Feasibility and Safety of Interleukin-1 Blockade to Treat Cardiac Sarcoidosis

IL-1 阻断治疗心脏结节病的可行性和安全性

• 批准号: 9890056
• 负责人: Antonio Abbate
• 金额: $ 22.62万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9890056
• 关键词: Address; Adrenal Cortex Hormones; Affect; African American; American Heart Association; Anti-Inflammatory Agents; Architecture; Arrhythmia; Attenuated; Biological Markers; C-reactive protein; Cardiac; Cardiac Electrophysiologic Techniques; Cardiac Sarcoidosis; Cardiomyopathies; Cardiovascular Diseases; Cardiovascular system; Cessation of life; Clinical; Clinical Trials; Collaborations; Complex; Controlled Clinical Trials; Country; Data; Diagnosis; Diagnostic; Disease; Double-Blind Method; Event; Functional disorder; Future; Granuloma; Granulomatous; Health; Heart; Heart Diseases; Heart failure; Human; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Interleukin-1; Interleukin-1 Receptors; Interleukin-6; International; Kineret; Lead; Leadership; Life; Literature; Liver; Lung; Measures; Michigan; Minority; Molecular; Monitor; Myocardial; Myocardial Ischemia; Myocarditis; Natural History; Organ; Outcome; Patients; Pharmaceutical Preparations; Phase; Pilot Projects; Placebos; Plasma; Population Heterogeneity; Predictive Value; Protein Biosynthesis; Recombinant Interleukin-1; Registries; Research; Research Personnel; Research Proposals; Resources; Role; Sarcoidosis; Severity of illness; Societies; Steroids; Subgroup; Surrogate Endpoint; Sweden; Testing; Tissues; Translating; Translational Research; Universities; Virginia; Woman; Work; adverse outcome; anakinra; base; body system; cardioprotection; chronic inflammatory disease; clinical application; clinical care; cytokine; design; effective therapy; heart rhythm; improved; improved outcome; innovation; interest; member; novel; novel therapeutics; phase 3 study; pre-clinical; pre-clinical research; randomized placebo-controlled clinical trial; recruit; response; safety and feasibility; side effect; standard care; targeted treatment; therapy development; translational scientist

SUMMARY Sarcoidosis is an inflammatory disease that can affect any organ system. Rarely, sarcoidosis can affect the heart, leading to life-threatening heart rhythm problems, heart failure, and death. There are no drugs specifically approved for the treatment of sarcoidosis. Remarkably, despite >50 years of use as the most common therapy for sarcoidosis, there is no proof that corticosteroid treatment works for cardiac sarcoidosis. Preliminary data indicate a role for interleukin-1, the prototypical cytokine, in granuloma formation in sarcoidosis and we have shown evidence of IL-1 inflammasome formation in cardiac tissue of patients with cardiac sarcoidosis. Clinical trials have shown that IL-1 blockers can improve outcomes in ischemic heart disease and heart failure. Our research seeks to evaluate whether IL-1 blockade with the IL-1 receptor antagonist, anakinra, can safely modulate systemic inflammation in patients with active cardiac sarcoidosis. IL- 1 blockade is a novel therapeutic strategy that has not been tested in cardiac sarcoidosis. We have designed a double-blind randomized placebo-controlled clinical trial of anakinra, an IL-1 receptor blocker, given for 4 weeks in 28 patients with cardiac sarcoidosis. We will determine feasibility of recruitment and tolerability of treatment with anakinra in cardiac sarcoidosis patients and determine the effects of anakinra on systemic inflammation as measured by C reactive protein and IL-6, inflammatory biomarkers shown to be surrogates for cardiovascular outcomes. The study will build on the collaboration of two CTSA hubs that are international leaders in cardiac sarcoidosis clinical care – Virginia Commonwealth University and the University of Michigan, under the translational research leadership of Dr. Antonio Abbate, an expert in cardiac inflammation. This proposal addresses urgent unmet needs that are common to both the National Center for Advancing Translational Sciences (NCATS) and the American Heart Association (AHA) - defined as the need of translating biomedical discoveries into clinical applications to improve human health and specifically of developing therapies to attenuate disease impact of cardiac sarcoidosis – a condition for which no targeted therapy exists. The results of this pilot study will serve as proof-of-concept data to conceive future phase III studies involving CTSA hubs across the country. A novel targeted treatment could bring about a much-needed paradigm shift in the treatment of cardiac sarcoidosis.

总结 结节病是一种炎症性疾病，可以影响任何器官系统。很少，结节病可以影响 心脏，导致危及生命的心律问题，心力衰竭和死亡。没有专门的药物 被批准用于治疗结节病值得注意的是，尽管作为最常见的治疗方法使用了超过50年， 对于结节病，没有证据表明皮质类固醇治疗对心脏结节病有效。 初步数据表明，白细胞介素-1，原型细胞因子，在肉芽肿形成中的作用， 我们已经证明在结节病患者的心脏组织中有IL-1炎性小体形成的证据， 心脏结节病临床试验表明，IL-1阻滞剂可以改善缺血性心脏病的预后 疾病和心力衰竭。我们的研究旨在评估IL-1受体阻断是否 拮抗剂阿那白滞素可以安全地调节活动性心脏结节病患者的全身炎症。白介素- 1阻断是一种新的治疗策略，尚未在心脏结节病中进行测试。我们设计了一个 阿那白滞素（一种IL-1受体阻滞剂，给药4周）的双盲随机安慰剂对照临床试验 28例心脏结节病患者。我们将确定招募的可行性和治疗的耐受性 与阿那白滞素在心脏结节病患者中的作用，并确定阿那白滞素对全身炎症的影响， 通过C反应蛋白和IL-6测量，炎症生物标志物显示为心血管疾病的替代物， 结果。该研究将建立在两个CTSA中心的合作基础上，这两个中心是心脏病领域的国际领导者。 结节病临床护理-弗吉尼亚联邦大学和密歇根大学，根据 Antonio Abbate博士是心脏炎症方面的专家。 该提案解决了国家促进发展中心和 翻译科学（NCATS）和美国心脏协会（AHA）-定义为需要翻译 将生物医学发现转化为临床应用，以改善人类健康，特别是开发治疗方法 以减轻心脏结节病的疾病影响-一种不存在靶向治疗的疾病。结果 这项试点研究的20%将作为概念验证数据，以构思未来涉及CTSA中心的III期研究 全国各地一种新的靶向治疗可能会带来急需的治疗模式转变 心脏结节病