Randomised clinical trial: the ileal bile acid transporter inhibitor A3309 vs. placebo in patients with chronic idiopathic constipation - a double-blind study: Randomised clinical trial: the ASBT/IBAT inhibitor A3309 in constipation
Abstract
BACKGROUND: One half of patients with constipation are not satisfied with available therapies, hence there is a need for more effective and well-tolerated drugs. AIM: To evaluate the effects of a specific inhibitor of the Ileal Bile Acid Transporter (IBAT; syn apical sodium-dependent bile acid transporter; ASBT) in patients with chronic idiopathic constipation (CIC) with focus on safety, colonic transit and efficacy signals. METHODS: This was a single-centre, prospective, randomised, double-blind, placebo-controlled study with a dose-escalating design in patients with CIC. In addition to evaluation of conventional safety and tolerability parameters, (i) colonic transit time (CTT) was measured using radio-opaque markers, (ii) metabolic parameters [lipid profile, C4 (7α-hydroxy-4-cholesten-3-one) and FGF19 (Fibroblast Growth Factor 19)] were evaluated, and (iii) constipation parameters, such as changes in stool frequency and consistency, were analysed. RESULTS: Thirty patients were randomised into five dose-levels (range: 0.1-10 mg/day) or to placebo. All patients completed a 14-day treatment period, and the safety/tolerability analysis was favourable. A3309, present in picomolar concentrations in plasma, induced up to a three-fold increase in bile acid synthesis (C4) and a reduction of plasma FGF19, as well as reduction in total and LDL cholesterol. CTT was reduced in the highest dose groups; the main acceleration was identified in the left colon. Efficacy parameters showed trends for increased number of spontaneous bowel movements and improved stool consistency. CONCLUSIONS: Ileal Bile Acid Transporter inhibition is a novel mechanism for treatment of patients with chronic idiopathic constipation and has additional benefits of improving metabolic parameters (EudraCT 2008-003255-72).
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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 [40]
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- Authors
- Simrén, M., Bajor, A., Gillberg, P.-G., Rudling, M., & Abrahamsson, H.
- Affiliations
- University of Gothenburg (SE)
- Albireo (Sweden) (SE)
- Karolinska University Hospital (SE)
- Corresponding author
- Simrén, M.
- Venue
- Alimentary Pharmacology & Therapeutics
- Publisher
- Wiley
- Published
- 2011-05-05
- Volume
- 34
- Issue
- 1
- Pages
- 41-50
- ISSN
- 0269-2813 (ISSN-L)
- OpenAlex
- W1826937932
- Cited by
- 114
- References
- 20
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 2 · 2023: 3 · 2022: 4 · 2021: 9 · 2020: 10 · 2019: 3 · 2018: 12 · 2017: 8 · 2016: 12 · 2015: 12 · 2014: 12 · 2013: 6 · 2012: 10
- FWCI
- 11.49
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Alimentary Pharmacology & Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- AstraZeneca
- Danone
- Kommunfullmäktige, Stockholms Stad
- Karolinska Institutet
- Vetenskapsrådet
- Sahlgrenska Universitetssjukhuset
- Topics
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Drug Solubulity and Delivery Systems
- Keywords
- chronic idiopathic constipation, colonic transit time, bile acid synthesis, C4, FGF19, LDL cholesterol, stool frequency, stool consistency, drug safety and tolerability
- MeSH terms
- Adult, Aged, Chronic Disease, Colon, Constipation, Defecation, Double-Blind Method, Female, Gastrointestinal Transit, Humans, Cholesterol, LDL, Male, Middle Aged, Placebo Effect, Treatment Outcome, Patient Satisfaction, Symporters, Organic Anion Transporters, Sodium-Dependent
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