We updated the design of this site on September 25th. Learn more.
Show more
ClinicalTrials.gov
ClinicalTrials.gov Menu

Longitudinal Study of Urea Cycle Disorders

This study is currently recruiting participants.
Verified July 2016 by Mendel Tuchman, Children's Research Institute
Sponsor:
ClinicalTrials.gov Identifier:
NCT00237315
First Posted: October 12, 2005
Last Update Posted: July 26, 2016
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):
Mendel Tuchman, 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 Phase
Brain Diseases, Metabolic, Inborn Amino Acid Metabolism, Inborn Errors Urea Cycle Disorders Phase 2

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 Mendel Tuchman, 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

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, Learn About Clinical Studies.


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: Kim Arang, MS, LCGC    310-206-6581    arangkim@mednet.ucla.edu   
Sub-Investigator: Stephen Cederbaum, MD         
Principal Investigator: Derek Wong, 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, 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: Susan Berry, MD       berry002@umn.edu   
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: Julie Martin    503-494-5313    martijul@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
Mendel Tuchman
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: Mendel Tuchman, MD Children's Research Institute
  More Information

Additional Information:
Publications:
Tuchman M, Lee B, Lichter-Konecki U, Summar ML, Yudkoff M, Cederbaum SD, Kerr DS, Diaz GA, Seashore MR, Lee HS, McCarter RJ, Krischer JP, Batshaw ML; Urea Cycle Disorders Consortium of the Rare Diseases Clinical Research Network. Cross-sectional multicenter study of patients with urea cycle disorders in the United States. Mol Genet Metab. 2008 Aug;94(4):397-402. doi: 10.1016/j.ymgme.2008.05.004. Epub 2008 Jun 17.
Krivitzky L, Babikian T, Lee HS, Thomas NH, Burk-Paull KL, Batshaw ML. Intellectual, adaptive, and behavioral functioning in children with urea cycle disorders. Pediatr Res. 2009 Jul;66(1):96-101. doi: 10.1203/PDR.0b013e3181a27a16.
Morgan TM, Schlegel C, Edwards KM, Welch-Burke T, Zhu Y, Sparks R, Summar M; Urea Cycle Disorders Consortium. Vaccines are not associated with metabolic events in children with urea cycle disorders. Pediatrics. 2011 May;127(5):e1147-53. doi: 10.1542/peds.2010-1628. Epub 2011 Apr 11. Erratum in: Pediatrics. 2011 Aug;128(2):390.
Ah Mew N, Krivitzky L, McCarter R, Batshaw M, Tuchman M; Urea Cycle Disorders Consortium of the Rare Diseases Clinical Research Network. Clinical outcomes of neonatal onset proximal versus distal urea cycle disorders do not differ. J Pediatr. 2013 Feb;162(2):324-9.e1. doi: 10.1016/j.jpeds.2012.06.065. Epub 2012 Aug 15.
Seminara J, Tuchman M, Krivitzky L, Krischer J, Lee HS, Lemons C, Baumgartner M, Cederbaum S, Diaz GA, Feigenbaum A, Gallagher RC, Harding CO, Kerr DS, Lanpher B, Lee B, Lichter-Konecki U, McCandless SE, Merritt JL, Oster-Granite ML, Seashore MR, Stricker T, Summar M, Waisbren S, Yudkoff M, Batshaw ML. Establishing a consortium for the study of rare diseases: The Urea Cycle Disorders Consortium. Mol Genet Metab. 2010;100 Suppl 1:S97-105. doi: 10.1016/j.ymgme.2010.01.014. Epub 2010 Feb 10. Review.
Gallagher RC, Lam C, Wong D, Cederbaum S, Sokol RJ. Significant hepatic involvement in patients with ornithine transcarbamylase deficiency. J Pediatr. 2014 Apr;164(4):720-725.e6. doi: 10.1016/j.jpeds.2013.12.024. Epub 2014 Jan 30.
Batshaw ML, Tuchman M, Summar M, Seminara J; Members of the Urea Cycle Disorders Consortium. A longitudinal study of urea cycle disorders. Mol Genet Metab. 2014 Sep-Oct;113(1-2):127-30. doi: 10.1016/j.ymgme.2014.08.001. Epub 2014 Aug 10. Review.
McGuire PJ, Lee HS; members of the Urea Cycle Disorders Consoritum, Summar ML. Infectious precipitants of acute hyperammonemia are associated with indicators of increased morbidity in patients with urea cycle disorders. J Pediatr. 2013 Dec;163(6):1705-1710.e1. doi: 10.1016/j.jpeds.2013.08.029. Epub 2013 Sep 29.
Waisbren SE, Gropman AL; Members of the Urea Cycle Disorders Consortium (UCDC), Batshaw ML. Improving long term outcomes in urea cycle disorders-report from the Urea Cycle Disorders Consortium. J Inherit Metab Dis. 2016 Jul;39(4):573-84. doi: 10.1007/s10545-016-9942-0. Epub 2016 May 23.
Patrick TB, Richesson R, Andrews JE, Folk LC. SNOMED CT coding variation and grouping for "other findings" in a longitudinal study on urea cycle disorders. AMIA Annu Symp Proc. 2008 Nov 6:11-5.
Richesson RL, Lee HS, Cuthbertson D, Lloyd J, Young K, Krischer JP. An automated communication system in a contact registry for persons with rare diseases: scalable tools for identifying and recruiting clinical research participants. Contemp Clin Trials. 2009 Jan;30(1):55-62. doi: 10.1016/j.cct.2008.09.002. Epub 2008 Sep 7.
Mitchell S, Ellingson C, Coyne T, Hall L, Neill M, Christian N, Higham C, Dobrowolski SF, Tuchman M, Summar M; Urea Cycle Disorder Consortium. Genetic variation in the urea cycle: a model resource for investigating key candidate genes for common diseases. Hum Mutat. 2009 Jan;30(1):56-60. doi: 10.1002/humu.20813.
Jain-Ghai S, Nagamani SC, Blaser S, Siriwardena K, Feigenbaum A. Arginase I deficiency: severe infantile presentation with hyperammonemia: more common than reported? Mol Genet Metab. 2011 Sep-Oct;104(1-2):107-11. doi: 10.1016/j.ymgme.2011.06.025. Epub 2011 Jul 13. Erratum in: Mol Genet Metab. 2012 Jan;105(1):159.
Wilson JM, Shchelochkov OA, Gallagher RC, Batshaw ML. Hepatocellular carcinoma in a research subject with ornithine transcarbamylase deficiency. Mol Genet Metab. 2012 Feb;105(2):263-5. doi: 10.1016/j.ymgme.2011.10.016. Epub 2011 Nov 7.
Burrage LC, Jain M, Gandolfo L, Lee BH; Members of the Urea Cycle Disorders Consortium, Nagamani SC. Sodium phenylbutyrate decreases plasma branched-chain amino acids in patients with urea cycle disorders. Mol Genet Metab. 2014 Sep-Oct;113(1-2):131-5. doi: 10.1016/j.ymgme.2014.06.005. Epub 2014 Jul 3.
Burrage LC, Sun Q, Elsea SH, Jiang MM, Nagamani SC, Frankel AE, Stone E, Alters SE, Johnson DE, Rowlinson SW, Georgiou G; Members of Urea Cycle Disorders Consortium, Lee BH. Human recombinant arginase enzyme reduces plasma arginine in mouse models of arginase deficiency. Hum Mol Genet. 2015 Nov 15;24(22):6417-27. doi: 10.1093/hmg/ddv352. Epub 2015 Sep 10.
Krivitzky LS, Walsh KS, Fisher EL, Berl MM. Executive functioning profiles from the BRIEF across pediatric medical disorders: Age and diagnosis factors. Child Neuropsychol. 2016;22(7):870-88. doi: 10.1080/09297049.2015.1054272. Epub 2015 Jul 6.
Waisbren SE, He J, McCarter R. Assessing Psychological Functioning in Metabolic Disorders: Validation of the Adaptive Behavior Assessment System, Second Edition (ABAS-II), and the Behavior Rating Inventory of Executive Function (BRIEF) for Identification of Individuals at Risk. JIMD Rep. 2015;21:35-43. doi: 10.1007/8904_2014_373. Epub 2015 Feb 25.

Responsible Party: Mendel Tuchman, MD, 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: July 26, 2016
Last Verified: July 2016

Keywords provided by Mendel Tuchman, Children's Research Institute:
Urea
Inherited metabolic disorders

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


To Top