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: 10078287
• 负责人: Antonio Abbate
• 金额: $ 26.5万
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10078287
• 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; feasibility testing; heart rhythm; improved; improved outcome; innovation; interest; member; novel; novel therapeutic intervention; phase 3 study; pre-clinical; pre-clinical research; randomized placebo-controlled clinical trial; recruit; response; safety and feasibility; side effect; standard care; systemic inflammatory response; 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.

摘要 结节病是一种炎症性疾病，可影响任何器官系统。结节病很少会影响到 心脏，导致危及生命的心律问题、心力衰竭和死亡。没有特别的药物 被批准用于治疗结节病。值得注意的是，尽管作为最常见的疗法使用了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。 初步数据显示，白介素1，典型的细胞因子，在肉芽肿形成中的作用 结节病和我们的证据表明，IL-1炎症小体形成在患者的心脏组织中 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。我们的研究试图评估IL-1是否与IL-1受体一起阻断 拮抗剂阿纳金拉可以安全地调节活动性心脏结节病患者的全身炎症。伊尔- 1阻断是一种新的治疗策略，尚未在心脏结节病中进行试验。我们设计了一种 IL-1受体阻滞剂阿那金拉的双盲随机安慰剂对照临床试验，疗程4周 心脏结节病28例。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应用Anakinra，并确定Anakinra对全身炎症的影响 通过C反应蛋白和IL-6检测，炎症生物标记物被证明是心血管疾病的替代品 结果。这项研究将建立在两个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，在 心脏炎症专家安东尼奥·阿巴特博士的翻译研究领导。 这项提案解决了国家推进中心共同存在的未得到满足的紧急需求 翻译科学(NCATS)和美国心脏协会(AHA)-定义为翻译的需要 生物医学发现进入临床应用，以改善人类健康，特别是开发治疗方法 减轻心脏结节病的疾病影响--这是一种没有针对性治疗的疾病。结果是 将作为概念验证数据，以构思未来涉及CTSA枢纽的第三阶段研究 在全国各地。一种新的靶向治疗可能会带来治疗中亟需的范式转变 心脏结节病。

项目成果

Methylphenidate Effects on Cortical Thickness in Children and Adults with Attention-Deficit/Hyperactivity Disorder: A Randomized Clinical Trial.

哌醋甲酯对患有注意力缺陷/多动症的儿童和成人皮质厚度的影响：一项随机临床试验。

• DOI: 10.3174/ajnr.a6560
• 发表时间: 2020
• 期刊: AJNR. American journal of neuroradiology
• 作者: Walhovd,KB;Amlien,I;Schrantee,A;Rohani,DA;Groote,I;Bjørnerud,A;Fjell,AM;Reneman,L
• 通讯作者: Reneman,L