Long-term Safety and Tolerability of Linerixibat in Cholestatic Pruritus Associated with Primary Biliary Cholangitis

The primary objective of this study is to evaluate the **safety** and **tolerability** of long-term **linerixibat** treatment in participants with **cholestatic pruritus** associated with **Primary Biliary Cholangitis (PBC)**. This is clinically relevant as it aims to ensure that the treatment is safe for prolonged use, which is crucial for managing a chronic condition like PBC.

Secondary objectives include:

• Characterizing the effects of long-term linerixibat treatment on disease burden and health-related quality of life (QoL) in participants with cholestatic pruritus in PBC.
• Characterizing the effects of long-term linerixibat treatment in participants with cholestatic pruritus in PBC.
• Evaluating the maintenance of efficacy of linerixibat on itch over 52 weeks.
• Evaluating the effect of linerixibat on health-related QoL.

The clinical trial involves a total of **210 participants** diagnosed with **cholestasis**, specifically focusing on those with cholestatic pruritus in primary biliary cholangitis (PBC). The study population includes both male and female participants aged between 18 to 80 years. Participants were selected based on their prior involvement in eligible linerixibat clinical studies, such as BAT117213, GLIMMER, or GLISTEN, and must have completed the main treatment periods in these studies. The trial includes individuals who are capable of providing informed consent and meet specific contraceptive requirements if applicable. The study does not specify any particular lifestyle considerations such as diet or physical activity. The trial population includes a vulnerable population, indicating that additional ethical considerations are in place to protect these participants.

The clinical trial is designed to evaluate the long-term safety and tolerability of **linerixibat** in participants with **cholestatic pruritus** associated with **primary biliary cholangitis** (PBC). This study is a Phase 3a, randomized, double-blind, controlled trial. The trial is expected to run from June 18, 2020, to February 2, 2027, with a maximum treatment period of 48 months. Participants will be administered linerixibat in tablet form, with a maximum daily dose of 80 mg, taken orally.

Participants eligible for inclusion are those aged 18 to 80 years who have completed the main treatment period in a prior eligible linerixibat clinical study. The study will begin with a screening visit to confirm eligibility based on inclusion criteria, including a history of PBC and associated pruritus. Female participants must adhere to specific contraceptive requirements and undergo pregnancy testing as per protocol guidelines.

Study visits are scheduled at regular intervals to monitor the frequency and severity of adverse events, with assessments conducted on Day 1, Week 1, and at Months 1, 2, 3, 6, 9, 12, 18, 24, 30, 36, 42, and 48. Additional visits may be scheduled as needed. The end-of-study visit will occur at the conclusion of the treatment period, followed by a final follow-up phone call 7 to 14 days after the last dose of the investigational product.

Participant involvement is expected to last up to 48 months, with conditions for early termination including non-compliance with study procedures, withdrawal of consent, or any adverse events that may compromise participant safety. The primary endpoint focuses on the safety profile of linerixibat, while secondary endpoints include changes in domain scores of the PBC-40 and BDI-II, as well as health-related quality of life measures. The trial aims to provide comprehensive data on the long-term use of linerixibat in managing symptoms of cholestatic pruritus in PBC patients.

The clinical trial involves the administration of **linerixibat**, an experimental medication developed by GlaxoSmithKline, for the treatment of **cholestatic pruritus** in participants with **Primary Biliary Cholangitis** (PBC). Linerixibat is provided in the form of tablets, with each tablet containing the active chemical substance linerixibat. The medication is administered orally, with a maximum daily dose of 80 mg. The treatment period for this study is set to a maximum of 48 weeks. The primary objective of the trial is to evaluate the long-term safety and tolerability of linerixibat in the specified patient population.

In addition to the experimental treatment, participants may receive standard-of-care therapy as deemed necessary by the clinical investigators. No placebo or comparator treatment is specified in the trial protocol. The study does not include a pediatric formulation of linerixibat, and the medication is classified as an orphan drug, indicating its use for a rare condition. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen.

The efficacy of the clinical trial evaluating **linerixibat** for the treatment of cholestatic pruritus in participants with Primary Biliary Cholangitis (PBC) will be assessed through several parameters. Primary endpoints include the frequency and severity of adverse events, which will be monitored from the start of treatment (Day 1) to the end of the study or until a follow-up phone call after early study withdrawal (Day 7 to 14 post-final dose). These assessments are scheduled for Day 1, Week 1, and at Months 1, 2, 3, 6, 9, 12, 18, 24, 30, 36, 42, and 48, with additional visits as needed.

Secondary endpoints involve changes in domain scores of the PBC-40 and BDI-II over time, as well as changes in clinically meaningful laboratory values, including liver parameters and lipids. For Group 1, changes in health-related quality of life (QoL) and EQ VAS (EQ-5D-3L) over time will be evaluated. For Group 2, the focus will be on responders, defined as those with a reduction of ≥2, ≥3, and ≥4 points in the Misery Index Score (MIS) at Week 24 and Week 52 of continuous treatment. Additionally, the maintenance of efficacy at Week 52 for those who were responders at Week 24 will be assessed, along with changes from baseline in monthly sleep and fatigue scores over 52 weeks of continuous treatment.