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

治疗 Churg-Strauss 综合征的抗 IL5 疗法：双盲、随机、安慰剂

• 批准号: 8012687
• 负责人: Benjamin Alexander Raby
• 金额: $ 28.86万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8012687
• 关键词: Address; Adrenal Cortex Hormones; Adverse effects; Antibodies; Antibody Therapy; Antineutrophil Cytoplasmic Antibodies; Applications Grants; Asthma; Azathioprine; Biological Markers; Biology; Blood; Bone Marrow; CD4 Positive T Lymphocytes; Case Report Form; Churg-Strauss Syndrome; Clinical; Clinical Trials; Communication; Complex; Consent Forms; Cyclophosphamide; Cytotoxic agent; Data; Disease; Disseminated eosinophilic collagen disease; Dose; Double-Blind Method; Educational workshop; Eosinophilia; Epidemiology; Gastrointestinal Diseases; Gastrointestinal tract structure; Genetic; Genomics; Goals; Grant; Heart; Human; Hypersensitivity; IL5 gene; Idiopathic Hypereosinophilic Syndromes; Incidence; Infiltration; Inflammation; Interleukin-5; Interleukins; Investigation; Lead; Learning; Lung; Manuals; Molecular; Monitor; National Institute of Allergy and Infectious Disease; Nervous system structure; Organ; Orphan Disease; Participant; Pathogenesis; Patients; Peripheral; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Placebos; Process; Production; Protocols documentation; Randomized; Rare Diseases; Research; Research Ethics Committees; Research Personnel; Role; Safety; Sampling; Serum; Serum Markers; Signal Transduction; Skin; Steroids; Surveys; Syndrome; System; Testing; Therapeutic; Tissue Survival; Tissues; Treatment Protocols; U-Series Cooperative Agreements; United States National Institutes of Health; Vasculitis; Work; body system; chemokine receptor; clinical research site; cytokine; design; double-blind placebo controlled trial; drug distribution; drug efficacy; effective therapy; eosinophil; human subject; insight; neutrophil; novel; open label; operation; programs; receptor expression; response; treatment duration; treatment response

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.

描述（由申请人提供）：Churg-Strauss综合征（CSS）是一种与哮喘、抗中性粒细胞胞浆抗体和嗜酸性粒细胞血管炎相关的复杂综合征，累及多个器官，包括肺、心脏、皮肤、胃肠道和神经系统。以嗜酸性粒细胞的显著组织浸润为特征，越来越清楚的是CSS可能是由于嗜酸性粒细胞功能和/或产生的失调。CSS疗法、皮质类固醇和细胞毒性剂（如环磷酰胺和硫唑嘌呤）具有多种全身性副作用，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。CSS患者白细胞介素（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。单克隆抗IL 5抗体治疗嗜酸性粒细胞增多综合征（包括哮喘）安全有效，可降低血液和骨髓中的嗜酸性粒细胞数量。我们对10名CSS患者给予开放标签抗IL 5治疗4个月，使全身类固醇剂量、外周嗜酸性粒细胞增多和CSS恶化显著减少。我们假设，抗IL 5治疗将安全地为CSS患者提供一种新的类固醇节约治疗选择，降低疾病活动的血清标志物，并允许类固醇减量。为了验证这一假设，我们计划在CSS患者中进行抗IL 5治疗的双盲安慰剂对照试验。NIAID临床试验计划（R34）资助支持在人类中进行的药物启动的临床试验（U 01）的规划和设计。在CSS患者未满足的治疗需求的背景下，我们提出了一个为期1年的计划，具体目标如下：1）准备U 01 CSS抗IL 5方案，包括操作手册和病例报告表2）组织U 01研究团队，包括临床研究中心，数据团队，统计团队，3）准备U 01 CSS抗IL 5安全性和数据监测计划和监督系统4）准备U 01 IRB知情同意书5）制定招聘策略6）与FDA和7）开发机制方案以评估抗IL 5对CSS中嗜酸性粒细胞生物学（例如生物标志物、基因组学）的影响。随着这些目标在1年提案过程中的完成，我们将有一个研究团队准备提交U 01申请，其中包括完整的方案、操作手册、表格、监督计划、研究药物批准（包括IND）和一个成熟的机制方案，以帮助我们更好地了解嗜酸性粒细胞生物学。除了为CSS患者提供有效，安全的治疗外，我们的最终目标是从CSS了解嗜酸性粒细胞生物学，以及哮喘和过敏。这项建议将有助于规划此类研究。 公众健康相关性（由申请人提供）：Churg-Strauss综合征（CSS）是一种与哮喘、高数量的血液嗜酸性粒细胞和多器官炎症相关的复杂综合征。CSS疗法通常无效或与副作用有关。由于这些患者的细胞因子白细胞介素-5（IL-5）水平升高，我们假设IL-5抗体将安全地为CSS患者提供一种新的类固醇保留治疗选择，这将降低疾病活动的血清标志物，并允许皮质类固醇逐渐减少。这项资助申请的目的是获得支持，以计划和组织CSS患者抗IL-5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和相关疾病的生物学。