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

Abstract: Coronavirus-19 (CoV) can cause physical dysfunction, morbidity, and death from hyper-inflammation, acuterespiratory 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 testpositive for CoV die from these complications. Senescent cells accumulate with age and drive frailty andchronic diseases. These cells can acquire a senescence-associated secretory phenotype (SASP) entailingrelease of many of the same factors as in CoV-induced cytokine storm. We found CoV antigens exacerbate theSASP, SASP factors increase CoV viral entry proteins, and SASP factors impair viral defense mechanisms innon-senescent cells. A coronavirus related to human CoV rapidly kills old but not young mice. We discovereddrugs that selectively eliminate senescent cells, senolytics. They alleviate age-related phenotypes and chronicdisorders 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 oldmice, monkeys, and elderly humans with multi-morbidity in a trial now underway in which 53 patients havebeen 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 torespiratory failure. Our hypothesis is that targeting senescent cells with Fisetin will delay or preventcomplications of CoV infection in those at great risk: elderly nursing home residents. Aim 1 is to test if Fisetinprevents progression of morbidity in nursing home residents with rt-PCR-proven CoV infection but no, mild, ormoderate symptoms (WHO/NIH Classification) in a double-blind, placebo-controlled, multicenter clinical trialacross nursing homes associated with the NIA-supported Translational Geroscience Network. The primaryoutcome in men and women age >65 (75 Fisetin-treated, 75 placebo) will be prevention of progression, basedon the WHO Ordinal Scale for Clinical Improvement of CoV. Other outcomes will be safety, need forsupplemental oxygen, escalation of care, and death. TGN-based nurses/study coordinators with their own PPEwill minimize impact on thinly-stretched nursing home staff. Fisetin can be provided to the study subjects infoods 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 Fisetindecreases SASP factors, senescent cell abundance, and viral entry proteins and reduces: progression tosevere 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, andlung fibrosis. This trial will pave the way for more nursing home trials of interventions not only for CoV, butother conditions in the frail elderly. The impact of this clinical trial will extend beyond the current CoV epidemic.