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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
  Purpose

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.


Condition Intervention Phase
Propionic Acidemia, Type I and/or Type II Methylmalonic Acidemia Carbamoyl-Phosphate Synthase I Deficiency Disease Ornithine Carbamoyltransferase Deficiency Drug: Carbaglu Drug: Placebo Drug: Standard of Care Treatment Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Short-Term Outcome of N-Carbamylglutamate in the Treatment of Acute Hyperammonemia

Resource links provided by NLM:


Further study details as provided by Mendel Tuchman, Children's Research Institute:

Primary Outcome Measures:
  • 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)


Secondary Outcome Measures:
  • 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.



Estimated Enrollment: 114
Actual Study Start Date: September 2012
Estimated Study Completion Date: December 2019
Estimated Primary Completion Date: June 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Active Comparator
Parallel Trial Comparing NCG + Standard of Care Treatment
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: Standard of Care Treatment
Active Comparator: Placebo Comparator
Placebo and Standard of Care Therapy
Drug: Placebo Drug: Standard of Care Treatment

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.

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   up to 99 Years   (Child, Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 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
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01599286


Contacts
Contact: Mendel Tuchman, MD 202-476-2549 mtuchman@childrensnational.org
Contact: Robert McCarter, ScD 202-476-3140 rmccarte@childrensnational.org

Locations
United States, California
University of California Los Angeles Recruiting
Los Angeles, California, United States, 90095
Contact: Rebecca Signer, MS, LCGC    310-206-6581    RSigner@mednet.ucla.edu   
Principal Investigator: Derek Wong, MD         
Lucile Packard Children's Hospital at Stanford Recruiting
Palo Alto, California, United States, 94304
Contact: Thu Quan, MBA, HCM    650-736-8166    tquan@stanford.edu   
Principal Investigator: Gregory M Enns, MD         
United States, Colorado
The Children's Hospital of Colorado Recruiting
Aurora, Colorado, United States, 80045
Contact: Curtis Coughlin, MS, MBe, CGC    303-724-2310    curtis.coughlin@childrenscolorado.org   
Contact: James Weisfeld-Adams, MD    303-724-2310    james.weisfeld-adams@childrenscolorado.org   
Principal Investigator: James Weisfeld-Adams, MD         
United States, District of Columbia
Children's National Medical Center Recruiting
Washington, D.C., District of Columbia, United States, 20010
Contact: Nicholas Ah Mew, MD    202-476-5863    nahmew@childrensnational.org   
Contact: Katie Rice, MPH, CCRP    202-621-0062    krice3@childrensnational.org   
Principal Investigator: Nicholas Ah Mew, MD         
United States, Massachusetts
Children's Hospital Boston Recruiting
Boston, Massachusetts, United States, 02115
Contact: Vera Anastasoaie    617-355-7346    vera.anastasoaie@childrens.harvard.edu   
Contact: Kyla Almeida, RN, BSN    617-919-4126    kyla.almeida@childrens.harvard.edu   
Principal Investigator: Gerard T Berry, MD         
United States, New York
Mount Sinai School of Medicine Recruiting
New York, New York, United States, 10029
Contact: Luca Fierro, MS, CGC    212-659-1477    luca.fierro@mssm.edu   
Principal Investigator: George Diaz, MD         
United States, Ohio
University Hospitals Cleveland Medical Center Recruiting
Cleveland, Ohio, United States, 44106
Contact: Audrey Lynn, PhD    216-844-7124    audrey.lynn@uhhospitals.org   
Contact: Kimberly Wallis, MS, LGC    216-983-0844    kimberly.wallis@uhhospitals.org   
Principal Investigator: Shawn McCandless, MD         
United States, Pennsylvania
The Children's Hospital of Philadelphia (CHOP) Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Genevieve Nesom    267-426-1368    nesomg@email.chop.edu   
Principal Investigator: Can Ficicioglu, MD, PhD         
University of Pittsburgh Recruiting
Pittsburgh, Pennsylvania, United States, 15224
Contact: Angela Leshinski, MBA, RD, LDN    412-692-5232    angela.leshinski@chp.edu   
Principal Investigator: Gerard Vockley, MD, PhD         
Sponsors and Collaborators
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
Investigators
Principal Investigator: Mendel Tuchman, MD Children's Research Institute
  More Information

Responsible Party: Mendel Tuchman, Scientific Director, Children's Research Institute, Children's Research Institute
ClinicalTrials.gov Identifier: NCT01599286     History of Changes
Other Study ID Numbers: NCGC0008
First Submitted: May 11, 2012
First Posted: May 16, 2012
Last Update Posted: October 6, 2017
Last Verified: October 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: This is a blinded study, the individual participant data will not be shared

Keywords provided by Mendel Tuchman, Children's Research Institute:
Hyperammonia
Propionic Acidemia (PA)
Methylmalonic Acidemia (MMA)
Late-Onset CPS1 Deficiency (CPSD)
Late-Onset Ornithine Transcarbamylase Deficiency (OTCD)
Carbaglu

Additional relevant MeSH terms:
Deficiency Diseases
Acidosis
Hyperammonemia
Propionic Acidemia
Amino Acid Metabolism, Inborn Errors
Carbamoyl-Phosphate Synthase I Deficiency Disease
Ornithine Carbamoyltransferase Deficiency Disease
Malnutrition
Nutrition Disorders
Acid-Base Imbalance
Metabolic Diseases
Pathologic Processes
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Urea Cycle Disorders, Inborn
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Mitochondrial Diseases
Genetic Diseases, X-Linked