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）是一种复杂综合征，与哮喘有关，抗中性嗜性胞质抗体和嗜酸性血管炎，涉及多个器官，包括肺，皮肤，皮肤，胃肠道和神经系统。以嗜酸性粒细胞的显着组织浸润为特征，越来越清楚CSS可能是由于嗜酸性粒细胞功能和/或产生的失调引起的。 CSS疗法，皮质类固醇和细胞毒性剂（例如环磷酰胺和硫唑嘌呤）具有多种全身副作用，无法提供长期治愈的潜力，并且通常无法产生临床益处。迄今为止，研究这种“孤儿疾病”的研究很少，其流行病学，发病机理和遗传学基本上仍然未知，并且尚未实现明显的治疗进展。 CSS患者的血液介菌（IL）-5的血液水平是调节嗜酸性粒细胞骨髓释放，激活和组织存活率的细胞因子。单克隆抗IL5抗体疗法在包括哮喘在内的低粒细胞综合症中安全有效，减少了血液和骨髓中的嗜酸性粒细胞数量。我们给出了开放式标签抗IL5至10个CSS患者4个月，从而大大降低了全身性类固醇剂量，周围嗜酸性粒细胞菌和CSS加重。我们假设抗IL5治疗将安全地为CSS患者提供一种新型的类固醇治疗疗法，可降低疾病活动的血清标志物，并允许进行类固醇锥形。为了检验这一假设，我们计划在CSS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）赠款支持人类研究人员发起的临床试验（U01）的计划和设计。 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表格5）制定招聘策略6）与FDA和药品赞助商合作以获取IND并制定药物分配计划7）制定机械方案，以评估抗IL5对CSS中嗜酸性粒细胞生物学的影响（例如，生物标志物，基因组学）。通过在1年提案的过程中完成这些目标后，我们将有一个研究团队准备提交带有完全开发的协议，操作手册，表格，监督计划，研究药物（包括IND）的U01应用程序（包括IND）以及一项已发达的机械协议，以帮助我们更好地了解嗜酸性粒细胞生物学。除了为CSS患者提供有效的安全疗法外，我们的最终目标是向CSS学习有关嗜酸性粒细胞生物学以及哮喘和过敏的知识。该提案将允许计划进行此类研究。 公共Helath相关性（由申请人提供）：Churg-Strauss综合征（CSS）是一种与哮喘，大量血液嗜酸性粒细胞和多个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介素5（IL-5）的水平升高，因此我们假设对IL-5的抗体将安全为CSS患者提供一种新型的类固醇治疗方案，从而降低疾病活性的血清标志物，并允许皮质类固醇类固醇缩减。该赠款应用的目的是获得支持和组织CSS患者抗IL5治疗的双盲安慰剂对照试验以及机械研究的支持，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。