Introduction Linaclotide, a minimally absorbed guanylate cyclase-C receptor agonist, is an investigational drug treatment for IBS-C. As part of the European Medicines Authority submission we evaluated the efficacy and safety of linaclotide 290 μg, administered once daily for 26 weeks (wks), in a Phase 3 trial of patients with IBS-C.
Methods In a randomised, double-blind, Phase 3 trial, IBS-C patients (modified Rome II criteria) with an overall complete spontaneous bowel movement (CSBM) frequency of <3/wk, an overall spontaneous bowel movement (SBM) frequency of ≤5/wk and an average abdominal pain score of ≥3 (0–10 scale) during a 2 wk baseline period were randomised to linaclotide or placebo for 26 wks of treatment. Efficacy parameters were analysed at 12 and 26 wks.
Results In total, 804 patients (female 90%; median age 44 years) received linaclotide (n=401) or placebo (n=403). During the 2 wk baseline period, 87% had abdominal pain every day (mean score 5.6; 0–10 scale) and 76% had no CSBMs (mean rate 0.2/wk). Significant improvements in linaclotide-treated patients were seen for both co-primary and all 12 secondary parameters. For the first co-primary parameter (≥30% reduction from baseline in mean abdominal pain or discomfort score with neither score worsening for ≥6 of the first 12 wks), 54.1% of linaclotide-treated patients and 38.5% of placebo-treated patients were responders (p<0.0001). For the second co-primary parameter (“considerably relieved” or “completely relieved” on the weekly degree-of-relief of IBS symptoms question for ≥6 of the first 12 wks), 39.4% of linaclotide-treated patients and 16.6% of placebo-treated patients were responders (p<0.0001). Similar improvements in both co-primary endpoints were seen at 26 wks (53.6% vs 36.0%, 37.2% vs 16.9%; both p<0.0001). Also, rates for sustained abdominal pain/discomfort response and sustained IBS degree-of-relief response at 12 and 26 wks were significantly greater in linaclotide-treated vs placebo-treated patients (all p<0.0001). Linaclotide significantly improved CSBMs, stool consistency, straining, bloating, SBMs, abdominal pain and abdominal discomfort vs placebo over 12 and 26 wks (p<0.0001). The most common adverse event (AE) was diarrhoea, causing discontinuation in 4.0% of linaclotide-treated and 0.2% of placebo-treated patients.
Conclusion Treatment of IBS-C with linaclotide produced statistically significant improvements in abdominal and bowel symptoms at 12 wks and were sustained over 26 wks. Diarrhoea was the most common AE.
Competing interests A J Lembo grant/research support from: Ironwood Pharmaceuticals, consultant for: Ironwood Pharmaceuticals/Salix/Prometheus/Alkermes/Ardelyx/GSK/Theravance, conflict with: lecture fees from Ironwood Pharmaceuticals, J Fortea Shareholder with: Almirall, Employee of: Almirall, C Diaz Employee of: Almirall, M Falques Employee of: Almirall, J Shao Employee of: Ironwood Pharmaceuticals, B J Lavins Employee of: Ironwood Pharmaceuticals, H A Schneier Employee of: Forest Research Institute, J M Johnston Employee of: Ironwood Pharmaceuticals.
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