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.

摘要