An Open-label Extension Study to Evaluate Long-term Efficacy and Safety of Odevixibat (A4250) in Children with Biliary Atresia (BOLD-EXT)

The primary objective of this study is to demonstrate a sustained effect of **odevixibat** on native liver survival (NLS) in children with **biliary atresia** who have completed study A4250-011 (BOLD). This is clinically relevant as it aims to prolong the function of the native liver, potentially reducing the need for liver transplantation in this pediatric population.

Secondary objectives include:

• Demonstrating a sustained effect of odevixibat on serum bile acids and prevention of liver fibrosis in children with biliary atresia.
• Evaluating the effect of odevixibat on lowering serum bile acids in patients who previously received placebo in Study A4250-011.
• Assessing the long-term safety and tolerability of repeated daily doses of odevixibat.
• Evaluating the effect of odevixibat on growth.
• Assessing the effect of odevixibat on sentinel events, defined as clinically significant ascites, bleeding gastroesophageal varices, thrombocytopenia (platelet count <150,000/μL), liver transplant, or death.

The clinical trial involves a total of **127 participants** diagnosed with **Biliary Atresia**, a rare liver disease. The study population includes both male and female subjects, with an age range that corresponds to pediatric patients. Participants were selected based on their completion of a prior study, A4250-011 (BOLD), and the trial focuses on evaluating the sustained effect of odevixibat on native liver survival. The trial population is considered vulnerable due to the pediatric nature of the participants. Lifestyle considerations such as diet and physical activity are not specified in the available data. The selection criteria emphasize the completion of a specific treatment period in a previous study, ensuring that participants have a consistent treatment history. The sponsor has not provided additional information regarding specific lifestyle factors or other health status details.

The clinical trial is designed to evaluate the long-term efficacy and safety of **odevixibat** in children with **biliary atresia** who have completed a prior study. This is an open-label extension study, which means that both the researchers and participants know which treatment is being administered. The trial aims to demonstrate a sustained effect of odevixibat on native liver survival. The study is expected to run until December 2029, with recruitment having started in December 2022.

Participants eligible for this trial must have completed the 104-week treatment period of the previous study, A4250-011. The primary endpoint is the time from the first dose of the study treatment to the first occurrence of liver transplant or death. Secondary endpoints include changes in various liver function scores and growth parameters over the course of the study.

The trial involves multiple study visits, starting with an inclusion (screening) visit to confirm eligibility. Follow-up visits are scheduled at Weeks 4, 13, 26, 39, 52, 78, and 104 to monitor changes in liver function and growth. The end-of-study visit will occur at the conclusion of the 104-week treatment period. Participants are expected to be involved in the study for the entire duration unless conditions arise that necessitate early termination, such as adverse effects or withdrawal of consent.

The investigational product, A4250, is administered orally in capsule form, with a maximum daily dose of 120 µg/kg. The study is not classified as low intervention and is categorized as a Phase III trial. The trial is specifically designed for a pediatric population, and the formulation of the investigational product is suitable for this demographic. The study is conducted under the sponsorship of Albireo AB, and the investigational product has been designated as an orphan drug, highlighting its use in treating a rare disease.

The clinical trial involves the administration of the experimental medication **A4250**, which contains the active substance **odevixibat**. This medication is provided in the form of a **capsule** and is intended for oral administration. The dosage is specified as 120 µg/kg microgram(s)/kilogram, with a maximum daily dose of 120 µg/kg. The treatment period is set for a maximum of 60 days. The formulation is specifically designed for pediatric use and is classified as an orphan drug, with the designation number EMA/OD/165/18. The medication is produced by ALBIREO AB and is identified by the sponsor product code A4250.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are mentioned. The focus is solely on evaluating the long-term efficacy and safety of odevixibat in children with biliary atresia. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen. The trial aims to demonstrate a sustained effect of odevixibat on native liver survival in the target population.

The efficacy of the clinical trial evaluating **odevixibat** in children with biliary atresia will be assessed through a series of primary and secondary endpoints. The primary endpoint is defined as the time from the date of the first dose of the study treatment to the first occurrence of liver transplant or death. This endpoint is crucial for determining the long-term efficacy of the treatment in maintaining native liver survival.

Secondary endpoints include several parameters measured at specific timepoints throughout the trial. These include changes in the aspartate aminotransferase (AST) to platelet ratio index (APRI) score and the fibrosis-4 (Fib-4) score from baseline to Weeks 4, 13, 26, 39, 52, 78, and 104. Additionally, changes in serum bile acids will be assessed at Weeks 26, 52, 78, and 104. Growth changes, defined as linear growth deficit compared to a standard growth curve, will be evaluated at Weeks 26, 52, 78, and 104. The time to onset of the first sentinel event during the 104-week treatment period and changes in the pediatric end-stage liver disease (PELD) score at specified intervals will also be measured. Furthermore, the proportion of patients who are alive and have not undergone a liver transplant at Weeks 26, 52, 78, and 104 will be recorded.

These efficacy parameters will be collected and analyzed at predetermined intervals to provide a comprehensive assessment of the treatment's impact on disease progression and patient outcomes. The use of validated scales and laboratory tests will ensure the reliability and accuracy of the data collected during the trial.