A Study to Assess Safety and Effectiveness of Elafibranor in Adult Participants With Primary Sclerosing Cholangitis.

A Phase II, Multicenter, Double-Blind, Randomised, Placebo-Controlled Study and Open Label Long Term Extension to Evaluate the Safety and Efficacy of Elafibranor in Adult Participants With Primary Sclerosing Cholangitis (PSC).

This study will evaluate the effects of elafibranor (the study drug) in participants with Primary Sclerosing Cholangitis (PSC) during the double-blind period, an initial 96 week open-label extension (OLE) period, and an optional open-label extension long-term (OLE-LT) period beyond OLE Week 96. PSC is a rare disease of the liver that leads to injury and destruction of bile ducts. Damage to bile ducts leads to buildup of bile in the liver, which then causes further damage, and leads to disease progression. This study will compare elafibranor to a placebo, a dummy treatment. The main objective of the trial will be to study the safety and side effects of the study drug, including long-term safety during the open-label extension periods. The trial will also study the study drug's effects on blood tests and other tests related to PSC disease activity.

Inclusion Criteria :

The following inclusion criteria apply to entry into the double-blind period and initial open-label extension (OLE) period up to OLE Week 96, unless otherwise specified.

• Participants with a diagnosis of Primary sclerosing cholangitis (PSC) as demonstrated by the presence of the following, and in the absence of apparent causes of secondary sclerosing cholangitis: i) Historical evidence of an elevated Alkaline phosphatase (ALP) > Upper Limit Normal (ULN) since at least 6 months prior to SV1. ii) Cholangiogram (e.g. magnetic resonance cholangiopancreatography (MRCP), endoscopic retrograde cholangiopancreatography (ERCP), percutaneous transhepatic cholangiography (PTC) with features compatible with large duct PSC.
• ALP ≥1.5x ULN during screening (with variability ≤30% based on two values).
• Total bilirubin ≤2.0x ULN at Screening Visit 1(SV1)
• Participants taking ursodeoxycholic acid (UDCA) at a total daily dose ≤23 mg/kg/day, with a minimum of 6 months of stable treatment prior to screening period and expected to remain on stable dose through the 12-week DBP. Minimum of 3 months off treatment prior to screening period if UDCA was recently discontinued.
• For participants with Inflammatory bowel disease (IBD): i) Participants with Crohn's disease must be in remission based on the investigator's clinical assessment and should be on stable treatment prior to randomisation and during screening. ii) Participants with ulcerative colitis must be in remission or have low activity disease as per the judgement of the investigator and should be on stable treatment prior to randomisation and during screening. iii) Current treatment for IBD is permitted, if the participant has been well controlled for ≥3 months prior to the screening period and is anticipated to remain on a stable dose of drugs for IBD treatment, including biologics, immunosuppressants, immunomodulators, or systemic corticosteroids. iv) Participants with IBD should have a colonoscopy performed within one year prior to the screening period showing no evidence of dysplasia or cancer.
• Medications for management of pruritus (e.g. cholestyramine, rifampin, naltrexone or sertraline) must be on a stable dose for ≥3 months prior to the screening period.
• Contraceptive use should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. -A female participant is eligible to participate if she is not pregnant or breastfeeding at screening, is willing not to become pregnant during the study and is willing to follow applicable protocol requirements related to this. - Male participants are eligible to participate if they agree to follow applicable protocol requirements related to contraception.
• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

Inclusion Criteria for Entry into Optional Open-Label Extension Long-Term (OLE-LT) Period Beyond Week 96

For entry into the optional OLE-LT period, participants:

• Must have completed the initial OLE period up to OLE Week 96
• Must not have permanently discontinued the study intervention during the initial OLE period
• Must, in the opinion of the investigator, benefit from continuing to receive study intervention The eligibility criteria assessed at Screening Visit 1 (SV1) for entry into the double-blind period are not reassessed for entry into the optional OLE-LT period.

Contraception requirements applicable during the OLE-LT period:

• Male participants: No contraception requirements apply.
• Female participants of childbearing potential: Must continue to use a highly effective contraceptive method during study intervention and for at least one month after the last dose. If using a hormonal contraceptive, an additional barrier method or a switch to a highly effective non-hormonal method is required.

Exclusion Criteria :

• History or presence of other concomitant chronic liver disease including: i) ImmunoglobulinG 4 (IgG4) related sclerosing cholangitis, or IgG4 ≥4x ULN at SV1. ii) Small duct PSC. iii) Documented history of secondary sclerosing cholangitis. iv) Presence of hepatitis B surface antigen (HBsAg) at screening. v) Hepatitis C virus (HCV) infection vi) Primary biliary cholangitis (PBC) or positive anti-mitochondrial antibody. vii) Alcohol-related liver disease. viii) Autoimmune hepatitis (AIH): Simplified Diagnostic Criteria of the IAIHG ≥6. ix) Presence of history of PSC-PBC or PSC-AIH overlap syndrome. x) Non-alcoholic steatohepatitis (NASH). SMD form protocol master data--23- INT / Version 1 Known history of alpha-1 antitrypsin deficiency
• Presence of percutaneous drain or bile duct stent at screening or within three months prior to screening.
• History of bacterial cholangitis within 60 days prior to the screening period, or participant on antibiotics for prophylaxis of recurrent cholangitis.
• History or any current suspicion of cholangiocarcinoma or elevated value of carbohydrate antigen 19-9 (CA19-9) >129 U/mL at SV1.
• Alpha-fetoprotein (AFP) >20 ng/mL with 4-phase liver computerised tomography (CT) or magnetic resonance imaging (MRI) suggesting presence of liver cancer.
• Participants with cirrhosis who are also classified as Child-Pugh B or C based on the Child-Pugh score. Participants with cirrhosis with Child-Pugh A score are allowed.
• History of clinically significant hepatic decompensation as described in the study protocol
• Presence or history of hepatocellular carcinoma.
• Medical conditions that may cause non-hepatic increases in ALP (e.g. Paget's disease).
• Medical conditions that may diminish life expectancy to <2 years, including known cancers.
• Participant has a positive test for human immunodeficiency virus (HIV) type 1 or 2 at SV1, or participant is known to have tested positive for HIV.
• Evidence of any other unstable or untreated clinically significant immunological, endocrine, neurological, gastrointestinal, haematologic, psychiatric diseases as evaluated by the investigator; other clinically significant conditions that are not well controlled
• Known malignancy or history of malignancy within the last 5 years, with the exception of local, successfully treated basal cell carcinoma or in-situ carcinoma of the uterine cervix.
• Participants with previous exposure to elafibranor
• ALT and/or AST >5x ULN
• Albumin <3.0 g/dL at SV1.
• Platelet count <100,000/microliter.
• International normalised ratio (INR) >1.3 due to altered hepatic function.
• Creatine phosphokinase (CPK) >2x ULN during screening period.
• Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m2