Randomised clinical trials: linaclotide phase 3 studies in IBS-C – a prespecified further analysis based on European Medicines Agency-specified endpoints

Authors


Correspondence to:

Prof. E. M. M. Quigley, Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland.

E-mail: e.quigley@ucc.ie

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%; < 0.001) and IBS degree-of-relief responders (Trial 31: 37.0% vs. 18.5%; Trial 302: 39.4% vs. 16.6%; < 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%; < 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 (< 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).

Ancillary