title: Randomised clinical trials: linaclotide phase 3 studies in IBS-C - a prespecified further analysis based on European Medicines Agency-specified endpoints.
abstract: BACKGROUND
  Treatment options that improve overall symptoms of irritable bowel syndrome with constipation (IBS-C) are lacking.
  
  
  OBJECTIVE
  A prespecified further analysis to evaluate the efficacy and safety of linaclotide, a guanylate cyclase C agonist, in patients with IBS-C, based on efficacy parameters prespecified for European Medicines Agency (EMA) submission.
  
  
  METHODS
  Two randomised, double-blind, multicentre Phase 3 trials investigated once-daily linaclotide (290 μg) for 12 weeks (Trial 31) or 26 weeks (Trial 302) in patients with IBS-C. Prespecified primary endpoints were the EMA-recommended co-primary endpoints: (i) 12-week abdominal pain/discomfort responders [≥30% reduction in mean abdominal pain and/or discomfort score (11-point scales), with neither worsening from baseline, for ≥6 weeks] and (ii) 12-week IBS degree-of-relief responders (symptoms 'considerably' or 'completely' relieved for ≥6 weeks).
  
  
  RESULTS
  Overall, 803 (Trial 31) and 805 patients (Trial 302) were randomised. A significantly greater proportion of linaclotide-treated vs. placebo-treated patients were 12-week abdominal pain/discomfort responders (Trial 31: 54.8% vs. 41.8%; Trial 302: 54.1% vs. 38.5%; P < 0.001) and IBS degree-of-relief responders (Trial 31: 37.0% vs. 18.5%; Trial 302: 39.4% vs. 16.6%; P < 0.0001). Similarly, significantly more linaclotide- vs. placebo-treated patients were responders for ≥13 weeks in Trial 302 (abdominal pain/discomfort: 53.6% vs. 36.0%; IBS degree-of-relief: 37.2% vs. 16.9%; P < 0.0001). The proportion of sustained responders (co-primary endpoint responders plus responders for ≥2 of the last 4 weeks of treatment) was also significantly greater with linaclotide vs. placebo in both trials (P < 0.001).
  
  
  CONCLUSIONS
  Linaclotide treatment significantly improved abdominal pain/discomfort and degree-of-relief of IBS-C symptoms compared with placebo over 12 and 26 weeks.
  
  
  BACKGROUND
  ClinicalTrials.gov (identifiers: NCT00948818 and NCT00938717).
authors.affiliation: Alimentary Pharmabiotic Centre, University College Cork, Ireland. e.quigley@ucc.ie
authors.forename: E M M
authors.initials: EM
authors.lastname: Quigley
authors.forename: J
authors.initials: J
authors.lastname: Tack
authors.forename: W D
authors.initials: WD
authors.lastname: Chey
authors.forename: S S
authors.initials: SS
authors.lastname: Rao
authors.forename: J
authors.initials: J
authors.lastname: Fortea
authors.forename: M
authors.initials: M
authors.lastname: Falques
authors.forename: C
authors.initials: C
authors.lastname: Diaz
authors.forename: S J
authors.initials: SJ
authors.lastname: Shiff
authors.forename: M G
authors.initials: MG
authors.lastname: Currie
authors.forename: J M
authors.initials: JM
authors.lastname: Johnston
mesh_terms: D015746:Abdominal Pain / Q000188:drug therapy / Q000503:physiopathology; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D003248:Constipation / Q000188:drug therapy* / Q000503:physiopathology; D004311:Double-Blind Method; D023381:Endpoint Determination; D005765:Gastrointestinal Agents / Q000627:therapeutic use*; D006801:Humans; D043183:Irritable Bowel Syndrome / Q000188:drug therapy* / Q000503:physiopathology; D010455:Peptides / Q000627:therapeutic use*; D012720:Severity of Illness Index; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D005765:Gastrointestinal Agents; D010455:Peptides; C523483:linaclotide