Inborn Errors of MetabolismPhase 2/3NCT00843921
N-Carbamylglutamate (Carbaglu) In The Treatment Of Hyperammonemia
A Phase 2/3 study testing N-carbamylglutamate in people with Inborn Errors of Metabolism, run by Mendel Tuchman at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 1 day to 70 years
- Conditions the study is for
- Inborn Errors of Metabolism
- What is being tested?
- N-carbamylglutamate
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 52 participants
- Where
- 1 siteUnited States
- Study dates
- Aug 2008to 30 Jun 2020
- Phase
- Phase 2/3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 1 day to 70 years
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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:
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- 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.
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
Childrens Research Institute
Washington D.C., District of Columbia, 20010
About this study
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.
Read the 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.
- Conditions
- Inborn Errors of Metabolism
- Being tested
- N-carbamylglutamate
- Keywords
- Hyperammonemia
- Medical subject headings
- Metabolism, Inborn Errors, Hyperammonemia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
N-carbamylglutamateDrug
Also called Carglumic acid, Carbaglu
100 mg/kg/day or 2.2 g/M2/day in 3-4 divided doses for 3 days
| Study group | Role | What they receive |
|---|---|---|
| Carbaglu | Experimental | 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 Receives: Drug: N-carbamylglutamate |
What is being measured
The primary outcome is the main question the study is designed to answer.
Rate of ureagenesis as determined by 13C enrichment of urea
Measured: 3 days of treatment
Secondary outcomes (5)
Plasma ammonia concentration
Measured: 3 days
Plasma amino acid levels
Measured: 3 days
Urine Orotic Acid
Only in patients with OTC deficiency
Measured: 3 days
Blood Urea Nitrogen (BUN)
Measured: 3 days
Routine safety laboratory tests (CBC, LFTs, Creatinine)
Measured: 3 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Feb 2009 (estimated)
- Study startAug 2008
- Primary completion25 Apr 2018
- Study completion30 Jun 2020 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Inborn Errors of MetabolismStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2/3
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 52 participants (actual)
Sponsor and investigators
- Lead sponsor
- Mendel Tuchman
- Sponsor type
- University, hospital or other
- Collaborators
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
- Responsible party
- Sponsor-investigator, Mendel Tuchman, Children's National Research Institute
- Investigators
- Mendel Tuchman, MD, Principal investigator, Children's National Research Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00843921
- Sponsor's protocol ID
- CNMC 3694
- Other IDs
- 1R01HD058567-01
- Status last verified
- Feb 2020
- First submitted
- 12 Feb 2009
- Last updated
- 17 Feb 2020
- Results posted
- No
- Data monitoring committee
- Yes
- Individual data sharing
- Yes: Individual participant data will be shared with that particular participant
Study at a glance
From the registry record, last updated by the sponsor on 17 Feb 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- N-Carbamylglutamate (Carbaglu) In The Treatment Of Hyperammonemia
- ClinicalTrials.gov ID
- NCT00843921
- Acronym / sponsor ID
- CNMC 3694
- Conditions
- Inborn Errors of Metabolism
- Keywords
- Hyperammonemia
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 52 participants (actual)
- Lead sponsor
- Mendel TuchmanUniversity, hospital or other
- Collaborators
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
- Study start
- Aug 2008
- Primary completion
- 25 Apr 2018 (actual)
- Study completion
- 30 Jun 2020 (estimated)
- First posted
- 13 Feb 2009 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Carbaglu | Experimental | Drug: N-carbamylglutamateInvestigate 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 |
Who may qualify
- Ages
- 1 day to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (12 listed)
- 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:
Key exclusion criteria (5 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| N-carbamylglutamateAlso: Carglumic acid, Carbaglu100 mg/kg/day or 2.2 g/M2/day in 3-4 divided doses for 3 days | Drug | Carbaglu |
Primary outcome
Rate of ureagenesis as determined by 13C enrichment of urea
Time frame: 3 days of treatment
5 secondary outcomes
Plasma ammonia concentration
Time frame: 3 days
Plasma amino acid levels
Time frame: 3 days
Urine Orotic Acid
Time frame: 3 days
Blood Urea Nitrogen (BUN)
Time frame: 3 days
Routine safety laboratory tests (CBC, LFTs, Creatinine)
Time frame: 3 days
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 17 Feb 2020.
- Individual participant dataSharing planned: Yes. Individual participant data will be shared with that particular participant
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Mendel Tuchman, MD principal investigator
Children's National Research Institute
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study testing N-carbamylglutamate in people with Inborn Errors of Metabolism, run by Mendel Tuchman at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 12 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 17 Feb 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Rate of ureagenesis as determined by 13C enrichment of urea (time frame: 3 days of treatment). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Feb 2020.