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

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

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

      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 Phase

Phase 2

Study Type


Primary Outcome


Secondary Outcome

 Number of Participants With Adverse Events


Propionic Acidemia



Study Arms / Comparison Groups

Description:  Active NCG & Standard of Care


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status


Estimated Enrollment


Start Date

September 2012

Completion Date

February 2015

Primary Completion Date

February 2015

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):

               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

          -  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

        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

          -  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




N/A - 4 Weeks

Accepts Healthy Volunteers



Mendel Tuchman, MD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations



Organization ID

NCGC 0007

Responsible Party


Study Sponsor

Mendel Tuchman


 Children's National Research Institute

Study Sponsor

Mendel Tuchman, MD, Principal Investigator, Children's National Research Institute

Verification Date

March 2017