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

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.

Study Overview

• Status: Completed
• Conditions: Methylmalonic Acidemia; Carbamoyl-Phosphate Synthase I Deficiency Disease; Propionic Acidemia, Type I and/or Type II; Ornithine Carbamoyltransferase Deficiency
• Intervention / Treatment: Drug: Carbaglu; Drug: Placebo

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: Interventional
• Enrollment (Actual): 35
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90095
      • University of California Los Angeles
    • Palo Alto, California, United States, 94304
      • Lucile Packard Children's Hospital at Stanford
  • Colorado
    • Aurora, Colorado, United States, 80045
      • The Children's Hospital of Colorado
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Children's Hospital Boston
  • New York
    • New York, New York, United States, 10029
      • Mount Sinai School of Medicine
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Cleveland Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • The Children's Hospital of Philadelphia (CHOP)
    • Pittsburgh, Pennsylvania, United States, 15224
      • University of Pittsburgh

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 97 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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 Names: Carglumic Acid
Active Comparator: Placebo Comparator; Placebo and Standard of Care Therapy	Drug: Placebo; Placebo that looks/tastes the same as NCG and is administered on the same schedule as the NCG intervention

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to the Primary Outcome (Earlier of Ammonia <50 µmol/L or Hospital Discharge)	The composite primary intention to treat (ITT) outcome of the earlier of time to reach an ammonia level of ≤50 µmol/L or hospital discharge. Data presented as a hazard ratio based on the time to reach an ammonia level of ≤50 µmol/L. The outcome measure was a survival analysis based on time to reach the earlier of an ammonia level of ≤50 µmol/L or time to discharge, which was considered to be a point where the patient was no longer at risk of neurological injury from ammonia. The outcome of survival analysis was a hazard ratio reflecting the ratio of probabilities in each group (drug vs placebo) of reaching the earlier of an ammonia level of ≤50 µmol/L or discharge. We measured multiple post-treatment ammonia levels at uncontrolled times during an episode, so it is difficult to compute a meaningful average that would not be biased by the frequency and timing of ammonia testing during episodes.	Average of all measurements of hyperammonemia, for up to 7 days

Collaborators and Investigators

• Sponsor: Mendel Tuchman
• Collaborators: Children's Hospital of Philadelphia; University of California, Los Angeles; Icahn School of Medicine at Mount Sinai; University of Pittsburgh; Children's Hospital Colorado; Boston Children's Hospital; Stanford University; Children's National Research Institute; University Hospitals Cleveland Medical Center
• Investigators: Principal Investigator: Mendel Tuchman, MD, Children's National Research Institute

Publications and helpful links

General Publications

• Amari S, Shahrook S, Namba F, Ota E, Mori R. Branched-chain amino acid supplementation for improving growth and development in term and preterm neonates. Cochrane Database Syst Rev. 2020 Oct 2;10(10):CD012273. doi: 10.1002/14651858.CD012273.pub2.

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2012
• Primary Completion (Actual): April 30, 2019
• Study Completion (Actual): April 30, 2020

Study Registration Dates

• First Submitted: May 11, 2012
• First Submitted That Met QC Criteria: May 14, 2012
• First Posted (Estimate): May 16, 2012

Study Record Updates

• Last Update Posted (Actual): February 15, 2021
• Last Update Submitted That Met QC Criteria: January 25, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Keywords: Hyperammonemia; Propionic Acidemia (PA); Methylmalonic Acidemia (MMA); Late-Onset CPS1 Deficiency (CPSD); Late-Onset Ornithine Transcarbamylase Deficiency (OTCD); Carbaglu
• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Nutrition Disorders; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Malnutrition; Metabolism, Inborn Errors; Brain Diseases, Metabolic; Mitochondrial Diseases; Brain Diseases, Metabolic, Inborn; Amino Acid Metabolism, Inborn Errors; Urea Cycle Disorders, Inborn; Acid-Base Imbalance; Ornithine Carbamoyltransferase Deficiency Disease; Acidosis; Deficiency Diseases; Propionic Acidemia; Hyperammonemia; Carbamoyl-Phosphate Synthase I Deficiency Disease
• Other Study ID Numbers: NCGC0008

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: This is a blinded study, the individual participant data will not be shared