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Liver Disease in Urea Cycle Disorders

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ClinicalTrials.gov Identifier: NCT04612764
Recruitment Status : Not yet recruiting
First Posted : November 3, 2020
Last Update Posted : July 21, 2021
Sponsor:
Collaborators:
Children's National Research Institute
Seattle Children's Hospital
Children's Hospital Colorado
Children's Hospital of Philadelphia
Information provided by (Responsible Party):
Lindsay Burrage, Baylor College of Medicine

Brief Summary:
This is a multi-center, cross-sectional study to assess risk for liver fibrosis and hepatic injury in individuals with urea cycle disorders (UCDs) using serum biomarkers, Fibroscan, and MRE. This study will be conducted at 5 sites of the Urea Cycle Disorders Consortium: Baylor College of Medicine in Houston, TX, Seattle Children's Hospital in Seattle, WA, Children's Hospital Colorado in Aurora, CO, Children's Hospital of Philadelphia in Philadelphia, PA, and Children's National Medical Center in Washington D.C.

Condition or disease
Urea Cycle Disorder Ornithine Transcarbamylase Deficiency Citrullinemia 1 ARGI Deficiency ASL Deficiency Argininosuccinic Aciduria ASS Deficiency Hyperargininemia

Detailed Description:

Urea cycle disorders (UCDs) are among the most common inborn errors of liver metabolism. With early diagnosis and improved treatments, the survival of individuals with UCDs has improved, and this improved survival has led to unmasking of some long-term complications such as hepatic dysfunction and progressive fibrosis in a subset of patients. Hepatic complications in UCDs are quite variable and dependent upon the specific metabolic defect.

Currently, there are no guidelines for monitoring hepatic complications or extent of liver disease in UCDs. The gold standard for staging of fibrosis or confirming cirrhosis has traditionally been liver biopsy, an invasive procedure with inherent risks, particularly in the setting of a UCD and compromised coagulation. Recently, non-invasive serum and imaging-based biomarkers have been introduced to assess hepatic fibrosis in adults and children who are at increased risk. Utilization of these technique in individuals with UCDs could be invaluable in both the research and clinical arenas.

The purpose of this study is:

1) To assess risk for increased fibrosis using serum biomarkers and/or VCTE in distal disorders (ASS1D, ASLD and ARG1D) as compared to OTCD 2 ) To assess risk for hepatic fibrosis (liver stiffness as measured by MRE) in individuals with UCDs who have abnormal serum biomarkers and/or VCTE as those who have normal values

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Study Type : Observational
Estimated Enrollment : 62 participants
Observational Model: Other
Time Perspective: Cross-Sectional
Official Title: Noninvasive Biomarkers of Hepatic Fibrosis in Urea Cycle Disorders
Estimated Study Start Date : September 1, 2021
Estimated Primary Completion Date : December 31, 2023
Estimated Study Completion Date : December 31, 2023





Primary Outcome Measures :
  1. Fibrotest [ Time Frame: One measurement made on the 1 day of the study visit (stage A) ]
    Fibrotest(TM)

  2. Fibroscan (liver stiffness) [ Time Frame: One measurement made on the 1 day of the study visit (stage A) ]
    Liver stiffness (kPa) as assessed by Fibroscan®

  3. Fibroscan (CAP) [ Time Frame: One measurement made on the 1 day of the study visit (stage A) ]
    Controlled Attenuation Parameter (CAPTM in dB/m) as assessed by Fibroscan®

  4. MRE [ Time Frame: One measurement made on the 1 day of the study visit (stage B) ]
    Liver stiffness (kPa) as measured by MRE


Secondary Outcome Measures :
  1. Albumin [ Time Frame: One measurement made on the 1 day of the study visit (stage A) ]
    Albumin

  2. Liver Enzymes [ Time Frame: One measurement made on the 1 day of the study visit (Stage A) ]
    Aspartate aminotransferase, Alanine aminotransaminase, and Gamma glutamyl transferase

  3. Total Bilirubin [ Time Frame: One measurement made on the 1 day of the study visit (stage A) ]
    Total Bilirubin

  4. Prothrombin time [ Time Frame: One measurement made on the 1 day of the study visit (stage A) ]
    Prothrombin time

  5. INR [ Time Frame: One measurement made on the 1 day of the study visit (stage A) ]
    INR

  6. AST-to-Platelet Ratio (APRI) [ Time Frame: One measurement made on the 1 day of the study visit (stage A) ]
    AST-to-Platelet Ratio (APRI)

  7. GGT-to-Platelet Ratio (GPR) [ Time Frame: One measurement made on the 1 day of the study visit (stage A) ]
    GGT-to-Platelet Ratio (GPR)

  8. Fibrosis-4 (FIB-4) Index [ Time Frame: One measurement made on the 1 day of the study visit (stage A) ]
    Fibrosis-4 (FIB-4) Index

  9. MRE [ Time Frame: One measurement made on the 1 day of the study visit (stage B) ]
    Fat fraction (%) as measured by MRE


Biospecimen Retention:   Samples Without DNA
Blood


Information from the National Library of Medicine

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Ages Eligible for Study:   6 Years to 65 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Individuals with urea cycle disorders
Criteria

Stage A

Inclusion Criteria:

  • Age > 6 years and < 65 years
  • Weight ≥ 11 kg at time of screening
  • A molecular or biochemical diagnosis of OTCD, ASS1D, ASLD, or ARG1D.

Exclusion Criteria:

  • Prior liver transplantation
  • Episode of acute hyperammonemia (≥100 umol/L) in the 30 days prior to enrollment
  • Confirmed diagnosis of chronic viral hepatitis, autoimmune liver disease, short gut, small bowel syndrome, alcohol liver disease, TPN requirement, or TPN-related cholestatic disease
  • Adults with BMI ≥ 45 kg/m2
  • Current pregnancy
  • Open wound near expected Fibroscan® probe application site
  • Use of implantable active medical device such as cardiac pacemaker or implantable cardioverter-defibrillator

Stage B Inclusion Criteria

• Participation in Stage A of this study

Exclusion Criteria

  • Individuals with claustrophobia or other inability to complete
  • Known diagnosis of hemochromatosis
  • Presence of implants or devices incompatible with MRI
  • Inability to breath-hold for 20 seconds for the elastography sequence
  • Current pregnancy
  • Confirmed diagnosis of chronic viral hepatitis, autoimmune liver disease, short gut, small bowel syndrome, alcohol liver disease, TPN requirement, or TPN-related cholestatic disease
  • Episode of documented acute hyperammonemia (ammonia ≥ 100 umol/L) in the 30 days prior to scheduled visit for Stage B

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04612764


Contacts
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Contact: Saima Ali, MSN 832-822-4183 saima.ali@bcm.edu

Locations
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United States, Colorado
Children's Hospital Colorado
Aurora, Colorado, United States, 80045
Contact: Brittany Murphy    720-777-8591    Brittany.Murphy@childrenscolorado.org   
Principal Investigator: Shawn McCandless, MD         
United States, District of Columbia
Children's National Medical Center
Washington, District of Columbia, United States, 20010
Contact: Kara Simpson, MS, CGC    202-476-6216    ksimpson@childrensnational.org   
Principal Investigator: Nicholas A Mew, MD         
United States, Pennsylvania
The Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104
Contact: Bianca Ferreira, MPH    267-426-1368    ferreirab@email.chop.edu   
Principal Investigator: Can Ficicioglu, MD, PhD         
United States, Washington
Seattle Children's Hospital
Seattle, Washington, United States, 98105
Contact: Linnea Brody, CRA    206-987-3012    Linnea.brody@seattlechildrens.org   
Principal Investigator: Christina Lam, MD         
Sponsors and Collaborators
Baylor College of Medicine
Children's National Research Institute
Seattle Children's Hospital
Children's Hospital Colorado
Children's Hospital of Philadelphia
Investigators
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Principal Investigator: Lindsay Burrage, MD, PhD Baylor College of Medicine
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Responsible Party: Lindsay Burrage, Principal Investigator, Baylor College of Medicine
ClinicalTrials.gov Identifier: NCT04612764    
Other Study ID Numbers: 5120
First Posted: November 3, 2020    Key Record Dates
Last Update Posted: July 21, 2021
Last Verified: July 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Lindsay Burrage, Baylor College of Medicine:
Liver disease
Fibroscan
Magnetic resonance elastography
Fibrotest
Additional relevant MeSH terms:
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Urea Cycle Disorders, Inborn
Ornithine Carbamoyltransferase Deficiency Disease
Citrullinemia
Argininosuccinic Aciduria
Hyperargininemia
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Amino Acid Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Metabolic Diseases
Genetic Diseases, X-Linked