Randomised clinical trial: The ileal bile acid transporter inhibitor A3309 vs. placebo in patients with chronic idiopathic constipation--a double-blind study

Aliment Pharmacol Ther. 2011 Jul;34(1):41-50. doi: 10.1111/j.1365-2036.2011.04675.x. Epub 2011 May 5.

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).

Publication types

  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Cholesterol, LDL / pharmacology
  • Chronic Disease
  • Colon / drug effects*
  • Constipation / drug therapy*
  • Defecation / drug effects
  • Double-Blind Method
  • Female
  • Gastrointestinal Transit / drug effects*
  • Humans
  • Male
  • Middle Aged
  • Organic Anion Transporters, Sodium-Dependent / antagonists & inhibitors*
  • Organic Anion Transporters, Sodium-Dependent / pharmacology
  • Patient Satisfaction
  • Placebo Effect
  • Symporters / antagonists & inhibitors*
  • Symporters / pharmacology
  • Treatment Outcome

Substances

  • Cholesterol, LDL
  • Organic Anion Transporters, Sodium-Dependent
  • Symporters
  • sodium-bile acid cotransporter