Study to Assess Efficacy, Safety, Tolerability, Pharmacokinetics (PK), and Pharmacodynamics (PD) of Obeticholic Acid (OCA) Compared to Placebo in Pediatric Participants With Biliary Atresia, Post-hepatoportoenterostomy

Study Overview
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Brief Summary
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This study will evaluate the efficacy, safety and tolerability, as well as PK/PD of OCA in eligible pediatric participants with biliary atresia with successful hepatoportoenterostomy (HPE, also known as a Kasai portoenterostomy). The double-blind period comprises of 2 phases: dose titration phase and age expansion treatment phase.

Official Title
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A Randomized, Double-blind, Placebo-controlled, Phase 2/3 Study to Assess the Efficacy, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Obeticholic Acid Compared to Placebo in Pediatric Subjects With Biliary Atresia, Post-hepatoportoenterostomy

Conditions
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Biliary Atresia

Intervention / Treatment
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* Drug: OCA
* Drug: Matching Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Male or female pediatric participants from birth to <18 years old. Note: Participants aged <2 years old will not be enrolled until after review of safety data during the planned interim analysis and agreement from the Data Safety Monitoring Board (DSMB) that there is sufficient safety data to enroll this age group. Diagnosis of non-syndromic biliary atresia. Demonstrated successful HPE as defined by total bilirubin <2 milligrams per deciliter (mg/dL) (34.2 micromoles per liter [μmol/L]) at least 3 months post-HPE procedure. Exclusion criteria: Prior liver transplant or active status on transplant list. Participants diagnosed with biliary atresia splenic malformation (BASM). Conjugated (direct) bilirubin ≥ upper limit of normal (ULN) of site-specific reference range. If conjugated bilirubin is not available: total bilirubin ≥2 mg/dL (34.2 mol/L). Platelets <120,000/μL International normalized ratio (INR) ≥1.5. Current or history of complications of decompensated chronic liver disease including: 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 Any evidence of portal hypertension based on imaging (e.g., cavernous transformation of portal vein, abdominal varices, etc.) Hepatocellular carcinoma Childs-Pugh B or C Height and weight Z-score <-2 per site-specific reference ranges. Acholic (pale) stools. Aspartate aminotransferase (AST) >4x ULN. Alanine aminotransferase >4x ULN GGT >500 Units per Liter (U/L) On anticoagulation therapy Albumin <3.5 grams per deciliter (g/dL). Inability to swallow tablets (i.e., tablet or mini-tablet formulations).

Ages Eligible for Study
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Minimum Age: 1 Day
Maximum Age: 18 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: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Participants receiving OCA<br>Participants will be randomized to receive OCA (starting at 1.5 milligrams [mg] adult equivalent dose [AED]) orally, with water, once daily. Dose will be titrated every 2 weeks in a stepwise manner for the first 6 weeks, starting at 1.5 mg AED and titrating through 3 mg AED to a maximum of 5 mg AED, as tolerated; a discussion with the Medical Monitor is encouraged when determining uptitration if considerable signs or symptoms have arisen. Following the 6-week dose titration phase, participants will continue at the tolerated dose for approximately 24 months in Age Expansion Treatment Phase. | Drug: OCA<br>* OCA will be administered.<br>|
| Placebo Comparator: Participants receiving Matching placebo<br>Participants will be randomized to receive matching placebo orally, with water, once daily. Dose will be titrated every 2 weeks in a stepwise manner for the first 6 weeks, starting at 1.5 mg AED and titrating through 3 mg AED to a maximum of 5 mg AED, as tolerated; a discussion with the Medical Monitor is encouraged when determining uptitration if considerable signs or symptoms have arisen. Following the 6-week dose titration phase, participants will continue at the tolerated dose for approximately 24 months in Age Expansion Treatment Phase. | Drug: Matching Placebo<br>* Matching Placebo will be administered.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to the First Occurrence of Composite Endpoint | To evaluate the effect of OCA compared to placebo in conjunction with established local standard of care on clinical outcomes in participants with biliary atresia who have had a successful Kasai procedure as measured by time to first occurrence of any of the following adjudicated events, derived as composite event endpoint of all-cause death, liver transplant, Pediatric end-stage liver disease (PELD) score ≥17/model of end-stage liver disease (MELD)≥15, Hospitalization (as defined by a stay of 24 hours or greater) for new onset or recurrence of Variceal bleed, hepatic encephalopathy (as defined by a West Haven score of ≥2), Spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis) and Clinically evident ascites related to poral hypertension (diuretic-resistant ascites requiring therapeutic paracentesis at a frequency of at least twice in a month) | Up to Week 64 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma concentration of unconjugated OCA (parent), glyco-OCA, tauro-OCA, and total OCA (molar sum of OCA and its active conjugates) | Plasma concentrations of OCA and its conjugates (glyco-OCA and tauro-OCA) will be determined using validated liquid-chromatography mass spectrometry/mass spectrometry methods | Up to Week 64 | 
| Change from Baseline in Gamma Glutamyl Transferase (GGT) | Blood samples will be calculated to assess GGT levels. | Baseline and up to Week 64 | 
| Change from Baseline in total and direct (conjugated) bilirubin | Blood samples will be calculated to assess total and direct (conjugated) bilirubin levels. | Baseline and up to Week 64 | 
| Change from Baseline in Fibroblast Growth Factor-19 (FGF-19) | Blood samples will be calculated to assess FGF-19 | Baseline and up to Week 64 | 
| Change from Baseline in 7-hydroxyl-4-cholesten-3-one (C4) | Blood samples will be calculated to assess C4 | Baseline and up to Week 64 | 
| Change from Baseline in endogenous bile acids | Blood samples will be calculated to assess endogenous bile acids | Baseline and up to Week 64 | 
| Change from Baseline in liver stiffness as assessed by transient elastography |  | Baseline and up to Week 64 | 
| Change from Baseline in plasma levels of fat-soluble vitamins (D and K) | Blood samples will be calculated to assess plasma levels of fat-soluble vitamins (D and K) | Baseline and up to Week 64 | 
| Safety and tolerability as assessed by the incidence of treatment-emergent adverse events (TEAEs) including serious adverse events (SAEs) |  | Up to Week 64 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Biliary Atresia, Placebo-controlled, Pharmacokinetics, Pharmacodynamics, Obeticholic Acid, Efficacy, Post-hepatoportoenterostomy