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

• Status: Terminated
• Trial end date: 2015-02-01
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Mendel Tuchman
• Collaborators: Boston Children's Hospital; Boston Children’s Hospital; Children's Hospital of Philadelphia; Children's National Research Institute; Children's Research Institute; Lucile Packard Children's Hospital; University Hospitals Cleveland Medical Center; University of California, Los Angeles; University of Colorado, Denver

Criteria

Inclusion Criteria

• 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):

1. Acidosis at presentation, pH <7.3 OR

2. Plasma acylcarnitine analysis either alone or as part of newborn screening, demonstrating C3 >4 mcmol/L OR

3. 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

4. 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.

Exclusion Criteria

• Had any prior hyperammonemic episode

• Administration of NCG within 7 days of participation in the study

• Use of any other investigational drug, biologic, or therapy, with the exception of sodium benzoate or sodium phenylacetate if the latter were administered prior to diagnosis by acylcarnitine analysis (diagnostic inclusion criterion 2), or organic acid analysis (diagnostic inclusion criteria 3 & 4)

• 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