PMID- 21606974 OWN - NLM STAT- MEDLINE DCOM- 20111123 LR - 20211020 IS - 1572-0241 (Electronic) IS - 0002-9270 (Print) IS - 0002-9270 (Linking) VI - 106 IP - 10 DP - 2011 Oct TI - A randomized placebo-controlled phase IIb trial of a3309, a bile acid transporter inhibitor, for chronic idiopathic constipation. PG - 1803-12 LID - 10.1038/ajg.2011.162 [doi] AB - 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 7alphaC4 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 7alphaC4 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. FAU - Chey, William D AU - Chey WD AD - Department of Medicine, University of Michigan Health System, Ann Arbor, 48109-5362, USA. wchey@med.umich.edu FAU - Camilleri, Michael AU - Camilleri M FAU - Chang, Lin AU - Chang L FAU - Rikner, Leif AU - Rikner L FAU - Graffner, Hans AU - Graffner H LA - eng PT - Clinical Trial, Phase II PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20110524 PL - United States TA - Am J Gastroenterol JT - The American journal of gastroenterology JID - 0421030 RN - 0 (Carrier Proteins) RN - 0 (Gastrointestinal Agents) RN - 0 (Membrane Glycoproteins) RN - 0 (bile acid binding proteins) SB - IM EIN - Am J Gastroenterol. 2014 May;109(5):782 CIN - Am J Gastroenterol. 2012 Jan;107(1):140; author reply 140-1. PMID: 22218036 CIN - Gastroenterology. 2012 Jul;143(1):262-4. PMID: 22633768 CIN - Z Gastroenterol. 2012 Jul;50(7):702-3. PMID: 22760684 MH - Abdominal Pain/chemically induced MH - Adult MH - Aged MH - Carrier Proteins/*antagonists & inhibitors MH - Chronic Disease MH - Constipation/*drug therapy MH - Defecation/drug effects MH - Diarrhea/chemically induced MH - Dose-Response Relationship, Drug MH - Double-Blind Method MH - Drug Administration Schedule MH - Female MH - Gastrointestinal Agents/administration & dosage/adverse effects/pharmacology/*therapeutic use MH - Humans MH - Male MH - Membrane Glycoproteins/*antagonists & inhibitors MH - Middle Aged MH - Treatment Outcome PMC - PMC3188811 EDAT- 2011/05/25 06:00 MHDA- 2011/12/13 00:00 CRDT- 2011/05/25 06:00 PHST- 2011/05/25 06:00 [entrez] PHST- 2011/05/25 06:00 [pubmed] PHST- 2011/12/13 00:00 [medline] AID - ajg2011162 [pii] AID - 10.1038/ajg.2011.162 [doi] PST - ppublish SO - Am J Gastroenterol. 2011 Oct;106(10):1803-12. doi: 10.1038/ajg.2011.162. Epub 2011 May 24.