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

Shin Fukudo, Hiroto Miwa, Atsushi Nakajima, Yoshikazu Kinoshita, Masanori Kosako, Kenta Hayashi, Hiraku Akiho, Kentaro Kuroishi, Jeffrey M. Johnston, Mark Currie, Toshifumi Ohkusa

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Background: A previous phase II dose-ranging study of linaclotide in a Japanese chronic constipation (CC) population showed that 0.5 mg was the most effective dose. This study aimed to verify the hypothesis that 0.5 mg of linaclotide is effective and safe in Japanese CC patients. Methods: This was a Japanese phase III randomized, double-blind, placebo-controlled (part 1), and long-term, open-label extension (part 2) study of linaclotide. CC patients (n = 186) diagnosed using the Rome III criteria were randomly assigned to linaclotide 0.5 mg (n = 95) or placebo (n = 91) for a 4-week double-blind treatment period in part 1, followed by an additional 52 weeks of open-label treatment with linaclotide in part 2. The primary efficacy endpoint was the change from baseline in weekly spontaneous bowel movement (SBM) frequency at the first week. Secondary endpoints included responder rate for complete SBM (CSBM), changes in stool consistency, and severity of straining. Key Results: Part 1: Change in weekly mean SBM frequency in the first week of treatment with linaclotide (4.02) was significantly greater than that with placebo (1.48, P < 0.001). Linaclotide produced a higher CSBM responder rate (52.7%) compared to placebo (26.1%, P < 0.001). Part 2: Patients continued to show improved SBM frequency with linaclotide. Through parts 1 and 2, the most common drug-related adverse event was mild and occasionally moderate diarrhea. Conclusions and Inferences: The results of this study indicate that a linaclotide dose of 0.5 mg/day is effective and safe in Japanese CC patients.

Original languageEnglish
Article numbere13487
JournalNeurogastroenterology and Motility
Volume31
Issue number1
DOIs
Publication statusPublished - 2019 Jan

Keywords

  • chronic constipation
  • diarrhea
  • guanylate cyclase C activator
  • linaclotide
  • stool consistency

ASJC Scopus subject areas

  • Physiology
  • Endocrine and Autonomic Systems
  • Gastroenterology

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