Evaluation of Elafibranor 80 mg on Alkaline Phosphatase Normalization in Adults with Primary Biliary Cholangitis Unresponsive or Intolerant to Ursodeoxycholic Acid

Trial ID: 2024-510695-20-00
Protocol: CLIN-60190-463
Sponsor: Ipsen Bioscience Inc.

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Diseases & Conditions

Primary biliary cholangitis

Objectives

The primary objective of this study is to evaluate the **efficacy** of daily oral administration of 80 mg elafibranor compared to placebo in adult participants with **Primary Biliary Cholangitis (PBC)**, specifically focusing on the normalization of alkaline phosphatase (ALP) levels. This is clinically relevant as ALP is a key biochemical marker in PBC, and its normalization is associated with improved clinical outcomes and prognosis in affected individuals.

Secondary objectives include: - Evaluating the efficacy of elafibranor on biochemical markers of response, patient-reported outcomes, and clinical outcome events of interest. - Assessing the safety and tolerability of elafibranor. - Investigating the effect of elafibranor on various biomarkers, including liver tests, non-invasive markers of fibrosis, biomarkers of pruritus, lipid parameters, PBC prognosis score, biomarkers of inflammation and immune response, biomarkers of bile acid synthesis, and bone mineral density. - Evaluating the pharmacokinetics (PK) of elafibranor and its metabolite GFT1007. - Exploring the association of biomarkers with clinical data on selected efficacy and safety endpoints. - Assessing the relationship between PK and pharmacodynamics (PD) endpoints.

Participants

The clinical trial involves a total of **45 participants** diagnosed with **Primary Biliary Cholangitis (PBC)**. The study population includes both male and female adults aged 18 years and older. Participants were selected based on specific criteria, including a historical diagnosis of PBC, and must have elevated alkaline phosphatase (ALP) levels within a defined range. Those taking ursodeoxycholic acid (UDCA) must have been on a stable dose for at least three months, while those intolerant to UDCA should have discontinued its use at least three months prior. Additionally, participants on medications for pruritus management must maintain a stable dose for a minimum of three months. The trial population includes individuals capable of providing informed consent and adheres to local contraceptive regulations. The study does not exclude vulnerable populations, ensuring a comprehensive evaluation of the treatment's efficacy across a diverse group of individuals.

Plans and Procedures

The clinical trial is designed as a **randomized**, parallel-group, double-blind, placebo-controlled, two-arm study to evaluate the efficacy of **elafibranor** 80 mg in adult participants with **Primary Biliary Cholangitis (PBC)** who have an inadequate response or intolerance to ursodeoxycholic acid. The primary objective is to assess the normalisation of alkaline phosphatase (ALP) levels over a 52-week period. Participants will be randomly assigned to receive either elafibranor or a placebo, with the study drug administered orally in the form of a film-coated tablet. The trial is expected to commence recruitment on October 21, 2024, and conclude by December 1, 2026.

Study visits are structured to include an initial screening visit to confirm eligibility based on inclusion criteria such as age, ALP levels, and prior treatment history. Participants must provide informed consent and meet specific diagnostic criteria for PBC. Following randomization, participants will attend follow-up visits at Weeks 4, 12, 24, 36, and 52 to monitor ALP levels, assess secondary endpoints, and evaluate safety through physical examinations, vital signs, and laboratory tests. The end-of-study visit will occur four weeks after the final dose to ensure comprehensive data collection on treatment-emergent adverse events and any clinically significant changes in health status.

The expected duration of participant involvement is approximately 56 weeks, including the treatment period and follow-up. Conditions that may lead to early termination from the study include the development of serious adverse events, non-compliance with study procedures, or withdrawal of consent. The trial aims to provide robust data on the efficacy and safety of elafibranor in this patient population, contributing to the understanding of its potential therapeutic benefits in managing PBC.

Treatment

The clinical trial involves the administration of **elafibranor**, an experimental medication, to evaluate its efficacy in adult participants with **Primary Biliary Cholangitis** (PBC) who have an inadequate response or intolerance to ursodeoxycholic acid. **Elafibranor** is provided in the form of a **film-coated tablet** and is administered orally. The dosage is set at 80 mg per day, with a maximum total dose of 29,120 mg over a treatment period of 52 weeks. The active substance, **elafibranor**, is of chemical origin and is manufactured by IPSEN BIOSCIENCE INC. The medication is classified as an orphan drug, with the designation number EU/3/19/2182.

In addition to the experimental treatment, a **placebo** is used as a comparator in this double-blind, placebo-controlled study. The placebo is designed to match the **elafibranor** film-coated tablet in appearance but does not contain any active pharmaceutical ingredients. The placebo is administered orally, following the same dosing schedule as the experimental medication, to maintain the study's blinding and ensure unbiased results.

Participant compliance with the dosing regimen is monitored throughout the study to ensure adherence to the prescribed treatment schedule. This monitoring is crucial for maintaining the integrity of the trial data and ensuring the reliability of the study outcomes. The trial's primary objective is to assess the effect of **elafibranor** on the normalization of alkaline phosphatase levels in the target population.

Efficacy

The efficacy of the clinical trial will be assessed by evaluating the effect of daily oral administration of **elafibranor** 80 mg compared to placebo in adult participants with Primary Biliary Cholangitis (PBC) on the normalisation of Alkaline Phosphatase (ALP). The primary endpoint is the percentage of participants achieving normalisation of ALP at Week 52. Secondary endpoints include the percentage of participants with normalisation of ALP levels at various time points (Week 4, Week 12, Week 24, and Week 36), changes from baseline in ALP levels, and the percentage of participants with a significant decrease in ALP levels from baseline. Additional secondary endpoints involve changes in Total Bilirubin (TB) levels, pruritus scores, quality of life assessments, and the occurrence of treatment-emergent adverse events.

Efficacy parameters will be measured and collected at specified time points throughout the trial, including baseline, Week 4, Week 12, Week 24, Week 36, and Week 52. The analysis will involve validated scales and laboratory tests to assess changes in ALP and TB levels, as well as patient-reported outcomes such as the PBC Worst Itch Numeric Rating Scale (NRS), 5-D itch score, Patient Global Impression of Severity (PGI-S) scores, and Patient Global Impression of Change (PGI-C) scores. The trial will also monitor changes in PBC-40 Quality of Life (QoL) scores and Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue Short Form 7a scores. The data collected will be analyzed to determine the efficacy of elafibranor in achieving the desired clinical outcomes in participants with PBC.

Inclusion and Exclusion Criteria

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Inclusion Criteria

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.

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Exclusion Criteria

History or presence of other concomitant liver diseases
History of hepatocellular carcinoma
Alpha-foetoprotein (AFP) >20 ng/mL with 4-phase liver computed tomography (CT) or magnetic resonance imaging (MRI) scans suggesting presence of liver cancer
(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
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
(18) Platelet count <75,000/µL
International normalised ratio >1.3 in the absence of anticoagulant therapy
Participants with known cirrhosis who have a Child-Pugh B or C score. Participants with cirrhosis with Child-Pugh A score are allowed.
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.
Significant renal disease, including nephritic syndrome, chronic kidney disease (defined as participants with evidence of significantly impaired kidney function or underlying kidney injury).
For female participants: known pregnancy, or has a positive serum pregnancy test, or is breastfeeding
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
Known hypersensitivity to the investigational product or to any of the excipients of elafibranor
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 the study
History of liver transplantation
History or presence of clinically significant hepatic decompensation
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
Medical condition with a life expectancy <2 years
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
Participants who are committed to an institution by virtue of an order issued either by the judicial or the administrative authorities

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Czechia	Not Recruiting	21 Oct 2024	3
France	Not Recruiting	21 Oct 2024	4
Germany	Not Recruiting	21 Oct 2024	5
Italy	Not Recruiting	21 Oct 2024	5
Poland	Not Recruiting	21 Oct 2024	4
Romania	Not Recruiting	21 Oct 2024	8
Spain	Not Recruiting	21 Oct 2024	6