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Longitudinal Study of Urea Cycle Disorders

This study is currently recruiting participants.
Verified October 2017 by Andrea Gropman, Children's Research Institute
Sponsor:
ClinicalTrials.gov Identifier:
NCT00237315
First Posted: October 12, 2005
Last Update Posted: November 1, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborators:
National Center for Research Resources (NCRR)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Rare Diseases Clinical Research Network
Information provided by (Responsible Party):
Andrea Gropman, Children's Research Institute
  Purpose
Urea cycle disorders (UCD) are a group of rare inherited metabolism disorders. Infants and children with UCD commonly experience episodes of vomiting, lethargy, and coma. The purpose of this study is to perform a long-term analysis of a large group of individuals with various UCDs. The study will focus on the natural history, disease progression, treatment, and outcome of individuals with UCD.

Condition
Brain Diseases, Metabolic, Inborn Amino Acid Metabolism, Inborn Errors Urea Cycle Disorders

Study Type: Observational
Study Design: Observational Model: Cohort
Time Perspective: Prospective
Official Title: Longitudinal Study of Urea Cycle Disorders

Resource links provided by NLM:


Further study details as provided by Andrea Gropman, Children's Research Institute:

Primary Outcome Measures:
  • Prevalence of specific morbid indicators of disease severity [ Time Frame: End of study ]
    hyperammonemia, developmental disabilities, long-term renal and hepatic effects, and case-fatality associated with the various forms of UCD

  • Relationship between various biomarkers and disease severity and progression [ Time Frame: End of study ]
    correlation between glutamine, ammonia, liver function (biomarkers) and severity scale and IQ in terms of outcome

  • Safety and efficacy of currently used and new UCD therapies [ Time Frame: End of study ]
    Interim events related to treatments (drugs, diet or liver transplant)


Estimated Enrollment: 1100
Study Start Date: February 2006
Estimated Study Completion Date: December 2019
Estimated Primary Completion Date: July 2019 (Final data collection date for primary outcome measure)
Detailed Description:

Urea cycle disorders are a group of rare genetic diseases that affect how protein is broken down in the body. UCDs are caused by a deficiency in one of six enzymes or two mitochondrial membrane transporters responsible for removing ammonia, a waste product of protein metabolism, from the bloodstream. Normally, ammonia is converted into urea and then removed from the body in the form of urine. In UCDs, however, ammonia accumulates unchecked and is not removed from the body. It then reaches the brain through the blood, where it causes irreversible brain damage and/or death.

All UCDs, except for one (ornithine transcarbamylase deficiency), are inherited as recessive traits. The purpose of this study is to perform a long-term analysis of a large group of individuals with various UCDs. Biochemical status, growth, and cognitive function will be assessed. Survival and cognitive outcome of the two most commonly used forms of treatment, alternate pathway therapy and transplantation, will be evaluated. In addition, this study will identify the biochemical changes that may predict future metabolic imbalances so that they may be corrected before clinical symptoms develop.

This observational study is funded through 2019. All participants will attend an initial study visit, which will include a medical and diet history, physical and neurological examinations, psychological testing, and blood tests. Participants will then be followed with subsequent study visits, which will last 2-3 hours each. Individuals with neonatal onset UCD will be assessed every 3 months until age 2 and every 6 months thereafter. Individuals with late onset UCD will be evaluated every 6 months. Psychological testing will take place every 2 years. Psychological testing will take from 30 minutes (for younger children) up to 3 hours, depending on test battery.

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   Child, Adult, Senior
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
>550 individuals with urea cycle disorders, up to a total of 1,100 enrolled
Criteria

Inclusion Criteria:

  • Diagnosis of NAGS deficiency, defined as the detection of a pathogenic mutation, and/or decreased (less than 20 % of control) NAGS enzyme activity in liver ,and/or hyperammonemia and first degree relative meets at least one of the criteria for NAGS deficiency
  • Diagnosis of CPS I deficiency, defined as decreased (less than 20 % of control) CPS I enzyme activity in liver, and/or an identified pathogenic mutation, and/or hyperammonemia and first degree relative meets at least one of the criteria for CPS I deficiency
  • Diagnosis of OTC deficiency, defined as the identification of a pathogenic mutation, and/or less than 20% of control of OTC activity in the liver, and/or elevated urinary orotate (greater than 20 uM/mM) in a random urine sample or after allopurinol challenge test, and/or hyperammonemia and first degree relative meets at least one of the criteria for OTC deficiency
  • Diagnosis of AS deficiency (Citrullinemia), defined as a greater than or equal to 10-fold elevation of citrulline in plasma, and/or decreased AS enzyme activity in cultured skin fibroblasts or other appropriate tissue, and/or identification of a pathogenic mutation in the AS gene, and/or hyperammonemia and first degree relative meets at least one of the criteria for AS Deficiency
  • Diagnosis of AL deficiency (Argininosuccinic Aciduria, ASA), defined as the presence of argininosuccinic acid in the blood or urine, and/or decreased AL enzyme activity in cultured skin fibroblasts or other appropriate tissue, and/or identification of a pathogenic mutation in the AL gene, and/or hyperammonemia and first degree relative meets at least one of the criteria for AL Deficiency
  • Diagnosis of ARG deficiency (Hyperargininemia), defined as a greater than or equal to 5-fold elevated arginine levels in the blood, and/or decreased arginase enzyme levels in red blood cells or other appropriate tissue, and/or identification of a pathogenic mutation in the ARG gene, and/or hyperammonemia and first degree relative meets at least one of the criteria for ARG Deficiency
  • Diagnosis of HHH Syndrome or ORNT deficiency, defined as a greater than or equal to 5-fold elevated plasma ornithine and homocitrulline levels in the urine, and/or a pathogenic mutation, and/or less than 20% residual labeled ornithine incorporation into protein in cultured fibroblasts, and/or hyperammonemia and first degree relative meets at least one of the criteria for HHH Syndrome or ORNT Deficiency
  • Diagnosis of CITR deficiency (Citrullinemia Type II), defined as elevated citrulline levels in the blood and a pathogenic mutation and/or hyperammonemia and first degree relative meets criteria for CITR Deficiency
  • Pending diagnosis of a UCD (UCD highly likely), defined as laboratory values highly suggestive of a UCD with symptomatic hyperammonemic episodes but without a verifiable diagnosis

Exclusion Criteria:

  • Hyperammonemia caused by an organic academia, lysinuric protein intolerance, mitochondrial disorder, congenital lactic academia, fatty acid oxidation defects, or primary liver disease
  • Rare and unrelated comorbidities (e.g., Down's syndrome, intraventricular hemorrhage in the newborn period, and extreme prematurity)
  Contacts and Locations
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): NCT00237315


Contacts
Contact: Jennifer Seminara, MPH 202-306-6489 jseminar@childrensnational.org

Locations
United States, California
University of California, Los Angeles Recruiting
Los Angeles, California, United States, 90095
Contact: Rebecca Singer, MS, LCGC    310-206-7470    RSigner@mednet.ucla.edu   
Sub-Investigator: Stephen Cederbaum, MD         
Principal Investigator: Derek Wong, MD         
University of California San Francisco Recruiting
San Francisco, California, United States, 94143
Contact: Vimal Vimal Gunasekaran       Vimal.Gunasekaran@ucsf.edu   
Principal Investigator: Renata C Gallagher, MD, PhD         
Stanford University Medical Center Recruiting
Stanford, California, United States, 94305
Contact: Thu Quan, MBA, HCM    650-736-8166    tquan@stanford.edu   
Principal Investigator: Gregory Enns, MD         
United States, Colorado
Children's Hospital Colorado Recruiting
Aurora, Colorado, United States, 80045
Contact: Curtis Coughlin, MS, CGC    303-724-2310    Coughlin.Curtis@tchden.org   
Principal Investigator: James Weisfeld-Adams, MD         
Principal Investigator: Curtis Coughlin, MS, CGC         
United States, District of Columbia
Children's National Medical Center Recruiting
Washington, D.C., District of Columbia, United States, 20010
Contact: Kara Simpson, MS, CGC    202-476-6216    ksimpson@childrensnational.org   
Principal Investigator: Nicholas Ah Mew, MD         
United States, Massachusetts
Children's Hospital Boston (UCDC New England Center) Recruiting
Boston, Massachusetts, United States, 02115
Contact: Vera Anastasoaie    617-355-7346    Vera.Anastasoaie@childrens.harvard.edu   
Principal Investigator: Susan Waisbren, MD         
Sub-Investigator: Harvey Levy, MD         
United States, Minnesota
University of Minnesota Recruiting
Minneapolis, Minnesota, United States, 55455
Contact: Sara Elsbecker, MS, RN, CPNP    612-626-5275    selsbeck10@umphysicians.umn.edu   
Principal Investigator: Susan Berry, MD         
United States, New York
Icahn School of Medicine at Mount Sinai Recruiting
New York, New York, United States, 10029
Contact: Luca Fierro    212-659-1477    luca.fierro@mssm.edu   
Principal Investigator: George A. Diaz, MD         
United States, Ohio
Case Western Medical College Recruiting
Cleveland, Ohio, United States, 44106
Contact: Audrey Lynn, PhD    216-844-7124    Audrey.Lynn@UHhospitals.org   
Principal Investigator: Shawn McCandless, MD         
United States, Oregon
Oregon Health and Science University Recruiting
Portland, Oregon, United States, 97239
Contact: Sondra Bloxam    503-494-4290    bloxam@ohsu.edu   
Principal Investigator: Cary Harding, MD         
United States, Pennsylvania
Children's Hospital of Philadelphia Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Irma Payan, RN    215-590-6236    Payan@email.chop.edu   
Principal Investigator: Marc Yudkoff, MD         
United States, Texas
Baylor College of Medicine Recruiting
Houston, Texas, United States, 77030
Contact: Mary Mullins, RN, BSN    832-822-4263    mullins@bcm.edu   
Principal Investigator: Sandesh Nagamani, MD         
United States, Washington
Children's Hospital and Regional Medical Center Recruiting
Seattle, Washington, United States, 98105
Contact: Linnea Brody, BS, MPH    206-987-3694    linnea.brody@seattlechildrens.org   
Principal Investigator: Lawrence Merritt, MD         
Canada, Ontario
The Hospital for Sick Children Recruiting
Toronto, Ontario, Canada, M5G 1X8
Contact: Liora Caspi    416-813-7654 ext 328027    liora.caspi@sickkids.ca   
Principal Investigator: Andreas Schulze, MD         
Germany
University of Heidelberg Recruiting
Heidelberg, Germany
Contact: Peter Burgard, PhD    ++49 [0]6221/56-32377    Peter.Burgard@med.uni-heidelberg.de   
Contact    ++49 [0]6221/56-37733      
Principal Investigator: Georg Hoffmann, MD         
Sub-Investigator: Peter Burgard, PhD         
Switzerland
University Children's Hospital Recruiting
Zurich, Switzerland, CH-8032
Contact: Tamar Stricker    +41 44-266-7111    Tamar.stricker@kispi.uzh.ch   
Principal Investigator: Matthias Baumgartner, MD         
Sub-Investigator: Tamar Stricker, MD         
Sponsors and Collaborators
Andrea Gropman
National Center for Research Resources (NCRR)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Rare Diseases Clinical Research Network
Investigators
Principal Investigator: Andrea Gropman, MD Children's Research Institute
Principal Investigator: Shawn McCandless, MD University Hospitals Cleveland Medical Center
Principal Investigator: Sandesh CS Nagamani, MD, FACMG Baylor College of Medicine
  More Information

Additional Information:
Publications:

Responsible Party: Andrea Gropman, Principal Investigator, Children's Research Institute
ClinicalTrials.gov Identifier: NCT00237315     History of Changes
Other Study ID Numbers: RDCRN 5101
U54RR019453 ( U.S. NIH Grant/Contract )
U54HD061221 ( U.S. NIH Grant/Contract )
First Submitted: October 10, 2005
First Posted: October 12, 2005
Last Update Posted: November 1, 2017
Last Verified: October 2017

Keywords provided by Andrea Gropman, Children's Research Institute:
Urea
Inherited metabolic disorders

Additional relevant MeSH terms:
Brain Diseases, Metabolic, Inborn
Disease
Brain Diseases
Urea Cycle Disorders, Inborn
Metabolism, Inborn Errors
Metabolic Diseases
Brain Diseases, Metabolic
Amino Acid Metabolism, Inborn Errors
Pathologic Processes
Central Nervous System Diseases
Nervous System Diseases
Genetic Diseases, Inborn