title: Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid.
abstract: OBJECTIVE
  We evaluated the efficacy and safety of obeticholic acid (OCA, α-ethylchenodeoxycholic acid) in a randomized controlled trial of patients with primary biliary cirrhosis who had an inadequate response to ursodeoxycholic acid therapy.
  
  
  METHODS
  We performed a double-blind study of 165 patients with primary biliary cirrhosis (95% women) and levels of alkaline phosphatase (ALP) 1.5- to 10-fold the upper limit of normal. Patients were randomly assigned to groups given 10 mg, 25 mg, or 50 mg doses of OCA or placebo, once daily for 3 months. Patients maintained their existing dose of ursodeoxycholic acid throughout the study. The primary outcome was change in level of ALP from baseline (day 0) until the end of the study (day 85 or early termination). We also performed an open-label extension of the trial in which 78 patients were enrolled and 61 completed the first year.
  
  
  RESULTS
  OCA was superior to placebo in achieving the primary end point. Subjects given OCA had statistically significant relative reductions in mean ALP from baseline to the end of the study (P < .0001 all OCA groups vs placebo). Levels of ALP decreased 21%-25% on average from baseline in the OCA groups and 3% in the placebo group. Sixty-nine percent (68 of 99) of patients given OCA had at least a 20% reduction in ALP compared with 8% (3 of 37) of patients given placebo (P < .0003). Among secondary end points, levels of γ-glutamyl transpeptidase decreased 48%-63%, on average, among subjects given OCA, vs a 7% decrease in the group given placebo; levels of alanine aminotransferase decreased 21%-35% on average among subjects given OCA vs none of the patients given placebo. Pruritus was the principal adverse event; incidence values in the OCA 10 mg, 25 mg, and 50 mg groups were 47% (not significantly different), 87% (P < .0003), and 80% (P < .006), respectively, vs 50% in the placebo group. In the extension study, levels of ALP continued to decrease to a mean level of 202 ± 11 U/L after 12 months vs 285 ± 15 U/L at baseline.
  
  
  CONCLUSIONS
  Daily doses of OCA, ranging from 10 to 50 mg, significantly reduced levels of ALP, γ-glutamyl transpeptidase, and alanine aminotransferase, compared with placebo, in patients with primary biliary cirrhosis who had inadequate responses to ursodeoxycholic acid. The incidence and severity of pruritus were lowest among patients who received 10 mg/d OCA. Biochemical responses to OCA were maintained in a 12-month open-label extension trial. ClinicalTrials.gov ID: NCT00550862.
authors.affiliation: Centre for Liver Research, NIHR Birmingham Liver Biomedical Research Unit, University of Birmingham, Birmingham, UK. Electronic address: g.hirschfield@bham.ac.uk.
authors.forename: Gideon M
authors.initials: GM
authors.lastname: Hirschfield
authors.affiliation: Division of Gastroenterology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Mason
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University School of Medicine, Richmond, Virginia; McGuire Research Institute, McGuire VA Medical Center, Richmond, VA.
authors.forename: Velimir
authors.initials: V
authors.lastname: Luketic
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Medical School, Rochester, Minnesota; School for the Science of Health Care Delivery, Arizona State University, Phoenix, Arizona.
authors.forename: Keith
authors.initials: K
authors.lastname: Lindor
authors.affiliation: Division of Hepatology, Henry Ford Health Systems, Detroit, Michigan.
authors.forename: Stuart C
authors.initials: SC
authors.lastname: Gordon
authors.affiliation: Division of Digestive and Liver Diseases, University of Texas, Southwestern Medical Center, Dallas, Texas.
authors.forename: Marlyn
authors.initials: M
authors.lastname: Mayo
authors.affiliation: Digestive Disease Institute, Virginia Mason Medical Center, Seattle, Washington.
authors.forename: Kris V
authors.initials: KV
authors.lastname: Kowdley
authors.affiliation: Department of Hepatology, Hopital Saint-Luc/CHUM Montreal, Canada.
authors.forename: Catherine
authors.initials: C
authors.lastname: Vincent
authors.affiliation: Department of Medicine, Mount Sinai School of Medicine, New York, New York; Division of Digestive Diseases, Beth Israel Medical Center, New York, New York.
authors.forename: Henry C
authors.initials: HC
authors.lastname: Bodhenheimer
authors.affiliation: Liver Unit, Hospital Clinic, IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain.
authors.forename: Albert
authors.initials: A
authors.lastname: Parés
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Trauner
authors.affiliation: Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Hanns-Ulrich
authors.initials: HU
authors.lastname: Marschall
authors.affiliation: Intercept Pharmaceuticals, San Diego, California.
authors.forename: Luciano
authors.initials: L
authors.lastname: Adorini
authors.affiliation: Intercept Pharmaceuticals, San Diego, California.
authors.forename: Cathi
authors.initials: C
authors.lastname: Sciacca
authors.affiliation: Intercept Pharmaceuticals, San Diego, California.
authors.forename: Tessa
authors.initials: T
authors.lastname: Beecher-Jones
authors.affiliation: Intercept Pharmaceuticals, San Diego, California.
authors.forename: Erin
authors.initials: E
authors.lastname: Castelloe
authors.affiliation: FGK Clinical Research, Munich, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Böhm
authors.affiliation: Intercept Pharmaceuticals, San Diego, California.
authors.forename: David
authors.initials: D
authors.lastname: Shapiro
mesh_terms: D000328:Adult; D000368:Aged; D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D002635:Chenodeoxycholic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D002756:Cholagogues and Choleretics / Q000008:administration & dosage* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008105:Liver Cirrhosis, Biliary / Q000097:blood / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D011537:Pruritus / Q000139:chemically induced; D017211:Treatment Failure; D016896:Treatment Outcome; D014580:Ursodeoxycholic Acid / Q000627:therapeutic use; D005723:gamma-Glutamyltransferase / Q000097:blood
chemical_list: D002756:Cholagogues and Choleretics; C464660:obeticholic acid; D002635:Chenodeoxycholic Acid; D014580:Ursodeoxycholic Acid; D005723:gamma-Glutamyltransferase; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase
keywords: Bile Acids; Cholestasis; Dose Study; FXR