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Cited by 169Gastrointestinal motility and disordersPelvic floor disorders treatmentsGastroesophageal reflux and treatments

Safety and efficacy of elobixibat for chronic constipation: results from a randomised, double-blind, placebo-controlled, phase 3 trial and an open-label, single-arm, phase 3 trial

Nakajima, Atsushi, Seki, Mitsunori, Taniguchi, Shinya, Ohta, Akira, Gillberg, Per-Göran, Mattsson, Jan P, Camilleri, Michael·2018·The Lancet Gastroenterology & Hepatology
DOI 10.1016/s2468-1253(18)30123-7
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Abstract

Background A subset of patients with constipation has reduced colonic bile acid concentrations, which are associated with slow colonic transit. In a previous study, elobixibat, a locally acting ileal bile acid transporter inhibitor, accelerated colonic transit in Japanese patients with functional constipation. In this study, we aimed to determine the efficacy of elobixibat for short-term treatment of chronic constipation, and safety, patient satisfaction, and quality of life with long-term treatment.Methods We did two phase 3 studies of patients aged 20-80 years in Japan with at least 6 months of chronic constipation, who satisfied Rome III criteria for functional constipation, including fewer than three spontaneous bowel movements per week. The first trial, including patients enrolled at 16 clinics, was a 2-week, randomised, double-blind, placebo-controlled study in which (after a 2-week run-in period) patients were randomly assigned (1:1) to either elobixibat 10 mg/day for 2 weeks or placebo. Randomisation was done with permuted block method (block size six) without stratification. Masking to treatment allocation was achieved with identical appearances of elobixibat and placebo, which were supplied in sealed, opaque containers. Group assignment was concealed from patients, investigators, and analysts. The second trial, including patients enrolled at 34 clinics or hospitals, was an open-label, 1-year study in which all patients received elobixibat; participants could titrate the dose to 5 mg/day or 15 mg/day, or maintain the 10 mg/day dose. In both studies, participants took the study drug as an oral tablet once per day before breakfast. The primary outcome of the 2-week randomised trial was the change from baseline (ie, last week of the 2-week run-in) in the frequency of spontaneous bowel movements during week 1 of treatment. The primary outcome of the 52-week open-label trial was safety (type, severity, and incidence of adverse drug reactions) at all times from treatment initiation. All efficacy analyses were based on the modified intention-to-treat (ITT) population without imputation for any missing data. Safety analyses included all patients who received at least one dose of study drug. These trials are registered with the Japan Pharmaceutical Information Center (numbers JapicCTI-153061 and JapicCTI-153062) and have been completed.Findings Between Nov 4, 2015, and June 11, 2016, we assigned 133 patients to treatment in the 2-week randomised trial: 70 to elobixibat (69 included in the modified ITT and safety populations) and 63 to placebo. The frequency of spontaneous bowel movements per week during week 1 of treatment was greater with elobixibat (least-squares mean 6·4, 95% CI 5·3-7·6) than with placebo (1·7, 1·2-2·2), p<0·0001). Between Oct 31, 2015, and March 15, 2017, we allocated 341 patients to 52 weeks of elobixibat (340 included in the modified ITT and safety populations). 163 (48%) patients in the 52-week trial had an adverse drug reaction, the most common of which were mild gastrointestinal disorders (in 135 [40%] patients). Inguinal hernia was reported in one patient with elobixibat in the 52-week study as a moderate adverse drug reaction. The most common adverse drug reactions in both trials were mild abdominal pain (13 [19%] patients with elobixibat and one [2%] with placebo in the 2-week randomised trial, and 82 [24%] patients in the 52-week trial) and diarrhoea (nine [13%] patients with elobixibat and none with placebo in the 2-week randomised trial and 50 [15%] in the 52-week trial).Interpretation Elobixibat resolved constipation in the short-term, and was well tolerated with both short-term and long-term treatment. The evidence supports the use of this novel approach to increase intracolonic concentrations of endogenous bile acid for the treatment of chronic constipation.Funding EA Pharma and Mochida Pharmaceutical.

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  • The elobixibat trial was only 2 weeks.

    “and this was only a 2-week trial”

    From Irritable bowel syndrome (2020) · cites this paper as [142]

  • A trial in Japan demonstrated that a 10mg dose of elobixibat was efficacious in patients with constipation, including IBS-C.

    “a trial in Japan demonstrated that a 10mg dose was efficacious in patients with constipation, including IBS-C”

    From Irritable bowel syndrome (2020) · cites this paper as [142]

  • Adverse events occurred in 30% of patients treated with elobixibat, particularly diarrhoea and abdominal pain.

    “adverse events occurred in 30% of patients, particularly diarrhoea and abdominal pain”

    From Irritable bowel syndrome (2020) · cites this paper as [142]

  • Studies on functional constipation patients treated with the ileal bile acid transporter inhibitor elobixibat demonstrated a causal relationship between elevated bile acid level and improved colonic transit.

    “Several studies on FC patients treated with an ileal BA transporter inhibitor (elobixibat) demonstrated a causal relationship between elevated BA level and improved colonic transit [ 40–43 ].”

    From Role of gut microbiota in functional constipation (2021) · cites this paper as [42]

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Authors
Nakajima, A., Seki, M., Taniguchi, S., Ohta, A., Gillberg, P.-G., Mattsson, J. P., & Camilleri, M.
Affiliations
  • Yokohama City University (JP)
  • EA Pharma (Japan) (JP)
  • Albireo (Sweden) (SE)
  • Mayo Clinic (US)
Corresponding author
Camilleri, Michael
ORCID
Venue
The Lancet Gastroenterology & Hepatology
Publisher
Elsevier BV
Published
2018-08
Volume
3
Issue
8
Pages
537-547
ISSN
  • 2468-1156 (ISSN-L)
  • 2468-1253
DOI
10.1016/s2468-1253(18)30123-7
OpenAlex
W2803710234
Cited by
169
References
31
Citations by year
2026: 16 · 2025: 17 · 2024: 24 · 2023: 12 · 2022: 25 · 2021: 23 · 2020: 30 · 2019: 13 · 2018: 8
FWCI
17.62
Type
journal article
Language
en
Open access
closed
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • The Lancet. Gastroenterology & hepatology (publishedVersion)
  • PubMed (publishedVersion)
Funders
EA Pharma Co., Ltd.
Topics
  • Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
  • Health Sciences › Medicine › Rheumatology › Pelvic floor disorders treatments
  • Health Sciences › Medicine › Gastroenterology › Gastroesophageal reflux and treatments
Keywords
elobixibat, chronic constipation, functional constipation, colonic transit, spontaneous bowel movements, adverse drug reactions, quality of life, patient satisfaction, long-term safety, dose titration, Rome III criteria, Japanese patients, drug safety and efficacy, open-label extension, modified intention-to-treat analysis
MeSH terms
Adult, Aged, Aged, 80 and over, Bile Acids and Salts, Carrier Proteins, Chronic Disease, Colon, Constipation, Dipeptides, Double-Blind Method, Female, Gastrointestinal Agents, Gastrointestinal Diseases, Gastrointestinal Transit, Humans, Male, Membrane Glycoproteins, Middle Aged, Quality of Life, Thiazepines, Abdominal Pain, Patient Satisfaction, Young Adult

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