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

This is a double-blind, placebo-controlled, 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 the entry to the study.

Safety tests consisting of complete blood count (CBC), liver and kidney function tests, and
coagulation profile (PTT/INR) will be performed before treatment, between days 3-5 of
treatment, and just prior to discontinuation of NCG. An electrocardiogram will be performed
before treatment and on the third day of treatment or before discharge if earlier.

Inclusion Criteria

o Aged older than 1 week with an established diagnosis of CPSD or OTCD (as follows):

- Diagnosed with late-onset CPSD 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

AND: Subject or subject's first-degree relative had plasma ammonia level ≥100 mcmol/L >1
week of age

OR

o An established diagnosis of PA or MMA (as follows):

- Diagnosed with PA by semi-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 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 (B12 dependency is defined by documented B12 responsiveness)

AND: Subject or subject's first-degree relative had plasma ammonia level at any time ≥100
mcmol/L

- 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

- If post-menarcheal must have a negative pregnancy test prior to administration of
study drug at each episode

- Signed informed consent by the subject or 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

- Planned participation in any other clinical trial

- Diagnosis of any medical condition causing hyperammonemia which is not PA/MMA, CPSD or
OTCD. Other urea cycle disorders will be excluded from this study

- 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

- Has had a liver transplant

- Is not expected to be compliant with this study in terms of returning to site for
subsequent episodes of hyperammonemia crises

- Is pregnant