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
Intervention: Carbaglu; Placebo
Intervention description: 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
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 35.0
Sex: All
Minimum age: 1 Week
Maximum age: 99 Years
Healthy volunteers: No
Keywords: Hyperammonemia; Propionic Acidemia (PA); Methylmalonic Acidemia (MMA); Late-Onset CPS1 Deficiency (CPSD); Late-Onset Ornithine Transcarbamylase Deficiency (OTCD); Carbaglu

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.
    

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