苯扎贝特治疗原发性胆汁性胆管炎的安慰剂对照试验。
A Placebo-Controlled Trial of Bezafibrate in Primary Biliary Cholangitis.
机构信息
From the Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, Hepatology and Gastroenterology Department, Saint-Antoine University Hospital, Assistance Publique-Hôpitaux de Paris (APHP) (C.C., O.C., S.L., F.G., R.P.), INSERM Unité Mixte de Recherche (UMR) S938 (C.C., O.C., S.L., R.P.) and the Biochemistry Laboratory (L.H., D.R.), Saint-Antoine University Hospital, APHP, INSERM Unité 1157/UMR 7203, Sorbonne University, the Biochemistry Laboratory, Tenon University Hospital, APHP (G.L.), and the Immunology Laboratory, INSERM UMR S996, Bichat University Hospital, APHP (L.C., S.C.-M.), Paris-Sud University, the Department of Clinical Pharmacology and Clinical Research Platform of the East of Paris, APHP (A.R., F.-H.A., T.S.), and Sorbonne University (T.S.), Paris, the Hepatology and Gastroenterology Department, Rouen University Hospital, Rouen (O.G.), the Hepatology and Gastroenterology Department, Pontchaillou University Hospital, Rennes (A.L.G.), the Hepatology and Gastroenterology Department, University Hospitals of Strasbourg, Institute of Viral and Liver Diseases, INSERM Unité 1110, Laboratory of Excellence HepSYS, University of Strasbourg, Strasbourg (F.H.), the Hepatology and Gastroenterology Department, Claude Huriez University Hospital, Lille (P.M.), the Hepatology and Gastroenterology Department, Orleans Hospital, Orleans (P.P.), the Hepatology and Gastroenterology Department, Dijon Bourgogne University Hospital, Dijon (A.M.), the Hepatology and Gastroenterology Department, University Hospital of Poitiers, Poitiers (C.S.), the Hepatology and Gastroenterology Department, Estaing University Hospital, Clermont-Ferrand (A.A.), the Hepatology and Gastroenterology Department, University Hospital of Limoges, Limoges (M.D.-G.), the Hepatology and Gastroenterology Department, Saint-Eloi University Hospital, Montpellier (D.L.), the Hepatology Department, Beaujon University Hospital, Clichy (O.R.), the Hepatology and Gastroenterology Department, Brabois University Hospital, Nancy (J.-P.B.), the Hepatology and Gastroenterology Department, University Hospital of Angers, Hemodynamics, Interaction, Fibrosis, and Tumor Invasiveness in Hepatic and Digestive Organs Laboratory, Unité Propre de Recherche de l'Enseignement Supérieur 3859, Structures Fédératives de Recherche 4208, Bretagne Loire University, Angers (J.B.), the Hepatology and Gastroenterology Department, Haut-Lévêque University Hospital, Pessac (V.L.), the Hepatology and Gastroenterology Department, Robert Debré University Hospital, Reims (A.H.-B.), the Hepatology and Gastroenterology Department, University Hospital of Amiens, Amiens (E.N.-K.), the Hepatology and Gastroenterology Department, Croix-Rousse University Hospital, Lyon (F.Z.), the Hepatology and Gastroenterology Department, University Hospital of Caen, Caen (I.O.-H.), the Hepatology and Gastroenterology Department, Michallon University Hospital, Grenoble (J.-P.Z.), and the Hepatology and Gastroenterology Department, Jean Verdier University Hospital, Bondy (G.N.) - all in France.
出版信息
N Engl J Med. 2018 Jun 7;378(23):2171-2181. doi: 10.1056/NEJMoa1714519.
BACKGROUND
Patients with primary biliary cholangitis who have an inadequate response to therapy with ursodeoxycholic acid are at high risk for disease progression. Fibrates, which are agonists of peroxisome proliferator-activated receptors, in combination with ursodeoxycholic acid, have shown potential benefit in patients with this condition.
METHODS
In this 24-month, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 100 patients who had had an inadequate response to ursodeoxycholic acid according to the Paris 2 criteria to receive bezafibrate at a daily dose of 400 mg (50 patients), or placebo (50 patients), in addition to continued treatment with ursodeoxycholic acid. The primary outcome was a complete biochemical response, which was defined as normal levels of total bilirubin, alkaline phosphatase, aminotransferases, and albumin, as well as a normal prothrombin index (a derived measure of prothrombin time), at 24 months.
RESULTS
The primary outcome occurred in 31% of the patients assigned to bezafibrate and in 0% assigned to placebo (difference, 31 percentage points; 95% confidence interval, 10 to 50; P<0.001). Normal levels of alkaline phosphatase were observed in 67% of the patients in the bezafibrate group and in 2% in the placebo group. Results regarding changes in pruritus, fatigue, and noninvasive measures of liver fibrosis, including liver stiffness and Enhanced Liver Fibrosis score, were consistent with the results of the primary outcome. Two patients in each group had complications from end-stage liver disease. The creatinine level increased 5% from baseline in the bezafibrate group and decreased 3% in the placebo group. Myalgia occurred in 20% of the patients in the bezafibrate group and in 10% in the placebo group.
CONCLUSIONS
Among patients with primary biliary cholangitis who had had an inadequate response to ursodeoxycholic acid alone, treatment with bezafibrate in addition to ursodeoxycholic acid resulted in a rate of complete biochemical response that was significantly higher than the rate with placebo and ursodeoxycholic acid therapy. (Funded by Programme Hospitalier de Recherche Clinique and Arrow Génériques; BEZURSO ClinicalTrials.gov number, NCT01654731 .).
背景
原发性胆汁性胆管炎患者对熊去氧胆酸治疗反应不足，疾病进展风险高。过氧化物酶体增殖物激活受体激动剂贝特类药物与熊去氧胆酸联合应用，已显示出对该疾病患者的潜在益处。
方法
在这项为期 24 个月的、双盲、安慰剂对照、3 期临床试验中，我们将根据巴黎 2 标准对 100 名对熊去氧胆酸治疗反应不足的患者进行随机分组，每天接受 400mg 苯扎贝特（50 名患者）或安慰剂（50 名患者）治疗，同时继续使用熊去氧胆酸治疗。主要终点是在 24 个月时完全生化缓解，定义为总胆红素、碱性磷酸酶、氨基转移酶和白蛋白水平正常，以及凝血酶原指数（凝血酶原时间的衍生测量值）正常。
结果
接受苯扎贝特治疗的患者中有 31%达到主要终点，而接受安慰剂治疗的患者中无一例达到主要终点（差异为 31 个百分点；95%置信区间为 10 至 50；P<0.001）。苯扎贝特组 67%的患者碱性磷酸酶水平正常，安慰剂组为 2%。瘙痒、疲劳和非侵入性肝纤维化指标（包括肝硬度和增强型肝纤维化评分）的变化结果与主要终点结果一致。两组各有 2 例患者发生终末期肝病并发症。苯扎贝特组肌酐水平从基线上升 5%，安慰剂组下降 3%。苯扎贝特组 20%的患者出现肌痛，安慰剂组 10%的患者出现肌痛。
结论
在对熊去氧胆酸单独治疗反应不足的原发性胆汁性胆管炎患者中，熊去氧胆酸联合苯扎贝特治疗的完全生化缓解率明显高于安慰剂和熊去氧胆酸治疗。（由 Program Hospitalier de Recherche Clinique 和 Arrow Génériques 资助；BEZURSO ClinicalTrials.gov 编号，NCT01654731）。
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