Efficacy and Safety Evaluation of Odevixibat in Pediatric Biliary Atresia Post-Kasai Hepatoportoenterostomy: A Double-Blind, Randomized, Placebo-Controlled Trial

The primary objective of this study is to evaluate the **efficacy** of repeated once-daily doses of odevixibat versus placebo in children with **biliary atresia** post Kasai hepatoportoenterostomy, based on native liver survival (NLS) for up to 104 weeks. This is clinically relevant as it aims to determine the potential of odevixibat to improve long-term liver function and survival in pediatric patients who have undergone this surgical procedure.

Secondary objectives include:

• To evaluate the effect of odevixibat compared to placebo on the time to onset of sentinel events.
• To evaluate the effect of odevixibat compared to placebo on total bilirubin levels after 13, 26, 52, and 104 weeks.
• To evaluate the effect of odevixibat compared to placebo on serum bile acids after 13, 26, 52, and 104 weeks.
• To assess the long-term safety and tolerability of repeated daily doses of odevixibat compared to placebo for 104 weeks in children with biliary atresia post Kasai hepatoportoenterostomy.

The clinical trial involves a total of **163 participants** diagnosed with **biliary atresia**. The study population includes both male and female subjects who have undergone Kasai hepatoportoenterostomy (HPE) and are eligible to start treatment within three weeks post-surgery. Participants are selected based on their clinical diagnosis of biliary atresia and must have had the Kasai HPE performed at an age of 90 days or younger. The trial focuses on a vulnerable population, given the young age and specific medical condition of the participants. The study does not specify any particular lifestyle considerations such as diet or physical activity. The selection criteria ensure that the participants are representative of the target population for evaluating the efficacy of odevixibat in improving native liver survival in children with biliary atresia.

The clinical trial is designed to evaluate the **efficacy** and safety of **odevixibat** in children diagnosed with **biliary atresia** who have undergone a Kasai hepatoportoenterostomy. This is a double-blind, randomized, placebo-controlled study, ensuring that neither the participants nor the researchers know who is receiving the active treatment or the placebo, thus minimizing bias. The trial is set to last for a maximum of 104 weeks, with the primary objective being to assess native liver survival during this period.

Participants will be randomly assigned to receive either odevixibat or a matching placebo, administered orally in capsule form. The study will commence with an inclusion visit, where eligibility criteria such as age at Kasai HPE (≤90 days) and the ability to start treatment within three weeks post-surgery will be confirmed. Following randomization, participants will undergo regular follow-up visits at specified intervals, including assessments at 13, 26, 52, and 104 weeks. These visits will involve monitoring of primary and secondary endpoints, such as time to liver transplant or death, total bilirubin levels, and serum bile acid levels.

The end-of-study visit will mark the conclusion of the participant's involvement, provided they have not reached any endpoints that necessitate early termination, such as liver transplant or death. Participants may also be withdrawn from the study if they experience significant adverse events or if they no longer meet the study criteria. The expected length of participant involvement is up to 104 weeks, contingent upon their health status and adherence to the study protocol.

The clinical trial involves the administration of **odevixibat**, an experimental medication, under the product name A4250. Odevixibat is provided in the form of a capsule and is intended for **oral use**. The medication is administered once daily, with a maximum daily dose of 120 µg/kg. The total maximum dose over the treatment period is 87,360 µg/kg. The treatment period extends up to 104 weeks. Odevixibat is a chemical substance developed by Albireo AB and is designated as an orphan drug with the designation number EU/3/18/2103. The formulation is specifically designed for pediatric use.

The study also includes a **placebo** group, which receives capsules that are visually identical to the odevixibat capsules but contain no active treatment. These placebo capsules are hard, white, opaque, and filled with pellets, intended for oral administration. The placebo serves as a comparator to evaluate the efficacy and safety of odevixibat in the study population. The placebo is not a pediatric formulation and does not contain any active substances.

The efficacy of odevixibat in the clinical trial will be assessed using several primary and secondary endpoints. The primary efficacy endpoint is the time from randomization to the first occurrence of liver transplant or death during the 104-week treatment period. This endpoint is crucial for evaluating the impact of odevixibat on native liver survival in children with **biliary atresia** who have undergone a Kasai hepatoportoenterostomy.

Secondary endpoints include the proportion of patients who are alive and have not undergone a liver transplant after 104 weeks, and the time to onset of the first sentinel event during the 104-week treatment period. Additional secondary endpoints involve measuring total bilirubin and serum bile acid levels at 13, 26, 52, and 104 weeks, as well as the time to a pediatric end-stage liver disease (PELD) score of 15 or higher. Safety parameters, including adverse events (AEs), serious adverse events (SAEs), findings from physical examinations, laboratory assessments (such as fat-soluble vitamins and lipids), and abdominal ultrasound results, will also be monitored.