A Study of Elafibranor in Adults with Primary Biliary Cholangitis and Inadequate Response or Intolerance to Ursodeoxycholic Acid

Prior treatment

• History or presence of other concomitant liver diseases
• International normalised ratio >1.3 in the absence of anticoagulant therapy
• History of alcohol abuse, or other substance abuse within 1 year prior
• Known hypersensitivity to the investigational product or to any of the excipients of elafibranor
• (12) Administration of the following medications is prohibited during the study, and prior to the study as per the timelines specified below: i.Systemic (oral or parenteral) use within 3 months prior to SV1 of: fibrates, seladelpar, glitazones, obeticholic acid, azathioprine, cyclosporine, methotrexate, mycophenolate, or long-term systemic corticosteroids (parenteral and oral chronic administration only); potentially hepatotoxic drugs (including α-methyl-dopa, valproic acid, isoniazid or nitrofurantoin) ii) Breat Cancer Resistance Protein (BRCP) inhibitors within 1 month prior to SV 1
• Participants with previous exposure to elafibranor
• Participants who are currently participating in, plan to participate in, or have participated in an investigational drug study or medical device study containing active substance within 30 days or 5 half-lives, whichever is longer

Other illness

• Significant renal disease, including nephritic syndrome, chronic kidney disease (defined as participants with evidence of significantly impaired kidney function or underlying kidney injury).
• History of hepatocellular carcinoma
• Any other condition that, in the opinion of the investigator, would interfere with study participation or completion, or would put the participant at risk, including a potential participant assessed as being at high risk of noncompliance with the study
• History of liver transplantation
• Known history of human immunodeficiency virus (HIV) infection
• Medical conditions that may cause non-hepatic increases in ALP (e.g. Paget’s disease)
• Evidence of any other unstable or untreated clinically significant conditions that are not well controlled
• Known malignancy or history of malignancy within the last 2 years, except for successfully treated localised basal cell carcinoma or squamous cell carcinoma of the skin; or in-situ carcinoma of the uterine cervix
• Alpha-foetoprotein (AFP) >20 ng/mL with 4-phase liver computed tomography (CT) or magnetic resonance imaging (MRI) scans suggesting presence of liver cancer

Lab values

• (18) Platelet count <75,000/µL
• 20 (a) Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2 per the Modification of Diet in Renal Disease (MDRD)-6 formula or on dialysis at SV1.
• For female participants: known pregnancy, or has a positive serum pregnancy test, or is breastfeeding
• Total bilirubin (TB) >2 × ULN. Participants with Gilbert’s syndrome are eligible with a TB above 2 × ULN if direct bilirubin is <30% of TB
• (Alanine aminotransferase) ALT and/or (aspartate aminotransferase) AST >5 × ULN
• (Creatine phosphokinase) CPK >2 × ULN

Age

• Medical condition with a life expectancy <2 years

Other

• Participants with known cirrhosis who have a Child-Pugh B or C score. Participants with cirrhosis with Child-Pugh A score are allowed.
• Regular alcohol intake in excess of the recommended limit of 2 standard drinks per day for men or 1 standard drink per day for women
• Mental instability or incompetence, such that the validity of informed consent or ability to be compliant with the study is uncertain
• History or presence of clinically significant hepatic decompensation
• Participants who are committed to an institution by virtue of an order issued either by the judicial or the administrative authorities

• Male or female participants age ≥18 years of age.
• Participants with a historical diagnosis of PBC as demonstrated by the presence of ≥2 of the following three historical diagnostic criteria: i. History of elevated ALP levels for ≥6 months prior to SV1. ii. Positive (Antimitochondrial antibody ) AMA titres (≥1/40 on immunofluorescence or M2 positive by enzyme linked immunosorbent assay) or positive PBC-specific antinuclear antibodies. iii. Liver biopsy consistent with PBC.
• ALP >1 × ULN and <1.67 × ULN.
• (a) Participants taking UDCA should have been on this medication for at least 12 months and at a stable dose for ≥ 6 months prior to SV1. Participants who are intolerant to UDCA may participate and should have taken the last dose of UDCA ≥3 months prior.
• (a) Participants taking medications for management of pruritus (e.g cholestyramine, naltrexone, sertraline or colchicine) must be on a stable dose for ≥3 months prior to screening.
• (b) Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies (Appendix 10.4). Male participants: • Male participants are eligible to participate if they agree to the following during the study intervention period and for at least 30 days after the last dose of study intervention: • Refrain from donating sperm. PLUS either: - Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agree to remain abstinent. OR - Must agree to use contraception / barrier as detailed below:  Agree to use a male condom and should also be advised of the benefit for a female partner to use a highly effective method of contraception as a condom may break or leak as there remains when having sexual intercourse with a woman of childbearing potential (WOCBP) who is not currently pregnant. Female participants • Female participants are eligible to participate if she is not pregnant or breastfeeding, and one of the following conditions applies: • Is a woman of nonchildbearing potential (WONCBP) as defined in Appendix 10.4. OR • Is a WOCBP abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) or using a systemic hormonal contraceptive method that is highly effective (with a failure of <1% per year) along with a barrier method (e.g. condom) or using a non-hormonal contraceptive method that is highly effective (with a failure rate of <1% per year) preferably with low user dependency, as described in Appendix 10.4 during the study intervention period and for at least 30 days after the last dose of study intervention. The investigator should evaluate the potential for contraceptive method failure (e.g. noncompliance, recently initiated) in relationship to the first dose of study intervention. • A WOCBP must have a negative highly sensitive pregnancy test (urine or serum, as required by local regulations) within 24 hours before the first dose of study intervention (see Section 8.4.6). • If a urine test cannot be confirmed as negative (e.g. an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive. • Additional requirements for pregnancy testing during and after study intervention are specified within the protocol. • The investigator is responsible for review of medical history, menstrual history and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
• Capable of giving signed informed consent as described in Appendix 10.1 which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.