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

• Status: Completed
• Trial end date: 2017-06-01
• Target enrollment: 0
• Participant gender: All

Summary

Primary sclerosing cholangitis (PSC), although uncommon, is a devastating and insidiously progressive liver disease, resulting from advancing inflammation, fibrosis and obliteration of the bile ducts in the liver, leading to cirrhosis and end-stage liver disease. Although prognosis in children may be somewhat better than that of adults, 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, and in a recent study may have actually worsened outcome. Childhood PSC is different from that of adult PSC in many ways, and children may derive more short-term, as well as long-term, benefit than adults. This unique multicenter study will carefully monitor the effects of withdrawal and restarting UDCA on liver injury and inflammation in children with PSC. The preliminary data will help in the design of a more definitive larger study to determine if UDCA has a beneficial role in the treatment of PSC in children. Funding Source - FDA OOPD

• Phase: Phase 1
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: University of Tennessee
• Collaborators: Ann & Robert H Lurie Children's Hospital of Chicago; Baylor College of Medicine; Children's Healthcare of Atlanta; Children's Hospital Los Angeles; Children's Hospital of Philadelphia; Icahn School of Medicine at Mount Sinai; Phoenix Children's Hospital; Texas Children's Hospital; University of California, San Francisco; University of Colorado, Denver; University of Pittsburgh; Yale University
• Treatments: Ursodeoxycholic Acid

Criteria

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