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

抗 IL5 和 Churg Strauss 综合征：双盲、安慰剂对照试验

• 批准号: 8721837
• 负责人: MICHAEL E WECHSLER
• 金额: $ 149.72万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8721837
• 关键词: Address; Adrenal Cortex Hormones; Adverse effects; Antibody Therapy; Antineutrophil Cytoplasmic Antibodies; Asthma; Azathioprine; Behavior Therapy; Biological Markers; Biology; Blood; Bone Marrow; CD4 Positive T Lymphocytes; Case Report Form; Churg-Strauss Syndrome; Clinical; Clinical Trials; Clinical Trials Design; Complex; Cyclophosphamide; Cytotoxic agent; Data Coordinating Center; Disease; Disseminated eosinophilic collagen disease; Dose; Double-Blind Method; Educational workshop; Enrollment; Eosinophilia; Epidemiology; Exposure to; Gastrointestinal Diseases; Gastrointestinal tract structure; Gene Expression; Genetic; Grant; Healthcare Systems; Heart; Hospitalization; IL5 gene; Incidence; Infiltration; Inflammation; Institutional Review Boards; Interleukin-5; Lead; Lung; Manuals; Measurement; Molecular; Molecular Profiling; National Institute of Allergy and Infectious Disease; Nervous system structure; Organ; Outcome; Pathogenesis; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Phase; Physicians; Placebos; Predisposition; Production; Protocols documentation; Pulmonary Function Test/Forced Expiratory Volume 1; Questionnaires; Rare Diseases; Research; Research Personnel; Respiratory physiology; Risk; Safety; Sampling; Serum; Sinusitis; Skin; Sputum; Steroids; Stress; Surveys; Symptoms; Syndrome; Testing; Therapeutic; Therapeutic immunosuppression; Tissue Sample; Tissue Survival; Tissues; United States National Institutes of Health; Vasculitis; Visit; Work; activity marker; cost; cytokine; design; double-blind placebo controlled trial; drug efficacy; effective therapy; eosinophil; eosinophilic inflammation; high risk; human subject; improved; insight; mepolizumab; molecular phenotype; novel; open label; operation; pilot trial; primary outcome; public health relevance; randomized placebo controlled trial; response; treatment duration; treatment response; urgent care

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.

描述（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血管炎，涉及多个器官，包括肺、心脏、皮肤、胃肠道和神经系统。 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，不具有长期治愈的潜力，并且通常无法产生临床益处。迄今为止，对这种“孤儿病”的研究还很少，其流行病学、发病机制和遗传学仍然很大程度上未知，并且尚未取得重大的治疗进展。由于 CSS 的特点是嗜酸性粒细胞组织浸润，因此 CSS 似乎是由于嗜酸性粒细胞功能和/或产生失调所致。 CSS 患者血液中白细胞介素 5 (IL-5) 水平升高，IL-5 是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。抗 IL-5 抗体疗法代表了一种直接针对 CSS 的主要病理生理机制、减少血液和骨髓中嗜酸性粒细胞数量的新型疗法。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 患者中进行了抗 IL5（美泊利单抗）的开放标签试点试验；给予 4 个月的抗 IL5 可减少 CSS 恶化、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 药物将安全地为 CSS 患者提供一种新的治疗方法，降低 CSS 恶化率，允许逐渐减少皮质类固醇激素，并改善疾病活动标志物。为了检验这一假设，我们提议在 54 名 CSS 患者中进行一项为期 1 年、双盲、随机安慰剂对照的抗 IL-5 试验。该试验为机制研究提供了独特的机会，从而鉴定 CSS 疾病的生物标志物 活性和抗 IL5 反应性，以及分子谱研究，这将有助于深入了解 CSS 遗传学和发病机制。 NIAID 临床试验规划补助金 (R34) 支持该临床试验提案 (U01) 的规划和设计：已制定方案、操作手册、病例报告表和 IRB 表；已制定药品采购和分配计划；我们组织了一个由CSS、嗜酸性粒细胞增多症和血管炎专家组成的U01研究小组，以及一个数据协调中心来执行这项试验和机制研究。随着这项研究的完成，我们将满足一个重大的未满足的需求，证明一种新型 CSS 疗法的有效性和安全性，获得对 CSS 发病机制的宝贵见解，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。