title: Randomised clinical trial: The ileal bile acid transporter inhibitor A3309 vs. placebo in patients with chronic idiopathic constipation--a double-blind study.
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.
  
  
  OBJECTIVE
  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).
authors.affiliation: Department of Internal Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. magnus.simren@medicine.gu.se
authors.forename: M
authors.initials: M
authors.lastname: Simrén
authors.forename: A
authors.initials: A
authors.lastname: Bajor
authors.forename: P-G
authors.initials: PG
authors.lastname: Gillberg
authors.forename: M
authors.initials: M
authors.lastname: Rudling
authors.forename: H
authors.initials: H
authors.lastname: Abrahamsson
mesh_terms: D000328:Adult; D000368:Aged; D008078:Cholesterol, LDL / Q000494:pharmacology; D002908:Chronic Disease; D003106:Colon / Q000187:drug effects*; D003248:Constipation / Q000188:drug therapy*; D003672:Defecation / Q000187:drug effects; D004311:Double-Blind Method; D005260:Female; D005772:Gastrointestinal Transit / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D029363:Organic Anion Transporters, Sodium-Dependent / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D017060:Patient Satisfaction; D015990:Placebo Effect; D027981:Symporters / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D016896:Treatment Outcome
chemical_list: D008078:Cholesterol, LDL; D029363:Organic Anion Transporters, Sodium-Dependent; D027981:Symporters; C071908:sodium-bile acid cotransporter