Long-term Safety and Efficacy Evaluation of Odevixibat in Alagille Syndrome Patients Completing Study A4250-012 (ASSERT)

The primary objective of this study is to demonstrate a sustained effect of **odevixibat** on pruritus in patients with Alagille Syndrome (ALGS) who have completed study A4250-012 (ASSERT). Pruritus is a significant clinical symptom in ALGS, often leading to considerable discomfort and impacting the quality of life. Addressing this symptom effectively can improve patient outcomes and overall well-being.

Secondary objectives include:

• To demonstrate a sustained effect of odevixibat on serum bile acids in patients with ALGS who have completed study A4250-012. This is clinically relevant as elevated bile acids are associated with liver dysfunction in ALGS.
• To evaluate the effect of odevixibat on parameters related to quality of life, which is crucial for understanding the broader impact of the treatment on patient health and daily functioning.
• To evaluate the long-term safety and tolerability of repeated daily doses of odevixibat in patients with ALGS, ensuring that the treatment is not only effective but also safe for prolonged use.

The clinical trial involves a total of **15 participants** diagnosed with **Alagille Syndrome**. The study population includes both male and female subjects, with an age range corresponding to categories 2 and 3, indicating a pediatric and adolescent demographic. Participants were selected based on their completion of the 24-week Treatment Period of Study A4250-012, and they must have provided signed informed consent and assent as appropriate. The trial population includes a vulnerable group, necessitating careful ethical considerations. Participants are required to be willing and able to use an electronic diary device as part of the study protocol. Additionally, sexually active participants must agree to use a reliable contraceptive method throughout the study duration and for 90 days following the last dose of the study drug. The trial does not specify any particular lifestyle considerations such as diet or physical activity.

The clinical trial is designed to evaluate the long-term safety and efficacy of **odevixibat** in patients with Alagille Syndrome. This study is an open-label, Phase III trial, which means that both the researchers and participants know which treatment is being administered. The trial is expected to last until April 16, 2027, with recruitment having started on January 14, 2022. Participants will be involved in the study for a maximum treatment period of 72 weeks. The trial involves the administration of KAYFANDA hard capsules, containing varying doses of odevixibat, taken orally.

The sequence of study visits begins with an inclusion (screening) visit, where eligibility is confirmed based on criteria such as the completion of a prior study (A4250-012), informed consent, and the ability to use an electronic diary device. Follow-up visits are scheduled throughout the study to monitor changes in pruritus, serum bile acid levels, and other health parameters. These visits will assess primary and secondary endpoints, including changes in scratching severity, sleep parameters, and quality of life scores. The end-of-study visit will conclude the participant's involvement, evaluating the overall impact of the treatment.

Participants are expected to remain in the study for the full duration unless conditions arise that necessitate early termination. Such conditions may include adverse reactions to the treatment, withdrawal of consent, or failure to adhere to study protocols. The trial aims to provide comprehensive data on the sustained effects of odevixibat, contributing valuable insights into its therapeutic potential for Alagille Syndrome.

The clinical trial involves the administration of **KAYFANDA** hard capsules, which contain the active substance **odevixibat**. The pharmaceutical form of the medication is a hard capsule, and it is available in four different dosages: 200 micrograms, 400 micrograms, 600 micrograms, and 1,200 micrograms. The capsules are intended for **oral use**. The maximum daily dose is 120 micrograms per kilogram of body weight, and the treatment period can extend up to 72 weeks. The active substance, odevixibat, is a chemical compound also known by synonyms such as AR-H064074, AZD8294, and A4250. The medication is manufactured by IPSEN PHARMA and is authorized for use in the European Union.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on evaluating the long-term safety and efficacy of odevixibat in patients with Alagille Syndrome. 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 pruritus in patients who have completed a previous study, A4250-012 (ASSERT).

The efficacy of the investigational product, **odevixibat**, in patients with Alagille Syndrome will be assessed through a series of primary and secondary endpoints over a 72-week period. The primary endpoint focuses on the change from baseline in scratching, as measured by the Albireo Observer-Reported Outcome (ObsRO) caregiver instrument. This assessment will provide insights into the sustained effect of odevixibat on pruritus, a common symptom in Alagille Syndrome.

Secondary endpoints include a variety of measures to comprehensively evaluate the efficacy of the treatment. These include:

• Change in serum bile acid levels from baseline to Week 72.
• Change from baseline through Week 72 in patient-reported and observer-reported itching and scratching severity scores for morning and evening assessments.
• Percentage of patients achieving a clinically meaningful decrease in pruritus at each visit, as measured by the Albireo ObsRO/patient-reported outcomes (PRO) instruments.
• Change from baseline to Week 72 in sleep parameters, including tiredness and number of awakenings, measured with the Albireo ObsRO/PRO instruments.
• Change from baseline to Week 72 in Pediatric Quality of Life Inventory (PedsQL) scores.
• Assessment of Global Symptom Relief from baseline to Weeks 4, 12, 24, 48, and 72, as measured by patient, caregiver, and clinician Global Impression of Symptoms (PGIS, CaGIS, CGIS) items.
• Assessment of Global Symptom Relief as measured by patient, caregiver, and clinician Global Impression of Change (PGIC, CaGIC, CGIC) items at Weeks 4, 12, 24, 48, and 72.

The efficacy assessments will be conducted using validated tools and instruments, ensuring the reliability and accuracy of the data collected. The schedule for these assessments is structured to capture both short-term and long-term effects of the treatment, with key timepoints at Weeks 4, 12, 24, 48, and 72. This comprehensive approach aims to provide a detailed understanding of the therapeutic impact of odevixibat on patients with Alagille Syndrome.