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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


Christophe Corpechot ... 其他 • 2018.06.07
相关阅读
• 更新版原发性胆汁性胆管炎诊断和治疗指导意见

摘要


背景

对熊去氧胆酸治疗应答不足的原发性胆汁性胆管炎患者疾病进展风险高。在这类患者中,贝特类药物与熊去氧胆酸联合治疗显示出潜在的益处,贝特类药物是过氧化物酶体增殖物激活受体的激动剂。

 

方法

在这项为期24个月的双盲、安慰剂对照、3期试验中,我们根据巴黎2标准,将对熊去氧胆酸应答不足的100例患者随机分组,除了继续接受熊去氧胆酸治疗外,还分别接受每日400 mg苯扎贝特(50例患者)或安慰剂(50例患者)治疗。主要结局为完全的生化应答,定义为24个月时总胆红素、碱性磷酸酶、氨基转移酶和白蛋白水平正常,并且凝血酶原指数(凝血酶原时间的一个衍生指标)正常。

 

结果

苯扎贝特组31%的患者和安慰剂组0%的患者出现主要结局(差异,31个百分点;95%置信区间[CI],10~50;P<0.001)。在67%的苯扎贝特组患者和2%的安慰剂组患者中观察到正常的碱性磷酸酶水平。在瘙痒、疲劳和肝纤维化无创检查指标(包括肝脏硬度和增强肝纤维化[Enhanced Liver Fibrosis]评分)的变化方面,结果均与主要结局的结果一致。每组2例患者出现终末期肝病并发症。苯扎贝特组肌酐水平较基线升高5%,安慰剂组肌酐水平较基线降低3%。20%的苯扎贝特组患者和10%的安慰剂组患者出现肌痛。

 

结论

在对熊去氧胆酸单独治疗应答不足的原发性胆汁性胆管炎患者中,熊去氧胆酸加用苯扎贝特治疗获得的完全生化应答率显著高于熊去氧胆酸加用安慰剂治疗的应答率(由Programme Hospitalier de Recherche Clinique和Arrow Génériques资助;BEZURSO在ClinicalTrials.gov注册号为NCT01654731)。





作者信息

Christophe Corpechot, M.D., Olivier Chazouillères, M.D., Alexandra Rousseau, Ph.D., Antonia Le Gruyer, M.D., François Habersetzer, M.D., Ph.D., Philippe Mathurin, M.D., Ph.D., Odile Goria, M.D., Pascal Potier, M.D., Anne Minello, M.D., Ph.D., Christine Silvain, M.D., Armand Abergel, M.D., Ph.D., Maryline Debette-Gratien, M.D., Ph.D., Dominique Larrey, M.D., Ph.D., Olivier Roux, M.D., Jean-Pierre Bronowicki, M.D., Ph.D., Jérôme Boursier, M.D., Ph.D., Victor de Ledinghen, M.D., Ph.D., Alexandra Heurgue-Berlot, M.D., Eric Nguyen-Khac, M.D., Ph.D., Fabien Zoulim, M.D., Ph.D., Isabelle Ollivier-Hourmand, M.D., Jean-Pierre Zarski, M.D., Ph.D., Gisèle Nkontchou, M.D., Sara Lemoinne, M.D., Ph.D., Lydie Humbert, Ch.E., Dominique Rainteau, Ph.D., Guillaume Lefèvre, Pharm.D., Ph.D., Luc de Chaisemartin, Pharm.D., Ph.D., Sylvie Chollet-Martin, M.D., Ph.D., Farid Gaouar, M.D., Farid-Hakeem Admane, V.M.D., Tabassome Simon, M.D., Ph.D., and Raoul Poupon, M.D.
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. Address reprint requests to Dr. Corpechot at the Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, Saint-Antoine University Hospital, Assistance Publique–Hôpitaux de Paris and Sorbonne University, 184 Rue du Faubourg Saint-Antoine, 75571 Paris CEDEX 12, France, or at christophe.corpechot@aphp.fr.

 

参考文献

1. Carey EJ, Ali AH, Lindor KD. Primary biliary cirrhosis. Lancet 2015;386:1565-1575.

2. European Association for the Study of the Liver. EASL clinical practice guidelines: the diagnosis and management of patients with primary biliary cholangitis. J Hepatol 2017;67:145-172.

3. Lindor KD, Gershwin ME, Poupon R, Kaplan M, Bergasa NV, Heathcote EJ. Primary biliary cirrhosis. Hepatology 2009;50:291-308.

4. Poupon RE, Balkau B, Eschwège E, Poupon R. A multicenter, controlled trial of ursodiol for the treatment of primary biliary cirrhosis. N Engl J Med 1991;324:1548-1554.

5. Poupon RE, Lindor KD, Cauch-Dudek K, Dickson ER, Poupon R, Heathcote EJ. Combined analysis of randomized controlled trials of ursodeoxycholic acid in primary biliary cirrhosis. Gastroenterology 1997;113:884-890.

6. Parés A, Caballería L, Rodés J. Excellent long-term survival in patients with primary biliary cirrhosis and biochemical response to ursodeoxycholic acid. Gastroenterology 2006;130:715-720.

7. Corpechot C, Abenavoli L, Rabahi N, et al. Biochemical response to ursodeoxycholic acid and long-term prognosis in primary biliary cirrhosis. Hepatology 2008;48:871-877.

8. Kumagi T, Guindi M, Fischer SE, et al. Baseline ductopenia and treatment response predict long-term histological progression in primary biliary cirrhosis. Am J Gastroenterol 2010;105:2186-2194.

9. Hirschfield GM, Mason A, Luketic V, et al. Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. Gastroenterology 2015;148(4):751-61.e8.

10. Nevens F, Andreone P, Mazzella G, et al. A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. N Engl J Med 2016;375:631-643.

11. Nakai S, Masaki T, Kurokohchi K, Deguchi A, Nishioka M. Combination therapy of bezafibrate and ursodeoxycholic acid in primary biliary cirrhosis: a preliminary study. Am J Gastroenterol 2000;95:326-327.

12. Iwasaki S, Ohira H, Nishiguchi S, et al. The efficacy of ursodeoxycholic acid and bezafibrate combination therapy for primary biliary cirrhosis: a prospective, multicenter study. Hepatol Res 2008;38:557-564.

13. Levy C, Peter JA, Nelson DR, et al. Pilot study: fenofibrate for patients with primary biliary cirrhosis and an incomplete response to ursodeoxycholic acid. Aliment Pharmacol Ther 2011;33:235-242.

14. Reig A, Sesé P, Parés A. Effects of bezafibrate on outcome and pruritus in primary biliary cholangitis with suboptimal ursodeoxycholic acid response. Am J Gastroenterol 2018;113:49-55.

15. Corpechot C, Chazouillères O, Poupon R. Early primary biliary cirrhosis: biochemical response to treatment and prediction of long-term outcome. J Hepatol 2011;55:1361-1367.

16. Corpechot C, Carrat F, Poujol-Robert A, et al. Noninvasive elastography-based assessment of liver fibrosis progression and prognosis in primary biliary cirrhosis. Hepatology 2012;56:198-208.

17. Kuiper EM, Hansen BE, de Vries RA, et al. Improved prognosis of patients with primary biliary cirrhosis that have a biochemical response to ursodeoxycholic acid. Gastroenterology 2009;136:1281-1287.

18. Lammers WJ, Hirschfield GM, Corpechot C, et al. Development and validation of a scoring system to predict outcomes of patients with primary biliary cirrhosis receiving ursodeoxycholic acid therapy. Gastroenterology 2015;149(7):1804-1812.e4.

19. Reich A, Heisig M, Phan NQ, et al. Visual analogue scale: evaluation of the instrument for the assessment of pruritus. Acta Derm Venereol 2012;92:497-501.

20. Poupon RE, Chrétien Y, Chazouillères O, Poupon R, Chwalow J. Quality of life in patients with primary biliary cirrhosis. Hepatology 2004;40:489-494.

21. Mayo MJ, Parkes J, Adams-Huet B, et al. Prediction of clinical outcomes in primary biliary cirrhosis by serum enhanced liver fibrosis assay. Hepatology 2008;48:1549-1557.

22. Carbone M, Sharp SJ, Flack S, et al. The UK-PBC risk scores: derivation and validation of a scoring system for long-term prediction of end-stage liver disease in primary biliary cholangitis. Hepatology 2016;63:930-950.

23. Ludwig J, Dickson ER, McDonald GS. Staging of chronic nonsuppurative destructive cholangitis (syndrome of primary biliary cirrhosis). Virchows Arch A Pathol Anat Histol 1978;379:103-112.

24. Carbone M, Mells GF, Pells G, et al. Sex and age are determinants of the clinical phenotype of primary biliary cirrhosis and response to ursodeoxycholic acid. Gastroenterology 2013;144(3):560-569.e7.

25. Lammers WJ, van Buuren HR, Hirschfield GM, et al. Levels of alkaline phosphatase and bilirubin are surrogate end points of outcomes of patients with primary biliary cirrhosis: an international follow-up study. Gastroenterology 2014;147(6):1338-49.e5.

26. Cheung AC, Lapointe-Shaw L, Kowgier M, et al. Combined ursodeoxycholic acid (UDCA) and fenofibrate in primary biliary cholangitis patients with incomplete UDCA response may improve outcomes. Aliment Pharmacol Ther 2016;43:283-293.

27. Zhao YY, Weir MA, Manno M, et al. New fibrate use and acute renal outcomes in elderly adults: a population-based study. Ann Intern Med 2012;156:560-569.

28. Ting RD, Keech AC, Drury PL, et al. Benefits and safety of long-term fenofibrate therapy in people with type 2 diabetes and renal impairment: the FIELD Study. Diabetes Care 2012;35:218-225.

29. Mychaleckyj JC, Craven T, Nayak U, et al. Reversibility of fenofibrate therapy-induced renal function impairment in ACCORD type 2 diabetic participants. Diabetes Care 2012;35:1008-1014.

30. Sica DA. Fibrate therapy and renal function. Curr Atheroscler Rep 2009;11:338-342.

31. Cuperus FJ, Halilbasic E, Trauner M. Fibrate treatment for primary biliary cirrhosis. Curr Opin Gastroenterol 2014;30:279-286.

32. Ghonem NS, Assis DN, Boyer JL. Fibrates and cholestasis. Hepatology 2015;62:635-643.

33. Honda A, Ikegami T, Nakamuta M, et al. Anticholestatic effects of bezafibrate in patients with primary biliary cirrhosis treated with ursodeoxycholic acid. Hepatology 2013;57:1931-1941.

34. Dohmen K, Mizuta T, Nakamuta M, Shimohashi N, Ishibashi H, Yamamoto K. Fenofibrate for patients with asymptomatic primary biliary cirrhosis. World J Gastroenterol 2004;10:894-898.

35. Nagasawa T, Inada Y, Nakano S, et al. Effects of bezafibrate, PPAR pan-agonist, and GW501516, PPARdelta agonist, on development of steatohepatitis in mice fed a methionine- and choline-deficient diet. Eur J Pharmacol 2006;536:182-191.

36. Jones D, Boudes PF, Swain MG, et al. Seladelpar (MBX-8025), a selective PPAR-δ agonist, in patients with primary biliary cholangitis with an inadequate response to ursodeoxycholic acid: a double-blind, randomised, placebo-controlled, phase 2, proof-of-concept study. Lancet Gastroenterol Hepatol 2017;2:716-726.

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