Clinical trial NCT01599286: Short-Term Outcome of N-Carbamylglutamate in the Treatment of Acute Hyperammonemia
Official title: Short-Term Outcome of N-Carbamylglutamate in the Treatment of Acute Hyperammonemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Propionic Acidemia, Type I and/or Type II
Methylmalonic Acidemia
Carbamoyl-Phosphate Synthase I Deficiency Disease
Ornithine Carbamoyltransferase Deficiency
Keywords: Hyperammonemia
Propionic Acidemia (PA)
Methylmalonic Acidemia (MMA)
Late-Onset CPS1 Deficiency (CPSD)
Late-Onset Ornithine Transcarbamylase Deficiency (OTCD)
Carbaglu
Lead sponsor: Children's National Research Institute
Sponsor class: OTHER
Collaborators: name: Children's National Research Institute
name: Boston Children's Hospital
name: University Hospitals Cleveland Medical Center
name: University of California, Los Angeles
name: Children's Hospital of Philadelphia
name: Stanford University
name: Icahn School of Medicine at Mount Sinai
name: University of Pittsburgh
name: Children's Hospital Colorado
First posted: 2012-05-16
Enrollment: 35
Sex: ALL
Minimum age (years): 1
Maximum age (years): 99
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

Detailed description: 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.

Eligibility criteria: 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 the absence of argininosuccinic acid

AND: Subject or subject's first-degree relative had plasma ammonia level ≥100 μmol/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 the 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 an 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 μmol/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 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 the site for subsequent episodes of hyperammonemia crises
* Is pregnant

Primary outcomes:
measure: Time to the Primary Outcome (Earlier of Ammonia <50 µmol/L or Hospital Discharge)
timeFrame: Average of all measurements of hyperammonemia, for up to 7 days
Secondary outcomes:
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of California Los Angeles
state: California
city: Palo Alto
country: United States
facility: Lucile Packard Children's Hospital at Stanford
state: California
city: Aurora
country: United States
facility: The Children's Hospital of Colorado
state: Colorado
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Boston
country: United States
facility: Children's Hospital Boston
state: Massachusetts
city: New York
country: United States
facility: Mount Sinai School of Medicine
state: New York
city: Cleveland
country: United States
facility: University Hospitals Cleveland Medical Center
state: Ohio
city: Philadelphia
country: United States
facility: The Children's Hospital of Philadelphia (CHOP)
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
Study officials:
affiliation: Children's National Research Institute
name: Mendel Tuchman, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Amari S, Shahrook S, Namba F, Ota E, Mori R. Branched-chain amino acid supplementation for improving growth and development in term and preterm neonates. Cochrane Database Syst Rev. 2020 Oct 2;10(10):CD012273. doi: 10.1002/14651858.CD012273.pub2.