Trial record 2 of 7 for:    "carbamoyl phosphate synthetase I deficiency"

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

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by Children's Research Institute
Sponsor:
Collaborators:
Children's Hospital Boston
University Hospital Case Medical Center
University of California, Los Angeles
Children's Hospital of Philadelphia
Lucile Packard Children's Hospital at Stanford
The Children's Hospital of Colorado
Information provided by (Responsible Party):
Children's Research Institute
ClinicalTrials.gov Identifier:
NCT01599286
First received: May 11, 2012
Last updated: August 12, 2014
Last verified: August 2014
  Purpose

The overall objective of this drug trial is to determine whether treatment of acute hyperammonemia with N-carbamyl-L-glutamate (NCG, Carglumic acid, NCG) 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 hyperammonemic episode.


Condition Intervention Phase
Propionic Acidemia (PA)
Methylmalonic Acidemia (MMA)
Late-onset CPS1 Deficiency (CPSD)
Late-onset Ornithine Transcarbamylase Deficiency (OTCD)
Drug: Carbaglu
Drug: Placebo
Drug: Standard Care Treatment
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, 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 Children's Research Institute:

Primary Outcome Measures:
  • Trajectory of change in ammonia during hospitalizations for hyperammonemia [ Time Frame: Admission, Post Dialysis, 12, 24, 36, 48 hours and daily for 7 days or until discharge. ] [ Designated as safety issue: Yes ]
    Change in ammonia and functional status.


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) ] [ Designated as safety issue: Yes ]

    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.



Estimated Enrollment: 144
Study Start Date: September 2012
Estimated Study Completion Date: March 2017
Estimated Primary Completion Date: March 2016 (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 2.2 g/m2/day for patients >25 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.

Drug: Standard Care Treatment
Active Comparator: Placebo comparator
Placebo and Standard of Care therapy.
Drug: Placebo Drug: Standard Care Treatment

Detailed Description:

This is a double-blind 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 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.

  Eligibility

Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

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 >150 mcmol/L >1 week of age

OR

o Aged older than 4 weeks with 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

AND: Subject or subject's first degree relative had initial metabolic decompensation or clinical presentation ≤4 weeks of age.

Subject or subject's first degree relative had plasma ammonia level at any time >150 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

4.2 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 or 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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01599286

Contacts
Contact: Mendel Tuchman, MD 202-476-2549 mtuchman@cnmc.org
Contact: Avital Cnaan, PhD 202- 476-4525 acnaan@cnmc.org

Locations
United States, California
University of California Los Angeles Recruiting
Los Angeles, California, United States, 90095
Contact: Naghmeh Dorrani, MS, CGC    310-825-8084    Ndorrani@mednet.ucla.edu   
Principal Investigator: Derek Wong, MD         
Lucile Packard Children's Hospital at Stanford Recruiting
Palo Alto, California, United States, 94304
Principal Investigator: Gregory M Enns, MD         
Sub-Investigator: Yael Wilnai, MD         
United States, Colorado
The Children's Hospital of Colorado Not yet recruiting
Aurora, Colorado, United States, 80045
Contact: Curtis R Coughlin, MS, CGC    303-724-2310    Coughlin.Curtis@tchden.org   
Principal Investigator: Renata C Gallagher, MD, PhD         
United States, District of Columbia
Children's National Medical Center Recruiting
Washington, District of Columbia, United States, 20010
Contact: Sandra Yang, MS, CGC    202-476-5566    syang@childrensmational.org   
Principal Investigator: Nicholas Ah Mew, MD         
United States, Massachusetts
Children's Hospital Boston Recruiting
Boston, Massachusetts, United States, 02115
Contact: Stephanie Newton, MS, CGC    617-919-4790    Stephanie.Newton@childrens.harvard.edu   
Principal Investigator: Gerard T Berry, MD         
United States, Ohio
University Hospitals of Cleveland/Rainbow Babies and Children's Hospital Recruiting
Cleveland, Ohio, United States, 44106
Contact: Christine W Heggie, RN, ND    216-844-7124    christine.heggie@uhhospitals.org   
Principal Investigator: Shawn McCandless, MD         
United States, Pennsylvania
The Children's Hospital of Philadelphia (CHOP) Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Irma Payan, RN, PNP    215-590-6236    Payan@email.CHOP.edu   
Principal Investigator: Marc Yudkoff, MD         
Sponsors and Collaborators
Children's Research Institute
Children's Hospital Boston
University Hospital Case Medical Center
University of California, Los Angeles
Children's Hospital of Philadelphia
Lucile Packard Children's Hospital at Stanford
The Children's Hospital of Colorado
Investigators
Principal Investigator: Mendel Tuchman, MD Children's Research Institute
  More Information

No publications provided

Responsible Party: Children's Research Institute
ClinicalTrials.gov Identifier: NCT01599286     History of Changes
Other Study ID Numbers: NCGC0008
Study First Received: May 11, 2012
Last Updated: August 12, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by 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:
Carbamoyl-Phosphate Synthase I Deficiency Disease
Amino Acid Metabolism, Inborn Errors
Hyperammonemia
Ornithine Carbamoyltransferase Deficiency Disease
Propionic Acidemia
Brain Diseases
Brain Diseases, Metabolic
Brain Diseases, Metabolic, Inborn
Central Nervous System Diseases
Genetic Diseases, Inborn
Genetic Diseases, X-Linked
Metabolic Diseases
Metabolism, Inborn Errors
Mitochondrial Diseases
Nervous System Diseases
Pathologic Processes
Urea Cycle Disorders, Inborn

ClinicalTrials.gov processed this record on October 22, 2014