Efficacy and Safety of 5-HT4 Receptor Agonist Minesapride for Irritable Bowel Syndrome with Constipation in a Randomized Controlled Trial

Abstract

BACKGROUND & AIMS:Treatment options for irritable bowel syndrome with constipation (IBS-C) are limited-new prokinetic drugs are needed. We evaluated the efficacy and safety of minesapride (DSP-6952), a partial agonist with high affinity for 5-HT4 receptors, in patients with IBS-C in Japan. METHODS:We performed a double-blind phase 2 study of 171 patients with Rome III-defined IBS-C at 33 centers in Japan, from December 2012 through August 2013. Patients were randomly assigned to groups given minesapride (1, 4, 12, or 40 mg) or placebo once daily for 4 weeks. The primary outcome was efficacy, defined as improvement in the weekly frequency of complete spontaneous bowel movements (CSBMs), abdominal symptoms, and IBS-C symptoms (according to the Japanese version of the IBS severity index score). For evaluation of safety, adverse events (AEs) were recorded. RESULTS:The least squares mean change from baseline in the weekly frequency of CSBMs was greater in all minesapride groups than in the placebo group at week 4 (40 mg vs placebo, P [ .040). The abdominal symptoms score improved in minesapride 40 mg group. The overall IBS severity index score decreased from baseline to week 4 in all treatment groups-especially in the 12 mg and 40 mg groups (P [ .048 and <.001 vs placebo, respectively). The proportions of patients with treatment-emergent AEs in the pooled minesapride and placebo groups were 55.0% and 60.0%, respectively. The most common treatment-emergent AE was diarrhea (in 42.9% and 37.1% of patients in the pooled minesapride and placebo groups, respectively). CONCLUSIONS:In a phase 2 trial of patients with IBS-C in Japan, minesapride increased stool frequency (measured by CSBMs), reduced abdominal and overall IBS-C symptoms, and was well tolerated. Japan Pharmaceutical Information Center trial no: JapicCTI-122041.

Randomised clinical trial: minesapride vs placebo for irritable bowel syndrome with predominant constipation

“…This is the first study to evaluate the efficacy and safety of novel 5‐HT 4 receptor agonist minesapride in patients with Rome IV defined IBS‐C. We previously reported the efficacy and safety of minesapride in patients with IBS‐C but they were diagnosed with Rome III criteria 20 . In the present study, minesapride failed to meet the primary endpoint, and no clear dose‐response relationship was found.…”

“…This study was intended to collect information required to determine the phase 3 study dose and design. Thus, on the basis of the results from a previous early phase 2 study, 20 and also in light of the feasibility of this study, the sample size per group was set to 100. The primary analysis population for the efficacy analysis was the modified intention‐to‐treat (mITT) population.…”

“…A QT/QTc study conducted according to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guideline showed that minesapride has no effect on QT prolongation 19 . In an early phase 2 study, Rome III‐defined patients with IBS‐C received minesapride at 1, 4, 12 or 40 mg/d once daily for 4 weeks 20 . Minesapride 40 mg/d led to increases in the number of complete spontaneous bowel movements (CSBMs), improvement in abdominal symptoms, and overall improvement in IBS symptoms, with favourable tolerability 20 .…”

“…In an early phase 2 study, Rome III‐defined patients with IBS‐C received minesapride at 1, 4, 12 or 40 mg/d once daily for 4 weeks 20 . Minesapride 40 mg/d led to increases in the number of complete spontaneous bowel movements (CSBMs), improvement in abdominal symptoms, and overall improvement in IBS symptoms, with favourable tolerability 20 . On the basis of these findings, minesapride 40 mg/d is expected to be efficacious in the treatment of IBS‐C.…”

Letter: placebo run‐in for IBS clinical trials—is it useful?

“…The authors applied a run‐in period, during which placebo was administered. They followed a similar approach in another recently published trial on minesapride in Rome III IBS‐C patients 2 …”