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

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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01599286
Recruitment Status : Active, not recruiting
First Posted : May 16, 2012
Last Update Posted : June 11, 2019
Sponsor:
Collaborators:
Children's National 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 National Research Institute

Tracking Information
First Submitted Date  ICMJE May 11, 2012
First Posted Date  ICMJE May 16, 2012
Last Update Posted Date June 11, 2019
Actual Study Start Date  ICMJE September 2012
Actual Primary Completion Date April 30, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 5, 2017)
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)
Original Primary Outcome Measures  ICMJE
 (submitted: May 14, 2012)
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.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 24, 2015)
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.
Original Secondary Outcome Measures  ICMJE
 (submitted: May 14, 2012)
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.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Short-Term Outcome of N-Carbamylglutamate in the Treatment of Acute Hyperammonemia
Official Title  ICMJE Short-Term Outcome of N-Carbamylglutamate in the Treatment of Acute Hyperammonemia
Brief 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Propionic Acidemia, Type I and/or Type II
  • Methylmalonic Acidemia
  • Carbamoyl-Phosphate Synthase I Deficiency Disease
  • Ornithine Carbamoyltransferase Deficiency
Intervention  ICMJE
  • 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
Study Arms  ICMJE
  • 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
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: April 4, 2017)
114
Original Estimated Enrollment  ICMJE
 (submitted: May 14, 2012)
144
Estimated Study Completion Date  ICMJE April 30, 2020
Actual Primary Completion Date April 30, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 99 Years   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01599286
Other Study ID Numbers  ICMJE NCGC0008
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Plan Description: This is a blinded study, the individual participant data will not be shared
Responsible Party Mendel Tuchman, Children's National Research Institute
Study Sponsor  ICMJE Mendel Tuchman
Collaborators  ICMJE
  • Children's National 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
Investigators  ICMJE
Principal Investigator: Mendel Tuchman, MD Children's National Research Institute
PRS Account Children's National Research Institute
Verification Date June 2019

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