CLINICAL TRIAL: A PHASE 3, RANDOMIZED, DOUBLE-BLIND, CROSS-OVER, ACTIVE-CONTROL

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 摘要 尿素循环障碍(UCDs)是一种先天性代谢疾病，可由以下任何一种酶的活性降低或缺失引起：氨基甲酰磷酸合成酶(CPS)、鸟氨酸转氨甲基酶(OTC)、精氨酸琥珀酸合成酶(ASS)、精氨酸琥珀酸裂解酶(ASL)或精氨酸酶(ARG)。这些疾病阻止了将废氮转化为尿素，并导致受影响患者的血液和大脑中积累了有毒水平的氨。 大多数患有UCDS的患者要么单独饮食，要么通过饮食限制氮加上口服丁苯钠(苯丁酸钠)和瓜氨酸或精氨酸来治疗。虽然丁苯醚是一种有效的治疗方法，但它也有一些缺点，如药丸负担高(成人每天约40片[20克]，或20公斤的儿童约4茶匙)，味道不佳，钠含量高。对于其他适应症，PBA的临床试验有一些证据表明，高药片负担可能会降低依从性治疗方案的可能性。 丁酸苯酯(PBA)的前药和活性化合物苯乙酸酯(PAA)的前药甘油三(4-苯基丁酸甘油酯)(GT4P或HPN-100)正在开发中，作为UCDS患者丁苯醚的替代疗法。预计HPN-100将提供类似的氮气清除能力，同时消除目前的味道、气味、钠含量和药丸负担等问题。 HPN-100在成人尿素循环障碍中的第二次临床试验是一项随机、主动对照、双盲、交叉研究。受试者将被随机分配接受HPN-100+NaPBA安慰剂或NaPBA+HPN 100安慰剂2周，然后交叉接受另一种治疗2周。 一、假说 根据静脉血氨水平的评估，HPN-100是一种与苯丁酸钠(NaPBA)一样有效的治疗尿素循环障碍的药物。 二、具体目标 这项研究的主要特殊目的是确定静脉氨法评估HPN-100对苯丁酸钠(NaPBA)的非劣性。

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 second clinical trial of HPN-100 in adults with urea cycle disorders is a randomized, active-controlled, double-blind, cross-over study. Subjects will be randomly assigned to receive either HPN-100 + NaPBA placebo or NaPBA + HPN 100 placebo for 2 weeks, and then crossed over to receive the other treatment for 2 weeks. I. HYPOTHESIS HPN-100 is as effective a medication for the treatment of urea cycle disorders as sodium phenylbutyrate (NaPBA) as assessed by venous ammonia levels. II. SPECIFIC AIMS The primary specific aim of this study is to establish the non-inferiority of HPN-100 to sodium phenylbutyrate (NaPBA) as assessed by venous ammonia.