Obeticholic Acid in Pediatric Subjects With Biliary Atresia

Study Overview
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Brief Summary
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This is a Phase 2, multicenter, open-label, single dose and multi-dose, dose-finding study with an optional open-label extension (OLE) to assess the safety, tolerability, and pharmacokinetics of obeticholic acid (OCA) in pediatric subjects with biliary atresia with successful hepatoportoenterostomy (HPE, also known as a Kasai portoenterosomy). The OLE will continue to evaluate safety, tolerability, pharmacodynamics, and efficacy of OCA. In addition, a change in vitamin A and D levels, and where possible the degree of change in liver stiffness, will be assessed during the OLE.

Official Title
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A Multicenter, Open-Label, Single- and Multiple-Dose, Dose-Finding Study, With an Optional Open-Label Extension to Assess the Safety, Tolerability, and Pharmacokinetics of Obeticholic Acid in Pediatric Subjects With Biliary Atresia

Conditions
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Biliary Atresia

Intervention / Treatment
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* Drug: OCA 0.1mg
* Drug: OCA 1.5mg
* Drug: OCA 5mg


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Male or female pediatric subjects ≥2 to <18 years old Diagnosis of biliary atresia Demonstrated successful HPE (also known as Kasai portoenterostomy) as defined by total bilirubin <2 mg/dL (34.2 μmol/L) at least 3 months post-HPE procedure. Able to swallow tablets (ie, tablet or mini-tablet formulation) Key Exclusion Criteria: Prior liver transplant or active status on transplant list Conjugated (direct) bilirubin ≥ULN of site specific reference range If conjugated bilirubin is not available: total bilirubin ≥2 mg/dL (34.2 μmol/L) Platelets <150,000/μL INR ≥1.5 Current or history of complications of decompensated chronic liver disease including: high-risk gastroesophageal varices and/or variceal bleeding clinically evident ascites related to portal hypertension hepatic encephalopathy prior placement of portosystemic shunt hepatopulmonary syndrome or portopulmonary hypertension hepatorenal syndrome Current intractable pruritus or requires systemic treatment for pruritus within 3 months of Screening (e.g., with bile acid sequestrants or rifampicin) Height and weight Z-score <-2 per site specific ranges Acholic (pale) stools AST >4x ULN ALT >4x ULN GGT >500 U/L Anticoagulation therapy Albumin <3.5 g/dL Ongoing current cholangitis Choledochal cystic disease Renal disease defined as serum creatinine >ULN for subject's age, prior to enrollment

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SD (1.5mg adult-equivalent dose of OCA) + MD Low dose (1.5mg adult-equivalent dose of OCA)<br>At Single Dose (SD) phase, eligible subjects will receive a 1.5 mg adult-equivalent, body weight-based single dose of OCA on Day 1. Enrollment in the Multiple Dose (MD) Phase will occur in a sequential fashion. At Day 28, the first 8 (±1) eligible subjects will be assigned to the Low Dose Cohort and will receive a 1.5 mg adult-equivalent dose of OCA daily for 4 weeks. The adult-equivalent dose is based on a 70-kg adult. 2 OCA tablet dose strength (0.1mg and 1.5mg) are available in the study and dose will be determined using weight based dosing chart. | Drug: OCA 0.1mg<br>* Tablets administered orally once daily.<br>* Other names: INT-747;Drug: OCA 1.5mg<br>* Tablets administered orally once daily.<br>* Other names: INT-747;|
| Experimental: SD (1.5mg adult-equivalent dose of OCA) + MD Medium dose (5mg adult-equivalent dose of OCA)<br>At Single Dose (SD) phase, eligible subjects will receive a 1.5 mg adult-equivalent, body weight-based single dose of OCA on Day 1. Upon safety and tolerability assessment in the Low Dose Cohort, 8 (±1) eligible subjects will be assigned to the Medium Dose Cohort and will receive a 5 mg adult-equivalent dose of OCA daily for 4 weeks. The adult-equivalent dose is based on a 70-kg adult. 3 OCA tablet dose strength (0.1mg, 1.5mg and 5mg tablets) are available in the study and dose will be determined using weight based dosing chart. | Drug: OCA 0.1mg<br>* Tablets administered orally once daily.<br>* Other names: INT-747;Drug: OCA 1.5mg<br>* Tablets administered orally once daily.<br>* Other names: INT-747;Drug: OCA 5mg<br>* Tablets administered orally once daily.<br>* Other names: INT-747;|
| Experimental: SD (1.5mg adult-equivalent dose of OCA) + MD High dose (10mg adult-equivalent dose of OCA)<br>At Single Dose (SD) phase, eligible subjects will receive a 1.5 mg adult-equivalent, body weight-based single dose of OCA on Day 1. Upon safety and tolerability assessment in the Medium Dose Cohort, 8 (±1) eligible subjects will be assigned to the High Dose Cohort and will receive a 10 mg adult-equivalent dose of OCA daily for 4 weeks. The adult-equivalent dose is based on a 70-kg adult. 3 OCA tablet dose strength (0.1mg, 1.5mg and 5mg tablets) are available in the study and dose will be determined using weight based dosing chart. | Drug: OCA 0.1mg<br>* Tablets administered orally once daily.<br>* Other names: INT-747;Drug: OCA 1.5mg<br>* Tablets administered orally once daily.<br>* Other names: INT-747;Drug: OCA 5mg<br>* Tablets administered orally once daily.<br>* Other names: INT-747;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability as assessed by the incidence of treatment-emergent adverse events (TEAEs) including serious adverse events (SAEs) |  | Day 1, 21, and 56. | 
| The plasma concentration of OCA and its conjugates (glyco-OCA and tauro-OCA) | Change in plasma concentrations of unconjugated OCA and its conjugates (glyco-OCA and tauro-OCA) will be quantitated, and total OCA concentration will be calculated in the SD and MD Phase. | Day 1, 21, and 56. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biomarkers of FXR-activation: change from baseline of the plasma value of Fibroblast Growth Factor-19 (FGF-19) |  | Day 1, 21, and 56 | 
| Biomarkers of FXR-activation: change from baseline of the plasma value of 7-hydroxyl-4-cholesten-3-one (C4) |  | Day 1, 21, and 56 | 
| Biomarkers of FXR-activation: change from baseline of the plasma value of Endogenous Bile Acids |  | Day 1, 21, and 56 | 
| Biomarkers of hepatobiliary function: Alkaline Phosphatase (ALP) |  | Time Frame: Day 1, 21, and 56 | 
| Biomarkers of hepatobiliary function: Aspartate Aminotransferase (AST) |  | Time Frame: Day 1, 21, and 56 | 
| Biomarkers of hepatobiliary function: Alanine Aminotransferase (ALT) |  | Time Frame: Day 1, 21, and 56 | 
| Biomarkers of hepatobiliary function: Gamma-Glutamyl Transpeptidase (GGT) |  | Time Frame: Day 1, 21, and 56 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Biliary Atresia, hepatoportoenterostomy (HPE), Kasai portoenterostomy, Liver, Obeticholic Acid