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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.
Aliment Pharmacol Ther 2013; 37(1):49-61AP

Abstract

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).

Authors+Show Affiliations

Alimentary Pharmabiotic Centre, University College Cork, Ireland. e.quigley@ucc.ieNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Clinical Trial, Phase III
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23116208

Citation

Quigley, E M M., et al. "Randomised Clinical Trials: Linaclotide Phase 3 Studies in IBS-C - a Prespecified Further Analysis Based On European Medicines Agency-specified Endpoints." Alimentary Pharmacology & Therapeutics, vol. 37, no. 1, 2013, pp. 49-61.
Quigley EM, Tack J, Chey WD, et al. Randomised clinical trials: linaclotide phase 3 studies in IBS-C - a prespecified further analysis based on European Medicines Agency-specified endpoints. Aliment Pharmacol Ther. 2013;37(1):49-61.
Quigley, E. M., Tack, J., Chey, W. D., Rao, S. S., Fortea, J., Falques, M., ... Johnston, J. M. (2013). Randomised clinical trials: linaclotide phase 3 studies in IBS-C - a prespecified further analysis based on European Medicines Agency-specified endpoints. Alimentary Pharmacology & Therapeutics, 37(1), pp. 49-61. doi:10.1111/apt.12123.
Quigley EM, et al. Randomised Clinical Trials: Linaclotide Phase 3 Studies in IBS-C - a Prespecified Further Analysis Based On European Medicines Agency-specified Endpoints. Aliment Pharmacol Ther. 2013;37(1):49-61. PubMed PMID: 23116208.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Randomised clinical trials: linaclotide phase 3 studies in IBS-C - a prespecified further analysis based on European Medicines Agency-specified endpoints. AU - Quigley,E M M, AU - Tack,J, AU - Chey,W D, AU - Rao,S S, AU - Fortea,J, AU - Falques,M, AU - Diaz,C, AU - Shiff,S J, AU - Currie,M G, AU - Johnston,J M, Y1 - 2012/11/01/ PY - 2012/08/14/received PY - 2012/08/20/revised PY - 2012/10/11/revised PY - 2012/10/11/accepted PY - 2012/11/3/entrez PY - 2012/11/3/pubmed PY - 2013/5/25/medline SP - 49 EP - 61 JF - Alimentary pharmacology & therapeutics JO - Aliment. Pharmacol. Ther. VL - 37 IS - 1 N2 - 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). SN - 1365-2036 UR - https://www.unboundmedicine.com/medline/citation/23116208/Randomised_clinical_trials:_linaclotide_phase_3_studies_in_IBS_C___a_prespecified_further_analysis_based_on_European_Medicines_Agency_specified_endpoints_ L2 - https://doi.org/10.1111/apt.12123 DB - PRIME DP - Unbound Medicine ER -