Evaluation of Bezafibrate 400 mg and 200 mg as Adjunctive Therapy in Primary Biliary Cholangitis with Suboptimal Ursodeoxycholic Acid Response: A Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of this study is to assess the effect of **bezafibrate** 200 mg and bezafibrate 400 mg versus placebo as adjunctive treatments in patients with primary biliary cholangitis (PBC) who exhibit a non-optimal biochemical response to ursodeoxycholic acid (UDCA) therapy. This evaluation is clinically relevant as it aims to determine the efficacy of bezafibrate in improving treatment outcomes for PBC patients who do not respond adequately to standard UDCA therapy, potentially offering an alternative therapeutic strategy.

Secondary objectives include comparing between groups: - Adverse effects, particularly on muscle, kidney, and liver. - Symptoms such as pruritus and fatigue, and quality of life (QoL). - Changes in standard liver function tests. - Changes in non-invasive markers of liver fibrosis. - Occurrence of clinical events including death, liver transplantation (LT), or liver complications. These objectives are crucial for understanding the broader impact of bezafibrate on patient health and safety, as well as its potential to improve clinical outcomes beyond biochemical markers.

The clinical trial involves participants diagnosed with **Primary Biliary Cholangitis (PBC)** who exhibit a non-optimal response to Ursodeoxycholic Acid (UDCA). The study population includes both male and female subjects aged between 18 and 79 years. Participants are required to have been on a stable dose of UDCA therapy for at least 12 months prior to inclusion. The trial does not involve a vulnerable population. Participants were selected based on specific diagnostic criteria, including elevated alkaline phosphatase levels, presence of antimitochondrial antibodies, or histologic features suggestive of PBC. Women of childbearing potential are required to use at least one barrier contraceptive during the study and for a specified period after the last dose. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the **efficacy** and safety of **bezafibrate** 200 mg and 400 mg as adjunctive treatments in patients with primary biliary cholangitis (PBC) who exhibit a non-optimal biochemical response to ursodeoxycholic acid (UDCA) therapy. This study is structured as a 12-month, double-blind, randomized, placebo-controlled trial, followed by a 12-month, double-blind, placebo-free extension phase. The trial employs a parallel-group design with a 1:1:1 randomization ratio, ensuring that participants are evenly distributed across the treatment groups. The primary objective is to assess the effect of bezafibrate versus placebo on achieving a complete biochemical response, defined by normal serum levels of alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT), aminotransferases (AST, ALT), and total bilirubin at 48 weeks of treatment.

Participants will be involved in the study for a total duration of 24 months, with the initial 12 months dedicated to the double-blind, placebo-controlled phase, and the subsequent 12 months to the placebo-free extension phase. The study will commence with an inclusion (screening) visit to confirm eligibility based on criteria such as age (18 to 79 years), diagnosis of PBC, and stable UDCA therapy. Following randomization, participants will attend regular follow-up visits to monitor safety and efficacy outcomes, including the assessment of adverse events and changes in biochemical markers. The end-of-study visit will occur at the conclusion of the 24-month period, where final evaluations will be conducted.

Participants may be withdrawn from the study prematurely if they experience serious adverse events, fail to adhere to the study protocol, or withdraw consent. The trial is expected to start recruitment on October 1, 2024, and aims to conclude by December 31, 2028. The study's rigorous design, including its double-blind and placebo-controlled nature, ensures the reliability and validity of the findings, contributing valuable insights into the management of PBC with bezafibrate as an adjunctive therapy.

The clinical trial involves the administration of **BEFIZAL 200 mg**, a **film-coated tablet** containing the active substance **bezafibrate**. This medication is administered orally with a maximum daily dose of 200 mg. The total dose over the treatment period can reach up to 134,400 mg. The treatment duration is set for a maximum of 96 weeks. The pharmaceutical form is designed to ensure the stability and bioavailability of the active ingredient. Participant compliance is monitored through regular assessments and pill counts to ensure adherence to the dosing schedule.

Another experimental treatment in the trial is **BEFIZAL L.P. 400 mg**, a **prolonged-release tablet** also containing **bezafibrate**. This formulation allows for a sustained release of the active substance, administered orally with a maximum daily dose of 400 mg. The total dose over the treatment period can reach up to 268,800 mg, with the treatment period also extending up to 96 weeks. The prolonged-release formulation is intended to maintain therapeutic levels of the drug over an extended period, reducing the frequency of administration and potentially improving patient compliance.

The trial also includes a **placebo** group, where participants receive a placebo equivalent to **BEZAFIBRATE 200 mg**. The placebo is administered in a manner identical to the active treatments to maintain the double-blind nature of the study. This control group is essential for evaluating the efficacy and safety of the active treatments by providing a baseline for comparison.

The efficacy of bezafibrate as an adjunctive treatment in patients with **primary biliary cholangitis** (PBC) and a non-optimal biochemical response to ursodeoxycholic acid (UDCA) therapy will be assessed in a 12-month, double-blind, randomized, placebo-controlled trial, followed by a 12-month, double-blind, placebo-free extension phase. The primary endpoint for evaluating efficacy is the proportion of patients achieving a complete biochemical response, defined by normal serum levels of alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT), aminotransferases (AST, ALT), and total bilirubin at 48 weeks of treatment.

Secondary endpoints include the proportion of patients experiencing serious adverse events (SAE) and/or adverse events (AE) at week 48, including creatinine levels greater than 150 μmol/L, CPK levels greater than 10 times the upper limit of normal (ULN), or ALT levels greater than 5 times ULN. Additionally, changes from baseline to week 48 in itch intensity, assessed by the Numeric Rating Scale (NRS) as recommended by the IFSI SIG/EADV Task Force Pruritus, will be measured. The proportion of patients with normal ALP levels at week 48 and changes from baseline to week 48 in liver stiffness measurement (LSM) assessed by Fibroscan will also be evaluated.