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N Engl J Med. 2018 Jun 7;378(23):2171-2181. doi: 10.1056/NEJMoa1714519.

A Placebo-Controlled Trial of Bezafibrate in Primary Biliary Cholangitis.

Author information

1
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.

Abstract

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 .).

PMID:
29874528
DOI:
10.1056/NEJMoa1714519
[Indexed for MEDLINE]

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