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、发病和急性炎症过度死亡 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中。 在美国，超过50%的CoV死亡发生在养老院，25-50%的养老院居民接受了测试。 冠状病毒感染者死于这些并发症衰老细胞随着年龄的增长而积累， 慢性病这些细胞可以获得衰老相关的分泌表型（SASP）， 释放许多与CoV诱导的细胞因子风暴相同的因子。我们发现冠状病毒抗原加剧了 SASP，SASP因子增加CoV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相关的冠状病毒迅速杀死老年小鼠，但不会杀死年轻小鼠。我们发现 选择性消除衰老细胞的药物，senolytics。它们可以缓解与年龄相关的表型和慢性 小鼠的疾病，现在正在临床试验中，其中已经发现它们可以减少衰老细胞的负担， 炎症和虚弱我们发现，非瑟酮，一种天然的黄酮类化合物，在老年人中具有良好的安全性。 小鼠，猴子和老年人与多发病率在一项试验中，目前正在进行的53名患者， 接受治疗非瑟酮降低β-冠状病毒感染小鼠的细胞因子风暴和死亡率。食品药品管理局- 我们批准的临床试验现已开始在老年住院CoV患者中进行，以防止进展为 呼吸衰竭我们的假设是，用非瑟酮靶向衰老细胞， 高风险人群中CoV感染的并发症：老年疗养院居民。目的1是测试非瑟酮是否 预防rt-PCR证实的CoV感染但无、轻度或 一项双盲、安慰剂对照、多中心临床试验中的中度症状（WHO/NIH分类） 与NIA支持的翻译老年科学网络相关的养老院。主 年龄>65岁的男性和女性（非瑟酮治疗组75例，安慰剂组75例）的结局将是预防疾病进展，基于 根据WHO冠状病毒临床改善等级量表。其他结果将是安全性， 补充氧气，加强护理，然后死亡TGN护士/研究协调员，配备个人防护设备 将对人手紧张的养老院工作人员的影响降到最低。非瑟酮可在以下时间提供给研究受试者： 饮食.目的2是测试非瑟酮是否延迟、预防或减轻过度炎症和ARDS/多发性硬化。 冠状病毒感染的老年疗养院居民的器官衰竭。在可行的情况下，我们将确定非赛丁是否 降低SASP因子、衰老细胞丰度和病毒进入蛋白，并减少： 严重或危重的冠状病毒、谵妄和缺氧。目的3是测试非瑟酮是否促进CoV的恢复- 受感染的疗养院居民随访6个月，包括抗体反应，身体功能， 肺纤维化这项试验将为更多的疗养院试验铺平道路，这些试验不仅针对CoV， 体弱老人的其他情况。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.