Efficacy and Safety Evaluation of Elafibranor in Primary Biliary Cholangitis Patients with Inadequate Ursodeoxycholic Acid Response: A Double-Blind, Placebo-Controlled Study

Trial ID: 2024-512232-30-00
Protocol: GFT505B-319-1
Sponsor: Ipsen Pharma

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Diseases & Conditions

Primary biliary cholangitis

Objectives

The primary objective of this study is to evaluate the effect of **elafibranor** (80 mg/day) on **cholestasis** over 52 weeks of treatment compared to placebo in patients with **Primary Biliary Cholangitis** (PBC) who have an inadequate response or intolerance to ursodeoxycholic acid. This is clinically relevant as cholestasis is a key pathological feature of PBC, and effective management can potentially improve patient outcomes and quality of life.

Secondary objectives include:

Evaluating the effect of elafibranor on the normalization of alkaline phosphatase (ALP) over 52 weeks compared to placebo.
Assessing the impact of elafibranor on pruritus over 52 weeks in patients with a baseline PBC Worst Itch NRS score of ≥4, compared to placebo.
Evaluating the effect of elafibranor on pruritus over 24 weeks in patients with a baseline PBC Worst Itch NRS score of ≥4, compared to placebo.

Participants

The clinical trial involves a total of **100 participants** diagnosed with **Primary Biliary Cholangitis** (PBC). The study population includes both male and female subjects, aged between 18 to 75 years. Participants were selected based on specific inclusion criteria, such as having a confirmed diagnosis of PBC, demonstrated by at least two of the following: a history of elevated alkaline phosphatase (ALP) levels, positive anti-mitochondrial antibodies, or a liver biopsy consistent with PBC. The trial includes individuals who are on stable doses of medications like statins, ezetimibe, or medications for pruritus management, and those who have been on ursodeoxycholic acid (UDCA) for at least 12 months or are unable to tolerate it. The study also considers lifestyle factors, requiring participants to have a stable medication regimen for at least three months prior to screening. The trial population is not limited to any specific gender, and it includes a vulnerable population, ensuring a comprehensive evaluation of the treatment's effects across a diverse group of individuals.

Plans and Procedures

The clinical trial is designed to evaluate the **efficacy** and safety of **elafibranor** 80 mg in patients with **Primary Biliary Cholangitis** who have an inadequate response or intolerance to ursodeoxycholic acid. This study is a double-blind, randomized, placebo-controlled trial with an open-label long-term extension. The trial will span approximately 72 weeks, with the primary endpoint assessed at 52 weeks. Participants will be randomly assigned to receive either elafibranor or a placebo, administered orally in the form of film-coated tablets.

The trial will commence with a screening visit to confirm eligibility based on specific inclusion criteria, such as age between 18 to 75 years, a confirmed diagnosis of Primary Biliary Cholangitis, and stable medication regimens. Following successful screening, participants will undergo randomization and begin the treatment phase. Study visits will occur at regular intervals to monitor safety, efficacy, and adherence to the protocol. These visits will include assessments of liver function, pruritus, and other relevant biomarkers.

The primary endpoint is defined as a response to treatment at week 52, characterized by a reduction in alkaline phosphatase (ALP) levels to less than 1.67 times the upper limit of normal (ULN) and total bilirubin (TB) levels at or below ULN, with a decrease in ALP of at least 15%. Secondary endpoints include changes in pruritus, ALP normalization, and various biochemical and clinical parameters over the course of the study.

Participants are expected to be involved in the study for the full duration of the treatment period, with the possibility of early termination if they experience significant adverse events, fail to comply with the study protocol, or withdraw consent. The end-of-study visit will include a comprehensive evaluation of the participant's health status and the collection of final data for analysis. The trial aims to provide valuable insights into the potential benefits and risks of elafibranor in this patient population.

Treatment

The clinical trial involves the administration of **elafibranor**, an investigational medication, to evaluate its efficacy and safety in patients with Primary Biliary Cholangitis 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 daily dose of 80 mg and a total maximum dose of 175,200 mg over the course of the study. The treatment period is designed to last up to 72 weeks. The active substance, **elafibranor**, is of chemical origin and is manufactured by IPSEN BIOSCIENCE INC. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol.

The study also includes a **placebo** group to serve as a comparator for evaluating the effects of **elafibranor**. The placebo is designed to match the investigational product in appearance but does not contain any active pharmaceutical ingredients. The placebo is administered in a manner consistent with the investigational product, ensuring blinding of the study participants and investigators. The use of a placebo control is critical for assessing the true efficacy and safety profile of **elafibranor** in the target patient population.

Efficacy

The efficacy of elafibranor in patients with **Primary Biliary Cholangitis** will be assessed through a series of predefined endpoints over a 52-week treatment period. The primary endpoint is the response to treatment at week 52, defined by a reduction in alkaline phosphatase (ALP) to less than 1.67 times the upper limit of normal (ULN) and total bilirubin (TB) levels at or below ULN, with a decrease in ALP of at least 15%. Secondary endpoints include ALP normalization at week 52, changes in pruritus from baseline through week 52 based on the PBC Worst Itch Numeric Rating Scale (NRS) for patients with a baseline score of 4 or higher, and changes in ALP at weeks 4, 13, 26, 39, and 52. Additional secondary endpoints involve various biochemical responses, including ALP and TB levels, and changes in biomarkers of inflammation, immune response, hepatic fibrosis, lipid parameters, and bile acids.

Measurements will be collected at specified time points using validated scales and laboratory tests. The PBC Worst Itch NRS will be used to assess changes in pruritus, while liver function and injury will be evaluated through standard laboratory tests measuring AST, ALT, GGT, 5' NT, total and conjugated bilirubin, albumin, INR, and fractionated ALP. Biomarkers of inflammation and immune response will be measured by hsCRP, fibrinogen, haptoglobin, TNF-α, IgG, and IgM. Non-invasive measures of hepatic fibrosis will be assessed using the ELF score and liver stiffness measured by transient elastography (TE). Lipid parameters will be evaluated by measuring total cholesterol, LDL-C, HDL-C, VLDL-C, and triglycerides. The study will also assess changes in bile acids and biomarkers of bile acid synthesis, including C4 and FGF-19.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Must have provided written informed consent and agree to comply with the study protocol
Males or females age of 18 to 75 years inclusive at first Screening Visit (SV)
PBC diagnosis as demonstrated by the presence of ≥ 2 of the following 3 diagnostic criteria: a. History of elevated ALP levels for ≥ 6 months prior to randomization (V1) b. Positive anti-mitochondrial antibodies (AMA) titers (> 1/40 on immunofluorescence or M2 positive by enzyme-linked immunosorbent assay [ELISA]) or positive PBC-specific antinuclear antibodies (ANA) c. Liver biopsy consistent with PBC
ALP ≥ 1.67x upper limit of normal (ULN)
Total bilirubin (TB) ≤ 2x ULN To ensure inclusion of a relevant ratio of patients with substantial risk of long-term clinical outcomes or moderate disease stage, approximately 10% of randomized patients will be moderately advanced per Rotterdam Criteria (TB > ULN or Albumin < lower limit of normal [LLN]) and approximately 20% will have a TB > 0.6 x ULN (patients at risk of progression)
Must have at least 4 available values for PBC Worst Itch Numeric Rating Scale (NRS) during each of the 7 day intervals in the 14 days prior to randomization (V1), for a total of at least 8 values for PBC Worst Itch NRS in the last 14 days prior to randomization (V1)
UDCA for at least 12 months (stable dose ≥ 3 months) prior to screening, or unable to tolerate UDCA treatment (no UDCA for ≥ 3 months) prior to screening (per country standard-of-care dosing)
If on colchicine must be on a stable dose for ≥ 3 months prior to screening
Medications for management of pruritus (e.g., cholestyramine, rifampin, naltrexone or sertraline) must be on a stable dose for ≥ 3 months prior to screening
Patients taking statins or ezetimibe must be on a stable dose for ≥ 2 months prior to screening
Females participating in this study must be of non-child bearing potential or must be using highly effective contraception for the full duration of the study and for 1 month after the last drug intake: •Non-child bearing potential: Cessation of menses for at least 12 months due to ovarian failure or surgical sterilization such as bilateral oophorectomy, or hysterectomy •Highly effective contraception methods include: a.Combined (estrogen and progrestogen containing) hormaonal contraception associated with inhibition of ovulation, oral, intravaginal or transdermal b.Progestogen-only hormonal contraception associated with inhibition of ovulation, oral, injectable or implantable c.Intrauterine device (IUD) d.Intrauterine hormoine release system (IUS) e.Bilateral tubal occlusion f.Vasectomized partner g.Sexual abstinence, if required by local IRB/IEC regulations and/or considered adequate by National laws (the reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the patient)
For patients who consent to have liver biopsy samples collected, patients in whom it is safe and practical to proceed with a liver biopsy, and who agree to have: a.1 liver biopsy during the Screening Period (if no historical biopsy within 6 months before screening is available) b.1 liver biopsy after 52-weeks of treatment

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Exclusion Criteria

History or presence of other concomitant liver disease including: a) Positive anti-hepatitis A virus (HAV) immunoglobulin M (IgM) antibodies or positive hepatitis B surface antigen (HBsAg) or positive anti-hepatitis C virus (HCV) ribonucleic acid (RNA) (tested for in case of known cured HCV infection or positive HCV Ab at screening) b) Primary sclerosing cholangitis (PSC) c) Alcoholic liver disease (ALD) d) Autoimmune hepatitis (AIH) or if treated for an overlap of PBC with AIH, or if there is suspicion and evidence of overlap AIH features, that cannot be explained alone by insufficient response to UDCA e) Nonalcoholic steatohepatitis (NASH) f)Gilbert's Syndrome (exclusion due to interpretability of bilirubin levels) g) Known history of alpha-1 antitrypsin deficiency
Clinically significant hepatic decompensation, including: a) History of liver transplantation, current placement on a liver transplant list, current Model for End-Stage Liver Disease-Sodium (MELD-Na) score ≥ 12 linked to hepatic impairment b) Patients with cirrhosis/portal hypertension complications, including known esophageal varices, ascites, history of variceal bleeds or related interventions (e.g., insertion of variceal bands or transjugular intrahepatic portosystemic shunts [TIPS]), and hepatic encephalopathy, history or presence of spontaneous bacterial peritonitis, hepatocellular carcinoma c) Hepatorenal syndrome (type I or II)
Medical conditions that may cause non-hepatic increases in ALP (e.g., Paget's disease) or which may diminish life expectancy to < 2 years, including known cancers
Patient has a positive test for Human Immunodeficiency Virus (HIV) Type 1 or 2 at screening, or patient is known to have tested positive for HIV
Evidence of any other unstable or untreated clinically significant immunological, endocrine, hematologic, gastrointestinal, neurological, or psychiatric disease as evaluated by the investigator; other clinically significant medical conditions that are not well controlled
History of alcohol abuse, defined as consumption of more than 30 g pure alcohol per day for men, and more than 20 g pure alcohol per day for women, or other substance abuse within 1 year prior to screening visit (SV1)
For female patients: known pregnancy, or has a positive serum pregnancy test, or lactating
Administration of the following medications are prohibited as specified below: a) 2 months prior to screening: fibrates and glitazones b) 3 months prior to screening: azathioprine, cyclosporine, methotrexate, mycophenolate, pentoxifylline, budesonide and other systemic corticosteroids (parenteral and oral chronic administration only); potentially hepatotoxic drugs (including α-methyl-dopa, sodium valproic acid isoniazid, or nitrofurantoin) c) 12 months prior to screening: antibodies or immunotherapy directed against ILs or other cytokines or chemokines d) For patients with previous exposure to OCA, OCA should be discontinued 3 months prior to screening
Patients 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 five half-lives, whichever is longer, prior to screening; for patients with previous exposure to seladelpar, seladelpar should be discontinued 3 months prior to screening
Patients with previous exposure to elafibranor
SV value ALT and/or AST > 5 x ULN
For patients with AT or TB>ULN at SV1, variability of AT or TB > 40%
SV value albumin<3.0 g/dl
Severely advanced patients according to Rotterdam criteria (TB > ULN and albumin < LLN)
SV value INR > 1.3 due to altered hepatic function
SV value CPK > 2 x ULN
Screening serum creatinine > 1.5 mg/dl
Significant renal disease, including nephritic syndrome, chronic kidney disease (defined as patients with markers of kidney failure damage or eGFR < 60 mL/min/1,73 m2) calculated by MDRD
Platelet count < 150 x 103/μL
AFP > 20 ng/mL with 4-phase liver CT or MRI imaging suggesting presence of liver cancer
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

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Belgium	Not Recruiting	01 Sept 2020	6
France	Not Recruiting	01 Sept 2020	20
Germany	Not Recruiting	01 Sept 2020	10
Italy	Not Recruiting	01 Sept 2020	4
Spain	Not Recruiting	01 Sept 2020	21