Efficacy and Safety of Obeticholic Acid in Pediatric Patients with Biliary Atresia Post-Hepatoportoenterostomy: A Randomized, Double-Blind, Placebo-Controlled Study

Trial ID: 2023-503926-37-00
Protocol: 747-308
Sponsor: Intercept Pharmaceuticals Inc.

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Diseases & Conditions

Congenital absence of bile ducts

Objectives

The primary objective of this study is to evaluate the effect of **obeticholic acid** (OCA) compared to placebo on clinical outcomes in pediatric subjects with biliary atresia who have undergone a successful Kasai procedure. This is measured by the time to the first occurrence of any component of a composite endpoint, which includes adjudicated events such as all-cause death, liver transplant, a Pediatric End-Stage Liver Disease (PELD) score of ≥17 or Model for End-Stage Liver Disease (MELD) score of ≥15, hospitalization for new onset or recurrence of variceal bleed, hepatic encephalopathy (West Haven score of ≥2), spontaneous bacterial peritonitis, and clinically evident ascites related to portal hypertension. The clinical relevance of this objective lies in its potential to improve long-term outcomes and quality of life for children with biliary atresia by delaying or preventing severe liver-related complications.

Secondary objectives include: - Evaluating the pharmacokinetics of OCA through measurements of unconjugated plasma OCA, glyco-OCA, tauro-OCA, and total OCA. - Assessing the pharmacodynamics of OCA by measuring biomarkers of farnesoid X receptor (FXR) activation, including plasma fibroblast growth factor 19 (FGF-19), 7-hydroxy-4-cholesten-3-one (C4), and endogenous bile acids. - Monitoring biomarkers of hepatobiliary function such as gamma-glutamyl transferase (GGT) and bilirubin levels. - Investigating the effect of OCA on liver stiffness using transient elastography. - Evaluating disease progression through plasma levels of fat-soluble vitamins D and K. - Assessing the safety and tolerability of OCA.

Participants

The clinical trial involves a total of **94 participants** diagnosed with **biliary atresia** who have undergone a successful Kasai procedure. The study population includes both male and female pediatric subjects ranging from birth to under 18 years of age. However, subjects under 2 years old will only be enrolled following a safety review and approval by the Data Safety Monitoring Board (DSMB). Participants are required to have demonstrated successful hepatoportoenterostomy (HPE), indicated by a total bilirubin level of less than 2 mg/dL at least three months post-procedure. The trial includes a vulnerable population, and both genders are represented. Participants' general health status is characterized by their post-HPE condition, and lifestyle considerations such as diet and physical activity are not specified. The selection process for the trial population is based on specific inclusion criteria, including the requirement for female subjects of childbearing potential to use highly effective contraception methods. The trial does not provide additional information on lifestyle factors or other health conditions beyond the primary diagnosis.

Plans and Procedures

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the efficacy, safety, tolerability, pharmacokinetics, and pharmacodynamics of **obeticholic acid** in pediatric subjects with biliary atresia, post-hepatoportoenterostomy. The trial is categorized as a Phase II/III study and is not considered low intervention. The trial is expected to commence recruitment on April 1, 2024, and conclude by February 29, 2028. Participants will be randomly assigned to receive either obeticholic acid or placebo, administered orally in tablet form. The maximum treatment period for participants is 24 months, with a maximum daily dose of 5 mg and a total dose not exceeding 3650 mg.

The study involves several key visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, diagnosis of non-syndromic biliary atresia, and successful hepatoportoenterostomy (HPE). Follow-up visits will be scheduled to monitor clinical outcomes, including time to first occurrence of events such as death, liver transplant, or hospitalization due to complications like variceal bleed or hepatic encephalopathy. The end-of-study visit will evaluate the primary and secondary endpoints, including pharmacokinetic exposure and biomarkers of hepatobiliary function.

Participant involvement is expected to last up to 24 months, with conditions for early termination including the occurrence of severe adverse events or non-compliance with the study protocol. The study aims to provide comprehensive data on the clinical outcomes and safety profile of obeticholic acid in this pediatric population, contributing to the understanding of its potential therapeutic benefits in managing biliary atresia post-HPE.

Treatment

The clinical trial involves the administration of **obeticholic acid** in two different formulations. The first experimental medication is OCA IR 0.1 mg, which is presented in a **tablet** form. This formulation is designed for **oral use** and is specifically tailored for pediatric patients. The active substance, obeticholic acid, is a chemical compound also known by synonyms such as DSP-1747, INT-747, and 6-alpha-ethylchenodeoxycholic acid. The maximum daily dose for this formulation is 5 mg, with a total maximum dose of 3650 mg over a treatment period of 24 weeks. The medication is manufactured by Intercept Pharmaceuticals Inc.

The second experimental medication is OCA 1.5 mg, also in **tablet** form and intended for **oral use**. Similar to the 0.1 mg formulation, it is a pediatric formulation containing the same active substance, obeticholic acid. The dosing regimen for this formulation is consistent with the 0.1 mg version, with a maximum daily dose of 5 mg and a total maximum dose of 3650 mg over 24 weeks. This formulation is also produced by Intercept Pharmaceuticals Inc.

The study includes a **placebo** group, which involves the administration of placebo tablets corresponding to the 0.1 mg and 1.5 mg active formulations. These placebo tablets are used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments. The placebo tablets do not contain any active substance and are not specifically formulated for pediatric use.

Efficacy

The efficacy of **obeticholic acid** in the clinical trial will be assessed through a composite primary endpoint. This endpoint includes the time to the first occurrence of any of the following clinical events: death (all-cause), liver transplant, a Pediatric End-Stage Liver Disease (PELD) score of ≥17 or Model for End-Stage Liver Disease (MELD) score of ≥15, hospitalization for new onset or recurrence of variceal bleed, hepatic encephalopathy (defined by a West Haven score of ≥2), spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis), and clinically evident ascites related to portal hypertension requiring therapeutic paracentesis at least twice a month.

Secondary endpoints will include pharmacokinetic (PK) exposure of obeticholic acid, measured as plasma levels of unconjugated obeticholic acid, glyco-obeticholic acid, tauro-obeticholic acid, and total obeticholic acid. Biomarkers of hepatobiliary function such as gamma-glutamyl transferase (GGT), total and direct bilirubin, and biomarkers of FXR activation like plasma FGF-19, C4, and endogenous bile acids will also be evaluated. Noninvasive assessment of liver stiffness through transient elastography, if available, and plasma levels of fat-soluble vitamins (D and K) will be monitored to assess disease progression. Safety and tolerability will be evaluated by monitoring treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), electrocardiogram (ECG) results, physical exams, clinical laboratory results, and vital signs.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Male or female pediatric subjects from birth to <18 years old Note: Subjects aged <2 years old will not be enrolled until after review of safety data during the planned interim analysis and agreement from the 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 mg/dL (34.2 μmol/L) at least 3 months post-HPE procedure.
Female subjects of childbearing potential must use ≥1 highly effective method (≤1% failure rate) of contraception from the initiation of Screening and until at least 20 days (5 half-lives), after the last dose of investigational product. Highly effective methods of contraception are considered to be those listed below: • Surgical sterilization (bilateral tubal occlusion, etc.) • Placement of an intrauterine device (IUD) or intrauterine system (e.g., intrauterine hormone-releasing system [IUS]). • Combined (estrogen and progesterone containing) hormonal contraceptive associated with inhibition of ovulation: − Oral − Intravaginal − Transdermal • Progesterone-only hormonal contraception associated with inhibition of ovulation: − Oral − Injectable − Implantable • In the context of this study, the goal of using a highly effective contraception method is to avoid the potential embryofetal risks from exposure to investigational medicinal products. Sexual abstinence, as a form of highly effective contraception, is defined as avoiding all types of sexual activity that could result in pregnancy during the entire period of the study treatment until at least 20 days (5 half-lives), after the last dose of investigational product. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study.
Male subjects who are sexually active with female partners of childbearing potential must agree to use a condom with spermicide and to use one other approved method of highly effective contraception from the time of initiation of the investigational product administration and until at least 20 days (5 half-lives), after the last dose of investigational product.
Male subjects, if permitted to donate sperm per local regulations, must refrain from sperm donation from Screening through at least 20 days (5 half-lives) after the last dose of investigational product.
Parent or guardian is willing to provide written informed consent and when appropriate, the subject is willing to assent and agree to comply with the study protocol.

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Exclusion Criteria

Prior liver transplant or active status on transplant list
Alanine aminotransferase >4x ULN
GGT >500 U/L
Anticoagulation therapy
Albumin <3.5 g/dL
Inability to swallow tablets (i.e., tablet or mini-tablet formulations)
Subjects 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 μmol/L)
Platelets <120,000/μL
International normalized ratio (INR) ≥1.5
Current or history of complications of decompensated chronic liver disease including: a.) gastroesophageal varices and/or variceal bleeding; b.) clinically evident ascites related to portal hypertension; c.) hepatic encephalopathy; d.) prior placement of portosystemic shunt; e.) hepatopulmonary syndrome or portopulmonary hypertension; f.) hepatorenal syndrome; g.) any evidence of portal hypertension based on imaging (e.g., cavernous transformation of portal vein, abdominal varices, etc.); h.) Hepatocellular carcinoma; i.) Childs-Pugh B or C
Height and weight Z-score <-2 per site-specific reference ranges
Acholic (pale) stools
Aspartate aminotransferase (AST) >4x ULN
History of known or suspected clinically significant hypersensitivity to OCA or any of its excipients
If female, known pregnancy, or has a positive urine pregnancy test (confirmed by a positive serum pregnancy test), or lactating
Subjects who are committed to an institution by virtue of an order issued either by the judicial or administrative authorities per local regulations
Subjects who are children of or related to investigational site staff members, site staff members otherwise supervised by the investigator, or sponsor employees directly involved in the conduct of the study

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Belgium	Not Recruiting	01 Apr 2024	4
France	Not Yet Recruiting	01 Apr 2024	5
Germany	Not Recruiting	01 Apr 2024	10
Italy	Not Recruiting	01 Apr 2024	11
The Netherlands	Not Recruiting	01 Apr 2024	—
Poland	Not Recruiting	01 Apr 2024	9
Spain	Not Recruiting	01 Apr 2024	7
Netherlands	—	—	4