Primary Sclerosing Cholangitis in Children

October 13, 2023 updated by: Arbor Research Collaborative for Health

Prospective Observational Study of Primary Sclerosing Cholangitis (PSC) in Children

Primary sclerosing cholangitis (PSC) is a rare liver disease that damages the liver's bile ducts. Bile ducts are tiny tubes that carry bile from the liver to the small intestine. Bile is a liquid produced by the liver that helps us absorb and use the nutrients in the food we eat. In people with PSC, the bile backs up into the liver and will damage it, causing scarring of the liver.

The purposes of this study are to:

  • Collect medical and other data to learn more about PSC, how it progresses, and identify factors that may cause the disease to progress more quickly.
  • Ask questions about how PSC symptoms affect your child's life to learn more about its impact on your child's daily functioning
  • Children with PSC who are seen at one of the participating clinical sites in the Childhood Liver Disease Research Network (ChiLDReN) will be asked to contribute information, DNA, and other specimens. The information and specimens will be available to investigators to carry out approved research aimed at learning more about the possible causes and long-term effects of PSC.

Study Overview

Status

Recruiting

Conditions

Detailed Description

Pediatric primary sclerosing cholangitis (PSC) is a rare autoimmune biliary fibrosing disease that leads to significant morbidity, the need for liver transplantation in ~50% of patients, and an increased risk for biliary and colorectal cancers in adulthood. The progression of the biliary disease in children is variable and risk factors associated with a more rapid progression of disease have not been adequately studied. Importantly, pediatric hepatologists have never previously collaborated with inflammatory bowel disease (IBD) specialists to rigorously explore interactions between colonic inflammation and liver disease. New non-invasive imaging modalities to measure fibrosis have not been explored in pediatric PSC. Furthermore, the impact that PSC has on the global functioning of children is not well understood, and likely underappreciated.

The natural history of pediatric PSC is poorly understood. This study aims to determine risk factors, including activity of co-existent IBD, associated with more rapid progression of disease, characterize the impact of PSC on global functioning, define the spectrum and prognostic value of biliary tract disease and liver fibrosis based on novel imaging techniques, and establish a biobank of specimens for future mechanistic studies aimed at discovering biomarkers pertaining to etiology and severity of PSC and novel mechanisms of immunopathogenesis of disease. This comprehensive observational and longitudinal study will delineate unique aspects of the natural history and severity of pediatric PSC and of associated IBD and provide necessary data for future therapeutic trials. It aims to provide a platform to discover and validate circulating and imaging biomarkers, which may serve as surrogate endpoints in future interventional studies.

Study Type

Observational

Enrollment (Estimated)

1000

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Canada
    • Ontario
      • Toronto, Ontario, Canada, M5G 1X8
        • Recruiting
        • The Hospital For Sick Children
        • Contact:
        • Sub-Investigator:
          • Vicky Ng, MD
        • Principal Investigator:
          • Binita Kamath, MD
        • Contact:
  • United States
    • California
      • Los Angeles, California, United States, 90027
        • Recruiting
        • Children's Hospital of Los Angeles
        • Sub-Investigator:
          • Rohit Kohli, MD
        • Principal Investigator:
          • Nisreen Soufi, MD
        • Contact:
    • Colorado
      • Aurora, Colorado, United States, 80045
        • Recruiting
        • Children's Hospital Colorado
        • Principal Investigator:
          • Shikha Sundaram, MD
        • Contact:
        • Sub-Investigator:
          • Ron Sokol, MD
        • Contact:
        • Sub-Investigator:
          • Michael Narkewicz, MD
        • Sub-Investigator:
          • Amy Feldman, MD
        • Sub-Investigator:
          • Dania Brigham, MD
    • Georgia
      • Atlanta, Georgia, United States, 30322
        • Recruiting
        • Children's Healthcare of Atlanta
        • Contact:
        • Principal Investigator:
          • Nitika Gupta, MD
        • Contact:
    • Illinois
      • Chicago, Illinois, United States, 60611
    • Indiana
      • Indianapolis, Indiana, United States, 46202
        • Recruiting
        • Riley Hospital for Children
        • Contact:
          • Wendy Morlan, RN, CCRP
          • Phone Number: 317-274-9601
          • Email: wmorlan@iu.edu
        • Contact:
          • Ann Klipsch, BSN, RN, CCRC
          • Phone Number: 317.944.9654
          • Email: aeye@iu.edu
        • Sub-Investigator:
          • Jean Molleston, MD
        • Principal Investigator:
          • Molly Bozic, MD
    • Ohio
      • Cincinnati, Ohio, United States, 45229
        • Recruiting
        • Cincinnati Children's Hospital Medical
        • Principal Investigator:
          • Alex Miethke, MD
        • Contact:
        • Contact:
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19104
        • Recruiting
        • The Children's Hospital of Philadelphia
        • Principal Investigator:
          • Kathleen Loomes, MD
        • Contact:
        • Contact:
      • Pittsburgh, Pennsylvania, United States, 15224
        • Recruiting
        • UPMC Children's Hospital of Pittsburgh
        • Sub-Investigator:
          • Veena Venkat, MD
        • Sub-Investigator:
          • James Squires, MD
        • Principal Investigator:
          • Simon Horslen, MD
        • Contact:
        • Contact:
    • Texas
      • Houston, Texas, United States, 77030
        • Recruiting
        • Texas Children's Hospital (Baylor College of Medicine)
        • Principal Investigator:
          • Mary Elizabeth Tessier, MD
        • Contact:
        • Contact:
    • Utah
      • Salt Lake City, Utah, United States, 84113
        • Recruiting
        • The University of Utah
        • Contact:
        • Sub-Investigator:
          • Stephen Guthery, MD
        • Principal Investigator:
          • Mark Deneau, MD
        • Sub-Investigator:
          • Kyle Jensen, MD
        • Sub-Investigator:
          • Linda Book, MD
        • Contact:
    • Washington
      • Seattle, Washington, United States, 98105
        • Recruiting
        • Seattle Children's Hospital
        • Sub-Investigator:
          • Pamela Valentino, MD
        • Contact:
        • Principal Investigator:
          • Niviann Blondet, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

2 years to 25 years (Child, Adult)

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

Participants are eligible for enrollment into the ChiLDReN PSC Study if they meet the inclusion criteria and if none of the exclusion criteria apply. Every effort will be made to enroll as diverse a patient population (racial, ethnic, sex, age, etc) as possible.

Description

Inclusion Criteria:

Patients with the clinical diagnosis of large or small duct PSC made at any time prior to enrollment are screened for eligibility to participate in this prospective cohort study. The site PI will determine eligibility following review of MRCP or ERCP images with the site radiologist to confirm presence of an abnormal cholangiogram at the time of diagnosis of large duct PSC. Liver histopathology obtained at the time of diagnosis of small duct PSC will be reviewed with the site pathologist prior to enrollment.

Individuals must meet all of the Inclusion criteria in order to be eligible to participate in the study:

  1. Aged 2 through 25 years at time of screening.

  2. Diagnosis of large duct PSC based on review of cholangiogram by MRC, ERC, or intraoperative cholangiogram (IOC) by the site radiologist and interpreted to be consistent with PSC, based on one or more of the following:

    • Focal structuring of the bile duct(s)
    • Dominant stricture of the common bile duct
    • Saccular dilatation of bile duct(s)
    • Beaded appearance of bile duct(s)
    • Pruning appearance of the distal bile duct branches

    AND/OR

  3. Diagnosis of small duct PSC based on review of liver histopathology by the site pathologist and interpreted to be compatible with PSC:

    • Probable small duct PSC: biopsy with ≥3 of 5 criteria: periductal edema, concentric inflammation, bile duct injury, ductular reaction, and neutrophils in bile ducts (cholangitis) OR...
    • Definitive small duct PSC: Periductal fibrosis/ "onion skinning" around interlobular bile ducts or smaller profiles
  4. Stated willingness to comply with all study procedures and availability for the duration of the study.
  5. Able to provide informed consent/assent

Participants for the imaging study are eligible if they are:

  1. Aged 8 through 25 years at the time of screening
  2. No absolute contraindication to MRI
  3. No skin condition that could be aggravated by MREL
  4. Meet all other eligibility criteria of the PSC Observational Study
  5. For whom none of the exclusion criteria apply

Exclusion Criteria:

An individual who meets any of the following criteria at baseline will be excluded from participation in this study.

  1. History of liver transplantation
  2. History bone marrow transplantation
  3. History of primary or acquired immunodeficiency predisposing to secondary sclerosing cholangitis, for instance: hyper-IgM syndrome, severe combined immunodeficiency (SCID) syndrome, common variable immunodeficiency (CVID) syndrome, cartilage hair hypoplasia syndrome, or HIV/AIDS
  4. History of histiocytosis, including Langerhans cell histiocytosis (LCH), or hemophagocytic lymphohistiocytosis (HLH)
  5. History of ischemic cholangitis
  6. History of portal vein thrombosis with biliopathy, veno-occlusive disease, or abdominal radiation vasculopathy
  7. History of recurrent pyogenic cholangitis
  8. History of biliary tract surgery for cholecystolithiasis prior to cholangiogram/liver biopsy evaluated to determine enrollment
  9. History of biliary tract surgery for choledochal cyst
  10. History of hepatocellular carcinoma, or hepatoblastoma
  11. History of surgical biliary trauma
  12. History of congenital cytomegalovirus (CMV) hepatitis
  13. History of Sickle Cell Disease
  14. History of cystic fibrosis, biliary atresia, Caroli disease/congenital hepatic fibrosis, or progressive familial intrahepatic cholestasis type 3/MDR3 disease
  15. History of cardiac hepatopathy.
  16. History of metabolic disorders, including Wilson's disease, glycogen storage disorder, Alpha-1 Antitrypsin deficiency
  17. Diagnosis of systemic lupus erythematosus (SLE)
  18. Concurrent pregnancy at the time of enrollment -

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
To characterize the major phenotypes of PSC including patients with large duct or small duct disease, with and without Inflammatory Bowel Disease (IBD), and with and without Auto Immune Hepatitis (AIH)
Time Frame: up to 10 years

Data will be collected on all phenotypes of PSC but attention is focused on how the intestinal inflammation and clinical activity of Inflammatory Bowel Disease (IBD) affect the progression of PSC, better classification of patients with features of Auto Immune Hepatitis (AIH), and the implications of bacterial cholangitis amongst all PSC phenotypes.

Collection of retrospective clinical and laboratory data from the time of diagnosis of PSC and annual timepoints thereafter. Information regarding clinically important timepoints, laboratory data and FibroScan Liver Stiffness Measurements (LSM) are collected prospectively.

Slides/images (if available) from each liver biopsy obtained at the time of diagnosis of PSC and thereafter and from the explanted liver recovered at the time of liver transplantation will undergo central review.

Cholangiography results (MRCP, ERCP) will also undergo central review.
up to 10 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
To identify the symptoms of PSC in children and the affects of those symptoms on the functional health of children.
Time Frame: up to 10 years

Identify deficits in the functional health of children with PSC and explore the association of these functional parameters with biochemical markers of liver disease severity and IBD activity. Symptoms and the impact the symptoms on the functional health of children is measured through the use of "Patient Reported Outcomes" and performance-based metrics.

The burden of disease on the quality of life for children with PSC is measured utilizing the Peds-QL questionnaires (parent proxy and self-report). Child self-report: 8-12 years, and 13-18 years. Young adult self-report: 18-25 years. Parent proxy report: 2-4 years, 5-7 years, 8-12 years, and 13-17 years.

Itch and fatigue identified as predominant symptoms in PSC are measured through the administration (at every visit) of the 5-D ITCH scale and the PedsQL multidimensional fatigue and PROMIS Sleep Scales.

Frailty parameters in children with PSC are measured through the Fried frailty criteria at every visit.
up to 10 years
Development of a repository for formalin fixed paraffin embedded (FFPE) liver biopsy tissue, serum, plasma, peripheral blood mononuclear cells (PBMCs), DNA and stool.
Time Frame: up to 10 years
Samples of peripheral blood mononuclear cells (PBMC), serum, plasma, DNA and stool are collected from participants at baseline and serum/plasma will be collected annually. In addition, any liver tissue previously collected or collected for clinical purposes in the future will be analyzed along with the PBMC, serum, plasma, DNA and stool within future mechanistic ancillary studies related to the diagnostic/prognostic biomarkers, and genetic, immune and microbial theories of pathogenesis.
up to 10 years
Utilizing imaging modalities measuring liver fibrosis, and large duct injury to correlate with other markers of fibrosis and biliary injury and predict progression of disease.
Time Frame: up to 10 years

The imaging modalities are utilized to explore the two pathophysiological processes of PSC, liver fibrosis and bile duct damage. Quantitative MRI techniques may be more sensitive to disease progression than standard clinical and laboratory tests, as the liver and bile ducts are being explored directly.

All participants will undergo a liver stiffness measurement (LSM) at baseline and annually. In addition to the LSM, participants who are eligible (eligibility criteria are different than those for the overall study) will be asked to undergo a research MRI at the baseline, Year 1 and Year 5 visits.
up to 10 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Arbor Research Collaborative for Health

Collaborators

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

  • Study Director: Ed Doo, MD, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
  • Study Director: Averell Sherker, MD, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
  • Principal Investigator: John Magee, MD, University of Michigan
  • Principal Investigator: Lisa Henn, PhD, Arbor Research Collaborative for Health
  • Study Chair: Cara Mack, MD, Medical College of Wisconsin-Milwaukee

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

December 30, 2021

Primary Completion (Estimated)

May 1, 2024

Study Completion (Estimated)

May 1, 2024

Study Registration Dates

First Submitted

August 6, 2019

First Submitted That Met QC Criteria

November 26, 2019

First Posted (Actual)

November 29, 2019

Study Record Updates

Last Update Posted (Actual)

October 16, 2023

Last Update Submitted That Met QC Criteria

October 13, 2023

Last Verified

October 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • PSC Study - ChiLDReN Network
  • 2U24DK062456 (U.S. NIH Grant/Contract)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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