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

The primary objective of this study is to evaluate the **efficacy** of volixibat compared to placebo in the treatment of pruritus associated with Primary Sclerosing Cholangitis (PSC). This is measured by the change in the Adult ItchRO tool, which is clinically relevant as pruritus significantly impacts the quality of life in patients with PSC.

Secondary objectives include:

• Evaluating the efficacy of volixibat versus placebo on the improvement of markers of **cholestasis**.
• Assessing the safety and tolerability of volixibat compared to placebo in participants with PSC-associated pruritus.
• Determining the efficacy of volixibat versus placebo for the treatment of pruritus based on the proportion of participants achieving a reduction of ≥2 points in the weekly averaged daily Adult ItchRO score from baseline through Week 24.
• Evaluating the quality of life in participants with PSC-associated pruritus treated with volixibat versus placebo.

The clinical trial involves a total of **282 participants** diagnosed with **Pruritus associated with Primary Sclerosing Cholangitis (PSC)**. The study population includes both male and female subjects, with an age range starting from 12 years in eligible regions, and 18 years otherwise. Participants were selected based on their confirmed diagnosis of PSC, consistent with the guidelines published by the AASLD, and an average daily Adult ItchRO score of 1 or higher during the two consecutive weeks leading to Visit 2. The trial allows the use of ursodeoxycholic acid and anti-pruritic medication, as well as the presence of concomitant Inflammatory Bowel Disease (IBD), provided additional criteria are met. The population includes vulnerable groups, and participants are required to provide informed consent and comply with all study visits and requirements through the end of the study, including the follow-up period.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy and safety of **volixibat** in treating **pruritus** associated with **Primary Sclerosing Cholangitis (PSC)**. The trial aims to assess the change in pruritus severity using the Adult ItchRO tool, comparing baseline scores with the average of the weekly averaged worst daily itch scores. The study involves the administration of volixibat, an **ileal bile acid transporter inhibitor**, in a hard capsule form, with a maximum daily dose of 160 mg and a total dose not exceeding 2000 mg over a treatment period of up to 124 days.

Participants will be involved in the study for an estimated duration from the recruitment start date in September 2021 until the end date in December 2025. The trial includes several key visits: an initial screening visit to confirm eligibility based on criteria such as age, confirmed PSC diagnosis, and baseline itch severity; subsequent follow-up visits to monitor treatment effects and safety; and a final end-of-study visit to assess overall outcomes. Participants are required to provide informed consent and comply with all study requirements, including the follow-up period.

Inclusion criteria specify that participants must be at least 12 years old in eligible regions, have a confirmed PSC diagnosis, and an average daily Adult ItchRO score of at least 1 during the two weeks leading to the second visit. The use of **ursodeoxycholic acid** and anti-pruritic medications is permitted under certain conditions, as is the presence of concomitant **Inflammatory Bowel Disease**. The study may terminate early for participants who do not adhere to the protocol or experience adverse effects that outweigh the potential benefits of continued participation.

The clinical trial involves the administration of **volixibat**, an experimental medication, in the form of a hard capsule. Volixibat is an ileal bile acid transporter inhibitor, chemically synthesized, and developed by Mirum Pharmaceuticals, Inc. The medication is administered orally. The maximum daily dose is 160 mg, with a total maximum dose of 2000 mg over the treatment period. The treatment duration is set for a maximum of 124 days. Participants are required to adhere to the dosing schedule, and compliance will be monitored throughout the study.

In addition to the experimental treatment, a **placebo** is used as a comparator in this double-blind, placebo-controlled study. The placebo is also provided in the form of a hard capsule for oral use. The placebo is designed to match the experimental medication in appearance to maintain blinding. Participants receiving the placebo will follow the same administration schedule as those receiving volixibat. Compliance with the placebo regimen will be similarly monitored to ensure adherence to the study protocol.

The efficacy of **volixibat** in the treatment of cholestatic pruritus in patients with Primary Sclerosing Cholangitis (PSC) will be assessed in a randomized, double-blind, placebo-controlled clinical trial. The primary endpoint for evaluating efficacy is the mean change in the Adult ItchRO tool, which measures the change in the average of the weekly averaged worst daily itch scores from baseline. This tool is a validated patient-reported outcome measure specifically designed to assess pruritus severity in adults.

Participants will be required to have an average daily Adult ItchRO score of at least 1 during the two consecutive weeks leading to Visit 2 to be eligible for the study. The trial will compare the efficacy of volixibat against a placebo, with the treatment administered in the form of hard capsules taken orally. The maximum treatment period is set at 124 days. The study aims to provide a comprehensive evaluation of volixibat's efficacy in reducing pruritus symptoms in the target patient population.