Increasing Ureagenesis in Inborn Errors of Metabolism With N-Carbamylglutamate

NCT01341379 | Withdrawn Phase 2 DMC

• 2 other identifiers: 10-007806R01HD058567
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

Hyperammonemia, which can cause brain damage, occurs in many different kinds of inborn errors of metabolism. The investigators propose to determine if short-term (3 day) treatment with N-carbamylglutamate can diminish hyperammonemia by enhancing ureagenesis in these patients. The investigators propose here a short-term (3 day) trial. If it succeeds, the investigators would consider more extensive long-term studies of the drug.

Conditions

Urea Cycle Disorders, Inborn; Inborn Errors of Metabolism; Propionic Acidemia; Methylmalonic Acidemia; Carbamyl Phosphate Synthetase Deficiency

Keywords

Ureagenesis; Urea cycle; Inborn errors of metabolism

Outcome Measures

Primary Outcomes (1)

• Rate of ureagenesis

  Goal is to determine whether a 3 day trial of N-carbamylglutamate increases ureagenesis in patients with urea cycle defects and other inborn errors of metabolism.

  3 days

Study Arms (1)

N-carbamylglutamate (Carbaglu)

EXPERIMENTAL

Drug: N-carbamylglutamate

Interventions

N-carbamylglutamate DRUG

N-carbamylglutamate: 200 mg/kg/day for 3 days, divided into 4 daily oral doses

Also known as: Carbaglu

N-carbamylglutamate (Carbaglu)

Eligibility Criteria

• Age: 3 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Age range: males or females, ages 3 years - 70 years
• Condition(s): N-acetylglutamate synthetase deficiency, propionic acidemia, methylmalonic acidemia, carbamylphosphate synthase deficiency, ornithine transcarbamylase deficiency and the syndrome of hyperammonemia, hypoglycemia and hyperinsulinemia.
• In addition, healthy volunteers will be studied (ages 18 years - 50 years).

You may not qualify if:

• Acutely ill on day of study (fever, evidence of hyperammonemia - ataxia, worsening obtundation, focal neurologic signs, seizures, increased intracranial pressure, vomiting, signs of acute respiratory or enteric illness, headache, confusion, disorientation, acute personality change).
• Girls 11 years of age must have a negative urine/serum pregnancy test within 1 week prior to testing unless having a menstrual period during week of test
• Lactating females
• Hyperammonemia probably refractory to N-carbamylglutamate: other urea cycle disorders (UCD), lysinuric protein intolerance, mitochondrial disorders, congenital lactic acidemia, fatty acid oxidation defects or primary liver disease.
• Amount of blood necessary for study exceeds safe limits.
• Any investigational drug use within 30 days prior to enrollment.
• Parents/guardians or subjects who, in the opinion of the PI, may be non-compliant with study schedules or procedures.
• Subjects who do not meet all the enrollment criteria may not be enrolled. Any violations of these criteria will be reported in accordance with Institutional Review Board (IRB) Policies and Procedures.

Sponsors & Collaborators

• Children's Hospital of Philadelphia: lead
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator

Related Publications (4)

• Ah Mew N, McCarter R, Daikhin Y, Nissim I, Yudkoff M, Tuchman M. N-carbamylglutamate augments ureagenesis and reduces ammonia and glutamine in propionic acidemia. Pediatrics. 2010 Jul;126(1):e208-14. doi: 10.1542/peds.2010-0008. Epub 2010 Jun 21.

  PMID: 20566609 RESULT

• Yudkoff M, Ah Mew N, Daikhin Y, Horyn O, Nissim I, Nissim I, Payan I, Tuchman M. Measuring in vivo ureagenesis with stable isotopes. Mol Genet Metab. 2010;100 Suppl 1(Suppl 1):S37-41. doi: 10.1016/j.ymgme.2010.02.017. Epub 2010 Feb 26.

  PMID: 20338795 RESULT

• Ah Mew N, Payan I, Daikhin Y, Nissim I, Nissim I, Tuchman M, Yudkoff M. Effects of a single dose of N-carbamylglutamate on the rate of ureagenesis. Mol Genet Metab. 2009 Dec;98(4):325-30. doi: 10.1016/j.ymgme.2009.07.010. Epub 2009 Jul 14.

  PMID: 19660971 RESULT

• Tuchman M, Caldovic L, Daikhin Y, Horyn O, Nissim I, Nissim I, Korson M, Burton B, Yudkoff M. N-carbamylglutamate markedly enhances ureagenesis in N-acetylglutamate deficiency and propionic acidemia as measured by isotopic incorporation and blood biomarkers. Pediatr Res. 2008 Aug;64(2):213-7. doi: 10.1203/PDR.0b013e318179454b.

  PMID: 18414145 RESULT

MeSH Terms

Conditions

Urea Cycle Disorders, Inborn; Metabolism, Inborn Errors; Propionic Acidemia; Methylmalonic acidemia; Carbamoyl-Phosphate Synthase I Deficiency Disease

Interventions

N-carbamylglutamate; carglumic acid

Condition Hierarchy (Ancestors)

Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Amino Acid Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Metabolic Diseases; Nutritional and Metabolic Diseases; Mitochondrial Diseases

Study Officials

• Marc Yudkoff, MD

  Children's Hospital of Philadelphia

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Division Chief

Study Record Dates

• First Submitted: April 22, 2011
• First Posted: April 25, 2011
• Study Start: December 1, 2010
• Primary Completion: August 1, 2012
• Study Completion: August 1, 2012
• Last Updated: May 29, 2014

Record last verified: 2014-05