Increasing Ureagenesis in Inborn Errors of Metabolism With N-Carbamylglutamate

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.

Study Overview

• Status: Withdrawn
• Conditions: Urea Cycle Disorders, Inborn; Inborn Errors of Metabolism; Propionic Acidemia; Methylmalonic Acidemia; Carbamyl Phosphate Synthetase Deficiency
• Intervention / Treatment: Drug: N-carbamylglutamate

Detailed 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.

• Study Type: Interventional
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years to 70 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: N-carbamylglutamate (Carbaglu)	Drug: N-carbamylglutamate; N-carbamylglutamate: 200 mg/kg/day for 3 days, divided into 4 daily oral doses; Other Names: Carbaglu

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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

Collaborators and Investigators

• Sponsor: Children's Hospital of Philadelphia
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Investigators: Principal Investigator: Marc Yudkoff, MD, Children's Hospital of Philadelphia

Publications and helpful links

General Publications

• 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.
• 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.
• 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 Genet Metab. 2010 Apr;99(4):440.
• 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.

Study record dates

Study Major Dates

• Study Start: December 1, 2010
• Primary Completion (Actual): August 1, 2012
• Study Completion (Actual): August 1, 2012

Study Registration Dates

• First Submitted: April 22, 2011
• First Submitted That Met QC Criteria: April 22, 2011
• First Posted (Estimate): April 25, 2011

Study Record Updates

• Last Update Posted (Estimate): May 29, 2014
• Last Update Submitted That Met QC Criteria: May 28, 2014
• Last Verified: May 1, 2014

More Information

Terms related to this study

• Keywords: Ureagenesis; Urea cycle; Inborn errors of metabolism
• Additional Relevant MeSH Terms: Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Brain Diseases, Metabolic; Mitochondrial Diseases; Brain Diseases, Metabolic, Inborn; Amino Acid Metabolism, Inborn Errors; Acid-Base Imbalance; Metabolism, Inborn Errors; Acidosis; Urea Cycle Disorders, Inborn; Propionic Acidemia; Carbamoyl-Phosphate Synthase I Deficiency Disease
• Other Study ID Numbers: 10-007806; R01HD058567 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No