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N-carbamylglutamate in the treatment of hyperammonemia

N-氨甲酰谷氨酸治疗高氨血症

基本信息

批准号：
9036417
负责人：
Mendel Tuchman
金额：
$ 64.55万
依托单位：
CHILDREN'S RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-05 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9036417
关键词：
Acute Age Ammonia Anisotropy Attenuated Benzoates Biological Markers Blood Brain Brain Injuries Carbamyl Phosphate Cell Energetics Cell membrane Cessation of life Chemicals Childhood Choline Clinical Clinical Research Cognitive Controlled Environment Country Creatine Data Defect Development Developmental Disabilities Dietary Proteins Diffusion Magnetic Resonance Imaging Disease Disease Outcome Encephalopathies Europe FDA approved Funding Glutamates Glutamine Goals Hereditary Disease Hospitalization Hyperammonemia Inborn Errors of Metabolism Inherited Intelligence Investigation Length Ligase Liver Liver Circulation Liver Failure Magnetic Resonance Imaging Measurement Measures Metabolic Diseases Modality N acetyl L glutamate N-acetylaspartate N-carbamylglutamate Neonatal Nervous System Trauma Neurocognitive Neurologic Neurons Nitrogen Ornithine carbamoyltransferase deficiency Orphan Outcome Outcome Measure Pathway interactions Patients Pediatric Hospitals Pharmaceutical Preparations Phenylacetates Phenylbutyrates Placebos Production Randomized Recovery Research Design Resolution Safety Secondary to Severities Surrogate Markers Symptoms Testing Urea analog design double-blind placebo controlled trial early childhood functional status improved instrument ketotic hyperglycinemia methylmalonic aciduria neonate outcome prediction prevent primary outcome response secondary outcome small molecule spectroscopic imaging standard care urea cycle white matter

项目摘要

DESCRIPTION (provided by applicant): The overall objective of this project is to determine whether treatment of acute hyperammonemia with N-carbamyl-L-glutamate (NCG) in propionic acidemia (PA), methylmalonic acidemia (MMA), carbamyl phosphate synthetase 1 deficiency (CPSD) and ornithine transcarbamylase deficiency (OTCD) changes the clinical outcome of disease. The specific aims are: 1. To determine whether NCG treatment of acute hyperammonemia in severe, neonatal-onset PA and MMA improves neurodevelopmental outcome, and whether it is safe. 2. To determine whether NCG treatment of acute hyperammonemia accelerates the resolution of hyperammonemia and clinical recovery in patients with severe PA and MMA and in those with partial CPSD and OTCD, and whether it is safe. 3. To determine whether, in metabolically stable patients, the effect of a 3-day NCG treatment on ureagenesis is predictive of the outcomes observed in Aims 1 and 2. This is a double blind, placebo controlled trial performed in seven children's hospitals across the country. The primary outcome measure for Aim 1 is neurocognitive development assessed using age-appropriate specific neurodevelopmental instruments. Primary outcomes of Aim 2 include the effect of NCG on the pace of resolution of hyperammonemia and its clinical symptoms and the length of hospitalization. The Aim 3 outcome is an assessment of the correlation between the short-term effect of NCG on ureagenesis rate and the clinical response to NCG long term and in acute clinical settings as determined by Aims 1 and 2. Our hypothesis is that NCG will improve clinical outcome in these disorders. These studies are designed to provide scientific evidence for NCG efficacy and safety which can be used to expand the indication of this drug, leading to FDA approval.

描述（由申请方提供）：本项目的总体目标是确定在丙酸血症（PA）、甲基丙二酸血症（MMA）、氨甲酰磷酸合成酶1缺乏症（CPSD）和鸟氨酸转氨甲酰酶缺乏症（OTCD）中使用N-氨甲酰-L-谷氨酸盐（NCG）治疗急性高氨血症是否会改变疾病的临床结局。具体目标是：1.确定NCG治疗重度、脑源性PA和MMA的急性高氨血症是否可改善神经发育结局，以及是否安全。2.确定NCG治疗急性高氨血症是否加速重度PA和MMA患者以及部分CPSD和OTCD患者的高氨血症消退和临床恢复，以及是否安全。3.确定在代谢稳定的患者中，3天NCG治疗对尿素生成的影响是否可预测目标1和2中观察到的结局。这是一项双盲，安慰剂对照试验，在全国七家儿童医院进行。目标1的主要结局指标是使用适合年龄的特定神经发育工具评估的神经认知发育。目标2的主要结局包括NCG对高氨血症缓解速度及其临床症状和住院时间的影响。目标3结局是评估NCG对尿素生成率的短期影响与NCG长期和急性临床环境中的临床应答之间的相关性，如目标1和2所确定。我们的假设是，NCG将改善这些疾病的临床结果。这些研究旨在为NCG的疗效和安全性提供科学证据，可用于扩大该药物的适应症，从而获得FDA批准。