Propionic Acidemia, Type I and/or Type IIPhase 2STONCT01599286
Short-Term Outcome of N-Carbamylglutamate in the Treatment of Acute Hyperammonemia
A Phase 2 study testing Carbaglu in people with Propionic Acidemia, Type I and/or Type II and Methylmalonic Acidemia, run by Mendel Tuchman at 9 sites in United States.
Trial summary
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… Read more about this study
- Who is it for?
- Ages 1 week to 99 years
- Conditions the study is for
- Propionic Acidemia, Type I and/or Type II, Methylmalonic Acidemia, Carbamoyl-Phosphate Synthase I Deficiency Disease
- What is being tested?
- Carbaglu
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 35 participants
- Where
- 9 sitesUnited States
- Study dates
- 1 Sep 2012to 30 Apr 2020
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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 week to 99 years
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- o Aged older than 1 week with an established diagnosis of CPSD or OTCD (as follows):
- Diagnosed with late-onset CPSD confirmed by detection of pathogenic mutation(s), and/or decreased (<20% of control) CPS enzyme activity in liver OR
- Diagnosed with late-onset OTCD by detection of pathogenic OTC mutation, OR decreased (<20% of control) OTC enzyme activity in liver OR elevated urinary orotate (greater than 20 µM/mM) following allopurinol loading with the absence of argininosuccinic acid
- 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):
Show all 14Show fewer
- 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
- Able to receive medications orally, by nasogastric (NG)-tube or by gastric (G)-tube
- No concomitant illness which would preclude safe participation as judged by the investigator
- If post-menarcheal must have a negative pregnancy test prior to administration of study drug at each episode
- Signed informed consent by the subject or the subject's legally acceptable representative
Who cannot join
- Administration of NCG within 7 days of participation in the study
- Use of any other investigational drug, biologic, or therapy
- Planned participation in any other clinical trial
- Diagnosis of any medical condition causing hyperammonemia which is not PA/MMA, CPSD or OTCD. Other urea cycle disorders will be excluded from this study
- Any clinical or laboratory abnormality or medical condition that, at the discretion of the investigator, may put the subject at additional risk by participating in this study
- Has had a liver transplant
- Is not expected to be compliant with this study in terms of returning to the site for subsequent episodes of hyperammonemia crises
- Is pregnant
Trial locations and contacts
9 sites in 1 country.
9 sites in 1 country
United States9 sites
The Children's Hospital of Colorado
Aurora, Colorado, 80045
Children's Hospital Boston
Boston, Massachusetts, 02115
University Hospitals Cleveland Medical Center
Cleveland, Ohio, 44106
University of California Los Angeles
Los Angeles, California, 90095
Mount Sinai School of Medicine
New York, New York, 10029
Lucile Packard Children's Hospital at Stanford
Palo Alto, California, 94304
The Children's Hospital of Philadelphia (CHOP)
Philadelphia, Pennsylvania, 19104
University of Pittsburgh
Pittsburgh, Pennsylvania, 15224
Children's National Medical Center
Washington D.C., District of Columbia, 20010
About this study
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.
Read the detailed description
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.
- Conditions
- Propionic Acidemia, Type I and/or Type II, Methylmalonic Acidemia, Carbamoyl-Phosphate Synthase I Deficiency Disease, Ornithine Carbamoyltransferase Deficiency
- Being tested
- Carbaglu, Placebo
- Keywords
- Hyperammonemia, Propionic Acidemia (PA), Methylmalonic Acidemia (MMA), Late-Onset CPS1 Deficiency (CPSD), Late-Onset Ornithine Transcarbamylase Deficiency (OTCD), Carbaglu
- Medical subject headings
- Propionic Acidemia, Methylmalonic acidemia, Carbamoyl-Phosphate Synthase I Deficiency Disease, Ornithine Carbamoyltransferase Deficiency Disease, Hyperammonemia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
CarbagluDrug
Also called Carglumic Acid
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.
PlaceboDrug
Placebo that looks/tastes the same as NCG and is administered on the same schedule as the NCG intervention
| Study group | Role | What they receive |
|---|---|---|
| Active Comparator | Experimental | Parallel Trial Comparing NCG + Standard of Care Treatment Receives: Drug: Carbaglu |
| Placebo Comparator | Active comparator | Placebo and Standard of Care Therapy Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Average of all measurements of hyperammonemia, for up to 7 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 May 2012 (estimated)
- Study start1 Sep 2012
- Primary completion30 Apr 2019
- Study completion30 Apr 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Propionic Acidemia, Type I and/or Type IIStudies 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
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 35 participants (actual)
Sponsor and investigators
- Lead sponsor
- Mendel Tuchman
- Sponsor type
- University, hospital or other
- Collaborators
- Children's National Research Institute, Boston Children's Hospital, University Hospitals Cleveland Medical Center, University of California, Los Angeles, Children's Hospital of Philadelphia, Stanford University, Icahn School of Medicine at Mount Sinai, University of Pittsburgh, Children's Hospital Colorado
- 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
- NCT01599286
- Sponsor's protocol ID
- NCGC0008
- Acronym
- STO
- Status last verified
- Jan 2021
- First submitted
- 11 May 2012
- Last updated
- 15 Feb 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- No: This is a blinded study, the individual participant data will not be shared
Publications
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.
PubMed 33006765
Study at a glance
From the registry record, last updated by the sponsor on 15 Feb 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Short-Term Outcome of N-Carbamylglutamate in the Treatment of Acute Hyperammonemia
- ClinicalTrials.gov ID
- NCT01599286
- Acronym / sponsor ID
- STO / NCGC0008
- Conditions
- Propionic Acidemia, Type I and/or Type II, Methylmalonic Acidemia, Carbamoyl-Phosphate Synthase I Deficiency Disease, Ornithine Carbamoyltransferase Deficiency
- Keywords
- Hyperammonemia, Propionic Acidemia (PA), Methylmalonic Acidemia (MMA), Late-Onset CPS1 Deficiency (CPSD), Late-Onset Ornithine Transcarbamylase Deficiency (OTCD), Carbaglu
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 35 participants (actual)
- Lead sponsor
- Mendel TuchmanUniversity, hospital or other
- Collaborators
- Children's National Research Institute, Boston Children's Hospital, University Hospitals Cleveland Medical Center, University of California, Los Angeles, Children's Hospital of Philadelphia, Stanford University, Icahn School of Medicine at Mount Sinai, University of Pittsburgh, Children's Hospital Colorado
- Study start
- 1 Sep 2012 (actual)
- Primary completion
- 30 Apr 2019 (actual)
- Study completion
- 30 Apr 2020 (actual)
- First posted
- 16 May 2012 (estimated)
- Results
- Posted 15 Feb 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Active Comparator | Experimental | Drug: CarbagluParallel Trial Comparing NCG + Standard of Care Treatment |
| Placebo Comparator | Active comparator | Drug: PlaceboPlacebo and Standard of Care Therapy |
Who may qualify
- Ages
- 1 week to 99 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (14 listed)
- Diagnosed with late-onset CPSD confirmed by detection of pathogenic mutation(s), and/or decreased (<20% of control) CPS enzyme activity in liver OR
- Diagnosed with late-onset OTCD by detection of pathogenic OTC mutation, OR decreased (<20% of control) OTC enzyme activity in liver OR elevated urinary orotate (greater than 20 µM/mM) following allopurinol loading with the absence of argininosuccinic acid
- AND: Subject or subject's first-degree relative had plasma ammonia level ≥100 μmol/L >1 week of age
- OR
- 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
Key exclusion criteria (8 listed)
- Administration of NCG within 7 days of participation in the study
- Use of any other investigational drug, biologic, or therapy
- Planned participation in any other clinical trial
- Diagnosis of any medical condition causing hyperammonemia which is not PA/MMA, CPSD or OTCD. Other urea cycle disorders will be excluded from this study
- Any clinical or laboratory abnormality or medical condition that, at the discretion of the investigator, may put the subject at additional risk by participating in this study
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 |
|---|---|---|
| CarbagluAlso: Carglumic AcidCarbaglu 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. | Drug | Active Comparator |
| PlaceboPlacebo that looks/tastes the same as NCG and is administered on the same schedule as the NCG intervention | Drug | Placebo Comparator |
Primary outcome
Time to the Primary Outcome (Earlier of Ammonia <50 µmol/L or Hospital Discharge)
Time frame: Average of all measurements of hyperammonemia, for up to 7 days
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.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 15 Feb 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 33006765Amari 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.
- Individual participant dataSharing planned: No. This is a blinded study, the individual participant data will not be shared
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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
9 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Carbaglu in people with Propionic Acidemia, Type I and/or Type II and Methylmalonic Acidemia, run by Mendel Tuchman at 9 sites 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 14 inclusion and 8 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: finished, as of the sponsor's last update on 15 Feb 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 9 sites 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 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.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 15 Feb 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
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?
Time to the Primary Outcome (Earlier of Ammonia <50 µmol/L or Hospital Discharge) (time frame: Average of all measurements of hyperammonemia, for up to 7 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01599286, which also lists 1 linked publication.
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 15 Feb 2021.