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.;Trial Acronym: ObetiCholic Acid in Pediatric Subjects with BiliaRy AtrEsia (CARE)

Biliary atresia is a disease of early infancy manifest by biliary obstruction
due to maldevelopment of the biliary tree, which is fatal without
hepatoportoenterostomy (HPE, also known as Kasai procedure). Following HPE, the
children progress along 2 paths: around half of the infants fail to get
adequate biliary drainage from their HPE procedure and they either receive
a liver transplant by 2 years of age or they die. In the other patients, those
who exhibit a good
response to the surgical HPE procedure, develop a progressive fibrotic disease
over the ensuing years. Nearly all of these patients develop cirrhosis by the
time they are 18 years old.
An essential regulator of bile acid homeostasis is the farnesoid X receptor
(FXR) which is a nuclear receptor expressed in multiple tissues, including the
liver and intestine. FXR is activated by endogenous bile acids and regulates
key response elements in both synthesis and release of bile acids by the liver.
Cholestatic conditions which impair delivery of bile acids to the intestine
greatly diminish the activation of intestinal FXR and, consequently, bile acid
synthesis is no longer properly regulated leading to sustained elevations in
hepatic bile acids.
Aside from HPE, there are no approved medicinal treatments for BA. OCA has
exhibited anti-cholestatic and hepatoprotective properties in in vitro and in
vivi studies. Based on the pathologic mechanisms leading to cholestasis and
fibrosis in chronic liver diseases, it is hypothesized that treatment with OCA
will improve liver function.

Primary Objectives
• Safety and tolerability
• PK of OCA and its conjugates
o SD PK Phase: To assess the PK of OCA and its conjugates after a single
low dose of OCA on Day 1 and determine subject eligibility for the MD
Phase
o MD Phase: To assess the steady-state PK of OCA and its conjugates for a
range of OCA doses

Secondary Objectives
• Pharmacodynamics (PD) of OCA as measured by markers of farnesoid X receptor
(FXR) activation and the biomarkers of hepatobiliary function

Exploratory Objectives
• Acceptability and swallowability
• Palatability (MD Phase only)

OLE Phase Objectives
• Long-term safety and tolerability
• Durability of the PD of OCA as measured by markers of FXR activation and the
biomarkers of hepatobiliary function
• Levels of vitamins A and D
• Noninvasive assessment of liver stiffness (e.g., FibroScan® transient
elastography [TE] or other ultrasound elastography of the liver) based on site
availability

This is a multicenter, open-label, SD and MD, dose-finding study followed by an
optional OLE to evaluate the safety, tolerability, PK, and PD of a range of OCA
doses in eligible pediatric subjects with biliary atresia with successful
hepatoportoenterostomy (HPE, also known as a Kasai portoenterosomy). The OLE
will continue to evaluate safety, tolerability, PD, 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.

Single- Dose (SD) Phase: All participants will receive an OCA dose equivalent
to 1.5- mg dose for an adult on Day 1, and on the basis of blood test results
taken after that single OCA dose, the dose for the MD-phase for the patient
will be determined.

Multi- Dose (MD) Phase: The patient will be assigned to 1 of three dose
groups: low (1.5 mg adult-equivalent), medium (5 mg adult-equivalent) or high
(10 mg adult-equivalent). The study doctor will explain to you which group you
will be assigned to. Patient will take that assigned dose every day for 28
days.

Phase Group assignments (adult equivalent dose)
Category 1
A 1.5 mg, once daily
B 5 mg, once daily
C 10 mg, once daily
Category 2
D 1.5 mg, once daily
E 5 mg, once daily
Category 3
F 1.5 mg, once daily
Category 4
G 0.75 mg, once daily
Category 5
H 0.75 mg, twice a week

Following HPE (hepatoportoenterostomy, also known as Kasai procedure), children
progress along 2 paths: around half of the infants fail to get adequate biliary
drainage from their HPE procedure and they either receive a liver transplant by
2 years of age or they die. In the other patients, those who exhibit a good
response to the surgical HPE procedure, develop a progressive fibrotic disease
over the ensuing years. Nearly all of these patients develop cirrhosis by the
time they are 18 years old.

Biliary tract occlusion with Biliary Atresia causes a rise in endogenous bile
acids to cytotoxic levels, causing inflammatory damage, an increase in
hepatocellular enzymes and apoptosis which over time results in hepatic
fibrosis and cirrhosis.
Obeticholicacid being a modified bile acid, and FXR agonist protects the liver
by:
- Regulation of bile synthesis and flow resulting in less cholestasis
- Inhibition of inflammation (in the liver and the rest of the body)
- Prevention of and/or reversal of scarring (i.e., fibrosis and/or cirrhosis)
- Prevention of and/or reduction in portal hypertension (i.e., high blood
pressure in the liver that causes numerous complications)

Based on the pathologic mechanisms in Biliary Atresia post-HPE, it is
hypothesized that treatment with OCA may improve survival with subject*s native
liver, prevent the onset of cirrhosis and subsequently delay/prevent liver
transplant.

Aside from HPE, there are no approved medicinal treatments for Biliary Atresia.
Moreover, as this is a rare disease ( in The Netherlands, approximately 10 new
patients per year), relatively little is known on this disease.

There are up to 15 scheduled visit (including screening visit) expected in this
trial. There is a 3-day visit and three 2-day visits where the subject will
have to stay overnight at the UMCG or stay nearby and return early next
morning. the second day for the 3 day visit and the first day for the other 3
overnight stays will be a PK day where the patient will have to stay at the
clinic about 8 hours before being released for the day. The following day the
patient will have to return the next day for a 24 hour blood sample. If the
patient is local, the burden of missing school and parents missing full day*s
work may be minimized. If the subject is not local this burden may increase.
The overnight stay at the clinic are not mandatory, but preferred, depending on
patients proximity to the site.

Due to the burden of number of visits on a family and their wages, reasonable
travel costs will be reimbursed.
Other possible monetary hardships may be considered if the investigative site
finds it necessary.

Blood samples will be collected during the study and collection of these
samples can irritate or be painful to the
arms, but will likely clear up. Children are able to have a cream placed on
those areas to numb the skin prior to the
blood draw.

Screening Phase: All subjects will be given the choice to receive placebo
during the Screening Phase.
Placebo tablets and placebo mini-tablets will be used at the Screening and Day
0 Visits to evaluate acceptability
and swallowability of a subject*s assigned dose regimen. Placebo may also be
dispensed at the Screening Visit
to take home and practice dosing administration techniques (at home) prior to
randomization on Day 0.