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The Effects of Interleukin-1 Blockade On Exercise Capacity In Patients With Recently Decompensated Systolic Heart Failure

IL-1 阻断对近期失代偿性收缩性心力衰竭患者运动能力的影响

基本信息

批准号：
10449103
负责人：
Antonio Abbate
金额：
$ 57.34万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10449103
关键词：
Activities of Daily Living Acute Admission activity Aerobic Exercise Aldosterone Angiotensin II Animal Model Anti-Inflammatory Agents Blood Vessels Breathing Cardiac Cardiopulmonary Clinical Clinical Trials Complex Coupling Data Diagnosis Disease Disease Marker Disease Progression Doctor of Pharmacy Doctor of Philosophy Doppler Echocardiography Double-Blind Method EFRAC Event Exertion Fatigue Fingers Functional disorder Heart failure Hospitalization Hospitals Human Impairment Incidence Inflammation Inflammatory Interleukin-1 Interruption Knowledge Life Expectancy Measures Mediator of activation protein Morbidity - disease rate Myocardial Norepinephrine Outcome Oxygen Oxygen Consumption Pathway interactions Patients Performance Pharmacology Phase Phase II Clinical Trials Phase III Clinical Trials Pilot Projects Placebos Play Plethysmography Prevalence Prognosis Quality of life Randomized Recombinants Relaxation Reporting Research Personnel Risk Factors Role Site Stroke Symptoms Syndrome Systolic heart failure Testing Work adjudication adverse outcome anakinra cardiac depression cost cytokine design disease natural history exercise capacity follow-up functional disability heart function hemodynamics hospital readmission human old age (65+)improved mortality novel novel therapeutic intervention older patient pressure primary endpoint readmission rates reduce symptoms secondary endpoint systemic inflammatory response therapy design treatment optimization treatment strategy uptake

项目摘要

Project Summary This application is for a Single-Site Investigator-Initiated Clinical Trial (R61/R33) entitled “Effects of Interleukin-1 blockade on exercise capacity in patients with recently decompensated systolic heart failure” submitted by Antonio Abbate MD, PhD and Benjamin Van Tassell, PharmD. Heart failure (HF) is a complex clinical syndrome characterized by fatigue and labored breathing upon exertion. Although current treatment options have extended life expectancy, prognosis for HF remains poor and HF is the leading cause of admission among elderly patients in the US. There is an urgent need to develop novel treatments to alleviate symptoms, slow disease progression, and reduce HF hospitalization. A significant correlation exists between declining cardiac function and increasing levels of inflammatory cytokines in HF patients. Among these cytokines, Interleukin-1 (IL-1) is a key mediator of systemic inflammation that becomes elevated in HF patients and may contribute to poor cardiac function. In animal models of HF, IL-1 is sufficient to cause significant depression of cardiac function, impaired cardiac reserve, and worsened cardiac remodeling. In a recent pilot study, 12 weeks treatment with recombinant human IL-1 receptor antagonist (IL-1Ra, anakinra) produced a significant improvement in aerobic exercise performance as measured by peak oxygen consumption (VO2). This proposal will support a randomized, double-blind, phase II clinical trial (n=102) to confirm the effect of IL-1 blockade to improve exercise capacity in HF patients and estimate the potential benefit of IL-1 blockade on HF readmission in patients with recently decompensated heart failure (HF). Eligible patients will be randomized to 24 weeks treatment with anakinra (n=68) or placebo (n=34). Results from this study will be used to optimize the treatment strategy and design a subsequent phase III clinical trial to evaluate long-term morbidity and mortality with IL-1 blockade in HF patients.

项目概要本申请适用于单中心研究者发起的临床试验 (R61/R33)，标题为“Effects of 白介素-1 阻断对近期失代偿性收缩性心力衰竭患者运动能力的影响” 由 Antonio Abbate 医学博士、博士和 Benjamin Van Tassell 药学博士提交。心力衰竭（HF）是一种复杂的疾病以疲劳和劳累时呼吸困难为特征的临床综合征。虽然目前的治疗选择延长了预期寿命，心力衰竭的预后仍然很差，心力衰竭是导致心力衰竭的主要原因美国老年患者入院。迫切需要开发新的治疗方法来缓解症状、减缓疾病进展并减少心力衰竭住院治疗。心脏功能下降与炎症水平增加之间存在显着相关性心力衰竭患者的细胞因子。在这些细胞因子中，白细胞介素-1 (IL-1) 是全身性细胞因子的关键介质。心力衰竭患者的炎症加剧，可能导致心功能不良。在动物中 HF 模型中，IL-1 足以导致心功能显着下降、心脏储备受损、以及心脏重塑恶化。在最近的一项试点研究中，重组人 IL-1 治疗 12 周受体拮抗剂（IL-1Ra、阿那白滞素）显着改善有氧运动表现通过峰值耗氧量 (VO2) 进行测量。该提案将支持一项随机、双盲、II 期临床试验（n=102）以确认效果 IL-1 阻断改善心力衰竭患者运动能力的研究并评估 IL-1 阻断的潜在益处近期失代偿性心力衰竭（HF）患者心力衰竭再入院的情况。符合条件的患者将随机接受阿那白滞素 (n=68) 或安慰剂 (n=34) 24 周治疗。本研究的结果将用于优化治疗策略并设计后续III期临床试验以评估长期效果 IL-1 阻断治疗心衰患者的发病率和死亡率。