Introduction Linaclotide, a minimally absorbed guanylate cyclase-C agonist, was evaluated in a Phase 3 trial. To fulfil EMA submission requirements, the efficacy, safety and effects of withdrawal of linaclotide 290 μg in patients with IBS-C were assessed.
Methods In a randomised, double-blind, placebo (PBO)-controlled trial, IBS-C patients (modified Rome II criteria), with an average of <3 complete spontaneous bowel movements (CSBM)/week (wk), ≤5 spontaneous bowel movements (SBM)/wk and abdominal pain ≥3 (0–10 scale) during a 2-wk baseline period, received oral, once-daily linaclotide or PBO for a 12-wk treatment period (TP). In a 4-wk randomised withdrawal period (RWP), linaclotide-treated patients were re-randomised to receive linaclotide or PBO, and PBO-treated patients to receive linaclotide.
Results 800 patients (median age 44; female 90.5%) received linaclotide (n=405) or PBO (n=395). For the first co-primary parameter (≥30% reduction from baseline in mean abdominal pain or discomfort score for ≥6 of the 1st 12 wks with neither score worsening), 54.8% of linaclotide-treated patients and 41.8% of PBO-treated patients responded (p=0.0002). For the second co-primary parameter (patients “considerably relieved”/“completely relieved” on the weekly degree-of-relief of IBS symptoms question for ≥6 of the 1st 12 wks), 37.0% of linaclotide-treated patients and 18.5% of PBO-treated patients responded (p<0.0001). Linaclotide significantly improved all secondary parameters (including CSBM frequency rate, stool consistency, bloating and severity of straining) vs PBO (except wk 12 EQ-5D VAS; p=0.06). Improvements occurred in wk 1 and were sustained throughout the TP. During the RWP, patients continuing linaclotide had sustained efficacy in abdominal pain/discomfort response and IBS degree-of-relief response, and patients switched to PBO had symptom recurrence to the level of PBO during treatment. In patients initially treated with PBO and switched to linaclotide, abdominal pain improved to the level of linaclotide patients during the TP. Similar trends were seen in other abdominal/bowel parameters. Diarrhoea was the most common AE, causing discontinuation in 5.7% of linaclotide-treated patients and 0.3% of PBO-treated patients.
Conclusion In patients with IBS-C, linaclotide significantly improved all primary and secondary abdominal pain and bowel symptom parameters with no evidence of rebound on stopping treatment.
Competing interests E M Quigley Consultant for: Ironwood Pharmaceuticals, 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, C Diaz Employee of: Almirall, J Fortea Shareholder with: Almirall, Employee of: Almirall, M Falques Employee of: Almirall, S Shiff Employee of: Forest Research Institute, K Shi Employee of: Forest Research Institute, H A Schneier Employee of: Forest Research Institute, J M Johnston Employee of: Ironwood Pharmaceuticals.
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