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

COVID-FIS：针对 COVID-19 的 FISETIN 缓解疗养院老年人功能障碍和过度炎症反应的 2 期安慰剂对照试点研究

• 批准号: 10208138
• 负责人: JAMES L. KIRKLAND
• 金额: $ 191.79万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10208138
• 关键词: Academic Medical Centers; Adult Respiratory Distress Syndrome; Age; Aging; Antibody Response; Antigens; Apoptotic; Benefits and Risks; Blood; COVID-19; Caring; Cell Aging; Cells; Cessation of life; Chronic Disease; Chronically Ill; Classification; Clinical; Clinical Trials; Communities; Connecticut; Controlled Clinical Trials; Coronavirus; Data; Defense Mechanisms; Delirium; Diabetes Mellitus; Double-Blind Method; Elderly; Epidemic; FDA approved; Failure; Fatty acid glycerol esters; Fibrosis; Flavonoids; Food; Frail Elderly; Functional disorder; Geriatric Nursing; Geroscience; Hour; Human; Impaired cognition; Impairment; Individual; Infection; Inflammation; Inflammatory Response; Influenza; Inhalation; Intensive Care; Intervention Trial; Investigational Drugs; Michigan; Minnesota; Monkeys; Morbidity - disease rate; Multi-Institutional Clinical Trial; Murine hepatitis virus; Mus; Myocardial Infarction; Natural Products; Normal Cell; Nurses; Nursing Homes; Odors; Outcome; Oxygen; Palliative Care; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phenotype; Physical Function; Pilot Projects; Placebos; Population; Prevention; Proteins; Pulmonary Fibrosis; Recovery; Research; Resistance; Respiratory Failure; Risk; Running; Safety; Sampling; Secondary Prevention; Skin; Strawberries; Stretching; Stroke; Structure of parenchyma of lung; Study Subject; Symptoms; Taste Perception; Temperature; Testing; Texas; Thinness; Thrombosis; Tissues; United States National Institutes of Health; Universities; Urine; Viral; Virus; Woman; adverse outcome; age related; base; coronavirus disease; cytokine release syndrome; fisetin; follow-up; forest; frailty; healthspan; human coronavirus; men; mortality; multiple chronic conditions; older patient; pathogen; prevent; primary outcome; secondary outcome; senescence; side effect

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.

抽象的 冠状病毒-19 (CoV) 可因过度炎症、急性炎症而导致身体功能障碍、发病和死亡 呼吸窘迫综合征（ARDS）和多器官衰竭，尤其是老年人或慢性病患者。 在美国，超过 50% 的冠状病毒死亡发生在疗养院，25-50% 的疗养院居民接受了检测 冠状病毒呈阳性的人死于这些并发症。衰老细胞随着年龄的增长而积累并导致身体虚弱 慢性疾病。这些细胞可以获得衰老相关的分泌表型（SASP），从而导致 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会加剧 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。与人类冠状病毒相关的冠状病毒会迅速杀死年老的老鼠，但不会杀死年轻的老鼠。我们发现 选择性消除衰老细胞的药物，senolytics。它们减轻与年龄相关的表型和慢性 小鼠的疾病，目前正在进行临床试验，其中发现它们可以减少衰老细胞的负担， 炎症、虚弱。我们发现非瑟酮（Fisetin）是一种天然产品类黄酮，在老年人中具有良好的安全性。 一项目前正在进行的试验中，有 53 名患者患有多种疾病，其中包括小鼠、猴子和老年人。 被治疗。非瑟酮降低了感染 β-冠状病毒的小鼠的细胞因子风暴和死亡率。 FDA- 我们批准的临床试验现已开始在老年住院冠状病毒患者中进行，以防止病情进展 呼吸衰竭。我们的假设是，用非瑟酮靶向衰老细胞将延迟或预防 高危人群中冠状病毒感染的并发症：老年疗养院居民。目标 1 是测试非瑟酮是否 预防经 rt-PCR 证实感染 CoV 的疗养院居民的发病率进展，但无、轻度或 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 支持的转化老年科学网络相关的疗养院。初级 年龄 > 65 岁的男性和女性（75 名非瑟汀治疗组，75 名安慰剂组）的结果将是预防进展，基于 世界卫生组织冠状病毒临床改善顺序量表。其他结果将是安全、需要 补充氧气、护理升级和死亡。 TGN 护士/研究协调员拥有自己的个人防护装备 将最大限度地减少对捉襟见肘的疗养院工作人员的影响。可以向研究对象提供非瑟酮 食物和饮料。目标 2 是测试 Fisetin 是否可以延迟、预防或减轻过度炎症和 ARDS/多重炎症 感染冠状病毒的老年疗养院居民出现器官衰竭。如果可行，我们将确定非瑟酮是否 减少 SASP 因子、衰老细胞丰度和病毒进入蛋白，并减少： 严重或危重冠状病毒、谵妄和缺氧。目标 3 是测试 Fisetin 是否促进 CoV- 的恢复 对受感染的疗养院居民进行长达 6 个月的随访，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，不仅针对冠状病毒，而且针对 体弱老人的其他情况。这项临床试验的影响将超越当前的冠状病毒流行。