title: Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial.
abstract: BACKGROUND
  The bile acid derivative 6-ethylchenodeoxycholic acid (obeticholic acid) is a potent activator of the farnesoid X nuclear receptor that reduces liver fat and fibrosis in animal models of fatty liver disease. We assessed the efficacy of obeticholic acid in adult patients with non-alcoholic steatohepatitis.
  
  
  METHODS
  We did a multicentre, double-blind, placebo-controlled, parallel group, randomised clinical trial at medical centres in the USA in patients with non-cirrhotic, non-alcoholic steatohepatitis to assess treatment with obeticholic acid given orally (25 mg daily) or placebo for 72 weeks. Patients were randomly assigned 1:1 using a computer-generated, centrally administered procedure, stratified by clinical centre and diabetes status. The primary outcome measure was improvement in centrally scored liver histology defined as a decrease in non-alcoholic fatty liver disease activity score by at least 2 points without worsening of fibrosis from baseline to the end of treatment. A planned interim analysis of change in alanine aminotransferase at 24 weeks undertaken before end-of-treatment (72 weeks) biopsies supported the decision to continue the trial (relative change in alanine aminotransferase -24%, 95% CI -45 to -3). A planned interim analysis of the primary outcome showed improved efficacy of obeticholic acid (p=0·0024) and supported a decision not to do end-of-treatment biopsies and end treatment early in 64 patients, but to continue the trial to obtain the 24-week post-treatment measures. Analyses were done by intention-to-treat. This trial was registered with ClinicalTrials.gov, number NCT01265498.
  
  
  RESULTS
  Between March 16, 2011, and Dec 3, 2012, 141 patients were randomly assigned to receive obeticholic acid and 142 to placebo. 50 (45%) of 110 patients in the obeticholic acid group who were meant to have biopsies at baseline and 72 weeks had improved liver histology compared with 23 (21%) of 109 such patients in the placebo group (relative risk 1·9, 95% CI 1·3 to 2·8; p=0·0002). 33 (23%) of 141 patients in the obeticholic acid developed pruritus compared with nine (6%) of 142 in the placebo group.
  
  
  CONCLUSIONS
  Obeticholic acid improved the histological features of non-alcoholic steatohepatitis, but its long-term benefits and safety need further clarification.
  
  
  BACKGROUND
  National Institute of Diabetes and Digestive and Kidney Diseases, Intercept Pharmaceuticals.
authors.affiliation: Saint Louis University, St Louis, MO, USA. Electronic address: tetriba@slu.edu.
authors.forename: Brent A
authors.initials: BA
authors.lastname: Neuschwander-Tetri
authors.affiliation: University of California San Diego, La Jolla, CA, USA.
authors.forename: Rohit
authors.initials: R
authors.lastname: Loomba
authors.affiliation: Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Arun J
authors.initials: AJ
authors.lastname: Sanyal
authors.affiliation: Columbia University, New York, NY, USA.
authors.forename: Joel E
authors.initials: JE
authors.lastname: Lavine
authors.affiliation: Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Van Natta
authors.affiliation: Duke University, Durham, NC, USA.
authors.forename: Manal F
authors.initials: MF
authors.lastname: Abdelmalek
authors.affiliation: Indiana University, Indianapolis, IN, USA.
authors.forename: Naga
authors.initials: N
authors.lastname: Chalasani
authors.affiliation: Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Dasarathy
authors.affiliation: Duke University, Durham, NC, USA.
authors.forename: Anna Mae
authors.initials: AM
authors.lastname: Diehl
authors.affiliation: University of California San Francisco, San Francisco, CA USA.
authors.forename: Bilal
authors.initials: B
authors.lastname: Hameed
authors.affiliation: Virginia Mason Medical Center, Seattle, WA, USA.
authors.forename: Kris V
authors.initials: KV
authors.lastname: Kowdley
authors.affiliation: Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Arthur
authors.initials: A
authors.lastname: McCullough
authors.affiliation: University of California San Francisco, San Francisco, CA USA.
authors.forename: Norah
authors.initials: N
authors.lastname: Terrault
authors.affiliation: Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Jeanne M
authors.initials: JM
authors.lastname: Clark
authors.affiliation: Johns Hopkins University, Baltimore, MD, USA.
authors.forename: James
authors.initials: J
authors.lastname: Tonascia
authors.affiliation: Washington University, St Louis, MO, USA.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Brunt
authors.affiliation: The National Cancer Institute, Bethesda, MD, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Kleiner
authors.affiliation: The National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Doo
mesh_terms: D000284:Administration, Oral; D002635:Chenodeoxycholic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D008076:Cholesterol, HDL / Q000378:metabolism; D008078:Cholesterol, LDL / Q000378:metabolism; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008099:Liver / Q000201:enzymology; D008103:Liver Cirrhosis / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy* / Q000201:enzymology; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects; D016896:Treatment Outcome; D015431:Weight Loss / Q000187:drug effects; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D002635:Chenodeoxycholic Acid; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C464660:obeticholic acid