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

• 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
• 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

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.

项目摘要 本申请是针对一项名为“研究者启动的单中心临床试验（R61/R33）的影响”的申请。 白细胞介素-1阻滞剂对近期失代偿收缩性心力衰竭患者运动能力的影响 由Antonio Abbate医学博士和Benjamin货车Tassell药学博士提交。心力衰竭（HF）是一种复杂的 一种临床综合症，特征是劳累时呼吸困难。虽然目前的治疗 选择延长了预期寿命，HF的预后仍然很差，HF是 在美国，老年患者中。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HF住院治疗。 心功能下降与炎症反应水平升高之间存在显著相关性。 HF患者中的细胞因子。在这些细胞因子中，白细胞介素-1（IL-1）是全身性炎症的关键介质， 在HF患者中炎症升高，可能导致心脏功能不良。在动物 HF模型，IL-1足以引起心脏功能的显著抑制，心脏储备受损， 心脏重塑恶化在最近的初步研究中，用重组人IL-1治疗12周， 受体拮抗剂（IL-1 Ra，阿那白滞素）产生了显着改善有氧运动性能， 用峰值耗氧量（VO 2）来衡量。 该提案将支持一项随机、双盲、II期临床试验（n=102），以确认其效果 IL-1阻断剂改善HF患者的运动能力，并评估IL-1阻断剂的潜在益处 近期失代偿性心力衰竭（HF）患者的HF再入院。符合条件的患者将被 随机分为阿那白滞素组（n=68）和安慰剂组（n=34），治疗24周。本研究的结果将用于 优化治疗策略，并设计后续的III期临床试验，以评估长期 IL-1阻断对HF患者发病率和死亡率的影响。