Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial

作者：Neuschwander-Tetri, Brent A.^*; Loomba, Rohit; Sanyal, Arun J.; Lavine, Joel E.; Van Natta, Mark L.; Abdelmalek, M**** F.; Cha****ni, Naga; Dasarathy, Srinivasan; Diehl, Anna Mae; Hameed, Bilal; Kowdley, Kris V.; McCullough, Arthur; Terrault, Norah; Clark, Jeanne M.; Tonascia, James; Brunt, Elizabeth M.; Kleiner, David E.; Doo, Edward

来源：Lancet, 2015, 385(9972): 956-965.

DOI：10.1016/S0140-6736(14)61933-4

• FATTY LIVER-DISEASE
• BILE-ACIDS
• GLUCOSE-METABOLISM
• INSULIN-RESISTANCE
• FXR
• AGONIST
• THERAPY
• NAFLD
• NASH
• RATS

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. @@@ Findings 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. @@@ Interpretation Obeticholic acid improved the histological features of non-alcoholic steatohepatitis, but its long-term benefits and safety need further clarifi cation.

• 出版日期2015-3-14