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

描述(由申请人提供)： 囊性纤维化是一种遗传性孤儿疾病，在美国约有3万人受到影响。出生后早期，中性粒细胞炎症在很大程度上促进了肺部疾病的发展，而肺部疾病是CF发病和死亡的主要原因。慢性支气管炎的另一个特征是氧化还原失衡，以前在血浆和气道液中都有表现。最近，申请人观察到CF的氧化还原失衡也发生在细胞内，在血液中性粒细胞中，以低水平的还原型谷胱甘肽(GSH)为特征。GSH是细胞内的主要抗氧化剂，调节中性粒细胞的许多功能。 NAC是一种GSH前体药物，在大剂量口服时能够补充中性粒细胞中的GSH。在2004-2005年，申请人进行了一项第一阶段研究，该研究证实了大剂量口服NAC(0.6-1g/d，每天3次，持续4周)对中度严重肺部疾病患者具有极好的安全性和耐受性。这项研究还产生了重要的数据，表明对CF中可见的氧化还原和炎性缺陷的药物疗效。接下来，他们向FDA提交了一份研究新药申请，进行第二阶段研究，目前正在进行中。这项为期12周的双盲安慰剂对照研究，旨在确定2.7g/d口服NAC对CF患者的治疗效果。根据以前在人类中的经验，申请人在这项第二阶段研究中没有预测到特别严重或严重的风险。通过临床监测和患者报告不良反应来确保治疗安全。药物效果通过痰中性粒细胞活体计数(一次结果测量，通过显微镜测量)和四个二次结果测量进行评估，即1秒内功能呼气容量(通过肺活量测量)、血中性粒细胞内GSH(通过流式细胞仪测量)、痰中性粒细胞弹性酶活性(通过酶联免疫吸附试验测量)和全血GSH(通过高效液相色谱测量)。 在第二阶段试验(支持的第一年)取得积极结果之前，申请人设想进行一项大型的第三阶段试验，并制定具体条款，以评估儿童疾病儿童群体(支持的第二年和第三年)的药物疗效。在患有囊性纤维化的儿童和成人中，中性粒细胞(一种白细胞)不受控制地进入肺部，导致组织破坏。申请者的目标是测试一种容易在体内发现的化学物质是否可以防止中性粒细胞进入肺部，并阻止患者出现的致命的肺功能下降。为此，药用级别的N-乙酰半胱氨酸将以高剂量口服。

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.