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

Primary Purpose

Propionic Acidemia, Type I and/or Type II, Methylmalonic Acidemia, Carbamoyl-Phosphate Synthase I Deficiency Disease

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Carbaglu
Placebo
Sponsored by
Mendel Tuchman
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Propionic Acidemia, Type I and/or Type II focused on measuring Hyperammonemia, Propionic Acidemia (PA), Methylmalonic Acidemia (MMA), Late-Onset CPS1 Deficiency (CPSD), Late-Onset Ornithine Transcarbamylase Deficiency (OTCD), Carbaglu

Eligibility Criteria

1 Week - 99 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University of California Los Angeles
  • Lucile Packard Children's Hospital at Stanford
  • The Children's Hospital of Colorado
  • Children's National Medical Center
  • Children's Hospital Boston
  • Mount Sinai School of Medicine
  • University Hospitals Cleveland Medical Center
  • The Children's Hospital of Philadelphia (CHOP)
  • University of Pittsburgh

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Active Comparator

Placebo Comparator

Arm Description

Parallel Trial Comparing NCG + Standard of Care Treatment

Placebo and Standard of Care Therapy

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Full Information

First Posted
May 11, 2012
Last Updated
January 25, 2021
Sponsor
Mendel Tuchman
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
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1. Study Identification

Unique Protocol Identification Number
NCT01599286
Brief Title
Short-Term Outcome of N-Carbamylglutamate in the Treatment of Acute Hyperammonemia
Acronym
STO
Official Title
Short-Term Outcome of N-Carbamylglutamate in the Treatment of Acute Hyperammonemia
Study Type
Interventional

2. Study Status

Record Verification Date
January 2021
Overall Recruitment Status
Completed
Study Start Date
September 1, 2012 (Actual)
Primary Completion Date
April 30, 2019 (Actual)
Study Completion Date
April 30, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Mendel Tuchman
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

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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. 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. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Propionic Acidemia, Type I and/or Type II, Methylmalonic Acidemia, Carbamoyl-Phosphate Synthase I Deficiency Disease, Ornithine Carbamoyltransferase Deficiency
Keywords
Hyperammonemia, Propionic Acidemia (PA), Methylmalonic Acidemia (MMA), Late-Onset CPS1 Deficiency (CPSD), Late-Onset Ornithine Transcarbamylase Deficiency (OTCD), Carbaglu

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
35 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Active Comparator
Arm Type
Experimental
Arm Description
Parallel Trial Comparing NCG + Standard of Care Treatment
Arm Title
Placebo Comparator
Arm Type
Active Comparator
Arm Description
Placebo and Standard of Care Therapy
Intervention Type
Drug
Intervention Name(s)
Carbaglu
Other Intervention Name(s)
Carglumic Acid
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo that looks/tastes the same as NCG and is administered on the same schedule as the NCG intervention
Primary Outcome Measure Information:
Title
Time to the Primary Outcome (Earlier of Ammonia <50 µmol/L or Hospital Discharge)
Description
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.
Time Frame
Average of all measurements of hyperammonemia, for up to 7 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
1 Week
Maximum Age & Unit of Time
99 Years
Accepts Healthy Volunteers
No
Eligibility 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 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Mendel Tuchman, MD
Organizational Affiliation
Children's National Research Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of California Los Angeles
City
Los Angeles
State/Province
California
ZIP/Postal Code
90095
Country
United States
Facility Name
Lucile Packard Children's Hospital at Stanford
City
Palo Alto
State/Province
California
ZIP/Postal Code
94304
Country
United States
Facility Name
The Children's Hospital of Colorado
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
Children's National Medical Center
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20010
Country
United States
Facility Name
Children's Hospital Boston
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
Mount Sinai School of Medicine
City
New York
State/Province
New York
ZIP/Postal Code
10029
Country
United States
Facility Name
University Hospitals Cleveland Medical Center
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44106
Country
United States
Facility Name
The Children's Hospital of Philadelphia (CHOP)
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
University of Pittsburgh
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15224
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
This is a blinded study, the individual participant data will not be shared
Citations:
PubMed Identifier
33006765
Citation
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.
Results Reference
derived

Learn more about this trial

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

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