Efficacy of Bezafibrate in Primary Sclerosing Cholangitis with Persistent Cholestasis Despite Ursodeoxycholic Acid Therapy: A Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of this study is to assess the efficacy of a 24-month treatment with **bezafibrate** (400 mg SR/d) compared to placebo, in addition to standard ursodeoxycholic acid (UDCA) therapy, in patients with **primary sclerosing cholangitis**. This is clinically relevant as it aims to address persistent cholestasis, a significant complication in this patient population, potentially improving disease management and patient outcomes.

Secondary objectives include:

• Comparing between groups the components of the primary composite outcome at 24 months (M24).
• Evaluating adverse effects, including inflammatory bowel disease (IBD) activity, and hepatic, muscular, and kidney function between groups.
• Assessing quality of life and scores for pruritus and fatigue at 12 months (M12) and M24.
• Comparing changes in liver tests between baseline (M0) and M24.
• Evaluating the occurrence of clinical events and transplant-free survival between groups.
• Assessing changes in serum markers of fibrosis (ELF score and Pro-C3) and cholangiographic abnormalities between M0 and M24.
• Monitoring the course of biomarkers, including microbiota, and their correlation with observed effects between M0 and M24.
• Determining the need for endoscopic procedures between M0 and M24.
• Evaluating changes in liver tests and creatinine levels 3 to 6 months after discontinuation of the experimental treatment.

The clinical trial focuses on evaluating the efficacy of a 24-month treatment with bezafibrate in addition to standard UDCA therapy for **primary sclerosing cholangitis**. The study population comprises both male and female participants aged between 18 and 75 years. The trial does not involve a vulnerable population. Participants were selected based on specific criteria, including a verified diagnosis of large duct primary sclerosing cholangitis through cholangiography and adherence to UDCA treatment for at least six months prior to inclusion. The trial also requires participants to have undergone a colonoscopy or endoscopy within specified timeframes, depending on their medical history. Women of childbearing potential must use effective contraception. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy of a 24-month treatment with **bezafibrate** in patients with **primary sclerosing cholangitis** who exhibit persistent cholestasis despite ongoing ursodeoxycholic acid therapy. The trial will involve the administration of bezafibrate at a dose of 400 mg per day in a prolonged-release tablet form, compared to a placebo. The study is expected to span a total duration of 24 months, with participant involvement lasting the same period unless early termination criteria are met.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis of large duct primary sclerosing cholangitis, and previous colonoscopy results. Following randomization, participants will attend regular follow-up visits to monitor treatment efficacy and safety, with assessments including serum alkaline phosphatase levels, liver stiffness, and quality of life measures. The primary endpoint is the proportion of patients achieving a reduction in serum alkaline phosphatase levels and maintaining normal serum bilirubin without an increase in liver stiffness at 24 months. Secondary endpoints include safety assessments, quality of life evaluations, and changes in biochemical liver tests.

The end-of-study visit will occur at the 24-month mark, where final assessments will be conducted to evaluate the long-term effects of the treatment. Participants may be withdrawn from the study early if they experience significant adverse events, fail to adhere to the study protocol, or choose to withdraw consent. The trial aims to provide valuable insights into the potential benefits of bezafibrate as an adjunct therapy in managing primary sclerosing cholangitis.

The clinical trial involves the administration of **bezafibrate**, marketed under the name BEFIZAL L.P. 400 mg, as the experimental medication. This medication is formulated as a **prolonged-release tablet** and is administered orally. The dosage is set at 400 mg per day, with a maximum treatment period of 24 months. Bezafibrate is a chemical substance, and its use in this trial is to evaluate its efficacy in treating primary sclerosing cholangitis with persistent cholestasis despite ursodeoxycholic acid therapy. The pharmaceutical form ensures a sustained release of the active ingredient, optimizing therapeutic effects over an extended period. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol.

The trial also includes a **placebo** group to serve as a comparator to the bezafibrate treatment. The placebo is designed to mimic the appearance of the bezafibrate tablets but does not contain any active pharmaceutical ingredients. The placebo is administered under the same conditions as the bezafibrate, ensuring that any observed effects can be attributed to the active treatment rather than other variables. This double-blind, placebo-controlled design is critical for assessing the true efficacy of bezafibrate in the study population.

In addition to the experimental and placebo treatments, all participants continue to receive standard-of-care therapy with ursodeoxycholic acid (UDCA) as part of their treatment regimen. This ensures that the trial evaluates the added benefit of bezafibrate over and above the current standard treatment for primary sclerosing cholangitis. The trial's design, including the use of a placebo and standard therapy, is structured to provide robust data on the efficacy and safety of bezafibrate in the target patient population.

The efficacy of the clinical trial will be assessed by evaluating the impact of a 24-month treatment with bezafibrate (400 mg SR/d) compared to placebo in patients with **primary sclerosing cholangitis**. The primary endpoint for efficacy is the proportion of patients achieving serum Alkaline Phosphatase (s-ALP) levels below 1.5 times the upper limit of normal (ULN) and a reduction of at least 15% from baseline at month 24 (M24), along with normal serum bilirubin levels and no increase in liver stiffness at M24 compared to baseline.

Secondary endpoints include the analysis of components of the primary composite outcome separately, such as the proportion of patients with complete normalization of s-ALP at M24, normal serum bilirubin, and no increase in liver stiffness. Additional secondary endpoints involve safety assessments, quality of life evaluations using the QMCF questionnaire, and scores for pruritus and fatigue measured by the VAS, 5D pruritus scale, and adapted PBC-40 questionnaire at baseline (M0), month 12 (M12), and M24. Changes in biochemical liver tests, including total and conjugated bilirubin, GGT, AST, ALT, albumin, and INR, will also be compared between groups. Furthermore, survival rates without liver transplantation or hepatic events, as well as PSC prognostic scores such as the MELD score, Revised PSC Mayo Risk Score, Hannover Score, and Amsterdam-Oxford prognostic model, will be evaluated at M0, M12, and M24.