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

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.

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