CLINICAL TRIAL: A PHASE 3, OPEN-LABEL STUDY OF THE SAFETY OF HPN-100 FOR THE LO

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 摘要 尿素循环障碍（UCD）是先天性代谢缺陷，可能由以下任何酶的活性降低或缺失引起：氨甲酰磷酸合成酶（CPS）、鸟氨酸转氨甲酰酶（OTC）、氨基琥珀酸合成酶（ASS）、氨基琥珀酸裂解酶（ASL）或氨基琥珀酸酶（ARG）。 这些疾病阻止了废氮转化为尿素，并导致受影响患者的血液和大脑中积累有毒水平的氨。 大多数患有UCD的患者通过单独饮食或饮食氮限制加上口服Buphenyl <$（苯丁酸钠）与瓜氨酸或精氨酸的长期管理。 虽然Buphenyl <$是一种有效的治疗方法，但它也有一些缺点，例如药丸负担高（成人每天约40片[20克]，20公斤儿童每天约4茶匙粉末），味道不好，钠含量高。 PBA用于其他适应症的临床试验中有一些证据表明，高药丸负担可能会降低治疗方案依从性的可能性。 甘油三（4-苯基丁酸酯）（GT 4P或HPN-100），苯基丁酸酯（PBA）（Buphenyl <$）的前药和活性化合物苯乙酸酯（PAA）的前药，正在开发中，作为UCD患者Buphenyl <$的替代疗法。 预计HPN-100将提供类似的氮清除能力，同时消除目前的不良味道，气味，钠含量和药丸负担问题。 这是一项在尿素循环障碍成人受试者中进行的HPN-100长期安全性研究。 将定期评估受试者的安全性和静脉氨控制。高氨血症事件将根据并发疾病、饮食和不依从药物等促成因素进行表征。 I. 假设 HPN-100是一种安全有效的药物，用于长期治疗患有尿素循环障碍的成人。 二. 具体目标 本研究的具体目的是评估HPN-100的长期安全性及其在UCD管理中对静脉氨的控制。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. ABSTRACT Urea cycle disorders (UCDs) are inborn errors of metabolism that can result from decreased or absent activity of any of the following enzymes: carbamyl phosphate synthetase (CPS), ornithine transcarbamylase (OTC), argininosuccinate synthetase (ASS), argininosuccinate lyase (ASL), or arginase (ARG). These disorders prevent the conversion of waste nitrogen into urea and result in the accumulation of toxic levels of ammonia in the blood and brain of affected patients. Most patients with UCDs are managed chronically either by diet alone or by dietary nitrogen restriction plus oral doses of Buphenyl¿ (sodium phenylbutyrate) with citrulline or arginine. Although an effective treatment, Buphenyl¿ has some disadvantages, such as a high pill burden (approximately 40 tablets [20 g] per day for an adult or 4 tsp of powder for a 20 kg child), unpleasant taste, and high sodium content. There is some evidence from clinical trials of PBA for other indications that the high pill burden may decrease the likelihood of compliance with the treatment regimen. Glyceryl tri (4-phenylbutyrate) (GT4P or HPN-100), a prodrug of phenylbutyrate (PBA) (Buphenyl¿) and a pre-prodrug of the active compound phenylacetate (PAA), is under development as an alternative therapy to Buphenyl¿ in patients with UCDs. HPN-100 is expected to provide similar nitrogen-scavenging ability while eliminating the current issues of bad taste, odor, sodium content, and pill burden. This is a long-term safety study of HPN-100 in adult subjects with urea cycle disorders. Subjects will be assessed regularly for safety and control of their venous ammonia. Hyperammonemic events will be characterized with respect to contributing factors such as intercurrent illness, diet, and noncompliance with medication. I. HYPOTHESIS HPN-100 is a safe and effective medication for the long-term treatment of adults with urea cycle disorders. II. SPECIFIC AIMS The specific aim of this study is to evaluate the long-term safety of HPN-100 and its control of venous ammonia in the management of UCDs.