PHASE 2 & 3 TRIALS OF HIGH-DOSE ORAL N-ACETYLCYSTEINE IN CYSTIC FIBROSIS

阶段2

• 批准号: 7212663
• 负责人: CAROL K CONRAD
• 金额: $ 20.1万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7212663
• 关键词: PHASE; TRIALS; DOSE; ORAL; ACETYLCYSTEINE

DESCRIPTION (provided by applicant): Cystic fibrosis is a genetic, orphan disease, affecting about 30,000 people in the United States. Early after birth, neutrophilic inflammation largely contributes to the development of lung disease, the main cause of morbidity and mortality in CF. Another hallmark of CF is redox imbalance, shown previously in plasma and airway fluid. Recently, the applicant observed that redox imbalance in CF also occurs intracellularly, in blood neutrophils, featuring low levels of reduced glutathione (GSH). GSH, the main cellular antioxidant, modulates many functions in neutrophils. NAC is a GSH prodrug, capable of replenishing GSH in neutrophils when used orally in high doses. In 2004 - 2005, the applicant conducted a Phase 1 study, which established excellent safety and tolerability of high-dose oral NAC (0.6 to 1 g/d, 3 times daily, for 4 weeks) in patients with moderately severe lung disease. This study also yielded important data suggesting drug efficacy towards both redox and inflammatory defects seen in CF. Next, they submitted an Investigational New Drug application to FDA for a Phase 2 study, which is currently ongoing. This double-blind, placebo-controlled study for 12 weeks and uncontrolled for an additional 12 weeks, aims at establishing treatment efficacy of 2.7 g/d of oral NAC in CF patients. Based on previous experience in humans, the applicant does not anticipate risks of particular severity or seriousness in this Phase 2 study. Treatment safety is ensured by clinical monitoring and patient reporting of adverse effects. Drug effects are assessed on sputum live neutrophil count (primary outcome measurement, measured by microscopy) and on four secondary outcome measurements, namely functional expiratory volume in 1 second (measured by spirometry), intracellular GSH in blood neutrophils (measured by flow cytometry), sputum neutrophil elastase activity (measured by enzyme-linked immunosorbent assay), and whole blood GSH (measured by high performance liquid chromatography). Pending positive results in the Phase 2 trial (first year of support), the applicant envisions a large Phase 3 trial with specific provisions to assay drug efficacy in the CF pediatric population (second and third years of support). In children and adults with cystic fibrosis, the uncontrolled entry of neutrophils, a type of white blood cell, into the lungs, contributes to tissue destruction. The applicant aims to test whether a chemical readily found in the body can prevent neutrophil entry in lungs and stop the fatal decline in lung function seen in patients. To this end, pharmaceutical-grade N-acetylcysteine will be given orally in high doses.

描述（由申请人提供）： 囊性纤维化是一种遗传性孤儿病，在美国影响约30，000人。 出生后早期，嗜酸性炎症在很大程度上促进了肺部疾病的发展，这是CF发病率和死亡率的主要原因。 CF的另一个标志是氧化还原失衡，先前在血浆和气道液中显示。 最近，申请人观察到CF中的氧化还原失衡也发生在细胞内，在血液嗜中性粒细胞中，其特征在于低水平的还原型谷胱甘肽（GSH）。 GSH是主要的细胞抗氧化剂，调节中性粒细胞的许多功能。 NAC是GSH前药，当以高剂量口服使用时能够补充中性粒细胞中的GSH。在2004 - 2005年，申请人进行了一项I期研究，该研究确定了高剂量口服NAC（0.6 - 1 g/d，每日3次，持续4周）在中重度肺病患者中的极佳安全性和耐受性。 这项研究还产生了重要的数据，表明药物对CF中观察到的氧化还原和炎症缺陷的疗效。 接下来，他们向FDA提交了一份研究性新药申请，用于目前正在进行的2期研究。 这项为期12周的双盲、安慰剂对照研究和另外12周的非对照研究旨在确定CF患者口服2.7 g/d NAC的治疗疗效。 根据既往人类经验，申请方预计本II期研究中不会出现特定严重程度或严重性的风险。 通过临床监测和患者不良反应报告确保治疗安全性。 根据痰液中性粒细胞计数评估药物作用（主要结果测量，通过显微镜测量）和四个次要结果测量，即1秒功能性呼气量（通过肺活量测定法测量）、血液中性粒细胞中的细胞内GSH（通过流式细胞术测量）、痰中性粒细胞弹性蛋白酶活性（通过酶联免疫吸附测定法测量）和全血GSH（通过高效液相色谱法测量）。 在2期试验（第一年支持）取得积极结果之前，申请人设想进行一项大型3期试验，并制定具体规定来测定CF儿科人群的药物疗效（第二年和第三年支持）。 在患有囊性纤维化的儿童和成人中，中性粒细胞（一种白色血细胞）不受控制地进入肺部，导致组织破坏。 申请人旨在测试体内容易发现的化学物质是否可以阻止中性粒细胞进入肺部，并阻止患者中观察到的致命性肺功能下降。 为此，将以高剂量口服药用级N-乙酰半胱氨酸。