We are updating the design of this site. Learn more.
Show more
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

This study is currently recruiting participants.
Verified October 2017 by Mendel Tuchman, Children's Research Institute
Sponsor:
ClinicalTrials.gov Identifier:
NCT01599286
First Posted: May 16, 2012
Last Update Posted: October 6, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborators:
Children's Research Institute
Boston Children’s Hospital
University Hospitals Cleveland Medical Center
University of California, Los Angeles
Children's Hospital of Philadelphia
Stanford University
Icahn School of Medicine at Mount Sinai
University of Pittsburgh
Children's Hospital Colorado
Information provided by (Responsible Party):
Mendel Tuchman, Children's Research Institute
May 11, 2012
May 16, 2012
October 6, 2017
September 2012
June 2019   (Final data collection date for primary outcome measure)
Trajectory of Change in Ammonia During Hospitalization for Hyperammonemia [ Time Frame: Admission, Post Dialysis, 12, 24, 36, 48 hours and daily for 7 days or until discharge ]
Change in ammonia and Functional Status Score (FSS)
Trajectory of Change in Ammonia During Hospitalization for Hyperammonemia [ Time Frame: Admission, Post Dialysis, 12, 24, 36, 48 hours and daily for 7 days or until discharge. ]
Change in ammonia and functional status.
Complete list of historical versions of study NCT01599286 on ClinicalTrials.gov Archive Site
Safety of NCG [ Time Frame: Admission, 12, 24, 36, 48 hours and daily until day 7 after episode (or discharge, whichever is sooner) ]

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 entry to the study.

Safety tests consisting of complete blood count (CBC), liver and kidney function tests, coagulation profile (PTT/INR) will be performed before treatment, on the third day of treatment, and just prior to discontinuation of NCG. A electrocardiogram test will be given before treatment and repeated on the third day of treatment (48 hours following the initial drug administration) or before discharge if earlier, to check for cardiac toxicity.

Safety of NCG [ Time Frame: Admission, 12, 24, 36, 48 hours and daily until day 7 after episode (or discharge, whichever is sooner) ]

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 entry to the study.

Safety tests consisting of complete blood count (CBC), liver and kidney function tests, coagulation profile (PTT/INR) will be performed before treatment, on the third day of treatment, and just prior to discontinuation of NCG.

Not Provided
Not Provided
 
Short-Term Outcome of N-Carbamylglutamate in the Treatment of Acute Hyperammonemia
Short-Term Outcome of N-Carbamylglutamate in the Treatment of Acute Hyperammonemia

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.

Interventional
Phase 2
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
  • Propionic Acidemia, Type I and/or Type II
  • Methylmalonic Acidemia
  • Carbamoyl-Phosphate Synthase I Deficiency Disease
  • Ornithine Carbamoyltransferase Deficiency
  • Drug: Carbaglu

    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.

    Other Name: Carglumic Acid
  • Drug: Placebo
  • Drug: Standard of Care Treatment
  • Experimental: Active Comparator
    Parallel Trial Comparing NCG + Standard of Care Treatment
    Interventions:
    • Drug: Carbaglu
    • Drug: Standard of Care Treatment
  • Active Comparator: Placebo Comparator
    Placebo and Standard of Care Therapy
    Interventions:
    • Drug: Placebo
    • Drug: Standard of Care Treatment
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
114
December 2019
June 2019   (Final data collection date for primary outcome measure)

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 absence of argininosuccinic acid

AND: Subject or subject's first-degree relative had plasma ammonia level ≥100 mcmol/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 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 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 mcmol/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 an 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 site for subsequent episodes of hyperammonemia crises
  • Is pregnant
Sexes Eligible for Study: All
up to 99 Years   (Child, Adult, Senior)
No
Contact: Mendel Tuchman, MD 202-476-2549 mtuchman@childrensnational.org
Contact: Robert McCarter, ScD 202-476-3140 rmccarte@childrensnational.org
United States
 
 
NCT01599286
NCGC0008
Yes
Not Provided
Plan to Share IPD: No
Plan Description: This is a blinded study, the individual participant data will not be shared
Mendel Tuchman, Children's Research Institute
Mendel Tuchman
  • Children's Research Institute
  • Boston Children’s Hospital
  • University Hospitals Cleveland Medical Center
  • University of California, Los Angeles
  • Children's Hospital of Philadelphia
  • Stanford University
  • Icahn School of Medicine at Mount Sinai
  • University of Pittsburgh
  • Children's Hospital Colorado
Principal Investigator: Mendel Tuchman, MD Children's Research Institute
Children's Research Institute
October 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP