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N-Carbamylglutamate (Carbaglu) In The Treatment Of Hyperammonemia

Primary Purpose

Inborn Errors of Metabolism

Status
Unknown status
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
N-carbamylglutamate
Sponsored by
Mendel Tuchman
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Inborn Errors of Metabolism focused on measuring Hyperammonemia

Eligibility Criteria

1 Day - 70 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Childrens Research Institute

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Carbaglu

Arm Description

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

Outcomes

Primary Outcome Measures

Rate of ureagenesis as determined by 13C enrichment of urea

Secondary Outcome Measures

Plasma ammonia concentration
Plasma amino acid levels
Urine Orotic Acid
Only in patients with OTC deficiency
Blood Urea Nitrogen (BUN)
Routine safety laboratory tests (CBC, LFTs, Creatinine)

Full Information

First Posted
February 12, 2009
Last Updated
February 13, 2020
Sponsor
Mendel Tuchman
Collaborators
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
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1. Study Identification

Unique Protocol Identification Number
NCT00843921
Brief Title
N-Carbamylglutamate (Carbaglu) In The Treatment Of Hyperammonemia
Official Title
N-Carbamylglutamate (Carbaglu) In The Treatment Of Hyperammonemia
Study Type
Interventional

2. Study Status

Record Verification Date
February 2020
Overall Recruitment Status
Unknown status
Study Start Date
August 2008 (undefined)
Primary Completion Date
April 25, 2018 (Actual)
Study Completion Date
June 30, 2020 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Mendel Tuchman
Collaborators
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
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: 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. 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. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Inborn Errors of Metabolism
Keywords
Hyperammonemia

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
52 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Carbaglu
Arm Type
Experimental
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
N-carbamylglutamate
Other Intervention Name(s)
Carglumic acid, Carbaglu
Intervention Description
100 mg/kg/day or 2.2 g/M2/day in 3-4 divided doses for 3 days
Primary Outcome Measure Information:
Title
Rate of ureagenesis as determined by 13C enrichment of urea
Time Frame
3 days of treatment
Secondary Outcome Measure Information:
Title
Plasma ammonia concentration
Time Frame
3 days
Title
Plasma amino acid levels
Time Frame
3 days
Title
Urine Orotic Acid
Description
Only in patients with OTC deficiency
Time Frame
3 days
Title
Blood Urea Nitrogen (BUN)
Time Frame
3 days
Title
Routine safety laboratory tests (CBC, LFTs, Creatinine)
Time Frame
3 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
1 Day
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Between 1 day - 70 years of age 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. 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: Recurrent hyperammonemic episodes (NH3 >70umol/l) with elevated plasma glutamine (>/= 800umol/l) Urinary orotate levels within normal limits (</= 5 umol/mmol urine creatinine) Absence of argininosuccinic acid in blood or urine 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Mendel Tuchman, MD
Organizational Affiliation
Children's National Research Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
Childrens Research Institute
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20010
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Individual participant data will be shared with that particular participant

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N-Carbamylglutamate (Carbaglu) In The Treatment Of Hyperammonemia

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