Short-term Outcome of N-Carbamylglutamate in the Treatment of Acute Hyperammonemia

The overall objective of this drug trial is to determine whether treatment of acute hyperammonemia with N-carbamyl-L-glutamate (NCG, Carglumic acid, NCG) 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 hyperammonemic episode.

This is a double-blind 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:

1. 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.

2. 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 entry to the study.

Safety tests consisting of complete blood count (CBC), liver and kidney function tests, coagulation profile (PTT/INR) will be performed before treatment, on the third day of treatment, and just prior to discontinuation of NCG.

• Propionic Acidemia (PA)
• Methylmalonic Acidemia (MMA)
• Late-onset CPS1 Deficiency (CPSD)
• Late-onset Ornithine Transcarbamylase Deficiency (OTCD)

• Drug: Carbaglu

  Chemical Composition: N-carbamoyl-L-glutamic acid (NCG) The daily dose will be 100 mg/kg/ day or 2.2 g/m2/day for patients >25 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: Placebo
• Drug: Standard Care Treatment

• Experimental: NCG
  Parallel trial comparing NCG + Standard of Care treatment
  Interventions:

  • Drug: Carbaglu
  • Drug: Standard Care Treatment
• Active Comparator: Placebo
  Placebo and Standard of Care therapy.
  Interventions:

  • Drug: Placebo
  • Drug: Standard Care Treatment

Inclusion Criteria:

• Aged 4 weeks to 18 years

• Established diagnosis of PA, MMA, CPSD or OTCD as follows (one of the following):

  • Diagnosed with PA by quantitative urine organic acid analysis, defined as 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 quantitative urine organic acid analysis, defined as elevation of methylmalonic acid and no evidence of vitamin B12 dependent disorder on plasma amino acid analysis OR
  • Diagnosed with late-onset CPSD by 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 absence of argininosuccinic acid

• Subject or subject's first degree relative who:

  • Had plasma ammonia level at any time >200 µmol/l
  • If diagnosed PA/MMA (per above) had initial hyperammonemia ≤ 4 weeks of age
  • If diagnosed CPSD/OTCD (per above) had initial hyperammonemia > 4 weeks of age
• 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

Exclusion Criteria:

• Administration of NCG within 7 days of participation in the study
• Use of any other investigational drug, biologic, or therapy.
• 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

• Children's Hospital of Philadelphia
• Children's Hospital Boston
• Case Western Reserve University
• Children's Hospital Colorado
• University of California, Los Angeles
• University of Washington