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

This study is currently recruiting participants. (see Contacts and Locations)
Verified October 2013 by University of Tennessee
Sponsor:
Collaborators:
Mount Sinai School of Medicine
Ann & Robert H Lurie Children's Hospital of Chicago
University of Colorado, Denver
University of California, San Francisco
University of Pittsburgh
Children's Hospital Medical Center, Cincinnati
Phoenix Children's Hospital
Children's Hospital of Philadelphia
Information provided by (Responsible Party):
Dennis Black, University of Tennessee
ClinicalTrials.gov Identifier:
NCT01088607
First received: March 12, 2010
Last updated: October 7, 2013
Last verified: October 2013
  Purpose

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


Condition Intervention Phase
Primary Sclerosing Cholangitis
Drug: ursodeoxycholic acid (UDCA) withdrawal and reinstitution
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Ursodeoxycholic Acid Therapy in Pediatric Primary Sclerosing Cholangitis: A Pilot Withdrawal/Reinstitution Trial

Resource links provided by NLM:


Further study details as provided by University of Tennessee:

Primary Outcome Measures:
  • 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. [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
    Phase I-4 weeks, Phase II-4 weeks, Phase III-8 weeks, Phase IV-8 weeks


Secondary Outcome Measures:
  • 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. [ Time Frame: 8 weeks ] [ Designated as safety issue: Yes ]
    Phase I-4 weeks, Phase II-4 weeks, Phase III-8 weeks, Phase IV-8 weeks


Estimated Enrollment: 50
Study Start Date: October 2010
Estimated Study Completion Date: April 2015
Estimated Primary Completion Date: September 2014 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: ursodeoxycholic acid (UDCA) withdrawal and reinstitution
    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.
    Other Names:
    • Ursodeoxycholic acid
    • URSO 250
    • URSO Forte
    • Actigall
    • Ursodiol
    • UDCA
Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   5 Years to 21 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01088607

Contacts
Contact: Dennis D Black, M.D. 901-287-5355 dblack@uthsc.edu

Locations
United States, Arizona
Phoenix Children's Hospital Recruiting
Phoenix, Arizona, United States, 85016
Contact: Tamir Miloh, MD    602-933-3020    tmiloh@phoenixchildrens.com   
Contact: Jamie Smith, BS, CCRP    602-933-3020    jsmith3@phoenixchildrens.com   
Principal Investigator: Tamir Miloh, MD         
United States, California
University of California, San Francisco Recruiting
San Francisco, California, United States, 94143
Contact: Philip Rosenthal, MD    415-476-5892    prosenth@peds.ucsf.edu   
Contact: Shannon Fleck    415-476-1539    FleckS@peds.ucsf.edu   
Principal Investigator: Philip Rosenthal, MD         
United States, Colorado
Children's Hospital Recruiting
Aurora, Colorado, United States, 80045
Contact: Ronald Sokol, MD    720-777-6669    Ronald.Sokol@childrenscolorado.org   
Contact: Todd Miller, MPH, CCRP    720-777-5304    Todd.Miller@childrenscolorado.org   
Principal Investigator: Ronald Sokol, MD         
Sub-Investigator: Shikha Sundaram, MD         
United States, Georgia
Children's Healthcare of Atlanta, Emory University School of Medicine Not yet recruiting
Atlanta, Georgia, United States, 30322
Contact: Saul Karpen, MD, PhD    404-712-9741    skarpen@emory.edu   
Contact: Liezl De La Cruz-Tracy, CCRC    404-785-0421    liezl.delacruz-tracy@choa.org   
Principal Investigator: Saul Karpen, MD, PhD         
United States, Illinois
Northwestern University Recruiting
Chicago, Illinois, United States, 60614
Contact: Estella Alonso, M.D.    773-975-8837    Ealonso@childrensmemorial.org   
Contact: Elizabeth Westfall    773-975-8523    Ewestfall@childrensmemorial.org   
Principal Investigator: Estella Alonso, MD         
Sub-Investigator: Jeffrey Brown, MD         
United States, New York
Mount Sinai School of Medicine Recruiting
New York, New York, United States, 07624
Contact: Ronen Arnon, MD    212-659-8060    ronen.arnon@mountsinai.org   
Contact: Sheetal Ramnath    212-659-8046    Sheetal.Ramnath@mountsinai.org   
Principal Investigator: Ronen Arnon, MD         
United States, Ohio
Cincinnati Children's Hospital Recruiting
Cincinnati, Ohio, United States, 45229
Contact: Alexander Miethke, M.D.    513-636-7713    Alexander.miethke@cchmc.org   
Contact: Julie Denlinger    513-636-7266    julie.denlinger@cchmc.org   
Principal Investigator: Alexander Miethke, MD         
United States, Pennsylvania
Children's Hospital of Philadelphia Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Matthew Ryan, MD       RYANMA@email.chop.edu   
Contact: Timothy Crisci    215-590-6853    CrisciT@email.chop.edu   
Principal Investigator: Matthew Ryan, MD         
University of Pittsburgh Recruiting
Pittsburgh, Pennsylvania, United States, 15213
Contact: Benjamin Shneider, M.D.    412-692-5180    benjamin.shneider@chp.edu   
Contact: Kathryn Bukauskas    412-692-7703    Kathryn.Bukauskas@chp.edu   
Principal Investigator: Benjamin Shneider, MD         
United States, Tennessee
University of Tennessee Health Science Center Recruiting
Memphis, Tennessee, United States, 38103
Contact: Dennis D Black, M.D.    901-287-5355    dblack@uthsc.edu   
Contact: Barbara Culbreath    901-287-5351    bculbreath@uthsc.edu   
Principal Investigator: Dennis D Black, MD         
Sponsors and Collaborators
University of Tennessee
Mount Sinai School of Medicine
Ann & Robert H Lurie Children's Hospital of Chicago
University of Colorado, Denver
University of California, San Francisco
University of Pittsburgh
Children's Hospital Medical Center, Cincinnati
Phoenix Children's Hospital
Children's Hospital of Philadelphia
Investigators
Principal Investigator: Dennis D Black, M.D. University of Tennessee Health Science Center
Principal Investigator: Benjamin Shneider, M.D. University of Pittsburgh
  More Information

Additional Information:
No publications provided

Responsible Party: Dennis Black, Professor of Pediatrics and Physiology, University of Tennessee
ClinicalTrials.gov Identifier: NCT01088607     History of Changes
Other Study ID Numbers: FD-003709
Study First Received: March 12, 2010
Last Updated: October 7, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by University of Tennessee:
Primary sclerosing cholangitis
Autoimmune hepatitis
Cholestatic liver disease
Cirrhosis
Children
Primary Sclerosing Cholangitis/Autoimmune Hepatitis Overlap

Additional relevant MeSH terms:
Cholangitis
Cholangitis, Sclerosing
Bile Duct Diseases
Biliary Tract Diseases
Digestive System Diseases
Ursodeoxycholic Acid
Cholagogues and Choleretics
Gastrointestinal Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on July 28, 2014