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| Name | Class |
|---|---|
| Children's National Research Institute | OTHER |
| Boston Children's Hospital | OTHER |
| University Hospitals Cleveland Medical Center | OTHER |
| University of California, Los Angeles |
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The overall objective of this drug trial is to determine whether the treatment of acute hyperammonemia with N-carbamyl-L-glutamate (NCG, Carglumic acid) in propionic acidemia (PA), methylmalonic acidemia (MMA), late-onset CPS1 deficiency (CPSD) and late-onset Ornithine transcarbamylase deficiency (OTCD) accelerates the resolution of hyperammonemia efficiently and safely.
The primary goal is to determine if the study drug (NCG) efficiently reduces ammonia levels following a hyperammonemia episode(s).
Secondly, the investigators want to know if treatment with this study drug (NCG) efficiently improves neurologic function, reduces plasma glutamine levels and lessens the duration of hospitalization after each episode of hyperammonemia.
This is a double-blind, placebo-controlled, randomized clinical drug trial to evaluate the efficacy of NCG in the treatment of two organic acidemias (severe PA and MMA), and two urea-cycle disorders (late-onset CPSD and OTCD).
Primarily, the investigators want to determine whether NCG treatment of acute hyperammonemia in severe, neonatal-onset PA, MMA, CPSD, and OTCD is efficacious and whether it is safe. The investigators will approach this task in two ways.
Assess Whether NCG Treatment is Effective
The objective of this study is to assess whether NCG is efficacious in treating hyperammonemia and improving outcome:
The investigators will realize this goal by randomizing each hyperammonemic episode from every subject to NCG (NCG)+standard treatment (NCG-STD) versus placebo+standard treatment (PLBO-STD) and subsequently gauging response with the primary outcome of plasma ammonia levels, in addition to the plasma glutamine, the Functional Status Scale, and the length of hospitalization.
Safety
The primary safety outcome of the study will be the assessed via the rate of Serious Adverse Events (SAEs), defined in this study as death or substantial prolongation of hospitalization, as patients are hospitalized as part of the entry to the study.
Safety tests consisting of complete blood count (CBC), liver and kidney function tests, and coagulation profile (PTT/INR) will be performed before treatment, between days 3-5 of treatment, and just prior to discontinuation of NCG. An electrocardiogram will be performed before treatment and on the third day of treatment or before discharge if earlier.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Active Comparator | Experimental | Parallel Trial Comparing NCG + Standard of Care Treatment |
|
| Placebo Comparator | Active Comparator | Placebo and Standard of Care Therapy |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Carbaglu | Drug | Carbaglu Chemical Composition: N-carbamoyl-L-glutamic acid (NCG) The daily dose will be 150 mg/kg/ day or 3.3 g/m2/day for patients >15 kg and will be administered for 7 days or until discharge, whichever is sooner. The doses are to be divided into 2 equal doses and administered orally or enterally by nasogastric or gastrostomy tube. Standard of care will prevail when choosing the mode of drug administration. The tablets must be dispersed in a minimum of 2.5-10 ml of water and ingested immediately or administered by fast-push through a syringe via a nasogastric or gastrostomy tube. The suspension has a slightly acidic taste. |
| Measure | Description | Time Frame |
|---|---|---|
| Time to the Primary Outcome (Earlier of Ammonia <50 µmol/L or Hospital Discharge) | The composite primary intention to treat (ITT) outcome of the earlier of time to reach an ammonia level of ≤50 µmol/L or hospital discharge. Data presented as a hazard ratio based on the time to reach an ammonia level of ≤50 µmol/L. The outcome measure was a survival analysis based on time to reach the earlier of an ammonia level of ≤50 µmol/L or time to discharge, which was considered to be a point where the patient was no longer at risk of neurological injury from ammonia. The outcome of survival analysis was a hazard ratio reflecting the ratio of probabilities in each group (drug vs placebo) of reaching the earlier of an ammonia level of ≤50 µmol/L or discharge. We measured multiple post-treatment ammonia levels at uncontrolled times during an episode, so it is difficult to compute a meaningful average that would not be biased by the frequency and timing of ammonia testing during episodes. | Average of all measurements of hyperammonemia, for up to 7 days |
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Inclusion Criteria
o Aged older than 1 week with an established diagnosis of CPSD or OTCD (as follows):
AND: Subject or subject's first-degree relative had plasma ammonia level ≥100 μmol/L >1 week of age
OR
o An established diagnosis of PA or MMA (as follows):
- Diagnosed with PA by semi-quantitative urine organic acid analysis, defined as the presence of elevated Methylcitric acid and normal methylmalonic acid levels and no evidence of biotin related disorders in the organic acid analysis
OR
- Diagnosed with MMA by semi-quantitative urine organic acid analysis, defined as an elevation of methylmalonic acid and no evidence of vitamin B12 dependent disorder on plasma amino acid analysis (B12 dependency is defined by documented B12 responsiveness)
AND: Subject or subject's first-degree relative had plasma ammonia level at any time ≥100 μmol/L
Exclusion Criteria
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| Name | Affiliation | Role |
|---|---|---|
| Mendel Tuchman, MD | Children's National Research Institute | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of California Los Angeles | Los Angeles | California | 90095 | United States | ||
| Lucile Packard Children's Hospital at Stanford |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 33006765 | Derived | Amari S, Shahrook S, Namba F, Ota E, Mori R. Branched-chain amino acid supplementation for improving growth and development in term and preterm neonates. Cochrane Database Syst Rev. 2020 Oct 2;10(10):CD012273. doi: 10.1002/14651858.CD012273.pub2. |
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This is a blinded study, the individual participant data will not be shared
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There were 65 eligible patients, 35 were enrolled with a randomization of hyperammonemia. Eligible patients were randomized at each episode of hyperammonemia. To be enrolled, a patient had to have an eligible episode of hyperammonemia and was then randomized to either placebo or NCG at each randomization. 13 patients had multiple randomizations, 22 only had one.
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| ID | Title | Description |
|---|---|---|
| FG000 | Episodes of N-Carbamylglutamate | Episodes where the participant was randomized to the NCG arm |
| FG001 | Episodes of Placebo | Episodes where the participant was randomized to the placebo arm |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | May 1, 2020 |
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| OTHER |
| Children's Hospital of Philadelphia | OTHER |
| Stanford University | OTHER |
| Icahn School of Medicine at Mount Sinai | OTHER |
| University of Pittsburgh | OTHER |
| Children's Hospital Colorado | OTHER |
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|
|
| Placebo | Drug | Placebo that looks/tastes the same as NCG and is administered on the same schedule as the NCG intervention |
|
| Palo Alto |
| California |
| 94304 |
| United States |
| The Children's Hospital of Colorado | Aurora | Colorado | 80045 | United States |
| Children's National Medical Center | Washington D.C. | District of Columbia | 20010 | United States |
| Children's Hospital Boston | Boston | Massachusetts | 02115 | United States |
| Mount Sinai School of Medicine | New York | New York | 10029 | United States |
| University Hospitals Cleveland Medical Center | Cleveland | Ohio | 44106 | United States |
| The Children's Hospital of Philadelphia (CHOP) | Philadelphia | Pennsylvania | 19104 | United States |
| University of Pittsburgh | Pittsburgh | Pennsylvania | 15224 | United States |
| COMPLETED |
|
| NOT COMPLETED |
|
65 participants were eligible based on diagnosis. There were 35 individual participants enrolled due to a hyperammonemia episode. 24 individuals had episodes where they were randomized to the NCG arm, and 23 had episodes where they were randomized to the placebo arm. 13 participants had multiple randomizations to both arms throughout the study, while 22 participants only had a single randomization to either placebo of NCG. 35 unique participants were randomized providing 106 randomized episodes.
| ID | Title | Description |
|---|---|---|
| BG000 | Episodes of N-carbamylglutamate (NCG) | Total number of episodes of hyperammonemia where a patient was randomized to the NCG arm A daily dose of 150 mg/kg/ day or 3.3 g/m2/day for patients >15 kg administered for 7 days or until discharge, whichever is sooner. |
| BG001 | Episodes of Placebo | Total number of episodes of hyperammonemia where a patient was randomized to the placebo arm Placebo that looks/tastes the same as NCG and is administered on the same schedule as the NCG intervention |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Episodes |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Customized | Count of Units | Episodes | Episodes |
| ||||||||||||||||||
| Sex: Female, Male | Count of Units | Episodes | Episodes |
| ||||||||||||||||||
| Ethnicity (NIH/OMB) | Count of Units | Episodes | Episodes |
| ||||||||||||||||||
| Race (NIH/OMB) | Count of Units | Episodes | Episodes |
|
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Time to the Primary Outcome (Earlier of Ammonia <50 µmol/L or Hospital Discharge) | The composite primary intention to treat (ITT) outcome of the earlier of time to reach an ammonia level of ≤50 µmol/L or hospital discharge. Data presented as a hazard ratio based on the time to reach an ammonia level of ≤50 µmol/L. The outcome measure was a survival analysis based on time to reach the earlier of an ammonia level of ≤50 µmol/L or time to discharge, which was considered to be a point where the patient was no longer at risk of neurological injury from ammonia. The outcome of survival analysis was a hazard ratio reflecting the ratio of probabilities in each group (drug vs placebo) of reaching the earlier of an ammonia level of ≤50 µmol/L or discharge. We measured multiple post-treatment ammonia levels at uncontrolled times during an episode, so it is difficult to compute a meaningful average that would not be biased by the frequency and timing of ammonia testing during episodes. | Patients were randomized to either study drug or placebo at each episode of hyperammonemia analysed by diagnosis. Data presented as a hazard ratio based on the time to reach an ammonia level of ≤50 µmol/L. Higher ratios reflect an NCG advantage. | Posted | Number | 95% Confidence Interval | Hazard Ratio | Average of all measurements of hyperammonemia, for up to 7 days | Episodes | Episodes |
|
|
|
During each hospitalization, once per day, up to 7 days.
Adverse Events were monitored/assessed without regard to the specific Adverse Event Term.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Placebo | Episodes where the patient was randomized to placebo | 10 | 24 | 6 | 24 | 9 | 24 |
| EG001 | N-carbamylglutamate (NCG) | Episodes where the patient was randomized to NCG | 14 | 25 | 8 | 25 | 11 | 25 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Gastrointestinal Disorders | Gastrointestinal disorders | SNOMED CT | Non-systematic Assessment |
| |
| Infections and Infestations | Infections and infestations | SNOMED CT | Non-systematic Assessment |
| |
| Injury | Injury, poisoning and procedural complications | SNOMED CT | Non-systematic Assessment |
| |
| Metabolic and Nutritional | Metabolism and nutrition disorders | SNOMED CT | Non-systematic Assessment |
| |
| Nervous System | Nervous system disorders | SNOMED CT | Non-systematic Assessment |
| |
| Respiratory | Respiratory, thoracic and mediastinal disorders | SNOMED CT | Non-systematic Assessment |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Blood/Lymphatic | Blood and lymphatic system disorders | SNOMED CT | Non-systematic Assessment |
| |
| Cardiac | Cardiac disorders | SNOMED CT | Non-systematic Assessment |
| |
| Gastrointestinal | Gastrointestinal disorders | SNOMED CT | Non-systematic Assessment |
| |
| General | General disorders | SNOMED CT | Non-systematic Assessment |
| |
| Infections | Infections and infestations | SNOMED CT | Non-systematic Assessment |
| |
| Injury/Procedure Complications | Injury, poisoning and procedural complications | SNOMED CT | Non-systematic Assessment |
| |
| Investigations | Investigations | SNOMED CT | Non-systematic Assessment |
| |
| Metabolism | Metabolism and nutrition disorders | SNOMED CT | Non-systematic Assessment |
| |
| Nervous System | Nervous system disorders | SNOMED CT | Non-systematic Assessment |
| |
| Product Issues | Product Issues | SNOMED CT | Non-systematic Assessment |
| |
| Psychiatric | Psychiatric disorders | SNOMED CT | Non-systematic Assessment |
| |
| Respiratory | Respiratory, thoracic and mediastinal disorders | SNOMED CT | Non-systematic Assessment |
| |
| Vascular | Vascular disorders | SNOMED CT | Non-systematic Assessment |
|
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Robert McCarter | Children's National Hospital | 202-476-3140 | RMcCarte@childrensnational.org |
| Oct 17, 2020 |
| Prot_SAP_000.pdf |
| ID | Term |
|---|---|
| D056693 | Propionic Acidemia |
| C537358 | Methylmalonic acidemia |
| D020165 | Carbamoyl-Phosphate Synthase I Deficiency Disease |
| D020163 | Ornithine Carbamoyltransferase Deficiency Disease |
| D022124 | Hyperammonemia |
| ID | Term |
|---|---|
| D000592 | Amino Acid Metabolism, Inborn Errors |
| D008661 | Metabolism, Inborn Errors |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D056806 | Urea Cycle Disorders, Inborn |
| D020739 | Brain Diseases, Metabolic, Inborn |
| D001928 | Brain Diseases, Metabolic |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D028361 | Mitochondrial Diseases |
| D040181 | Genetic Diseases, X-Linked |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| C528449 | carglumic acid |
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| Title | Measurements |
|---|---|
|
| 12 - <18 years |
|
| 18+ years |
|
| Male |
|
| Not Hispanic or Latino |
|
| Unknown or Not Reported |
|
| Asian |
|
| Native Hawaiian or Other Pacific Islander |
|
| Black or African American |
|
| White |
|
| More than one race |
|
| Unknown or Not Reported |
|