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: 8332555
• 负责人: MICHAEL E WECHSLER
• 金额: $ 158.09万
• 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/8332555
• 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)：丘格-施特劳斯综合征(CS)是一种复杂的综合征，以哮喘、嗜酸性炎症和脉管炎为特征，累及多个器官，包括肺、心脏、皮肤、胃肠道和神经系统。CS疗法(如皮质类固醇、环磷酰胺、硫唑嘌呤)有多种副作用，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。由于css的特点是嗜酸性组织的渗透，因此css似乎是由于嗜酸性粒细胞功能和/或产生的失调所致。白介素5(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，在慢性粒细胞综合征患者中，其血液中的IL-5水平升高。抗IL-5抗体治疗代表了一种新的治疗方法，它直接针对CS的主要病理生理机制，减少血液和骨髓中的嗜酸性粒细胞数量。该药对高嗜酸性粒细胞综合征和嗜酸性哮喘安全有效。我们在10名CS患者中进行了抗IL5(甲波利单抗)的开放标签试点试验；给予为期4个月的抗IL5可减少CS的恶化、外周血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CS患者提供一种新的治疗方法，可以降低CS的恶化发生率，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，我们提出了一项为期一年的双盲随机安慰剂对照试验，对54名CS患者进行了抗IL-5试验。这项试验为机制研究提供了一个独特的机会，这将导致识别css病的生物标志物。 活性和抗IL5反应性，以及分子图谱研究，将提供对CS遗传学和发病机制的洞察。NIAID临床试验计划拨款(R34)支持了这项临床试验计划(U01)的规划和设计：已经制定了方案、操作手册、病例报告表和IRB表；已经制定了药物获取和分配计划；我们已经组织了一个由CS、嗜酸性粒细胞增多症和脉管炎专家组成的U01研究小组，以及一个将执行这项试验和机制研究的数据协调中心。随着这项研究的完成，我们将满足一个重要的未得到满足的需求，展示一种新的CS疗法的有效性和安全性，获得对CS发病机制的有价值的见解，并更好地了解CS和其他嗜酸性粒细胞疾病的异常嗜酸性细胞生物学。