Urea Cycle Disorders Consortium Research

OTHER CLINICAL TRIALS FOR UCD

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Ureas Cycle Disorders Consortium Research Centers

In 2003, the National Institutes of Health (NIH) developed the pioneering Rare Diseases Clinical Research Network (RDCRN) in order to promote and fund collaborative research on rare diseases. To answer this call, the Urea Cycle Disorders Consortium (UCDC), comprised of 5 academic centers, and led by Dr. Mark L. Batshaw of Children’s National Medical Center, was founded with the collaboration of the National Urea Cycle Disorders Foundation. The UCDC was awarded a 5-year grant by NIH-RDCRN to study urea cycle disorders. Only 11 rare disease consortiums received this prestigious award. Five years later, in 2008, the RDCRN offered another round of funding to rare diseases researchers through a highly competitive grant process. The UCDC applied, received the highest score of all applications, and was awarded another 5-year grant to continue UCD research. In 2014, UCDC received its third consecutive award, attaining a perfect score of 10 on the grant review. Additional funding is being provided by matching grants from private family foundations. The National Urea Cycle Disorders Foundation provides funding for neuroimaging studies at the Georgetown University site, and plans to fund 2 additional new research centers in 2015 (Stanford University and University of California San Francisco).

The purpose of the UCDC is to perform cutting-edge research to improve the understanding of UCD and to accelerate new treatments. The UCDC includes teams of doctors, nurses, research coordinators and research laboratories at 14 academic centers in the US, Canada and Europe working together and in close collaboration with the National Urea Cycle Disorders Foundation. One of the key roles the Foundation plays is ensuring the needs and wishes of UCD patients and families are met as we strive to improve their lives and learn more about preventing the effects of urea cycle disorders.

"The collaboration has provided a unique environment which has led to discoveries that have improved outcome for affected patients that we could have only dreamed about before the Rare Disease Clinical Research Network came into being," says Dr. Batshaw.  Rare diseases affect over 25 million Americans, but only a handful have any treatments available. Since 2003, the UCDC and NUCDF have assisted in the development and FDA approval of three new drugs to treat urea cycle disorders by bringing together stakeholders, developing clinical trial protocols, and conducting clinical trials at the UCDC sites. The UCDC collaboration now extends internationally to include the inborn error of metabolism researcher groups in Japan, Australia, and Europe.

Many patients and families with urea cycle disorders struggle to obtain an accurate diagnosis and access life-saving treatment. The UCDC sites are "centers of excellence" for diagnosis, treatment and monitoring, and have improved both identification and outcomes for patients.

Dr. Tuchman states that "the creation and funding of the UCDC has been the culmination of many years of clinical and research work...patients with UCD now have new hopes for a better future as a result of the projects conducted by the UCDC." The UCDC has helped develop newborn screening technology to improve diagnosis, and conducts research on brain function using advanced neuroimaging techniques at the Georgetown site (Dr. Andrea Gropman). These neuroimaging techniques are unlocking the mysteries of the effects of UCD on brain function and are the foundation for developing new treatments to prevent these devastating effects.

The UCDC also trains the next generation of clinicians and researchers, and provides education on UCDs to healthcare professionals and the public through its partnership with the National Urea Cycle Disorders Foundation.

 

UCDC Principal Investigators:

Lead Principal Investigator

Mark L. Batshaw, M.D., Children's National Medical Center

Co-Principal Investigators

Mendel Tuchman, M.D., Children's National Medical Center

Marshall Summar, MD, Children's National Medical Center

Cynthia Le Mons, National Urea Cycle Disorders Foundation

UCDC Research Centers and Site Investigators:

  • Children’s National Medical Center, Washington, D.C. (Nicholas Ah-Mew, M.D.)
  • Georgetown University (Andrea Gropman, M.D.)
  • Children’s Hospital of Philadelphia, PA (Marc Yudkoff, M.D)
  • Baylor College of Medicine (Sandesh Nagamani, MD., Brendan Lee, M.D.)
  • University of Minnesota Amplatz Childen's Hospital (Susan Berry, M.D.)
  • University of California at Los Angeles (UCLA), CA (Derek Wong, M.D.)
  • Mount Sinai School of Medicine, New York, NY (George Diaz, M.D.)
  • Rainbow and Babies Hospital, Cleveland, OH (Shawn McCandless, M.D.)
  • Children's Hospital of Boston/Harvard, Boston, MA (Harvey Levy, M.D., Gerald Berry, M.D.)
  • Oregon Health & Science University, Portland, OR (Cary Harding, M.D.)
  • Seattle Children's Hospital, Seattle, WA (J. Lawrence Merritt, M.D.)
  • Children's Hospital Denver, Colorado (Renata Gallagher, M.D.)
  • Hospital for Sick Children, Toronto, Canada (Andres Schulze, M.D.)
  • University Children's Hospital, Zurich, Switzerland (Mattias Baumgartner, M.D., Tamar Stricker, M.D.)
  • Centre for Pediatric and Adolescent Medicine, Heidelberg, Germany (Georg Hoffman, M.D., Stephan Kolker, M.D., Peter Burgard, Ph.D.)

PARTICIPATING IN UCD Consortium RESEARCH

STUDIES OPEN FOR ENROLLMENT

Longitudinal Study of Urea Cycle Disorders:  The goal of the Longitudinal Study is to improve the treatment and overall health of persons with UCD by collecting information on the growth, development and outcomes of the study participants over time.  Participation in this study is critical; the more information that is collected, the better we will be able to understand the disorders, how they affect patients and families, and how treatment and short and long-term outcomes can be improved. The Longitudinal Study is making it possible to determine:

How effective are the different treatments and diets that are currently in use and are there better treatments that could be used?
What are the triggers that lead to hyperammonemia and subsequent hospital stays?
Which of the biochemical laboratory tests commonly ordered during a metabolic clinic visit are the best at determining the severity of the urea cycle disorder?
How common are hyperammonemic episodes, developmental disabilities and various other long-term health concerns for people with UCD?
How common are the different UCDs in the general population (incidence and prevalence)?
How do persons with UCD and family members cope with the disease and how can their physicians improve the coping process?

How To Participate: First, enroll in the UCDC Contact Registry, or contact the research coordinator at the UCDC research center nearest to you (request latest contact information here). The coordinator will make sure that the potential participant is eligible for the study.  Once eligibility is confirmed, the individual will be asked to visit the UCDC research center for an initial study visit. Travel expenses are covered by the study.  Follow-up visits are arranged at the participant’s local metabolic physician’s office if possible.  Participants return to the UCDC center for a study visit every to six or twelve months, depending on age.  Study visits are very similar to any regular metabolic clinic visit.  Participants and their families are asked to provide information about the participant’s medical history and family history.  A physical examination is performed and blood and urine collected for standard biochemical studies. Parents or patients are asked to complete a brief questionnaire about how their daily life is going.  Participants undergo neuropsychological testing at specific intervals according to age.  This testing is used to identify differences in how a person’s brain processes information and learns.  Some of these processes include problem solving, how well language is expressed or understood, memory and attention, and brain's ability to plan and organize (called "executive function").  This information assists researchers in understanding the effects of UCD on brain function and in developing new treatments and therapies to improve the lives of patients.

Neuroimaging Study - Mechanisms of Brain Injury in Inborn Errors of Metabolism:  Many inborn errors of metabolism, including urea cycle disorders, are associated with irreversible brain injury.  It is not clear how metabolite intoxication or depletion of substrates accounts for the specific cognitive and neurologic findings observed in patients with UCDs.  Neuroimaging is a powerful diagnostic and research tool which can provide information about the timing, extent, reversibility, and possible mechanism of neural injury in a non-invasive manner.  The goal of the study is to use advances in neuroimaging (MRI, fMRI, MRS) to improve understanding of underlying neural mechanisms that contribute to cognitive, pathologic (white matter disturbances). To date, the neuroimaging study has made it possible to detect metabolic and structural abnormalities in the brains of individuals with OTC deficiency by evaluating heterozygous female carriers and late onset males.  This research focuses on on:

Ammonia, a well recognized neurotoxin, and the manner in which it exerts effects on the central nervous system (CNS).
Effects of acute versus chronic hyperammonemia at the cell and neurocircuitry level.
Role of glutamine in hyperammonemic encephalopathy (rise in plasma glutamine levels preceding hyperammonemia; difference between plasma levels and CNS levels; why is glutamine chronically elevated in brain even with normal ammonia levels).
Determine patterns of neuroanatomic damage in OTCD, and examine neural mechanism of cognitive and motor system abnormalities.

Participants in the neuroimaging study will need to travel to the study site (travel and lodging paid) at Children’s National Medical Center, undergo physical and neurological examinations and laboratory testing (ammonia, plasma amino acids, urine organic acids) and MRI scanning.

How to Participate: For information, contact Ileana Pacheco, Study Coordinator

N-carbamylglutamate (NCLG) treatment in N-acetylglutamate synthetase deficiency (NAGS), partial carbamyl phosphate synthetase deficiency (CPS1) or partial ornithine transcarbamylase deficiency (OTC):  Recent study showed Carbaglu® to be effective and/or curative for NAGS deficiency in limited patient studies*. This research study is now being expanded to partial CPS and OTC deficiencies, and two other inborn errors of metabolism, propionic acidemia and methylmalonic aciduria.  The study measures the effect of the medication Carbaglu on the rate at which the body converts ammonia into urea (ureagenesis). 

Participants must travel to a study site: Children's National Medical Center, Washington DC, Case Western Reserve, Cleveland OH, or Children's Hospital Philadelphia PA, for 3 day-long study (travel and lodging paid).  Participants will be studied twice, off NCLG, and three days following oral administration of the drug. 

*(M. Tuchman, Potential cure for N-acetylglutamate deficiency with N-carbamylglutamate. NUCDF Newsletter Vol XIV 2005; L. Caldovic, H. Marizono, Y. Daikhn, I. Nissim, R. McCarter, M. Yudkoff, M. Tuchman, Restoration of ureagenesis in N-acetylglutamate synthetase deficiency by N-carbamylglutamate. J Pediatr 2004; 145:552-4; Help Isn’t Just for Kids at Children’s, Washington Post 12/28/05)

Trial Information: ClinicalTrials.gov

How to Participate: For information, contact the Study Coordinator

Randomized, Double-Blind, Crossover Study of Sodium Phenylbutyrate (Buphenyl™) and Low-Dose Arginine Compared to High-Dose Arginine Alone on Liver Function, Ureagenesis and Subsequent Nitric Oxide Production in Patients with Argininosuccinic Aciduria (ASA):  Unlike the other urea cycle disorders, ASA can cause liver damage or hepatitis leading to liver failure.  The cause of this damage is not known.  Since argininosuccinic acid is found in this disorder and not the other urea cycle disorders, it is theorized that it may be the toxic substance causing liver damage.  This study is to determine if treatment of ASA patients with sodium phenylbutyrate (Buphenyl™) along with low-dose arginine improves outcomes.

Participants must have a confirmed diagnosis of ASA and be at least 3 years old.  Participants must travel to Baylor College of Medicine in Houston, Texas, for initial evaluation and every six months thereafter.  Laboratory studies (including liver function, phenylbutyrate and phenylacetate levels) will be monitored.

How to Participate:  Study full, no longer recruiting participants.

For more information or questions regarding any of the studies, contact NUCDF Executive Director.

More About Clinical Trials

RDCRN Featured in the Wall Street Journal!

 

Urea Cycle Disorders Research Centers

“I have been a participant or observer in many efforts to bring together families and researchers in regard to a specific disorder or group of disorders, and I have never seen one in which there was such a superb collaboration and focus on the common goal.” 

Hugo Moser, M.D., Adrenoleukodystrophy Researcher (“Lorenzo’s Oil”), Kennedy-Krieger Institute, NIH Monitor UCDC 2003

"The NUCDF has been instrumental in improving the quality of life for patients and their families by helping enhance research on the prevention, diagnosis and treatment of urea cycle disorders. The Foundation has been critical to the success of the Urea Cycle Disorders Research Consortium. Ms. Cynthia Le Mons, Executive Director of the NUCDF, has strengthened the collaboration between the NUCDF and the UCD research consortium by serving as Co-Principal Investigator. She has been an extremely effective leader."

Mendel Tuchman, M.D.

Co-Principal Investigator, UCDC

Scientific Director, Children's Research Institute

Children's National Medical Center