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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.
Neurogastroenterol Motil. 2019 01; 31(1):e13487.NM

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.

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 1, Development, Astellas Pharma Inc., Tokyo, Japan.Regulatory Affairs-Japan, Astellas Pharma Inc., Tokyo, Japan.Astellas Pharma Inc., Tokyo, Japan.Japan-Asia Data Science, Development, Astellas Pharma Inc., Tokyo, Japan.Ironwood Pharmaceuticals Inc., Cambridge, Massachusetts.Ironwood Pharmaceuticals Inc., Cambridge, Massachusetts.Department of Internal Medicine, Kashiwa Hospital, Jikei University School of Medicine, Kashiwa, Japan.

Pub Type(s)

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

Language

eng

PubMed ID

30353619

Citation

Fukudo, Shin, et al. "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." Neurogastroenterology and Motility : the Official Journal of the European Gastrointestinal Motility Society, vol. 31, no. 1, 2019, pp. e13487.
Fukudo S, Miwa H, Nakajima A, et al. 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. Neurogastroenterol Motil. 2019;31(1):e13487.
Fukudo, S., Miwa, H., Nakajima, A., Kinoshita, Y., Kosako, M., Hayashi, K., Akiho, H., Kuroishi, K., Johnston, J. M., Currie, M., & Ohkusa, T. (2019). 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. Neurogastroenterology and Motility : the Official Journal of the European Gastrointestinal Motility Society, 31(1), e13487. https://doi.org/10.1111/nmo.13487
Fukudo S, et al. 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. Neurogastroenterol Motil. 2019;31(1):e13487. PubMed PMID: 30353619.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Fukudo,Shin, AU - Miwa,Hiroto, AU - Nakajima,Atsushi, AU - Kinoshita,Yoshikazu, AU - Kosako,Masanori, AU - Hayashi,Kenta, AU - Akiho,Hiraku, AU - Kuroishi,Kentaro, AU - Johnston,Jeffrey M, AU - Currie,Mark, AU - Ohkusa,Toshifumi, Y1 - 2018/10/23/ PY - 2018/06/28/received PY - 2018/09/02/revised PY - 2018/09/07/accepted PY - 2018/10/26/pubmed PY - 2020/1/21/medline PY - 2018/10/25/entrez KW - chronic constipation KW - diarrhea KW - guanylate cyclase C activator KW - linaclotide KW - stool consistency SP - e13487 EP - e13487 JF - Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society JO - Neurogastroenterol Motil VL - 31 IS - 1 N2 - 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. SN - 1365-2982 UR - https://www.unboundmedicine.com/medline/citation/30353619/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_ L2 - https://doi.org/10.1111/nmo.13487 DB - PRIME DP - Unbound Medicine ER -