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：
8866465
负责人：
Antonio Abbate
金额：
$ 21.29万
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/8866465
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 Future Health Heart failure Hospitalization Human Incidence Inflammatory Inflammatory Response Interleukin-1 Measures Medical Morbidity - disease rate Myocardial Infarction Myocardial dysfunction Myocarditis 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 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）：尽管当前的早期再灌注策略，急性心肌梗塞（AMI）仍然是发病率和死亡率的主要原因。许多患者在课程中早期死亡，而生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。确实，尽管AMI治疗的改善和早期死亡率的降低，但HF的发病率和流行率仍在前所未有的率上升。因此，紧急未满足的需要进行其他治疗，以防止AMI后HF。 IL-1封锁可能代表了预防HF的完全新颖的方法，可能会改善生活质量，降低住院，降低成本以及最终改善长期生存。心肌的最初缺血损伤会引起强烈的炎症反应，从而进一步损害并促进心脏功能障碍和HF。白介素-1（IL-1）是与损伤组织反应有关的典型炎症细胞因子。在AMI中，IL-1活性增加并扩增炎症反应并诱导心脏细胞死亡。 Anakinra是人类IL-1受体拮抗剂（RHIL-1RA）的重组形式，该形式获得了FDA批准用于治疗类风湿关节炎的重组形式，并且在治疗多种炎症性疾病方面非常有效。我们最近在急性ST段升高心肌梗死（STEMI）的患者中完成了2项试验安全性和可行性研究，即VCU-ART（n = 10）和VCU-ART2（n = 30），每天1：1随机1：1每天100毫克或安慰剂。 Anakinra的耐受性良好，很少发生不良事件。在两项试验的综合分析中，Anakinra与炎症标志物的显着降低（-50％，p = 0.01）以及3个月（5％vs 30％，p = 0.035）的趋势显着降低（-50％，p = 0.01）。我们提出了一项随机，双盲的，多中心的试点研究，具有两种不同的Anakinra方案（每天两次与每天两次），以确定Anakinra对STEMI期间急性炎症反应的最大影响，并估计Anakinra对STEMI后12个月的HF发生率的影响。尽管当前的试点研究可能没有足够的能力来检测死亡率或再培育率的统计学上的差异，但本研究将提供对潜在效应，然后可以在更大的III期临床试验（作为R1应用的一部分）中探索。