Long-term Outcome of N-Carbamylglutamate Treatment in Propionic Acidemia and Methylmalonic Acidemia

NCT01597440 | Terminated Phase 2 Results DMC

• 1 other identifier: NCGC 0007
• Study Type: interventional
• Target: 1
• Locations: 1 country
• Sites: 7

Brief Summary

Background: Very few drugs exist that treat hyperammonemia, specifically PA and MMA. Diet restrictions and alternate pathway agents are the current primary treatments, but they frequently fail to prohibit brain damage. Orthotopic liver transplantation cures the hyperammonemia of urea cycle disorders, but organ availability is limited and the procedure is highly invasive and requires life-long immunosuppression. A drug that could repair or stimulate a dysfunctional urea cycle such as this would have several advantages over current therapy. A drug called N-carbamyl-L-glutamate, Carglumic acid (NCG or Carbaglu)has recently been found to be virtually curative of another urea cycle defect called NAGS deficiency. In this disorder, treatment with NCG alone normalizes ureagenesis, blood ammonia and glutamine levels, allows normal protein tolerance and restores health. Knowledge from this study is being applied to acquired hyperammonemia, specifically in patients with propionic PA and MMA, to try and improve neurodevelopmental outcomes by improving the hyperammonemia. Aims: The overall objective of this project is to determine whether treatment of acute hyperammonemia with Carglumic acid in propionic acidemia (PA), methylmalonic acidemia (MMA) changes the long-term outcome of disease and to determine if it is effective in restoring urine ammonia levels to normal levels.

Conditions

Propionic Acidemia; Methylmalonic Acidemia

Keywords

Propionic acidemia (PA); Methylmalonic acidemia (MMA); Carbaglu NCG; Hyperammonia

Outcome Measures

Primary Outcomes (1)

• Neurodevelopment

  Neurodevelopmental outcome as measured by Cognitive Composite (Bayley III), Motor Composite (Bayley III) and Functional Status Scale and safety of NCG treatment as measured by adverse events and laboratory blood tests

  30 months

Secondary Outcomes (1)

• Number of Participants With Adverse Events

  Start of episode through 7 days or discharge (if earlier)

Study Arms (2)

N-Carbamylglutamate

EXPERIMENTAL

Active NCG \& Standard of Care

Drug: N-carbamylglutamate; Other: Standard of Care

Placebo

PLACEBO COMPARATOR

Standard of Care therapy

Other: Standard of Care

Interventions

N-carbamylglutamate DRUG

Active NCG \& Standard of Care Chemical Composition: N-carbamyl-L-glutamic acid (NCG) The daily dose will be 100 mg/kg/ day. 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. This drug will be administered for 7 days after admission or until discharge (whichever is sooner).

Also known as: Carbaglu, NCG

N-Carbamylglutamate

Standard of Care OTHER

Standard of Care

N-Carbamylglutamate; Placebo

Eligibility Criteria

• Age: 1 Hour - 4 Weeks
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Aged 4 weeks or younger (0-28 days)
• \>36 weeks gestational age at birth
• Birth weight ≥2500 g
• Plasma ammonia level at presentation \>150 mcmol/L
• PA or MMA presumed or established diagnosis as follows (one of the following):
• Acidosis at presentation, pH \<7.3 OR
• Plasma acylcarnitine analysis either alone or as part of newborn screening, demonstrating C3 \>4 mcmol/L OR
• Diagnosed, or sibling diagnosed with PA by semi-quantitative urine organic acid analysis, defined as presence of elevated methylcitric acid and no evidence of biotin related disorders in the organic acid analysis OR
• Diagnosed, or sibling 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
• 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
• Signed informed consent by the subject's legally acceptable representative
• After initial enrollment, criteria 3 or 4 (definitive diagnosis of the patient) must be fulfilled prior to discharge from initial admission in order to remain in the study.

You may not qualify if:

• Had any prior hyperammonemic episode
• Administration of NCG within 7 days of participation in the study
• Planned participation in any other clinical trial
• Diagnosis of any medical condition causing hyperammonemia which is not PA or MMA.
• 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
• Had a liver transplant or is scheduled for a liver transplant
• Is not expected to be compliant with this study in terms of returning to site for subsequent episodes of hyperammonemia crises or for long-term follow-up

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
• Lucile Packard Children's Hospital: collaborator
• University of Colorado, Denver: collaborator

Study Sites (7)

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

University Hospitals of Cleveland/Rainbow Babies and Children's Hospital

Cleveland, Ohio, 44106, United States

Location

The Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

MeSH Terms

Conditions

Propionic Acidemia; Methylmalonic acidemia

Interventions

N-carbamylglutamate; carglumic acid; Standard of Care

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

Intervention Hierarchy (Ancestors)

Quality Indicators, Health Care; Quality of Health Care; Health Services Administration; Health Care Quality, Access, and Evaluation

Results Point of Contact

• Title: Dr. Mendel Tuchman
• Organization: Children's National Health System

mtuchman@childrensnational.org

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: MD

Study Record Dates

• First Submitted: May 10, 2012
• First Posted: May 14, 2012
• Study Start: September 1, 2012
• Primary Completion: February 1, 2015
• Study Completion: February 1, 2015
• Last Updated: April 26, 2017
• Results First Posted: April 26, 2017

Record last verified: 2017-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (7)