Interleukin-1 blockade in acute myocardial infarction

急性心肌梗死中白介素-1 阻断

基本信息

批准号：
8623428
负责人：
Antonio Abbate
金额：
$ 21.41万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8623428
关键词：
Acute Acute myocardial infarction Acute-Phase Reaction Adverse event Biological Markers C-reactive protein Cardiac Cause of Death Cell Death Cessation of life Clinical Development Disease Disease-Free Survival Dose Double-Blind Method Drug Kinetics Enrollment Ensure FDA approved Feasibility Studies Functional disorder Future Heart failure Hospitalization Human Incidence Inflammation Inflammatory Inflammatory Response Interleukin-1 Measures Medical Morbidity - disease rate Myocardial Infarction Myocardium Nature Outcome Patients Phase III Clinical Trials Pilot Projects Placebos Prevalence Prevention Provider Quality of life Randomized Recombinants Recurrence Regimen Reperfusion Therapy Resolution Rheumatoid Arthritis Risk Safety Serum Symptoms Testing Time Tissues anakinra base clinical practice cost cytokine design high risk hospital readmission improved inflammatory marker mortality novel strategies prevent public health relevance response to injury safety study trend

项目摘要

DESCRIPTION (provided by applicant): Acute myocardial infarction (AMI) remains a major cause of morbidity and mortality despite current strategies for early reperfusion. Many patients die early during the course, and those who survive are at increased risk of death from adverse cardiac remodeling and heart failure (HF). Indeed, despite the improvement in AMI treatment and the reduction in early mortality, the incidence and prevalence of HF continue to rise to unprecedented rates. There is hence an urgent unmet need for additional treatments to prevent HF after AMI. IL-1 blockade may represent a completely novel approach for the prevention of HF potentially leading to improved quality of life, reduced hospitalizations, reduced costs, and ultimately improved long-term survival. The initial ischemic damage to the myocardium initiates an intense inflammatory response resulting in further damage and promoting cardiac dysfunction and HF. Interleukin-1 (IL-1) is the prototypical inflammatory cytokine involved in the tissue response to injury. In AMI, IL-1 activity is increased and amplifies the inflammatory response and induces cardiac cell death. Anakinra is a recombinant form of human IL-1 receptor antagonist (rhIL-1Ra) that is FDA approved for the treatment of rheumatoid arthritis and is highly effective in the treatment of several inflammatory diseases. We recently completed 2 pilot safety and feasibility studies, VCU-ART (n=10) and VCU-ART2 (n=30), in patients with acute ST-segment elevation myocardial infarction (STEMI), randomized 1:1 to anakinra 100 mg daily or placebo for 14 days. Anakinra was well tolerated and associated with very few adverse events. In the combined analysis of both trials, anakinra was associated with a significant reduction in inflammatory markers (-50%, P=0.01) and a trend toward reduced incidence of symptomatic HF at 3 months (5% vs 30%, P=0.035). We propose a randomized, double-blinded, multi-center, pilot study with two different anakinra regimens (twice daily vs daily) to determine the maximum effect of anakinra on the acute inflammatory response during STEMI and to estimate the effect of anakinra on the incidence of HF up to 12 months after STEMI. Although the current pilot study is likely not sufficiently powered to detect statistically signifiant differences in the mortality or rehospitalization rates, this study will provide an estimate of the potential effect, which could be then explored in a larger phase III clinical trial (as part of a R1 application).

描述（由申请人提供）：尽管目前有早期再灌注策略，但急性心肌梗塞（AMI）仍然是发病和死亡的主要原因。许多患者在病程中早期死亡，而那些幸存的患者因不良心脏重塑和心力衰竭（HF）而死亡的风险增加。事实上，尽管 AMI 治疗有所改善并且早期死亡率有所下降，心力衰竭的发病率和患病率仍然以前所未有的速度上升。因此，迫切需要额外的治疗来预防 AMI 后的 HF。 IL-1 阻断可能代表一种全新的预防心力衰竭的方法，可能会改善生活质量、减少住院次数、降低费用，并最终改善长期生存。心肌最初的缺血性损伤会引发强烈的炎症反应，导致进一步损伤并促进心功能障碍和心力衰竭。白细胞介素-1 (IL-1) 是参与组织对损伤反应的典型炎症细胞因子。在 AMI 中，IL-1 活性增加并放大炎症反应并诱导心肌细胞死亡。阿那白滞素是人 IL-1 受体拮抗剂 (rhIL-1Ra) 的重组形式，经 FDA 批准用于治疗类风湿性关节炎，对多种炎症性疾病的治疗非常有效。我们最近完成了 2 项试点安全性和可行性研究，即 VCU-ART (n=10) 和 VCU-ART2 (n=30)，受试者为急性 ST 段抬高型心肌梗死 (STEMI) 患者，按 1:1 随机分配至阿那白滞素 100 mg每日一次或安慰剂 14 天。阿那白滞素具有良好的耐受性，且不良事件很少。在两项试验的综合分析中，阿那白滞素与炎症标志物显着减少（-50%，P=0.01）以及 3 个月时症状性心力衰竭发生率降低的趋势相关（5% vs 30%，P=0.035）。我们提出了一项随机、双盲、多中心的试点研究，采用两种不同的阿那白滞素治疗方案（每日两次与每日两次），以确定阿那白滞素对 STEMI 期间急性炎症反应的最大作用，并估计阿那白滞素对发病率的影响STEMI 后 12 个月内发生 HF。尽管目前的试点研究可能不足以检测死亡率或再住院率的统计显着差异，但本研究将提供对死亡率或再住院率的估计。潜在的影响，然后可以在更大规模的 III 期临床试验中进行探索（作为 R1 申请的一部分）。