A Placebo-Controlled Trial of Bezafibrate in Primary Biliary Cholangitis

Christophe Corpechot (1, 1) , Olivier Chazouillères (1, 1) , Alexandra Rousseau (2) , Antonia Le Gruyer (3, 4) , François Habersetzer (5) , Philippe Mathurin (6, 7) , Odile Goria (8) , Pascal Potier (9) , Anne Minello (10) , Christine Silvain (11) , Armand Abergel (12) , Maryline Debette-Gratien (13) , Dominique Larrey (14, 15) , Olivier Roux (16) , Jean-Pierre Bronowicki (17) , Jérôme Boursier (18, 19) , Victor de Ledinghen (20) , Alexandra Heurgue-Berlot (21) , Eric Nguyen-Khac (22) , Fabien Zoulim (23) , Isabelle Ollivier-Hourmand (24) , Jean-Pierre Zarski (25) , Gisèle Nkontchou (26) , Sara Lemoinne (1, 1) , Lydie Humbert (27) , Dominique Rainteau (27) , Guillaume Lefèvre (28, 1, 29, 7) , Luc de Chaisemartin (30) , Sylvie Chollet-Martin (30) , Farid Gaouar (1) , Farid Admane (2) , Tabassome Simon (2, 31) , Raoul Poupon (1, 1)

1 CHU Saint-Antoine [AP-HP]
2 CIC Paris-Est - Centre d'investigation clinique Paris Est [CHU Pitié Salpêtrière]
3 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Ponchaillou]
4 Centre Hospitalier Universitaire [Rennes]
5 IVH - Institut de Recherche sur les Maladies Virales et Hépatiques
6 Hôpital Claude Huriez [Lille]
7 LIRIC - Lille Inflammation Research International Center - U 995
8 CHU Rouen
9 CHRO - Centre Hospitalier Régional d'Orléans
10 Service d'Hépato-Gastro-Entérologie (CHU de Dijon)
11 CHU de Poitiers - Centre hospitalier universitaire de Poitiers = Poitiers University Hospital
12 CHU Estaing [Clermont-Ferrand]
13 Service d'Hépato-gastro-entérologie et Nutrition [CHU Dupuytren 1, Limoges]
14 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
15 Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB)
16 Service d’Hépatologie [Hôpital Beaujon]
17 CHU Nancy - Centre Hospitalier Universitaire de Nancy
18 HIFIH - Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques
19 CHU Angers - Centre Hospitalier Universitaire d'Angers
20 Hôpital Haut-Lévêque [CHU Bordeaux]
21 Hôpital universitaire Robert Debré [Reims]
22 Service d'Hépato Gastroenterologie [CHU Amiens-Picardie]
23 Service d'Hépatologie [Hôpital de la Croix-Rousse - HCL]
24 Service d'Hépato-Gastro-Enterologie et Nutrition [CHU Caen]
25 CHUGA - Centre Hospitalier Universitaire [CHU Grenoble]
26 Hôpital Jean Verdier [AP-HP]
27 UP11 - Université Paris-Sud - Paris 11
28 LBM UMR 7203 - Laboratoire des biomolécules
29 CHU Tenon [AP-HP]
30 AP-HP - Hôpital Bichat - Claude Bernard [Paris]
31 SU - Sorbonne Université

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.)

Mots clés: Ursodeoxycholic Acid; Biochemical Response; Fenofibrate Therapy; Combination Therapy; Obeticholic Acid; Renal-Function; Cirrhosis; Outcomes; Prognosis; Multicenter

Domaines: Médecine humaine et pathologie

Christophe Corpechot, Olivier Chazouillères, Alexandra Rousseau, Antonia Le Gruyer, François Habersetzer, et al.. A Placebo-Controlled Trial of Bezafibrate in Primary Biliary Cholangitis. New England Journal of Medicine, 2018, 378 (23), pp.2171-2181. ⟨10.1056/NEJMoa1714519⟩. ⟨hal-01951595⟩