Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial.
Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial.
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DOI：
10.1016/s0140-6736(14)61933-4
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发表时间：
2015-03-14
期刊：
影响因子：
168.9
通讯作者：
Doo, Edward
中科院分区：
文献类型：
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作者：
Neuschwander-Tetri, Brent A.;Loomba, Rohit;Sanyal, Arun J.;Lavine, Joel E.;Van Natta, Mark L.;Abdelmalek, Manal F.;Chalasani, 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
胆汁酸衍生物6-乙基鹅去氧胆酸（奥贝胆酸）是法尼醇X核受体的有效激活剂，可减少脂肪肝动物模型中的肝脏脂肪和纤维化。我们评估了奥贝胆酸在成人非酒精性脂肪性肝炎患者中的疗效。我们在美国的医疗中心进行了一项多中心、双盲、安慰剂对照、平行组、随机临床试验，在非酒精性、非酒精性脂肪性肝炎患者中评估口服奥贝胆酸（每日25 mg）或安慰剂治疗72周。使用计算机生成的集中管理程序，按临床中心和糖尿病状态分层，以1：1的比例随机分配患者。主要结局指标是肝脏组织学集中评分的改善，定义为非酒精性脂肪肝疾病活动性评分从基线至治疗结束降低至少2分，而纤维化未恶化。计划在治疗结束（72周）活检前24周对丙氨酸转氨酶变化进行中期分析，支持继续试验的决定（丙氨酸转氨酶的相对变化-24%，95%CI-45至-3）。对主要结局的计划中期分析显示奥贝胆酸的疗效改善（p= 0.0024），并支持在64例患者中不进行治疗结束活检和早期结束治疗的决定，而是继续试验以获得24周的治疗后措施。通过意向治疗进行分析。该试验在ClinicalTrials.gov注册，编号NCT 01265498。在2011年3月16日至2012年12月3日期间，141名患者被随机分配接受奥贝胆酸，142名患者接受安慰剂。奥贝胆酸组110例患者中有50例（45%）在基线和72周时进行活检，与安慰剂组109例患者中的23例（21%）相比，肝脏组织学改善（相对风险1.9，95%CI 1.3至2.8; p= 0.0002）。奥贝胆酸组141例患者中有33例（23%）出现瘙痒，而安慰剂组142例患者中有9例（6%）出现瘙痒。奥贝胆酸改善了非酒精性脂肪性肝炎的组织学特征，但其长期益处和安全性需要进一步阐明。国立糖尿病、消化和肾脏疾病研究所，Intercept Pharmaceuticals。
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. 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. 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. Obeticholic acid improved the histological features of non-alcoholic steatohepatitis, but its long-term benefits and safety need further clarification. National Institute of Diabetes and Digestive and Kidney Diseases, Intercept Pharmaceuticals.