title: 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.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01642914.
authors.affiliation: Dartmouth-Hitchcock Medical Center, Lebanon, NH, United States of America.
authors.forename: Brian E
authors.initials: BE
authors.lastname: Lacy
authors.affiliation: University of Iowa Hospitals and Clinics, Iowa City, IA, United States of America.
authors.forename: Ron
authors.initials: R
authors.lastname: Schey
authors.affiliation: Forest Laboratories LLC, a subsidiary of Actavis plc, Jersey City, NJ, United States of America.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Shiff
authors.affiliation: Ironwood Pharmaceuticals, Cambridge, MA, United States of America.
authors.forename: Bernard J
authors.initials: BJ
authors.lastname: Lavins
authors.affiliation: Forest Laboratories LLC, a subsidiary of Actavis plc, Jersey City, NJ, United States of America.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Fox
authors.affiliation: Forest Laboratories LLC, a subsidiary of Actavis plc, Jersey City, NJ, United States of America.
authors.forename: Xinwei D
authors.initials: XD
authors.lastname: Jia
authors.affiliation: Forest Laboratories LLC, a subsidiary of Actavis plc, Jersey City, NJ, United States of America.
authors.forename: Rick E
authors.initials: RE
authors.lastname: Blakesley
authors.affiliation: Ironwood Pharmaceuticals, Cambridge, MA, United States of America.
authors.forename: Xinming
authors.initials: X
authors.lastname: Hao
authors.affiliation: Ironwood Pharmaceuticals, Cambridge, MA, United States of America.
authors.forename: Jacquelyn A
authors.initials: JA
authors.lastname: Cronin
authors.affiliation: Ironwood Pharmaceuticals, Cambridge, MA, United States of America.
authors.forename: Mark G
authors.initials: MG
authors.lastname: Currie
authors.affiliation: Ironwood Pharmaceuticals, Cambridge, MA, United States of America.
authors.forename: Caroline B
authors.initials: CB
authors.lastname: Kurtz
authors.affiliation: Ironwood Pharmaceuticals, Cambridge, MA, United States of America.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Johnston
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, MA, United States of America.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Lembo
mesh_terms: D015746:Abdominal Pain / Q000188:drug therapy / Q000503:physiopathology; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002908:Chronic Disease; D003248:Constipation / Q000188:drug therapy* / Q000503:physiopathology; D004311:Double-Blind Method; D005260:Female; D005765:Gastrointestinal Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D005765:Gastrointestinal Agents; D010455:Peptides; C523483:linaclotide