COVID-FIS: A PHASE 2 PLACEBO-CONTROLLED PILOT STUDY IN COVID-19 OF FISETIN TO ALLEVIATE DYSFUNCTION AND EXCESSIVE INFLAMMATORY RESPONSE IN OLDER ADULTS IN NURSING HOMES

摘要 冠状病毒-19(CoV)可导致身体功能障碍、发病率和死于急性、高度炎症。 呼吸窘迫综合征(ARDS)和多器官衰竭，特别是在老年人或慢性病患者。 在美国，50%的冠状病毒死亡病例发生在疗养院，25%-50%的疗养院居民进行了检测 冠状病毒阳性死于这些并发症。衰老的细胞随着年龄的增长而积累，并导致虚弱和 慢性病。这些细胞可以获得一种衰老相关的分泌表型(SASP)， 释放许多与冠状病毒诱导的细胞因子风暴相同的因子。我们发现冠状病毒抗原会加剧 SASP、SASP因子增加冠状病毒进入蛋白，SASP因子损害病毒防御机制 非衰老细胞。一种与人类冠状病毒有关的冠状病毒会迅速杀死老年小鼠，但不会杀死小鼠。我们发现 有选择地消除衰老细胞的药物和抗衰老药物。它们可以缓解与年龄相关的表型和慢性 目前正在进行临床试验，发现它们可以减轻衰老的细胞负担， 发炎，虚弱。我们发现，非瑟酮是一种天然产物类黄酮，在老年人中具有良好的安全性 在一项正在进行的试验中，老鼠、猴子和老年人类患有多种疾病，其中53名患者 已经接受了治疗。非瑟素可降低β冠状病毒感染小鼠的细胞因子风暴和死亡率。一个FDA- 我们批准的临床试验现在已经在住院的老年冠状病毒患者中开始，以防止进展到 呼吸衰竭。我们的假设是，用Fisetin靶向衰老细胞将延缓或防止 高危人群中冠状病毒感染的并发症：养老院老年居民。目标1是测试是否存在 预防患有RT-PCR证实的冠状病毒感染但无、轻度或 一项双盲、安慰剂对照、多中心临床试验的中度症状(WHO/NIH分类) 与NIA支持的翻译老年科学网络相关的疗养院。初级阶段 65岁的男性和女性(75人接受非赛汀治疗，75人服用安慰剂)的结果将是基于预防进展的 世界卫生组织冠状病毒临床改进评分表的研究其他结果将是安全的，需要 补充氧气，护理升级，以及死亡。以TGN为基础的护士/学习协调员拥有自己的个人防护装备 将最大限度地减少对紧张的养老院工作人员的影响。可向研究对象提供非瑟丁 食物和饮料。目标2是测试非赛汀是否延缓、预防或缓解炎症和ARDS/多器官功能障碍。 老年疗养院居民感染冠状病毒后的器官衰竭。如果可行，我们将确定是否存在 减少SASP因子、衰老细胞丰度和病毒进入蛋白，并减少进展到 严重或严重的冠状病毒、精神错乱和低氧。目标3是测试非瑟丁是否促进冠状病毒的恢复- 被感染的疗养院居民随访6个月，包括抗体反应、身体功能和 肺纤维化。这项试验将为更多的疗养院干预试验铺平道路，不仅是针对CoV，而且 其他情况在虚弱的老年人身上。这项临床试验的影响将超越目前的冠状病毒疫情。

ABSTRACT Coronavirus-19 (CoV) can cause physical dysfunction, morbidity, and death from hyper-inflammation, acute respiratory distress syndrome (ARDS), and multi-organ failure, particularly in older or chronically-ill individuals. Across the US, >50% of CoV deaths are in nursing homes and 25-50% of nursing home residents who test positive for CoV die from these complications. Senescent cells accumulate with age and drive frailty and chronic diseases. These cells can acquire a senescence-associated secretory phenotype (SASP) entailing release of many of the same factors as in CoV-induced cytokine storm. We found CoV antigens exacerbate the SASP, SASP factors increase CoV viral entry proteins, and SASP factors impair viral defense mechanisms in non-senescent cells. A coronavirus related to human CoV rapidly kills old but not young mice. We discovered drugs that selectively eliminate senescent cells, senolytics. They alleviate age-related phenotypes and chronic disorders in mice and are now in clinical trials, in which they have been found to reduce senescent cell burden, inflammation, and frailty. We found that Fisetin, a natural product flavonoid, has a favorable safety profile in old mice, monkeys, and elderly humans with multi-morbidity in a trial now underway in which 53 patients have been treated. Fisetin decreased cytokine storm and mortality in mice infected with β-coronavirus. An FDA- approved clinical trial of ours has now begun in older hospitalized CoV patients to prevent progression to respiratory failure. Our hypothesis is that targeting senescent cells with Fisetin will delay or prevent complications of CoV infection in those at great risk: elderly nursing home residents. Aim 1 is to test if Fisetin prevents progression of morbidity in nursing home residents with rt-PCR-proven CoV infection but no, mild, or moderate symptoms (WHO/NIH Classification) in a double-blind, placebo-controlled, multicenter clinical trial across nursing homes associated with the NIA-supported Translational Geroscience Network. The primary outcome in men and women age >65 (75 Fisetin-treated, 75 placebo) will be prevention of progression, based on the WHO Ordinal Scale for Clinical Improvement of CoV. Other outcomes will be safety, need for supplemental oxygen, escalation of care, and death. TGN-based nurses/study coordinators with their own PPE will minimize impact on thinly-stretched nursing home staff. Fisetin can be provided to the study subjects in foods and drinks. Aim 2 is to test if Fisetin delays, prevents, or alleviates hyper-inflammation and ARDS/multi- organ failure in CoV-infected elderly nursing home residents. When feasible, we will ascertain if Fisetin decreases SASP factors, senescent cell abundance, and viral entry proteins and reduces: progression to severe or critical CoV, delirium, and hypo-oxygenation. Aim 3 is to test if Fisetin promotes recovery of CoV- infected nursing home residents followed up to 6 months, including antibody response, physical function, and lung fibrosis. This trial will pave the way for more nursing home trials of interventions not only for CoV, but other conditions in the frail elderly. The impact of this clinical trial will extend beyond the current CoV epidemic.