Short-Term Outcome of N-Carbamylglutamate in the Treatment of Acute Hyperammonemia
Condition: Propionic Acidemia, Type I and/or Type II; Methylmalonic Acidemia; Carbamoyl-Phosphate Synthase I Deficiency Disease; Ornithine Carbamoyltransferase Deficiency
MeSH terms: Ornithine Carbamoyltransferase Deficiency Disease; Carbamoyl-Phosphate Synthase I Deficiency Disease; Propionic Acidemia; Acidosis; Deficiency Diseases; Hyperammonemia
Study type: Interventional
Phase: Phase 2

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.
    

Intervention name(s): Carbaglu; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Carbaglu Chemical Composition: N-carbamoyl-L-glutamic acid (NCG)
The daily dose will be 150 mg/kg/ day or 3.3 g/m2/day for patients >15 kg and will be administered for 7 days or until discharge, whichever is sooner. The doses are to be divided into 2 equal doses and administered orally or enterally by nasogastric or gastrostomy tube. Standard of care will prevail when choosing the mode of drug administration.
The tablets must be dispersed in a minimum of 2.5-10 ml of water and ingested immediately or administered by fast-push through a syringe via a nasogastric or gastrostomy tube. The suspension has a slightly acidic taste.; Placebo that looks/tastes the same as NCG and is administered on the same schedule as the NCG intervention
Other intervention name(s): Carglumic Acid
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Hyperammonemia; Propionic Acidemia (PA); Methylmalonic Acidemia (MMA); Late-Onset CPS1 Deficiency (CPSD); Late-Onset Ornithine Transcarbamylase Deficiency (OTCD); Carbaglu