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

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

Interventions

DRUG

N-carbamylglutamate

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).

OTHER

Standard of Care

Standard of Care

Sponsors & Collaborators

• Children's National Research Institute

  collaborator OTHER

• Boston Children's Hospital

  collaborator OTHER

• University Hospitals Cleveland Medical Center

  collaborator OTHER

• University of California, Los Angeles

  collaborator OTHER

• Children's Hospital of Philadelphia

  collaborator OTHER

• Lucile Packard Children's Hospital

  collaborator OTHER

• University of Colorado, Denver

  collaborator OTHER

• Mendel Tuchman

  lead OTHER

Principal Investigators

• Mendel Tuchman, MD · Children's National Research Institute

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Model

PARALLEL

Eligibility

Min Age

1 Hour

Max Age

4 Weeks

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2012-09-30

Primary Completion

2015-02-28

Completion

2015-02-28

Countries

• United States

Study Locations