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

• Status: Completed
• Trial end date: 2020-04-30
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Mendel Tuchman
• Collaborators: Boston Children's Hospital; Boston Children’s Hospital; Children's Hospital Colorado; Children's Hospital of Philadelphia; Children's National Research Institute; Children's Research Institute; Icahn School of Medicine at Mount Sinai; Stanford University; University Hospitals Cleveland Medical Center; University of California, Los Angeles; University of Pittsburgh

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