Evaluation of Elafibranor Safety and Efficacy in Adult Patients with Primary Sclerosing Cholangitis: A Phase II Multicenter, Double-Blind, Randomized, Placebo-Controlled Study
- Trial ID
- 2024-511370-72-00
- Protocol
- CLIN-60190-453
- Sponsor
- Ipsen Bioscience Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to assess the **safety** and tolerability of daily oral administration of elafibranor at doses of 80 mg and 120 mg compared to placebo in adult participants with **Primary Sclerosing Cholangitis** (PSC) after 12 weeks of treatment. This evaluation is crucial as it determines the potential of elafibranor as a therapeutic option for managing PSC, a chronic liver disease with limited treatment options.
Secondary objectives include: - Evaluating the effect of elafibranor on markers of cholestasis and hepatobiliary injury compared to placebo after 12 weeks of treatment. - Assessing the impact on non-invasive markers of hepatic fibrosis, using liver stiffness measurement by transient elastography (FibroScan®) and serum-based biomarkers of fibrosis and disease activity. - Characterizing the pharmacokinetics (PK) of elafibranor and its metabolite GFT1007 using a Population PK approach, including identification of covariates impacting PK variability. - Evaluating the maintenance of efficacy and the long-term effect of elafibranor up to 120 mg during the open-label extension on markers of cholestasis and hepatobiliary injury.
Participants
The clinical trial involves a total of **46 participants** diagnosed with **Primary Sclerosing Cholangitis** (PSC). The study population comprises both male and female adults aged between **18 to 75 years**. Participants were selected based on specific inclusion criteria, including a confirmed diagnosis of PSC and the absence of secondary causes of sclerosing cholangitis. The health status of participants is generally stable, with requirements for controlled levels of alkaline phosphatase and bilirubin. Lifestyle considerations include the stability of any ongoing treatment for inflammatory bowel disease (IBD) and pruritus management, with participants required to maintain stable medication doses for at least three months prior to the screening period. The trial does not involve a vulnerable population, and all participants are capable of providing informed consent. The selection process ensures that participants are well-characterized in terms of their medical condition and treatment history, providing a robust basis for assessing the safety and tolerability of the investigational drug.
Plans and Procedures
The clinical trial is designed to evaluate the **safety** and **efficacy** of **elafibranor** in adult participants with **Primary Sclerosing Cholangitis** (PSC). This is a Phase II, multicenter, double-blind, randomized, placebo-controlled study with an open-label long-term extension. The trial will assess the effects of daily oral administration of elafibranor at doses of 80 mg and 120 mg compared to a placebo over a 12-week treatment period, followed by an open-label extension to evaluate long-term safety and tolerability. The trial is expected to conclude by July 2026, with recruitment having commenced in April 2023.
Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on specific inclusion criteria, such as age, diagnosis of PSC, and laboratory values. The screening process will ensure that participants have stable conditions and meet the necessary health requirements. Following the screening, participants will be randomized to receive either elafibranor or a placebo. The study includes regular follow-up visits to monitor safety, collect data on adverse events, and assess changes in laboratory parameters. The end-of-study visit will occur after the completion of the treatment period, where final assessments will be conducted.
The expected duration of participant involvement is approximately 108 weeks, including the initial 12-week double-blind period and the subsequent open-label extension. Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with study procedures, or if the investigator deems it necessary for their safety. The trial's primary endpoints include the number and percentage of participants experiencing treatment-emergent adverse events (TEAEs) and changes in clinical laboratory tests. Secondary endpoints focus on changes in alkaline phosphatase (ALP) levels and other liver function tests, as well as pharmacokinetic parameters of elafibranor.
Treatment
The clinical trial involves the administration of **elafibranor**, a dual PPARα/δ agonist with a 3.8-fold selectivity for activation of PPARα over PPARδ. Elafibranor is provided in the form of a **film-coated tablet** and is manufactured by IPSEN BIOSCIENCE INC. The trial includes two dosage regimens of elafibranor: 80 mg and 120 mg. The tablets are administered orally once daily. The maximum treatment period for both dosages is 108 weeks. The primary objective is to evaluate the safety and tolerability of these dosages in adult participants with Primary Sclerosing Cholangitis (PSC) over a 12-week period, with a long-term extension to assess safety up to 120 mg.
The study also includes a **placebo** group, which serves as a comparator to the active treatment groups. The placebo is designed to match the elafibranor tablets in appearance but does not contain the active substance. The placebo is administered under the same conditions as the active treatment, ensuring blinding of participants and investigators to treatment allocation. This design allows for a robust assessment of the efficacy and safety of elafibranor by comparing outcomes between the active treatment and placebo groups.
Efficacy
The efficacy of **elafibranor** in the treatment of Primary Sclerosing Cholangitis (PSC) will be assessed through a series of predefined endpoints in a Phase II, multicenter, double-blind, randomized, placebo-controlled study, followed by an open-label long-term extension. The primary efficacy endpoints during the double-blind period (DBP) include the number and percentage of participants experiencing treatment-emergent adverse events (TEAEs), treatment-related TEAEs, serious adverse events (SAEs), and adverse events of special interest (AESIs). Additionally, clinically significant changes from baseline in physical examination findings, vital signs, electrocardiograms (ECGs), and laboratory tests, including haematology, chemistry, liver tests, and renal tests, will be evaluated.
Secondary efficacy endpoints during the DBP focus on changes in alkaline phosphatase (ALP) levels. These include relative and absolute changes from baseline in ALP at Week 12, the number and percentage of participants with a ≥40% decrease in ALP, and those achieving ALP levels of <1.3x and <1.5x the upper limit of normal (ULN) at Week 12. Additional secondary endpoints involve changes in other liver function markers such as ALT, AST, GGT, 5’ nucleotidase, total bilirubin, and albumin. Non-invasive hepatic fibrosis markers, including ELF test, LSM assessed by FibroScan®, and serum markers like PAI-1 and TGF-β, will also be measured. Pharmacokinetic parameters, such as AUC0-24, Cmax, and Tmax, will be evaluated during a 24-hour dosing period.
During the open-label extension (OLE), efficacy will be further assessed by monitoring changes in ALP at Weeks 52 and 96. The number and percentage of participants achieving a ≥40% decrease in ALP from baseline at these timepoints will be recorded. These assessments will provide comprehensive data on the efficacy of elafibranor in managing PSC over both short and long-term treatment periods.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male or female participants must be 18 to 75 years of age inclusive, at the time of signing the informed consent.
- 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.
- 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.
- Total bilirubin ≤2.0x ULN at SV1.
- 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.
- 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
- 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 by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
- 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
- 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.
- 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 ongoing or planned long-term (a year or more) 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.
- lpha-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, 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).
- 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.
- 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.
- 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.
- Participants with previous exposure to elafibranor.
- 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.
- 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.
- Albumin <3.0 g/dL at SV1, unless related to a non-hepatic aetiology.
- Platelet count <100,000/microliter at SV1.
- International normalised ratio (INR) >1.3 due to altered hepatic function at SV1.
- CPK >2x ULN during screening period.
- 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.
- Significant renal disease, including nephritic syndrome, chronic kidney disease (defined as participants with evidence of impaired kidney function or underlying kidney injury).
- For female participants: known pregnancy, or has a positive serum pregnancy test, or lactating.
- 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.
- History of alcohol abuse, or other substance abuse within 1 year prior to SV1.
- 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.
- Known hypersensitivity to the investigational product or to any of the formulation excipients of the elafibranor or placebo tablet.
- Mental instability or incompetence, such that the validity of informed consent or ability to be compliant with the study is uncertain.
- 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.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Not Recruiting | 24 Apr 2023 | 8 |
 Italy | Not Recruiting | 24 Apr 2023 | 5 |
 Portugal | Not Recruiting | 24 Apr 2023 | 2 |
 Spain | Not Recruiting | 24 Apr 2023 | 7 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Placebo of Elafibranor | Placebo | N/A | — | — | — | N/A |
elafibranor | Test | FILM-COATED TABLET | ORAL USE | 120 | 85 | PRD10198915 |
elafibranor | Test | FILM-COATED TABLET | ORAL USE | 80 | 108 | PRD10198916 |