Clinical trial NCT04400890
Conditions: COVID-19
Keywords: Coronavirus SARS-CoV-2 COVID Vitamin D3 Cholecalciferol Supplement Polyphenol Resveratrol Stilbene phytoalexin
Sponsor: Marvin McCreary, MD
Start date: 2020-09-13; Completion date: 2021-03-01
Enrollment: 105 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Resveratrol is a plant polyphenol (that is sold commercially as a supplement) that might help fight coronavirus as well as help protect the body from the effects of disease (COVID-19) caused by the infection. In this proof-of-concept pilot study we will compare the effects of resveratrol to placebo to assess the safety of the resveratrol and explore effectiveness.

Detailed description:
This randomized placebo-controlled trial is for the outpatient treatment of (Coronavirus Disease 2019) COVID-19. The purpose of this trial is to evaluate the safety and explore the effectiveness of resveratrol, a plant polyphenol, being re-purposed for patients with early COVID-19. Published in vitro data supports that this polyphenol inhibits coronavirus replication while separately published in silico (computer molecular docking analysis) reports have identified specific molecular targets of resveratrol against (Severe Acute Respiratory Syndrome - Coronavirus 2) SARS-CoV-2. Animal studies also demonstrate that resveratrol is effective at preventing lung injury and death in certain animal models of viral infections. Furthermore, the products long history as an anti-inflammatory might prevent the cytokine storm that is associated with worse outcomes in COVID-19.

200 subjects, 45 and older, (100 receiving the plant polyphenol, 100 receiving placebo) will be enrolled in study to compare whether taking resveratrol will reduce the rate of hospitalization. Subjects will take capsules 4 times a day for a minimum of 7 days (up to 15 days depending on duration of symptoms) plus both groups will receive Vitamin D3 100,000 IU to augment the effects of resveratrol. Resveratrol will be given as 1gm 4 times per day. Placebo tablets will contain brown rice flour in visually identical capsules. The primary outcome measure for this trial is reduction in hospitalization at 21 days from enrollment.

Arms: arm 1: Resveratrol 1000mg four times per day for 15 days. Vitamin D3 100,000 IU on day 1 arm 2: Placebo capsules 4 times per day for 15 days. Vitamin D3 100,000 IU on day 1
Interventions: intervention 1: Resveratrol intervention 2: Vitamin D3
Intervention descriptions: intervention 1: Resveratrol vs placebo given for 15 days. intervention 2: Vitamin D3 100,000 IU given on day one.

Protocol documents:
Prot_SAP_001.pdf: 
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RANDOMIZED DOUBLE-BLIND PLACEBO-
CONTROLLED PROOF-OF-CONCEPT TRIAL OF 
RESVERATROL FOR THE OUTPATIENT 
TREATMENT OF MILD CORONAVIRUS DISEASE 
(COVID-19) 
Unique Protocol Identification Number: McCreary2020 
National Clinical Trial (NCT) Identified Number: NCT04400890 
Investigational New Drug (IND) Number: 150033 
Mt Carmel IRB Number: 200412-4 
Principal Investigator: Marvin R McCreary, MD 
IND/IDE Sponsor: Marvin R McCreary, MD 
Funded by: Marvin R McCreary, MD 
September 08, 2020 
 
 
 
 
 


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Table of Contents 
Statement of Compliance .............................................................................................................................................. 5 
1 Protocol Summary ...................................................................................................................................................... 6 
1.1 Synopsis ............................................................................................................................................................... 6 
1.2 Schema ................................................................................................................................................................ 7 
1.3 Schedule of Activities (SoA) ................................................................................................................................. 8 
2 Introduction ................................................................................................................................................................ 9 
2.1 Study Rationale .................................................................................................................................................... 9 
2.2 Background .......................................................................................................................................................... 9 
2.2.1 Figure 1. – Summary of resveratrol effects on virus and host .................................................................... 12 
2.3 Risk/Benefit Assessment.................................................................................................................................... 13 
2.3.1 Safety and Drug Interactions ...................................................................................................................... 13 
2.3.2 Known Potential Risks ................................................................................................................................. 14 
2.3.3 Known Potential Benefits ........................................................................................................................... 15 
2.3.3 Assessment of Potential Risks and Benefits ............................................................................................... 15 
3 Objectives and Endpoints ......................................................................................................................................... 16 
4 Study Design ............................................................................................................................................................. 17 
4.1 Overall Design .................................................................................................................................................... 17 
4.2 Scientific Rationale for Study Design ................................................................................................................. 19 
4.3 Justification for Dose ......................................................................................................................................... 19 
4.4 End of Study Definition ...................................................................................................................................... 22 
5 Study Population ...................................................................................................................................................... 23 
5.1 Inclusion Criteria ................................................................................................................................................ 23 
5.2 Exclusion Criteria ............................................................................................................................................... 24 
5.3 Lifestyle Considerations ..................................................................................................................................... 27 
5.4 Screen Failures ................................................................................................................................................... 27 
5.5 Strategies for Recruitment and Retention ......................................................................................................... 27 
6 Study Intervention .................................................................................................................................................... 28 
6.1 Study Intervention(s) Administration ................................................................................................................ 28 
6.1.1 Study Intervention Description ................................................................................................................... 28 
6.1.2 Dosing and Administration ......................................................................................................................... 30 
6.2 Preparation/Handling/Storage/Accountability .................................................................................................. 30 
6.2.1 Acquisition and accountability .................................................................................................................... 30 
6.2.2 Formulation, Appearance, Packaging, and Labeling ................................................................................... 30 
6.2.3 Product Storage and Stability ..................................................................................................................... 30 
6.2.4 Preparation ................................................................................................................................................. 30 
6.3 Measures to Minimize Bias: Randomization and Blinding ................................................................................. 31 
6.4 Study Intervention Compliance ......................................................................................................................... 31 
6.5 Concomitant Therapy ........................................................................................................................................ 31 
6.5.1 Rescue Medicine ......................................................................................................................................... 32 
7 Study Intervention Discontinuation and Participant Discontinuation/Withdrawal ................................................. 33 
7.1 Discontinuation of Study Intervention .............................................................................................................. 33 
7.2 Participant Discontinuation/Withdrawal from the Study .................................................................................. 33 
7.3 Lost to Follow-Up ............................................................................................................................................... 33 
8 Study Assessments and Procedures ......................................................................................................................... 35 


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8.1 Efficacy Assessments ......................................................................................................................................... 35 
8.2 Safety and Other Assessments .......................................................................................................................... 35 
8.3 Adverse Events and Serious Adverse Events ..................................................................................................... 35 
8.3.1 Definition of Adverse Events (AE) ............................................................................................................... 35 
8.3.2 Definition of Serious Adverse Events (SAE) ................................................................................................ 36 
8.3.3 Classification of an Adverse Event .............................................................................................................. 36 
8.3.4 Time Period and Frequency for Event Assessment and Follow-Up ............................................................ 39 
8.3.5 Adverse Event Reporting ............................................................................................................................ 39 
8.3.6 Serious Adverse Event Reporting................................................................................................................ 39 
8.3.7 Reporting Events to Participants ................................................................................................................ 40 
8.3.8 Events of Special Interest ........................................................................................................................... 40 
8.3.9 Reporting of Pregnancy .............................................................................................................................. 41 
8.4 Unanticipated Problems .................................................................................................................................... 41 
8.4.1 Definition of Unanticipated Problems (UP) ................................................................................................ 41 
8.4.2 Unanticipated Problem Reporting .............................................................................................................. 41 
8.4.3 Reporting Unanticipated Problems to Participants .................................................................................... 42 
9 Statistical Considerations ......................................................................................................................................... 43 
9.1 Statistical Hypotheses ........................................................................................................................................ 43 
9.2 Sample Size Determination................................................................................................................................ 43 
9.3 Populations for Analyses ................................................................................................................................... 44 
9.4 Statistical Analyses............................................................................................................................................. 45 
9.4.1 General Approach ....................................................................................................................................... 45 
9.4.2 Analysis of the Primary Efficacy Endpoint(s) .............................................................................................. 45 
9.4.3 Analysis of the Secondary Endpoint(s) ....................................................................................................... 45 
9.4.4 Safety Analyses ........................................................................................................................................... 46 
9.4.5 Baseline Descriptive Statistics .................................................................................................................... 46 
9.4.6 Planned Interim Analyses ........................................................................................................................... 46 
9.4.7 Sub-Group Analyses .................................................................................................................................... 46 
9.4.8 Tabulation of Individual Participant Data ................................................................................................... 47 
9.4.9 Exploratory Analyses .................................................................................................................................. 47 
10 Supporting Documentation and Operational Considerations ................................................................................ 49 
10.1 Regulatory, Ethical, and Study Oversight Considerations ................................................................................ 49 
10.1.1 Informed Consent Process ........................................................................................................................ 49 
10.1.2 Study Discontinuation and Closure ........................................................................................................... 49 
10.1.3 Confidentiality and Privacy ....................................................................................................................... 50 
10.1.4 Future Use of Stored Specimens and Data ............................................................................................... 51 
10.1.6 Safety Oversight ........................................................................................................................................ 51 
10.1.7 Clinical Monitoring .................................................................................................................................... 51 
10.1.8 Quality Assurance and Quality Control ..................................................................................................... 52 
10.1.9 Data Handling and Record Keeping .......................................................................................................... 52 
10.1.10 Protocol Deviations................................................................................................................................. 53 
10.1.11 Publication and Data Sharing Policy ....................................................................................................... 53 
10.1.12 Conflict of Interest Policy ........................................................................................................................ 53 
10.2 Additional Considerations ............................................................................................................................... 54 
10.3 Abbreviations ................................................................................................................................................... 54 


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10.4 Protocol Amendment History .......................................................................................................................... 57 
11 References .............................................................................................................................................................. 58 
12 Appendix ................................................................................................................................................................. 67 
12.1 Resveratrol ....................................................................................................................................................... 67 
12.1.1 Product Label ............................................................................................................................................ 67 
12.1.2 Certificate of Analysis ............................................................................................................................... 68 
12.1.3Stability Report .......................................................................................................................................... 69 
12.1.4 GMP Certificate ........................................................................................................................................ 72 
12.2 Placebo ............................................................................................................................................................ 73 
12.2.1 Certificate of Analysis ............................................................................................................................... 73 
12.3 Vitamin D3 (Cholecalciferol) ............................................................................................................................ 74 
12.3.1 Product Label ............................................................................................................................................ 75 
12.3.2 Certificate of Analysis ............................................................................................................................... 76 
12.3.3 Stabilty Report .......................................................................................................................................... 77 
12.3.4 GMP Certification ..................................................................................................................................... 78 
12.4 Sample Patient Packet Items ........................................................................................................................... 79 
12.4.1 Sample Drug Diary .................................................................................................................................... 79 
12.5 Patient Surveys ................................................................................................................................................ 80 
12.5.1 – Daily Questionnaire ............................................................................................................................... 81 
12.5.2 – PRO-CTCAE Questionnaire (Day 1, 8, & 15) ........................................................................................... 85 
 
 
 


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STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with International Council on Harmonisation Good Clinical 
Practice (ICH GCP) and the following: 
o 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 46, 21 CFR 
Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812). 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are responsible 
for the conduct, management, or oversight of NIH-funded clinical trials have completed Human Subjects 
Protection and ICH GCP Training. 


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1 PROTOCOL SUMMARY 
1.1 SYNOPSIS 
Title: 
RANDOMIZED DOUBLE-BLIND PLACEBO-CONTROLLED PROOF-OF-CONCEPT TRIAL OF 
RESVERATROL FOR THE OUTPATIENT TREATMENT OF MILD CORONAVIRUS DISEASE 
(COVID-19)  
Study 
Description: 
Proof of concept trial to determine the safety and explore the efficacy of using 
resveratrol and vitamin D3 to treat patients with mild COVID-19 
Objectives: 
Primary 
Objective: 
To compare the 21-day hospitalization rate among early or mild 
stage COVID-19 patients taking a 15-day regimen of resveratrol 
pus vitamin D3 to that for patients taking an identical placebo 
regimen. 
Secondary 
Objectives: 
Decrease morbidity and mortality in terms of reduced days of 
symptoms, reduced rate of ICU admission, reduced rate of 
mechanical ventilation, and reduced mortality. 
Endpoints: 
Primary 
Endpoint: 
Hospitalization rate 
Secondary 
Endpoints: 
ICU Admission rate, invasive ventilation 
rates, duration of symptoms, and mortality 
rates. 
Study 
Population: 
200 hundred patients (100 per group) 45 years and older who test positive for SARS-
COV2 who have mild COVID-19 based on WHO Baseline Severity Categorization 
Phase: 
2 
Description of 
Sites/Facilities 
Enrolling 
Participants: 
Outpatients presenting to COVID-19 testing sites of Mt Carmel Health Systems in 
Columbus, OH, which may include drive-thru testing centers, emergency departments, 
urgent care centers. 
Description of 
Study 
Intervention: 
Patients will be placed on a 15-day course of two 500 mg resveratrol capsules 4 times 
per day, versus the same dosing frequency of placebo.   Both groups will receive 
100,000 IU on day one only. 
Study Duration: up to 6 months 
Participant 
Duration: 
60 days 


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1.2 SCHEMA 
 
 
Screening
Prior to Enrollment
•Total n=200
•Review electronic report of newly positive SARS-CoV2 test results of patients 45 and older
•If old records are available, clinicians  to prescreen for exclusion criteria
•Contact potenially eligible participants by phone to discuss interest in study
•Patient referred to an online site to review a video discribing the study, risk, benefits.
•Patient given the opportunity to ask questions
•Obtain informed consent electronically
•Screen potential participants by inclusion and exclusion criteria
•Obtain history, document
Randomization
•Intervention Group 1 (n=100)
•Placebo (n=100)
Baseline Survey & Start treatment
Day1
•Patient take Vitamin D3 100,000 IU on day and starts treatment or placebo
•Patients will receive an baseline assessment using Patient-Reported Outcomes version of the 
Common Terminology Criteria for Adverse Events (PRO-CTCAE™).
Treatment or placebo and daily online survey
Day 2-15
•Participant to take 2 capsules of intervention or placebo 4 times per day for 15 days.
•Participant will receive a daily online survey to assess for signs and symptoms of COVID-19 and to report 
potential side effects.  If a patient has not completed an online survey within 24 hours, the patient will be 
contacted via phone to check their status.
Weekly PRO-CTCAE Survey
Day 8, 15, 21
•Patients will questionnaire with 7 day look back of adverse events based on the Patient-Reported Outcomes 
version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE™).
Follow-up assessments for efficacy
Between day 21-30
•Clinicians will perform a chart review to assess patient outcomes as well as contact patient for an exit interview 
via phone.
Long term assesment
Day 30 and Day 60
•Participant Completes PRO-CTCAE to evaluate for adverse events
Follow-up assessments of study endpoints and safety
Study Completion
•Data analysis
•Possible long term follow up of adverse events as outlined in section 8.3


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1.3 SCHEDULE OF ACTIVITIES (SOA) 
 
Day 30 & Day 60 - Final follow ups to assessement for adverse events
Particpant completes PRO-CTCAE (final look back of adverse events) 
Day 21 - Assessment for efficacy / Weekly Assessment of Adverse Events
Participant completes PRO-CTCAE (7 day look back of symptoms)
within 10 days research team assesses 21-day outcome (interview or 
chart review)
Day 16 - Complete treatment / Weekly Assessment of Adverse Events
Participant completes treatment
Participant completes PRO-CTCAE (7 day look 
back of symptoms
Safety Monitor reviews PRO-CTCAE results 
within 48 hours
Day 9- 15 - treatment continues
Participant continues treatment
Completes brief daily online survey of symptoms
Day 8 - Weekly Assessment for Adverse Events
Patient completes PRO-CTCAE (7 day look back of Sx)
Safety monitor reviews PRO-CTCAE results with 48 hours
Day 2-7 - treatment continues
Patients continues treatment
Completes brief daily online survey of symptoms
Day 1 or 2 - Patient receives study packet/supplies
Patient starts treatment 2 capsules 4x/day
Patient take Vitamin D3 100,000 IU on first day
if day 2, completes brief online survey
Day 1 Results Available
Results from previous day 
reviewed by research team
Potential participants 
contacted for consent
Randomization
Participants complete 
baseline PRO-CTCAE
Patient sent study 
packet/supplies


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2 INTRODUCTION 
2.1 STUDY RATIONALE 
Resveratrol (RV) is a polyphenol produced by plants in response to injury or infection.  It is found in 
grapes, peanuts, and other common foods. RV has been associated with a variety positive health effects 
in areas of inflammation, cardiovascular diseases, cognitive disease, cancer, diabetes, and infectious 
disease (Tomé-Carneiro, et al., 2013) (specifically including viral diseases (Abba, Hassim, Hamzah, & 
Noordin, 2015)). RV is readily available commercially as a plant extract and can be produced by 
genetically engineered yeast (Li, et al., 2015).   COVID-19 is the disease caused by a novel coronavirus 
(SARS-CoV2) that can result in life threatening complications, including lung injury and stroke.   While 
there are numerous trials investigating treatment options, there are no proven effective treatment 
options.  Multiple lines of preclinical data suggest that RV may be effective against coronavirus (See 
Figure 1). 
 
2.2 BACKGROUND 
Coronavirus (CoV) is characterized by surface spike proteins than bind to a region of the Angiotensin-
converting enzyme 2 (ACE2) of the respiratory tract. Binding to the ACE2 is required for entry into the 
affected cell and is dependent upon a transmembrane serine protease (TMPRSS2) (Hoffmann, et al., 
2020).  After entry into the cell a variety of processes occur, including the down regulation of ACE2 
(Kuba, et al., 2005) as well as the subsequent destruction of the pneumocyte.  The deficiency in ACE2 
caused by SARS is associated with lung injury (Yan, Xiao, & Lin, 2020).  Damage to the pneumocyte 
triggers the release of inflammatory mediators, and the subsequent release of cytokines (IL1, IL6, TNF-α) 
and reactive oxygen species.  While these effects are part of the host defense mechanism, the resultant 
inflammation is destructive to the alveoli.  A “cytokine storm” results in further damage to the alveoli 
and the development of Acute Respiratory Distress Syndrome (ARDS) (Mehta, et al., 2020). 
  
In addition to ACE2 being a binding site for CoV, it is also associated with protective effects in SARS 
induced lung injury (Nicholls & Peiris, 2005) (Gu, et al., 2016).  ACE2 may attenuate vascular 
permeability, inflammatory cell infiltration, pulmonary edema, hyaline membrane formation, and 
prevent acute lung injury (Yan, Xiao, & Lin, 2020).  RV has been shown to upregulate ACE2 (Moran, et al., 
2017).  The upregulation of ACE2 by RV may provide protective effects in COVID-19 (Imai, et al., 2005) 
(Yan, Xiao, & Lin, 2020) (Horne & Vohl, 2020) (Magrone, Magrone, & Jirillo, 2020). 
  
RV’s antiviral, anti-inflammatory, and antioxidant properties may be helpful in reducing the clinical 
effects of COVID. (See Figure 1). RV has demonstrated antiviral effects in a variety of animal and human 
disease (Abba, Hassim, Hamzah, & Noordin, 2015).  Specific to CoV, in vitro studies demonstrate that RV 
inhibits MERS-CoV infection by decreasing nucleocapsid protein resulting in reduced viral production 
and increased cell survival. (Lin, et al., 2017).  Starting at the first steps in the infection in silico modeling 
suggests that RV may interfere with the binding of CoV spike protein to the ACE2 receptor (Wahedi, 
Ahmad , & Sajjad , 2020) (Rane, Chatterjee, Kumar, & Ray, 2020). RV has been shown to downregulate 


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TMPRSS2 (Wilson, et al., 2017).  Noting that after CoV binds to ACE2, TMPRSS2 may be required to 
activate cell entry of CoV into the host cell (Shulla, et al., 2011), the downregulation of TMPRSS2 by RV 
could help reduce the infectivity of the virus.  In silco analysis also suggests that resveratrol may inhibit 
COVID-19 RNA Dependent Polymerase and Papain-like Protease (El-Aziz, Shehata, Awad, & El-Sohaimy, 
2020) (Ranjbar, Jamshidi, & Torabi, 2020) which could explain the inhibition of nucleocapsid protein 
described by Lin et al 2017. In silico analysis also demonstrates potential inhibition of the coronavirus 
main proteinase (Mpro) (Mishra, Pathak, & Tripathi, 2020) which would be additional mechanism of 
inhibiting viral replication. 
  
Coronavirus is associated with the potential for excessive inflammation.  CoV has been shown to 
activate Toll-Like Receptor 4 leading to an unbalanced inflammatory response and damaging 
inflammation (Olejnik, Hume, & Mühlberger, 2018).  RV has been demonstrated to inhibit TLR4 
activation (Sun, et al., 2018). CoV has been shown to increase pro-inflammatory cytokines IL-1, IL-6 
(Conti, et al., 2020), CCL5 (RANTES) (Patterson, et al., 2020) and TNF-α (Wang, et al., 2007).  Suppression 
of inflammation has been shown to be therapeutic in a variety of illnesses.  RV has been shown to 
reduce inflammation via a variety of mechanisms (Zhu, Lei, & Dong, 2017) including decreasing the 
release of inflammatory cytokines in the macrophages of patients with COPD (Culpitt, et al., 2003). RV 
has also been shown to inhibit the proinflammatory transcription factor NF-κB (Ren, et al., 2013) and 
inhibition of NF-κB has been shown to increase survival in a mouse model of SARS-COV1 (DeDiego, et al., 
2014). The anti-inflammatory effects of RV may be beneficial in mitigating the cytokine storm that is 
associated with ARDS and high mortality of COVID-19 (Mehta, et al., 2020). 
  
Oxidant stress is associated with viral infections. Inflammatory cytokines trigger the release of reactive 
oxygen species (ROS). Excessive release of ROS damages both infected as well as healthy cells and may 
play a role in heart and lung tissue damage in COVID-19. The use of antioxidants has been proposed in 
the treatment of COVID-19 (Wang & Zhang, 2020). RV’s antioxidant properties may provide additional 
outcome benefits. 
 
Prevention of lung injury would be a main treatment goal in COVID-19.  The cytokine storm associated is 
one of the main mechanisms on injury. Therefore, it is notable that a mouse model of cytokine storm 
showed a 100% mortality reduced to 0% in resveratrol treated mice with minimal lung injury in the 
treated group (Alghetaa, et al., 2018).  Furthermore, the cytokine storm of COVID-19 leads to ARDS.  A 
mouse model of ARDS uses lipopolysaccharide (LPS) as a model of ARDS caused by sepsis (Chen, Bai, & 
Wang, 2010).  RV has demonstrated protective effects in LPS induced lung injury (Hu, Chen, Li, Jiang, & 
Zhu, 2019) (Jiang, et al., 2016).  The proposal by Jaing is RV’s inhibition of NLRP3 inflammasomes. 
Inhibition of NLRP3 inflammasomes in another proposed therapeutic target in COVID-19 (Shah, 2020) 
(Yap, Moriyama, & Iwasaki, 2020). 
  
As the above discussion regarding RV’s effects are largely based on in vitro models of disease, there is 
always a concern regarding whether in vitro models will translate into in vivo efficacy. Multiple animal 
studies have shown that RV does improve outcomes in animal models of viral infections. A porcine 


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model of pseudorabies virus shows that piglets inoculated with the virus had no mortality at an orally 
administered RV dose of 30mg/kg (a dose comparable to an easily achievable human dose) compared to 
a 40% mortality in the untreated group. Specifically, that study showed alveolar destruction in the 
untreated group vs mild lung injury in the treated group.  The proposed mechanism is inhibition of IκB 
kinase  (Zhao, et al., 2018).  It is notable that a drug prediction analysis of SARS-CoV2 suggests that IκB 
kinase inhibition is a potential target for COVID-19 (Fagone, et al., 2020). Similarly, a murine model of 
H1N1 influenza showed dose dependent inhibition of viral replication and showed a 60% survival rate in 
RV treated mice compared to 20% in placebo treated mice (Palamara, et al., 2005). In Respiratory 
Syncytial Virus infected mice, RV treated mice showed significantly less lung damage compared to 
untreated mice (Zang, et al., 2011). 
  
Recently, case reports have described an increased risk of stroke associated with COVID-19.  This has 
been attributed to coronavirus attaching to ACE2 receptors of vascular endothelium leading to 
endothelial injury (Markus & Brainin, 2020) (Akshay Avula, 2020).  Excessive complement activation has 
been proposed as an additional mechanism of thrombotic microangiopathy and complement inhibition 
has been proposed as an adjunctive treatment to decrease the severity of COVID-19 (Campbell & 
Kahwash, 2020).  RV has been shown to inhibit complement activation in mice (Wu, et al., 
2015).  Activation of TLR4 by CoV may be the trigger associated with increased Platelet Activating Factor 
(PAF). RV has been show in inhibit PAF (Shigematsu, et al., 2003) which may be protective in the setting 
of cerebral ischemia (Lei, Tu, Wang, Tu, & Shi, 2019). RV has been associated with a variety 
vasoprotective effects (Das & Das, 2010) (Gracia-Sancho, Villarreal, Zhang, & García-Cardeña, 2010). One 
of the vasoprotective mechanisms reported is increased endothelial nitric oxide (Xia, Förstermann, & Li, 
2014). Nitric oxide is an antioxidant and signaling molecule that has been shown to inhibit viral 
replication, viral protein synthesis, and viral RNA synthesis in SARS-CoV (Åkerström, et al., 2005) 
(Åkerström, Gunalan, Keng, Tan, & Mirazimi, 2009). These mechanisms may decrease the risk of stroke 
in COVID-19. 
  
Given the scale of the health and economic impacts of COVID-19, any treatment that can reduce 
hospitalizations could have a significant impact in this pandemic. RV is generally recognized as safe and 
has been shown to have positive health benefits in human trials. Prior research in human trials related 
to lung disease, in vitro studies of RV for coronavirus, and animal studies of RV in other viral infections 
support investigating RV as a treatment for coronavirus disease (COVID-19) (see summary in Figure 1). 
Given that RV is readily available and could be cheaply scaled up through the fermentation of yeast, it is 
potentially a scalable solution to treat coronavirus disease. 
 
 
 


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2.2.1 FIGURE 1. – SUMMARY OF RESVERATROL EFFECTS ON VIRUS AND HOST 
 
 
 
 
 
 
 
Targets for Resveratrol
Inhibits Spike protein 
docking to ACE2 
receptor
Inhibits TMPRSS2
Inhibitis CoV entry 
into cell at ACE2
Mechanisms that 
directly inhibit 
the virus
Decreased viral 
nucelocapsid protein 
expression
Inhibit coronavirus 
production
Increase endothelial 
Nitric Oxide 
production
Inhibits coronavirus 
replication
vasoprotective
Mechanisms that 
may decrease risk 
of COVID 
associated stroke 
/ vascular injury
Inhibits Platelet 
Activitating Factor
Inhibition of the 
Complement System
Suppression of TLR4
Inhibition NF-κB
Increases survival in 
mouse model of SAR-
CoV1
Down regulation of 
IL-6 and TNF-α
Mechanisms that 
could prevent  
Cytokine Storm / 
ARDS
promotes 
antioxidant effects
Disruption of 
CCL5/RANTES
Upregulation of ACE2
Protects against 
severe acute lung 
injury
May adversely 
increase binding site 
for SAR-COV2
Inhibition on 
inflammasomes


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2.3 RISK/BENEFIT ASSESSMENT 
2.3.1 SAFETY AND DRUG INTERACTIONS 
 
To characterize toxicity, RV has been dosed at 200mg/kg/day in rats and 600mg/kg/day in dogs with no 
observed adverse effects (NOAEL) as measured by clinical observations, hematology, ophthalmology, 
cardiovascular, and neurotoxicity evaluation along with evaluation of organ weights, histopathology and 
gross pathology (Johnson, et al., 2011).  
 
While human clinical trials have shown RV to generally be safe and well tolerated at doses of up to 5g, 
dose related gastrointestinal upset has been reported (Ramírez-Garza, et al., 2018). There are some 
additional concerns of adverse effects based primarily on in vitro studies and animal models (Shaito, et 
al., 2020). High doses are associated with inhibition of cytochrome P450 (specifically CYP3A4, CYP2D6, & 
CYP2C9), which could result in some drug interactions, most concerning for drugs with a narrow 
therapeutic window. Drug interactions with nicardipine, warfarin, HIV protease inhibitors, anti-
arrhythmics, calcium cancel agonists, and antihistamines, and immunosuppressants have been reported 
in animal models (Shaito, et al., 2020). Hydroxychloroquine and chloroquine, drugs with narrow 
therapeutic window, are being investigated for use in COVID-19, are notably metabolized by CYP2C8 and 
CYP3A4. With the exception of a patient with multiple myeloma undergoing chemotherapy plus high 
dose RV who became dehydrated and developed renal failure (cast nephropathy), other studies of RV in 
humans have not shown adverse effects of hematologic, hepatic, thyroid, and renal functions (Tomé-
Carneiro, et al., 2013). 
 
Medication that have been reported in the literature as co-administered medications with resveratrol 
include amoxicillin, aspirin, atorvastatin, bortezomib, buspirone, caffeine, carbamazepine, 
cholinesterase inhibitors, dextromethorphan, DHA, EPA, epigallocatechin-3-gallate, inositol, 
hydroxychloroquine,  glibenclamide, lactoferrin, losartan, meloxicam, memantine, metformin, 
methotrexate, N-acetylcysteine, orlistat, Pegylated-Interferon-α2b, piperine,  prednisolone, PUFA, r-tPA 
(activase), Ribavirin, sulfasalazine, vitamin D3, as well as generic descriptions of the inclusion of “anti-
hypertensive drugs,” “anti-thrombotics,” “beta-blockers,” “glucose-lowering drugs,” “statins,” “NSAIDS,” 
and patient’s “usual medications”. 
 
Despite the extensive list of medications that have reportedly been co-administered with resveratrol 
there is little published information about reported adverse events/adverse interactions associated with 
these co-administered medications.  There are multiple reports of benefits/synergistic effects.  The 2 
most useful references for adverse events and drug interactions are “Drug Interaction Potential of 
Resveratrol” (Detampel, Beck, Krähenbühl, & Huwyler, 2012) and “Potential Adverse Effects of 
Resveratrol: A Literature Review” (Shaito, et al., 2020).  The source literature that is the basis of concern 
for CYP interactions is largely based on healthy volunteer studies in “Resveratrol Modulates Drug- and 
Carcinogen-Metabolizing Enzymes in a Healthy Volunteer Study” (Chow, et al., 2010) and “Effect of 


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Resveratrol on the Pharmacokinetics of Carbamazepine in Healthy Human Volunteers” (Bedada & 
Nearati, 2015) which measured an increase in carbamezapine levels when coadminstered with RV. 
 
Of the few relevant clinical trials that mention drug interactions, “Resveratrol Does Not Benefit Patients 
With Nonalcoholic Fatty Liver Disease” (Chachay, et al., 2014) uses 1500mg BID and states “Previous 
reports have discussed the potential for drug bioavailability interactions as a result of inhibition of the 
phase I drug metabolism enzyme CYP3A4 by resveratrol. No symptom attributed to drug metabolism 
was observed, and usual medication prescriptions remained unchanged.”  Likewise in “Resveratrol as an 
effective adjuvant therapy in the management of rheumatoid arthritis: a clinical study” (Khojah, Ahmed, 
Abdel-Rahman, & Elhakeim, 2018) uses 1000mg daily while subjects medications include “leflunomide, 
hydroxychloroquine, sulfasalazine, methotrexate, prednisolone, and various nonsteroidal anti-
inflammatory drugs” states "RSV dose administered without reported adverse events" 
 
As previously mentioned, RV upregulates ACE2 which has previously been shown to reduce 
inflammation and may be protective against ARDS. However, since ACE2 is also the binding site for 
SARS-CoV2, a controversial hypothesis was recently published suggesting that the upregulation of ACE2 
by blood pressure medication ACE Inhibitors (ACEI) and Angiotensin Receptor Blockers (ARBs) may 
increase the risk of infection (Fang, Karakiulakis, & Roth, 2020). This has been countered by a position 
statement from the European Society of Cardiology (ESC) that states that there is evidence in animal 
models showing that ACEI and ARBs may be protective in COVID-19 and there are no human evidence 
showing harm. ESC recommends patients continue ACEI and ARBs (European Society of Cardiology, 
2020). There is early evidence is human that ACEI and ARBs may be protective in COVID-19 infection 
(Sanchis-Gomar F, 2020). On March 17, 2020, the American Heart Association, the Heart Failure Society 
of America, and the American College of Cardiology put out a joint statement advocating for patients to 
continue ACEIs and ARBs as prescribed and that changes in medications in the setting of COVID-19 
should be completed only after careful assessment (American Heart Association, 2020).  More recently 
ACEI and ARBs use has been associated with improved clinical outcomes in COVID-19 patients (Meng, et 
al., 2020). 
2.3.2 KNOWN POTENTIAL RISKS 
There are some concerns of adverse effects based primarily on in vitro studies and animal models 
(Shaito, et al., 2020).  While human clinical trials have shown RV to generally be safe and well tolerated 
at single oral doses of up to 5g, dose related gastrointestinal upset has been reported (Ramírez-Garza, et 
al., 2018). High doses are associated with inhibition of cytochrome P450 (specifically CYP3A4, CYP2D6, & 
CYP2C9), which could result in some drug interactions, most concerning for drugs with a narrow 
therapeutic window. Drug interactions with nicardipine, warfarin, HIV protease inhibitors, anti-
arrhythmics, calcium cancel agonists, antihistamines, and immunosuppressants have been reported in 
animal models (Shaito, et al., 2020). Hydroxychloroquine and chloroquine, drugs that are being 
investigated for use in COVID-19, are notably metabolized by CYP2C8 and CYP3A4. RV has been reported 
to enhance the replication of Hepatitis C virus in vitro (Nakamura, et al., 2010). 
 


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Noting that RV is associated with upregulation of ACE2 and ACE2 is the binding site for SARS-CoV2, 
increased ACE2 may facilitate viral entry into the cell (Yan, Xiao, & Lin, 2020). 
2.3.3 KNOWN POTENTIAL BENEFITS 
• 
RV may inhibit binding of SARS-CoV2 to the ACE2 receptor which would inhibit viral entry 
• 
RV inhibits TMPRSS2 which could inhibit viral entry into the cell 
• 
RV may inhibit viral protein synthesis, viral RNA synthesis, and viral productions 
• 
RV increases Nitric Oxide (NO), which may independently inhibit viral replication 
• 
RV may be protective from COVID associated stroke by: 
o inhibits Platelet Activating Factor (PAF)  
o inhibiting complement activation 
o vasoprotective effects of nitric oxide 
• 
RV upregulate ACE2 receptor which has been shown to be protective of lung injury 
• 
RV may protect against the effects of the “cytokine storm” storm of COVID-19 by: 
o Inhibiting TLR4 
o Inhibiting NF-κB 
o Inhibiting IL-6 
o Inhibiting TNF-α 
o Inhibiting CCL5 (RANTES) 
o Antioxidant effects 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS 
The main risk of the proposed treatment in prior human studies is GI upset from resveratrol and a 
theoretical increase risk of infection by coronavirus.  GI upset/diarrhea could lead to dehydration and 
potentially increased risk of renal injury. This is countered by the multiple mechanisms that could prove 
beneficial in COVID-19. 


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3 OBJECTIVES AND ENDPOINTS 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
Reduction in hospitalization rates. 21-day hospitalization or death, 
defined as admission to any hospital 
for the treatment of COVID-19, or 
death, within 21 days of 
randomization for this study (date of 
randomization = day 0). 
Based on reported typical 
course of illness for COVID-19 
most patients will have 
declared their need for 
hospitalization in less than 21 
days 
Secondary 
Reduction in ICU admission 
invasive ventilation rates, and 
ECMO usage rates 
ICU admission or death, defined as 
admission to any intensive care unit 
(ICU) due to worsening symptoms of 
COVID-19, or death, among patients 
who are hospitalized within 21 days 
of randomization (date of 
randomization = day 0). 
Invasive ventilation or death, 
defined as ventilatory support which 
requires insertion of an 
endotracheal tube, or death. 
ECMO usage or death, defined as the 
usage of extracorporeal membrane 
oxygenation machine as an 
alternative for the management of 
respiratory failure, or death. 
Based on reported typical 
course of illness for COVID-19 
most patients will have 
declared their need for ICU 
admission/invasive 
ventilation/ECMO usage in 
less than 21 days 
Tertiary/Exploratory 
Reduction in morbidity and 
mortality 
Reduction in signs and symptoms 
based on results of daily surveys. 
Will also observe mortality rates 
between groups. 
There are mechanisms that 
would suggest improvements 
in morbidity and mortality, 
but this study will likely not 
have the statistical power to 
draw firm conclusions. 


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4 STUDY DESIGN 
4.1 OVERALL DESIGN 
This study will be a phase 2, double-blind, placebo-controlled, randomized trial to evaluate the safety 
and explore the efficacy of resveratrol plus vitamin D3 based on the hypothesis that resveratrol with the 
adjuncts can reduce hospitalization rates of patient with COVID-19. 
  
Patient Screening and Consent: Potential subjects will present to the Mount Carmel Health System’s 
Emergency Departments, drive through testing stations, or other affiliated ambulatory testing center 
and undergo testing for SARS-CoV-2 following currently established guidelines and process. Upon 
confirmation of initial eligibility, research personnel will contact the patient via phone and briefly 
explaining the study.  For patients that express interest in learning more about the study, they will be 
provided with a website linking to an animated video explaining the study’s purpose, risks, and benefits 
of the trial (see Appendix 12.5 for link to video).  If the patient expresses their interest in participating in 
a COVID-19 trial, they will then have a phone discussion with research personnel to complete 
verification of all inclusion and no exclusion criteria. If the patient meets any exclusion criteria, they will 
be thanked for their time and entered into the study screening log.  Patients meeting all inclusion and 
no exclusion criteria will be consented for participation in the trial. The consent process will request 
access to their health information that is part of any healthcare provider or outpatient visit, or 
hospitalization that occurs during the 60-day study period. Upon consent, designated personnel will 
arrange pickup or delivery of the next numbered study agent packet.  Participant will be provided 
written and online video explanation of the study regimen.  
  
Treatment Concealment:  Due to reports of patients self-medicating with investigational drugs (e.g., 
chloroquine) in the setting of COVID-19, we do not intend to reveal the trial substance until after the 
study is complete.   Patients will be informed that they are receiving a “commercially available dietary 
supplements” which will be described as a “plant extract” that is commonly found in a variety of foods, 
but the use of RV will not be disclosed.  The use of Vitamin D3 will be open-label for both groups.  At the 
end of the study, they will be informed of which study agent they received. 
  
During the enrollment process and after providing consent to participate, subjects will complete a short, 
online form providing their contact information.  Subjects will also be asked to provide the contact 
information of a spouse, family member or other person in the event the investigator or study personnel 
lose contact with the subject, so that the subject’s status can be determined.  The online form is HIPAA-
compliant and meets HIPAA regulations for data security.  Completion of the form will generate an 
anonymous study ID associated with that subject and which will be used for other study-related data 
collection.  The study ID does not use any HIPAA-designated identifiers such as birthdate, social security 
number, etc. 
  
Randomization:  The random allocation list will be blocked and stratified by a third-party group or 
individual.  During the trial, only the third-party group and DSMB will have access to the randomization 


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list, which will be stored on a password-protected computer and/or password-protected file (e.g., 
REDCap, Excel) by the third-party group or individual.  The study personnel will create identical-looking 
packets with identical-appearing study agents containing a 15-day dosing regimen according to the 
random allocation list.  Study personnel will be blinded to the contents of the distributed packets. 
  
Participant Monitoring and Follow-up:  Starting on day 1, and continuing daily for 15 days, subjects will 
be contacted via e-mail or text message (according to the subject’s preference.  Messages will include a 
reminder to take their study medication as scheduled and complete the daily survey (see appendix 
12.6.1) each evening prior to going to bed.  Subjects will be asked to complete a short questionnaire 
covering: 1) symptoms they had that day that may be related to COVID-19 (e.g., fever, cough, dyspnea), 
their frequency and severity; 2) report any other related or non-related medical events;  3) any 
medications they have taken to relieve symptoms, or other new medications they have not previously 
reported to study personnel; and 4) any visits they have made to healthcare providers, outpatient 
centers or hospitals, and details regarding those visits.  Subjects will be reminded to contact their 
primary care physician if they experience symptoms that are worsening or that are concerning to 
them.  For any such contact, they should inform their physician or other healthcare provider that they 
are enrolled in a clinical trial involving a dietary supplement. 
  
Participants with complete on online PRO-CTCAE questionnaire on days 1, 8 (+1 day), 15 (+1 day), 21 (+1 
day), 30, and 60 to monitor for adverse events. 
  
Subjects who do not complete questionnaires will receive a reminder Xe-mails.  All patients will be 
called for a phone interview after 21 days.  If subjects cannot be contacted via phone, study personnel 
will attempt to contact the spouse/family member/friend who is listed as the secondary contact in order 
to determine the subject’s status.  A subject will be considered lost to follow-up if their status 
concerning hospitalization during the study period cannot be verified. 
  
Outcome Assessment and Other Key Variables.  Hospitalizations will be determined based on query of 
subject and/or the subject’s secondary contact.  The subject’s medical records will be requested from 
the admitting hospital (and discharging hospital, if separate) via a HIPAA authorization. 
  
Additional outcomes will include assessing number of days with fever and to assess symptoms, including 
dyspnea and fatigue.    Questionnaires to assess symptoms will be based on the PRO-CTCAE (see 
appendix 12.6) (National Cancer Institute, 2020). 
  
Conditions that the CDC defines as being high risk for developing severe COVID-19, and pertinent 
medications will be recorded.  Given the prior safety history of RV and given the potential risks to 
healthcare workers exposed to COVID-19 patients, we do not intend to obtain laboratory studies as part 
of this trial.   
  


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Assessment for Blinding Integrity and Treatment Adherence.  Patients will be asked if they thought they 
received resveratrol or placebo at 21 (±2) days after enrollment.  Patients will be asked report the 
number of remaining capsules at end of day 16.   
 
4.2 SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
There is no established standard of care for COVID-19 prior to hospitalization. Therefore, this study 
seeks to establish superiority of the study intervention over a placebo. Due to the previously established 
safety and tolerability of the study intervention, limited sample size, and time pressure during the 
COVID-19 pandemic, no dose-response study will be performed at this time. 
4.3 JUSTIFICATION FOR DOSE 
 
STUDY AGENT:  RESVERATROL 
Human clinical trials of RV have used a wide range of dosages (from 10mg to 5g).  RV is generally well 
tolerated with few side effects reported (notable exception being worse outcome in multiple myeloma 
treatment given a high (single daily 5g) dosage associated with diarrhea/dehydration/renal injury) 
(Berman, Motechin, Wiesenfeld, & Holz, 2017).  An in vitro study of CoV has shown half maximal 
inhibitory concentration (IC50) of RV as 5.5 µg/ml (Zhang, 2015). While RV is well absorbed, there 
notably is extensive first pass intestinal and hepatic metabolism of RV. In a study of a single 500mg dose 
of RV, serum plasma concentration of free-RV reached an average of only 71ng/ml while sulfated-RV 
reached an average 1516 ng/ml and glucuronated-RV reached 4083 ng/ml (Sergides, Chirilă, Silvestro, 
Pitta, & Pittas, 2016).  The in vitro study showing an IC50 of 5.5 µg/ml (5500 ng/ml) cited above referred 
to unmetabolized RV. It is unclear to what extent sulfated and glucuronated forms of RV would be 
metabolically active in vivo against CoV. If only the free form RV is metabolically active against CoV it 
would be difficult to achieve adequate blood levels to accomplish viral inhibition.    Recent molecular 
modelling of RV derivatives support the concept that glucuronated-RV would be biologically active 
against SARS-CoV2 by inhibition of papain-like protease and RNA-dependent RNA polymerase.  
Furthermore, the binding affinity of glucuronated-RV was demonstrated to be superior to the free form 
of RV (Ranjbar, Jamshidi, & Torabi, 2020).  Considering that human trials have shown benefit in even 
small (10mg) dosing of RV (Berman, Motechin, Wiesenfeld, & Holz, 2017) it would be reasonable to 
hypothesize that sulfated and/or glucuronated RV are (directly or indirectly, see below) biologically 
active.  In vitro studies have demonstrated that glucuronated RV to be comparably biologically active 
(Lu, et al., 2013). Tissue concentration of RV is not well understood, but one study of the IV volume of 
distribution suggested significant extravascular distribution, and a mouse study showed preferential 
accumulation is tissues (Walle, 2011). Furthermore, it has been suggested that human tissue sulfatases 
and glucuronidases may locally convert the conjugates back to free-RV (Walle, 2011).  The half-life of 
free-RV is measured at 5 hours, while the half-life of sulfated and glucuronated RV are both about 8 
hours (Sergides, Chirilă, Silvestro, Pitta, & Pittas, 2016).   


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The dosing schedule planned for this study is based on attempting to maximize the plasma levels (and 
presumably tissue levels) of resveratrol in order to attempt to approach or exceed the minimum 
inhibitory concentration of the resveratrol against SARS-CoV2.  There are not any reported toxic plasma 
levels associated with orally administered resveratrol.  The main limiting factor in the dosing is the 
concern for GI side effects which is infrequent at doses of 1gm or less (Almeida, et al., 2009) (Boocock, 
et al., 2007) (Brown, et al., 2010).  This goal of viral inhibition is in addition to the anti-inflammatory host 
benefits. 
Prior pharmacokinetic studies have consistently shown low plasma levels of unconjugated RV, with 
substantially higher levels of sulfated-RV and glucuronidated-RV.  The Area Under the Curve (AUC) for 
glucuronidated-RV is inconsistent in the literature. (Boocock, et al., 2007) (Brown, et al., 2010) (Sergides, 
Chirilă, Silvestro, Pitta, & Pittas, 2016).  There is evidence that the glucuronidated-RV is equally 
biologically active (Lu, et al., 2013). The is also in vivo evidence that sulfated-RV can serve as a reservoir 
for unconjugated RV via intracellular sulfatases (Patel, et al., 2013). 
Estimates of steady state concentration (Css) are based on prior pharmacokinetic studies of Area Under 
the Curve (AUC) divided by the dosing frequency planned for this study (Css=AUC/ τ) noted below (see 
Table 1).  Prior literature has shown a consistent measurement in the measurement of unconjugated RV, 
but a wide range of measured resveratrol conjugates.  Boocock and Brown measured AUC for 0.5, 1.0, 
2.5, and 5gm dosages (Boocock, et al., 2007) (Brown, et al., 2010).  Sergides measures AUC based on a 
single 500mg dose (Sergides, Chirilă, Silvestro, Pitta, & Pittas, 2016). Bioavailability of RV Glucuronide 
from Sergides, et al notably is a magnitude higher than reported by Boocock or Brown.  Based on a 1gm 
dosage every 6 hours, Css for unconjugated RV will range from 84 ng/ml (Brown), to 91 ng/ml (Boocock), 
to 70 ng/ml (extrapolated from Sergides).  Considering that the RV conjugates are expected to be 
biologically relevant it worth noting that the cumulative Css of RV (including unconjugated, sulfonated, & 
glucuronidated RV) could range from 2638 ng/ml (Brown) to 2708 ng/ml (Boocock), possibly up to 
18,500 ng/ml based on extrapolation on the Sergides data.   
Assuming RV conjugates are biologically active against SARS-CoV2, the Sergides data suggests that 4gm 
daily dosing will exceeded the IC50.  The Brown and Boocock data suggest that the oral dosing would 
not exceed the IC50 of coronavirus. 
 


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TABLE 1: AUC & estimated Steady State Serum Concentration 
 
*Sergides did not differentiate glucuronidated RV forms 
 
STUDY AGENT: VITAMIN D3 
Vitamin D3 (D3) is a fat-soluble vitamin used in this study to enhance the anti-inflammatory effects of 
RV.  While D3 is known for its role in calcium and phosphorus regulation, there is also evidence that it 
has roles in immunity, inflammation, and cardiovascular health (Maity, Bora, & Sur, 2018).  Vitamin D 
has a role of providing innate immunity including the production of the antimicrobial cathelicidin in 
respiratory epithelial cells (Hansdottir, et al., 2008).  Supplementation of D3 is associated with a 
decrease in the incidence of viral respiratory infections (Gysin, Dao, Gysin, Lytvyn, & Loeb, 2016). 
Specific to this study, D3 has been shown to have a synergistic effect with RV and magnifies RV’s effect 
on the inhibition of IL-6 and TNF-α (Maity, Bora, & Sur, 2018) which may play a significant role in the 
cytokine storm of COVID-19. 
 
D3 deficiency is common worldwide.  D3 levels of 30-50ng/ml can modulate inflammatory activities 
(Zhang, et al., 2012). A single dose of D3 at 100,000 IU (2500mcg) has been shown to reach a mean 
concentration of 42 ± 9 ng/ml in healthy volunteers. (Ilahi, Armas, & Heaney, 2008) which would be 
consistent with a level adequate enough to have anti-inflammatory benefits. Vitamin D toxicity is rate 
Total Daily dose in gm
unconjugated RV
4'O glucuronide RV
3'O glucuronide RV
Sulfate RV
Cumulative RV 
Measurements in 
ng/ml 
AUC 1gm (Brown) 
503 
3774 
2087 
9464 
15828 
Css 6hr dosing 
4 
84 
629 
348 
1577 
2638 
AUC 1gm (Boocock) 
544.8 
3059 
2589 
10053 
16245.8 
Css 6hr dosing 
4 
91 
510 
432 
1676 
2708 
AUC 0.5gm (Brown) 
175 
1331 
875 
3558 
5939 
Css 6hr dosing 
2 
29 
222 
146 
593 
990 
 
AUC 0.5gm (Boocock) 
224 
1919 
1287 
4049 
7479 
Css 6hr dosing 
2 
37 
320 
216 
675 
990 
 
AUC 0.5gm (Sergides) 
154 
    33535* 
12050 
45739 
Css 6hr dosing 
2 
26 
      5589* 
2008 
7623 


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and has been defined by serum levels of >150ng/ml.  A daily dose of up to 10,000 IU per day has been 
described at the upper limit for supplementation in adults (Holick, et al., 2011). Single doses of up with 
2,000,000 units (in an accidental overdose) has been well tolerated (Ouweland, Fleuren, Drabbe, & 
Vollaard, 2014). 
 
Both treatment group and placebo group will receive a single 100,000 IU D3 to differentiate the effects 
of RV from potential beneficial effects of D3.  The use of D3 will be open label for both groups. 
 
4.4 END OF STUDY DEFINITION 
 
A participant is considered to have completed the study after they have completed a minimum of 7 days of 
treatment, noting patient will be permitted to discontinue treatment after having 3 days of resolution of fever, 
fatigure, and dyspnea and they has been followed up with 60 days of enrollment by way of completing the last 
online survey, exit interview and/or chart review. 
The study is considered complete after the last enrolled participant has completed the study. 


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5 STUDY POPULATION 
5.1 INCLUSION CRITERIA 
The World Health Organization has categorized baseline severity (see table 1).  For this study we will be 
targeting Mild COVID-19 based on their initial ability to be managed as an outpatient and known 
estimates for admission rates.  Patients who test positive but are asymptomatic (such as being tested for 
contact tracing) will be excluded from the study as there are no defined estimated for admission rates 
for asymptomatic patients (patients who become symptomatic can be considered for enrollment).   
 
Furthermore, patients age 45 and greater will be selected for this study due to their higher admission 
rates.  In order to be able to detect a difference in treatment efficacy, a population with a higher 
admission rate is desirable in order keep the sample size (and its associated cost) down.  Noting that, in 
general, the younger population is more social and may have higher rates of infection, but lower rates of 
admission including younger age patients in the study would likely skew the population to a low 
hospitalization rate with resultant difficulty detecting a difference between groups.  In addition, in order 
to avoid unnecessary testing and exposure of healthcare workers to patients with COVID-19, pregnancy 
will be assessed via self-report of pregnancy potential and report of last menstrual period.  The risk of 
pregnancy will be low in this age group. 
 
Patient must test positive for SARS-CoV2 based on an FDA approved test.  Due to low false positive rates 
and to minimize risk to healthcare providers, minimize the use of PPE and discomfort to the patient, 
repeat confirmatory testing will not be utilized. 
• 
Outpatients in Central Ohio 
• 
Age ≥45 years 
• 
Mild COVID-19 based on WHO Baseline Severity Categorization (see Table 1) 
• 
Symptom duration ≤ 7 days  
• 
Patient must have access to the internet or a smartphone to complete surveys 
• 
English-speaking patients 
 
Table 1:  Baseline Severity Categorization 
Disease Severity 
Description 
SARS-CoV-2 Infection 
without Symptoms 
• 
Positive testing by standard reverse transcription polymerase chain 
reaction (RT-PCR) assay or equivalent test 
• 
No Symptom 
Mild COVID-19 
• 
Positive testing by standard RT-PCR assay or equivalent test 
• 
Symptoms of mild illness could include fever, cough, sore throat,  
• 
malaise, headache, muscle pain, gastrointestinal symptoms,  
without shortness of breath or dyspnea 
• 
No clinical signs indicative of Moderate, Severe, or Critical Severity 


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Moderate COVID-19 
• 
Positive testing by standard RT-PCR assay or equivalent test 
• 
Symptoms of moderate illness, which could include any symptoms  
of mild illness or shortness of breath with exertion 
• 
Clinical signs suggestive of moderate illness with COVID-19, such  
as respiratory rate ≥ 20 breaths per minute, saturation of oxygen (SaO2) 
>93% on room air at sea level, heart rate ≥ 90 beats per  
minute 
• 
No clinical signs indicative of Severe or Critical Severity 
Severe COVID-19 
• 
Positive testing by standard RT-PCR assay or equivalent test 
• 
Symptoms suggestive of severe systemic illness with COVID-19,  
which could include any symptoms of moderate illness or shortness  
of breath at rest, or respiratory distress 
• 
Clinical signs indicative of severe systemic illness with COVID-19, such as 
respiratory rate ≥ 30 breaths per minute, heart rate ≥ 125 beats per 
minute, saturation of oxygen (SaO2) <93% on room air at sea level or 
PaO2/FiO2 <300 mmHg 
• 
No criteria for Critical Severity 
Critical COVID-19 
• 
Positive testing by standard RT-PCR assay or equivalent test 
• 
Evidence of critical illness, defined by at least one of the following: 
• 
Respiratory failure defined based on resource utilization requiring at 
least one of the following: endotracheal intubation and mechanical 
ventilation, oxygen delivered by high flow nasal cannula (heated, 
humidified, oxygen delivered via reinforced nasal cannula at flow rates > 
20 L/min with fraction of delivered oxygen ≥ 0.5), noninvasive positive 
pressure ventilation, ECMO, or clinical diagnosis of respiratory failure 
(i.e., clinical need for one of the preceding therapies, but preceding 
therapies not able to be administered in setting of resource limitation) 
• 
Shock (Defined by systolic blood pressure <90mmHg, or diastolic blood 
pressure <60 mmHg or requiring vasopressors) 
• 
Multi-organ dysfunction / failure 
Source:  WHO R&D Blueprint novel coronavirus 
5.2 EXCLUSION CRITERIA 
• 
Diagnosed or suspected cognitive impairment that would prevent the patient from cooperating with 
study procedures, as judged by the screening clinician. 
• 
Asymptomatic patients (e.g. patients who were screened without symptoms but tested positive). 
• 
Known history of cirrhosis, hepatic impairment, or Hepatitis C 
• 
Known of history of renal impairment as measured by an eGFR of < 60 mL/min. 
• 
Patients receiving chemotherapy or who are on chronic immunosuppressants. 
• 
Allergy to grapes or rice. 
• 
Co-morbidities with a high likelihood of hospitalization within 30 days (e.g., current cancer 
treatment, severe COPD or CHF) 
• 
Currently pregnant 


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• 
Hospitalization 
• 
Co-administration of “statins” and PDE-5 inhibitors must be withheld while on study treatment (see 
section 6.5). 
• 
Due to concerns of patients taking immunosuppressants and drug interactions in medications with a 
narrow therapeutic index the use of the the following medications will be exclusionary (Blix, Viktil, 
Moger, & Reikvam, 2010) (Shaito, et al., 2020).  
Immunosuppressants 
Generic Name Common Examples 
    
"Blood Thinners" / NOACs 
warfarin Coumadin 
rivaroxaban Xarelto 
apixaban Eliquis 
dabigatran Pradaxa 
HIV Protease Inhibitors 
atazanavir  Reyataz 
darunavir  Prezista 
fosamprenavir  Lexiva 
indinavir  Crixivan 
lopinavir/ritonavir Kaletra 
nelfinavir  Viracept 
ritonavir  Norvir 
saquinavir  Invirase 
tipranavir  Aptivus 
atazanavir/cobicistat  Evotaz 
darunavir/cobicistat Prezcobix 
Immunosuppresants 
Janus Kinase Inhibitors 
tofacitinib  Xeljanz 
Calcineurin Inhibitors 
cyclosporine Neoral, Sandimmune, SangCya 
tacrolimus Astagraf XL, Envarsus XR, Prograf 
mTOR inhibitors 
sirolimus  Rapamune 
everolimus  Afinitor, Zortress 
IMDH inhibitors 
azathioprine Azasan, Imuran 
leflunomide Arava 
mycophenolate  CellCept, Myfortic 
Biologics 


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abatacept Orencia 
adalimumab Humira 
anakinra Kineret 
certolizumab Cimzia 
etanercept Enbrel 
golimumab Simponi 
infliximab Remicade 
ixekizumab Taltz 
natalizumab Tysabri 
rituximab Rituxan 
secukinumab Cosentyx 
tocilizumab Actemra 
ustekinumab Stelara 
vedolizumab Entyvio 
Monoclonal Antibodies 
basiliximab  Simulect 
daclizumab  Zinbryta 
other 
hydroxychloroquine Plaquenil 
chloroquine Aralen 
Seizure medications 
carbamazepine Tegretol 
phenobarbital Luminol 
phenytoin Dilantin 
valproate Depakote 
Cardiac medications 
amiodarone Cardarone, Pacerone 
digoxin Lanoxin 
flecainide Tambocor 
sotalol Betapace 
Psychiatric medications 
lithium Eskalith 
  
Pulmonary medications 
theophylline Elixophyllin, Theochron 
  
Antibiotics 
rifampin Rifadin, Mycobutin 
 


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5.3 LIFESTYLE CONSIDERATIONS 
During this study, participants will be asked to: 
• 
Discontinue/avoid any dietary supplements not prescribed by their usual healthcare providers 
• 
Women of child-bearing potential will be asked to take a home pregnancy test (provided) prior 
to the start of the study intervention and report the results via online survey.  They will also be 
also be asked to use some form of contraception during the 15-days they are on the study 
treatment. 
5.4 SCREEN FAILURES 
Screen failures are defined as participants who consent to participate in the clinical trial but are not 
subsequently randomly assigned to the study intervention or entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure participants, to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, screen 
failure details, eligibility criteria, and any serious adverse event (SAE). 
 
Individuals who do not meet the criteria for participation in this trial (screen failure) because of a lack of 
symptoms at the time they tested positive (e.g. tested positive for contact tracing purposes, but was 
asymptomatic at the time of screen) may be rescreened if symptoms develop. Rescreened participants 
should be assigned the same participant number as for the initial screening. 
 
5.5 STRATEGIES FOR RECRUITMENT AND RETENTION 
An IRB approved HIPAA waiver will allow for recruitment by contacting patients who test positive for 
SARS-CoV2 and directly providing information about the trial to the potential participant.  All potential 
participants will be screened for capacity to consent by a study clinician. 
Retention will be facilitated by daily reminder emails/surveys and phone calls to participants who do not 
respond to the online survey. 
Dose reduction to 1 capsule 4 times per day will be offered to patients considering withdrawing due to 
GI side effects or who rate their diarrhea as frequently or higher on the PRO-CTCAE 5 point scale. 


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6 STUDY INTERVENTION 
6.1 STUDY INTERVENTION(S) ADMINISTRATION 
6.1.1 STUDY INTERVENTION DESCRIPTION 
Chemistry, Manufacturing, and Control: 
Study Agent: Resveratrol 
Established Name:  Trans-Resveratrol 
Trade Name: Vita-Age 98% Pure Trans Resveratrol 
Manufacturer by Vita-Age, 505-938 Howe Street, Vancouver, B.C. V6Z 1N9, 
Canada under Good Manufacturing Practices (GMP) 
Extracted from Japanese Knotweed Root 
Dosage Form:  Relabeled bottled containing size 00 capsules of resveratrol 
from commercially available bottles. Labeling with reflect the route of 
administration for this study. 
Strength:  500mg resveratrol per capsule 
Route of Administration: 2 oral capsules 4 times per day 
Lot Number for resveratrol raw material: U-F-HZ20200110 (88260-1)  
Certificate of Analysis #1 by Vita-Age (see appendix 12.1.2a) 
Lot Number for prepared capsules:  20680  
Certificate of Analysis #2 for prepared capsules by Labs-Mart Inc, 1938 94 Street NW, Edmonton, AB, 
Canada (see appendix 12.1.2b) 
PubChem CID for resveratrol:  445154 https://pubchem.ncbi.nlm.nih.gov/compound/Resveratrol 
Product Label in English (see appendix for full label):  
 
 
 
 
Resveratrol 


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Study Agent: Placebo 
Established Name:  Placebo 
Manufacturer by Vita-Age, 505-938 Howe Street, Vancouver, B.C. V6Z 1N9, Canada under Good 
Manufacturing Practices (GMP) 
Dosage Form:  Size 00 capsules containing brown rice flour (sourced from Moore’s Flour Mill, 6150 Mill 
Lane, Redding, CA 96002) to be prepared to be visually indistinct from the treatment capsules.  Rice 
starch is Generally Recognized as Safe (GRAS) NTIS# PB80128804 
Route of Administration: 2 oral capsules 4 times per day 
Lot Number of brown rice flour:  041620  
Certificate of Analysis for Stabilized Brown Rice Flour (see appendix 12.2.1). 
Lot Number of prepared capsules:  20677 
Certificate of Analysis for prepared Placebo Capsules (see appendix 12.2.2) 
 
Study Agent:  Vitamin D3  
Established Name:  Cholecalciferol 
Manufacturer:  Ortho Molecular Products, 1991 Duncan Place, 
Woodstock, IL 60098. 
Dosage Form:  50,000 I.U.   
Route of Administration: Two capsules once (100,000 IU total), orally on 
day 1 of the study provided in factor sealed blister pack. 
Batch Number:  WIP LOT# 83654 
Certificate of Analysis:  See Appendix 12.3.3 
PubChem CID for Cholecalciferol:  5280795 
https://pubchem.ncbi.nlm.nih.gov/compound/5280795 
Product Label:  
 
 
 
 
 
Cholecalciferol 


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6.1.2 DOSING AND ADMINISTRATION 
 
Treatment Group:  Two capsules containing resveratrol 500mg each will be taken 4 times per day.  A 15-
day supply of 120 capsules in manufacturer sealed bottles.  Instruction to keep out of reach of children.  
Placebo Group: 
Placebo group will be administered as two size 00 capsules (that are similar in appearance to the 
treatment capsules) to be taken 4 times per day.  A 15-day supply of 120 capsules in manufacturer 
sealed bottles.  Instruction to keep out of reach of children. 
Both Groups: 
Both groups will take a single 100,000 IU dose of Vitamin D3 on day 1 of the study, supplied as two 
50,000 IU capsules contained in factor sealed blister packs.  The use of D3 will be open label for both 
groups. 
 
6.2 PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
The investigator (or designated study personnel) is responsible for ensuring adequate accountability of 
study drug. This includes acknowledgement of receipt of each shipment of study drug (date, quantity, 
and condition), and subject dispensing records. Study dispensing records will document the dispensing 
of the study drug to individual subjects including the date dispensed, subject ID number, and initial of 
the person dispensing the study drug.  Due to concerns of coronavirus contamination, unused study 
supplies will not be accepted for return and will be disposed of by the participant. 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
How Supplied:  Participants will receive a manufacturer sealed bottle containing 120 capsules each (15-
day supply) of the study agent capsules. Each size 00 capsule will contain either placebo (brown rice 
flour) or 500mg resveratrol (Vita-Age, Vancouver, BC, Canada).  
 
6.2.3 PRODUCT STORAGE AND STABILITY 
Storage at room temperature.  Keep out of exposure to sunlight.  Stability ≥ 2 years. 
6.2.4 PREPARATION 
Unmodified commercially available RV capsules and manufacturer prepared placebo capsules contained 
in manufacturer sealed bottles will be re-labelled with the study instructions.  The bottles that have 
been prepared with study instruction will be turned over to an independent statistical consulting service 
(professors from Capital University department of Mathematics, Computer Science, and Physics) who 
will prepare the randomization table.  Steps will be put in place to temporarily differentiate placebo vs 
RV bottles.  Tamper-resistant serialized (sequentially numbered) stickers will be assigned to placebo or 
RV and affixed to the appropriate bottles.  Bottles will be returned to the research team differentiated 


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only by their unique serial number.  The randomization table will be kept by OSU’s consulting service 
and forwarded to the DSMB.  The research team will only get access to the randomization list only after 
the completion of the study. 
 
6.3 MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
After receipt of the intervention supplement and placebo, the third-party group will manage the 
randomization table.  Research staff will be blinded to the randomization process.   
 
6.4 STUDY INTERVENTION COMPLIANCE 
Participants will document their compliance daily. 
Noting that many patients will have a short duration of symptoms (in order to avoid unnecessary side 
effects), patients will be allowed to discontinue treatment after a minimum of 7 days if they have been 
symptom free for 3 days.  Completion of a minimum of 7 days of treatment whose symptoms have 
resolved will be consider compliant with treatment. 
In case of a single missed dosage, patient will be asked to divide the 2 missed capsules amongst their 
next 2 dosages.  Patient is not to take more than 3 capsules at a time, and no more than 9 capsules in a 
day. 
At the end of the study, participants will report the number of remaining capsules in their bottles at the 
end of 15 days. 
 
6.5 CONCOMITANT THERAPY 
For this protocol, a prescription medication is defined as a medication that can be prescribed only by a 
properly authorized/licensed clinician. Medications to be reported in the Case Report Form (CRF) are 
concomitant prescription medications, over-the-counter medications, and supplements. 
 
Patients will be asked to discontinue any over-the-counter supplements/vitamins not prescribed by their 
physicians.  Participants taking vitamin D prescribed by their physician will be asked to discontinue 
vitamin D for 1 month. 
 
Patients on “statin” cholesterol lowering medication (e.g. simvastatin, lovastatin, etc.) and PDE-5 
inhibitors (Viagra, Cialis, etc.) who would like to enroll in this study will be asked to discontinue these 
medications while on the study medication due to concerns for drug interactions. (Detampel, Beck, 
Krähenbühl, & Huwyler, 2012). 
 


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Patients on NSAIDs will be cautioned about increase risk of GI side effects and to avoid maximum dose 
NSAIDS.  Patients on chronic high dose NSAIDS will be excluded from the study. 
 
Noting that resveratrol is associated with increased insulin sensitivity, diabetics will be cautioned that 
the supplement could increase their risk of hypoglycemia and that they should monitor their blood 
glucose closely. (Poulsen, et al., 2013) 
 
See also the exclusion criteria (section 5.2) for list of contraindicated medications. 
 
Non-Trial Investigational Agents:  During their participation in the study, subjects will be instructed 
against participating in other interventional clinical trials, or otherwise avoid taking non-trial 
investigational agents, unless they are hospitalized and/or their physician judges that participation in 
another clinical trial is necessary for obtaining the best health outcome after infection with SARS-CoV-2.  
If patient is prescribed hydroxychloroquine or chloroquine, they will be instructed to discontinue RV. 
6.5.1 RESCUE MEDICINE 
  
Not applicable. 


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7 STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1 DISCONTINUATION OF STUDY INTERVENTION 
Discontinuation from study intervention does not mean discontinuation from the study, and remaining 
study procedures should be completed as indicated by the study protocol.  If a clinically significant 
finding is identified (including, but not limited to changes from baseline) after enrollment, the 
investigator or qualified designee will determine if any change in participant management is needed. 
Any new clinically relevant finding will be reported as an adverse event (AE). 
The study agent will be discontinued if the patient is admitted to the hospital. 
The data to be collected at the time of study intervention discontinuation will include the following: 
• 
Interview that participant regard their concern for discontinuation and assess for side 
effects/safety concerns. 
 
7.2 PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
Participants are free to withdraw from participation in the study at any time upon request. An 
investigator may discontinue or withdraw a participant from the study for the following reasons:  
• 
Subject withdraws consent 
• 
Subject voluntarily withdraws from treatment 
• 
Subject is unable to tolerate continued study drug administration 
• 
Significant study intervention non-compliance  
• 
Subject experiences a Grade 3 or higher adverse event attributed to the study drug by the 
investigator 
• 
Subject experiences a Grade 3 or higher clinically significant laboratory abnormality attributed 
to the study drug by the investigator 
• 
Subject’s clinical condition has worsened to be considered “severe” or “critical” 
• 
If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation.  
• 
Subject becomes pregnant 
• 
Subject becomes lost to follow-up 
The reason for participant discontinuation or withdrawal from the study will be recorded on the Case 
Report Form (CRF). 
Patients that discontinue/withdraw from the study will continue to be followed for a minimum of 21 
days after randomization to assess outcomes/hospitalization rates as allowed. 
7.3 LOST TO FOLLOW-UP 
 
A participant will be considered lost to follow-up if we are unable to determine the patient’s outcome 


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via participant survey, email correspondence, phone call to participant, phone call to secondary contact, 
and if information regarding their condition cannot be determined  via the electronic medical record 
including after attempting to obtain records from surrounding hospital systems (Ohio State University 
and OhioHealth).  Vital record search will also be used, if necessary, to determine outcomes in 
participants lost to follow up. 


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8 STUDY ASSESSMENTS AND PROCEDURES 
8.1 EFFICACY ASSESSMENTS 
Outcome Assessment and Other Key Variables.  Hospitalizations will be determined based on query of 
subject and/or the subject’s secondary contact.  The subject’s medical records will be requested from 
the admitting hospital (and discharging hospital, if separate) via a HIPAA authorization. 
 
Additional outcomes will include daily reporting of fever to assess number of days with fever and assess 
severity of dyspnea and fatigue.   Questionnaires to assess symptoms and adverse events will be used to 
monitor patients based on the PRO-CTCAE (see appendix 12.6) (National Cancer Institute, 2020). 
 
Conditions that the CDC defines as being high risk for developing severe COVID-19, and pertinent 
medications will be recorded.   
 
Adverse events will be recorded using PRO-CTCAE and CTCAE.  
8.2 SAFETY AND OTHER ASSESSMENTS 
Safety Monitoring.  This study while only be initiated after approval by Mt Carmel Health System’s 
Research Advisory Review Committee (RARC), Institutional Review Board (IRB), and the Food and Drug 
Administration (FDA). 
An independent Data and Safety Monitoring Board (DSMB) will been convened to assess the progress of 
a clinical study, the safety data, and critical efficacy endpoints (if appropriate) and provide 
recommendations. The members of the DSMB serve in an individual capacity and provide their expertise 
and recommendations. The DSMB will review cumulative study data to evaluate safety, study conduct, 
and scientific validity and data integrity of the study. The charter for the DSMB was developed by the 
Trinity Health research department. 
In addition to daily self-assessment via survey, participants will be provided with a consumer grade 
finger pulse oximeter.  They will be instructed to (at minimum) record their resting pulse oximeter 
reading of pulse rate and oxygen saturation each evening.  Patients will be instructed to seek medical 
attention for best resting oxygen saturation (SaO2) <94% on room air, or resting heart rate ≥ 90 beats 
per minute. Patients will be cautioned faulty readings and techniques for accurate readings.  Consumer 
grade pulse oximeters report an accuracy of +/- 2%. 
 
8.3 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
 
For this study, an adverse event is defined as “any untoward medical occurrence associated with the use 
of a drug in humans, whether or not considered drug related.” [21 CFR 312.32(a)] At the dosing used in 
this study, the investigators do not anticipate a higher than minimal risk of adverse events which occur 


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due to the use of resveratrol.  Data on adverse events will be collected for this study via the online 
questionnaires based on as selection of PRO-CTCAE questions as well as exit interviews graded according 
to the Common Terminology Criteria for Adverse Events (CTCAE) and assessed for their potential 
relationship to the study agent (see: https://evs.nci.nih.gov/ftp1/CTCAE/About.html). 
 
Data safety monitoring will be conducted by an independent Data Safety Monitoring Board.  The DSMB 
biostatistician will prepare reports for the principal investigator which summarizes the adverse events 
and serious adverse events, by group (labelled ‘A’ and ‘B’), type of event and frequency.  An initial 
planned interim safety analysis of the first 100 participants by the DSMB will occur after the first 21-day 
data is collected from the 100th participant.  Enrollment of new subjects will be paused pending the 
results of DSMB review the first 100 participants.  The study will resume enrollment upon DSMB 
approval.  The monitoring Institutional Review Board (IRB) will receive all serious adverse event reports 
generated for this trial.  Decisions regarding stopping the trial for safety reasons will be made after 
consultation with the IRB and/or DSMB. 
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) 
  
A serious adverse event is an adverse event that, in the opinion of the investigator or sponsor, results in: 
1) death or is life-threatening (immediate risk of death); 2) hospitalization or prolongation of existing 
hospitalization; 3) persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions (aka disability); or 4) congenital anomaly / birth defect. 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
  
8.3.3.1 Severity of Event 
 In general, grade categories are described as follows: 
– Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; no 
intervention indicated 
– Grade 2 Moderate; minimal, local, or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of daily life 
– Grade 3 Severe or medically significant but not immediately life threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL 
– Grade 4 Life-threatening consequences; urgent intervention indicated. 
– Grade 5 Death related to AE. 
8.3.3.2 Relationship to Study Intervention 
All adverse events (AEs) must have their relationship to study intervention assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and his/her clinical judgment. 


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The degree of certainty about causality will be graded using the categories below. In a clinical trial, the 
study product must always be suspect 
  
• 
Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test result, 
occurs in a plausible time relationship to study intervention administration and cannot be explained by 
concurrent disease or other drugs or chemicals. The response to withdrawal of the study intervention 
(dechallenge) should be clinically plausible. The event must be pharmacologically or phenomenologically 
definitive, with use of a satisfactory rechallenge procedure if necessary. 
• 
Probably Related – There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. The clinical event, including an abnormal laboratory test result, occurs within a 
reasonable time after administration of the study intervention, is unlikely to be attributed to concurrent 
disease or other drugs or chemicals, and follows a clinically reasonable response on withdrawal 
(dechallenge). Rechallenge information is not required to fulfill this definition. 
• 
Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose 
temporal relationship to study intervention administration makes a causal relationship improbable (e.g., 
the event did not occur within a reasonable time after administration of the study intervention) and in 
which other drugs or chemicals or underlying disease provides plausible explanations (e.g., the 
participant’s clinical condition, other concomitant treatments). 
• 
Not Related – The AE is completely independent of study intervention administration, and/or 
evidence exists that the event is definitely related to another etiology. There must be an alternative, 
definitive etiology documented by the clinician. 
8.3.3.3 Expectedness 
Research physicians will be responsible for determining whether an adverse event (AE) is expected or 
unexpected.  An AE will be considered unexpected if the nature, severity, or frequency of the event is 
not consistent with the risk information previously described for the study intervention 
 
Expected RV AE 
Diarrhea 
Nausea 
Gas/Bloating 
Expected COVID AE 
Fever 
Fatigue 
Dry Cough 
Loss of appetite 
Body Aches 
Shortness of breath 
Mucus/phlegm 
Sore Throat 
Headache 
Chills 
Loss of smell/taste 
Stuffy nose 
Nausea or Vomiting 
Diarrhea 
Stroke 
Conjunctivitis 
Lower extremity numbness, 
swelling, pain 
“COVID Toes” 
Arrhythmias 
Heart Attacks 
Cardiomyopathy 
Pulmonary Embolism 
Death  
  
 


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8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
  
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel by way of participant online survey results and interviews of a study participant 
presenting for medical care, or upon review by a study monitor. 
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate case report form (CRF). Information to be collected includes event description, time of 
onset, clinician’s assessment of severity, relationship to study product (assessed only by those with the 
training and authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs 
occurring while on study must be documented appropriately regardless of relationship. All AEs will be 
followed to adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any 
time during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
 
Research clinicians will record all reportable events with start dates occurring any time after informed 
consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study 
participation.  At each study visit, the investigator will inquire about the occurrence of AE/SAEs since the 
last visit.  Events will be followed for outcome information until resolution or stabilization. 
8.3.5 ADVERSE EVENT REPORTING 
All adverse events (AEs) will be recorded in the Case Report Form (CRF), and will be reviewed on an 
ongoing basis by the investigator and DSMB. The Principal Investigator shall be solely responsible for 
complying, within the required timelines, with any safety reporting obligation to competent Health 
Authorities and the IRB, as defined in applicable laws and regulations. For the purposes of this section, 
safety data includes adverse events, product quality complaints (PQCs), and special situations including 
pregnancies.  
8.3.6 SERIOUS ADVERSE EVENT REPORTING 
  
The study clinician will immediately report to the sponsor any serious adverse event, whether or not 
considered study intervention related, including those listed in the protocol and must include an 
assessment of whether there is a reasonable possibility that the study intervention caused the event. 
Study endpoints that are serious adverse events (e.g., all-cause mortality) must be reported in 
accordance with the protocol unless there is evidence suggesting a causal relationship between the 
study intervention and the event (e.g., death from anaphylaxis).  


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All serious adverse events (SAEs) will be followed until satisfactory resolution or until the site 
investigator deems the event to be chronic or the participant is stable.  
 
The study sponsor will be responsible for notifying the Food and Drug Administration (FDA) of any 
unexpected fatal or life-threatening suspected adverse reaction as soon as possible, but in no case later 
than 7 calendar days after the sponsor's initial receipt of the information.  In addition, the sponsor must 
notify FDA and all participating investigators in an Investigational New Drug (IND) safety report of 
potential serious risks, from clinical trials or any other source, as soon as possible, but in no case later 
than 15 calendar days after the sponsor determines that the information qualifies for reporting. 
 
Any SAE identified by research personnel must be reported to the Principal Investigator with notification 
copied to the DSMB as soon as practicable, but within 24 hours.   
 
• 
Initial reporting: IND application principal investigator/sponsor must report any suspected 
adverse reaction or adverse reaction to study treatment that is both serious and unexpected. 
 
Unexpected fatal or life-threatening suspected adverse reactions represent especially important 
safety information and must be reported to FDA as soon as possible but no later than 7 calendar 
days following the sponsor’s initial receipt of the information. 
 
• 
Follow-up reporting: Any relevant additional information obtained by the sponsor that pertains 
to a previously submitted IND safety report must be submitted as a Follow-up IND Safety 
Report. Such report should be submitted without delay, as soon as the information is available 
but no later than 15 calendar days after the sponsor receives the information. 
• 
All IND safety reports must be submitted on Form 3500A  
https://www.fda.gov/media/69876/download 
 
 
8.3.7 REPORTING EVENTS TO PARTICIPANTS 
  
Participants will be contacted as soon as practicable, via email, phone, or letter about any adverse 
events defined at “potentially related,” “probably related,” or “definitely related” to the study that are 
specifically related to the individual participant.  A record of the communication will be recorded in the 
REDCap data collection system.   
 
Upon completion of the study, participant will be emailed a summary of the study results written in 
layman terminology describing aggregate results of the study including a summary of adverse events 
and unanticipated problems believed to be related to the study. 
8.3.8 EVENTS OF SPECIAL INTEREST 
  


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Any identified events not covered above, such as discovery of abnormal lab test results, study 
intervention overdose, or events that raise concern by the research clinician will be reported to the 
principal investigator and/or DSMB. 
8.3.9 REPORTING OF PREGNANCY 
  
If patient reports pregnancy during the study, they will be asked to discontinue the study intervention.  Consent to 
follow the pregnancy outcome will be requested. 
 
8.4 UNANTICIPATED PROBLEMS 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
  
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; 
• 
Related or probably related to participation in the research (“probably related” means there is a 
reasonable probability that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
8.4.2 UNANTICIPATED PROBLEM REPORTING 
  
The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review Board 
(IRB) and DSMB. The UP report will include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number 
• 
A detailed description of the event, incident, experience, or outcome 
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP  
• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:   
 


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• 
UPs that are serious adverse events (SAEs) will be reported to the IRB and DSMB as soon as 
practicable but within 48 hours of the investigator becoming aware of the event.  
• 
Any other UP will be reported to the IRB and DSMB within 7 days of the investigator becoming 
aware of the problem.  
• 
All UPs should be reported to appropriate institutional officials (as required by an institution’s 
written reporting procedures), the supporting agency head (or designee), and the Office for 
Human Research Protections (OHRP) within 7 days of the IRB’s receipt of the report of the 
problem from the investigator. 
• 
https://www.hhs.gov/ohrp/regulations-and-policy/guidance/reviewing-unanticipated-
problems/index.html 
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS 
  
Participants will be contacted as soon as practicable, via email, phone, or letter about any adverse 
events defined by study that are specifically related to the participant.  A record of the communication 
will be recorded in the REDCap data collection system.   
 
Upon completion of the study, participant will be emailed a summary of the study results written in 
layman terminology describing aggregate results of the study including a summary of adverse events 
and unanticipated problems believed to be related to the study. 
 
 


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9 STATISTICAL CONSIDERATIONS 
9.1 STATISTICAL HYPOTHESES 
• 
Primary Efficacy Endpoint(s): 
Hospitalization (less frequent is better) 
Null hypothesis: There is no difference between resveratrol and placebo with respect to the proportion of 
patients hospitalized or deceased within 21 days of randomization. 
Alternative hypothesis: There is a difference between resveratrol and placebo with respect to the proportion 
of patients hospitalized or deceased within 21 days of randomization. 
• 
Secondary Efficacy Endpoint(s): 
 
ICU admission (less frequent is better) 
Null hypothesis: There is no difference between resveratrol and placebo among patients who 
are hospitalized within 21 days of randomization with respect to the proportion of patients 
admitted to the ICU or deceased. 
Alternative hypothesis: There is a difference between resveratrol and placebo among patients 
who are hospitalized within 21 days of randomization with respect to the proportion of patients 
admitted to the ICU or deceased. 
 
Invasive ventilation (less frequent is better) 
Null hypothesis: There is no difference between resveratrol and placebo among patients who 
are hospitalized within 21 days of randomization with respect to the proportion of patients 
receiving invasive ventilation or deceased. 
Alternative hypothesis: There is a difference between resveratrol and placebo among patients 
who are hospitalized within 21 days of randomization with respect to the proportion of patients 
receiving invasive ventilation or deceased. 
 
Extracorporeal membrane oxygenation (ECMO) (less frequent is better) 
Null hypothesis: There is no difference between resveratrol and placebo among patients who 
are hospitalized within 21 days of randomization with respect to the proportion of patients 
receiving ECMO or deceased. 
Alternative hypothesis: There is a difference between resveratrol and placebo among patients 
who are hospitalized within 21 days of randomization with respect to the proportion of patients 
receiving ECMO or deceased. 
 
 
9.2 SAMPLE SIZE DETERMINATION 
 
The maximum total number of randomized subjects is capped at 200 by FDA request. We present power 
analyses of the primary outcome measure (hospitalization) assuming multiple placebo arm 


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hospitalization rates and effect sizes, as well as for secondary outcome measures. No interim analyses 
for efficacy are planned, and none are included in the following power calculations. 
The primary outcome measure is hospitalization within 21 days of randomization. We provide 
conservative power estimates by assuming a binary outcome with 5% non-informative loss to follow-up 
before 21 days. We anticipate this relatively low rate of loss because the endpoint is designed to be 
evaluable by chart review unless the subject withdraws consent. Hypotheses are as specified in the 
previous section, and the Z statistic for a two-proportion test is used. The primary Kaplan-Meier analysis 
will yield slightly better power by treating the outcomes of patients lost to follow-up as censored at the 
time of last follow-up. 
The rate of hospitalization among confirmed cases of COVID-19 ranges between 21% in the 45-54 age 
bracket, up to 31% for patient’s >85 (CDC, 2020).  We assumed a mid-point hospitalization rate of 25% 
for the initial sample size calculation. To achieve 80% power at the 5% two-sided significance level with 
complete follow-up on 95 subjects per arm with two-sample proportion test, we require a 10% or lower 
hospitalization rate in the resveratrol arm, compared to a 25% rate in the placebo arm (estimated by 
power.prop.test, R statistical software). This corresponds to an odds ratio of 1 / 3. 
The required resveratrol arm event rate for various placebo arm event rates are plotted in Figure 3. This 
curve applies to the power for all outcome measures, with lower rates of all secondary outcome events 
expected to be lower in both arms. 
 
9.3 POPULATIONS FOR ANALYSES 
 
 


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• 
Intention-to-treat (ITT) population: all randomized participants. 
• 
Safety population: all randomized participants who report taking at least one dose of their 
assigned medication. 
9.4 STATISTICAL ANALYSES 
9.4.1 GENERAL APPROACH 
Uncensored data will be summarized by percentages, means and standard deviations, or medians and 
ranges as appropriate for each variable’s distribution. Data subject to censoring (e.g., hospitalization) 
will be summarized by Kaplan-Meier estimate. 
 
Unless otherwise noted, all hypothesis tests will be two-sided and at the 5% significance level. Similarly, 
confidence intervals will be two-sided and at the 95% confidence level. Declarations of superiority will 
be declared if the corresponding hypothesis test is significant and the direction of the estimated 
treatment effect is favorable to resveratrol. 
 
In addition to local hypothesis tests, we will use a multiple testing procedure to control the familywise 
Type I error at 5% for the primary and secondary endpoints together. The primary efficacy endpoint 
(hospitalization) will be tested at the 5% significance level; then, if the primary endpoint null hypothesis 
is rejected, the two secondary endpoints (ICU admission, invasive ventilation) will be tested via the 
Bonferroni-Holm procedure. No multiple testing adjustment will be made for exploratory or safety 
analyses. 
 
Hospitalization, ICU admission, and invasive ventilation endpoints are composites that include death 
within 21 days of randomization. 
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
The primary efficacy endpoint is hospitalization for any cause within 21 days after randomization, as 
established by medical record review.  Outcomes of subjects who withdraw consent or are otherwise 
lost to follow-up before 21 days will be considered missing. The intention to treat population for the 
hospitalization endpoint will be used for analysis. A logistic regression model will be fit with age, sex, 
race, ethnicity, risk group (see Sec 9.4.7), and randomized group as covariates, with the coefficient to 
randomized group as the primary estimand. Missing outcome data will be imputed using multiple 
imputation based on predictions from the logistic regression model of the outcome. Sensitivity analyses 
will include analyses in which patients lost to follow-up are assumed to not have been hospitalized, and 
tipping-point analyses systematically and comprehensively varying assumptions about missing outcomes 
on the treatment and placebo arms independently. 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
The secondary endpoints are ICU admission or death and invasive ventilation or death within 21 days 
after randomization, as established by medical record review. Outcomes of subjects who withdraw 


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consent or are otherwise lost to follow-up before 21 days will be considered missing. The intention to 
treat population for each endpoint will be used for analysis. Estimation and testing procedures will 
follow those of the primary efficacy endpoint. 
9.4.4 SAFETY ANALYSES 
Adverse events will be coded according to the Common Terminology Criteria for Adverse Events 
(CTCAE), and each AE will be counted at most once per participant. Severity, frequency, and relationship 
of AEs to the study intervention will be presented by System Organ Class and preferred term groupings. 
Start date, stop date, severity, relationship, expectedness, outcome, and duration will be reported for 
each AE. Adverse events leading to premature discontinuation from the study intervention and serious 
treatment-emergent AEs will be tabulated. The safety population will be used for safety analyses. 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
Intervention groups will be compared on baseline characteristics, including demographics and baseline 
risk factors. Sample proportions, means and standard errors, or medians and ranges will be provided as 
appropriate for each distribution. No inferential statistics will be used. Descriptive statistics will be 
reported for the intention-to-treat population. 
9.4.6 PLANNED INTERIM ANALYSES 
  
An independent DSMB will monitor safety data on a continual basis throughout the trial. One interim 
analysis will be carried out after the first 100 patients have completed the initial 21-day study period. 
After 100 patients have been randomized, enrollment will pause until all randomized patients have 
completed at least 21 days of follow-up to evaluate the primary endpoint and the interim analysis has 
been completed. The DSMB can recommend enrollment suspension or study termination for reasons of 
safety. Study enrollment will be suspended by the PI when (1) any subject experiences a Grade 3 or 
higher adverse event toxicity (defined in 8.3.3.1) that is probably, or definitely related to the study 
agent, or when (2) stopping is indicated by the statistical stopping rule defined below. An enrollment 
suspension under either scenario will trigger an ad hoc safety review by the DSMB. Following DSMB 
review and recommendation, the IRB and FDA will determine whether study enrollment will resume. 
 
The interim and final analyses will use the Hwang-Shih-DeCani alpha spending function with parameter 
gamma = -4 (O’Brien-Fleming–like) for the upper (superiority) bound under the null hypothesis with 
total one-sided Type I error 2.5%, and for the lower (safety or futility) bound under the alternative 
hypothesis with total Type II error 20% (80% power). Under the assumption of a binding futility bound 
and a placebo arm hospitalization rate of 25%, the probability of declaring futility at the interim analysis 
is 3% if the resveratrol arm hospitalization rate is 10% (alternative hypothesis), 55% if the resveratrol 
arm hospitalization rate is 25% (null hypothesis), and 75% if the resveratrol arm hospitalization rate is 
30%. The R package gsDesign will be used to determine stopping boundaries. 
 
9.4.7 SUB-GROUP ANALYSES 
Stratified versions of the primary and secondary efficacy endpoint analyses will constitute exploratory 
subgroup analyses, with each variable analyzed separately. Variables defining strata are as follows. 


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• 
Age (65 or older versus 64 or younger) 
• 
Sex 
• 
Race 
• 
Ethnicity 
• 
Presence of at least one factor indicating membership in a high-risk group: 
o Blood disorder, including sickle cell disease or taking blood thinners. 
o Chronic kidney disease. 
o Chronic liver disease. 
o Compromised immune system (e.g., on chemotherapy, high dose steroids, 
immunosuppressant medications, HIV/AIDS). 
o Heart disease. 
o Lung disease. 
o Neurologic disease. 
• 
ACE inhibitor / ACE Receptor Blocker (ARB) use. 
Age is included due to known association with risk of complications due to COVID-19. Sex, race, and 
ethnicity are included in compliance with the NIH policy on the Inclusion of Women and Minorities as 
Participants in Research Involving Human Subjects. Comorbidity and concomitant medication risk factors 
are combined to limit the multiplicity of comparisons. 
 
A formal multiplicity-corrected subgroup analysis procedure will be carried out via credible subgroups 
(Schnell, 2016). A logistic regression model will be fit with age and presence of at least one factor 
indicating membership in a high-risk group, their interactions with study arm, and study arm alone. 
Bounds for the benefiting subpopulation of patients, defined by age (as a continuous variable) and risk 
category will be computed at the 80% credible level. 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
 Individual participant data will not be presented. 
9.4.9 EXPLORATORY ANALYSES 
  
Three classes of exploratory analyses will be executed in the modified intention-to-treat populations for 
the respective outcome measures: 
1. Analyses of morbidity and mortality 
2. Log-rank tests for non-covariate-adjusted differences in survival curves through 21 days post-
randomization 
3. Covariate-adjusted analyses 
Morbidity and mortality will be analyzed following the procedure for the primary efficacy endpoint, in 
the modified intention-to-treat population for each endpoint. 


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Of primary interest for efficacy endpoints is the event rate at 21 days post-randomization. However, we 
will also report log-rank tests comparing survival curves between randomized arms throughout the 
follow-up period. 
Cox proportional hazards fits will be reported, including effect estimates, standard errors, and tests for 
study arm, age, sex, race, and presence of at least one factor indicating membership in a high-risk group. 


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10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
10.1.1 INFORMED CONSENT PROCESS 
  
10.1.1.1 Consent/assent and Other Informational Documents Provided to participants 
• 
Institutional Review Board (IRB)-Approved Consent form 
• 
Slides summarizing animated presentation of the study 
 
10.1.1.2 Consent Procedures and Documentation 
• 
Partial Waiver of Authorization for recruitment purposes obtain from the IRB.  Patients will be 
recruited from electronic reports of potential participants. 
• 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation.  The consent process will be 
completed online. The patient will be provided with an animated presentation (approximately 3-5 
minutes in length) explaining the study and its risks, and benefits. Consent forms will be IRB-
approved, and the participant will be asked to read and review the document.  The participant will 
be given the opportunity to ask the investigator any questions that may arise.  The participant will 
be provided with a link to the Office of Human Resources Protection “About Research Participation” 
webpage as an addition resource.  Participants will have the opportunity to carefully review the 
written consent form and ask questions prior to signing. The participants will have the opportunity 
to discuss the study with their family or surrogates or think about it prior to agreeing to participate. 
The participant will electronically sign the informed consent document prior to any procedures 
being done specifically for the study. Participants must be informed that participation is voluntary 
and that they may withdraw from the study at any time, without prejudice. A copy of the informed 
consent document will be given to the participants for their records. The informed consent process 
will be conducted and documented, and the form signed, before the participant undergoes any 
study-specific treatment. The rights and welfare of the participants will be protected by emphasizing 
to them that the quality of their medical care will not be adversely affected if they decline to 
participate in this study 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
  
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to, study participants, investigator, or/and regulatory 


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authorities.  If the study is prematurely terminated or suspended, the Principal Investigator (PI) will 
promptly inform study participants, the Institutional Review Board (IRB), and will provide the reason(s) 
for the termination or suspension.  Study participants will be contacted, as applicable, and be informed 
of changes to study visit schedule. 
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping    
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination that the primary endpoint has been met 
• 
Determination of futility 
 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the sponsor, IRB and/or Food and Drug Administration (FDA).] 
10.1.3 CONFIDENTIALITY AND PRIVACY 
  
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, and the sponsor(s) and their interventions. This confidentiality is extended to the clinical 
information relating to participants. Therefore, the study protocol, documentation, data, and all other 
information generated will be held in strict confidence. No information concerning the study or the data 
will be released to any unauthorized third party without prior written approval of the sponsor.  
 
All research activities will be conducted in as private a setting as possible. 
 
The study monitor, other authorized representatives of the sponsor, representatives of the Institutional 
Review Board (IRB), or regulatory agencies may inspect all documents and records required to be 
maintained by the investigator, including but not limited to, medical records (office, clinic, or hospital) 
and pharmacy records for the participants in this study. The clinical study site will permit access to such 
records. 
 
The study participant’s contact information will be securely stored electronically, in a HIPAA Compliant, 
password secured database, for internal use during the study. At the end of the study, all records will 
continue to be kept in a secure location for as long a period as dictated by the reviewing IRB, 
Institutional policies, or sponsor requirements. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
stored in the REDCap (Harris, et al., 2009) data collection platform. Access to protected health 
information will be restricted to the research clinician. Individual participants and their research data 
will be identified by an anonymized unique study identification number for statistical analysis and 
scientific reporting. The study data entry and study management systems used by clinical sites and 
research staff will be secured and password protected. At the end of the study, all study databases will 
be de-identified and archived at an encrypted, firewall and password protected research data repository 


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managed by Mount Carmel Health System Information Security (IS) and the Mount Carmel Health 
System Office of Research Affairs (ORA). 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA 
  
Data collected for this study will be analyzed and stored in the REDCap Data Collection software 
platform on a HIPAA compliant server maintained by Trinity Health Systems (the parent company of Mt 
Carmel Health Systems. After the study is completed, the de-identified, archived data will be 
transmitted to and stored in the REDCap system. 
 
There will be no biological specimens collected as a part of this trial. 
 
When the study is completed, access to study data and/or samples will be provided through research 
data repository managed by Mount Carmel Health System Information Security (IS) and the Mount 
Carmel Health System Office of Research Affairs (ORA). 
 
10.1.5 Key Roles and Study Governance 
Principal Investigator 
Safety Monitor 
DSMB - Members 
 Marvin McCreary, MD 
Ashley Patel, MD 
Lynn Shaffer, PhD (Chair) 
 Mt Carmel Health Systems 
Mt Carmel Health Systems 
 Brian Hamburg, MD 
 
 
 Sean Lansing, PhD 
  
 
  
  
10.1.6 SAFETY OVERSIGHT 
  
Safety oversight will be under the direction of a Data and Safety Monitoring Board (DSMB) composed of 
individuals with the appropriate expertise, including Lynn Shaffer, PhD (statistics, epidemiology), Brian 
Hamburg, MD (pulmonologist), and Sean Lansing (ethics). Members of the DSMB should be independent 
from the study conduct and free of conflict of interest, or measures should be in place to minimize 
perceived conflict of interest.  The DSMB will receive data to assess safety and efficacy data on each arm 
of the study after each quartile of participants have completed the study. The DMSB will operate under 
the rules of an approved charter that will be written and reviewed at the organizational meeting of the 
DSMB. At this time, each data element that the DSMB needs to assess will be clearly defined. The DSMB 
will provide its input to Principal Investigator 
10.1.7 CLINICAL MONITORING 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of 
the trial is in compliance with the currently approved protocol/amendment(s), with International 


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Conference on Harmonisation Good Clinical Practice (ICH GCP), and with applicable regulatory 
requirement(s).  
 
• 
The principal investigator or designee will at least weekly review the results of the patient 
survey data assess patient’s progress and condition. 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
  
Each clinical site will perform internal quality management of study conduct, data collection, 
documentation, and completion. 
 
Quality control (QC) procedures will be implemented beginning with the data entry system and data QC 
checks that will be run on the database will be generated. Any missing data or data anomalies will be 
communicated to the site(s) for clarification/resolution. 
 
Principal investigator and/or safety monitor will verify that the clinical trial is conducted and data are 
generated , documented (recorded), and reported in compliance with the protocol, International 
Conference on Harmonisation Good Clinical Practice (ICH GCP) and applicable regulatory requirements. 
 
The investigational site will provide direct access to all trial related source data/documents, and reports 
for the purpose of monitoring and inspection by local and regulatory authorities. 
10.1.9 DATA HANDLING AND RECORD KEEPING 
10.1.9.1 Data Collection and Management Responsibilities 
Data will be collected electronically via the REDCap (Research Electronic Data Capture) platform (Harris, 
et al., 2009).  
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
investigator. The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. 
 
A copy of the patient’s consent form will be provided to the Mt Carmel Health Systems Medical Record 
Department to be recording in the patient’s Electronic Medical Record. 
 
Data recorded in the electronic case report form (eCRF) derived from source documents should be 
consistent with the data recorded on the source documents.  
 
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse reactions 
data) and clinical laboratory data will be entered into REDCap, a 21 CFR Part 11-compliant data capture 
system provided by the Trinity Health. The data system includes password protection and internal 
quality checks, such as automatic range checks, to identify data that appear inconsistent, incomplete, or 
inaccurate. Clinical data will be entered directly from the source documents. 


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10.1.9.2 Study Records Retention 
Study documents should be retained for a minimum of 3 years after the completion of the study, a 
minimum of 2 years after the last approval of a marketing application in an International Conference on 
Harminosation (ICH) region and until there are no pending or contemplated marketing applications in an 
ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical development 
of the study intervention. These documents should be retained for a longer period, however, if required 
by local regulations. No records will be destroyed without the written consent of the sponsor, if 
applicable. It is the responsibility of the sponsor to inform the investigator when these documents no 
longer need to be retained. 
10.1.10 PROTOCOL DEVIATIONS 
  
A protocol deviation is any noncompliance with the clinical trial protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), or Manual of Procedures (MOP) requirements. The 
noncompliance may be either on the part of the participant, the investigator, or the study site staff. As a 
result of deviations, corrective actions are to be developed by the site and implemented promptly.  
 
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
 
It is the responsibility of the site investigator to use continuous vigilance to identify and report 
deviations within 7 working days of identification of the protocol.  Protocol deviations must be sent to 
the reviewing Institutional Review Board (IRB) per their policies. The site investigator is responsible for 
knowing and adhering to the reviewing IRB requirements.  
10.1.11 PUBLICATION AND DATA SHARING POLICY 
  
This study will comply with the Clinical Trials Registration and Results Information Submission rule. As 
such, this trial will be registered at ClinicalTrials.gov, and results information from this trial will be 
submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish results in a peer 
reviewed journal. 
10.1.12 CONFLICT OF INTEREST POLICY 
  
The independence of this study from any actual or perceived influence, such as by the pharmaceutical industry, is 
critical.  Therefore, any actual conflict of interest of persons who have a role in the design, conduct, analysis, 
publication, or any aspect of this trial will be disclosed and managed. Furthermore, persons who have a perceived 
conflict of interest will be required to have such conflicts disclosed and managed in a way that is appropriate to 


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their participation in the design and conduct of this trial.   
 
10.2 ADDITIONAL CONSIDERATIONS 
 
Not applicable 
10.3 ABBREVIATIONS 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
COC 
Certificate of Confidentiality 
CONSORT Consolidated Standards of Reporting Trials 
CoV 
Coronavirus 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
D3 
Vitamin D3 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DSMB 
Data Safety Monitoring Board 
DRE 
Disease-Related Event 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Forms 
eGFR 
Estimated Glomerular Filtration Rate 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 


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FFR 
Federal Financial Report 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
GWAS 
Genome-Wide Association Studies 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ISO 
International Organization for Standardization 
ITT 
Intention-To-Treat 
LSMEANS Least-squares Means 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
MSDS 
Material Safety Data Sheet 
NCT 
National Clinical Trial 
NIH 
National Institutes of Health 
NIH IC 
NIH Institute or Center 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
PPE 
Personal Protective Equipment 


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PRO-CTCAE Patient Reported Outcome - CTCAE 
QA 
Quality Assurance 
QC 
Quality Control 
RV 
Resveratrol 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SARS 
Severe Acute Respiratory Syndrome 
SMC 
Safety Monitoring Committee 
SOA 
Schedule of Activities 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
US 
United States 
 
 
 
 


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10.4 PROTOCOL AMENDMENT HISTORY 
Version 
Date 
Description of Change  
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damage, increases expression of heme oxygenase-1, and has anti-complement, anti-oxidative, 
and anti-apoptotic effects in a murine model of membranous nephropathy. PLOS ONE, 10(5). 
Retrieved from https://academic.microsoft.com/paper/834440514 
Xia, N., Förstermann, U., & Li, H. (2014). Resveratrol and Endothelial Nitric Oxide. Molecules, 19(10), 
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Yan, T., Xiao, R., & Lin, G. (2020). Angiotensin-converting enzyme 2 in severe acute respiratory syndrome 
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COVID-19. Journal of Immunology. Retrieved from 
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Zang, N., Xie, X., Deng, Y., Wu, S., Wang, L., Peng, C., . . . Liu, E. (2011). Resveratrol-Mediated Gamma 
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Monocyte/Macrophage Proinflammatory Cytokine Production by Targeting MAPK Phosphatase-


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1. Journal of Immunology, 188(5), 2127-2135. Retrieved from 
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Zhao, X., Tong, W., Song, X., Jia, R., Li, L., Zou, Y., . . . Yin, Z. (2018). Antiviral Effect of Resveratrol in 
Piglets Infected with Virulent Pseudorabies Virus. Viruses, 10(9), 457. Retrieved from 
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Zhu, X.-d., Lei, X.-p., & Dong, W.-b. (2017). Resveratrol as a potential therapeutic drug for respiratory 
system diseases. Drug Design Development and Therapy, 11, 3591-3598. Retrieved from 
https://academic.microsoft.com/paper/2771823836 
 


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12 APPENDIX  
12.1 RESVERATROL  
12.1.1 PRODUCT LABEL 
 


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12.1.2A CERTIFICATE OF ANALYSIS FOR RESVERATROL RAW MATERIAL 
 
 
 


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12.1.2B THIRD PARTY CERTIFICATE OF ANALYSIS FOR RESVERATROL RAW MATERIAL 
 


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12.1.3 Certificate of Analysis for Prepared Capsules 
  


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12.1.3 STABILITY REPORT 
 


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12.1.4 GMP CERTIFICATE 
 


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12.2 PLACEBO 
12.2.1 CERTIFICATE OF ANALYSIS FOR BROWN RICE FLOUR 
 


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12.2.2 CERTIFICATE OF ANALYSIS FOR PREPARED CAPSULES 
 


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12.3 VITAMIN D3 (CHOLECALCIFEROL) 
12.3.1 PRODUCT LABEL 
 


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12.3.2 CERTIFICATE OF ANALYSIS 
 
 
 


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12.3.3 STABILTY REPORT 
 


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12.3.4 GMP CERTIFICATION 
 
 
 


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12.4 SAMPLE PATIENT PACKET ITEMS 
12.4.1 SAMPLE DRUG DIARY 
Front Page 
 
Back Page 
 
 


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12.5 WELCOME VIDEO 
 
https://www.youtube.com/embed/0bVxe1KlAy4?feature=oembed 
 


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12.6 PATIENT SURVEYS 
12.6.1 – DAILY QUESTIONNAIRE  
 


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These are DRAFT example questions. 
Questions will be finalized before patient 
enrollment. 
Note that questions will be formatted for 
electronic viewing and will have conditional 
formatting such that only relevant questions 
will be visible. 


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12.6.2 – PRO-CTCAE QUESTIONNAIRE (DAY 1, 8, & 15, 21, 30, AND 60) 
 
These are DRAFT example question.  Questions 
will be finalized before patient enrollment 
Note that questions will be formatted for 
electronic viewing and will have conditional 
formatting such that only relevant questions will 
be visible. 


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