Longitudinal Study of Urea Cycle Disorders - Full Text View

Sponsor:	Children's Research Institute
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):	Children's Research Institute
ClinicalTrials.gov Identifier:	NCT00237315

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 II

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

Resource links provided by NLM:

Genetics Home Reference related topics: argininosuccinic aciduria citrullinemia N-acetylglutamate synthase deficiency ornithine translocase deficiency succinic semialdehyde dehydrogenase deficiency

MedlinePlus related topics: Brain Diseases Metabolic Disorders

Drug Information available for: Carbamide Carbamide peroxide

U.S. FDA Resources

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

Estimated Enrollment:	550
Study Start Date:	February 2006
Estimated Study Completion Date:	July 2014
Estimated Primary Completion Date:	July 2014 (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. There is a 50% risk of dying or acquiring a severe disability from UCDs, and currently therapy is considered inadequate. 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 2014. 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 at 6 months, 18 months, 4 years, 8 years, 15 years, and 18 years/adult of age. Psychological testing will take from 30 minutes (for younger children) up to 3 hours, depending on test battery.

Eligibility

Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No
Sampling Method:	Non-Probability Sample

Study Population

550 individuals with urea cycle disorders

Criteria

Inclusion Criteria:

Diagnosis of NAGS deficiency, defined as the detection of a pathogenic mutation or decreased (less than 20 % of control) NAGS enzyme activity in liver
Diagnosis of CPS I deficiency, defined as decreased (less than 20 % of control) CPS I enzyme activity in liver or an identified pathogenic mutation
Diagnosis of OTC deficiency, defined as the identification of a pathogenic mutation, linkage analysis in an affected family, less than 20% of control of OTC activity in the liver, or elevated urinary orotate (greater than 20 uM/mM) following allopurinol loading with absence of argininosuccinic acid
Diagnosis of AS deficiency (Citrullinemia), defined as a greater than or equal to 10-fold elevation of citrulline in plasma, decreased AS enzyme activity in cultured skin fibroblasts or other appropriate tissue, or identification of a pathogenic mutation in the AS gene
Diagnosis of AL deficiency (Argininosuccinic Aciduria, ASA), defined as the presence of argininosuccinic acid in the blood or urine, decreased AL enzyme activity in cultured skin fibroblasts or other appropriate tissue, or identification of a pathogenic mutation in the AL gene
Diagnosis of ARG deficiency (Hyperargininemia), defined as a greater than or equal to 5-fold elevated arginine levels in the blood, decreased arginase enzyme levels in red blood cells or other appropriate tissue, or identification of a pathogenic mutation in the ARG gene
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, or a pathogenic mutation in the ORNT1gene (SLC25A15)
Diagnosis of CITR deficiency (Citrullinemia Type II), defined as elevated citrulline levels in the blood and a pathogenic mutation in the citrin gene
Pending diagnosis of a UCD, 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

Please refer to this study by its ClinicalTrials.gov identifier: 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: Naghmeh Dorrani, MS, CGC 310-825-8084 Ndorrani@mednet.ucla.edu
Sub-Investigator: Stephen Cederbaum, MD
Principal Investigator: Derek Wong, MD
United States, Colorado
The Children's Hospital, Aurora	Recruiting
Aurora, Colorado, United States, 80045
Contact: Curtis Coughlin, MS, CGC 303-724-2310 Coughlin.Curtis@tchden.org
Principal Investigator: Renata C. Gallagher, MD, PhD
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: Uta Lichter-Konecki, MD, PhD
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
Sub-Investigator: Margretta Seashore, 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
Mount Sinai School of Medicine	Recruiting
New York, New York, United States, 10029
Contact: Nina Schrager 212-241-6805 nina.schrager@mssm.edu
Principal Investigator: George A. Diaz, MD
United States, Ohio
Case Western Medical College	Recruiting
Cleveland, Ohio, United States, 44106
Contact: Christine Heggie, BSN, ND 216-844-7124 Christine.Heggie@UHhospitals.org
Principal Investigator: Douglas Kerr, MD
Sub-Investigator: Shawn McCandless, MD
United States, Oregon
Oregon Health and Science University	Recruiting
Portland, Oregon, United States, 97239
Contact: Tina Marrone 503-418-3620 marronet@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: Brendan Lee, MD, PhD
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: Munazzah Ambreen 416-813-7654 ext 2646 munazzah.ambreen@sickkids.ca
Sub-Investigator: Annette Feigenbaum, MD
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

Children's Research Institute

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:	Mark L. Batshaw, MD	Childrens National Medical Center
Principal Investigator:	Mendel Tuchman, MD	Childrens National Medical Center

More Information

Additional Information:

Urea Cycle Disorders Consortium website This link exits the ClinicalTrials.gov site

Publications:

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.

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. Epub 2011 Apr 11. Erratum in: Pediatrics. 2011 Aug;128(2):390.

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. Epub 2008 Jun 17.

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. Epub 2008 Sep 7.

Mitchell S, Ellingson C, Coyne T, Hall L, Neill M, Christian N, Higham C, Dobrowolski SF, Tuchman M, Summar M; the Urea Cycle Disorder Consortium. Genetic variation in the urea cycle: a model resource for investigating key candidate genes for common diseases. Hum Mutat. 2008 Jul 29; [Epub ahead of print]

Responsible Party:	Children's Research Institute
ClinicalTrials.gov Identifier:	NCT00237315 History of Changes
Other Study ID Numbers:	RDCRN 5101, U54RR019453, U54HD061221
Study First Received:	October 10, 2005
Last Updated:	February 8, 2012
Health Authority:	United States: Federal Government

Keywords provided by Children's Research Institute:

Urea
Inherited metabolic disorders

Additional relevant MeSH terms:

Amino Acid Metabolism, Inborn Errors
Brain Diseases
Brain Diseases, Metabolic
Metabolic Diseases
Metabolism, Inborn Errors

Urea Cycle Disorders, Inborn
Brain Diseases, Metabolic, Inborn
Genetic Diseases, Inborn
Central Nervous System Diseases
Nervous System Diseases

ClinicalTrials.gov processed this record on February 09, 2012