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）会导致身体功能障碍，发病率和死亡，急性 呼吸窘迫综合征（ARDS）和多器官衰竭，尤其是在老年人或慢性病中。 整个美国，> 50％的COV死亡在护士之家，25-50％的护士居民进行测试 COV死于这些并发症的阳性。衰老细胞随着年龄的增长而累积，并使脆弱的细胞累积 慢性疾病。这些细胞可以获取与感应相关的秘书表型（SASP） 与COV诱导的细胞因子风暴相同的许多因素的释放。我们发现COV抗原加剧了 SASP，SASP因子增加了COV病毒进入蛋白，而SASP因素会损害病毒防御机制 非阳性细胞。与人类COV有关的冠状病毒迅速杀死了老鼠，但没有杀死年轻的老鼠。我们发现了 有选择地消除感觉细胞的药物，鼻溶液。他们减轻与年龄有关的表型和慢性 小鼠的疾病，现在正在临床试验中，发现它们可以减少感觉细胞伯嫩， 炎症和脆弱。我们发现，天然产物类黄酮的菲塞丁在旧的 现在正在进行的试验中，小鼠，猴子和老年人患有多元车的人，其中53例患者患有 Fisetin在感染了β-核纳病毒的小鼠中发展了细胞因子风暴和死亡率。 FDA- 我们的批准的我们的临床试验已经开始在老年住院的COV患者中，以防止进展 呼吸衰竭。我们的假设是，用fisetin靶向感觉细胞会延迟或防止 COV感染的并发症患有很大的风险：老年护士居民。目标1是测试fisetin是否 防止患有RT-PCR预先证实的COV感染的护士居民发病率的进展，但没有 在双盲，安慰剂对照，多中心临床试验中中等症状（WHO/NIH分类） 在与NIA支持的翻译Geroscience网络相关的护士房屋之间。主要 男性和女性的结果> 65岁（75 fisetin治疗，75个安慰剂）将是基于进展的预防 关于COV临床改进的WHO序数。其他结果将是安全，需要 补充氧气，护理升级和死亡。基于TGN的护士/研究协调员与自己的PPE 将最大程度地减少对稀疏的护士家庭工作人员的影响。可以向研究对象提供fisetin 食物和饮料。 AIM 2是测试Fisetin的延迟，防止或减轻过度炎症和ARDS/MULTI-ARD COV感染的老年护理居民中的器官故障。当可行时，我们将确定fisetin是否 减少SASP因子，感觉细胞抽象和病毒进入蛋白质并减少：进展到 严重或关键的COV，del妄和低氧。 AIM 3是测试Fisetin是否促进COV-的恢复 受感染的护士居民居民跟踪长达6个月，包括抗体反应，身体功能和 肺纤维化。该审判将为更多护士家庭试验铺平道路，不仅是COV，而且还在 脆弱的其他条件。该临床试验的影响将超出当前COV流行。