A Multicenter Randomized, Double-blind, Phase 2, Placebo Controlled Study to Determine the Safety and Efficacy of Ivacaftor (VX-770) for the Treatment of Chronic Obstructive Pulmonary Disease

慢性阻塞性肺疾病(COPD)的治疗需要新的疗法， 每年的医疗费用超过400亿美元，是导致死亡的第三大原因 在美国，这是健康差距的主要来源，在南方腹地的比例过高。 与囊性纤维化(CF)一样，COPD的特点是粘液阻塞，与 肺功能加速丧失和超额死亡率。香烟烟雾表现出各种各样的 体内外对呼吸道上皮功能的有害影响及我们的初步数据 表明它还会导致CFTR活性的显著减少，从而导致明显的 粘液纤毛运输减少。此外，CFTR功能障碍独立地与 患有慢性支气管炎和呼吸困难，即使戒烟也会持续，并可能 通过激活野生型CFTR，在体外和体内被CFTR增强剂IVAVAFTOR逆转， 导致粘液纤毛运输的强劲增长。与前所未有的临床相结合 通过增强粘液纤毛清除率改善慢性阻塞性肺疾病患者的疗效 用异烟肼处理CFTR突变，这些数据表明CFTR代表了一种可行的 慢性阻塞性肺疾病慢性支气管炎患者粘液淤积的治疗目标(可能 仅在美国就代表了800多万名患者)。在这个项目中，我们将调查 假设iVacaftor可以增强表现为COPD的患者的CFTR活性 慢性支气管炎。尽管我们的初步数据令人信服，但关于大多数 信息量大、反应灵敏的终点和剂量选择要求进行本报告中概述的研究 申请。为了解决这一问题，我们设计了创新的第二阶段，随机、双重- 确定异烟肼(VX-770)安全性和有效性的盲法安慰剂对照试验 治疗慢性阻塞性肺疾病(多中心课题研究)， 并将解决COPD和呼吸道上皮生物学领域的一些关键问题 使用最新的方法评估CFTR活性、上皮功能、粘液纤毛清除、 和临床结果。本课题研究将测试在COPD患者中是否可以增加MCC 慢性支气管炎患者，即使在没有先天性肺炎的情况下也能改善人类疾病 Cftr基因突变。该试验将提供初步的概念证明，以评估 CFTR增强剂在慢性阻塞性肺疾病中的疗效，我们还将基于以下因素检验不同的效果 种族/民族、社会经济地位和吸烟状况。如果成功，结果可能会 建立一种新的治疗模式来解决COPD患者的粘液功能障碍，这是一种重要的 与死亡率和疾病进展独立相关的发病原因。

New therapies are needed for the treatment of chronic obstructive pulmonary disease (COPD), which accounts for over $40 billion in annual healthcare costs, is the 3rd leading cause of death in the U.S., and is major source of health disparity, being over-represented in the Deep South. Like cystic fibrosis (CF), COPD is characterized by mucus obstruction that is associated with accelerated loss of lung function and excess mortality. Cigarette smoke exhibits a variety of deleterious effects on airway epithelial function in vitro and in vivo and our preliminary data indicates it also causes a significant reduction in CFTR activity that leads to a pronounced decrement in mucociliary transport. Furthermore, CFTR dysfunction is independently associated with chronic bronchitis and dyspnea, can persist despite smoking cessation, and can be reversed by the CFTR potentiator ivacaftor in vitro and in vivo by activating wild-type CFTR, resulting in a robust increase in mucociliary transport. Combined with unprecedented clinical improvement via augmented mucociliary clearance observed in CF patients with a responsive CFTR mutation treated with ivacaftor, these data indicate that CFTR represents a viable therapeutic target to address mucus stasis in COPD patients with chronic bronchitis (potentially representing over 8 million patients in the U.S. alone). In this project, we will investigate the hypothesis that ivacaftor can augment CFTR activity in individuals with COPD who exhibit chronic bronchitis. Though our preliminary data are compelling, questions regarding the most informative and responsive endpoints and dose selection mandate the studies outlined in this application. To address this, we have designed an innovative Phase 2, Randomized, Double- blind, Placebo Controlled Pilot Trial to Determine the Safety and Efficacy of Ivacaftor (VX-770) for the Treatment of Chronic Obstructive Pulmonary Disease (The Multicenter TOPIC study), and will address a number of key questions to the field of COPD and airway epithelial biology using the latest methods for assessing CFTR activity, epithelial function, mucociliary clearance, and clinical outcomes. The TOPIC study will test whether MCC can be augmented in COPD patients with chronic bronchitis, ameliorating human disease even in the absence of congenital mutations in the CFTR gene. The trial will provide an initial proof of concept evaluating the efficacy of CFTR potentiators in COPD, and we will also examine differential effects based on race/ethnicity, socio-economic status, and smoking status. If successful, the results could establish a novel treatment paradigm to address mucus dysfunction in COPD, an important cause of morbidity that is independently associated with mortality and disease progression.