Evaluation of Bezafibrate and Obeticholic Acid Combination Therapy on Alkaline Phosphatase Levels in Primary Biliary Cholangitis Patients

The primary objective of this study is to evaluate the effects of the combination of **obeticholic acid** (OCA) and **bezafibrate** (BZF) on **alkaline phosphatase** (ALP) levels in comparison to BZF alone in subjects with **primary biliary cholangitis** (PBC). This is clinically relevant as ALP is a key biochemical marker used to assess liver function and disease progression in PBC, and its reduction is associated with improved clinical outcomes.

Secondary objectives include:

• Assessing the effects of the combination of OCA plus BZF versus BZF alone on biochemical disease markers, including gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), total and conjugated bilirubin, and lipid panel.
• Evaluating the effects on biomarkers of bile acid synthesis and homeostasis, including 7α-hydroxy-4 cholesten-3-one (C4) and bile acids.
• Assessing the safety and tolerability of the combination therapy compared to BZF alone.

The clinical trial involves a total of **55 participants** diagnosed with **primary biliary cholangitis**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically represent adults and older adults. Participants were selected based on specific inclusion criteria, such as having a defined or probable diagnosis of primary biliary cholangitis, qualifying alkaline phosphatase (ALP) and/or bilirubin liver biochemistry values, and their history of taking ursodeoxycholic acid (UDCA) for at least 12 months or not taking UDCA for 3 months prior to the study. The trial includes a vulnerable population, indicating that special considerations are in place to ensure their safety and well-being. Lifestyle factors such as diet, physical activity, and habits were not specified in the available data.

The clinical trial is designed as a **Phase 2a**, double-blind, randomized, active-controlled, parallel-group study. The primary objective is to evaluate the efficacy, safety, and tolerability of **bezafibrate** in combination with **obeticholic acid** in subjects diagnosed with **primary biliary cholangitis**. The trial will assess the effects of the combination therapy on alkaline phosphatase (ALP) levels compared to bezafibrate alone. The study is expected to commence recruitment on January 23, 2023, and conclude by March 21, 2025, with a total duration of approximately 26 months.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a defined or probable diagnosis of primary biliary cholangitis, specific liver biochemistry values, and prior use of ursodeoxycholic acid. Following successful screening, participants will be randomized into treatment groups. The trial includes a baseline visit, followed by regular follow-up visits to monitor safety, efficacy, and tolerability, with the primary endpoint being the change in ALP from baseline to Week 12. Secondary endpoints include safety assessments, response rates, and normalization rates of various liver enzymes and lipid panels at Week 12.

The expected length of participant involvement is approximately 12 weeks, with conditions for early termination including adverse events, withdrawal of consent, or non-compliance with the study protocol. The end-of-study visit will involve final assessments to ensure participant safety and collect data for analysis. The trial is structured to maintain scientific rigor and integrity, ensuring that the data collected will contribute to understanding the therapeutic potential of the combination treatment in managing primary biliary cholangitis.

The clinical trial involves the administration of **bezafibrate**, a chemical compound, in two different formulations. The first formulation, identified by the sponsor product code BZF 200 IR, is presented as a **tablet**. This formulation is administered **orally**. The dosage is specified in milligrams, with a maximum daily dose and total dose amount set at 9999 mg. The treatment period is also capped at 9999 days. The second formulation, BZF 100 IR, is similarly presented as a **tablet** and administered **orally**. It shares the same dosage and treatment period specifications as the BZF 200 IR formulation. Both formulations are not pediatric and are used as comparator treatments in the trial.

The experimental medication in this trial is **obeticholic acid**, marketed under the name Ocaliva 5 mg film-coated tablets. This medication is also a chemical compound and is administered **orally** in the form of **film-coated tablets**. The dosage is measured in milligrams, with a maximum daily dose and total dose amount of 9999 mg. The treatment period is limited to 9999 days. Ocaliva is designated as an orphan drug and is used as the test treatment in the study. The trial aims to evaluate the efficacy, safety, and tolerability of bezafibrate in combination with obeticholic acid in subjects with primary biliary cholangitis.

The efficacy of the clinical trial will be assessed by evaluating the effects of the combination of **obeticholic acid** (OCA) and **bezafibrate** (BZF) on alkaline phosphatase (ALP) levels in subjects with primary biliary cholangitis (PBC). The primary efficacy endpoint is the change in ALP from baseline to Week 12 during the double-blind phase. Secondary efficacy endpoints include response rates of ≥10%, ≥20%, ≥30%, and ≥40% reduction from baseline at Week 12, as well as normalization rates of ALP at Week 12. Additional secondary endpoints involve normalization rates at Week 12 of gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), total and conjugated bilirubin, and lipid panel. Changes from baseline to Week 12 in GGT, ALT, AST, ALP, total and conjugated bilirubin, lipid panel, 7α-hydroxy-4-cholesten-3-one (C4), and bile acids will also be measured.