Safety and Efficacy Study of Ursodeoxycholic Acid Therapy in Pediatric Primary Sclerosing Cholangitis

Primary sclerosing cholangitis (PSC), a devastating and insidiously progressive cholestatic
liver disease, results from advancing inflammation, fibrosis and obliteration of the intra-
and extrahepatic bile ducts, leading to cirrhosis and end-stage liver disease. PSC is an
uncommon disorder (prevalence in the US of 8-14/100,000 with even lower prevalence in
children). Although prognosis in children may be somewhat better, approximately one third of
pediatric patients require transplantation by adulthood. Other than transplantation, there is
to date no therapy conclusively proven to improve the long-term outcome. Ursodeoxycholic acid
(UDCA) improves biochemical markers of liver disease, although in high doses does not clearly
improve the long-term outcome in adults. Furthermore, a recent large adult trial of high-dose
UDCA therapy suggested a higher incidence of serious adverse events and poor outcomes with
UDCA treatment, leading many centers to discontinue UDCA therapy in adult patients. Childhood
PSC is different from the adult disease including a stronger association with both autoimmune
markers and histologic features and a trend to higher transaminases at diagnosis.
Furthermore, in response to intermediate-dose UDCA therapy, there is a more striking and
prompt improvement in biochemistries as compared to adults. In light of the prompt
normalization of liver enzymes and the fact that UDCA is well tolerated in children,
pediatric hepatologists are reluctant to generalize the adult UDCA study results to children
and to stop UDCA therapy. This presents a significant dilemma: Should UDCA therapy be stopped
in pediatric PSC patients to avoid a possible adverse influence on long-term prognosis at the
risk of losing a possible beneficial effect on disease progression in children? Additional
factors in children with PSC/autoimmune hepatitis (AIH) overlap are the long-term adverse
effects of corticosteroids and azathioprine use. If UDCA therapy is effective as monotherapy,
these complications may be avoided. Therefore, we propose a preliminary UDCA withdrawal and
reinstitution trial in pediatric PSC patients to collect data to support the design of a
larger, longer-term randomized, placebo-controlled trial of UDCA therapy in childhood PSC.
This pilot study, which will utilize the infrastructure and participating centers of the
STOPSC (Studies of Primary Sclerosing Cholangitis) consortium, will test the following
hypotheses: 1) UDCA therapy yields a rapid biochemical response in children with PSC, thus
withdrawal would lead to increased biochemical evidence of disease. 2) UDCA therapy
suppresses liver and biliary inflammation in children with PSC, thus withdrawal of therapy
would result in a burst of inflammatory activity and an increase in serum cytokine
biomarkers, 3) Biochemical control of childhood PSC with histologic features of AIH is
dependent upon treatment with immunosuppression in addition to UDCA, therefore childhood PSC
without histologic features of AIH will worsen significantly with UDCA withdrawal compared to
PSC with histological features of AIH.

Inclusion Criteria:

1. Male or female < 21 years of age, no racial or ethnic restrictions

2. Pediatric PSC diagnosed as per the criteria developed by STOPSC (2 of 3 required):

- Serum GGT increased more than 50% above the upper limit of normal for age

- Endoscopic retrograde cholangiopancreatography (ERCP), percutaneous transhepatic
cholangiography (PTC) or magnetic resonance cholangiopancreatography (MRCP)
findings of intrahepatic and/or extrahepatic bile duct irregularities consistent
with PSC

- Liver biopsy abnormalities consistent with chronic biliary injury Note that these
criteria will include patients with small duct PSC who have normal biliary
imaging with the required biochemical and histologic criteria.

3. Patients with PSC/AIH overlap will also be included who meet the criteria for PSC plus
have liver histologic features of AIH.

4. Biochemically quiescent liver disease defined by an ALT and GGT < 2.0 X upper limit of
normal (ULN) measured on two separate occasions > 2 weeks apart

5. Prior and on-going UDCA therapy at a dose of at least 13 mg/kg/day or 600 mg/day for
more than 6 months

6. Ability to swallow pills

7. Quiescent inflammatory bowel disease (IBD) as reflected by a modified Pediatric
Ulcerative Colitis Activity Index score of less than 6 or a modified Pediatric Crohn's
Disease Activity Index score of less than 15.

8. Not excluded by the STOPSC pediatric PSC exclusion criteria (see Appendix) that are
designed to minimize misdiagnosis due to other primary liver diseases, previous
biliary injury/surgery, therapies, or systemic disorders that may secondarily affect
the liver and/or biliary tract.

9. Subjects will remain on all current medications, including those for IBD and
immunosuppressive therapy.

10. Female subjects of childbearing age will be required to have a pregnancy test, and if
sexually active, will be required to use an accepted method of birth control during
the course of the study.

11. Parent or legal guardian must be willing to provide signed and dated informed consent
documentation. Assent from the child or adolescent will be obtained as appropriate.

Exclusion Criteria:

1. Evidence of decompensated cirrhosis:

- Cirrhosis as defined by biopsy findings or evidence of portal hypertension with
no other known cause and:

- Platelet count < 100,000 or,

- Spleen palpable more than 2 cm below the left costal margin or,

- Ascites or,

- Varices or other GI manifestation of portal hypertension

- Decompensated liver disease defined by:

- Serum total bilirubin (TB) > 5 mg/dl and direct bilirubin (DB) > 1 mg/dl or,

- Prothrombin time (PT) prolonged by more than 3 seconds after parenteral
vitamin K administration or,

- Ascites requiring diuretic therapy or,

- Serum albumin < 3 g/dl

2. Evidence of acute liver failure:

- No prior history of liver disease and

- PT > 20 seconds or INR > 2.0 unresponsive to parenteral vitamin K administration
or,

- PT > 15 seconds or international normalized ratio (INR) > 1.5 with change in
mental status ascribable to hepatic encephalopathy

3. History of cholangitis or bile duct strictures requiring intervention

4. Liver transplantation