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Randomised clinical trials: linaclotide phase 3 studies in IBS ‐C – a prespecified further analysis based on European Medicines Agency‐specified endpoints
Author(s) -
Quigley E. M. M.,
Tack J.,
Chey W. D.,
Rao S. S.,
Fortea J.,
Falques M.,
Diaz C.,
Shiff S. J.,
Currie M. G.,
Johnston J. M.
Publication year - 2013
Publication title -
alimentary pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.308
H-Index - 177
eISSN - 1365-2036
pISSN - 0269-2813
DOI - 10.1111/apt.12123
Subject(s) - medicine , placebo , clinical endpoint , irritable bowel syndrome , constipation , abdominal pain , clinical trial , gastroenterology , alternative medicine , pathology
Summary Background Treatment options that improve overall symptoms of irritable bowel syndrome with constipation ( IBS ‐C) are lacking. Aim 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). Conclusion Linaclotide treatment significantly improved abdominal pain/discomfort and degree‐of‐relief of IBS‐C symptoms compared with placebo over 12 and 26 weeks. Trial registration: ClinicalTrials.gov(identifiers: NCT00948818 and NCT00938717).