Interleukin-1 blockade in recently decompensated heart failure

描述(由申请人提供)：本申请是一项名为“最近失代偿性心力衰竭患者的白细胞介素1阻断”的临床试验先导研究(R34)，由Antonio Abbate医学博士和Benjamin Van Tassell药学博士提交。心力衰竭(HF)是一种复杂的临床综合征，以劳累和劳累为特征。尽管目前的治疗方案延长了预期寿命，但心力衰竭的预后仍然很差，而且心力衰竭是美国老年患者入院的主要原因。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的住院时间。心衰患者心功能下降与炎性细胞因子水平升高之间存在显著相关性。在这些细胞因子中，白介素1(IL-1)是全身炎症的关键介质 在心力衰竭患者中升高，并可能导致心功能不佳。在动物模型中 心衰时，IL-1足以导致心功能显著降低，心脏储备受损，心脏重塑加重。在最近的一项概念验证研究中，2 用重组人IL-1受体拮抗剂(IL-1ra，anakinra)治疗数周后，以最大耗氧量(VO2)和呼吸机效率(VE/VCO2斜率)衡量的有氧运动能力有显著改善。我们将进行一项随机、双盲、先导性研究(n=60)，以证实IL-1阻断对改善心力衰竭患者运动能力的效果，并评估IL-1阻断对近期失代偿性心力衰竭(HF)患者再次入院的潜在益处。符合条件的患者将被随机分为Anakinra治疗12周(n=20)、Anakinra治疗2周(+10周安慰剂治疗，n=20)或12周安慰剂治疗(n=20)。这项先导性研究的结果将被用于优化治疗策略，并设计后续的III期临床试验，以评估使用IL-1阻断治疗心力衰竭患者的长期发病率和死亡率。

DESCRIPTION (provided by applicant): This application is for a Clinical Trial Pilot Study (R34) entitled "Interleukin-1 blockade in recently decompensated 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 proof-of-concept study, 2 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) and ventilator efficiency (VE/VCO2 slope). We will conduct a randomized, double-blind, pilot study (n=60) to confirm the effect of IL-1 blockade to improve exercise capacity in HF patients and estimate the potential benefit of IL-1 blockade o HF readmission in patients with recently decompensated heart failure (HF). Eligible patients will be randomized to 12 weeks treatment with anakinra (n=20), 2 weeks treatment with anakinra (+10 weeks placebo treatment, n=20), or 12 weeks placebo treatment (n=20). Results from this pilot 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.