Urea Cycle DisorderNCT04602325
Systemic Biomarkers of Brain Injury From Hyperammonemia
An observational study of Urea Cycle Disorder and Organic Acidemia, run by Children's National Research Institute at 1 site in United States.
Trial summary
Ammonia is a waste product of protein and amino acid catabolism and is also a potent neurotoxin. High blood ammonia levels on the brain can manifest as cytotoxic brain edema and vascular compromise leading to intellectual and developmental disabilities. Read more about this study
- Who is it for?
- Ages 7 to 18 years
- Conditions the study is for
- Urea Cycle Disorder, Organic Acidemia, Maple Syrup Urine Disease
- Type of treatment
- Pill or oral medicine
- How many people
- 24 participants
- Where
- 1 siteUnited States
- Study dates
- 9 Jul 2020to May 2027
- Phase
- Observational
- Are there results?
- Not yet: the study is under way
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 7 to 18 years
- All sexes
- No healthy volunteers
- Child, Adult
Study population: Eligible subjects will be recruited from the patient population at Children's National Hospital in Washington, DC. Study population will consist of those patients with inherited hyperammonemias, acute metablic disorders, fatty acid oxidation disorders, and hypoxic-ischemic encephalopathy.
Who may be able to join
- Inherited Hyperammonemias:
- A clinical diagnosis of 1 of 7 diagnosed urea cycle disorders:
- N-acetylglutamate Synthetase Deficiency (NAGS)
- Carbamyl Phosphate Synthetase Deficiency (CPSD)
- Ornithine Transcarbamylase Deficiency (OTCD)
- Argininosuccinate Synthetase Deficiency (ASD)
Show all 25Show fewer
- Argininosuccinate Lyase Deficiency (ALD)
- Arginase Deficiency (AD)
- Hyperammonemia-Hyperornithinemia-Homocitrullinuria (HHH)
- A clinical diagnosis of 1 of 2 organic acidemias:
- Propionic Acidemia (PA)
- Methylmalonic Acidemia (MMA)
- Acute metabolic disorder without hyperammonemia, with neurological sequelae
- Maple Syrup Urine Disease (MSUD)
- Glutaric Acidemia (GA1)
- Acute metabolic disorder without hyperammonemia and without neurological sequelae
- Fatty Acid Oxidation Disorders:
- Medium Chain-Acyl CoA Dehydrogenase Deficiency
- Very Long Chain-Acyl CoA Dehydrogenase Deficiency
- Trifunctional Protein Deficiency
- Long Chain Hydroxyacyl-CoA Dehydrogenase Deficiency
- Carnitine Palmitoyltransferase I or II Deficiency
- Carnitine/Acylcarnitine Translocase Deficiency
- Primary Carnitine Transport Deficiency
- Hypoxic-Ischemic Encephalopathy
Who cannot join
- Prior Solid-Organ Transplant
- Use of any other investigational drug, biologic, or therapy or any clinical or laboratory abnormality or medical condition that, as determined by the investigator, may interfere with or obscure the biomarker measurements
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site, 1 recruiting
- Recruiting
Children's National Research Institute
Washington D.C., District of Columbia, 20010
Katie Rice, MPH, CCRP, krice3@childrensnational.org
Nicholas Ah Mew, MD
About this study
Ammonia is a waste product of protein and amino acid catabolism and is also a potent neurotoxin. High blood ammonia levels on the brain can manifest as cytotoxic brain edema and vascular compromise leading to intellectual and developmental disabilities. The following aims are proposed:
Aim 1 of this study will be to determine the chronology of biomarkers of brain injury in response to a hyperammonemic (HA) brain insult in patients with an inherited hyperammonemic disorder.
Aim 2 will be to determine if S100B, NSE, and UCHL1 are altered in patients with two other inborn errors of metabolism, Maple Syrup Urine Disease (MSUD) and Glutaric Acidemia (GA1).
Read the detailed description
Ammonia is a waste product of protein and amino acid catabolism and is also a potent neurotoxin. The onslaught of high blood ammonia levels on the brain can manifest as cytotoxic brain edema and vascular compromise leading to intellectual and developmental disabilities. In addition, clinical hyperammonemia recurs at varying intervals, which can increase the cumulative damage to the brain and the chance of irreversible coma and death during a hyperammonemia episode due to vascular compromise or brain herniation. The threshold of tolerance for elevated blood ammonia is very low and concentrations above 100 µM can cause brain dysfunction manifested as nausea, vomiting, lethargy, and abnormal behavior; higher concentrations can cause coma and even death. Failure to remove ammonia can be due to inherited defects of the urea cycle, some defects in amino acid catabolism, and degradation of fatty acids.
Aim 1 - To determine the chronology of biomarkers of brain injury - S100B, NSE, and UCHL1 - in response to a hyperammonemic (HA) brain insult in patients with an inherited hyperammonemic disorder. We hypothesized that elevations of S100B, NSE, and UCHL1 will parallel the rise in blood ammonia. These biomarkers will be measured concurrently to ammonia levels throughout hospitalizations for HA until normalization of patient's blood ammonia and mental status.
Aim 2 - To determine if S100B, NSE, and UCHL1 are altered in patients with two other inborn errors of metabolism in which the primary pathology is neurological injury, Maple Syrup Urine Disease (MSUD) and Glutaric Acidemia (GA1). We hypothesize that neuronal and astroglial injury in these disorders may also result in increased levels of S100B, NSE, and UCHL1.
Metabolic patients will be enrolled either during a hospitalization or in outpatient clinic, but outpatient enrollment is preferred. Metabolic patients typically have multiple laboratory tests performed at their outpatient visits. We will obtain the discarded blood samples from such laboratory tests in order to measure S100B, NSE, and UCHL1 levels at baseline (normal blood ammonia), which will provide data on biomarker levels following recovery from a hyperammonemic episode.
During hospitalization for metabolic decompensation or for hypoxic-ischemic encephalopathy, sequential measurements of S100B, NSE and UCHL1 levels will be obtained from discarded blood samples. We will obtain S100B, NSE, and UCHL1 levels from collected discarded blood samples at all subjects' next outpatient visit following their hospitalization, to determine if levels return to baseline.
- Conditions
- Urea Cycle Disorder, Organic Acidemia, Maple Syrup Urine Disease, Glutaric Acidemia I, Fatty Acid Oxidation Disorder, Hypoxic-Ischemic Encephalopathy
- Keywords
- N-acetylglutamate Synthetase Deficiency, Carbamyl Phosphate Synthetase Deficiency, Ornithine Transcarbamylase Deficiency, Argininosuccinate Synthetase Deficiency, Argininosuccinate Lyase Deficiency, Arginase Deficiency, Hyperammonemia-Hyperornithinemia-Homocitrullinuria, Medium Chain-Acyl CoA Dehydrogenase Deficiency, Very Long Chain-Acyl CoA Dehydrogenase Deficiency, Trifunctional Protein Deficiency, Long Chain Hydroxyacyl-CoA Dehydrogenase Deficiency, Carnitine Palmitoyltransferase I or II Deficiency, Carnitine/Acylcarnitine Translocase Deficiency, Primary Carnitine Transport Deficiency
- Medical subject headings
- Urea Cycle Disorders, Inborn, Maple Syrup Urine Disease, Glutaric Acidemia I, Hypoxia-Ischemia, Brain, N-acetyl glutamate synthetase deficiency, Carbamoyl-Phosphate Synthase I Deficiency Disease, Ornithine Carbamoyltransferase Deficiency Disease, Citrullinemia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| Inherited Hyperammonemias | A clinical diagnosis of 1 of 7 diagnosed urea cycle disorders: 1. N-acetylglutamate Synthetase Deficiency (NAGS) 2. Carbamyl Phosphate Synthetase Deficiency (CPSD) 3. Ornithine Transcarbamylase Deficiency (OTCD) 4. Argininosuccinate Synthetase Deficiency (ASD) 5. Argininosuccinate Lyase Deficiency (ALD) 6. Arginase Deficiency (AD) 7. Hyperammonemia-Hyperornithinemia-Homocitrullinuria (HHH) A clinical diagnosis of 1 of 2 organic acidemias: 1. Propionic Acidemia (PA) 2. Methylmalonic Acidemia (MMA) | |
| Acute Metabolic Disorder + Neurological Sequelae | Acute metabolic disorder without hyperammonemia but with neurological sequelae: 1. Maple Syrup Urine Disease (MSUD) 2. Glutaric Acidemia (GA1) | |
| Fatty Acid Oxidation Disorders | Acute metabolic disorder without hyperammonemia and without neurological sequelae: 1. Medium Chain-Acyl CoA Dehydrogenase Deficiency 2. Very Long Chain-Acyl CoA Dehydrogenase Deficiency 3. Trifunctional Protein Deficiency 4. Long Chain Hydroxyacyl-CoA Dehydrogenase Deficiency 5. Carnitine Palmitoyltransferase I or II Deficiency 6. Carnitine/Acylcarnitine Translocase Deficiency 7. Primary Carnitine Transport Deficiency | |
| Hypoxic-Ischemic Encephalopathy | Patients with hypoxic-ischemic encephalopathy |
What is being measured
The primary outcome is the main question the study is designed to answer.
Biomarker Brain Injury Chronology
Determine the chronology of biomarkers of brain injury (S100B, NSE, and UCHL1) in response to a hyperammonemic (HA) brain insult in patients with an inherited hyperammonemic disorder
Measured: 2 Years
Secondary outcomes (1)
Brain Injury Protein Alterations
Determine if S100B, NSE, and UCHL1 are altered in patients with two other inborn errors of metabolism in which the primary pathology is neurological injury, Maple Syrup Urine Disease (MSUD) and Glutaric Acidemia (GA1)
Measured: 2 Years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Oct 2020
- Study start9 Jul 2020
- Primary completionJul 2026 (estimated)
- Study completionMay 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Urea Cycle DisorderStudies of the same condition, open and under way.
- More trials run by Children's National Research InstituteThe sponsor's other registered studies.
- 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
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 24 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Children's National Research Institute
- Sponsor type
- University, hospital or other
- Collaborators
- National Center for Advancing Translational Sciences (NCATS)
- Responsible party
- Principal investigator, Nicholas Ah Mew, Children's National Research Institute
- Investigators
- Nicholas Ah Mew, MD, Principal investigator, Children's National Research InstituteLjubica Caldovic, PhD, Study chair, Children's National Research Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04602325
- Sponsor's protocol ID
- 14021
- Other IDs
- R21TR003166-01
- Status last verified
- Feb 2024
- First submitted
- 20 Oct 2020
- Last updated
- 7 Feb 2024
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Study at a glance
From the registry record, last updated by the sponsor on 7 Feb 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Systemic Biomarkers of Brain Injury From Hyperammonemia
- ClinicalTrials.gov ID
- NCT04602325
- Acronym / sponsor ID
- 14021
- Conditions
- Urea Cycle Disorder, Organic Acidemia, Maple Syrup Urine Disease, Glutaric Acidemia I, Fatty Acid Oxidation Disorder, Hypoxic-Ischemic Encephalopathy
- Keywords
- N-acetylglutamate Synthetase Deficiency, Carbamyl Phosphate Synthetase Deficiency, Ornithine Transcarbamylase Deficiency, Argininosuccinate Synthetase Deficiency, Argininosuccinate Lyase Deficiency, Arginase Deficiency, Hyperammonemia-Hyperornithinemia-Homocitrullinuria, Medium Chain-Acyl CoA Dehydrogenase Deficiency
- Study type
- Observational
- Recruitment status
- Recruiting
- Enrolment
- 24 participants (estimated)
- Lead sponsor
- Children's National Research InstituteUniversity, hospital or other
- Collaborators
- National Center for Advancing Translational Sciences (NCATS)
- Study start
- 9 Jul 2020 (actual)
- Primary completion
- Jul 2026 (estimated)
- Study completion
- May 2027 (estimated)
- First posted
- 26 Oct 2020 (actual)
- 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.
Ammonia is a waste product of protein and amino acid catabolism and is also a potent neurotoxin. High blood ammonia levels on the brain can manifest as cytotoxic brain edema and vascular compromise leading to intellectual and developmental disabilities. The following aims are proposed:
Aim 1 of this study will be to determine the chronology of biomarkers of brain injury in response to a hyperammonemic (HA) brain insult in patients with an inherited hyperammonemic disorder.
Aim 2 will be to determine if S100B, NSE, and UCHL1 are altered in patients with two other inborn errors of metabolism, Maple Syrup Urine Disease (MSUD) and Glutaric Acidemia (GA1).
Detailed description
Ammonia is a waste product of protein and amino acid catabolism and is also a potent neurotoxin. The onslaught of high blood ammonia levels on the brain can manifest as cytotoxic brain edema and vascular compromise leading to intellectual and developmental disabilities. In addition, clinical hyperammonemia recurs at varying intervals, which can increase the cumulative damage to the brain and the chance of irreversible coma and death during a hyperammonemia episode due to vascular compromise or brain herniation. The threshold of tolerance for elevated blood ammonia is very low and concentrations above 100 µM can cause brain dysfunction manifested as nausea, vomiting, lethargy, and abnormal behavior; higher concentrations can cause coma and even death. Failure to remove ammonia can be due to inherited defects of the urea cycle, some defects in amino acid catabolism, and degradation of fatty acids.
Aim 1 - To determine the chronology of biomarkers of brain injury - S100B, NSE, and UCHL1 - in response to a hyperammonemic (HA) brain insult in patients with an inherited hyperammonemic disorder. We hypothesized that elevations of S100B, NSE, and UCHL1 will parallel the rise in blood ammonia. These biomarkers will be measured concurrently to ammonia levels throughout hospitalizations for HA until normalization of patient's blood ammonia and mental status.
Aim 2 - To determine if S100B, NSE, and UCHL1 are altered in patients with two other inborn errors of metabolism in which the primary pathology is neurological injury, Maple Syrup Urine Disease (MSUD) and Glutaric Acidemia (GA1). We hypothesize that neuronal and astroglial injury in these disorders may also result in increased levels of S100B, NSE, and UCHL1.
Metabolic patients will be enrolled either during a hospitalization or in outpatient clinic, but outpatient enrollment is preferred. Metabolic patients typically have multiple laboratory tests performed at their outpatient visits. We will obtain the discarded blood samples from such laboratory tests in order to measure S100B, NSE, and UCHL1 levels at baseline (normal blood ammonia), which will provide data on biomarker levels following recovery from a hyperammonemic episode.
During hospitalization for metabolic decompensation or for hypoxic-ischemic encephalopathy, sequential measurements of S100B, NSE and UCHL1 levels will be obtained from discarded blood samples. We will obtain S100B, NSE, and UCHL1 levels from collected discarded blood samples at all subjects' next outpatient visit following their hospitalization, to determine if levels return to baseline.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Inherited Hyperammonemias | – | –A clinical diagnosis of 1 of 7 diagnosed urea cycle disorders: 1. N-acetylglutamate Synthetase Deficiency (NAGS) 2. Carbamyl Phosphate Synthetase Deficiency (CPSD) 3. Ornithine Transcarbamylase Deficiency (OTCD) 4. Argininosuccinate Synthetase Deficiency (ASD) 5. Argininosuccinate Lyase Deficiency (ALD) 6. Arginase Deficiency (AD) 7. Hyperammonemia-Hyperornithinemia-Homocitrullinuria (HHH) A clinical diagnosis of 1 of 2 organic acidemias: 1. Propionic Acidemia (PA) 2. Methylmalonic Acidemia (MMA) |
| Acute Metabolic Disorder + Neurological Sequelae | – | –Acute metabolic disorder without hyperammonemia but with neurological sequelae: 1. Maple Syrup Urine Disease (MSUD) 2. Glutaric Acidemia (GA1) |
| Fatty Acid Oxidation Disorders | – | –Acute metabolic disorder without hyperammonemia and without neurological sequelae: 1. Medium Chain-Acyl CoA Dehydrogenase Deficiency 2. Very Long Chain-Acyl CoA Dehydrogenase Deficiency 3. Trifunctional Protein Deficiency 4. Long Chain Hydroxyacyl-CoA Dehydrogenase Deficiency 5. Carnitine Palmitoyltransferase I or II Deficiency 6. Carnitine/Acylcarnitine Translocase Deficiency 7. Primary Carnitine Transport Deficiency |
| Hypoxic-Ischemic Encephalopathy | – | –Patients with hypoxic-ischemic encephalopathy |
Who may qualify
- Ages
- 7 to 18 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
- Study population
- Eligible subjects will be recruited from the patient population at Children's National Hospital in Washington, DC. Study population will consist of those patients with inherited hyperammonemias, acute metablic disorders, fatty acid oxidation disorders, and hypoxic-ischemic encephalopathy.
Key inclusion criteria (25 listed)
- Inherited Hyperammonemias:
- Acute metabolic disorder without hyperammonemia, with neurological sequelae
- Acute metabolic disorder without hyperammonemia and without neurological sequelae
- Hypoxic-Ischemic Encephalopathy
Key exclusion criteria (2 listed)
- Prior Solid-Organ Transplant
- Use of any other investigational drug, biologic, or therapy or any clinical or laboratory abnormality or medical condition that, as determined by the investigator, may interfere with or obscure the biomarker measurements
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Biomarker Brain Injury Chronology
Time frame: 2 Years
Determine the chronology of biomarkers of brain injury (S100B, NSE, and UCHL1) in response to a hyperammonemic (HA) brain insult in patients with an inherited hyperammonemic disorder
1 secondary outcome
Brain Injury Protein Alterations
Time frame: 2 Years
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 7 Feb 2024.
- Individual participant dataSharing planned: Undecided
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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.
Nicholas Ah Mew, MD principal investigator
Children's National Research Institute
Ljubica Caldovic, PhD study chair
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?
An observational study of Urea Cycle Disorder and Organic Acidemia, run by Children's National Research Institute 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 25 inclusion and 2 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: looking for participants now, as of the sponsor's last update on 7 Feb 2024. 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.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Katie Rice, MPH, CCRP (202-476-6191, krice3@childrensnational.org), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Biomarker Brain Injury Chronology (time frame: 2 Years). 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 7 Feb 2024.