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: 8897967
• 负责人: MICHAEL E WECHSLER
• 金额: $ 147.4万
• 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 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8897967
• 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; Health; 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; asthmatic patient; 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; randomized placebo controlled trial; response; targeted treatment; 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（由申请人提供）：Churg-Strauss综合征（CSS）是一种以哮喘、嗜酸性粒细胞炎症和血管炎为特征的复杂综合征，累及多器官，包括肺、心脏、皮肤、胃肠道和神经系统。CSS疗法（如皮质类固醇、环磷酰胺、硫唑嘌呤）有多种副作用，不能提供长期治愈的潜力，而且往往不能产生临床效益。迄今为止，对这种“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，并且没有实现显著的治疗进展。由于CSS以嗜酸性组织浸润为特征，因此CSS似乎是由于嗜酸性细胞功能和/或生产失调所致。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、激活和组织存活的细胞因子。抗il -5抗体治疗代表了一种新的治疗方法，直接针对CSS的主要病理生理机制，降低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增多性哮喘安全有效。我们在10名CSS患者中进行了抗il - 5 （mepolizumab）的开放标签试点试验；给予4个月的抗il - 5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，降低CSS加重率，允许皮质类固醇逐渐减少，并改善疾病活动标志物。为了验证这一假设，我们建议在54例CSS患者中进行为期1年的抗il -5随机安慰剂对照试验。该试验为机制研究提供了一个独特的机会，将导致识别CSS疾病的生物标志物