oral linaclotide (145 or 290 μg) or placebo once daily for 12 weeks. Eligible patients met Rome II criteria for chronic constipation upon entry with an average abdominal bloating score ≥5 (self-assessment: 0 10-point numerical rating scale) during the 14-day baseline period. Patients reported abdominal symptoms (including bloating) and bowel symptoms daily; adverse events were monitored. The primary responder endpoint required patients to have ≥3 complete spontaneous bowel movements/week with an increase of ≥1 from baseline, for ≥9 of 12 weeks. The primary endpoint compared linaclotide 145 μg vs. placebo.

Results: The intent-to-treat population included 483 patients (mean age=47.3 years, female=91.5%, white=67.7%). The primary endpoint was met by 15.7% of linaclotide 145 μg patients vs. 7.6% of placebo patients (P<0.05). Both linaclotide doses significantly improved abdominal bloating vs. placebo (P<0.05 for all secondary endpoints, controlling for multiplicity). Approximately one-third of linaclotide patients (each group) had ≥50% mean decrease from baseline in abdominal bloating vs. 18% of placebo patients (P<0.01). Diarrhea was reported in 6% and 17% of linaclotide 145 and 290 μg patients, respectively, and 2% of placebo patients. AEs resulted in premature discontinuation of 5% and 9% of linaclotide 145 μg and 290 μg patients, respectively, and 6% of placebo patients.

Conclusions: Once-daily linaclotide (145 and 290 μg) significantly improved bowel and abdominal symptoms in chronic idiopathic constipation patients with moderate-to-severe baseline abdominal bloating; in particular, linaclotide significantly improved abdominal bloating compared to placebo, an important finding given the lack of agents available to treat abdominal bloating in chronic idiopathic constipation patients.

Trial registration: ClinicalTrials.gov NCT01642914.

Conflict of interest statement

Competing Interests: The authors have read the journal's policy and have the following competing interests: Drs. Brian E. Lacy (BEL) and Anthony J. Lembo (AJL) have served as paid consultants to Forest Laboratories and Ironwood Pharmaceuticals. Bernard J. Lavins, Xinming Hao, Jacquelyn A. Cronin, Mark G. Currie, Caroline B. Kurtz, and Jeffrey M. Johnston (BJL, XH, JAC, MGC, CBK, and JMJ) are employees of Ironwood Pharmaceuticals and own stock/stock options in Ironwood Pharmaceuticals. Steven J. Shiff, Susan M. Fox, Xinwei D. Jia, and Rick E. Blakesley (SJS, SMF, XDJ, and REB) are employees of Forest Laboratories and also own stock/stock options in Actavis plc. Actavis plc acquired Forest Laboratories, LLC in July 2014. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Patient Flow Through the Trial.

Screen failures who were rescreened and failed a second time during the screening period were counted once as screen failures. Screen failures who were rescreened, entered the baseline period, and then failed during the baseline period were counted once as pretreatment failures.

Fig 2. Primary Endpoint.

Intent-to-treat Population; Responder = patient who had ≥ 3 CSBMs and an increase of ≥ 1 CSBM from baseline, in the same week, for at least 9 of the 12 treatment-period weeks. Note: Primary endpoint for linaclotide 145 μg vs. placebo; secondary endpoint for linaclotide 290 μg vs. placebo. CSBM = complete spontaneous bowel movement; ITT = intent to treat; Lin = linaclotide; n = number of patients meeting the responder endpoint; N = number of patients in the ITT population. * P

Fig 3. Percent Change from Baseline in Abdominal Bloating by Week.

Intent-to-treat Population; % change from baseline in abdominal bloating during each week of the treatment period. % changes from baseline are the least-squares means from an analysis of covariance (ANCOVA) model. Note: % change from baseline in abdominal bloating at each treatment period week was an additional endpoint for both linaclotide dose groups vs. placebo. Both linaclotide doses are associated with greater improvement than placebo at all individual treatment weeks (all reported individual P values < 0.05 for both linaclotide groups vs. placebo; P values were obtained from an ANCOVA model with treatment group and geographic region as factors and baseline abdominal bloating score as a covariate).

Fig 4. Incremental Percent Improvement in Abdominal Bloating at Week 12.

Intent-to-treat Population; % improvement in abdominal bloating at week 12 (end of the treatment period). Note: The distribution of % improvement in abdominal bloating at week 12 was a secondary endpoint for both linaclotide dose groups. (P < 0.01 for both linaclotide groups vs. placebo; P values were obtained from a Kolmogorov-Smirnov test for equality of distribution.)