Evaluation of the Efficacy and Safety of Obeticholic Acid and Bezafibrate in Patients with Primary Biliary Cholangitis Unresponsive or Intolerant to Ursodeoxycholic Acid

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.

The secondary objectives are to assess the effects of the combination of OCA and BZF compared to BZF alone on:

• Biochemical disease markers, including gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), total and conjugated bilirubin, and a lipid panel.
• Biomarkers of bile acid synthesis and homeostasis, including 7α-hydroxy-4-cholesten-3-one (C4) and bile acids.
• Safety and tolerability of the treatment regimen.

The clinical trial involves a total of **7 participants** diagnosed with **Primary Biliary Cholangitis (PBC)**. The study population includes both male and female subjects, aged 18 years and older, who have a definite or probable diagnosis of PBC as per the EASL and AASLD guidelines. Participants are required to have qualifying alkaline phosphatase (ALP) and/or bilirubin liver biochemistry values. The trial includes individuals who have been taking ursodeoxycholic acid (UDCA) for at least 12 months with a stable dose for at least 3 months prior to the start of the study, or those who have not taken UDCA for 3 months before the study commencement. The selection process considered individuals from a vulnerable population, ensuring a comprehensive assessment of the trial's primary objective. Lifestyle factors such as diet and physical activity were not specified in the available data.

The clinical trial is designed as a **randomized**, **double-blind**, and controlled study to evaluate the efficacy, safety, and tolerability of **obeticholic acid** in combination with **bezafibrate** in subjects with **Primary Biliary Cholangitis (PBC)**. The trial aims to assess the effects of this combination on alkaline phosphatase (ALP) levels compared to bezafibrate alone. The study is structured to include a series of visits over a period of 59 weeks, with the estimated end date set for October 31, 2025.

Participants will undergo an initial screening visit to confirm eligibility based on criteria such as a definite or probable diagnosis of PBC, specific liver biochemistry values, and age of 18 years or older. Following successful screening, participants will be randomized to receive either the active treatment or placebo. The trial includes a baseline visit, followed by regular follow-up visits to monitor safety and efficacy endpoints, including changes in ALP and other liver function tests. The primary endpoint is the change in ALP from baseline to Week 12, while secondary endpoints include response rates and normalization rates of various liver enzymes and lipid panels.

The expected duration of participant involvement is approximately 59 weeks, with conditions for early termination including adverse events or withdrawal of consent. The study will conclude with an end-of-study visit to assess final outcomes and ensure participant safety. Throughout the trial, participants will receive either the active treatment or placebo in a blinded manner to maintain the integrity of the study results.

The clinical trial involves the administration of **OCALIVA**, which contains the active substance **obeticholic acid**. OCALIVA is provided in tablet form and is manufactured by Intercept Pharmaceuticals Inc. The tablets are available in two dosages: 5 mg and 10 mg. The maximum daily dose is 10 mg, with a total maximum dose of 14,605 mg over a treatment period of 59 days. The route of administration is oral. OCALIVA is classified under the ATC code A05AA04 and is designated as an orphan drug with the designation number EU/3/10/753. Participant compliance with the dosing schedule will be monitored throughout the trial.

Another experimental treatment in the trial is **Bezalip**, which contains the active substance **bezafibrate**. Bezalip is provided as a film-coated tablet, while Bezalip Mono is available as a prolonged-release tablet. Both formulations are manufactured by TEVA UK Limited. The maximum daily dose for bezafibrate is 400 mg, with a total maximum dose of 718,000 mg over a 59-day treatment period. The administration route is oral. Bezalip is classified under the ATC code C10AB02. The bezafibrate used in the trial has been purchased, repackaged, and relabeled specifically for clinical trial use.

The trial also includes the use of placebos to maintain the double-blind design. A placebo for bezafibrate and a placebo for obeticholic acid are utilized. These placebos do not contain any active substances and are used to ensure that the effects observed in the trial can be attributed to the active treatments rather than psychological or other non-specific effects. The placebos are administered in a manner consistent with the active treatments to maintain blinding.

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 endpoint is the change in ALP from baseline to Week 12 during the double-blind period. Secondary endpoints include response rates of ≥10%, ≥20%, ≥30%, and ≥40% reduction from baseline and normalization rates of ALP at Week 12. Additionally, normalization rates at Week 12 for gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), ALP, total and conjugated bilirubin, and a lipid panel will be assessed. Changes from baseline to Week 12 in GGT, ALT, AST, total and conjugated bilirubin, a lipid panel, 7α-hydroxy-4-cholesten-3-one (C4), and bile acids will also be evaluated.