CLINICAL TRIAL: A PHASE 2, OPEN-LABEL, SWITCH-OVER, DOSE-ESCALATION STUDY OF THE

临床试验：2 期、开放标签、转换、剂量递增研究

• 批准号: 7950694
• 负责人: Brendan Lee
• 金额: $ 2.04万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7950694
• 关键词: Acute; Adult; Affect; Alternative Therapies; Amino Acids; Ammonia; Arginine; Benzoates; Blood; Brain; Carbamyl Phosphate; Caregivers; Catabolism; Child; Citrulline; Clinical Research; Clinical Trials; Computer Retrieval of Information on Scientific Projects Database; Data; Development; Diet; Dietary intake; Disadvantaged; Disease; Dose; Encephalopathies; Enzymes; Excretory function; Funding; Gastrointestinal tract structure; Glutamine; Glycerol; Glycine; Grant; Half-Life; Heterogeneity; Hospitalization; Human Genetics; Hydrolysis; Hyperammonemia; Impairment; Inborn Errors of Metabolism; Injection of therapeutic agent; Inpatients; Institution; Intervention; Kidney; Life; Ligase; Liver; Maintenance Therapy; Marketing; Metabolic; Mole the mammal; Mutation; Nature; Neonatal; Neurologic; Nitrogen; Odors; Oils; Oral; Oral Administration; Ornithine Carbamoyltransferase; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phenylacetates; Phenylbutyrates; Plasma; Powder dose form; Prodrugs; Protein-Restricted Diet; Proteins; Recording of previous events; Research; Research Personnel; Resources; Safety; Severities; Sodium; Sodium phenylbutyrate; Source; Supplementation; Tablets; Taste Perception; Time; Treatment Protocols; Tubular formation; United States; United States National Institutes of Health; Urea; Urine; Venous; Visit; absorption; arginase; argininosuccinate lyase; argininosuccinate synthase; base; carbamoyl phosphate synthetase deficiency; diaries; effective therapy; enzyme deficiency; experience; glomerular filtration; infancy; late disease onset; liver transplantation; nitrogen compounds; open label; pharmacokinetic characteristic; pill; prevent; sodium phenylacetate; urea cycle; urinary; wasting

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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), 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. GT4P 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 phase 2, open-label, switch-over, dose-escalation study in patients with UCDs who are taking Buphenyl¿ as maintenance therapy. For each patient, GT4P will be introduced as a replacement for Buphenyl¿ gradually over a dose-escalation phase of up to 9 weeks, which may include up to 10 inpatient visits. GT4P will be a safe, well-tolerated alternative to Buphenyl¿ for patients with urea cycle disorders. SPECIFIC AIMS The primary objective of this study is to evaluate the safety and tolerability of GT4P compared to Buphenyl¿ in patients with urea cycle disorders (UCDs). Secondary objectives are to assess: ¿ plasma and urine pharmacokinetic (PK) characteristics of GT4P and Buphenyl¿ metabolites. ¿ preliminary evidence of efficacy (as assessed by venous ammonia levels and urinary excretion of phenylacetylglutamine [PAGN]). ¿ amino acid levels. ¿ convenience and comfort associated with drug treatment as assessed by the patient or caregiver. ¿ compliance with study drug treatment as assessed by diary data. BACKGROUND AND SIGNIFICANCE The urea cycle is required for excretion of excess nitrogen compounds generated by dietary intake and protein catabolism. Human genetic deficiencies of urea cycle enzymes are well known and usually present in the neonatal period or early infancy with metabolic crises and subsequent neurological impairment. Each disease has significant variability in severity based on the heterogeneity of mutations and other factors. Urea cycle disorders 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). Treatment of urea cycle disorders relies on two strategies. The first is reduction of nitrogen load through the use of a protein-restricted diet. The second approach uses "alternative" or latent enzymatic pathways of the liver to conjugate glutamine or glycine to carrier molecules and arginine supplementation to increase urinary excretion of nitrogenous products. Nitrogen-scavenging drugs for UCDs include sodium benzoate, sodium phenylacetate, and sodium phenylbutyrate (Buphenyl¿). Sodium phenylacetate, together with sodium benzoate (10%/10%) are marketed as AMMUNOL¿ Injection, which is administered intravenously as an acute treatment for hyperammonemia in patients with UCDs. Most patients with UCDs are managed chronically either by diet alone or by dietary nitrogen restriction plus oral doses of sodium phenylbutyrate with citrulline or arginine. Patient with UCDs who are treated with sodium phenylbutyrate may still experience episodes of hyperammonemic encephalopathy requiring hospitalization and immediate aggressive metabolic intervention. Orthotopic liver transplantation may also be considered for patients with severe disease. Buphenyl¿ (sodium phenylbutyrate) tablets and powder have been approved for marketing in the United States since 1996 as an adjunctive therapy in the long-term management of patients with UCDs involving deficiencies of CPS, OTC, or ASS. It is also indicated in all patients with neonatal-onset deficiency (enzyme deficiency presenting in the first 28 days of life) and in patients with late-onset disease who have a history of hyperammonemic encephalopathy.1 Buphenyl¿ is orally administered in these patients to increase the excretion of nitrogen through conjugation with glutamine, providing an alternative waste elimination pathway that circumvents the urea cycle. Following oral administration, phenylbutyrate is converted to phenylacetate, which is then conjugated with glutamine in the liver and kidneys and excreted as phenylacetylglutamine (PAGN).2 Phenylacetylglutamine is excreted by both renal glomerular filtration and tubular secretion. The nitrogen content of PAGN per mole is identical to that of urea (both contain 2 moles of nitrogen). Although an effective treatment, Buphenyl¿ has some disadvantages. It has 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. Buphenyl¿ also has a short half-life and therefore must be administered 3 to 6 times per day. Glyceryl tri (4-phenylbutyrate) (GT4P), 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. In the gastrointestinal tract or following absorption, GT4P is very rapidly enzymatically hydrolyzed to glycerol and PBA. So like Buphenyl¿, GT4P is expected to provide a means of waste nitrogen disposal that circumvents the urea cycle. In distinct contrast to Buphenyl¿, GT4P is odorless, colorless, tasteless oil. Additionally, there is no sodium burden on the patients with GT4P and a substantially reduced pill burden due to the concentrated nature of the drug. Results from the one previous clinical study conducted with GT4P suggest that GT4P will be safe and well tolerated and may be preferred by patients and their caregivers.

该副本是使用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这是调查员的机构。 尿素循环疾病（UCD）是先天的代谢错误，可能是由于以下任何一种酶的改善或没有活性而引起的：甲状腺基磷酸磷酸合成酶（CPS），鸟氨酸经钙基酰基酶（OTC），精氨酸氨基糖酸合成酶（ASS），argininoscications，argininoscications lyase（Ascrinate lyase（As），或arngin as and angin as and angin as and arcin（As）这些疾病阻止了废物氮转化为尿素，并导致受影响患者血液和大脑中氨水的积累。 大多数UCD患者通过饮食单独或饮食氮限制加上口服剂量的buphenyl？（苯基丁酸钠）用柑橘类或精氨酸来治疗。 甘油三（4-苯基丁酸）（GT4P），一种苯基丁酸苯甲酸苯甲酸苯甲酸苯酚（PBA）（buphenyl¿）和活性化合物苯乙酸酯（PAA）的预生产，作为对UCDS患者的buphenyl的替代治疗。预计GT4P将提供类似的氮消除能力，同时消除当前的味道不良，气味，钠含量和伯恩药丸。 这是一项针对UCD的患者的2阶段，开放标签，转换，剂量升级研究，以维持疗法为维持疗法。对于每位患者，将在长达9周的剂量降低阶段逐渐引入GT4P作为替代Buphenyl。最多包括10个住院就诊。 对于尿素周期疾病的患者，GT4P将是Buphenyl的安全，耐受性良好的替代品。 具体目标 这项研究的主要目的是评估尿素周期疾病（UCDS）患者中GT4P的安全性和耐受性。 次要目标是评估： GT4P和buphenyl€代谢物的血浆和尿液药代动力学（PK）特征。 »效率的初步证据（通过静脉氨水水平和苯乙酰谷氨酰胺的尿液排泄[PAGN]评估）。 »氨基酸水平。 »患者或护理人员评估的药物治疗相关的便利性和舒适性。 »通过日记数据评估的研究药物治疗。 背景和意义 尿素周期是由饮食摄入和蛋白质分解代谢产生的极端氮化合物所必需的。尿素周期酶的人类遗传缺陷是众所周知的，通常存在于新生儿时期或婴儿期出现代谢危机和随后的神经系统障碍。根据突变和其他因素的异质性，每种疾病的严重程度有显着差异。尿素循环疾病可能是由于以下任何一种酶的降低或不存在活性而导致的：磷酸磷酸磷酸磷酸合成酶（CPS），鸟氨酸鸟氨酸经钙基酶（OTC），ArginInoscinate concinate consythetthetlase（ASS），精氨酸糖氨基糖酸酯酶（ASL）酯化酶（ASL），或Arginase（ASL），或Arginase（Asl），或argase（argase）。 尿素周期疾病的治疗取决于两种策略。首先是通过使用蛋白质限制饮食减少氮负荷。第二种方法使用肝脏的“替代”或潜在的酶促途径将谷氨酰胺或甘氨酸与载体分子和补充精氨酸结合起来，以增加硝基产物的极端极端。 UCDS的氮扫描药物包括苯甲酸钠，苯乙酸钠和苯基丁酸钠（buphenyl¿）。苯乙酸钠以及苯甲酸钠（10％/10％）被销售为Ammunol研讨会，该注射剂是静脉内治疗UCDS患者高氨血症的急性治疗。 大多数UCD患者通过饮食或饮食氮限制加上口服苯基丁酸钠的饮食氮或精氨酸来治疗。接受苯基丁酸钠治疗的UCD患者仍可能会经历需要住院和立即进行侵略性代谢干预的高症脑病发作。对于严重疾病的患者，还可以考虑原位肝移植。 自1996年以来，buphenyl¿（苯丁酸钠）片剂和粉末在美国自1996年以来已被批准用于营销，作为涉及CPS，OTC或ASS的UCD患者的长期治疗，用于长期治疗。在所有有新生儿发作性缺乏症（酶缺乏症在生命的前28天中呈缺乏症）和患有高症脑病病史的患者的患者中也均表明。1 在这些患者中，对buphenyl知识通过与谷氨酰胺结合来增加氮的极端，从而提供了一种绕开尿素周期的替代废物消除途径。口服给药后，将苯丁酸转化为苯乙酸酯，然后将其与肝脏和肾脏中的谷氨酰胺偶联，以及独家作为苯乙酰谷氨酰胺（PAGN）.2苯基乙酰谷氨酰胺通过两种肾肾上腺肿瘤和管状的分泌都超过。每个分子的PAGN的氮含量与尿素的氮含量相同（均包含2个氮分子）。 尽管是有效的治疗方法，但buphenyl却有一些灾难。它具有高药丸伯嫩（成人每天约40片[20 g]或20公斤儿童的4茶匙粉末），不愉快的味道和高钠含量。 buphenyl课的半衰期也短，因此必须每天给予3至6次。 甘油三（4-苯基丁酸）（GT4P），一种苯基丁酸苯甲酸苯甲酸苯甲酸苯酚（PBA）（buphenyl¿）和活性化合物苯乙酸酯（PAA）的预生产，作为对UCDS患者的buphenyl的替代治疗。在胃肠道或滥用后，GT4P非常快速地将酶水解为甘油和PBA。因此，像buphenyl知识一样，GT4P有望提供一种避免尿素周期的废物氮处理方式。 与buphenyl面前的形成鲜明对比的是，GT4P无味，无色，无味的油。此外，由于药物的浓缩性质，GT4P患者的患者没有钠燃烧，药丸燃烧大大降低。先前使用GT4P进行的一项临床研究的结果表明，GT4P将是安全且耐受性良好的，并且可能受到患者及其护理人员的首选。