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Long-term Outcome of N-Carbamylglutamate Treatment in Propionic Acidemia and Methylmalonic Acidemia

Primary Purpose

Propionic Acidemia, Methylmalonic Acidemia

Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
N-carbamylglutamate
Standard of Care
Sponsored by
Mendel Tuchman
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Propionic Acidemia focused on measuring Propionic acidemia (PA), Methylmalonic acidemia (MMA), Carbaglu NCG, Hyperammonia

Eligibility Criteria

1 Hour - 4 Weeks (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria

  • 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):

    1. Acidosis at presentation, pH <7.3 OR
    2. Plasma acylcarnitine analysis either alone or as part of newborn screening, demonstrating C3 >4 mcmol/L OR
    3. 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
    4. 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.

Exclusion Criteria

  • 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

Sites / Locations

  • University of California Los Angeles
  • Lucile Packard Children's Hospital at Stanford
  • The Children's Hospital of Colorado
  • Children's National Medical Center
  • Children's Hospital Boston
  • University Hospitals of Cleveland/Rainbow Babies and Children's Hospital
  • The Children's Hospital of Philadelphia

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

N-Carbamylglutamate

Placebo

Arm Description

Active NCG & Standard of Care

Standard of Care therapy

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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.

Full Information

First Posted
May 10, 2012
Last Updated
March 15, 2017
Sponsor
Mendel Tuchman
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
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1. Study Identification

Unique Protocol Identification Number
NCT01597440
Brief Title
Long-term Outcome of N-Carbamylglutamate Treatment in Propionic Acidemia and Methylmalonic Acidemia
Official Title
Long-term Outcome of N-Carbamylglutamate Treatment in Propionic Acidemia and Methylmalonic Acidemia
Study Type
Interventional

2. Study Status

Record Verification Date
March 2017
Overall Recruitment Status
Terminated
Why Stopped
insufficient enrollment
Study Start Date
September 2012 (undefined)
Primary Completion Date
February 2015 (Actual)
Study Completion Date
February 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Mendel Tuchman
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

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief 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. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Propionic Acidemia, Methylmalonic Acidemia
Keywords
Propionic acidemia (PA), Methylmalonic acidemia (MMA), Carbaglu NCG, Hyperammonia

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
1 (Actual)

8. Arms, Groups, and Interventions

Arm Title
N-Carbamylglutamate
Arm Type
Experimental
Arm Description
Active NCG & Standard of Care
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Standard of Care therapy
Intervention Type
Drug
Intervention Name(s)
N-carbamylglutamate
Other Intervention Name(s)
Carbaglu, NCG
Intervention Description
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).
Intervention Type
Other
Intervention Name(s)
Standard of Care
Intervention Description
Standard of Care
Primary Outcome Measure Information:
Title
Neurodevelopment
Description
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
Time Frame
30 months
Secondary Outcome Measure Information:
Title
Number of Participants With Adverse Events
Description
Safety is measured by tracking and detailing the number and type of adverse events and their severity based on the CTCAE.
Time Frame
Start of episode through 7 days or discharge (if earlier)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
1 Hour
Maximum Age & Unit of Time
4 Weeks
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria 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 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. Exclusion Criteria 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Mendel Tuchman, MD
Organizational Affiliation
Children's National Research Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of California Los Angeles
City
Los Angeles
State/Province
California
ZIP/Postal Code
90095
Country
United States
Facility Name
Lucile Packard Children's Hospital at Stanford
City
Palo Alto
State/Province
California
ZIP/Postal Code
94304
Country
United States
Facility Name
The Children's Hospital of Colorado
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
Children's National Medical Center
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20010
Country
United States
Facility Name
Children's Hospital Boston
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
University Hospitals of Cleveland/Rainbow Babies and Children's Hospital
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44106
Country
United States
Facility Name
The Children's Hospital of Philadelphia
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
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.

Learn more about this trial

Long-term Outcome of N-Carbamylglutamate Treatment in Propionic Acidemia and Methylmalonic Acidemia

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