Efficacy and Safety Evaluation of Volixibat in Treating Cholestatic Pruritus in Primary Biliary Cholangitis: A Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of this study is to evaluate the **efficacy** of volixibat compared to placebo for the treatment of pruritus in participants with Primary Biliary Cholangitis (PBC), as measured by the change in the Adult ItchRO tool. This is clinically relevant as pruritus is a common and distressing symptom in PBC, significantly impacting patients' quality of life.

Secondary objectives include:

• Evaluating the efficacy of volixibat versus placebo on the improvement of markers of cholestasis in participants with PBC.
• Assessing the efficacy of volixibat versus placebo for the treatment of pruritus in participants with PBC.
• Evaluating the safety and tolerability of volixibat versus placebo in participants with PBC-associated pruritus.
• Assessing the quality of life in participants with PBC-associated pruritus treated with volixibat versus placebo.

The clinical trial involves a total of **150 participants** diagnosed with **Primary Biliary Cholangitis (PBC)**, specifically experiencing **cholestatic pruritus**. The study population includes both male and female subjects aged 18 years and older, as per the inclusion criteria. Participants were selected based on their confirmed diagnosis of PBC in accordance with the AASLD guidelines, and the presence of pruritus associated with PBC, as assessed by the Adult ItchRO tool. The trial allows the use of UDCA and anti-pruritic medications under specific conditions. The population includes individuals from vulnerable groups, ensuring a comprehensive evaluation of the treatment's efficacy across diverse demographics. Lifestyle factors such as diet and physical activity were not specified as part of the selection criteria.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the efficacy and safety of **volixibat** in treating **cholestatic pruritus** in patients with **primary biliary cholangitis** (PBC). The trial is set to run from July 2022 to October 2027, with an estimated duration of 124 weeks for each participant. The study involves the administration of volixibat in a hard capsule form, with a maximum daily dose of 160 mg and a total dose not exceeding 2000 mg. Participants will be randomly assigned to receive either volixibat or a placebo, both administered orally.

The trial will commence with a screening visit to confirm eligibility based on criteria such as age (≥18 years), a confirmed diagnosis of PBC, and the presence of pruritus as assessed by the Adult ItchRO tool. Participants must provide informed consent and agree to comply with all study requirements. Following the screening, participants will undergo a series of study visits, including baseline assessments and regular follow-up visits to monitor efficacy and safety outcomes. The primary endpoint is the mean change in the Adult ItchRO score from baseline to the end of the double-blind treatment phase. Secondary endpoints include changes in serum bile acid levels, total bilirubin levels, alkaline phosphatase levels, and quality of life measures.

The study will conclude with an end-of-study visit, where final assessments will be conducted to evaluate the overall impact 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 comprehensive data on the therapeutic potential of volixibat in managing pruritus associated with PBC, contributing to the understanding of its safety and efficacy profile.

The clinical trial involves the administration of **volixibat**, an experimental medication, in the form of a hard capsule. The active substance, volixibat, is of chemical origin and is manufactured by Mirum Pharmaceuticals, Inc. The medication is administered orally, with a maximum daily dose of 160 mg and a maximum total dose of 2000 mg over a treatment period of up to 124 days. The dosing schedule is designed to ensure optimal efficacy while maintaining participant safety. Compliance with the dosing regimen is monitored throughout the study to ensure adherence to the protocol.

In addition to the experimental treatment, a placebo is used as a comparator in this double-blind, placebo-controlled study. The placebo is also presented in the form of a hard capsule for oral use, ensuring that the administration method is consistent with the experimental treatment. The use of a placebo allows for the assessment of the efficacy and safety of volixibat in treating cholestatic pruritus in patients with primary biliary cholangitis. The study design includes measures to maintain blinding and ensure unbiased results.

The efficacy of **volixibat** in the treatment of cholestatic pruritus in patients with Primary Biliary Cholangitis (PBC) will be assessed through a randomized, double-blind, placebo-controlled clinical trial. The primary endpoint for evaluating efficacy is the mean change in the Adult ItchRO score, comparing baseline with the average of the weekly averaged daily itch scores to the end of the double-blind study treatment. This tool is specifically designed to measure pruritus severity in adults with PBC.

Secondary endpoints include several biochemical and patient-reported outcomes: mean changes in serum bile acid (sBA) levels, total bilirubin levels, and alkaline phosphatase (ALP) levels. Additionally, changes in the Primary Biliary Cholangitis Quality of Life Measure (PBC-40), Patient-Reported Outcomes Measurement Information System (PROMIS®) fatigue score, and PROMIS sleep score from baseline to the end of the double-blind study treatment will be evaluated. The proportion of participants achieving a reduction of ≥ 2 points in the weekly averaged daily Adult ItchRO score from baseline to the end of the study will also be assessed. Furthermore, the incidence of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), events of clinical interest (ECIs), and adverse events leading to discontinuation of the study drug, as well as the incidence of clinically relevant laboratory abnormalities, will be monitored.