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Dose-finding study of linaclotide in Japanese patients with chronic constipation: A phase II randomized, double-blind, and placebo-controlled study.
Neurogastroenterol Motil. 2018 12; 30(12):e13442.NM

Abstract

BACKGROUND

Based on the previous phase II/III studies of irritable bowel syndrome with constipation (IBS-C) in Japan that demonstrated the efficacy and safety of linaclotide 0.5 mg/d, we evaluated linaclotide at doses of 0.5 mg/d and lower in the treatment of Japanese patients with chronic constipation (CC).

METHODS

This was a phase II randomized, double-blind, placebo-controlled, dose-finding study of linaclotide for Japanese patients with CC (n = 382, 64 men, 318 women, age 20-75). After a baseline period of two weeks, patients were randomized to receive placebo (n = 80), or 0.0625 mg (n = 82), 0.125 mg (n = 71), 0.25 mg (n = 73) or 0.5 mg (n = 76) of linaclotide during a two-week treatment period. The primary efficacy endpoint was change from baseline in weekly spontaneous bowel movement (SBM) frequency during the first week. Secondary endpoints included complete SBM (CSBM) responder rates and IBS-QOL. Safety and adverse events were also evaluated.

KEY RESULTS

The change in SBM frequency during the first week (mean) was 3.89, 3.11, 3.87, and 3.85 for 0.0625 mg, 0.125 mg, 0.25 mg, and 0.5 mg for linaclotide, significantly higher than for placebo (1.91, P < 0.05). The CSBM responder, which is an important parameter, showed the greatest improvement at the 0.5 mg during the 2 week. The most frequent adverse event in the linaclotide groups was diarrhea.

CONCLUSIONS & INFERENCES

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.

Authors+Show Affiliations

Department of Behavioral Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan.Department of Gastroenterology and Hepatology, Yokohama City University, Yokohama, Japan.Department of Gastroenterology, Faculty of Medicine, Shimane University, Izumo, Japan.Japan-Asia Clinical Development 2, Development, Astellas Pharma Inc., Tokyo, Japan.Japan-Asia Clinical Development 2, Development, Astellas Pharma Inc., Tokyo, Japan.Japan-Asia Clinical Development 2, Development, Astellas Pharma Inc., Tokyo, Japan.Japan-Asia Data Science, Development, Astellas Pharma Inc., Tokyo, Japan.A consultant for Ironwood Pharmaceuticals Inc., Cambridge, MA, USA.Ironwood Pharmaceuticals Inc., Cambridge, MA, USA.Department of Internal Medicine, Kashiwa Hospital, Jikei University School of Medicine, Kashiwa, Japan.

Pub Type(s)

Clinical Trial, Phase II
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30084233

Citation

Fukudo, Shin, et al. "Dose-finding Study of Linaclotide in Japanese Patients With Chronic Constipation: a Phase II Randomized, Double-blind, and Placebo-controlled Study." Neurogastroenterology and Motility : the Official Journal of the European Gastrointestinal Motility Society, vol. 30, no. 12, 2018, pp. e13442.
Fukudo S, Miwa H, Nakajima A, et al. Dose-finding study of linaclotide in Japanese patients with chronic constipation: A phase II randomized, double-blind, and placebo-controlled study. Neurogastroenterol Motil. 2018;30(12):e13442.
Fukudo, S., Miwa, H., Nakajima, A., Kinoshita, Y., Kosako, M., Nakagawa, A., Akiho, H., Kuroishi, K., Johnston, J. M., Currie, M., & Ohkusa, T. (2018). Dose-finding study of linaclotide in Japanese patients with chronic constipation: A phase II randomized, double-blind, and placebo-controlled study. Neurogastroenterology and Motility : the Official Journal of the European Gastrointestinal Motility Society, 30(12), e13442. https://doi.org/10.1111/nmo.13442
Fukudo S, et al. Dose-finding Study of Linaclotide in Japanese Patients With Chronic Constipation: a Phase II Randomized, Double-blind, and Placebo-controlled Study. Neurogastroenterol Motil. 2018;30(12):e13442. PubMed PMID: 30084233.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Dose-finding study of linaclotide in Japanese patients with chronic constipation: A phase II randomized, double-blind, and placebo-controlled study. AU - Fukudo,Shin, AU - Miwa,Hiroto, AU - Nakajima,Atsushi, AU - Kinoshita,Yoshikazu, AU - Kosako,Masanori, AU - Nakagawa,Ayako, AU - Akiho,Hiraku, AU - Kuroishi,Kentaro, AU - Johnston,Jeffrey M, AU - Currie,Mark, AU - Ohkusa,Toshifumi, Y1 - 2018/08/07/ PY - 2018/03/27/received PY - 2018/07/06/accepted PY - 2018/8/8/pubmed PY - 2019/11/5/medline PY - 2018/8/8/entrez KW - abdominal pain KW - constipation KW - guanylate cyclase C activator KW - linaclotide KW - stool consistency SP - e13442 EP - e13442 JF - Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society JO - Neurogastroenterol Motil VL - 30 IS - 12 N2 - BACKGROUND: Based on the previous phase II/III studies of irritable bowel syndrome with constipation (IBS-C) in Japan that demonstrated the efficacy and safety of linaclotide 0.5 mg/d, we evaluated linaclotide at doses of 0.5 mg/d and lower in the treatment of Japanese patients with chronic constipation (CC). METHODS: This was a phase II randomized, double-blind, placebo-controlled, dose-finding study of linaclotide for Japanese patients with CC (n = 382, 64 men, 318 women, age 20-75). After a baseline period of two weeks, patients were randomized to receive placebo (n = 80), or 0.0625 mg (n = 82), 0.125 mg (n = 71), 0.25 mg (n = 73) or 0.5 mg (n = 76) of linaclotide during a two-week treatment period. The primary efficacy endpoint was change from baseline in weekly spontaneous bowel movement (SBM) frequency during the first week. Secondary endpoints included complete SBM (CSBM) responder rates and IBS-QOL. Safety and adverse events were also evaluated. KEY RESULTS: The change in SBM frequency during the first week (mean) was 3.89, 3.11, 3.87, and 3.85 for 0.0625 mg, 0.125 mg, 0.25 mg, and 0.5 mg for linaclotide, significantly higher than for placebo (1.91, P < 0.05). The CSBM responder, which is an important parameter, showed the greatest improvement at the 0.5 mg during the 2 week. The most frequent adverse event in the linaclotide groups was diarrhea. CONCLUSIONS & INFERENCES: 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. SN - 1365-2982 UR - https://www.unboundmedicine.com/medline/citation/30084233/Dose_finding_study_of_linaclotide_in_Japanese_patients_with_chronic_constipation:_A_phase_II_randomized_double_blind_and_placebo_controlled_study_ L2 - https://doi.org/10.1111/nmo.13442 DB - PRIME DP - Unbound Medicine ER -