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

E. M.M. Quigley, J. Tack, W. D. Chey, S. S. Rao, J. Fortea, M. Falques, C. Diaz, S. J. Shiff, M. G. Currie, J. M. Johnston

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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).

Original languageEnglish (US)
Pages (from-to)49-61
Number of pages13
JournalAlimentary Pharmacology and Therapeutics
Volume37
Issue number1
DOIs
StatePublished - Jan 1 2013

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Irritable Bowel Syndrome
Constipation
Randomized Controlled Trials
Abdominal Pain
Placebos
Guanylate Cyclase
linaclotide
Therapeutics
Safety

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology
  • Pharmacology (medical)

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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. / 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.

In: Alimentary Pharmacology and Therapeutics, Vol. 37, No. 1, 01.01.2013, p. 49-61.

Research output: Contribution to journalArticle

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. / Randomised clinical trials : Linaclotide phase 3 studies in IBS-C - A prespecified further analysis based on European Medicines Agency-specified endpoints. In: Alimentary Pharmacology and Therapeutics. 2013 ; Vol. 37, No. 1. pp. 49-61.
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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. 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).",
author = "Quigley, {E. M.M.} and J. Tack and Chey, {W. D.} and Rao, {S. S.} and J. Fortea and M. Falques and C. Diaz and Shiff, {S. J.} and Currie, {M. G.} and Johnston, {J. M.}",
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T1 - Randomised clinical trials

T2 - 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.

PY - 2013/1/1

Y1 - 2013/1/1

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).

AB - 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).

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