Dose‐finding study of linaclotide in Japanese patients with chronic constipation: A phase II randomized, double‐blind, and placebo‐controlled study

Abstract

Our results suggest that 0.0625, 0.125, 0.25, and 0.5 mg/d are effective doses of linaclotide for treating CC in Japanese patients. ClinicalTrials.gov: NCT02425722, supported by Astellas Pharma, Inc.

High‐dose linaclotide is effective and safe in patients with chronic constipation: A phase III randomized, double‐blind, placebo‐controlled study with a long‐term open‐label extension study in Japan

“…The primary efficacy endpoint was the change from baseline in SBM frequency in the first week of treatment, as previously approved for other constipation trials by Japanese Pharmaceuticals and Medical Devices Agency (PMDA) . The secondary endpoints included the following: complete SBM (CSBM, defined as an SBM for which the patient reported a feeling of complete evacuation), 50% responder rate (to be a CSBM 50% responder, a patient had to be a weekly responder for at least 2 of the 4 double‐blind treatment period weeks; to be a weekly CSBM responder, a patient had to report in the same week at least three CSBMs and an increase in at least one CSBM from baseline), stool consistency, straining, abdominal bloating, abdominal pain/discomfort, responder rates for relief of CC‐related parameters (global assessment of relief of CC symptoms, improvement in abnormal bowel habits, and relief of abdominal symptoms; weekly responders of relief for each parameter were defined as patients with a score of 1 or 2 at each weekly evaluation point, and patients who were weekly responders for at least 2 of the 4 weeks of the double‐blind treatment period were considered to be overall responders), proportion of patients who had an SBM/CSBM within 24 hours after the start of the initial administration of the study drug, time to first SBM, and IBS‐QOL .…”

“…9.4) (SAS Institute Inc., Cary, NC, USA). Sample sizes estimated to provide more than 90% power to detect a difference in the primary endpoint between placebo and linaclotide 0.5 mg were based on the phase II clinical study data, using asymptotic normal approximation with a two‐sided significance level of 0.05. In total, 170 patients (85 patients for each group) were selected for randomization.…”

“…16 The recommended doses of linaclotide from these studies are 0.29 mg for IBS-C and 0.145 mg for CC. [12][13][14][15][16] By contrast, results [8][9][10] obtained in Japan have been somewhat different. A phase II study of IBS-C patients showed 0.5 mg per day of linaclotide to be the optimal dose.…”

“…10 Additionally, a phase II study of CC patients also showed that 0.5 mg per day of linaclotide is the optimal dose in this patient population. 8 Therefore, we sought to confirm our hypothesis that 0.5 mg of linaclotide in CC patients is effective and safe by conducting a phase III study in Japan.…”

“…We previously performed randomized placebo‐controlled trials of linaclotide in Japanese patients with CC or irritable bowel syndrome with constipation (IBS‐C) . Linaclotide is a 14‐amino acid peptide which acts as a novel guanylate cyclase C (GC‐C) activator .…”