BEZAFIBRATE for Primary sclerosing cholangitis

Inclusion criteria

• {"criterion_text":"- •\tMales or females ≥ 18 and ≤ 75 years\n- •\tLarge duct PSC verified by retrograde, operative, percutaneous or magnetic resonance cholangiography (MRC) demonstrating intrahepatic and /or extrahepatic biliary duct changes consistent with PSC\n- •\tColonoscopy (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 all-grade dysplasia or endoscopy of the ileal reservoir (already done or scheduled before randomization) within the last 2 years in patients with ileo-anal anastomosis.\n- •\tALP ≥ 1.5 ULN\n- •\tTraitement par l'AUDC (13-23 mg/kg/j) depuis ≥ 6 mois avant l'inclusion (Arrondi à l’unité le plus proche, par exemple 12.5 mg/kg/j arrondi à 13 mg/kg/j)\n- •\tUsing contraceptive in women of childbearing potential. Women of childbearing potential, i.e. fertile, following menarche and until becoming post-menopaused unless permanently sterile, who are sexually active have to apply a highly effective method of birth control with a low failure rate (i.e. less than 1% per year) when used constantly and correctly.\n- •\tAffiliation to a social security system (AME excepted)\n- •\tSigned informed consent"}

Exclusion criteria

• {"criterion_text":"- •\tChild-Pugh score B or C\n- •\tTreatment with a fibrate within the last 3 months inclusion\n- •\tCurrent 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 Mayo score > 2 in patients with ulcerative colitis (UC), unclassed colitis or a Crohn’s Disease Activity Index (CDAI) > 150 in patients with Crohn’s disease (CD)\n- •\tDosage change of treatment for associated IBD ≤3 months prior to inclusion\n- •\tCurrent or history of colonic cancer or all-grade dysplasia described at the last colonoscopy (Patients with a history of colon cancer and treated by total colectomy without recurrence for at least 5 years are eligible)\n- •\tAny other cause of liver damage ((positive test for HBV, HCV, or HIV, excessive alcohol consumption, hemochromatosis, Wilson's disease, α1-antitrypsin deficiency, celiac disease\n- •\tCurrent or recent history (within 2 years) of Autoimmune hepatitis defined by the presence of interface hepatitis documented on liver 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\n- •\tSecondary causes of sclerosing cholangitis including IgG4-associated cholangitis (elevated serum IgG4 > 4 ULN)\n- •\tHistory of acute cholangitis in the last 3 months prior to inclusion or current acute cholangitis or suspected cholangiocarcinoma.\n- •\tEndoscopic treatment for bile duct stenosis ≤ 3 months prior to inclusion or planned within 3 months post randomization date\n- •\tHistory of or established or suspected hepatobiliary carcinoma\n- •\tCurrent or recent history (within 2 years) of clinically detectable Ascites or digestive hemorrhage\n- •\tAny severe comorbidity that may reduce life expectancy\n- •\tHistory of malignancy diagnosed or treated within 2 years (recent localized treatment of squamous or non-invasive basal skin cancers is permitted; cervical carcinoma in situ is allowed if appropriately treated prior to Screening)\n- •\tKnown hypersensitivity to bezafibrate, any of the components of Befizal© or other fibrates\n- •\tKnown photosensitivity or photoallergy reactions to fibrate\n- •\tPatient with congenital galactosemia, glucose malabsorption, or lactase deficiency because of presence of lactose in 400 mg SR tablets of bezafibrate and in placebo tablets\n- •\tPregnancy (or desire for)\n- •\tRenal insufficiency (clearance < 60 ml/min or serum creatinine level > 130 μmole/L)\n- •\tBreastfeeding\n- •\tParticipation in any other interventional study or in the exclusion period any other interventional study\n- •\tTotal bilirubin in the last 3 months > 50 μmole/L (3 mg/dl)\n- •\tGilbert syndrome defined as unconjugated bilirubinemia > LSN in the last 3 months (according to the laboratory reference value)\n- •\tAlbumin in the last 3 months < LLN (according to the laboratory reference value)\n- •\tProthrombin index in the last 3 months < 70%\n- •\tPlatelets count in the last 3 months < 100000/mm3\n- •\tALT or AST > 5 ULN in the last 3 months\n- •\tPrior liver transplantation"}

Primary endpoints

• {"endpoint_text":"- Proportion of patients with serum Alkaline Phosphatase < 1.5 ULN and a reduction of at least 15% from baseline at M24 and normal serum bilirubin and no increase of liver stiffness at M24 compared to baseline (delta M24–M0 ≤ 0).","definition_or_measurement_approach":"Proportion of patients meeting all of: serum ALP < 1.5xULN AND at least 15% reduction from baseline at month 24; normal serum bilirubin; and no increase in liver stiffness at M24 compared to baseline (delta M24–M0 ≤ 0). Measurements: serum ALP, serum bilirubin, liver stiffness (elastometry) at baseline and M24."}

Secondary endpoints

• {"endpoint_text":"- To compare between groups -\tComponents of the primary composite outcome analyzed separately: Proportion of patients with: -\tserum Alkaline Phosphatase < 1.5 ULN at M24 and at least 15% of decrease from baseline at M24; -\tcomplete normalization of s-ALP at M24 (s-ALP ≤ 1.0 ULN at M24); -\tnormal serum bilirubin; -\tno increase in liver stiffness at M24","definition_or_measurement_approach":"Components of primary composite analyzed separately at M24 using serum ALP, normalization (≤1.0 ULN), bilirubin levels, and liver stiffness comparisons to baseline."}
• {"endpoint_text":"- To compare between groups -\tSafety endpoint: Percentage of patients with clinical (including increased IBD activity) or biological","definition_or_measurement_approach":"Safety: percentage of patients with clinical adverse events (including increased IBD activity) or biological abnormalities (elevation of creatinine, ALT, AST and CPK) recorded during the study."}
• {"endpoint_text":"- To compare between groups: -\tQuality of life (QMCF questionnaire – Questionnaire de la maladie chronique du foie) and scores for pruritus (measured by VAS and 5D pruritus scale) and fatigue (measured by adapted PBC-40 questionnaire (M0, M12 and M24))","definition_or_measurement_approach":"Patient-reported QoL assessed using QMCF at M0, M12, M24; pruritus by VAS and 5D scale; fatigue by adapted PBC-40 at M0, M12, M24."}
• {"endpoint_text":"- To compare between groups: Changes in Patient-Reported Outcomes (PRO) specific for PSC (45).","definition_or_measurement_approach":"Changes in PSC-specific PRO measures over time (M0, M12, M24)."}
• {"endpoint_text":"- To compare between groups: -\tChanges in biochemical liver tests other than ALP, including total and conjugated bilirubin, GGT, AST, ALT, albumin, and INR,","definition_or_measurement_approach":"Biochemical liver tests measured at scheduled visits (M0, M12, M24) including bilirubin, GGT, AST, ALT, albumin, INR and others; comparison of changes from baseline."}
• {"endpoint_text":"- To compare between group survival rate without liver transplantation or hepatic events (ascites, variceal bleeding, encephalopathy, acute cholangitis, cholangiocarcinoma, hepatocellular carcinoma or serum total bilirubin > 100 μmol/L for at least 3 months). PSC Prognostic scores including the MELD score, the Revised PSC Mayo Risk Score, the Hannover Score and the Amsterdam-Oxford prognostic model (M0, M12, M24)","definition_or_measurement_approach":"Event-free survival without liver transplantation or specified hepatic events; assessment of prognostic scores (MELD, Revised PSC Mayo, Hannover, Amsterdam-Oxford) at M0, M12, M24."}

France

Earliest CTIS Part Ii Submission Date

03-09-2024

Latest Decision Or Authorization Date

10-09-2024

Processing Time Days

7

Number Of Sites

35

Number Of Participants

130

Primary sponsor

Full Name

Assistance Publique Hopitaux De Paris

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

France