short-term outcome of n-carbamylglutamate in the treatment of acute hyperammonemia

Conditions: Propionic Acidemia, Type I and/or Type II; Methylmalonic Acidemia; Carbamoyl-Phosphate Synthase I Deficiency Disease; Ornithine Carbamoyltransferase Deficiency

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.

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

Keywords: hyperammonemia propionic acidemia (pa) methylmalonic acidemia (mma) late-onset cps1 deficiency (cpsd) late-onset ornithine transcarbamylase deficiency (otcd) carbaglu