Efficacy of 24 Month of Bezafibrate in Primary Sclerosing Cholangitis With Persistent Cholestasis Despite Ursodeoxycholic Acid Therapy

Inclusion Criteria:

• Males or females ≥ 18 and ≤ 75 years
• Large duct PSC verified by retrograde, operative, percutaneous or magnetic resonancecholangiography (MRC) demonstrating intrahepatic and /or extrahepatic biliary ductchanges consistent with PSC
• Colonoscopy (already done or scheduled before randomization) within the last 5 years (or within 6 months if IBD is associated to PSC) with neither cancer nor allgradedysplasia or endoscopy of the ileal reservoir (already done or scheduled beforerandomization) within the last 2 years in patients with ileo-anal anastomosis
• ALP ≥ 1.5 ULN at baseline
• Treatment with stable dose of UDCA (15-20 mg/kg/d) for ≥ 6 months before inclusion (rounded to the nearest unit, e.g 14.5 mg/kg/d would be 15mg/kg/d).
• Using contraceptive in childbearing women
• Affiliation to a social security system (AME excepted)
• Signed informed consent

Exclusion Criteria:

• Child-Pugh score B or C
• Ascites or digestive hemorrhage (or history of)
• Total bilirubin in the last 3 months > 50 μmole/L (3 mg/dl)
• Gilbert syndrome defined as unconjugated bilirubinemia > 12 μmol/L
• Albumin in the last 3 months < ULN (according to the laboratory reference value)
• Prothrombin index in the last 3 months < 70%
• Platelets count in the last 3 months < 100000/mm3
• ALT or AST > 5 ULN in the last 3 months
• Prior liver transplantation
• Treatment with a fibrate within the last 3 months inclusion or with a statin atinclusion
• Current active IBD defined as either current use of systemic corticosteroid therapy > 10 mg/day or budesonide > 3 mg /day or immunosuppressive drugs (cyclosporine,tacrolimus, mycophenolate mofetil, mTor inhibitors, JAK inhibitors) or a partial Mayoscore > 2 in patients with ulcerative colitis (UC) or a Crohn's Disease Activity Index (CDAI) > 150 in patients with Crohn's disease (CD)
• Dose change of treatment for associated IBD ≤3 months prior to inclusion
• Current or history of colonic cancer or all-grade dysplasia described at the lastcolonoscopy (Patients with a history of colon cancer and treated by total colectomywithout recurrence for at least 5 years are eligible)
• Any other cause of liver damage ((positive test for HBV, HCV, or HIV, excessivealcohol consumption, hemochromatosis, Wilson's disease, α1-antitrypsin deficiency,celiac disease, autoimmune hepatitis defined by the presence of at least 2 of the 3following criteria; 1) AST or ALT > 5 ULN, 2) Positive anti smooth muscle autoantibodies or serum IgG > 1.5 ULN, 3) interface hepatitis on liver biopsy)
• Secondary causes of sclerosing cholangitis including IgG4-associated cholangitis (elevated serum IgG4 > 4 ULN)
• History of acute cholangitis in the last 3 months prior to inclusion or current acutecholangitis
• Endoscopic treatment for bile duct stenosis ≤ 3 months prior to inclusion or plannedwithin 3 months post randomization date
• History of or established or suspected hepatobiliary carcinoma.
• Any severe comorbidity that may reduce life expectancy
• History of malignancy diagnosed or treated within 2 years (recent localized treatmentof squamous or non-invasive basal skin cancers is permitted; cervical carcinoma insitu is allowed if appropriately treated prior to Screening)
• Known hypersensitivity to bezafibrate, any of the components of Befizal© or otherfibrates
• Known photosensitivity or photoallergy reactions to fibrate
• Patient with congenital galactosemia, glucose malabsorption, or lactase deficiencybecause of presence of lactose in 400 mg SR tablets of bezafibrate and in placebotablets
• Pregnancy (or desire for)
• Renal insufficiency (clearance < 60 ml/min or serum creatinine level > 130 μmole/L)
• Breastfeeding
• Participation in any other interventional study or in the exclusion period any otherinterventional study
• Autoimmune hepatitis defined by the presence of interface hepatitis documented onliver biopsy and at least 1 of the 2 following criteria: 1) AST or ALT > 5 ULN, 2)Positive anti smooth muscle auto antibodies or serum IgG > 1.5 ULN
• Results of colonoscopy not available or > 5 years (or > 6 months if IBD is associatedto PSC) or with cancer or all-grade dysplasia or results of endoscopy of the ilealreservoir not available or > 2 years in patients with ileo-anal anastomosis Randomization exclusion criteria:
• Positive test for HBV (positive HBs Ag), HCV (positive HCV RNA), or HIV (positiveserology)
• Pregnancy (or desire for in the 2 next years)
• Secondary causes of sclerosing cholangitis including IgG4-associated cholangitis (elevated serum IgG4 > 4 ULN)
• Autoimmune hepatitis defined by the presence of interface hepatitis documented onliver biopsy and at least 1 of the 2 following criteria: 1) AST or ALT > 5 ULN, 2)Positive anti smooth muscle auto antibodies or serum IgG > 1.5 ULN
• Current acute cholangitis