COVID-FISETIN: Pilot in Covid-19 of Fisetin to Alleviate Dysfunction and Inflammation

• ClinicalTrials.gov Identifier: NCT04476953
• Recruitment Status: Enrolling by invitation
• First Posted: July 20, 2020
• Last Update Posted: August 13, 2020
• Sponsor: Mayo Clinic
• Information provided by (Responsible Party): James L. Kirkland, Mayo Clinic

Study Description

Brief Summary:

The purpose of this study is to test whether Fisetin, a senolytic drug, can assist in preventing an increase in the disease's progression and alleviate complications of coronavirus due to an excessive inflammatory reaction.

Condition or disease	Intervention/treatment	Phase
COVID-19	Drug: Placebo; Drug: Fisetin	Phase 2

Detailed Description:

To determine if Fisetin treatment can prevent deterioration of oxygenation status as measured by S/F ratio: SpO2/ FiO2, as well as prevent deterioration in physical function (frailty) and hyper-inflammation, other measures of oxygenation status (progression to supplemental oxygen requirement, assisted breathing/ ventilation), and progression from mild/ moderate to severe/ critical proven COVID-19 (CoV) infection (WHO/NIH Baseline Severity Classification) in non-ICU hospitalized patients and to evaluate the safety and tolerability of Fisetin in this patient population.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 70 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: COVID-FISETIN: A Phase 2 Placebo-Controlled Pilot Study in Covid-19 of Fisetin to Alleviate Dysfunction and Excessive Inflammatory Response in Hospitalized Adults
• Actual Study Start Date: August 3, 2020
• Estimated Primary Completion Date: July 2021
• Estimated Study Completion Date: July 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Treatment Group; Subjects will receive treatment drug Fisetin	Drug: Fisetin; ~20 mg/kg/day oral, NG or D tube course for 2 consecutive days; Other Name: 3,3',4',7-tetrahydroxyflavone
Placebo Comparator: Placebo Group; Subjects will receive placebo	Drug: Placebo; Placebo looks exactly like the study drug, but it contains no active ingredient.

Outcome Measures

Primary Outcome Measures :

1. Serious Adverse Events [ Time Frame: 6 months ]
   Number of participants to experience serious adverse events and hypersensitivity reactions.
2. Change in oxygenation status [ Time Frame: baseline, Day 3, 7, 10, 14, 17 and 30; Months 3 and 6 ]
   change in oxygenation levels as measured by S/F ratio (SPO2/FiO2)

Secondary Outcome Measures :

1. COVID-19 Severity Category [ Time Frame: 6 months ]
   Number of participants to progress to severe or critical classification measure by the WHO/ NIH Baseline Severity Classification criteria descriptions of SARS-CoV-2 infection without symptoms, Mild COVID-19 (CoV), Moderate CoV, Severe CoV and Critical CoV

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria - Patients must meet all of the following inclusion criteria to be enrolled in this study.

1. Men or women 60 years of age or older

   OR

   Age 18 - 59 years WITH at least one of the following comorbidities:

   • BMI greater than or equal to 35
   • Diabetes
   • Asthma/ Chronic Obstructive Pulmonary Disease (COPD)
   • Previous Myocardial Infarction
   • Previous Stroke/ Cerebrovascular Accident (CVA)
   • Hypertension/ Atherosclerosis/ Peripheral Vascular Disease
   • Smoking and/or vaping
   • Other conditions associated with senescent cell accumulation (i.e. previous chemotherapy or radiation)
2. SpO2 greater than or equal to 85% on room air within previous 72 hours AND 2 L of oxygen or less by nasal cannula (or on room air) at time of enrollment.
3. Willing and able to provide written informed consent or have a legally authorized representative (LAR) who will provide informed consent.
4. SARS-CoV-2 infection confirmed by PCR test at Mayo Clinic's Central Laboratory within 72 hours before randomization.

Exclusion Criteria - Patients who meet any of the following exclusion criteria are not to be enrolled in this study.

General Exclusion Criteria

1. Presence of any condition that the Investigator or the subject's attending physician believes would put the subject at risk or would preclude the patient from successfully completing the trial.
2. Mechanically-ventilated (including V-V ECMO or V-A ECMO).
3. Severe or critical CoV (WHO/ NIH Categorization; Table 3) at time of randomization.
4. Pregnant and/or lactating. Women of childbearing potential (WCBP) must have a negative pregnancy test within 72 hours prior to randomization.
5. WCBP who are unwilling to abstain from sex or use an adequate method of contraception from the time of the first IP administration through 48 hours after the last IP administration. (Section 5.10)

6. Men who are unwilling to abstain from sex with WCBP or use an adequate method of contraception from the time of the first IP administration through 48 hours after the last IP administration. (Section 5.10)

   Laboratory Exclusion Criteria

7. Total bilirubin >3X upper limit of normal or as per clinical judgment.
8. Serum aspartate transaminase (AST) or alanine aminotransferase (ALT) >4x the upper limits of normal or as per clinical judgment.
9. Hemoglobin <7 g/dL; white blood cell count ≤ 2,000/mm3 (< or = 2.0 x 109/L) or > or = 20,000/mm3 (> or = 20 x 109/L); platelet count < or = 60,000/µL (< or = 60 x 109/L); absolute neutrophil count < or = 1 x 109/L; lymphocyte count <0.5 x 109/L at screening or as per clinical judgment.
10. Unstable (as per clinical judgment) major cardiovascular, renal, endocrine, immunological, or hepatic disorder.
11. eGFR <25 ml/ min/ 1.73 m2 or as per clinical judgment.
12. Plasma glucose >300 or as per clinical judgment.

13. Cystatin C >3x upper limit of normal or as per clinical judgment.

    Clinical History Exclusion Criteria

14. Human immunodeficiency virus infection.
15. Known active hepatitis B or C infection.
16. Invasive fungal infection.
17. Uncontrolled (as per clinical judgement) pleural/pericardial effusions or ascites.

18. New/active invasive cancer except non-melanoma skin cancers.

    Medication Exclusion Criteria (See Appendices 1-3 for additional information)

19. Known hypersensitivity or allergy to Fisetin.
20. Patients currently using medications which utilize CYP450 2C9 for metabolism. These medications include: Fosphenytoin, Phenytoin, Warfarin, Glimepiride, Diclofenac, Bosentan, and Glyburide. Patients taking Losartan may participate if Losartan can be held until study Day 3 and the patient is otherwise eligible.
21. Patients currently using medications which utilize CYP2C9, CYP2C19, CYP1A2, OATP1B1. These medications include: Olanzapine, Clozapine, Theophylline, Tizanidine, Warfarin, Rameltoen, Tacrine, Duloxetine, Mexiletine, Riluzole, and Atomoxetine. Patients taking Colchicine may participate if Colchicine can be reduced by half until study Day 3 and the patient is otherwise eligible. Patients taking Venlafaxine may participate if Venlafaxine can be held until study Day 3 and the patient is otherwise eligible.
22. Patients currently using medications which are strong inhibitors of CYP3A4. These medications include: Atazanavir, Ceritinib, Clarithromycin, Darunavir, Idelalisib, Indinavir, Itraconazole, Ketoconazole, Lopinavir, Mefipristone, Nefazodone, Nelfinavir, Ombitasivir-paritaprevir-ritonivir, Ombitasivir-paritaprevir-ritonivir-plus dasabuvir, Posaconazole, Saquinavir, Telithromycin, Tucatinib, and Voriconazole.
23. Patients currently using antifungals. If antifungals are absolutely necessary from an infectious disease perspective, then they will be allowed only if the levels are subtherapeutic or therapeutic.

24. Patients currently using any of the following medications (unless willing to discontinue the medication during the study):

    • Cardiac: digoxin, flecainide, amiodarone
    • Psychiatric: lithium, thioridazine
    • Neurologic: carbamazepine, phenobarbital
    • Antimicrobial/fungal: aminoglycosides (e.g. amikacin, gentamicin, kanamycin, neomycin, netilmicin, paromomysin, streptomycin, tobramycin), rifampin
    • Anticoagulants/ Antiplatelets: warfarin
    • Others: methotrexate, nitroglycerin, St. John's wort, tyrosine kinase inhibitors, tacrine, diclofenac
25. Participation in other clinical trials involving treatment for COVID-19. Note that institutional standard of care treatment of COVID-19 including glucocorticoids, hydroxychloroquine, azithromycin and/or remdesivir are not excluded from the study.

Contacts and Locations

Locations

United States, Minnesota

Mayo Clinic in Rochester

Rochester, Minnesota, United States, 55905

Sponsors and Collaborators

Mayo Clinic

Investigators

• Principal Investigator: James L Kirkland; Mayo Clinic

More Information

Additional Information:

Mayo Clinic Clinical Trials 

• Responsible Party: James L. Kirkland, Principal Investigator, Mayo Clinic
• ClinicalTrials.gov Identifier: NCT04476953
• Other Study ID Numbers: 20-003936
• First Posted: July 20, 2020
• Last Update Posted: August 13, 2020
• Last Verified: August 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No