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Increasing Ureagenesis in Inborn Errors of Metabolism With N-Carbamylglutamate

Primary Purpose

Urea Cycle Disorders, Inborn, Inborn Errors of Metabolism, Propionic Acidemia

Status

Withdrawn

Phase

Phase 2

Locations

Study Type

Interventional

Intervention

N-carbamylglutamate

About this trial

This is an interventional treatment trial for Urea Cycle Disorders, Inborn focused on measuring Ureagenesis, Urea cycle, Inborn errors of metabolism

Eligibility Criteria

3 Years - 70 Years (Child, Adult, Older Adult)All SexesAccepts Healthy Volunteers

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.

Sites / Locations

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

N-carbamylglutamate (Carbaglu)

Arm Description

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Full Information

NCT ID

NCT01341379

First Posted

April 22, 2011

Last Updated

May 28, 2014

Sponsor

Children's Hospital of Philadelphia

Collaborators

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

1. Study Identification

Unique Protocol Identification Number

NCT01341379

Brief Title

Increasing Ureagenesis in Inborn Errors of Metabolism With N-Carbamylglutamate

Official Title

Increasing Ureagenesis in Inborn Errors of Metabolism With N-Carbamylglutamate

Study Type

Interventional

2. Study Status

Record Verification Date

May 2014

Overall Recruitment Status

Withdrawn

Why Stopped

Lack of funding

Study Start Date

December 2010 (undefined)

Primary Completion Date

August 2012 (Actual)

Study Completion Date

August 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Children's Hospital of Philadelphia

Collaborators

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

Keywords

Ureagenesis, Urea cycle, Inborn errors of metabolism

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

0 (Actual)

8. Arms, Groups, and Interventions

Arm Title

N-carbamylglutamate (Carbaglu)

Arm Type

Experimental

Intervention Type

Drug

Intervention Name(s)

N-carbamylglutamate

Other Intervention Name(s)

Carbaglu

Intervention Description

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

Primary Outcome Measure Information:

Title

Rate of ureagenesis

Description

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.

Time Frame

3 days

10. Eligibility

Sex

All

Minimum Age & Unit of Time

3 Years

Maximum Age & Unit of Time

70 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Marc Yudkoff, MD

Organizational Affiliation

Children's Hospital of Philadelphia

Official's Role

Principal Investigator

12. IPD Sharing Statement

Citations:

PubMed Identifier

20566609

Citation

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.

Results Reference

result

PubMed Identifier

20338795

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(Suppl 1):S37-41. doi: 10.1016/j.ymgme.2010.02.017. Epub 2010 Feb 26.

Results Reference

result

PubMed Identifier

19660971

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

Results Reference

result

PubMed Identifier

18414145

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 biomarkers. Pediatr Res. 2008 Aug;64(2):213-7. doi: 10.1203/PDR.0b013e318179454b.

Results Reference

result

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Increasing Ureagenesis in Inborn Errors of Metabolism With N-Carbamylglutamate

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