Obeticholic Acid in Pediatric Subjects With Biliary Atresia (CARE)

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

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.

Study Overview

• Status: Terminated
• Conditions: Biliary Atresia
• Intervention / Treatment: Drug: OCA 0.1mg; Drug: OCA 1.5mg; Drug: OCA 5mg

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Brussel, Belgium, 1200
    • Clinques University Saint-Luc
• France
  • Paris, France, 75015
    • APHP- Hopital Necker Enfants Malades
  • Toulouse, France, 31059
    • CHU de Toulouse Purpan-Hopital des Enfants
  • ME
    • Lille, ME, France, 59037
      • CHU Lille
  • Paca
    • Marseille, Paca, France, 13385
      • Hôpital de la Timone
• Germany
  • Lower Saxony
    • Hannover, Lower Saxony, Germany, 30625
      • Hannover Medical School, Children's Hospital, Paediatric Gastroenterology and Hepatology,
• Israel
  • Beer Sheva, Israel, 84101
    • Soroka University Medical Center
  • Jerusalem, Israel, 91120
    • Hadassah Medical Center
  • Jerusalem, Israel, 9103102
    • Shaare-Zedek Medical Center
  • Petach Tikva, Israel, 4920235
    • Schneider Children's Medical Center
• Italy
  • Bergamo, Italy, 24127
    • Centre for Paediatric Hepatology
  • Turin, Italy, 10126
    • Regina Margherita Children's Hospital
• Netherlands
  • Groningen, Netherlands, 9713 GZ
    • University Medical Center Gröningen-Beatrix, children's Hospital
• Poland
  • Warsaw, Poland
    • Instytut Pomnik-Centrum Zdrowia Dziecka
• Spain
  • Barcelona, Spain
    • Passeig Vall d'Hebron
  • Málaga, Spain
    • Hospital Materno-Infantil de Malaga
• United Kingdom
  • West Midlands
    • Birmingham, West Midlands, United Kingdom, B4 6NH
      • Birmingham Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Key Inclusion Criteria:

1. Male or female pediatric subjects ≥2 to <18 years old
2. Diagnosis of biliary atresia
3. 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.
4. Able to swallow tablets (ie, tablet or mini-tablet formulation)

Key Exclusion Criteria:

1. Prior liver transplant or active status on transplant list
2. Conjugated (direct) bilirubin ≥ULN of site specific reference range
3. If conjugated bilirubin is not available: total bilirubin ≥2 mg/dL (34.2 μmol/L)
4. Platelets <150,000/μL
5. INR ≥1.5

6. Current or history of complications of decompensated chronic liver disease including:

   1. high-risk gastroesophageal varices and/or variceal bleeding
   2. clinically evident ascites related to portal hypertension
   3. hepatic encephalopathy
   4. prior placement of portosystemic shunt
   5. hepatopulmonary syndrome or portopulmonary hypertension
   6. hepatorenal syndrome
7. Current intractable pruritus or requires systemic treatment for pruritus within 3 months of Screening (e.g., with bile acid sequestrants or rifampicin)
8. Height and weight Z-score <-2 per site specific ranges
9. Acholic (pale) stools
10. AST >4x ULN
11. ALT >4x ULN
12. GGT >500 U/L
13. Anticoagulation therapy
14. Albumin <3.5 g/dL
15. Ongoing current cholangitis
16. Choledochal cystic disease
17. Renal disease defined as serum creatinine >ULN for subject's age, prior to enrollment

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

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); 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; Tablets administered orally once daily.; Other Names: INT-747; 6alpha-ethylchenodeoxycholic acid (6-ECDCA); Obeticholic Acid; Drug: OCA 1.5mg; Tablets administered orally once daily.; Other Names: INT-747; 6alpha-ethylchenodeoxycholic acid (6-ECDCA)
Experimental: SD (1.5mg adult-equivalent dose of OCA) + MD Medium dose (5mg adult-equivalent dose of OCA); 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; Tablets administered orally once daily.; Other Names: INT-747; 6alpha-ethylchenodeoxycholic acid (6-ECDCA); Obeticholic Acid; Drug: OCA 1.5mg; Tablets administered orally once daily.; Other Names: INT-747; 6alpha-ethylchenodeoxycholic acid (6-ECDCA); Drug: OCA 5mg; Tablets administered orally once daily.; Other Names: INT-747; 6alpha-ethylchenodeoxycholic acid (6-ECDCA)
Experimental: SD (1.5mg adult-equivalent dose of OCA) + MD High dose (10mg adult-equivalent dose of OCA); 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; Tablets administered orally once daily.; Other Names: INT-747; 6alpha-ethylchenodeoxycholic acid (6-ECDCA); Obeticholic Acid; Drug: OCA 1.5mg; Tablets administered orally once daily.; Other Names: INT-747; 6alpha-ethylchenodeoxycholic acid (6-ECDCA); Drug: OCA 5mg; Tablets administered orally once daily.; Other Names: INT-747; 6alpha-ethylchenodeoxycholic acid (6-ECDCA)

What is the study measuring?

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	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

Collaborators and Investigators

• Sponsor: Intercept Pharmaceuticals
• Investigators: Study Director: Lynda Szczech, MD, Intercept Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2015
• Primary Completion (Actual): March 9, 2023
• Study Completion (Actual): March 9, 2023

Study Registration Dates

• First Submitted: March 18, 2022
• First Submitted That Met QC Criteria: April 4, 2022
• First Posted (Actual): April 11, 2022

Study Record Updates

• Last Update Posted (Actual): March 28, 2023
• Last Update Submitted That Met QC Criteria: March 24, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: Liver; Biliary Atresia; Kasai portoenterostomy; hepatoportoenterostomy (HPE); Obeticholic Acid
• Additional Relevant MeSH Terms: Digestive System Diseases; Congenital Abnormalities; Biliary Tract Diseases; Bile Duct Diseases; Digestive System Abnormalities; Biliary Atresia; Gastrointestinal Agents; Cathartics; Chenodeoxycholic Acid
• Other Study ID Numbers: 747-206

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No