Redefining Therapy In Early COPD: RETHINC

 描述（由申请人提供）：目前COPD定义为FEV 1/FVC<0.7。然而，越来越多的证据表明，COPD的肺功能测定定义可能是不够的。事实上，许多当前和以前的吸烟者具有“正常”的FEV 1/FVC（>0.7），被GOLD委员会称为GOLD 0，被COPD基金会称为SG 0，表现出COPD的症状，由于这些症状和临床上显著的加重而导致的残疾。当仔细研究时，该组有证据表明，隐匿性气流阻塞与简单肺量计未检测到的气道疾病一致，这表明许多GOLD 0吸烟者有慢性阻塞性肺疾病的症状，与COPD一致，但不符合当前的管理指南。由于这一人群很大，这些未确诊的慢性肺部疾病患者造成的健康负担是显著的，他们是否会从治疗中受益完全未知。然而，这些患者中有很大一部分已经在社区接受了支气管扩张剂治疗，而没有指导或证据。本试验将检验以下总体假设：肺功能测定值在GOLD 0范围内（FEV 1/FVC>0.7）的有症状的当前和既往吸烟者将从吸入性支气管扩张剂治疗中获益，即使他们目前被排除在当前GOLD和COPD基金会指南建议之外。无论结果如何，源于这一假设的临床试验都将产生深远的影响。如果接受治疗的受试者出现症状获益，那么我们将提供证据来改变当前的治疗指南。如果治疗对这一群体没有好处，这将为社区医生提供重要的指导。我们的具体目标将在一项双盲、随机对照、平行组、为期12周的试验中实现，该试验在570名尽管肺量测定“正常”（FEV 1/FVC>0.7）但仍有症状（定义为CAT=10）的受试者中进行，该试验比较了支气管扩张剂治疗与安慰剂治疗。具体而言，我们提出了以下目标：（1）确定当前和既往有症状的吸烟者（GOLD 0）是否将从茚达特罗75 mcg qd（一种长效β激动剂（LABA））治疗中获益，与安慰剂相比，通过SGRQ = 4分改善的比例和其他患者报告的结局来衡量改善;（2）确定与安慰剂相比，该组是否会从茚达特罗治疗中受益并改善生理功能（肺功能，6分钟步行测试）;（3）根据其他生理测量的事后分析确定反应的预测因素。我们的首要目标是确定支气管扩张剂治疗对轻度COPD症状和生理改善的价值。由于这些数据从未被收集，医生目前也没有任何证据可以作为治疗决策的基础，这项简单实用的研究结果可能会对我们对这种疾病的理解以及我们适当治疗早期COPD患者的能力产生重大影响。

 DESCRIPTION (provided by applicant): Currently COPD is defined by an FEV1/FVC<0.7. However, mounting evidence suggests that this spirometric definition of COPD may be insufficient. Indeed, many current and former smokers with a "normal" FEV1/FVC (>0.7), termed GOLD 0 by the GOLD committee and SG 0 by the COPD Foundation, manifest symptoms of COPD, disability due to those symptoms and clinically significant exacerbations. When carefully studied, this group has evidence of occult airflow obstruction consistent with airway disease not detected by simple spirometry suggesting that many GOLD 0 smokers with symptoms have chronic obstructive lung disease consistent with COPD, but do not fit into current management guidelines. Because this population is large, the health burden posed by these people with undiagnosed chronic lung disease is significant and whether they would benefit from therapy is entirely unknown. Yet a significant percentage of these patients are already being treated in the community with bronchodilators without guidance or evidence. The trial proposed here will test the following overarching hypothesis: symptomatic current and former smokers with spirometric values in the GOLD 0 range (FEV1/FVC>0.7) will derive benefit from inhaled bronchodilator therapy, even though they are currently excluded from the current GOLD and COPD Foundation guideline recommendations. The clinical trial that stems from this hypothesis will have far reaching impact regardless of the outcome. If treated subjects experience symptomatic benefit, then we would provide evidence to alter current treatment guidelines. If treatment provides no benefit in this group, this would provide important guidance for community physicians. Our specific aims will be achieved in a double blind, randomized controlled parallel group 12 week trial of bronchodilator therapy versus placebo in 570 subjects who have symptoms (defined as CAT=10) despite "normal" spirometry (FEV1/FVC>0.7). Specifically, we propose the following aims: (1) Determine whether current and former smokers with symptoms (GOLD 0), will benefit from therapy with indacaterol 75 mcg qd, a long-acting beta agonist (LABA), as compared to placebo with improvements as measured by the proportion experiencing improvement in SGRQ = 4 points and other patient reported outcomes; (2) Determine whether this group will benefit from therapy with indacaterol as compared to placebo with improvements in physiology (lung function, 6 minute walk test); (3) Identify predictors of response based on post-hoc analyses of other physiological measurements. Our over-riding goal is to determine the value of bronchodilator therapy for symptom and physiologic improvement in mild COPD. As these data have never been collected and physicians currently have no evidence on which to base treatment decisions, the outcome of this simple, pragmatic study could have significant impact on both our understanding of this disease and our ability to appropriately treat patients with early COPD.