Efficacy and Safety of Bezafibrate 400 mg and Bezafibrate 200 mg as Adjunctive Treatments in Patients With Primary Biliary Cholangitis and Non-optimal Biochemical Response to Ursodeoxycholic Acid Therapy

Prior treatment

• Any of the following medications used in the past 3 months before inclusion: bezafibrate, fenofibrate, ciprofibrate, gemfibrozil, obeticholic acid, budesonide, any other systemic corticosteroids, azathioprine, mycophenolate mofetil, cyclosporine, tacrolimus, sirolimus, everolimus, methotrexate.
• Use of statins in the month before inclusion

Other illness

• History of LT
• Any other chronic hepatic comorbidities (HCV, HBV, NASH, alcoholic liver disease, hemochromatosis, Wilson's disease, α1-antitrypsin deficiency, celiac disease)
• Untreated hypo or hyperthyroidism (Hashimoto or Graves autoimmune thyroiditis)
• Conditions that may cause non-hepatic increases in ALP (Paget's disease, osteodystrophy, hyperparathyroidism, dysglobulinemia)
• History of or established or suspected hepatocellular carcinoma
• History of malignancy diagnosed or treated within 2 years (recent localized treatment of squamous or non-invasive basal skin cancers is permitted)
• Known hypersensitivity to bezafibrate, any of the components of Befizal© or other fibrates

Lab values

• Any of the following signs of advanced chronic liver disease:
  • Total bilirubin \> 2.0 xULN
  • Serum albumin \< 32 g/l
  • Platelet count \< 100,000/mm3
  • INR \> 1.3 or prothrombin index \< 60%
  • Child-Pugh score B or C
  • MELD score ≥ 14
  • History ≤ 24 months or presence of cirrhotic decompensation
  • Patients on the waiting list for LT
• GFR estimated by CKI-EPI equation \< 60 mL/min
• AST or ALT \> 3.0 xULN
• Autoimmune hepatitis (AIH) overlap syndrome defined by at least 2 of the following 3 criteria including the histologic one:
  • ALT \> 5.0 xULN
  • IgG \> 20 g/l or presence of anti-smooth muscle or anti-SLA antibodies
  • Histologic features characteristic of, or compatible with AIH
• Gilbert's syndrome or chronic hemolysis (hyperbilirubinemia with an unconjugated to total bilirubin ratio ≥ 75%)
• Patient with congenital galactosemia, glucose malabsorption, or lactase deficiency because of presence of lactose in LP tablets of bezafibrate

Age

• Any severe comorbidity that may reduce life expectancy ≤ 2 years

Other

• CPK \> 5.0 xULN
• Pregnancy or lactating
• Known intolerance to bezafibrate
• Known photosensitivity reactions or photoallergy reactions to fibrates
• Participation in any other interventional study in the past 6 months

• Age ≥ 18 and \< 80 years
• Diagnosis of PBC based on at least 2 of the following criteria (EASL clinical practice guidelines 2017):
  • Elevated ALP level
  • Presence of antimitochondrial antibody (immunofluorescence titer ≥ 1:40 or positive antigen-specific test), specific antinuclear immunofluorescence (nuclear dots or perinuclear rims) or positive antigen-specific test for anti-gp210 or anti-Sp100 antibodies
  • Records of histologic features suggestive of, or compatible with PBC
• UDCA therapy for the past 12 months (stable dose ≥ 12 mg/kg/d for ≥ 3 months prior to inclusion).
• Non-optimal response to UDCA defined by at least one of the following criteria (ratios of absolute values to ULN rounded to the first decimal digit) observed at least 2 times at ≥ 4 weeks interval in the past 3 months, including at the inclusion visit assessment:
• ALP \> 1.0 xULN
• GGT \> 3.0 xULN
• ALT or AST \> 1.0 xULN
• Total and conjugated bilirubin \> 1.0 xULN
• Women of childbearing potential must use at least one barrier contraceptive during the study and for at least 90 days after the last dose.
• Affiliation to a social security system (AME excepted).
• Signed informed consent.