Long-term Outcome of N-Carbamylglutamate Treatment in Propionic Acidemia and Methylmalonic Acidemia
Condition: Propionic Acidemia; Methylmalonic Acidemia
MeSH terms: Amino Acid Metabolism, Inborn Errors; Propionic Acidemia; Acidosis
Intervention: N-carbamylglutamate; Standard of Care
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).; Standard of Care
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 1.0
Sex: All
Minimum age: 1 Hour
Maximum age: 4 Weeks
Healthy volunteers: No
Keywords: Propionic acidemia (PA); Methylmalonic acidemia (MMA); Carbaglu NCG; Hyperammonia

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.
    

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
             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