Increasing Ureagenesis in Inborn Errors of Metabolism With N-Carbamylglutamate

Inborn Errors of Metabolism Clinical Trial

Official title:

Increasing Ureagenesis in Inborn Errors of Metabolism With N-Carbamylglutamate

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT01341379
• Other study ID #: 10-007806
• Secondary ID: R01HD058567
• Status: Withdrawn
• Phase: Phase 2
• First received: April 22, 2011
• Last updated: May 28, 2014
• Start date: December 2010
• Est. completion date: August 2012

Study information

• Verified date: May 2014
• Source: Children's Hospital of Philadelphia
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationUnited States: Federal Government
• Study type: Interventional

Clinical Trial 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.

Description:

• To determine whether brief (3 day) treatment with N-carbamylglutamate can improve ureagenesis in adult healthy controls and patients with the following inborn errors of metabolism: N-acetylglutamate synthetase deficiency, propionic acidemia, methylmalonic acidemia, carbamylphosphate synthase deficiency, ornithine transcarbamylase deficiency and the syndrome of hyperammonemia, hypoglycemia and hyperinsulinemia (HHH Syndrome).

• To determine if such treatment improves other indicators of abnormal nitrogen metabolism such as elevated blood levels of glutamine, glycine and alanine.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: August 2012
• Est. primary completion date: August 2012
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 3 Years to 70 Years

Eligibility

Inclusion Criteria:

• 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).

Exclusion Criteria:

• 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.

Study Design

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Acidosis
• Amino Acid Metabolism, Inborn Errors
• Carbamoyl-Phosphate Synthase I Deficiency Disease
• Carbamyl Phosphate Synthetase Deficiency
• Inborn Errors of Metabolism
• Metabolism, Inborn Errors
• Methylmalonic Acidemia
• Propionic Acidemia
• Urea Cycle Disorders, Inborn

Intervention

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

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
Children's Hospital of Philadelphia	Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

References & 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. — View Citation

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. Erratum in: Mol — View Citation

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 biomarke — View Citation

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:S37-41. doi: 10.1016/j.ymgme.2010.02.017. Epub 2010 Feb 26. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No

External Links

•   Urea Cycle Research Consortium