Propionic AcidemiaPhase 2NCT01597440
Long-term Outcome of N-Carbamylglutamate Treatment in Propionic Acidemia and Methylmalonic Acidemia
A Phase 2 study testing N-carbamylglutamate in people with Propionic Acidemia and Methylmalonic Acidemia, run by Mendel Tuchman at 7 sites in United States.
Trial summary
Background: Very few drugs exist that treat hyperammonemia, specifically PA and MMA. Diet restrictions and alternate pathway agents are the current primary treatments, but they frequently fail to prohibit brain damage. Read more about this study
- Who is it for?
- Ages 1 hour to 4 weeks
- Conditions the study is for
- Propionic Acidemia, Methylmalonic Acidemia
- What is being tested?
- N-carbamylglutamate
- 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
- 1 participants
- Where
- 7 sitesUnited States
- Study dates
- Sep 2012to Feb 2015
- 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 hour to 4 weeks
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- Aged 4 weeks or younger (0-28 days)
- >36 weeks gestational age at birth
- Birth weight ≥2500 g
- Plasma ammonia level at presentation >150 mcmol/L
- PA or MMA presumed or established diagnosis as follows (one of the following):
- Acidosis at presentation, pH <7.3 OR
Show all 13Show fewer
- Plasma acylcarnitine analysis either alone or as part of newborn screening, demonstrating C3 >4 mcmol/L OR
- Diagnosed, or sibling diagnosed with PA by semi-quantitative urine organic acid analysis, defined as presence of elevated methylcitric acid and no evidence of biotin related disorders in the organic acid analysis OR
- Diagnosed, or sibling diagnosed with MMA by semi-quantitative urine organic acid analysis, defined as elevation of methylmalonic acid and no evidence of vitamin B12 dependent disorder on plasma amino acid analysis
- 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
- Signed informed consent by the subject's legally acceptable representative
- After initial enrollment, criteria 3 or 4 (definitive diagnosis of the patient) must be fulfilled prior to discharge from initial admission in order to remain in the study.
Who cannot join
- Had any prior hyperammonemic episode
- Administration of NCG within 7 days of participation in the study
- Use of any other investigational drug, biologic, or therapy, with the exception of sodium benzoate or sodium phenylacetate if the latter were administered prior to diagnosis by acylcarnitine analysis (diagnostic inclusion criterion 2), or organic acid analysis (diagnostic inclusion criteria 3 \& 4)
- Planned participation in any other clinical trial
- Diagnosis of any medical condition causing hyperammonemia which is not PA or MMA.
- Any clinical or laboratory abnormality or medical condition that, at the discretion of the investigator, may put the subject at an additional risk by participating in this study
- Had a liver transplant or is scheduled for a liver transplant
- Is not expected to be compliant with this study in terms of returning to site for subsequent episodes of hyperammonemia crises or for long-term follow-up
Trial locations and contacts
7 sites in 1 country.
7 sites in 1 country
United States7 sites
The Children's Hospital of Colorado
Aurora, Colorado, 80045
Children's Hospital Boston
Boston, Massachusetts, 02115
University Hospitals of Cleveland/Rainbow Babies and Children's Hospital
Cleveland, Ohio, 44106
University of California Los Angeles
Los Angeles, California, 90095
Lucile Packard Children's Hospital at Stanford
Palo Alto, California, 94304
The Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, 19104
Children's National Medical Center
Washington D.C., District of Columbia, 20010
About this study
Background: Very few drugs exist that treat hyperammonemia, specifically PA and MMA. Diet restrictions and alternate pathway agents are the current primary treatments, but they frequently fail to prohibit brain damage.
Orthotopic liver transplantation cures the hyperammonemia of urea cycle disorders, but organ availability is limited and the procedure is highly invasive and requires life-long immunosuppression.
Read more
A drug that could repair or stimulate a dysfunctional urea cycle such as this would have several advantages over current therapy. A drug called N-carbamyl-L-glutamate, Carglumic acid (NCG or Carbaglu)has recently been found to be virtually curative of another urea cycle defect called NAGS deficiency. In this disorder, treatment with NCG alone normalizes ureagenesis, blood ammonia and glutamine levels, allows normal protein tolerance and restores health. Knowledge from this study is being applied to acquired hyperammonemia, specifically in patients with propionic PA and MMA, to try and improve neurodevelopmental outcomes by improving the hyperammonemia.
Aims: The overall objective of this project is to determine whether treatment of acute hyperammonemia with Carglumic acid in propionic acidemia (PA), methylmalonic acidemia (MMA) changes the long-term outcome of disease and to determine if it is effective in restoring urine ammonia levels to normal levels.
Read the detailed description
Methods/Design This 5-year, Phase II, double-blind study aims to recruit and enroll 34 PA and MMA patients during acute episodes of hyperammonemia.
The primary aim is to circumvent the long-term neurodevelopmental decline due to having a prolonged levels of ammonia during crisis in the blood and urine. After treatment and crisis resolution with Carbaglu or placebo and standard of care therapy, measures of neurodevelopmental outcomes (Bayley II and Functional Status Scale) are being measured at 9, 15,21 and 30 months post-discharge from the hospital. Safety of NCG treatment will also be monitored as measured by close examination of adverse events and laboratory blood tests. To test for the effectiveness of NCG, longitudinal models to evaluate the groupwise difference (NCG vs. Placebo) in the trajectory of change in neurodevelopmental outcomes and safety analyses between drug and placebo patients.
Subsequent Episodes At any time after the initial episode, participants may present to the hospital with PA- or MMA-associated symptoms. If the plasma ammonia level verified as a bonafide episode of HA (plasma ammonia is ≥ 100 µmol/l), that participant will receive the same study medication that they received during their initial episode in a double-blinded fashion, (i.e. If the participant received NCG at the time of initial randomization, he/she will continue to receive NCG at each subsequent HA episode. If the participant received PLBO at the time of initial randomization, he/she will continue to receive PLBO at each subsequent HA episode). Only the pharmacist will know if the participant receives NCG or PLBO. The same study assessments (previously stated) will be conducted at each qualifying HSA episode.
- Conditions
- Propionic Acidemia, Methylmalonic Acidemia
- Being tested
- N-carbamylglutamate, Standard of Care
- Keywords
- Propionic acidemia (PA), Methylmalonic acidemia (MMA), Carbaglu NCG, Hyperammonia
- Medical subject headings
- Propionic Acidemia, Methylmalonic acidemia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
N-carbamylglutamateDrug
Also called Carbaglu, NCG
Active NCG \& Standard of Care Chemical Composition: N-carbamyl-L-glutamic acid (NCG) The daily dose will be 100 mg/kg/ day. 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.
This drug will be administered for 7 days after admission or until discharge (whichever is sooner).
Standard of CareOther
Standard of Care
| Study group | Role | What they receive |
|---|---|---|
| N-Carbamylglutamate | Experimental | Active NCG \& Standard of Care Receives: Drug: N-carbamylglutamate; Other: Standard of Care |
| Placebo | Placebo comparator | Standard of Care therapy Receives: Other: Standard of Care |
What is being measured
The primary outcome is the main question the study is designed to answer.
Neurodevelopment
Neurodevelopmental outcome as measured by Cognitive Composite (Bayley III), Motor Composite (Bayley III) and Functional Status Scale and safety of NCG treatment as measured by adverse events and laboratory blood tests
Measured: 30 months
Secondary outcomes (1)
Number of Participants With Adverse Events
Safety is measured by tracking and detailing the number and type of adverse events and their severity based on the CTCAE.
Measured: Start of episode through 7 days or discharge (if earlier)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 May 2012 (estimated)
- Study startSep 2012
- Primary completionFeb 2015
- Study completionFeb 2015
Why it stopped: insufficient enrollment
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.
- Other trials for Propionic AcidemiaStudies 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
- 1 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, Lucile Packard Children's Hospital, University of Colorado, Denver
- 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
- NCT01597440
- Sponsor's protocol ID
- NCGC 0007
- Status last verified
- Mar 2017
- First submitted
- 10 May 2012
- Last updated
- 26 Apr 2017
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- No: A single participant was enrolled before the study closed. There are no analyses and if data are shared, this may compromise the confidentiality of this single participant from a very rare disease.
Study at a glance
From the registry record, last updated by the sponsor on 26 Apr 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Long-term Outcome of N-Carbamylglutamate Treatment in Propionic Acidemia and Methylmalonic Acidemia
- ClinicalTrials.gov ID
- NCT01597440
- Acronym / sponsor ID
- NCGC 0007
- Conditions
- Propionic Acidemia, Methylmalonic Acidemia
- Keywords
- Propionic acidemia (PA), Methylmalonic acidemia (MMA), Carbaglu NCG, Hyperammonia
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: insufficient enrollment
- Enrolment
- 1 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, Lucile Packard Children's Hospital, University of Colorado, Denver
- Study start
- Sep 2012
- Primary completion
- Feb 2015 (actual)
- Study completion
- Feb 2015 (actual)
- First posted
- 14 May 2012 (estimated)
- Results
- Posted 26 Apr 2017
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Background: Very few drugs exist that treat hyperammonemia, specifically PA and MMA. Diet restrictions and alternate pathway agents are the current primary treatments, but they frequently fail to prohibit brain damage.
Orthotopic liver transplantation cures the hyperammonemia of urea cycle disorders, but organ availability is limited and the procedure is highly invasive and requires life-long immunosuppression.
A drug that could repair or stimulate a dysfunctional urea cycle such as this would have several advantages over current therapy. A drug called N-carbamyl-L-glutamate, Carglumic acid (NCG or Carbaglu)has recently been found to be virtually curative of another urea cycle defect called NAGS deficiency. In this disorder, treatment with NCG alone normalizes ureagenesis, blood ammonia and glutamine levels, allows normal protein tolerance and restores health. Knowledge from this study is being applied to acquired hyperammonemia, specifically in patients with propionic PA and MMA, to try and improve neurodevelopmental outcomes by improving the hyperammonemia.
Aims: The overall objective of this project is to determine whether treatment of acute hyperammonemia with Carglumic acid in propionic acidemia (PA), methylmalonic acidemia (MMA) changes the long-term outcome of disease and to determine if it is effective in restoring urine ammonia levels to normal levels.
Detailed description
Methods/Design This 5-year, Phase II, double-blind study aims to recruit and enroll 34 PA and MMA patients during acute episodes of hyperammonemia.
The primary aim is to circumvent the long-term neurodevelopmental decline due to having a prolonged levels of ammonia during crisis in the blood and urine. After treatment and crisis resolution with Carbaglu or placebo and standard of care therapy, measures of neurodevelopmental outcomes (Bayley II and Functional Status Scale) are being measured at 9, 15,21 and 30 months post-discharge from the hospital. Safety of NCG treatment will also be monitored as measured by close examination of adverse events and laboratory blood tests. To test for the effectiveness of NCG, longitudinal models to evaluate the groupwise difference (NCG vs. Placebo) in the trajectory of change in neurodevelopmental outcomes and safety analyses between drug and placebo patients.
Subsequent Episodes At any time after the initial episode, participants may present to the hospital with PA- or MMA-associated symptoms. If the plasma ammonia level verified as a bonafide episode of HA (plasma ammonia is ≥ 100 µmol/l), that participant will receive the same study medication that they received during their initial episode in a double-blinded fashion, (i.e. If the participant received NCG at the time of initial randomization, he/she will continue to receive NCG at each subsequent HA episode. If the participant received PLBO at the time of initial randomization, he/she will continue to receive PLBO at each subsequent HA episode). Only the pharmacist will know if the participant receives NCG or PLBO. The same study assessments (previously stated) will be conducted at each qualifying HSA episode.
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 |
|---|---|---|
| N-Carbamylglutamate | Experimental | Drug: N-carbamylglutamate, Other: Standard of CareActive NCG \& Standard of Care |
| Placebo | Placebo comparator | Other: Standard of CareStandard of Care therapy |
Who may qualify
- Ages
- 1 hour to 4 weeks
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (13 listed)
- Aged 4 weeks or younger (0-28 days)
- >36 weeks gestational age at birth
- Birth weight ≥2500 g
- Plasma ammonia level at presentation >150 mcmol/L
- PA or MMA presumed or established diagnosis as follows (one of the following):
Key exclusion criteria (8 listed)
- Had any prior hyperammonemic episode
- Administration of NCG within 7 days of participation in the study
- Use of any other investigational drug, biologic, or therapy, with the exception of sodium benzoate or sodium phenylacetate if the latter were administered prior to diagnosis by acylcarnitine analysis (diagnostic inclusion criterion 2), or organic acid analysis (diagnostic inclusion criteria 3 \& 4)
- Planned participation in any other clinical trial
- Diagnosis of any medical condition causing hyperammonemia which is not PA or MMA.
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: Carbaglu, NCGActive NCG \& Standard of Care Chemical Composition: N-carbamyl-L-glutamic acid (NCG) The daily dose will be 100 mg/kg/ day. 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. This drug will be administered for 7 days after admission or until discharge (whichever is sooner). | Drug | N-Carbamylglutamate |
| Standard of CareStandard of Care | Other | N-Carbamylglutamate, Placebo |
Primary outcome
Neurodevelopment
Time frame: 30 months
Neurodevelopmental outcome as measured by Cognitive Composite (Bayley III), Motor Composite (Bayley III) and Functional Status Scale and safety of NCG treatment as measured by adverse events and laboratory blood tests
1 secondary outcome
Number of Participants With Adverse Events
Time frame: Start of episode through 7 days or discharge (if earlier)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 Apr 2017.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No. A single participant was enrolled before the study closed. There are no analyses and if data are shared, this may compromise the confidentiality of this single participant from a very rare disease.
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Propionic Acidemia
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
7 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 N-carbamylglutamate in people with Propionic Acidemia and Methylmalonic Acidemia, run by Mendel Tuchman at 7 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 13 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: stopped early, as of the sponsor's last update on 26 Apr 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 7 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. Some participants in this study may receive a placebo. 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 26 Apr 2017). 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?
Neurodevelopment (time frame: 30 months). 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 26 Apr 2017.