Anti- IL5 therapy for Churg-Strauss Syndrome: a double blind randomized, placebo-

描述(申请人提供)：Churg-Strauss综合征(CS)是一种与哮喘、抗中性粒细胞胞浆抗体和嗜酸性血管炎相关的复杂综合征，涉及多个器官，包括肺、心脏、皮肤、胃肠道和神经系统。以嗜酸性粒细胞在组织中的大量渗透为特征，越来越明显的是，慢性萎缩性胃炎可能是由于嗜酸性粒细胞功能和/或产生的失调所致。CS疗法、皮质类固醇和细胞毒性药物，如环磷酰胺和硫唑嘌呤，具有多种全身副作用，不具有长期治愈的潜力，而且往往无法产生临床益处。到目前为止，对这种“孤儿疾病”的研究还很少，其流行病学、发病机制和遗传学在很大程度上仍不为人所知，也没有重大的治疗进展。白介素5是一种调节嗜酸性粒细胞骨髓释放、激活和组织存活的细胞因子，在慢性粒细胞综合征患者中，其血液中的白介素5水平升高。抗IL5单抗治疗包括哮喘、血和骨髓嗜酸性粒细胞减少等高嗜酸性粒细胞综合征是安全有效的。我们给10名CS患者服用4个月的开放标签抗IL5，可显著减少全身类固醇剂量、外周血嗜酸性粒细胞增多和CS恶化。我们假设，抗IL5治疗将安全地为CS患者提供一种新的非类固醇治疗方案，减少疾病活动性的血清标志物，并允许类固醇逐渐减少。为了验证这一假设，我们计划在CS患者中进行抗IL5治疗的双盲安慰剂对照试验。NIAID临床试验计划(R34)赠款支持由研究人员发起的人体临床试验(U01)的规划和设计。针对CS患者未得到满足的治疗需求，我们提出了一项为期一年的计划，具体目标如下：1)制定U01 CS抗IL5方案，包括操作手册和病例报告表2)组织U01研究团队，包括临床研究站点、数据团队、统计团队、和通信系统3)准备U01 CS抗IL5安全和数据监测计划和监督系统4)准备U01 IRB知情同意表5)制定招募策略6)与FDA和药品赞助商合作获得IND并制定药物分配计划7)制定机制方案以评估抗IL5对CS中嗜酸细胞生物学的影响(例如生物标记物、基因组学)。随着这些目标在1年计划的过程中完成，我们将有一个研究团队准备好提交U01申请，其中包括全面开发的方案、操作手册、表格、监督程序、研究药物的批准(包括IND)，以及帮助我们更好地了解嗜酸性粒细胞生物学的开发的机械方案。除了为css患者提供有效、安全的治疗外，我们的最终目标是向css学习嗜酸性粒细胞生物学，以及哮喘和过敏。这项提议将允许进行此类研究的规划。 公共卫生相关(申请人提供)：丘格-施特劳斯综合征(CS)是一种复杂的综合征，与哮喘、高嗜酸性粒细胞增多和多器官炎症有关。Css疗法通常无效或与副作用相关。由于这些患者的细胞因子白介素5(IL-5)水平升高，我们假设IL-5的抗体将安全地为CS患者提供一种新的非激素治疗方案，该方案将降低疾病活动性的血清标记物，并允许皮质类固醇逐渐减少。这项拨款申请的目的是为了获得支持，以计划和组织一项针对CS患者的抗IL5治疗的双盲安慰剂对照试验以及机制研究，以便我们可以更好地了解嗜酸性粒细胞及其相关疾病的生物学。

DESCRIPTION (provided by applicant): Churg-Strauss syndrome (CSS) is a complex syndrome associated with asthma, anti-neutrophil cytoplasmic antibodies, and eosinophilic vasculitis involving multiple organs including the lungs, heart, skin, gastrointestinal tract, and nervous system. Characterized by significant tissue infiltration by eosinophils, it has become increasingly clear that CSS may be due to dysregulation of eosinophil function and/or production. CSS therapies, corticosteroids and cytotoxic agents such as cyclophosphamide and azathioprine, have multiple systemic side effects, do not offer the potential for long-term cure, and often fail to yield clinical benefit. To date, research to study this 'orphan disease' has been minimal, its epidemiology, pathogenesis, and genetics remain largely unknown, and no significant therapeutic advances have been realized. Blood levels of interleukin (IL)-5, a cytokine regulating eosinophil bone marrow release, activation, and tissue survival, are increased in CSS patients. Monoclonal Anti-IL5 antibody therapy is safe and effective in hypereosinophilic syndromes including asthma, decreasing eosinophil numbers in blood and bone marrow. We gave open label anti-IL5 to 10 CSS patients for 4 months, yielding significant reduction of systemic steroid dose, peripheral eosinophilia, and CSS exacerbations. We hypothesize that Anti-IL5 therapy will safely provide CSS patients a novel steroid-sparing treatment option that decreases serum markers of disease activity, and allows for steroid tapering. To test this hypothesis, we plan a double blind placebo controlled trial of Anti-IL5 therapy in CSS patients. The NIAID Clinical Trial Planning (R34) Grant supports the planning and design of investigator-initiated clinical trials (U01) in humans. In the context of the unmet treatment needs of CSS patients, we propose a 1 year program with the following specific aims: 1) Prepare a U01 CSS Anti-IL5 Protocol, with Manual of Operations & Case Report forms 2) Organize a U01 study team including clinical research sites, data team, statistical team, and communications systems 3) Prepare U01 CSS Anti-IL5 safety & data monitoring plan and oversight systems 4) Prepare U01 IRB informed consent forms 5) Develop recruitment strategies 6) Work with FDA & pharmaceutical sponsor to obtain IND and develop drug distribution plan 7) Develop mechanistic protocols to assess effect of anti-IL5 on eosinophil biology in CSS (e.g. biomarkers, genomics). With completion of these aims over the course of the 1 year proposal, we will have a research team in place ready to submit a U01 application with fully developed protocol, operations manual, forms, oversight program, approval of study medication (including an IND), and a developed mechanistic protocol to help us better understand eosinophil biology. In addition to providing effective, safe therapy for CSS patients, our ultimate goal is to learn from CSS about eosinophil biology, as well as asthma, and allergies. This proposal will allow for planning of such research to occur. PUBLIC HELATH RELEVANCE (provided by applicant): Churg-Strauss syndrome (CSS) is a complex syndrome associated with asthma, high numbers of blood eosinophils and inflammation of multiple organs. CSS therapies are often ineffective or associated with side effects. Since levels of the cytokine interleukin-5 (IL-5) are elevated in these patients, we hypothesize that antibodies to IL-5 will safely provide CSS patients with a novel steroid-sparing treatment option that will decrease serum markers of disease activity, and allow for corticosteroid tapering. The goal of this grant application is to obtain support to plan and organize a double blind placebo controlled trial of anti-IL5 therapy in CSS patients as well as mechanistic studies, so that we may gain a better understanding of the biology of the eosinophil and associated disorders.