Anti IL5 and Churg Strauss Syndrome: a double blind, placebo controlled trial

描述（由申请人提供）：Churg-Strauss综合征（CSS）是一种复杂的综合征，其特征为哮喘、嗜酸性粒细胞炎症和累及多个器官（包括肺、心脏、皮肤、胃肠道和神经系统）的血管炎。CSS疗法（例如皮质类固醇、环磷酰胺、硫唑嘌呤）具有多种副作用，不提供长期治愈的潜力，并且通常不能产生临床益处。迄今为止，研究这种“孤儿病”的研究很少，其流行病学，发病机制和遗传学在很大程度上仍然未知，并且没有实现重大的治疗进展。由于CSS的特征在于嗜酸性组织浸润，因此CSS似乎是由于嗜酸性粒细胞功能和/或产生的失调。CSS患者的白细胞介素-5（IL-5）（一种调节嗜酸性粒细胞骨髓释放、活化和组织存活的细胞因子）的血液水平升高。抗IL-5抗体治疗代表了一种新的治疗方法，直接靶向CSS的主要病理生理机制，减少血液和骨髓中的嗜酸性粒细胞数量。该药物对嗜酸性粒细胞增多综合征和嗜酸性粒细胞性哮喘安全有效。我们在10名CSS患者中进行了一项抗IL 5（美泊利单抗）的开放标签初步试验;给予抗IL 5 4个月可减少CSS加重、外周嗜酸性粒细胞增多和全身皮质类固醇剂量。因此，我们假设抗IL-5将安全地为CSS患者提供一种新的治疗方法，可降低CSS加重率，允许皮质类固醇减量，并改善疾病活动标志物。为了验证这一假设，我们提出了一个为期1年，双盲，随机安慰剂对照试验抗IL-5在54 CSS患者。这项试验提供了一个独特的机会，机制研究，将导致确定的生物标志物的CSS疾病 活性和抗IL 5反应性，以及分子谱研究，将提供深入了解CSS遗传学和发病机制。NIAID临床试验规划补助金（R34）支持本临床试验提案（U 01）的规划和设计：已制定方案、操作手册、病例报告表和IRB表;已制定药物采购和分发计划;我们组织了一个U 01研究小组，由CSS、嗜酸性粒细胞增多症和血管炎方面的专家组成，和一个数据协调中心，将执行这项试验和机制研究。随着这项研究的完成，我们将满足一个重要的未满足的需求，证明一种新的CSS疗法的有效性和安全性，获得对CSS发病机制的有价值的见解，并更好地了解CSS和其他嗜酸性粒细胞疾病中的异常嗜酸性粒细胞生物学。

DESCRIPTION (provided by applicant): Churg-Strauss syndrome (CSS) is a complex syndrome characterized by asthma, eosinophilic inflammation, and vasculitis involving multiple organs, including the lungs, heart, skin, gastrointestinal tract, and nervous system. CSS therapies (e.g. corticosteroids, cyclophosphamide, azathioprine) have multiple side effects, do not offer potential for long-term cure, and often fail to yield clinical benefit. To date, researchto study this 'orphan disease' has been minimal, its epidemiology, pathogenesis, and genetics remain largely unknown, and no significant therapeutic advances have been realized. As CSS is characterized by eosinophilic tissue infiltration, it appears that CSS is due to dysregulation of eosinophil function and/or production. Blood levels of interleukin-5 (IL-5), a cytokine regulating eosinophil bone marrow release, activation, and tissue survival, are increased in CSS patients. Anti-IL-5 antibody therapy represents a novel treatment that directly targets a primary pathophysiologic mechanism in CSS, decreasing eosinophil numbers in blood and bone marrow. This agent is safe and effective in hypereosinophilic syndromes and in eosinophilic asthma. We did an open label pilot trial of anti-IL5 (mepolizumab) in 10 CSS patients; anti-IL5 given for 4 months reduced CSS exacerbations, peripheral eosinophilia, and systemic corticosteroid dose. We thus hypothesize that anti-IL-5 will safely provide CSS patients a novel treatment that reduces CSS exacerbation rates, allows for corticosteroid tapering, and improves disease activity markers. To test this hypothesis, we propose a 1-year, double-blind, randomized placebo-controlled trial of anti-IL-5 in 54 CSS patients. This trial offers a unique opportunity for mechanistic studies that will result in identification of biomarkers of CSS disease activity and anti-IL5 responsiveness, and for molecular profiling studies that will provide insight into CSS genetics and pathogenesis. An NIAID Clinical Trial Planning Grant (R34) supported the planning and design of this clinical trial proposal (U01): a protocol, manuals of operations, case report forms, and IRB forms have been developed; plans for drug acquisition and distribution have been made; and we have organized a U01 study team with experts in CSS, eosinophilia, and vasculitis, and a data coordinating center that will execute this trial and mechanistic studies. With completion of this research, we will fulfill a significant unmet need, demonstrating efficacy and safety of a novel CSS therapy, gaining valuable insight into CSS pathogenesis, and a better understanding of aberrant eosinophil biology in CSS and other eosinophilic disorders.