• E M M Quigley, J Tack, W D Chey, S S Rao, J Fortea, M Falques, C Diaz, S J Shiff, M G Currie, and J M Johnston.
• Alimentary Pharmabiotic Centre, University College Cork, Ireland. e.quigley@ucc.ie
• Aliment. Pharmacol. Ther. 2013 Jan 1; 37 (1): 49-61.

BackgroundTreatment options that improve overall symptoms of irritable bowel syndrome with constipation (IBS-C) are lacking.AimA 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.MethodsTwo 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).ResultsOverall, 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).ConclusionLinaclotide treatment significantly improved abdominal pain/discomfort and degree-of-relief of IBS-C symptoms compared with placebo over 12 and 26 weeks.Trial RegistrationClinicalTrials.gov (identifiers: NCT00948818 and NCT00938717).© 2012 Blackwell Publishing Ltd.

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