Primary biliary cholangitis MedDRA version: 20.0 Level: LLT Classification code 10034176 Term: PBC System Organ Class: 100000004871
Conditions
Interventions
Product Name: Elafibranor
Product Code: GFT505
Pharmaceutical Form: Tablet
INN or Proposed INN: Elafibranor
CAS Number: 824932-88-9
Sponsors
Genfit SA
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Must have provided written informed consent (IC) 2. Males or females 18 to 75 years of age 3. Definite or probable PBC diagnosis as demonstrated by the presence of at least 2 of the following 3 diagnostic factors: o History of elevated ALP levels for at least 6 months prior to Day 0 (randomization visit) o Positive Anti-Mitochondrial Antibodies (AMA) titers (> 1/40 on immunofluorescence or M2 positive by enzyme-linked immunosorbent assay (ELISA) or positive PBC-specific antinuclear antibodies o Liver biopsy consistent with PBC 4. ALP = 1.67x upper limit of normal (ULN) ('Inadequate response to UDCA') 5. Taking UDCA for at least 12 months (stable dose for = 6 months) prior to screening visit 6. Contraception: Females participating in this study must be of non-childbearing potential or must be using highly efficient contraception for the full duration of the study and for 1 month after the end of treatment, as described below: a) Cessation of menses for at least 12 months due to ovarian failure b) Surgical sterilization such as bilateral oopherectomy, hysterectomy, or medically documented ovarian failure c) If requested by local IRB regulations and/or National laws, sexual abstinence may be considered adequate (the reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject) d) Using a highly effective non-hormonal method of contraception (bilateral tubal occlusion, vasectomised partner or intra-uterine device) e) Double contraception with barrier and highly effective hormonal method of contraception (oral, intravaginal or transdermal combined estrogen and progestogen hormonal contraception associated with inhibition of ovulation, oral, injectable or implantable progestogen-only hormonal contraception associated with inhibition of ovulation or intrauterine hormone-releasing system). The hormonal contraception must be started at least one month prior to randomization. 7. Must agree to comply with the trial protocol. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 32 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 13
Exclusion criteria
Exclusion criteria: 1. History or presence of other concomitant liver diseases including: • Positive hepatitis B surface antigen (HBsAg) at Screening • Positive HCV RNA (tested for in case of known cured HCV infection, or positive HCV Ab at screening) • Alcoholic liver disease • Primary sclerosing cholangitis (PSC) • Definite autoimmune hepatitis (AIH), or 'AIH-PBC overlap syndrome'; the existence of AIH is defined as continuing use of budesonide or other systemic corticosteroid therapy, and/or azathioprine, and/or other immunosuppressive therapy following an historical AIH diagnosis (EASL 2015). 'AIH-PBC overlap syndrome' is based upon fulfilment of the 'Paris criteria' (Chazouillères 1998) for both AIH (ALT =5x ULN; IgG =2x ULN or smooth muscle antibody; interface hepatitis), and PBC(ALP =2x ULN; AMA, and non-suppurative bile duct injury/destruction), requiring corticosteroid therapy for disease management, either currently or in the past. • Biopsy confirmed Nonalcoholic Steatohepatitis (NASH) • Known history of alpha-1 antitrypsin deficiency, or other metabolic forms of chronic liver disease • Gilbert's Syndrome (due to interpretability of bilirubin levels)2. Screening CPK > ULN 3. Screening ALT or AST > 5 ULN 4. Screening total bilirubin > 2 ULN 5. Screening serum creatinine > 1.5 mg/dl 6. Significant renal disease, including nephritic syndrome, chronic kidney disease (defined as patients with markers of kidney damage or estimated glomerular filtration rate [eGFR] of less than 60 mL/min/1.73 m2). 7. Patients with moderate or severe hepatic impairment (defined as Child-Pugh B/C) 8. Platelet count <150 X 10 3/microliter 9. Albumin <3.5 g/dL 10. Presence of clinical complications of PBC or clinically significant hepatic decompensation, including: • Current Model for End Stage Liver Disease (MELD) score = 15; current placement on a liver transplant list, or history of undergoing liver transplantation • Any record of complications of cirrhosis and/or portal hypertension such as: o Gastroesophageal variceal bleeding and endoscopic therapy and/or transjugular intrahepatic portosystemic shunt [TIPS] insertion o Ascites formation requiring intervention, e.g. diuretic therapy o Spontaneous bacterial peritonitis o Hepatic encephalopathy o Confirmed or suspected hepatocellular carcinoma 11. Hepatorenal syndrome (type I or II) Administration of the following medications is prohibited as specified below: • From pre-randomization to EOT or V5 visit: indomethacin • 2 months preceding screening and throughout the trial (up to the last study visit):: fibrates or obeticholic acid, glitazones • 3 months prior to screening and throughout the trial (up to the last study visit) ): azathioprine, colchicine, cyclosporine, methotrexate, mycop
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the efficacy of elafibranor 80 and 120 mg with respect to relative change from baseline in serum ALP levels compared to placebo.;Primary end point(s): The primary endpoint of the study is to evaluate the efficacy of elafibranor 80 mg or 120 mg with respect to relative change from baseline in serum ALP levels compared to placebo.;Timepoint(s) of evaluation of this end point: Baseline ; Secondary Objective: To assess the following end-points at week 12 o the response to treatment based on composite endpoints: o ALP 15% decrease in ALP o ALP 40% decrease in ALP • response according to Paris I, Paris II, Toronto I, Toronto II, UK-PBC risk score • ALP response rates of 10%, 20% and 40% decrease • response based on the percent of patients who normalized ALP and patients who normalized bilirubin and patients who normalized albumin • the change from baseline in ALT, AST, GGT, 5'nucleotidase, total bilirubin, conjugated bilirubin and albumin • the change from baseline in: o lipid parameters o bile acids : o C4, FGF19 o IgM o inflammatory and liver fibrosis markers • the change from baseline in: o 5D-itch scale, PBC 40 QOL, VAS • the tolerability and safety of elafibranor 80 and 120 mg in patients with PBC | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • Response rate in elafibranor 80mg and 120 mg and placebo groups with response defined as ALP less than 1.67 times ULN and total bilirubin within normal limits and ALP reduction > 15%. • Response rate in elafibranor 80mg and 120 mg and placebo groups with response defined as ALP less than 2 times ULN and total bilirubin within normal limits and ALP reduction > 40% • Response rate according to Paris I, Paris II, Toronto I, Toronto II, UK PBC risk score • Alkaline phosphatase response rates of 10%, 20% and 40% decrease • Response rate in elafibranor 80mg and 120 mg and placebo groups with response defined as percent of patients with normalized ALP at the end of treatment • Response rate in elafibranor 80mg and 120 mg and placebo groups with response defined as percent of patients with normalized bilirubin at the end of treatment • Response rate in elafibranor 80mg and 120 mg and placebo groups with response defined as percent of patients with normalized albumin at the end of treatment • Changes from baseline in: o Gamma-glutamyl transferase (GGT) o Alanine aminotransferase (ALT) o Aspartate aminotransferase (AST) o 5’nucleotidase o Bilirubin (total and conjugated) o Albumin o total cholesterol, LDL-chol, HDL-Chol, Triglycerides o Bile acids : CDCA, cholic acid, litocholic acid, DCA o C4, FG19 o IgM o Quality of Life: PBC 40 QOL o Pruritus: 5-D Pruritus Questionnaire and Visual Analogue Score (VAS) o Biomarkers of inflammation and liver fibrosis: TNF-a, TGF-ß, IL-6, CK-18 and lysophosphatidic acid • Plasma concentrations of elafibranor and its main metabolite and exposure-response | — |
Countries
France, Germany, Spain, United Kingdom, United States
Contacts
Public ContactSophie Megnien
Genfit SA
Outcome results
None listed