ELAFIBRANOR for Primary sclerosing cholangitis

Inclusion criteria

• {"criterion_text":"- Male or female participants must be 18 to 75 years of age inclusive, at the time of signing the informed consent.\n- Participants with a diagnosis of 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 ALP >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.\n- ALP ≥1.5x ULN during screening (with variability ≤40% based on two consecutive values). The interval between the two measurements should be of at least 2 weeks (and up to 4 weeks). The baseline value will be the average of all values obtained during screening plus the baseline visit measurement (obtained prior to treatment initiation). • If the mean value of both ALP values is ≥1.5x ULN and the variability between values is ≤40%, the participant is eligible (even if one of the two values is <1.5x ULN). • In cases where one of the two values is >1.5x ULN, but the mean value is <1.5x ULN, or if the variability between values is >40%, an additional value during screening may be obtained at least 2 weeks (and up to 4 weeks) after the previous measurement during screening. • In cases where an additional value is checked, the participant will be eligible if the variability between the second and the third value is ≤ 40%, and the mean value of all ALP values during screening is ≥1.5x ULN. • Once the two consecutive values have been checked as per the above, if the ALP variability for a participant is >40% but ≤45%, and the fluctuations are deemed to be consistent with the historical laboratory values of the participant based on the clinical judgment of the investigator, the participant may be eligible. In this case, the investigator should provide a summary of the case and their assessment in writing to both the CRO’s medical monitor and sponsor’s medical representative for review and sponsor agreement. • In cases of ineligibility, the candidate may be subsequently rescreened at investigator’s discretion as per Section 5.4, and enrolled if stable qualifying values are demonstrated. • All ALP values during screening should be analysed via the central laboratory.\n- Total bilirubin ≤2.0x ULN at SV1.\n- If taking UDCA, the participant should have: i) Total daily dose ≤23 mg/kg/day. ii) Minimum of 6 months of stable treatment prior to screening period and expected to remain on stable dose through the 12-week DBP.iii) Minimum of 3 months off treatment prior to screening period if UDCA was recently discontinued.\n- For participants with 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. This provision regarding stability of IBD treatment applies to the following, among others: • 5-aminosalicylic acid drugs. • Azathioprine; 6-mercaptopurine; methotrexate. • Budesonide (within recommended doses for management of IBD). In addition to oral formulation, topical application of budesonide (rectal foam or enema) is allowed. • Other systemic corticosteroids. • Biologics (e.g. anti-tumour necrosis factor or anti-integrin therapies). • Other immunosuppressants or immunomodulators used for IBD treatment. iv) Participants with IBD should have a colonoscopy performed within two years prior to the screening period showing no evidence of dysplasia or cancer\n- 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.\n- Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.\n- 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."}

Exclusion criteria

• {"criterion_text":"- History or presence of other concomitant chronic liver disease including: i) Immunoglobulin G4 (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 defined by positive anti-HCV antibody and positive HCV ribonucleic acid (RNA) (Note: Participants with positive anti-HCV antibody due to previously treated HCV infection, may be enrolled if a confirmatory HCV RNA is undetectable and sustained viral response has been documented). vi) PBC or history of positive anti-mitochondrial antibody. vii) Alcoholic 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) NASH. xi) Known history of alpha-1 antitrypsin deficiency.\n- Medical conditions that may diminish life expectancy to <2 years, including known cancers.\n- 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.\n- 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.\n- 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.\n- Administration of the following medications are prohibited as specified below: i) 3 months prior to the screening period: fibrates and glitazones. ii) 3 months prior to the screening period: cyclosporine, mycophenolate, pentoxifylline, and chronic systemic corticosteroids (except as specified in inclusion criteria 6 as part of management of IBD at an ongoing stable dose) (NOTE: Short courses ≤21 days of tapered oral steroids in the previous 3 months for a non-hepatic and non-IBD related indication would not be exclusionary if tapering was completed at least 6 weeks prior to screening); potentially hepatotoxic drugs (including α-methyl-dopa, sodium valproic acid, isoniazid, or nitrofurantoin). iii) Obeticholic acid. iv) 2 months prior to the screening period: systemic antibiotics (e.g. minocycline, vancomycin, metronidazole) specifically for prophylaxis of recurrent cholangitis or for treatment of PSC. Note: Short (up to 30 days) antibiotic courses are permitted during the study if medically necessary.\n- 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, prior to the screening period. If the previous trial was for an experimental therapy being studied for potential benefit in PSC, and the potential therapeutic agent was proven to have no beneficial effect in PSC and there are no safety concerns, the participant may enroll after 30 days or 5 half-lives, whichever is longer. For therapeutic agents being studied for potential benefit in PSC for which it is still unclear if there may be a potential benefit, participant may enroll after 6 months.\n- Participants with previous exposure to elafibranor.\n- Electrocardiogram (ECG) with QT interval corrected by Fridericia’s formula (QTcF) >450 msec in males or QTcF >470 msec in females for participants without bundle branch block. For participants with bundle branch block or other intraventricular conduction delay, a longer QTcF >480 msec would be exclusionary.\n- LT and/or AST >5x ULN, or variability >50% based on two consecutive values during screening and as described below. The interval between the two measurements should be of at least 2 weeks (and up to 4 weeks). For both ALT and AST, the baseline value for the purposes of monitoring for drug-induced liver injury (DILI) will be the average of all values obtained during screening plus the baseline visit measurement (obtained prior to treatment initiation). • For ALT and/or AST, if both measurements during screening are ≤5x ULN and the variability between values is ≤50%, the participant is eligible. • For ALT and/or AST, in cases where one of the two values is >5x ULN, or if the variability between values is >50%, an additional value during screening may be obtained at least 2 weeks (and up to 4 weeks) after the previous measurement. If the repeat value is <5x ULN, the average of all values during screening is <5x ULN, and the variability from the previous value is ≤50%, the participant may be eligible. • For AST and/or ALT, if both values are <1.5x ULN, there is no limit to the variability between values for eligibility. • In cases of ineligibility, the candidate may be subsequently rescreened at investigator’s discretion as per Section 5.4, and enrolled if stable qualifying values are demonstrated. • All AST and ALT values during screening should be analysed via the central laboratory.\n- Albumin <3.0 g/dL at SV1, unless related to a non-hepatic aetiology.\n- Presence of percutaneous drain or bile duct stent at screening or within three months prior to screening.\n- Platelet count <100,000/microliter at SV1.\n- International normalised ratio (INR) >1.3 due to altered hepatic function at SV1.\n- CPK >2x ULN during screening period.\n- Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m 2 per modification of diet in renal disease study (MDRD)-6 formula at SV1. Note: In cases of decreased eGFR where the investigator believes the value may not be representative of the actual eGFR of the potential participant, re-test after adequate hydration is allowed.\n- Significant renal disease, including nephritic syndrome, chronic kidney disease (defined as participants with evidence of impaired kidney function or underlying kidney injury).\n- For female participants: known pregnancy, or has a positive serum pregnancy test, or lactating.\n- 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.\n- History of alcohol abuse, or other substance abuse within 1 year prior to SV1.\n- A positive drug screen at screening would be exclusionary unless it can be explained by a prescribed medication. Note: Cannabis and related products are permitted.\n- Known hypersensitivity to the investigational product or to any of the formulation excipients of the elafibranor or placebo tablet.\n- History of bacterial cholangitis within 60 days prior to the screening period, or participant on ongoing or planned long-term (a year or more) antibiotics for prophylaxis of recurrent cholangitis.\n- Mental instability or incompetence, such that the validity of informed consent or ability to be compliant with the study is uncertain.\n- 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.\n- History or any current suspicion of cholangiocarcinoma or elevated value of carbohydrate antigen 19-9 (CA19-9) >129 U/mL at SV1.\n- lpha-fetoprotein (AFP) >20 ng/mL with 4-phase liver computerised tomography (CT) or magnetic resonance imaging (MRI) suggesting presence of liver cancer.\n- 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.\n- History of clinically significant hepatic decompensation, including: i) History of liver transplantation, current placement on a liver transplant list, current model for end-stage liver disease (MELD)-Na score ≥12 due to hepatic impairment (MELD-Na will be calculated only when MELD >11). ii) Evidence of complications of cirrhosis, including hepatic decompensation or evidence of significant portal hypertension complications including presence of ascites requiring treatment; history or presence of spontaneous bacterial peritonitis; presence of hepatic encephalopathy grade 2 or higher per West-Haven criteria; history of oesophageal variceal bleeding or related interventions (e.g. oesophageal variceal banding, or transjugular intrahepatic portosystemic shunt placement). Note: Participants with grade 1 varices may be eligible to enrol. iii) Hepatorenal syndrome (type I or II).\n- Presence or history of hepatocellular carcinoma.\n- Medical conditions that may cause non-hepatic increases in ALP (e.g. Paget’s disease)."}

Primary endpoints

• {"endpoint_text":"- DBP: Number and percentage of participants who • experience TEAEs, treatment-related TEAEs, SAEs, and AESIs • develop clinically significant changes from baseline in physical examination findings, vital signs, and ECG • develop clinically significant changes from baseline in haematology, chemistry, liver tests, renal tests (including urinalysis), and other laboratory tests and procedures","definition_or_measurement_approach":"Safety and tolerability during the Double-Blind Period assessed as counts and percentages of participants experiencing treatment-emergent adverse events (TEAEs), treatment-related TEAEs, serious adverse events (SAEs), adverse events of special interest (AESIs), and clinically significant changes from baseline in physical exam, vital signs, ECG and laboratory tests."}
• {"endpoint_text":"- OLE: Number and percentage of participants who • experience TEAEs, treatment-related TEAEs, SAEs, and AESIs • develop clinically significant changes from baseline in physical examination findings, vital signs and ECG • develop clinically significant changes from baseline in haematology, chemistry, liver tests, renal tests (including urinalysis), and other laboratory tests and procedures","definition_or_measurement_approach":"Long-term safety and tolerability during the Open-Label Extension assessed as counts and percentages of participants experiencing TEAEs, treatment-related TEAEs, SAEs, AESIs and clinically significant changes from baseline in physical exam, vital signs, ECG and laboratory tests."}

Secondary endpoints

• {"endpoint_text":"- DBP - objective 1: • Relative change from baseline in ALP at Week 12 • Number and percentage of participants with ≥40% decrease from baseline in ALP at Week 12 • Absolute change from baseline in ALP at Week 12 • Number and percentage of participants with ALP: <1.3x ULN and <1.5x ULN at Week 12","definition_or_measurement_approach":"Biochemical efficacy endpoints assessing changes in alkaline phosphatase (ALP) from baseline to Week 12, including relative and absolute changes and responder thresholds (≥40% decrease; ALP <1.3x and <1.5x ULN)."}
• {"endpoint_text":"- DBP - objective 1: • Number and percentage of participants who normalised ALP at Week 12 • Change from baseline in ALT, AST, GGT, 5’ nucleotidase, total bilirubin, conjugated bilirubin, albumin and fractionated ALP at Week 12","definition_or_measurement_approach":"Secondary biochemical endpoints measuring normalization of ALP and changes in other liver-related laboratory parameters from baseline to Week 12."}
• {"endpoint_text":"- DBP - objective 2: • Change from baseline in ELF test at Week 12 • Change from baseline in LSM assessed by FibroScan ® at Week 12","definition_or_measurement_approach":"Non-invasive fibrosis endpoints: change in ELF (enhanced liver fibrosis) score and liver stiffness measurement (LSM) by FibroScan from baseline to Week 12."}
• {"endpoint_text":"- DBP - objective 2: • Change from baseline in other non-invasive hepatic fibrosis serum markers as measured by PAI-1, TGF-β, marker of type V collagen formation (Pro-C5), and marker of type III collagen formation (Pro-C3) at Week 12 • Change from baseline in FIB-4 and APRI at Week 12 • Change from baseline in CK-18 (M65 and M30) at Week 12","definition_or_measurement_approach":"Additional non-invasive serum fibrosis and cell-death biomarkers assessed as changes from baseline to Week 12."}
• {"endpoint_text":"- DBP - secondary PK: • Individual PK parameters (during a dosing period of 24 hours) after single administration and at steady state: - AUC0-24 (area under the plasma concentration-time curve from time 0 to 24 hours) - Cmax (maximum (peak) plasma drug concentration) - Tmax (time to maximum plasma concentration)","definition_or_measurement_approach":"Pharmacokinetic endpoints measured from plasma concentrations over 24 hours to derive AUC0-24, Cmax and Tmax after single dose and at steady state."}
• {"endpoint_text":"- DBP - secondary PK: • Population PK parameters: - CL (apparent clearance of drug from plasma) - VZ (apparent volume of distribution)","definition_or_measurement_approach":"Population PK parameters (clearance and volume of distribution) estimated using population PK modelling."}
• {"endpoint_text":"- OLE: • Relative change from baseline in ALP at Week 52 and Week 96 of treatment in OLE • Number and percentage of participants with ≥40% decrease from baseline in ALP at Week 52 and Week 96 of treatment in OLE • Absolute change from baseline in ALP at Week 52 and Week 96 of treatment in OLE","definition_or_measurement_approach":"Long-term efficacy endpoints assessing ALP changes and responder rates at Weeks 52 and 96 during the Open-Label Extension."}

Italy

Earliest CTIS Part Ii Submission Date

07-08-2024

Latest Decision Or Authorization Date

18-12-2025

Processing Time Days

498

Number Of Sites

5

Number Of Participants

5

Portugal

Earliest CTIS Part Ii Submission Date

07-08-2024

Latest Decision Or Authorization Date

18-12-2025

Processing Time Days

498

Number Of Sites

3

Number Of Participants

2

Germany

Earliest CTIS Part Ii Submission Date

07-08-2024

Latest Decision Or Authorization Date

18-12-2025

Processing Time Days

498

Number Of Sites

3

Number Of Participants

8

Spain

Earliest CTIS Part Ii Submission Date

07-08-2024

Latest Decision Or Authorization Date

18-12-2025

Processing Time Days

498

Number Of Sites

7

Number Of Participants

7

Primary sponsor

Full Name

Ipsen Bioscience Inc.

Organisation Type

Pharmaceutical company

Country Of Registered Address

United States

Contract research organisations

Name

Icon Clinical Research Limited

Responsibilities

Operational and sponsor duties (codes listed in sponsorDuties for this third party)

Name

Parexel International (IRL) Limited

Responsibilities

safety management

Third parties

• {"country":"Ireland","full_name":"Icon Clinical Research Limited","duties_or_roles":"Codes: [1,10,11,12,13,2,4,5,6,7,8,9]","organisation_type":"Pharmaceutical company"}
• {"country":"Ireland","full_name":"Parexel International (IRL) Limited","duties_or_roles":"safety management","organisation_type":"Pharmaceutical company"}
• {"country":"France","full_name":"Eurofins Adme Bioanalyses","duties_or_roles":"Analytical chemistry","organisation_type":"Pharmaceutical company"}