Trial Outcomes & Findings for Short-Term Outcome of N-Carbamylglutamate in the Treatment of Acute Hyperammonemia (NCT NCT01599286)

Last Updated: 2021-02-15

Results Overview

The composite primary intention to treat (ITT) outcome of the earlier of time to reach an ammonia level of ≤50 µmol/L or hospital discharge. Data presented as a hazard ratio based on the time to reach an ammonia level of ≤50 µmol/L. The outcome measure was a survival analysis based on time to reach the earlier of an ammonia level of ≤50 µmol/L or time to discharge, which was considered to be a point where the patient was no longer at risk of neurological injury from ammonia. The outcome of survival analysis was a hazard ratio reflecting the ratio of probabilities in each group (drug vs placebo) of reaching the earlier of an ammonia level of ≤50 µmol/L or discharge. We measured multiple post-treatment ammonia levels at uncontrolled times during an episode, so it is difficult to compute a meaningful average that would not be biased by the frequency and timing of ammonia testing during episodes.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

35 participants

Primary outcome timeframe

Average of all measurements of hyperammonemia, for up to 7 days

Results posted on

2021-02-15

Participant Flow

There were 65 eligible patients, 35 were enrolled with a randomization of hyperammonemia. Eligible patients were randomized at each episode of hyperammonemia. To be enrolled, a patient had to have an eligible episode of hyperammonemia and was then randomized to either placebo or NCG at each randomization. 13 patients had multiple randomizations, 22 only had one.

Unit of analysis: Episodes

Participant milestones

Participant milestones
Measure	Episodes of N-Carbamylglutamate Episodes where the participant was randomized to the NCG arm	Episodes of Placebo Episodes where the participant was randomized to the placebo arm
Overall Study STARTED	24 54	23 52
Overall Study COMPLETED	24 54	23 52
Overall Study NOT COMPLETED	0 0	0 0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Episodes of N-carbamylglutamate (NCG) n=52 Episodes Total number of episodes of hyperammonemia where a patient was randomized to the NCG arm A daily dose of 150 mg/kg/ day or 3.3 g/m2/day for patients \>15 kg administered for 7 days or until discharge, whichever is sooner.	Episodes of Placebo n=54 Episodes Total number of episodes of hyperammonemia where a patient was randomized to the placebo arm Placebo that looks/tastes the same as NCG and is administered on the same schedule as the NCG intervention	Total n=106 Episodes Total of all reporting groups
Age, Customized 0 - <5 years	10 Episodes n=52 Episodes	16 Episodes n=54 Episodes	26 Episodes n=106 Episodes
Age, Customized 5 - <12 years	27 Episodes n=52 Episodes	22 Episodes n=54 Episodes	49 Episodes n=106 Episodes
Age, Customized 12 - <18 years	1 Episodes n=52 Episodes	4 Episodes n=54 Episodes	5 Episodes n=106 Episodes
Age, Customized 18+ years	14 Episodes n=52 Episodes	12 Episodes n=54 Episodes	26 Episodes n=106 Episodes
Sex: Female, Male Female	33 Episodes n=52 Episodes	34 Episodes n=54 Episodes	67 Episodes n=106 Episodes
Sex: Female, Male Male	19 Episodes n=52 Episodes	20 Episodes n=54 Episodes	39 Episodes n=106 Episodes
Ethnicity (NIH/OMB) Hispanic or Latino	13 Episodes n=52 Episodes	17 Episodes n=54 Episodes	30 Episodes n=106 Episodes
Ethnicity (NIH/OMB) Not Hispanic or Latino	39 Episodes n=52 Episodes	36 Episodes n=54 Episodes	75 Episodes n=106 Episodes
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Episodes n=52 Episodes	1 Episodes n=54 Episodes	1 Episodes n=106 Episodes
Race (NIH/OMB) American Indian or Alaska Native	0 Episodes n=52 Episodes	0 Episodes n=54 Episodes	0 Episodes n=106 Episodes
Race (NIH/OMB) Asian	21 Episodes n=52 Episodes	19 Episodes n=54 Episodes	40 Episodes n=106 Episodes
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Episodes n=52 Episodes	1 Episodes n=54 Episodes	1 Episodes n=106 Episodes
Race (NIH/OMB) Black or African American	11 Episodes n=52 Episodes	11 Episodes n=54 Episodes	22 Episodes n=106 Episodes
Race (NIH/OMB) White	17 Episodes n=52 Episodes	19 Episodes n=54 Episodes	36 Episodes n=106 Episodes
Race (NIH/OMB) More than one race	2 Episodes n=52 Episodes	3 Episodes n=54 Episodes	5 Episodes n=106 Episodes
Race (NIH/OMB) Unknown or Not Reported	1 Episodes n=52 Episodes	1 Episodes n=54 Episodes	2 Episodes n=106 Episodes

PRIMARY outcome

Timeframe: Average of all measurements of hyperammonemia, for up to 7 days

Population: Patients were randomized to either study drug or placebo at each episode of hyperammonemia analysed by diagnosis. Data presented as a hazard ratio based on the time to reach an ammonia level of ≤50 µmol/L. Higher ratios reflect an NCG advantage.

Outcome measures

Outcome measures
Measure	PA/MMA Episodes n=90 Episodes All episodes where a patient diagnosed with PA/MMA was randomized to either placebo or NCG	CPS1D/OTCD Episodes n=16 Episodes All episodes where a patient diagnosed with CPS1D/OTCD was randomized to either placebo or NCGPatients PA/MMA who received study drug
Time to the Primary Outcome (Earlier of Ammonia <50 µmol/L or Hospital Discharge)	1.37 Hazard Ratio Interval 0.88 to 2.13	0.79 Hazard Ratio Interval 0.22 to 2.81

Adverse Events

Placebo

Serious events: 6 serious events

Other events: 9 other events

Deaths: 10 deaths

N-carbamylglutamate (NCG)

Serious events: 8 serious events

Other events: 11 other events

Deaths: 14 deaths

Serious adverse events

Serious adverse events
Measure	Placebo n=24 participants at risk Episodes where the patient was randomized to placebo	N-carbamylglutamate (NCG) n=25 participants at risk Episodes where the patient was randomized to NCG
Gastrointestinal disorders Gastrointestinal Disorders	16.7% 4/24 • Number of events 9 • During each hospitalization, once per day, up to 7 days. Adverse Events were monitored/assessed without regard to the specific Adverse Event Term.	20.0% 5/25 • Number of events 7 • During each hospitalization, once per day, up to 7 days. Adverse Events were monitored/assessed without regard to the specific Adverse Event Term.
Infections and infestations Infections and Infestations	8.3% 2/24 • Number of events 2 • During each hospitalization, once per day, up to 7 days. Adverse Events were monitored/assessed without regard to the specific Adverse Event Term.	16.0% 4/25 • Number of events 4 • During each hospitalization, once per day, up to 7 days. Adverse Events were monitored/assessed without regard to the specific Adverse Event Term.
Injury, poisoning and procedural complications Injury	4.2% 1/24 • Number of events 1 • During each hospitalization, once per day, up to 7 days. Adverse Events were monitored/assessed without regard to the specific Adverse Event Term.	4.0% 1/25 • Number of events 1 • During each hospitalization, once per day, up to 7 days. Adverse Events were monitored/assessed without regard to the specific Adverse Event Term.
Metabolism and nutrition disorders Metabolic and Nutritional	4.2% 1/24 • Number of events 1 • During each hospitalization, once per day, up to 7 days. Adverse Events were monitored/assessed without regard to the specific Adverse Event Term.	4.0% 1/25 • Number of events 1 • During each hospitalization, once per day, up to 7 days. Adverse Events were monitored/assessed without regard to the specific Adverse Event Term.
Nervous system disorders Nervous System	0.00% 0/24 • During each hospitalization, once per day, up to 7 days. Adverse Events were monitored/assessed without regard to the specific Adverse Event Term.	12.0% 3/25 • Number of events 4 • During each hospitalization, once per day, up to 7 days. Adverse Events were monitored/assessed without regard to the specific Adverse Event Term.
Respiratory, thoracic and mediastinal disorders Respiratory	0.00% 0/24 • During each hospitalization, once per day, up to 7 days. Adverse Events were monitored/assessed without regard to the specific Adverse Event Term.	4.0% 1/25 • Number of events 1 • During each hospitalization, once per day, up to 7 days. Adverse Events were monitored/assessed without regard to the specific Adverse Event Term.

Other adverse events

Other adverse events
Measure	Placebo n=24 participants at risk Episodes where the patient was randomized to placebo	N-carbamylglutamate (NCG) n=25 participants at risk Episodes where the patient was randomized to NCG
Blood and lymphatic system disorders Blood/Lymphatic	12.5% 3/24 • Number of events 4 • During each hospitalization, once per day, up to 7 days. Adverse Events were monitored/assessed without regard to the specific Adverse Event Term.	16.0% 4/25 • Number of events 6 • During each hospitalization, once per day, up to 7 days. Adverse Events were monitored/assessed without regard to the specific Adverse Event Term.
Cardiac disorders Cardiac	4.2% 1/24 • Number of events 1 • During each hospitalization, once per day, up to 7 days. Adverse Events were monitored/assessed without regard to the specific Adverse Event Term.	4.0% 1/25 • Number of events 1 • During each hospitalization, once per day, up to 7 days. Adverse Events were monitored/assessed without regard to the specific Adverse Event Term.
Gastrointestinal disorders Gastrointestinal	16.7% 4/24 • Number of events 9 • During each hospitalization, once per day, up to 7 days. Adverse Events were monitored/assessed without regard to the specific Adverse Event Term.	16.0% 4/25 • Number of events 8 • During each hospitalization, once per day, up to 7 days. Adverse Events were monitored/assessed without regard to the specific Adverse Event Term.
General disorders General	12.5% 3/24 • Number of events 5 • During each hospitalization, once per day, up to 7 days. Adverse Events were monitored/assessed without regard to the specific Adverse Event Term.	4.0% 1/25 • Number of events 2 • During each hospitalization, once per day, up to 7 days. Adverse Events were monitored/assessed without regard to the specific Adverse Event Term.
Infections and infestations Infections	12.5% 3/24 • Number of events 4 • During each hospitalization, once per day, up to 7 days. Adverse Events were monitored/assessed without regard to the specific Adverse Event Term.	4.0% 1/25 • Number of events 1 • During each hospitalization, once per day, up to 7 days. Adverse Events were monitored/assessed without regard to the specific Adverse Event Term.
Injury, poisoning and procedural complications Injury/Procedure Complications	4.2% 1/24 • Number of events 1 • During each hospitalization, once per day, up to 7 days. Adverse Events were monitored/assessed without regard to the specific Adverse Event Term.	4.0% 1/25 • Number of events 1 • During each hospitalization, once per day, up to 7 days. Adverse Events were monitored/assessed without regard to the specific Adverse Event Term.
Investigations Investigations	0.00% 0/24 • During each hospitalization, once per day, up to 7 days. Adverse Events were monitored/assessed without regard to the specific Adverse Event Term.	12.0% 3/25 • Number of events 6 • During each hospitalization, once per day, up to 7 days. Adverse Events were monitored/assessed without regard to the specific Adverse Event Term.
Metabolism and nutrition disorders Metabolism	16.7% 4/24 • Number of events 9 • During each hospitalization, once per day, up to 7 days. Adverse Events were monitored/assessed without regard to the specific Adverse Event Term.	24.0% 6/25 • Number of events 7 • During each hospitalization, once per day, up to 7 days. Adverse Events were monitored/assessed without regard to the specific Adverse Event Term.
Nervous system disorders Nervous System	8.3% 2/24 • Number of events 3 • During each hospitalization, once per day, up to 7 days. Adverse Events were monitored/assessed without regard to the specific Adverse Event Term.	16.0% 4/25 • Number of events 4 • During each hospitalization, once per day, up to 7 days. Adverse Events were monitored/assessed without regard to the specific Adverse Event Term.
Product Issues Product Issues	4.2% 1/24 • Number of events 1 • During each hospitalization, once per day, up to 7 days. Adverse Events were monitored/assessed without regard to the specific Adverse Event Term.	0.00% 0/25 • During each hospitalization, once per day, up to 7 days. Adverse Events were monitored/assessed without regard to the specific Adverse Event Term.
Psychiatric disorders Psychiatric	0.00% 0/24 • During each hospitalization, once per day, up to 7 days. Adverse Events were monitored/assessed without regard to the specific Adverse Event Term.	4.0% 1/25 • Number of events 2 • During each hospitalization, once per day, up to 7 days. Adverse Events were monitored/assessed without regard to the specific Adverse Event Term.
Respiratory, thoracic and mediastinal disorders Respiratory	4.2% 1/24 • Number of events 1 • During each hospitalization, once per day, up to 7 days. Adverse Events were monitored/assessed without regard to the specific Adverse Event Term.	4.0% 1/25 • Number of events 1 • During each hospitalization, once per day, up to 7 days. Adverse Events were monitored/assessed without regard to the specific Adverse Event Term.
Vascular disorders Vascular	4.2% 1/24 • Number of events 1 • During each hospitalization, once per day, up to 7 days. Adverse Events were monitored/assessed without regard to the specific Adverse Event Term.	0.00% 0/25 • During each hospitalization, once per day, up to 7 days. Adverse Events were monitored/assessed without regard to the specific Adverse Event Term.

Additional Information

Robert McCarter

Children's National Hospital

Phone: 202-476-3140

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place