Efficacy and Safety Evaluation of Elafibranor in Adult Patients with Primary Biliary Cholangitis: A Phase III Randomized, Double-Blind, Placebo-Controlled Study

The primary objective of this study is to evaluate the **efficacy** of daily oral administration of elafibranor 80 mg compared to placebo, based on the time to the occurrence of clinical outcome events in adult participants with **Primary Biliary Cholangitis** (PBC) and cirrhosis. This is clinically relevant as it aims to determine the potential of elafibranor in delaying or preventing significant clinical events in this patient population, which could lead to improved long-term outcomes and quality of life.

Secondary objectives include:

• Assessing the safety and tolerability of daily long-term oral administration of elafibranor 80 mg compared to placebo in adult participants with PBC and cirrhosis.
• Evaluating the efficacy of elafibranor on various efficacy measures, including biochemical and clinical markers of response, disease-related symptoms, patient-reported outcomes (PROs) including other disease-related symptoms, quality of life (QOL), individual components of the composite primary endpoint, and liver-related mortality.
• Evaluating the pharmacokinetics (PK) of elafibranor and its metabolite GFT1007 in adult participants with PBC and cirrhosis using a Population PK approach, including identification of covariates impacting PK variability.

The clinical trial involves a total of **154 participants** diagnosed with **Primary Biliary Cholangitis** (PBC) and cirrhosis. The study population includes both male and female adults, aged 18 years and older, who have a definite or probable diagnosis of PBC and are classified as Child Pugh A or Child Pugh B. Participants were selected based on their ability to provide informed consent and comply with the study's requirements. The trial includes individuals from a vulnerable population, and contraceptive use is required to align with local regulations. The participants' general health status is characterized by the presence of cirrhosis, and no specific lifestyle considerations such as diet or physical activity are highlighted in the trial data provided.

The clinical trial is a **Phase III**, randomized, parallel-group, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of **elafibranor** 80 mg on long-term clinical outcomes in adult participants with **Primary Biliary Cholangitis** (PBC). The trial aims to compare the daily oral administration of elafibranor to a placebo, focusing on the time to the occurrence of clinical outcome events in participants with PBC and cirrhosis. The study is expected to last for a maximum duration of 3.5 years, with an estimated end date of May 31, 2029.

Participants will be randomly assigned to receive either elafibranor or a placebo, with the study maintaining a double-blind design to ensure unbiased results. The trial will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor safety and efficacy, and an end-of-study visit to assess final outcomes. The primary endpoint is event-free survival, defined as the time from randomization to either adjudicated disease progression or death. Secondary endpoints include the percentage of participants experiencing treatment-emergent adverse events, changes in physical examination findings, vital signs, and laboratory parameters, among others.

Participant involvement is expected to last from the baseline visit until four weeks after the end of treatment, with regular assessments conducted at specified intervals, such as every six months. Conditions that may lead to early termination from the study include the occurrence of serious adverse events or significant protocol deviations. The trial will adhere to strict eligibility criteria, including age, diagnosis of PBC, and cirrhosis status, to ensure the safety and appropriateness of participant inclusion.

The clinical trial involves the administration of **elafibranor**, an experimental medication, in the form of a **film-coated tablet**. Elafibranor is a chemical compound developed by IPSEN BIOSCIENCE INC. The dosage for this trial is set at 80 mg per day, administered orally. The maximum treatment period is 84 days, with a total maximum dose amounting to 204,480 mg. The primary objective of the trial is to evaluate the efficacy of elafibranor in improving long-term clinical outcomes in adult participants diagnosed with **Primary Biliary Cholangitis** (PBC) and cirrhosis. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the treatment regimen.

In addition to the experimental treatment, a **placebo tablet** is used as a comparator in this double-blind, placebo-controlled study. The placebo is designed to mimic the appearance of the elafibranor tablet but contains no active pharmaceutical ingredients. The placebo is administered orally, following the same schedule as the experimental medication, to maintain the study's blinding and integrity. The use of a placebo allows for a controlled comparison to assess the true efficacy and safety of elafibranor in the target population.

The efficacy of the clinical trial will be assessed by evaluating the primary endpoint of **event-free survival**, which is defined as the time from randomization to either adjudicated disease progression or death, whichever occurs first. This will be measured from baseline until four weeks after the end of treatment, with a maximum duration of 3.5 years. Secondary endpoints include the percentage of participants experiencing treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and adverse events of special interest (AESIs), as well as changes in physical examination findings, vital signs, and electrocardiogram (ECG) readings. These will also be assessed from baseline until four weeks after the end of treatment.

Additional secondary endpoints involve changes from baseline in various laboratory parameters, including alkaline phosphatase (ALP), total bilirubin (TB), and liver stiffness measurement (LSM) using vibration-controlled transient elastography (VCTE) with Fibroscan®. These parameters will be evaluated at specific time points: Month 6, Month 12, and every 12 months up to the end of treatment. The trial will also assess changes in lipid parameters, hepatic function, and patient-reported outcomes such as the PBC Worst Itch Numeric Rating Scale (NRS) and the Patient Global Impression of Severity (PGI-S). These assessments will be conducted every six months up to the end of treatment.

Pharmacokinetic parameters, including the area under the plasma concentration-time curve (AUC0-24), maximum plasma drug concentration (Cmax), and time to reach maximum plasma concentration (Tmax), will be measured at Day 1/Baseline, Month 6, and Month 12 during a dosing period of 24 hours. The trial will also monitor changes in the model for end-stage liver disease (MELD) 3.0 score and Child Pugh grade from screening until the end of treatment. These comprehensive assessments will provide a robust evaluation of the efficacy of elafibranor 80 mg in adult participants with primary biliary cholangitis (PBC) and cirrhosis.