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.

概括 结节病是一种可以影响任何器官系统的炎症性疾病。结节病很少会影响 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 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已使用超过 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。 初步数据表明白介素 1（原型细胞因子）在肉芽肿形成中的作用 结节病患者的心脏组织中存在 IL-1 炎症小体形成的证据 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的预后 疾病和心力衰竭。我们的研究旨在评估 IL-1 受体是否能阻断 IL-1 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。白细胞介素- 1 阻断是一种新颖的治疗策略，尚未在心脏结节病中进行过测试。我们设计了一个 阿那白滞素（一种 IL-1 受体阻滞剂）的双盲随机安慰剂对照临床试验，给予 4 周 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 在心脏结节病患者中使用阿那白滞素，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 进行测量，炎症生物标志物被证明可以替代心血管疾病 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，隶属于 心脏炎症专家 Antonio Abbate 博士的转化研究领导力。 该提案解决了国家推进中心共同的紧迫的未满足需求 转化科学 (NCATS) 和美国心脏协会 (AHA) - 定义为翻译的需要 将生物医学发现应用于临床应用以改善人类健康，特别是开发疗法 减轻心脏结节病的疾病影响——这种疾病没有针对性的治疗方法。结果 该试点研究的数据将作为概念验证数据，以构想未来涉及 CTSA 中心的 III 期研究 全国各地。一种新颖的靶向治疗可能会带来急需的治疗范式转变 心脏结节病。