Try our beta test site
IMPORTANT: Listing of a study on this site does not reflect endorsement by the National Institutes of Health. Talk with a trusted healthcare professional before volunteering for a study. Read more...

N-Carbamylglutamate (Carbaglu) In The Treatment Of Hyperammonemia

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2016 by Children's Research Institute
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Information provided by (Responsible Party):
Mendel Tuchman, Children's Research Institute Identifier:
First received: February 12, 2009
Last updated: August 15, 2016
Last verified: August 2016
This study is based on the hypothesis that a new drug N-carbamylglutamate (Carbaglu®) will enhance the ability of the liver to dispose of toxic ammonia which accumulates in several metabolic diseases including urea cycle disorders and organic acid disorders.

Condition Intervention Phase
Inborn Errors of Metabolism
Drug: N-carbamylglutamate
Phase 2
Phase 3

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: N-Carbamylglutamate (Carbaglu) In The Treatment Of Hyperammonemia

Resource links provided by NLM:

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

Primary Outcome Measures:
  • Rate of ureagenesis as determined by 13C enrichment of urea [ Time Frame: 3 days of treatment ]

Secondary Outcome Measures:
  • Plasma ammonia concentration [ Time Frame: 3 days ]
  • Plasma amino acid levels [ Time Frame: 3 days ]
  • Urine Orotic Acid [ Time Frame: 3 days ]
    Only in patients with OTC deficiency

  • Blood Urea Nitrogen (BUN) [ Time Frame: 3 days ]
  • Routine safety laboratory tests (CBC, LFTs, Creatinine) [ Time Frame: 3 days ]

Estimated Enrollment: 70
Study Start Date: August 2008
Estimated Study Completion Date: July 2018
Estimated Primary Completion Date: July 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Carbaglu
Investigate whether a 3-day treatment with NCG can improve or restore urea genesis capacity in patients with NAGS, CPSI, or OTC deficiency or PA or MMA using surrogate markers: [13C] label incorporation into urea and plasma levels of ammonia, urea nitrogen (BUN) and amino acids
Drug: N-carbamylglutamate
100 mg/kg/day or 2.2 g/M2/day in 3-4 divided doses for 3 days
Other Name: Carglumic acid, Carbaglu

Detailed Description:

Hyperammonemia associated with several rare inherited disorders frequently causes mental retardation, developmental disabilities and death. The overall goal of this study is to investigate the short-term efficacy and safety of the orphan drug, N-Carbamyl-L-glutamate (Carbaglu®, abbreviated as NCG), for the treatment of hyperammonemia in rare inherited disorders: carbamyl phosphate synthetase I (CPSI) deficiency, NAGS deficiency, ornithine transcarbamylase (OTC) deficiency, propionic acidemia (PA) and methylmalonic acidemia (MMA).

The primary aims are:

  1. To investigate whether 3-day treatment with NCG can improve or restore ureagenesis capacity in patients with NAGS, CPSI or OTC deficiency using as surrogate markers: [13C] label incorporation into urea and plasma levels of ammonia, urea and glutamine. In addition, to determine whether treatment with NCG in OTC deficiency increases the production of a nitrogen containing intermediate, orotic acid, as a mechanism for eliminating nitrogen in lieu of urea.
  2. To investigate whether ureagenesis capacity is deficient in patients with PA and MMA and whether 3-day treatment with NCG can improve or restore ureagenesis capacity in all or some of these patients.
  3. To evaluate the safety of short-term (3-day) treatment with NCG in the above patients using clinical and laboratory parameters.

The hypothesis is that ureagenesis capacity as evidenced by [13C] incorporation into urea is deficient in each of these five disorders and that treatment with NCG will improve or restore ureagenesis in patients affected by them. The study will be conducted in the General Clinical Research Centers (GCRC) of the Children's National Medical Center, Washington, D.C. and the Children's Hospital of Philadelphia. Patients (1 day to 70 years of age) with any of the five disorders are eligible for the study. They will all be tested in a short-term trial using surrogate markers (incorporation of [13C] label from Na-acetate into urea, and plasma levels of ammonia, urea and glutamine) before and immediately following 3 days of treatment with NCG. The patients will also be evaluated for short-term safety of NCG using clinical and laboratory parameters. The results of this study will provide important efficacy data, which should help to bring Carbaglu®) to the US market for the benefit of patients with any of these orphan diseases found to be responsive to NCG in this trial.


Ages Eligible for Study:   up to 70 Years   (Child, Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Between 1 day - 70 years of age
  2. Viable neonates, neonates with uncertain viability are excluded Diagnosed with one of the following five inborn errors of metabolism: NAGS, CPSI,PA, MMA, or OTC deficiency.
  3. Diagnostic requirements:

    • NAGS deficiency - Identification of pathogenic mutation and/or decreased (<20% of control) NAGS enzyme activity in liver
    • CPSI deficiency - decreased (<20% of control) CPSI enzyme activity in liver deficiency of liver CPSI in the presence of normal or substantial activity of OTC (Tuchman et al 1980) and/or molecular confirmation of deleterious mutations (Summary et al 2003).
    • High level of clinical suspicion of NAGS or CPSI deficiency - Failure to meet diagnostic criteria for either NAGS or CPSI deficiency as listed above, but:

      1. Recurrent hyperammonemic episodes (NH3 >70umol/l) with elevated plasma glutamine (>/= 800umol/l)
      2. Urinary orotate levels within normal limits (</= 5 umol/mmol urine creatinine)
      3. Absence of argininosuccinic acid in blood or urine
      4. Low or normal level of citrulline (</=92umol/l) and arginine (</= 179 umol/l) and ornithine (</=159umol/l) within normal limits in blood
    • OTC deficiency- Identification of pathogenic mutation and/or-pedigree analysis consistent with familial hyperammonemia segregating in an x-linked semi-dominant pattern and/or -<20% of control OTC activity in liver and/or -elevated urinary orotate (>20%umol/mmol creatinine) after allopurinol challenge test
    • PA and MMA- diagnostic urine organic acid analysis and confirmation of absence of responsiveness to biotin and vitamin B12 respectively.

Exclusion Criteria:

  • Subjects acutely ill on day of the study
  • Pregnant females- documentation of a negative pregnancy test within a week prior to testing is required for females 12 years and older, unless having a menstrual period during that week or other circumstances which preclude pregnancy (e.g. hysterectomy, menopause)
  • Subjects with hyperammonemia caused by other urea cycle disorders, lysinuric protein intolerance, mitochondrial disorders, congenital lactic academia, fatty acid oxidation defects and primary liver disease
  • Subjects requiring a peripherally inserted central catheter (PICC) for blood draws may need to be moderately sedated and are excluded
  • Subjects with hemoglobin < 9 g/dl
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT00843921

Contact: Mendel Tuchman, MD 202-476-2549

United States, District of Columbia
Childrens Research Institute Recruiting
Washington, District of Columbia, United States, 20010
Contact: Mendel Tuchman, MD    202-476-2549   
Principal Investigator: Mendel Tuchman, MD         
Sponsors and Collaborators
Mendel Tuchman
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Principal Investigator: Mendel Tuchman, MD Children's Research Institute
  More Information

Responsible Party: Mendel Tuchman, MD, Children's Research Institute Identifier: NCT00843921     History of Changes
Other Study ID Numbers: CNMC 3694
1R01HD058567-01 ( US NIH Grant/Contract Award Number )
Study First Received: February 12, 2009
Last Updated: August 15, 2016
Individual Participant Data  
Plan to Share IPD: Yes
Plan Description: Individual participant data will be shared with that particular participant

Keywords provided by Children's Research Institute:

Additional relevant MeSH terms:
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Metabolic Diseases
Pathologic Processes processed this record on April 26, 2017