A randomized placebo-controlled phase IIb trial of a3309, a bile acid transporter inhibitor, for chronic idiopathic constipation

Am J Gastroenterol. 2011 Oct;106(10):1803-12. doi: 10.1038/ajg.2011.162. Epub 2011 May 24.


Objectives: A3309 is a minimally absorbed ileal bile acid (BA) transporter (IBAT) inhibitor. We conducted an 8-week, multicenter, randomized, double-blind, placebo-controlled, parallel group, phase IIb study, which evaluated A3309 in patients with chronic idiopathic constipation (CIC).

Methods: Patients with CIC (modified Rome III criteria and <3 complete (CSBM) spontaneous bowel movements (SBMs)/week during the 2-week baseline) were randomized to 5, 10, or 15 mg A3309 or placebo once daily. The primary end point was change in SBM number during week 1 compared with baseline. Other bowel and abdominal symptoms were assessed as secondary end points. Serum 7αC4 and lipids were evaluated as biomarkers of BA synthesis/loss.

Results: In all, 190 patients (mean 48 years, 90% female) were randomized. Mean increase (95% confidence interval) in SBM for week 1 were 1.7 (0.7-2.8) for placebo vs. 2.5 (1.5-3.5), 4.0 (2.9-5.0), and 5.4 (4.4-6.4) for 5 mg, 10 mg (P<0.002), and 15 mg (P<0.001) A3309, respectively. Increased stool frequency was maintained over 8 weeks. Time to first SBM and CSBM were significantly reduced in the 10- and 15-mg A3309 groups compared with placebo. Straining and bloating decreased with A3309 compared with placebo (P<0.05). Increased 7αC4 and reduced low-density lipoprotein cholesterol with A3309 suggested increased BA synthesis and BA loss. The most common adverse events (AEs) were abdominal pain and diarrhea, which occurred most commonly in the 15-mg A3309 group. No drug-related serious AEs were observed.

Conclusions: A3309 increased stool frequency and improved constipation-related symptoms in CIC; effects were maintained over 8 weeks of treatment.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abdominal Pain / chemically induced
  • Adult
  • Aged
  • Carrier Proteins / antagonists & inhibitors*
  • Chronic Disease
  • Constipation / drug therapy*
  • Defecation / drug effects
  • Diarrhea / chemically induced
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Drug Administration Schedule
  • Female
  • Gastrointestinal Agents / administration & dosage
  • Gastrointestinal Agents / adverse effects
  • Gastrointestinal Agents / pharmacology
  • Gastrointestinal Agents / therapeutic use*
  • Humans
  • Male
  • Membrane Glycoproteins / antagonists & inhibitors*
  • Middle Aged
  • Treatment Outcome


  • Carrier Proteins
  • Gastrointestinal Agents
  • Membrane Glycoproteins
  • bile acid binding proteins