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

NCT01088607 | Completed Phase 1 DMC

• 1 other identifier: FD-003709
• Study Type: interventional
• Target: 27
• Locations: 1 country
• Sites: 12

Brief 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

Conditions

Primary Sclerosing Cholangitis

Keywords

Primary sclerosing cholangitis; Autoimmune hepatitis; Cholestatic liver disease; Cirrhosis; Children; Primary Sclerosing Cholangitis/Autoimmune Hepatitis Overlap

Outcome Measures

Primary Outcomes (1)

• The primary outcome will be the change in alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (GGT) or biomarkers for inflammation in study subjects at baseline compared to the end of Phase III (UDCA discontinuation) of the study.

  Phase I-4 weeks, Phase II-4 weeks, Phase III-8 weeks, Phase IV-8 weeks

  16 weeks

Secondary Outcomes (1)

• A secondary outcome will be the change in ALT, GGT or biomarkers for inflammation in study subjects at the end of Phase III (UDCA discontinuation) compared to the end of Phase IV (UDCA reinstitution) of the study.

  8 weeks

Study Arms (1)

UDCA Withdrawal and Reinstitution

EXPERIMENTAL

Each study subject will undergo serial UDCA withdrawal and reinstitution.

Drug: ursodeoxycholic acid (UDCA)

Interventions

ursodeoxycholic acid (UDCA) DRUG

Pediatric PSC patients already receiving UDCA therapy will enter a four-phase trial consisting of baseline data collection (phase I, 4 weeks), 50% reduction in UDCA dose (phase II, 4 weeks), discontinuation of UDCA (phase III, 8 weeks) and reinstitution of therapy at a dose of 20 mg/kg/day (phase IV, 8 weeks). Surveillance and endpoint evaluation for each phase will include liver chemistries and clinical data. Comparisons will be made between baseline and the end of phase III (primary outcome) and between the end of phase III and the end of phase IV (secondary outcome). Serum cytokine biomarkers will be measured and compared between baseline and the end of phase III and between the end of phases III and IV.

Also known as: Ursodeoxycholic acid, URSO 250, URSO Forte, Actigall, Ursodiol, UDCA

UDCA Withdrawal and Reinstitution

Eligibility Criteria

• Age: 5 Years - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Male or female \< 21 years of age, no racial or ethnic restrictions
• 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.
• Patients with PSC/AIH overlap will also be included who meet the criteria for PSC plus have liver histologic features of AIH.
• 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
• 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
• Ability to swallow pills
• 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.

You may not qualify if:

• Subjects will remain on all current medications, including those for IBD and immunosuppressive therapy.
• 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.
• 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.
• 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
• Evidence of acute liver failure:

Sponsors & Collaborators

• University of Tennessee: lead
• Icahn School of Medicine at Mount Sinai: collaborator
• Ann & Robert H Lurie Children's Hospital of Chicago: collaborator
• University of Colorado, Denver: collaborator
• University of California, San Francisco: collaborator
• University of Pittsburgh: collaborator
• Phoenix Children's Hospital: collaborator
• Children's Hospital of Philadelphia: collaborator
• Children's Healthcare of Atlanta: collaborator
• Children's Hospital Los Angeles: collaborator
• Baylor College of Medicine: collaborator
• Yale University: collaborator

Study Sites (12)

Phoenix Children's Hospital

Phoenix, Arizona, 85016, United States

Location

Children's Hospital Los Angeles

Los Angeles, California, 90027, United States

Location

University of California, San Francisco

San Francisco, California, 94143, United States

Location

Children's Hospital Colorado

Aurora, Colorado, 80045, United States

Location

Yale New Haven Children's Hospital

New Haven, Connecticut, 06510, United States

Location

Children's Healthcare of Atlanta, Emory University School of Medicine

Atlanta, Georgia, 30322, United States

Location

Northwestern University

Chicago, Illinois, 60614, United States

Location

Mount Sinai School of Medicine

New York, New York, 07624, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

University of Pittsburgh

Pittsburgh, Pennsylvania, 15213, United States

Location

University of Tennessee Health Science Center

Memphis, Tennessee, 38103, United States

Location

Texas Children's Hospital

Houston, Texas, 77030, United States

Location

MeSH Terms

Conditions

Cholangitis, Sclerosing; Hepatitis, Autoimmune; Fibrosis

Interventions

Ursodeoxycholic Acid

Condition Hierarchy (Ancestors)

Cholangitis; Bile Duct Diseases; Biliary Tract Diseases; Digestive System Diseases; Hepatitis, Chronic; Hepatitis; Liver Diseases; Autoimmune Diseases; Immune System Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Deoxycholic Acid; Cholic Acids; Bile Acids and Salts; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Cholanes

Study Officials

• Dennis D Black, M.D.

  University of Tennessee

  PRINCIPAL INVESTIGATOR

• Benjamin Shneider, M.D.

  Baylor College of Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 12, 2010
• First Posted: March 17, 2010
• Study Start: October 1, 2010
• Primary Completion: December 1, 2016
• Study Completion: June 1, 2017
• Last Updated: October 26, 2017

Record last verified: 2017-09

Locations

US (12)