Informative Clinical Studies in Asthma

描述（由申请人提供）：尽管哮喘治疗取得了重大进展，但这种日益常见且可能使人衰弱的疾病患者的最佳临床治疗仍在不断变化。我们为哮喘临床研究网络（ACRN）提出的第一项试验来自基于专家的指南，该指南建议患有轻度至中度持续性哮喘症状的个体（约占需要慢性哮喘治疗的患者的50%）应使用控制剂治疗，如吸入皮质类固醇（ICS）。然而，这可能会导致许多不需要这种治疗的人过度治疗。来自一项已完成的ACRN试验的数据表明，60%以上使用持续ICS控制症状的患者在停药后没有出现病情恶化。我们对该试验的回顾性分析表明，痰嗜酸性粒细胞的变化可以识别80%能够成功停止吸入皮质类固醇的患者。如果得到证实，这种工具可以防止对一大群哮喘患者进行不必要的治疗，估计每年可节省20亿美元。它还可以识别需要进一步治疗的患者。我们提出一项双盲、安慰剂对照研究来检验这一假设。我们的第二项试验侧重于病情更严重的患者，这些患者占哮喘相关发病率的不成比例。对于尽管接受了ICS和长效激动剂治疗，但症状仍然存在的患者，需要替代目前推荐的高剂量ICS治疗。较新的药物，如白三烯调节剂，可能对这类患者有益。我们将研究在中度至重度哮喘患者中，在ICS和长效激动剂中添加白三烯改性剂与增加ICS剂量并继续使用长效激动剂的效果。两项试验都将哮喘恶化作为主要结局。在第二项试验中，我们还将研究对ICS治疗的反应是否与糖皮质激素受体基因编码的单倍型变异有关，以及对白三烯修饰剂的反应是否与LTC4合成酶启动子的多态性有关。后一种分析可能允许我们个体化治疗，从而最大限度地提高效益，减少毒性，降低成本。

DESCRIPTION (provided by applicant): Despite significant advances in the treatment of asthma, optimal clinical therapy for patients with this increasingly common and potentially debilitating disease is still in flux. The first trial we propose for the Asthma Clinical Research Network (ACRN) emerges from expert-based guidelines recommending that individuals with mild-moderate persistent asthma symptoms, who comprise about 50% of patients requiring chronic asthma therapy, should be treated with controller agents such as inhaled corticosteroids (ICS). However, this may lead to over-treatment of many individuals who do not require such therapy. Data from a completed ACRN trial suggest that more than 60% of patients whose symptoms were controlled with continuous ICS did not experience exacerbations when discontinuing this medication. Our retrospective analysis of this trial suggests that changes in sputum eosinophils may identify 80% of the patients who can successfully discontinue inhaled corticosteroids. If confirmed, such a tool could prevent unnecessary treatment for a large cohort of asthmatics and result in an estimated $2 billion of savings per year. It could also identify patients requiring further therapy. We propose a double blind, placebo-controlled study to test this hypothesis. Our second trial focuses on patients with more severe disease, who account for a disproportionate amount of asthma-related morbidity. For patients whose symptoms persist in spite of treatment with ICS and a long-acting -agonist, alternatives are needed to the current recommendation of treatment with higher doses of ICS. Newer agents, such as leukotriene modifiers, may be beneficial for such patients. We will examine the effect of adding a leukotriene modifier to ICS and a long-acting -agonist vs. increasing the dosage of ICS with continuation of a long-acting -agonist among patients with moderate to severe asthma. Both trials will use asthma deteriorations as the primary outcome. In the second trial, we will also examine if the response to ICS therapy is associated with haplotypic variations in the gene coding for the glucocorticoid receptor and if the response to leukotriene modifiers is associated with polymorphisms of the LTC4 synthase promoter. This latter analysis may permit us to individualize therapy and therefore maximize benefit, decrease toxicity, and decrease cost.