奥贝胆酸治疗原发性胆汁性胆管炎的安慰剂对照临床试验。
A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis.
机构信息
From University Hospitals KU Leuven, Leuven, Belgium (F.N.); University of Bologna, Bologna (P.A., G.M.), Program for Autoimmune Liver Disease, International Center for Digestive Health, Department of Medicine and Surgery, University of Milan-Bicocca, Milan (P.I.), Humanitas Clinical and Research Center, Rozzano (P.I.), and University of Padua, Padua (A.F.) - all in Italy; Royal Prince Alfred Hospital, Camperdown, NSW, Australia (S.I.S.); University of California Davis Medical Center, Sacramento (C.B.), Scripps Clinic, La Jolla (P.J.P.), and Intercept Pharmaceuticals, San Diego (R.H.-R., T.M., S.S., R.P., L.M., M.P., D.S.) - all in California; Radboud University Nijmegen Medical Center, Nijmegen (J.P.H.D.), University of Amsterdam, Amsterdam (U.B.), University Medical Center Utrecht, Utrecht (K.J.E.), and University Medical Center Rotterdam, Rotterdam (B.H.) - all in the Netherlands; Maria Sklodowska-Curie Memorial Cancer Center, Warsaw, Poland (J.R.); Medical University of Vienna, Vienna (M.T.); Newcastle University Medical School, Newcastle upon Tyne (D.E.J.), and the Centre for Liver Research, NIHR Biomedical Research Unit, University of Birmingham, Birmingham (G.M.H.) - both in the United Kingdom; Liver Center Munich, Department of Medicine II, University of Munich, Munich, Germany (S.H.); Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University and Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond (V.L.), and the Liver Institute of Virginia, Newport News (M.S.) - all in Virginia; the Liver Unit, Hospital Vall d'Hebron, Universitat Autonoma de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas del Instituto de Salud Carlos III, Barcelona (V.V.); Centre Hospitalier de l'Université de Montréal-St. Luc, Montreal (C.V.); University Health Network Toronto Western Hospital, Toronto (H.S.); Arizona State University, Tempe (K.D.L.); Sahlgrenska Academy, University of Gothenburg,
出版信息
N Engl J Med. 2016 Aug 18;375(7):631-43. doi: 10.1056/NEJMoa1509840.
BACKGROUND
Primary biliary cholangitis (formerly called primary biliary cirrhosis) can progress to cirrhosis and death despite ursodiol therapy. Alkaline phosphatase and bilirubin levels correlate with the risk of liver transplantation or death. Obeticholic acid, a farnesoid X receptor agonist, has shown potential benefit in patients with this disease.
METHODS
In this 12-month, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 217 patients who had an inadequate response to ursodiol or who found the side effects of ursodiol unacceptable to receive obeticholic acid at a dose of 10 mg (the 10-mg group), obeticholic acid at a dose of 5 mg with adjustment to 10 mg if applicable (the 5-10-mg group), or placebo. The primary end point was an alkaline phosphatase level of less than 1.67 times the upper limit of the normal range, with a reduction of at least 15% from baseline, and a normal total bilirubin level.
RESULTS
Of 216 patients who underwent randomization and received at least one dose of obeticholic acid or placebo, 93% received ursodiol as background therapy. The primary end point occurred in more patients in the 5-10-mg group (46%) and the 10-mg group (47%) than in the placebo group (10%; P<0.001 for both comparisons). Patients in the 5-10-mg group and those in the 10-mg group had greater decreases than those in the placebo group in the alkaline phosphatase level (least-squares mean, -113 and -130 U per liter, respectively, vs. -14 U per liter; P<0.001 for both comparisons) and total bilirubin level (-0.02 and -0.05 mg per deciliter [-0.3 and -0.9 μmol per liter], respectively, vs. 0.12 mg per deciliter [2.0 μmol per liter]; P<0.001 for both comparisons). Changes in noninvasive measures of liver fibrosis did not differ significantly between either treatment group and the placebo group at 12 months. Pruritus was more common with obeticholic acid than with placebo (56% of patients in the 5-10-mg group and 68% of those in the 10-mg group vs. 38% in the placebo group). The rate of serious adverse events was 16% in the 5-10-mg group, 11% in the 10-mg group, and 4% in the placebo group.
CONCLUSIONS
Obeticholic acid administered with ursodiol or as monotherapy for 12 months in patients with primary biliary cholangitis resulted in decreases from baseline in alkaline phosphatase and total bilirubin levels that differed significantly from the changes observed with placebo. There were more serious adverse events with obeticholic acid. (Funded by Intercept Pharmaceuticals; POISE ClinicalTrials.gov number, NCT01473524; Current Controlled Trials number, ISRCTN89514817.).
背景
原发性胆汁性胆管炎（以前称为原发性胆汁性肝硬化）尽管进行了熊去氧胆酸治疗，仍可进展为肝硬化和死亡。碱性磷酸酶和胆红素水平与肝移植或死亡的风险相关。法尼醇 X 受体激动剂奥贝胆酸已显示出对该疾病患者的潜在益处。
方法
在这项为期 12 个月、双盲、安慰剂对照、3 期试验中，我们随机分配了 217 名对熊去氧胆酸反应不足或发现熊去氧胆酸副作用无法耐受的患者，接受奥贝胆酸 10mg 治疗（10mg 组）、奥贝胆酸 5mg 并在适用时调整至 10mg（5-10mg 组）或安慰剂。主要终点是碱性磷酸酶水平低于正常上限的 1.67 倍，与基线相比至少降低 15%，且总胆红素水平正常。
结果
在 216 名接受随机分组并至少接受一剂奥贝胆酸或安慰剂的患者中，93%接受了熊去氧胆酸作为背景治疗。主要终点在 5-10mg 组（46%）和 10mg 组（47%）中比安慰剂组（10%；两者比较均 P<0.001）更常见。与安慰剂组相比，5-10mg 组和 10mg 组的碱性磷酸酶水平（分别为 -113 和 -130U/升，分别为 -14U/升；两者比较均 P<0.001）和总胆红素水平（分别为 -0.02 和 -0.05mg/分升[-0.3 和 -0.9μmol/升]，分别为 0.12mg/分升[2.0μmol/升]；两者比较均 P<0.001）均有更大的降低。12 个月时，非侵入性肝纤维化测量指标的变化在任何治疗组与安慰剂组之间均无显著差异。瘙痒在奥贝胆酸组比安慰剂组更常见（5-10mg 组为 56%，10mg 组为 68%，安慰剂组为 38%）。5-10mg 组严重不良事件的发生率为 16%，10mg 组为 11%，安慰剂组为 4%。
结论
在原发性胆汁性胆管炎患者中，奥贝胆酸联合熊去氧胆酸或作为单药治疗 12 个月，与安慰剂相比，碱性磷酸酶和总胆红素水平均有显著降低。奥贝胆酸有更多的严重不良事件。（由 Intercept 制药公司资助；POISE ClinicalTrials.gov 编号，NCT01473524；当前对照试验编号，ISRCTN89514817。）
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