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

NCT01599286 | Completed Phase 2 Results DMC

• 1 other identifier: NCGC0008
• Study Type: interventional
• Target: 35
• Locations: 1 country
• Sites: 9

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.

Conditions

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

Outcome Measures

Primary Outcomes (1)

• 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

Study Arms (2)

Active Comparator

EXPERIMENTAL

Parallel Trial Comparing NCG + Standard of Care Treatment

Drug: Carbaglu

Placebo Comparator

ACTIVE COMPARATOR

Placebo and Standard of Care Therapy

Drug: Placebo

Interventions

Carbaglu DRUG

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.

Also known as: Carglumic Acid

Active Comparator

Placebo DRUG

Placebo that looks/tastes the same as NCG and is administered on the same schedule as the NCG intervention

Placebo Comparator

Eligibility Criteria

• Age: 1 Week - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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
• \- 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Mendel Tuchman: lead
• Children's National Research Institute: collaborator
• Boston Children's Hospital: collaborator
• University Hospitals Cleveland Medical Center: collaborator
• University of California, Los Angeles: collaborator
• Children's Hospital of Philadelphia: collaborator
• Stanford University: collaborator
• Icahn School of Medicine at Mount Sinai: collaborator
• University of Pittsburgh: collaborator
• Children's Hospital Colorado: collaborator

Study Sites (9)

University of California Los Angeles

Los Angeles, California, 90095, United States

Location

Lucile Packard Children's Hospital at Stanford

Palo Alto, California, 94304, United States

Location

The Children's Hospital of Colorado

Aurora, Colorado, 80045, United States

Location

Children's National Medical Center

Washington D.C., District of Columbia, 20010, United States

Location

Children's Hospital Boston

Boston, Massachusetts, 02115, United States

Location

Mount Sinai School of Medicine

New York, New York, 10029, United States

Location

University Hospitals Cleveland Medical Center

Cleveland, Ohio, 44106, United States

Location

The Children's Hospital of Philadelphia (CHOP)

Philadelphia, Pennsylvania, 19104, United States

Location

University of Pittsburgh

Pittsburgh, Pennsylvania, 15224, United States

Location

Related Publications (1)

• 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.

  PMID: 33006765 DERIVED

MeSH Terms

Conditions

Propionic Acidemia; Methylmalonic acidemia; Carbamoyl-Phosphate Synthase I Deficiency Disease; Ornithine Carbamoyltransferase Deficiency Disease; Hyperammonemia

Interventions

carglumic acid

Condition Hierarchy (Ancestors)

Amino Acid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Metabolic Diseases; Nutritional and Metabolic Diseases; 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; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Robert McCarter
• Organization: Children's National Hospital

RMcCarte@childrensnational.org

202-476-3140

Study Officials

• Mendel Tuchman, MD

  Children's National Research Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Scientific Director, Children's Research Institute

Study Record Dates

• First Submitted: May 11, 2012
• First Posted: May 16, 2012
• Study Start: September 1, 2012
• Primary Completion: April 30, 2019
• Study Completion: April 30, 2020
• Last Updated: February 15, 2021
• Results First Posted: February 15, 2021

Record last verified: 2021-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (9)