Conditions: Respiratory Viral Infection
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 17
Healthy volunteers: no

Brief summary:
Zinc and green tea supplementation have both been independently studied for supporting immune health during cold and flu-like illness in non-hospitalized patients with clinical trials demonstrating promising but inconsistent results. Combination therapy may offer an improved effect as the antioxidant compounds found in green tea have been shown to increase cellular zinc concentrations thereby inhibiting viral replication. This study seeks to evaluate the effect of combination supplementation using established doses of zinc and green tea extract on symptom duration and severity from cold and flu-like illness, including COVID-19, in adult community patients enrolled in a randomized placebo-controlled trial.

Detailed description:

Arms:
arm 1: Randomized patients will take three (3) capsules taken orally two (2) hours following a meal twice daily x5 days and be blinded to study assignment. arm 2: Randomized patients will take three (3) capsules taken orally two (2) hours following a meal twice daily x5 days and be blinded to study assignment.

Interventions: intervention 1: zinc-green tea extract-ascorbic acid intervention 2: Placebo
Intervention descriptions: intervention 1: Compounded capsules containing each zinc citrate, green tea extract, and ascorbic acid. intervention 2: Compounded capsules containing microcrystalline cellulose.

Protocol document:
Prot_SAP_000.pdf: 
Evaluation of zinc and green tea extract 
supplementation on reduction in symptom duration 
and severity associated with community respiratory 
viral infections: a randomized control trial 
(ZiPhenol Study) 
Protocol Number: 1 
National Clinical Trial (NCT) Identified Number:  04898023 
Principal Investigator: Syed Naqvi, MD 
<IND/IDE> Sponsor: Ryan Camden, PharmD 
IND Number: 152998 
Funded by: University of Missouri School of Medicine 
Version Number:  v.1.6 
23 February 2023 
 
Summary of Changes from Previous Version: 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
1.1, 6.1 
Removed EGCG dosing information 
IRB requested to remove EGCG dosing 
detail as amount from the wholesaler green 
tea extract product is described as ≥50% 
EGCG vs an exact amount. 
4.1, 6.2 
Added ‘or designated pharmacist’ when 
describing duties of IDS staff 
This added language was requested by IDS 
staff so to capture the use of other MUHC 
pharmacists for after-hours dispensing 
operations if needed. 
4.3 
Updated mg/capsule of elemental zinc 
Back updating text within this section to 
reflect compounding changes made in an 
earlier protocol version (v1.4). 


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6.1, 6.2 
Changed fill weight target of placebo capsules 
to 300mg ± 10% 
Following the preparation of several 
batches of placebo capsules to-date it has 
been observed that there is a relatively high 
rate of poor capsulation (i.e. rejected 
capsules) of these capsules leading to waste 
of the microcrystalline cellulose material 
used to make them as well as the empty 
capsule supply on hand.  Lowering fill 
weight helps improve the yield of 
successful placebo capsules made during 
the capping process thus warranting a 
protocol update. The microcrystalline 
cellulose material is inert and possesses no 
pharmaceutical activity thus lowering the 
fill weight of placebo capsules is immaterial 
to study outcome measures. 
6.1 
The zinc citrate per capsule amount was 
added to the elemental zinc amount 
description 
This additional detail was requested by IDS 
staff. 
6.2 
Changed beyond-use date from 30 days to 180 
days 
Initial selection for the beyond-use date 
was based on guidance from the Missouri 
Board of Pharmacy, which recommended 
use of clinical judgement. As such, a very 
conservative (and arbitrary) short dating of 
30 days was used. Due to slower than 
expected enrollment this has led to several 
batches of study product having to be 
wasted. IDS staff recommended using the 
United States Pharmacopeia (USP) 795 
standards for non-sterile compounding 
instead of the Missouri Board guidance. 
USP states more definitely the beyond-use 
date for compounded solid dosage forms 
can be up to 180 days. 
6.2 
Removed language ‘at the direction of the 
primary investigator’  
This removal was requested by IDS staff as 
their standard operating procedures 
includes routine disposal of unused study 
drug without notifying the primary 
investigator.  


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10.1 
Updated structure of Independent Safety 
Monitor (ISM) 
ISM personnel description updated to 
reflect current personnel; frequency of 
monitoring changed to percentages of 
enrollment target to accommodate the 
slower than anticipated enrollment. 


  
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Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................. 1 
1 
PROTOCOL SUMMARY ............................................................................................................................... 1 
1.1 
Synopsis ................................................................................................................................................ 1 
1.2 
Schema ................................................................................................................................................. 2 
1.3 
Schedule of Activities (SoA) ............................................................................................................... 4 
2 
INTRODUCTION ............................................................................................................................................ 4 
2.1 
Study Rationale .................................................................................................................................... 4 
2.2 
Background........................................................................................................................................... 5 
2.3 
Risk/Benefit Assessment .................................................................................................................... 8 
2.3.1 
Known Potential Risks ..................................................................................................... 8 
2.3.2 
Known Potential Benefits ................................................................................................ 8 
2.3.3 
Assessment of Potential Risks and Benefits ................................................................ 8 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................................ 9 
4 
STUDY DESIGN ........................................................................................................................................... 10 
4.1 
Overall Design .................................................................................................................................... 10 
4.2 
Scientific Rationale for Study Design.............................................................................................. 11 
4.3 
Justification for Dose ......................................................................................................................... 11 
4.4 
End of Study Definition ..................................................................................................................... 14 
5 
STUDY POPULATION ................................................................................................................................ 14 
5.1 
Inclusion Criteria ................................................................................................................................ 14 
5.2 
Exclusion Criteria ............................................................................................................................... 14 
5.3 
Lifestyle Considerations .................................................................................................................... 15 
5.4 
Screen Failures .................................................................................................................................. 15 
5.5 
Strategies for Recruitment and Retention ...................................................................................... 15 
6 
STUDY INTERVENTION ............................................................................................................................ 16 
6.1 
Study Intervention(s) Administration ............................................................................................... 16 
6.1.1 
Study Intervention Description ..................................................................................... 16 
6.1.2 
Dosing and Administration ............................................................................................ 17 
6.2 
Preparation/Handling/Storage/Accountability ................................................................................ 17 
6.2.1 
Acquisition and accountability ...................................................................................... 17 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ................................................ 18 
6.2.3 
Product Storage and Stability ....................................................................................... 18 
6.2.4 
Preparation ...................................................................................................................... 18 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................................... 19 
6.4 
Study Intervention Compliance ........................................................................................................ 19 
6.5 
Concomitant Therapy ........................................................................................................................ 19 
6.5.1 
Rescue Medicine ............................................................................................................ 20 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .................................................................................................................... 20 
7.1 
Discontinuation of Study Intervention ............................................................................................. 20 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................................... 21 
7.3 
Lost to Follow-Up ............................................................................................................................... 21 
8 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................................... 21 
8.1 
Efficacy Assessments ....................................................................................................................... 21 
8.2 
Safety and Other Assessments ....................................................................................................... 23 
8.3 
Adverse Events and Serious Adverse Events ............................................................................... 25 


  
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8.3.1 
Definition of Adverse Events (AE) ............................................................................... 25 
8.3.2 
Definition of Serious Adverse Events (SAE) .............................................................. 25 
8.3.3 
Classification of an Adverse Event .............................................................................. 25 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 26 
8.3.5 
Adverse Event Reporting .............................................................................................. 27 
8.3.6 
Serious Adverse Event Reporting ............................................................................... 28 
8.3.7 
Reporting Events to Participants ................................................................................. 30 
8.3.8 
Events of Special Interest ............................................................................................. 30 
8.3.9 
Reporting of Pregnancy ................................................................................................ 30 
8.4 
Unanticipated Problems .................................................................................................................... 30 
8.4.1 
Definition of Unanticipated Problems (UP) ................................................................. 30 
8.4.2 
Unanticipated Problem Reporting ................................................................................ 31 
8.4.3 
Reporting Unanticipated Problems to Participants ................................................... 31 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 31 
9.1 
Statistical Hypotheses ....................................................................................................................... 31 
9.2 
Sample Size Determination .............................................................................................................. 32 
9.3 
Populations for Analyses .................................................................................................................. 33 
9.4 
Statistical Analyses............................................................................................................................ 33 
9.4.1 
General Approach .......................................................................................................... 33 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) ............................................................. 33 
9.4.3 
Analysis of the Secondary Endpoint(s) ....................................................................... 33 
9.4.4 
Safety Analyses .............................................................................................................. 34 
9.4.5 
Baseline Descriptive Statistics ..................................................................................... 35 
9.4.6 
Planned Interim Analyses ............................................................................................. 35 
9.4.7 
Sub-Group Analyses ..................................................................................................... 35 
9.4.8 
Tabulation of Individual participant Data .................................................................... 35 
9.4.9 
Exploratory Analyses ..................................................................................................... 36 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 36 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ........................................................... 36 
10.1.1 
Informed Consent Process ........................................................................................... 36 
10.1.2 
Study Discontinuation and Closure ............................................................................. 37 
10.1.3 
Confidentiality and Privacy ........................................................................................... 37 
10.1.4 
Future Use of Stored Specimens and Data ............................................................... 38 
10.1.5 
Key Roles and Study Governance .............................................................................. 38 
10.1.6 
Safety Oversight ............................................................................................................. 38 
10.1.7 
Clinical Monitoring .......................................................................................................... 39 
10.1.8 
Quality Assurance and Quality Control ....................................................................... 39 
10.1.9 
Data Handling and Record Keeping ............................................................................ 39 
10.1.10 
Protocol Deviations ........................................................................................................ 41 
10.1.11 
Publication and Data Sharing Policy ........................................................................... 41 
10.1.12 
Conflict of Interest Policy. ............................................................................................. 42 
10.2 
Additional Considerations ................................................................................................................. 42 
10.3 
Abbreviations ...................................................................................................................................... 42 
10.4 
Protocol Amendment History ........................................................................................................... 44 
11 References ........................................................................................................................................................... 46 
 


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STATEMENT OF COMPLIANCE 
 
This trial will be conducted in accordance with the International Conference on Harmonization 
Good Clinical Practice (ICH GCP), applicable United States (US) Code of Federal Regulations 
(CFR), and the University of Missouri School of Medicine Terms and Conditions of Award. The 
Principal Investigator will assure that no deviation from, or changes to the protocol will take 
place without prior agreement from the Investigational New Drug (IND) or Investigational Device 
Exemption (IDE) sponsor, funding agency and documented approval from the Institutional 
Review Board (IRB), except where necessary to eliminate an immediate hazard(s) to the trial 
participants. All personnel involved in the conduct of this study have completed Human Subjects 
Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the IRB for review and approval.  Approval of both the protocol and the consent 
form must be obtained before any participant is enrolled.  Any amendment to the protocol will 
require review and approval by the IRB before the changes are implemented to the study.  All 
changes to the consent form will be IRB approved; a determination will be made regarding 
whether a new consent form needs to be obtained from participants who provided consent, 
using a previously approved consent form. 
1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title: 
Evaluation of zinc and green tea extract supplementation on reduction in 
symptom duration and severity associated with community respiratory 
viral infections: a randomized control trial (ZiPhenol Study) 
Study Description: 
Zinc and green tea supplementation have both been independently 
studied for supporting immune health during cold and flu-like illness in 
non-hospitalized patients with clinical trials demonstrating promising but 
inconsistent results. However, combination therapy may offer an 
improved effect as the antioxidant compound, epigallocatechin gallate 
(EGCG), found in green tea has been demonstrated in-vitro to increase 
intracellular concentrations of free zinc. Elevation of intracellular zinc is 
associated with inhibition of RNA-dependent RNA polymerase, which is 
the enzyme required for viral replication in the host cell. This study seeks 
to evaluate the effect of combination supplementation using established 
doses of zinc and green tea extract (EGCG) on symptom duration and 
severity from cold and flu-like illness, including COVID-19, in adult 
community patients enrolled in a randomized placebo-controlled trial. 
Objectives: 
Primary Objective: 
Determine the impact of combination supplementation against placebo on 
symptom duration and severity in non-hospitalized adult patients acutely 
infected with a respiratory viral illness  
 
Secondary Objectives:  


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1. Compare adverse events of combination supplementation against 
placebo 
2. Compare patient-reported morbidity events of days missed from work 
or school and hospitalization or physician office visit(s) for respiratory viral 
illness related complications associated with combination 
supplementation versus placebo 
Endpoints: 
Primary Endpoint: 
Rate of recovery from cold and flu-like symptoms will be determined by 
quantifying the proportion of patients achieving a daily total symptom 
severity score of 0 or 1 using an established 12 symptom scoring system 
with a severity scale ranging from 0-absent to 3-very severe for each 
symptom (max of 36 points) through seven days of follow-up. 
Secondary Endpoints: 
1. Rates of patient-reported adverse events including nausea, vomiting, 
indigestion, worsening of shortness of breath or difficulty breathing, 
allergic reaction including skin rash, and need to seek medical care (e.g. 
hospitalization or physician visit) for a suspected study drug related 
adverse effect 
2. Rates of patient-reported days missed from work or school and 
hospitalization or physician office visit(s) for respiratory viral illness related 
complications 
Study Population: 
100 patients aged 18 years and older seeking medical care at University of 
Missouri Health Care Emergency Department for cold and flu-like illness 
will be targeted for enrollment. Men and women of all ethnicities will be 
included. 
Phase: 
2 
Description of 
Sites/Facilities Enrolling 
Participants: 
University of Missouri Health Care (MUHC) is a Level 1 Trauma Academic 
Medical Center in central Missouri with over 600 staffed beds. The 
Emergency and Trauma Center experiences nearly 80,000 patient visits 
each year from a diverse population and has a dedicated research center 
that conducts a broad range of research initiatives. Currently, over 30 
publications have been indexed by PubMed from the MUHC Emergency 
Medicine Department. 
Description of Study 
Intervention: 
Enrolled patients will be randomized (1:1) to either placebo or 
combination supplementation consisting of zinc 33mg, green tea extract 
267mg, and ascorbic acid 67mg each per capsule. Study subjects will be 
instructed to take three (3) capsules of either placebo or combination 
supplementation two (2) hours following a meal twice daily for five days. 
Patients will be followed-up for a period of seven consecutive days 
following randomization. 
Study Duration: 
May 30, 2022 - June 1, 2023 
Participant Duration: 
8 days (including day of enrollment) 
 
 
1.2 
SCHEMA 


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Prior to  
Enrollment 
 
 
 
 
 
 
 
 
 
 
Visit 1 
Time Point  
 
 
 
Visit 2 
Time Point  
 
 
Visit 3 
Time Point  
 
Visit 4 
Time Point 
 
Visit 5 
Time Point 
 
Visit 6 
Time Point 
 
Visit 7 
Time Point 
 
Visit 8 
Time Point 
 
 
Total N = 100:  Obtain informed consent. Screen potential participants by inclusion and 
exclusion criteria; obtain history, document. 
Perform baseline assessments 
Provide study drug based on randomization assignment and discharge study subject home 
Patients to begin taking study drug evening of day of randomization 
 
Telephone visit by research personnel to collect primary and secondary endpoints 
Telephone visit by research personnel to collect primary and secondary endpoints 
Final Assessment 
Telephone visit by research personnel 
to collect primary and secondary 
endpoints 
Comb. Supplementation 
N = 50 
Placebo 
N = 50 
Telephone visit by research personnel to collect primary and secondary endpoints 
Randomize 
Telephone visit by research personnel to collect primary and secondary endpoints 
Telephone visit by research personnel to collect primary and secondary endpoints 
Telephone visit by research personnel to collect primary and secondary endpoints 


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1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
Procedures 
Screening/Enrollment/
Baseline 
Visit 1, Day 1 
Study Visit 2, Day 2 
Study Visit 3, Day 3 
Study Visit 4, Day 4 
Study Visit 5, Day 5 
Study Visit 6, Day 6 
Study Visit 7, Day 7 
Study Visit 8, Day 8 
Informed consent 
X 
 
 
 
 
 
 
 
Demographics± 
X 
 
 
 
 
 
 
 
Medical history± 
X 
 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
Administer study intervention 
X-----------------------------------------------------------------------------------X 
Daily telephone visits for 
collection of study endpoints 
X-----------------------------------------------------------------------------------X 
Concomitant medication 
review 
X-----------------------------------------------------------------------------------X 
Physical exam (including 
height and weight) ± 
X 
 
 
 
 
 
 
 
Vital signs± 
X 
 
 
 
 
 
 
 
Height± 
X 
 
 
 
 
 
 
 
Weight± 
X 
 
 
 
 
 
 
 
Hematology ± 
X 
 
 
 
 
 
 
 
Serum chemistry± a 
X 
 
 
 
 
 
 
 
EKG (as indicated) ± 
X 
 
 
 
 
 
 
 
Adverse event review and 
evaluation 
X-----------------------------------------------------------------------------------X 
Radiologic/Imaging 
assessment± 
X 
 
 
 
 
 
 
 
 
Other assessments (e.g., 
immunology assays, 
pharmacokinetic) ± 
X 
 
 
 
 
 
 
 
 
± - Indicates procedures done as part of routine care and not specific to study methods 
a – Basic metabolic panel or complete metabolic panel 
 
2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
RNA viruses are common causes of respiratory infections in humans with limited treatments available, 
especially non-prescription options. Zinc and green tea supplementation have both been independently 
studied for supporting immune health during cold and flu-like illness in non-hospitalized patients with 
clinical trials demonstrating promising but inconsistent results. However, combination therapy may offer 
an improved effect as the antioxidant compound, epigallocatechin gallate (EGCG), found in green tea 
has been demonstrated in-vitro to increase intracellular concentrations of free zinc. Elevation of 
intracellular zinc is associated with inhibition of RNA-dependent RNA polymerase, which is the enzyme 
required for viral replication in the host cell. This study aim seeks to evaluate the effect of combination 
supplementation using established doses of zinc and green tea extract (EGCG) on symptom duration and 


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severity from cold and flu-like illness, including COVID-19, in community patients enrolled in a 
randomized placebo-controlled trial. 
2.2 
BACKGROUND  
RNA viruses (e.g. rhinovirus, influenza, coronavirus, etc.) are common causes of respiratory infections in 
humans contributing to significant morbidity. It is estimated that over 500 million non-influenza 
respiratory infections occur each year in the U.S costing $40 billion annually due to absenteeism and 
healthcare related expenditures.1 This disease burden has significantly increased in recent months as 
COVID-19 continues to impact patients across the world with over 7 million U.S. cases at the time of this 
writing.2 Currently, no Food and Drug Administration (FDA) approved oral therapy exists for preventing 
or treating non-influenza respiratory viral infections including COVID-19 thus the urgent need for 
research in developing new therapeutic options. 
 
The COVID-19 pandemic has galvanized the medical community to innovate treatment options in real-
time with little historical drug therapy experience to guide decision-making. Early attempts to manage 
the disease included repurposing existing FDA approved drug therapy with conflicting results. Among 
these agents included the antimalarial drugs chloroquine and hydroxychloroquine, azithromycin, and 
the antiretroviral lopinavir/ritonavir (Kaletra®).3 In May 2020 the FDA issued an emergency use 
authorization (EUA) for the intravenous antiviral agent remdesivir for treatment of severe COVID-19.4 
This EUA was expanded to include treatment in all hospitalized patients regardless of disease severity;4 
however, most patients with COVID-19 and other non-influenza respiratory viral illnesses do not require 
hospital stay leaving them with limited treatment options. Recently the FDA authorized use of newer 
therapies for COVID-19 in non-hospitalized patients including nirmatrelvir-ritonavir and molnupiravir, 
however, these are recommended for those only at high risk of progressing to severe disease leaving 
many healthier patients without options for disease management. This gap in care provides impetus to 
explore alternative treatment strategies including novel use of over-the-counter (OTC) products and 
supplements. 
 
Zinc is associated with antiviral activity and has been demonstrated to improve recovery time in non-
hospitalized patients with an acute viral respiratory illness.5 This effect is thought to be dependent on 
the availability of free or ionized zinc (iZn) released from the dosage form,6 and it has been observed 
that viral replication is inhibited in-vitro following increases in intracellular free zinc.7,8,9,10 However, 
ionized zinc is poorly permeable through the cell membrane and a high degree of variability exists 
between currently available zinc supplements in terms of free zinc bioavailability.11 Inconsistent real-
world results with current over-the-counter (OTC) zinc lozenge products and other dosage forms 
warrant further investigation into approaches to overcome some of these limitations of zinc 
supplementation. 
 
Green tea extract (GTE) is a commonly found dietary supplement with a variety of purposes for 
improving human health including weight loss, anti-inflammatory, cancer prevention, and cardiovascular 
health.12 Recently, few published and unpublished data described here indicate the ability of the 
primary catechin compound found in GTE, epigallocatechin-3-gallate (EGCG), to act as an effective zinc 


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ionophore.13,14 This activity has been demonstrated in-vitro using human embryonic kidney cells 
(HEK293) and concentrations of EGCG (0.1 - 1.5 µM) achievable with established doses for human 
consumption (figure 1, unpublished data), and appears to be dependent on the extracellular zinc 
concentration (figure 2, unpublished data). 
 
 
 
 


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The ability of EGCG to increase intracellular zinc for up to four hours in cell culture may translate to an 
improved effect of zinc supplementation in-vivo within the clinical context of an acute viral respiratory 
illness. This concept has been popularized following the COVID-19 pandemic with treatment protocols 
including hydroxychloroquine/chloroquine and zinc sulfate demonstrating mixed results and has 
prompted the development of several ongoing clinical studies.15 Previous clinical investigations of EGCG 
for non-COVID-19 viral illness have been limited to prevention of cold and flu-like infections with 
promising results.16,17 However, combination with zinc supplementation was not evaluated nor were 
patients with active viral infection enrolled in these studies. Currently, only one active study could be 
identified on clinicaltrials.gov that seeks to investigate the effect of EGCG on COVID-19 illness.18 This 
study did not include concomitant zinc supplementation nor did it evaluate the effect of 
supplementation on an acute infection. 
 
Ascorbic acid is a well-known supplement often promoted for immune health during the cold and flu 
season despite inconsistent clinical data supporting its use in this manner. However, in the context of 
the proposed study supplement, ascorbic acid is intended to be used to enhance EGCG bioavailability as 
previously described in the literature.19,20,21,22 A similar approach will be used to formulate the zinc and 
EGCG combination supplement as described within this study protocol.23 


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2.3 
RISK/BENEFIT ASSESSMENT   
 
2.3.1 KNOWN POTENTIAL RISKS  
 
Risk to study subjects is anticipated to be in accordance with those associated with using the study drug 
components individually. The most common side effect expected is nausea as a 12-month clinical trial 
evaluating EGCG against placebo using a dosing scheme similar to the current proposal found an 
incidence of 10.2% vs. 4.8%, respectively.24 Taking study drug two hours following a meal is expected to 
limit nausea, but residual risk cannot be eliminated altogether. Secondly, hepatotoxicity has been 
reported with EGCG supplementation, but risk is associated with treatment durations beyond 2-4 weeks 
and doses higher than 800 mg/day.25,26 Our protocol includes only five days of treatment at a dose of 
800 mg/day thus liver injury is not an anticipated risk to patients. Furthermore, patients with a history of 
chronic liver disease will be excluded. Zinc supplementation at the proposed doses may also contribute 
to increased risk a nausea/vomiting. A case report of severe nausea and vomiting occurred in a 17-year-
old male 30 minutes following an acute ingestion of 570mg elemental zinc; however, no other 
complications were observed.27 Clinical studies evaluating zinc lozenges for the treatment of cold and 
flu-like illness have reported increased incidence of gastrointestinal upset as compared to placebo. One 
such trial using a total daily elemental zinc dose up to 207mg observed a rate of nausea and stomach 
distress of 13.5% with zinc vs 10.7% that was associated with placebo.28 No studies of zinc lozenge 
therapy for cold and flu have reported any serious adverse effects,5 however, long-term use of zinc 
supplementation has been associated with copper and iron deficiency.29 Although the current protocol 
includes only five days of treatment patients with a history of copper or iron deficiency will be excluded.  
 
2.3.2 KNOWN POTENTIAL BENEFITS  
 
Potential benefits of this study include elucidation of a novel combination of common dietary 
supplements to improve immune health during an acute respiratory viral illness in non-hospitalized 
patients. Positive results would be supportive to bring such a combination product to market with the 
intent to be used during an active infection as opposed to prevention. Most OTC remedies and herbal 
supplements are marketed for immune health as a preventative strategy, but few options exist for 
patients that are acutely ill. Common cough and cold products available to patients during an active 
infection are designed to only reduce severity of symptoms as opposed to improving immune health 
with the goal of shortening the disease process. This gap in care is of significance as it is estimated that 
over 500 million non-influenza respiratory infections occur each year accounting for $40 billion annually 
in direct and indirect costs stemming from absenteeism and health-care related expenditures.1 
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
 
The risk-benefit assessment of this study intervention is considered favorable given the unmet clinical 
need for alternative therapies to help reduce the disease burden of community respiratory viral 
infections, including COVID-19. The study drug components are each a well-known dietary supplement 
with established dosing ranges and side effect profiles and are already individually used to help prevent 
or reduce cold and flu-like symptoms. Combination supplementation has not been evaluated in the 
method being proposed, but the additive risk of nausea is expected. The administration of study drug 


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two hours after a meal is anticipated to lower gastrointestinal disturbance, and the short duration of 
therapy planned will limit any possible long-term adverse effects associated with the higher doses of 
zinc and EGCG being used.  
 
3 
OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
Determine the impact of 
combination supplementation 
against placebo on symptom 
duration and severity in non-
hospitalized adult patients acutely 
infected with a respiratory viral 
illness, including COVID-19 
Rate of recovery from cold and flu-
like symptoms defined as achieving a 
daily total symptom severity score of 
0 or 1 within 7 days using an 
established 12 symptom scoring 
system with a severity scale ranging 
from 0-absent to 3-very severe for 
each symptom (max of 36 points). 
The 12 symptom domains include: 
nasal drainage, nasal congestion, 
sneezing, scratchy throat, sore 
throat, cough, headache, hoarseness, 
muscle ache, shivering or feverish, 
tiredness and difficulty in 
concentration. Mean total symptom 
severity scores and time to recovery 
will be compared between groups. 
The follow-up period will be seven 
consecutive days following 
randomization. 
 
The primary outcome is 
derived from 
established clinical trial 
methodology 
evaluating the 
effectiveness of zinc 
supplementation for 
cold and flu-like illness. 
We selected this 
measure to maintain 
consistency within the 
published literature 
and to best assess 
patient relevant 
outcomes. 
Secondary 
 
 
1. Compare adverse events of 
combination supplementation 
against placebo 
2. Compare patient-reported 
morbidity events of days missed 
from work or school and 
hospitalization or physician office 
visit(s) for respiratory viral illness 
related complications associated 
with combination supplementation 
versus placebo 
1. Rates of patient-reported adverse 
events including nausea, vomiting, 
indigestion, worsening of shortness 
of breath or difficulty breathing, 
allergic reaction including skin rash, 
and need to seek medical care (e.g. 
hospitalization or physician visit) for a 
suspected study drug related adverse 
effect 
2. Rates of patient-reported days 
missed from work or school and 
hospitalization or physician office 
Relevant safety 
endpoints were 
selected from 
established clinical 
trials assessing zinc and 
EGCG supplementation 
individually. Morbidity 
events of missed days 
from work or school or 
need to seek medical 
care for worsening 
respiratory illness is 
relevant to assess the 


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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
visit(s) for respiratory viral illness 
related complications 
difference in disease 
burden between 
supplementation and 
placebo. 
Tertiary/Exploratory  
 
 
Determine the impact of 
combination supplementation 
against placebo on symptom 
duration and severity in the COVID-
19 positive subgroup of enrolled 
patients 
Rate of recovery from cold and flu-
like symptoms defined as achieving a 
daily total symptom severity score of 
0 or 1 within 7 days using an 
established 12 symptom scoring 
system with a severity scale ranging 
from 0-absent to 3-very severe for 
each symptom (max of 36 points). 
The 12 symptom domains include: 
nasal drainage, nasal congestion, 
sneezing, scratchy throat, sore 
throat, cough, headache, hoarseness, 
muscle ache, shivering or feverish, 
tiredness and difficulty in 
concentration. Mean total symptom 
severity scores and time to recovery 
will be compared between groups. 
This exploratory 
outcome is of interest 
given the continuous 
efforts to improve the 
management of COVID-
19 associated disease, 
and advance the 
medical knowledge on 
possible remedies to 
better improve 
outcomes in non-
hospitalized patients. 
Positive findings would 
garner interest to 
design a randomized 
control study 
exclusivity enrolling 
COVID-19 patients 
 
 
4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
 
This is a double-blind, placebo-controlled, randomized phase 2 study evaluating the combination of zinc 
citrate, green tea extract, and ascorbic acid supplementation given for five days on reduction in 
symptom duration and severity associated with an acute community respiratory viral infection, including 
COVID-19. Patients presenting to MUHC emergency department (ED) seeking routine care for 
respiratory viral illness related symptoms will be screened for study eligibility by ED medical staff. A 
target of 100 eligible patients will be consented and enrolled into the trial by key study personnel in the 
ED at the time of their visit. A study prescription will be generated by an authorized study team member 
also at the time of visit and will be sent to the MUHC investigational research pharmacist or designated 
pharmacist for processing. This will include 1:1 randomization of the study subject to one of the two 
study arms (n=50 for each arm), filling of prescription with required documentation and labeling, and 
coordination with ED research services for final dispensing to the patient. Study patients will be 
discharged from the ED with their study drug before returning home later that day. Due to the time 
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during normal business hours (Monday – Friday; 0800 – 1630) will be targeted for enrollment, however, 
after hours enrollment may occur based on availability of investigational drug services pharmacy staff or 
designated pharmacist. Use of a placebo control and treatment blinding is required to limit observer and 
recall bias given the subjectivity of the outcomes of measure. Patients enrolled will be instructed to 
discontinue any current OTC products that contain any of the components of the study drug to mitigate 
confounding of treatment effect. Common cough and cold products that do not share ingredients with 
study drug will be allowed, and daily utilization will be quantified as name and number of products used 
and doses of each taken daily. This strategy will allow standard-of-care treatment via patient directed 
symptom management using traditional OTC cough and cold medicines, while minimizing bias in 
evaluation of study outcomes. Placebo assignment is assessed to be ethical as no FDA approved therapy 
for the prevention or treatment of non-influenza respiratory viral illness exists.  
 
A separate study is planned that will collect blood samples in 10 patients to assess serum concentrations 
of zinc and EGCG, and a complete metabolic panel (CMP) following five days of taking study drug. 
Baseline serum zinc levels will be collected at time of study enrollment in the MUHC ED while post-
treatment serum concentrations of zinc and EGCG will be obtained on the fifth day of taking study drug. 
Patients will be instructed to report to the MUHC emergency department approximately two hours 
following taking a dose of study drug to have their blood drawn for the aforementioned testing. CMP 
assays will be processed locally at MUHC while serum zinc samples will be sent to Mayo Clinic, and EGCG 
samples will be sent to the University of Missouri Metabolomics Center for analysis. Patients will be 
selected using the same criteria as those enrolled in the placebo-controlled trial, but will not be 
randomized to blinded treatment given the logistical requirements necessitating accurate blood 
sampling. These patients will also not be a part of primary and secondary endpoint collection via daily 
telephone visits.  The purpose of this study is to simply describe peak serum levels of zinc and EGCG 
following multiple dosing of the study drug, as well as to assess the rate of transaminitis if any is to 
occur. A separate consent form will be used for this aspect of the research. 
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
No oral drug therapy or dietary supplement has been FDA approved for the prevention or reduction in 
symptom duration of non-influenza viral respiratory illness including the ‘common cold’ and COVID-19. 
Recently the FDA authorized use of newer therapies for COVID-19 in non-hospitalized patients including 
nirmatrelvir-ritonavir and molnupiravir, however, these are recommended for those only at high risk of 
progressing to severe disease leaving many healthier patients without options for disease management. 
Since no established FDA approved standard-of-care currently exists a placebo-controlled trial presents 
little to no ethical challenge. Furthermore, the primary and secondary outcomes are self-reported 
measures by study participants and the subjectivity of these endpoints necessitates a placebo group for 
statistical comparisons that minimize recall and observer bias.  
 
4.3 
JUSTIFICATION FOR DOSE 
Zinc Citrate 
Zinc is an essential trace element with a wide therapeutic index, and deficiency is common in developing 
nations and in the elderly (normal range: 10 - 16.8 µM).30 Zinc deficiency has been associated with 


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increased pneumonia risk, and supplemental doses greater than 75 mg/day have been associated with a 
reduction in the duration of the common cold.31 A total daily dose of elemental zinc up to 207mg given 
for seven days has been studied in adults with common cold,28,32 and doses ranging between 100 to 150 
mg/day have been administered for months at a time for other indications with few adverse effects 
reported.33 A recent study specifically evaluating zinc lozenges (78mg elemental zinc/day) administered 
for five days for common cold reported side effects of taste disturbances (52%) and dry or sore mouth 
(24%) that occurred at a greater rate than placebo (7% and 2%, respectively).34 However, no serious 
events were reported.  
 
The dose of zinc selected for this study is based on a pharmacokinetic evaluation of serum zinc 
concentrations over time following oral administration of 45mg elemental zinc provided as gluconate 
given under fasting, with food, and two hours post meal conditions in ten young healthy volunteers, 23 
± 2 years (mean ± SD) with an average weight of 70 ± 8 kgs.35 This dose of zinc was able to raise the 
serum concentration (Cmax) by 2.45 µM from baseline (11 ± 2 µM) when administered two hours after a 
meal, while no appreciable increase was observed when zinc was administered with food. The selected 
dose of elemental zinc given as citrate (33 mg/capsule) for the current study is anticipated to raise 
serum concentrations (Cmax) in a similar fashion and in a dose proportional manner whereby a ~5 µM 
increase is expected with a doubling of the dose (i.e. 100mg vs 45mg). The 5 µM increase in Cmax is 
desired as the ability of EGCG to raise intracellular zinc levels appears to be dependent on the 
extracellular zinc concentration. Unpublished in-vitro data have demonstrated 10 µM zinc necessitating 
higher concentrations of EGCG to significantly elevate intracellular zinc (figure 2, unpublished data). 
Assuming patients enrolled have a serum zinc concentration near 10 µM at baseline (based on studies in 
healthy volunteers and those with viral respiratory disease),35,36 a higher dose of zinc would be required 
to achieve serum levels (Cmax) near 20 µM. This higher extracellular zinc concentration would allow for 
lower concentrations of EGCG to significantly increase intracellular zinc (figure 1, unpublished data), 
which is desirable given the relatively poor bioavailability of orally administered EGCG.  Although zinc 
gluconate was the form of zinc utilized for pharmacokinetic study, zinc citrate has been demonstrated to 
display similar characteristics as zinc gluconate in healthy volunteers with comparable bioavailability 
(61.3% vs 60.9%, respectively).37 
 
Zinc toxicity has been rarely reported, but ingestion of 10 - 30 grams of zinc sulfate (2.5 - 7.5 grams of 
elemental zinc) can be lethal in adults.38 Chronic intake of 450 - 1600mg daily can cause anemia, copper 
deficiency, and myeloneuropathies.38 Total daily exposure of zinc used in the current study proposal is 
well below these harmful doses and will be limited to five days in duration. Additionally, twice daily 
dosing would not be expected to lead to systemic accumulation as the elimination half-life of orally 
administered zinc is 1.1 hours.35 Elimination of zinc is mostly through the feces therefore renal 
impairment would not be expected to alter clearance.  
 
Green Tea Extract 
EGCG is a polyphenolic compound found predominately in green tea (Camellia sinesis), but is also found 
in other foods including a variety of fruits and nuts albeit in smaller amounts. A 250 mL cup of brewed 
green tea contains approximately 25 - 60mg of EGCG along with variable amounts of caffeine.39 Green 
tea extract is often sold as a dietary supplement containing 50% or more of EGCG by weight and 
contains little to no caffeine allowing for higher dosing of the antioxidant catechin compounds found in 
whole plant tea drinks.  EGCG displays a wide therapeutic index with doses studied ranging from 150 - 


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2,400 mg in subjects without serious adverse effects.40 EGCG is metabolized via methylation by catechol-
O-methyltransferase (COMT) as well as degradation by colonic bacteria with metabolites excreted 
through both urinary and fecal routes. Drug interaction studies have indicated that EGCG is not 
expected to inhibit the CYP enzymes 1A2, 2D6, 2C9, or 3A4 to any clinically significant degree following 
repeated doses of 800 mg/day.41 
 
Study dosing of EGCG was selected based on published pharmacokinetic data detailing serum 
concentrations over time following single and multiple doses of 400mg twice daily in healthy volunteers. 
A single dose of 400mg taken with food corresponded to an average EGCG Cmax of 0.38 ± 0.18 µM, 
while fasting conditions yielded a mean Cmax of 1.65 ± 0.87 µM in healthy volunteers (average age of 42 
years and weight of 75 ± 20 kgs).42 A multiple dose study evaluating 400mg twice daily taken with food 
for four weeks demonstrated a mean Cmax of 0.34 ± 0.14 µM in a separate but similar volunteer 
population indicating little to no accumulation with this dosing schedule.43 These serum concentrations 
were simulated in-vitro to establish a dose response curve of EGCG to increase intracellular zinc 
concentrations (figure 1, unpublished data).  Results indicate the ability of obtainable concentrations of 
EGCG from a dosing schedule of 400mg twice daily to significantly increase intracellular zinc levels in 
human kidney cells under experimental conditions. The current study proposal will evaluate the effect of 
this activity in-vivo providing translational evidence for combination supplementation to improve 
immune health during an acute respiratory viral illness.  
 
Safety and toxicity data on EGCG have been thoroughly summarized by formal drug safety panels 
including the European Food and Safety Authority (EFSA) and United States Pharmacopeia Convention 
(USP).44,45 Common mild side effects reported with standard dosing include gastrointestinal symptoms 
especially when taken in a fasting state, but rare cases of hepatoxicity have been reported. The EFSA 
and USP concluded that doses equal to or greater than 800mg of EGCG per day taken for four months or 
longer are associated with elevations of alanine aminotransferase (ALT) and aspartate 
transaminase (AST) in a small percentage (less than 10%) of the population.44,45 The strongest evidence 
for safety and hepatotoxicity risk of EGCG comes from the Minnesota Green Tea Trial (MGTT).46 This was 
a randomized, placebo-controlled, double-blind trial investigating the effects of daily EGCG (843 
mg/day) for 12 months in 1075 post-menopausal women. 538 subjects were randomized to EGCG and 
the difference in biomarkers for the development of breast cancer was compared against placebo 
(n=537). The most common side effect reported that occurred significantly more often than placebo was 
nausea (10.2% vs 4.8%, p =0.001), while no differences were seen in rates of serious adverse events 
(2.2% vs 1.5%). Liver enzyme elevations in patients taking EGCG occurred more frequently compared to 
placebo (6.7% vs 0.7%, p < 0.001), however, the average increase in ALT was only 5.4 U/L and was 
reversible after stopping therapy. Overall, green tea extracts are generally considered safe for human 
consumption with liver injury occurring rarely with doses less than or equal to 800 mg/day of EGCG and 
taken less than two weeks in duration.44,45 
 
Ascorbic Acid 
Vitamin C is an essential nutrient for human health and must be obtained through dietary 
supplementation. Clinical uses of ascorbic acid include treatment of scurvy, enhancing absorption of 
iron, acidification of urine, skin care, and prevention and treatment of the common cold. Although the 
immunomodulatory properties of vitamin C are favorable the purpose for the proposed study is to 
enhance absorption of EGCG.47,48,49,50 This is achieved by combining 200mg of ascorbic acid with 


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standard and high doses of EGCG, which has been previously described.51 Safe dosing of vitamin C has 
been established up to 2000 mg/day where higher doses are associated with diarrhea and 
gastrointestinal upset.52 Total daily exposure with the designed dosing protocol (400mg) is well below 
the recommended daily limit and thus no serious adverse effects are expected. 
 
4.4 
END OF STUDY DEFINITION 
 
The end of the study is defined as completion of the last visit or procedure shown in the SoA in the trial 
globally. The study period will be terminated early if the IRB, Independent Safety Monitor, or study 
investigators determine that the study jeopardizes patient safety beyond an expected risk level at any 
time. 
 
5 
STUDY POPULATION 
 
5.1 
INCLUSION CRITERIA 
 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
1. Provision of signed and dated informed consent form 
2. Stated willingness to comply with all study procedures and availability for the duration of the 
study  
3. Male or female, aged 18 years and older  
4. Ability to take oral medication and be willing to adhere to the prescribed dosing regimen 
5. Self-reported cold or flu symptoms for < 72 hours 
 
Men and women of all ethnicities will be included. 
 
5.2 
EXCLUSION CRITERIA 
 
An individual who meets any of the following criteria will be excluded from participation in this study: 
1. Pregnant or actively seeking to become pregnant 
2. Positive for influenza with planned treatment with oseltamivir or baloxavir 
3. Current or planned treatment with an FDA regulated drug (including those under EUA) for 
COVID-19 
4. Chronic liver disease (i.e. baseline liver function tests (LFTs) > 1.5x the ULN or established 
cirrhosis) 
5. Chronic renal failure stage 4 or greater 
6. History of kidney stones 
7. Acute secondary bacterial infection at the time of enrollment 
8. Requiring hospitalization for any reason at the time of enrollment 
9. History of copper or iron deficiency 
10. Current prescription for quinolone antibiotics, tetracycline antibiotics, or penicillamine at the 
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11. Allergy/intolerance to any of the active ingredients under investigation including zinc citrate, 
green tea extract, and ascorbic acid (vitamin C) 
12. Patients without decision making capacity 
13. Currently enrolled in another clinical trial for a respiratory viral infection 
5.3 
LIFESTYLE CONSIDERATIONS 
 
During this study, participants are asked to: 
• 
discontinue any OTC supplements containing the active ingredients of study treatment 
beginning the first day of randomization and during the entire follow-up period 
• 
record daily usage of OTC cough and cold preparations with product(s) names and daily doses 
taken using a ‘sick’ diary (not required but will be encouraged) 
 
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 
positive influenza test with intention to be treated with oseltamivir or baloxavir may be rescreened. 
Rescreened participants should be assigned the same participant number as for the initial screening. 
 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
 
Patients will be recruited through the emergency department at MUHC during study months of May 
2022 – June 2023. Patients seeking routine care for respiratory viral illness related symptoms will be 
screened by ED medical staff for eligibility and if appropriate will be consented by key study personnel 
members for enrollment. The target number of subjects to be enrolled during the study period occurring 
May 2022 – June 2023 is 100 (50 patients randomized to placebo and 50 to the supplementation group). 
This target is derived from similarly conducted studies evaluating zinc supplementation (without green 
tea) in a comparable adult population as identified with the current proposal. The anticipated accrual 
rate is approximately 5-10 patients each week based on current MUHC ED patient visit volumes and 
prevalence of cold and flu-like illness during the study time period. MUHC is considered a safety net 
hospital and therefore treat patients regardless of their insurance status. This designation will allow 
underrepresented populations equal opportunity to participate in this study. Advertisements will be 
used including a flyer containing the University of Missouri School of Medicine logo that will be placed in 
select clinic spaces, and an email announcement distributed through the study site’s email system to 
help increase awareness of study opportunity for interested patients or their caregivers. 
 


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6 
STUDY INTERVENTION 
 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
6.1.1 STUDY INTERVENTION DESCRIPTION 
 
The compounded supplementation study product includes select amounts of zinc citrate, green tea 
extract, and ascorbic acid that have been mixed together using geometric dilution to form a light brown 
fine powder, and is capsulated using a capsule machine with size 0 empty gelatin capsules resulting in a 
measured weight of 438mg ± 10% per capsule. The per capsule amount of each supplement component 
is as follows: 
 
267mg of green tea extract/capsule 
104mg of zinc citrate (33mg elemental zinc)/capsule 
67mg ascorbic acid/capsule 
 
The finished goods specification sheets, safety data sheets, and certificate of analysis (CoA) for each 
respective supplement has been provided by the supplier and have been attached as addendums. 
 
 
Addendum A – zinc citrate specification sheet, safety data sheet, and CoA 
Addendum B – green tea extract (≥50% EGCG) specification sheet, safety data sheet, and CoA 
Addendum C – ascorbic acid specification sheet, safety data sheet, and CoA 
 
Zinc citrate is a white crystalline powder containing 32% zinc by weight. Zinc is a naturally occurring 
element that is essential for human health, and various salts are available over-the-counter (OTC) for 
supplementation purposes. The FDA approved zinc product is zinc sulfate for injection.53 
 
Green tea extract is a brown powder-like substance derived from the stems and leaves of Camellia 
sinensis through an extraction process using water and organic solvents such as ethanol. A variety of 
green tea extracts are available over-the-counter for supplementation and contain little to no caffeine. 
Extract products contain high amounts of antioxidant catechin compounds the most abundant of which 
is epigallocatechin-3-gallate (EGCG). The EGCG content of most available green tea extract products is 
50% by weight, but variability exists due to inconsistencies in manufacturing processes. The FDA 
approved a green tea extract product in 2006 called Veregen® (sinecatechins) ointment,54 which was the 
first prescription botanical accepted by the governing body. 
 
Ascorbic Acid commonly known as vitamin C is available as a white crystalline powder and available 
over-the counter for oral supplementation. It is an essential nutrient naturally found in food sources and 
is FDA approved for the treatment of scurvy.55 
 
Placebo capsules will be filled with microcrystalline cellulose, which is refined wood pulp commonly 
used in food production as an anti-caking or bulking agent. It is a chemically inert compound with no 
appreciable absorption following oral administration, and has been rarely reported to induce an allergic 
reaction. The per capsule amount of microcrystalline cellulose is as follows: 


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300mg ± 10% of microcrystalline cellulose/capsule 
The certificate of analysis for microcrystalline cellulose is attached as an addendum.  
 
Addendum D - microcrystalline cellulose CoA 
6.1.2 DOSING AND ADMINISTRATION 
 
Eligible patients will be randomized 1:1 to one of the following treatment groups with the following 
dosing schedule: 
1. Zinc/EGCG/ascorbic acid blend: three (3) capsules taken orally two (2) hours following a meal 
twice daily x5 days. 
2. Placebo: three (3) capsules taken orally two (2) hours following a meal twice daily x5 days 
 
The per capsule and total daily dose of each of the individual supplement components is as follows: 
267mg green tea extract/capsule (1,600 mg/day) 
33mg elemental zinc/capsule (200 mg/day) 
67mg ascorbic acid/capsule (400 mg/day) 
The per capsule and total daily dose of each of the placebo component is as follows: 
300mg microcrystalline cellulose/capsule (1,800 mg/day) 
 
Patients will be instructed to begin taking their assigned study product starting the evening of 
enrollment day and to continue for five consecutive days. For missed doses study participants will be 
instructed not to double up on doses and to take the prescribed dose at the next scheduled 
administration time. Study product should be stored away from children so to avoid unintended 
administration by unauthorized study participants. 
 
Study participants who will be undergoing blood sampling procedures will not be randomized or receive 
placebo. 
 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
Active ingredients for the zinc/EGCG/ascorbic acid blend will be procured from a U.S. based 
supplements supplier (www.bulksupplements.com; FDA registration number: 17938017996) at the 
following amounts factoring in a 20% waste tolerance and available package size. 
1. Zinc citrate – 200g 
2. Green tea extract (≥50% EGCG) – 500g 
3. Ascorbic acid – 200g 
Placebo ingredients will be procured from the MUHC investigation pharmacy services at the following 
amounts factoring in a 20% waste tolerance and available package size. 


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1. Microcrystalline cellulose – 1kg 
Compounded capsules of both the study supplement product and placebo will be assessed for weight 
variability with a 10% variance allowed. Capsules will be prepared in small batches throughout the study 
period based on the anticipated weekly accrual rate of enrollment. Each batch will be assigned a unique 
lot number, their own compound log, and up to a 180 day expiration date. Storage will occur in the 
investigational drug pharmacy where compounded capsules will be kept in a standard amber colored 
prescription bottle with a desiccant placed within the bottle to absorb any ambient moisture. 
Temperature monitoring will occur daily by the investigation drug pharmacist with a target range of 
20°C – 25°C per United States Pharmacopoeia (USP) and the supplement manufacture’s 
recommendations. The investigational drug pharmacist or designated pharmacist will receive a study 
prescription from an authorized prescriber following patient enrollment for processing, which includes 
assignment of randomization, filling of prescription with required documentation and labeling, and 
coordination with the ED study staff for delivery to the patient in the ED.  Study patients will be 
discharged from the ED with their study drug before returning home later that day. Unused study drug 
returned by participants will be received by the investigational drug pharmacy for proper 
documentation, storage, and eventual destruction.  
 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
Study products will be prepared using University of Missouri Health Care (MUHC) pharmacy 
compounding resources using traditional practices of geometric dilution and capsulation. Compounding 
and dispensing of study supplement and placebo will be in compliance with Missouri Board of Pharmacy 
regulation 20 CSR 2220.2.400 Compounding Standards of Practice. White, opaque size 0 gelatin capsules 
will be used to prepare both study supplement and placebo, and will be dispensed into amber 
prescription bottles with tamper resistant tops for patient delivery. Labeling of study product will be in 
such a way to maintain blinding, but will include all information as required by state and federal 
regulations including: 1) The date the prescription was filled; 2) A prescription number or other unique 
identifier; 3) The patient’s name; 4) The prescriber’s directions for use; 5) The prescriber’s name; 6) The 
pharmacy/institution’s name, address, and contact information; 7) blinded name of study drug 
dispensed. The Federal Investigational Drug Caution Statement—"CAUTION: Drug limited by Federal 
(United States) Law to investigational use only."—will be applied to the study drug products. 
 
6.2.3 PRODUCT STORAGE AND STABILITY 
 
Storage requirements for study products will be in accordance with the individual component 
manufacture recommendations and USP. This includes keeping compounded capsules in a dry and cool 
environment with a target temperature of 20°C – 25°C. To minimize moisture a desiccant will be placed 
in the bulk bottles containing prepared study supplement and placebo capsules, respectively. An 
expiration date of up to 180 days will be given to compounded capsules to limit any unknown loss of 
potency that may occur with a long-dated expiration. This dating is in accordance with United States 
Pharmacopeia (USP) General Chapter 795 guidance for non-sterile compounding. 
 
6.2.4 PREPARATION 
 


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Study capsules for combination supplementation will be prepared by compounding each of the three 
individual components using a porcelain mortar and pestle and method of geometric dilution. The mixed 
fine powder will be used to fill white colored size 0 gelatin capsules using a capsule machine with a 100 
capsule capacity. A 10% variability tolerance will be permitted for under/over filling of each capsule with 
a target weight of 438mg per capsule. Placebo capsules will be prepared in a similar fashion using 
microcrystalline cellulose with identical capsules and a fill weight target of 300mg ± 10%. All 
compounding will occur on site at MUHC in a dedicated non-sterile compounding room located in the 
inpatient pharmacy. 
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
 
Randomization will be performed using an online generator (http://www.randomization.com) that 
assigns study subjects to a single treatment arm using randomly permuted blocks. The investigational 
drug pharmacist will conduct maintenance of trial randomization codes and appropriate blinding. 
Double blinding will be used to limit recall and observer bias given the subjectivity of the primary 
outcome. Opaque, white colored capsules of the same size will be used to prepare both study 
supplement and placebo capsules to conceal treatment assignment. Serious adverse events requiring 
medical care that are suspected to be caused from the study drug or an unintentional ingestion of study 
drug by non-study participants will initiate un-blinding procedures. This will include contacting research 
pharmacy personnel or their designee by medical staff treating the adverse event. Research pharmacy 
personnel are available during normal business hours, however, their designee (other MUHC inpatient 
pharmacists) will be available 24 hours a day, seven days a week. Treating medical staff will be 
immediately informed of the study subject’s randomization assignment by the research pharmacist or 
their designee for purposes of emergent medical care; recording of the unblinding will be performed by 
the research pharmacist and notification will be sent to the primary investigator and Independent Safety 
Monitor within 24 hours. Documentation of an unblinding event will include: identification of participant 
unblinded, reason for unblinding, date and time of unblinding, how unblinding information was 
obtained, and which research team member(s) have been unblinded. Study participants will be removed 
from the study if they experience an adverse event that requires medical care due to complications from 
worsening respiratory viral illness or study drug. Patients not removed will be contacted daily via 
telephone visits for seven consecutive days by MUHC emergency department research staff starting the 
day after enrollment day for collection of primary and secondary outcome data elements. MUHC 
emergency department research staff are trained technicians autonomous of study teams for purposes 
of clinical trial and facilitate independent data collection for study endpoints.  Following the seven days 
of follow-up patients will be dismissed from study participation and will be instructed to follow-up with 
their primary care provider for any future medical needs. 
 
6.4 
STUDY INTERVENTION COMPLIANCE 
 
Compliance of study intervention will be assessed by MUHC emergency department research staff via 
daily telephone visits. Occurrences of non-compliance will be patient-reported and include number of 
missed doses for any given day during the on-treatment follow-up period.  
 
6.5 
CONCOMITANT THERAPY 


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Patients enrolled will be instructed to discontinue any current OTC products that contain any of the 
components of the study drug to mitigate confounding of treatment effect. Common cough and cold 
products that do not share ingredients with study drug will be allowed, and daily utilization will be 
quantified as name and number of products used and doses of each taken daily using a patient ‘sick’ 
diary. This strategy will allow standard-of-care treatment via patient directed symptom management 
using traditional OTC cough and cold medicines, while minimizing bias in evaluation of study outcomes.  
 
6.5.1 RESCUE MEDICINE 
 
The study site and sponsor will not supply OTC cough and cold rescue medication. Obtainment of this 
type of therapy will be at the discretion of the study participants with the restriction that no product 
should include any amount of the study supplement individual components of zinc, green tea, or 
ascorbic acid (vitamin C).  
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
 
Discontinuation from study supplement or placebo 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). 
 
Adverse events necessitating discontinuation from the study including removing patients from follow-up 
telephone visits for any remaining outcome related data collection include any event that would lead to 
a patient requiring hospitalization. This includes hospitalization related to a suspected adverse event 
from study drug resulting in unblinding procedures or for worsening respiratory status. Patient self-
discontinuation of study intervention due to intolerance affecting future compliance will allow patients 
to remain in the study to complete any remaining telephone visits for primary and secondary endpoint 
data collection. Efforts to promote compliance including reinforcing patients to administer study 
product two hours following a meal will be employed before discontinuing patients from study 
intervention, but patient refusal to continue with treatment will be considered a dropout with an 
attempt to collect remaining telephone visits for completeness of endpoint related data capture.  
 
The data to be collected at the time of study intervention discontinuation will include the following: 
• 
Date of study discontinuation 
• 
Reason for discontinuation 
• 
Number of study days completed prior to discontinuation of treatment/study withdrawal 
• 
Total number of patient-reported doses taken of study drug prior to discontinuation of 
treatment/study withdrawal 
 


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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: 
 
• 
Pregnancy 
• 
Significant study intervention non-compliance  
• 
If any clinical adverse event (AE) necessitating hospitalization 
• 
Disease progression which requires hospitalization 
• 
If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
The reason for participant discontinuation or withdrawal from the study will be recorded. Subjects who 
sign the informed consent form and are randomized but do not receive the study intervention may be 
replaced.  Subjects who sign the informed consent form, and are randomized and receive the study 
intervention, and subsequently withdraw, or are withdrawn or discontinued from the study may also be 
replaced. 
7.3 
LOST TO FOLLOW-UP 
 
A participant will be considered lost to follow-up if he or she fails to return for seven consecutive 
scheduled telephone visits and is unable to be contacted by the study site staff.  
 
The following actions must be taken if a participant fails to return a missed telephone contact for a 
required study visit: 
• 
The site will attempt to contact the participant to reschedule the missed visit within the same 
business day as the originally scheduled appointment, counsel the participant on the 
importance of maintaining the assigned visit schedule, and ascertain if the participant wishes to 
and/or should continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, 3 telephone call attempts within 
the same business day). These contact attempts should be documented in the participant’s 
medical record or study file.  
• 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
EFFICACY ASSESSMENTS  
 
Patients presenting to MUHC emergency department for cold and flu-like symptoms during the study 
period will be assessed for eligibility by the admitting physician based on protocol inclusion and 


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exclusion criteria as previously detailed. Standard evaluation and collection of patient overall health 
status including past medical history, vital signs, physical exam, necessary imaging, and laboratory 
assessment will be completed as part of routine care associated with the emergency department visit. 
Patients enrolled into the study will be randomized and provided study drug the same day of their 
emergency department visit such that patients will not discharge from the emergency department until 
they have received their study drug and corresponding instructions for study participation. Testing 
results including COVID-19 status or positive influenza will be communicated via telephone contact to 
study patients as part of routine care follow-up and in accordance with MUHC emergency department 
procedures. Patients meeting exclusion criteria following results of study related testing information will 
be instructed to discontinue study intervention and follow-up with their primary care provider or other 
non-study related healthcare provider for appropriate management. 
 
Upon receiving study drug and following discharge from the emergency department study subjects will 
begin self-administering study product as outlined in section 6.1.2 of this protocol the evening of the 
day of enrollment. Research staff from the MUHC emergency department will begin contacting patients 
the following day and daily thereafter for a total of seven consecutive days as described in section 1.3 of 
this protocol. The following data elements are to be collected each day via telephone visits for the 
efficacy endpoints: 
 
 
Primary efficacy endpoints: 
Symptom 
Severity Score 
0 – absent, 1- mild, 2- moderately sever, 3 – very severe 
nasal drainage 
 
nasal congestion 
 
sneezing 
 
scratchy throat 
 
sore throat 
 
cough 
 
headache 
 
hoarseness 
 
muscle ache 
 
shivering or feverish 
 
tiredness  
 
difficulty in concentration 
 
Total Severity Score (max: 36 points) 
 
 
Recovery from cold and flu-like illness 
defined as daily total symptom 
severity score of 0 or 1 
Yes or No 
day 2 
 
day 3 
 
day 4 
 
day 5 
 
day 6 
 


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day 7 
 
day 8 
 
 
 
Secondary efficacy endpoints: 
Morbidity Event 
Yes or No 
missed days from work or school 
    number of days 
 
hospitalization or physician office visit(s) for 
respiratory viral illness related complications 
 
 
Additional data elements to be collected with each daily telephone visit that do not pertain to the 
primary and secondary endpoints, but remain clinically relevant include patient reported use of any OTC 
cough and cold medicine(s) for which MUHC emergency department research staff will record the 
number of the different products used, each product(s) name, and the number of doses of each product 
taken by the patient. Patients will be encouraged to record their OTC medication use using a ‘sick’ diary, 
but this will not be a formal requirement of the protocol. Study subjects will also be asked about how 
many doses were missed in the preceding 24 hours during the daily telephone visits conducted by 
MUHC emergency department research staff. For patients that withdraw early from the study the 
following information will be collected at their last visit if possible: 
• 
Date of study discontinuation 
• 
Reason for discontinuation 
• 
Number of study days completed prior to discontinuation of treatment/study withdrawal 
• 
Total number of patient-reported doses taken of study drug prior to discontinuation of 
treatment/study withdrawal 
 
Relevant patient demographic information including: age, sex, ethnicity, history of asthma, COPD, 
diabetes, COVID-19 status, hospitalization for respiratory condition within the past year will be obtained 
using existing health record data. 
 
Study subjects participating in blood sampling procedures will not be contacted daily for collection of 
efficacy assessments.   
 
8.2 
SAFETY AND OTHER ASSESSMENTS 
 
Patients presenting to MUHC emergency department for cold and flu-like symptoms during the study 
period will be assessed for eligibility by the admitting physician based on protocol inclusion and 
exclusion criteria as previously detailed. Standard evaluation and collection of patient overall health 
status including past medical history, vital signs, physical exam, necessary imaging, and laboratory 
assessment will be completed as part of routine care associated with the emergency department visit. 
Patients enrolled into the study will be randomized and provided study drug the same day of their 
emergency department visit such that patients will not discharge from the emergency department until 
they have received their study drug and corresponding instructions for study participation. Testing 
results including COVID-19 status or positive influenza will be communicated via telephone contact to 
study patients as part of routine care follow-up and in accordance with MUHC emergency department 


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procedures. Patients meeting exclusion criteria following results of study related testing information will 
be instructed to discontinue study intervention and follow-up with their primary care provider or other 
non-study related healthcare provider for appropriate management.  
 
Upon receiving study drug and following discharge from the emergency department study subjects will 
begin self-administering study product as outlined in section 6.1.2 of this protocol the evening of the 
day of enrollment. Research staff from the MUHC emergency department will begin contacting patients 
the following day and daily thereafter for a total of seven consecutive days as described in section 1.3 of 
this protocol. The following data elements are to be collected each day via telephone visits for the safety 
endpoints: 
 
 
Safety endpoints: 
Adverse Effect 
Yes or No 
nausea 
 
vomiting 
 
indigestion 
 
worsening of shortness of breath or difficulty 
breathing 
 
allergic reaction 
    skin rash 
    hives 
    swelling of lips or tongue 
 
hospitalized or physician visit for study drug 
related adverse effect 
 
 
Additional data elements to be collected with each daily telephone visit that do not pertain to the 
primary and secondary endpoints, but remain clinically relevant include patient reported use of any OTC 
cough and cold medicine(s) for which MUHC emergency department research staff will record the 
number of the different products used, each product(s) name, and the number of doses of each product 
taken by the patient. Patients will be encouraged to record their OTC medication use using a ‘sick’ diary, 
but this will not be a formal requirement of the protocol. Study subjects will also be asked about how 
many doses were missed in the preceding 24 hours during the daily telephone visits conducted MUHC 
emergency department research staff. For patients that withdraw early from the study the following 
information will be collected at their last visit if possible: 
• 
Date of study discontinuation 
• 
Reason for discontinuation 
• 
Number of study days completed prior to discontinuation of treatment/study withdrawal 
• 
Total number of patient-reported doses taken of study drug prior to discontinuation of 
treatment/study withdrawal 
 
Relevant patient demographic information including: age, sex, ethnicity, history of asthma, COPD, 
diabetes, COVID-19 status, hospitalization for respiratory condition within the past year will be obtained 
using existing health record data. 
 


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Study subjects participating in blood sampling procedures will not be contacted daily for collection of 
pre-defined safety assessments. 
   
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
 
Adverse event means any untoward medical occurrence associated with the use of an intervention in 
humans, whether or not considered intervention-related (21 CFR 312.32 (a)). 
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 
An adverse event or suspected adverse reaction is considered "serious" if, in the view of either the 
investigator or Independent Safety Monitor, it results in any of the following outcomes: Death, a life-
threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a 
persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions, or a congenital anomaly/birth defect. Important medical events that may not result in death, 
be life-threatening, or require hospitalization may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse (21CFR312.32). 
 
8.3.2.1 EXPECTEDNESS  
 
The principle investigator along with co-investigators 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. 
 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
8.3.3.1 SEVERITY OF EVENT 
 
For adverse events (AEs) not included in the protocol defined grading system, the following guidelines 
will be used to describe severity.  
 
• 
MILD: Awareness of signs or symptoms, but easily tolerated and are of minor irritant type 
causing no loss of time from normal activities. Symptoms do not require therapy or a 
medical evaluation; signs and symptoms are transient. 


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• 
MODERATE: Events introduce a low level of inconvenience or concern to the participant and 
may interfere with daily activities, but are usually improved by simple therapeutic measures; 
moderate experiences may cause some interference with functioning 
• 
SEVERE:  Events interrupt the participant’s normal daily activities and generally require 
systemic drug therapy or other treatment; they are usually incapacitating 
 
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. 
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:  The adverse event is clearly related to the investigational 
agent/procedure – i.e. an event that follows a reasonable temporal sequence from 
administration of the study intervention, follows a known or expected response pattern to 
the suspected intervention, that is confirmed by improvement on stopping and 
reappearance of the event on repeated exposure and that could not be reasonably 
explained by the known characteristics of the subject’s clinical state. 
• 
POSSIBLY RELATED:  An adverse event that follows a reasonable temporal sequence from 
administration of the study intervention follows a known or expected response pattern to 
the suspected intervention, but that could readily have been produced by a number of other 
factors. 
• 
NOT RELATED:  The adverse event is clearly not related to the investigational 
agent/procedure - i.e. another cause of the event is most plausible; and/or a clinically 
plausible temporal sequence is inconsistent with the onset of the event and the study 
intervention and/or a causal relationship is considered biologically implausible.  
 
8.3.3.3 EXPECTEDNESS  
 
The principle investigator along with co-investigators 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. 
 
• 
UNEXPECTED - nature or severity of the event is not consistent with information about the 
condition under study or intervention in the protocol, consent form, product brochure, or 
investigator brochure. 
• 
EXPECTED - event is known to be associated with the intervention or condition under study.  
  
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
 


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The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits 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, 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.  
 
Study research technicians will record all reportable events via daily telephone visits with start dates 
occurring  sometime near 24 hours after informed consent is obtained and continue until 2 days (for 
non-serious AEs and SAEs) after the last planned day of study drug administration (total of 7 days).  At 
each study visit, study research technicians will inquire about the occurrence of AE/SAEs since the last 
visit.  Events will be followed for outcome information until resolution or stabilization. 
 
Solicited events will include patient self-reported:  
• 
Nausea 
• 
Vomiting 
• 
Indigestion 
• 
Worsening of shortness of breath or difficulty breathing 
• 
Allergic reaction 
o  skin rash 
o  hives 
o swelling of lips or tongue 
• 
Hospitalized or physician visit for study drug related adverse effect 
 
Unsolicited events will include any patient self-reported adverse event that is provided without 
prompting by the research technician and that is not related/similar to any of the solicited events being 
collected. 
 
8.3.5 ADVERSE EVENT REPORTING  
 
Formal data safety monitoring will occur every two weeks by an Independent Safety Monitor. A review 
of events necessitating unblinding of study subjects, overall rate of solicited and unsolicited adverse 
events, as well as the rate of patient reported self-dropout due to intolerance will be continuously 
monitored throughout the study period. If the overall dropout rate exceeds 10% at any time or a study 
subject experiences a serious adverse event the Investigational Review Board (IRB) will be notified 
within five business days for review. The study period will be terminated early if the IRB, Independent 


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Safety Monitor, or study investigators determine that the study jeopardizes patient safety beyond an 
expected risk level at any time. 
 
8.3.6 SERIOUS ADVERSE EVENT REPORTING 
 
The study research team including technicians and co-investigators will immediately report to the 
primary investigator and Independent Safety Monitor 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 (a 
physician research team member must determine probability of adverse event occurring due to study 
drug). Study endpoints that are serious adverse events (e.g. hospitalization for either a suspected study 
drug related adverse event or worsening respiratory status from viral infection) 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., hospitalization from anaphylaxis). In that case, members of the 
research team or other involved party such as the investigational drug pharmacist in cases of unblinding 
must report the event to the primary investigator and Independent Safety Monitor within 24 hours. The 
primary investigator must report any unexpected serious adverse event to the IRB within 5 business 
days. 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 primary investigator 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 5 business days after the primary investigator’s receipt of the information.  In addition, primary 
investigator 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 5 business days after the primary investigator determines that the information 
qualifies for reporting.  See below flow chart for serious adverse event reporting scheme: 
 
 


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Yes 
Maintained in Clinical Study Database 
No 
Yes 
Unexpected 
No 
Maintained in Clinical Study Database 
Yes 
Patient self-reported adverse event 
during scheduled telephone visits 
Maintained in Clinical Study Database 
Serious  
No 
Positive Causality 
Maintained in Clinical Study Database 
Probably Related to 
Study Drug 
Yes 
Follow-Up Days 1-7 
(Beginning Day After Study Enrollment) 
Report to IRB  and FDA within 5 Business Days 
for Review 
No 


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8.3.7 REPORTING EVENTS TO PARTICIPANTS  
 
Patients will not be informed of adverse events apart from those self-reported by them during 
secondary endpoint data collection. Incidental findings from study enrollment will be communicated via 
telephone contact to study patients as part of routine care follow-up and in accordance with MUHC 
emergency department procedures. 
 
8.3.8 EVENTS OF SPECIAL INTEREST  
A separate study is planned that will collect blood samples in 10 patients to assess serum 
concentrations of zinc and EGCG, and a complete metabolic panel (CMP) following five days of taking 
study drug. Patients will be selected using the same criteria as those enrolled in the placebo-controlled 
trial, but will not be randomized to blinded treatment given the logistical requirements necessitating 
accurate blood sampling. These patients will also not be a part of primary and secondary endpoint 
collection via daily telephone visits.  The purpose of this study is to simply describe peak serum levels of 
zinc and EGCG following multiple dosing of the study drug, as well as to assess the rate of transaminitis if 
any is to occur. Occurrences of transaminitis for which the alanine transaminase (ALT) is >3x the ULN 
AND the total bilirubin is >2xULN will prompt reporting to the FDA within 5 business days. A separate 
consent form will be used for this aspect of the research. 
 
8.3.9 REPORTING OF PREGNANCY  
 
Pregnant patients or those planning to become pregnant will be excluded from study participation. If a 
patient enrolled becomes pregnant anytime during the follow-up period then the study drug will be 
stopped and the patient will be discontinued from the study. The IRB will not be notified unless the 
patient meets reporting criteria from experiencing a serious adverse event.  
 
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 possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility 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. 


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8.4.2  UNANTICIPATED PROBLEM REPORTING  
 
The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review Board 
(IRB) and to the lead principal investigator (PI). 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:   
 
• 
UPs that are serious adverse events (SAEs) will be reported to the IRB within 5 business days and 
to the primary investigator and Independent Safety Monitor within 24 hours of the investigator 
becoming aware of the event.  
• 
Any other UP will be reported to the IRB and primary investigator within 5 businesbusiness 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 48 hours of the IRB’s receipt of the report of the 
problem from the investigator. 
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS   
 
Patients will not be informed of unanticipated problems apart from those self-reported by them during 
primary and secondary endpoint data collection, or those necessitating premature termination or 
suspension of the study as a whole. 
 
9 
STATISTICAL CONSIDERATIONS  
 
9.1 
STATISTICAL HYPOTHESES 
 
• 
Primary Efficacy Endpoint(s):  
 
1. Combination supplementation with zinc, green tea extract, and ascorbic acid is associated with a 
decrease in duration and severity of cold and flu-like symptoms following five days of treatment 
as compared to placebo (superiority analysis). Analysis will be conducted following seven days 
of follow-up.  
 
• 
Secondary Efficacy Endpoint(s): 


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1. Rates of adverse events including, nausea, vomiting, indigestion, worsening of shortness of 
breath or difficulty breathing, allergic reaction (skin rash, hives, swelling of lips or tongue), and 
hospitalized or physician visit for study drug related adverse effect will not occur more 
frequently with combination supplementation with zinc, green tea extract, and ascorbic acid as 
compared to placebo (superiority analysis). Analysis will be conducted following seven days of 
follow-up. 
2. Rates of patient-reported days missed from work or school and hospitalization or physician 
office visit(s) for respiratory viral illness related complications will occur less frequently with 
combination supplementation with zinc, green tea extract, and ascorbic acid as compared to 
placebo (superiority analysis). Analysis will be conducted following seven days of follow-up. 
 
9.2 
SAMPLE SIZE DETERMINATION 
The target number of subjects to be enrolled during the study period occurring May 2022 – June 2023 is 
100 (50 patients randomized to placebo and 50 to the supplementation group). This target is derived 
from a similarly conducted study evaluating zinc supplementation (without green tea extract) in a 
comparable adult population as identified with the current proposal.34 Based on an assumption that 60% 
of patients taking study drug and 30% in the placebo group would recover from cold and flu-like 
symptoms after five days of treatment a total of 84 patients would be sufficient to reach 80% power 
with a two tailed p value <0.05 to detect differences between groups. The power calculation was 


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performed using an online tool located at https://clincalc.com/stats/samplesize.aspx with the following 
calculations performed: 
 
The anticipated dropout rate is 5% based on a large randomized control study evaluating safety of EGCG 
following 12 months of treatment using a similar daily dosage as the current proposal.24 No interim 
analysis is planned; power calculation is for primary endpoint only.  
The primary outcome will be compared using the Chi-square test. Secondary outcomes will be assessed 
using the Chi-square test for categorical data and student’s t-test for continuous data. An exploratory 
analysis comparing the primary outcome among COVID-19 only patients will also be conducted. All 
inferential testing will be based on intention-to-treat. 
 
9.3 
POPULATIONS FOR ANALYSES 
 
All endpoints will be assessed using intention-to-treat analysis. This will include all randomized 
participants.  
 
9.4 
STATISTICAL ANALYSES 
 
9.4.1 GENERAL APPROACH 
 
Descriptive statistics for continues data will be expressed at means with standard deviations and 
categorical data will be expressed as percentage of total cohort. Inferential testing will use two-tailed p 
value <0.05 with 95% confidence intervals to determine statistical significance.  
 
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
 
The primary endpoint will be determined from observing the proportion of patients (expressed as 
percentage) recovered from cold and flu-like symptoms (defined as scoring 0 or 1 daily total symptom 
severity score) following seven days of follow-up. Recovery from cold and flu-like symptoms will be 
categorically assessed as a single endpoint. The difference in recovery rates between study drug and 
placebo will be compared using Chi-squared test and be expressed with 95% confidence intervals. 
Analysis will be performed based on intention-to-treat. Missing data will be handled by last observation 
carried forward based on most recent self-reported total daily symptom severity score.  
 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
 
Secondary endpoints are independent of findings from the primary endpoint.  
 
Rates of adverse events will be determined as a percentage of those subjects self-reporting an event 
compared to the total cohort following seven days of follow-up. Adverse events will be categorically 
expressed as a single endpoint. Difference in adverse events will be compared using Chi-squared test 
with incidence rates expressed as percentages. Analysis will be performed based on intention-to-treat. 
Missing data will be handled by last observation carried forward based on most recent self-reported 
adverse event (or lack thereof). 


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Rates of missed days of work or school will be determined as a percentage of those subjects self-
reporting a missed day compared to the total cohort following seven days of follow-up. Missed days will 
be both categorically expressed as a single endpoint with incidence rates expressed as percentages as 
well as mean days missed with standard deviation. Difference in missed days will be compared using 
Chi-squared test for categorically expressed missed days (occurrence of any missed day(s) during study 
follow-up) and student’s t-test for mean days missed. Analysis will be performed based on intention-to-
treat. Missing data will be handled by last observation carried forward based on most recent self-
reported missed day (or lack thereof). 
Rates of seeking medical care including physician office visits or hospitalization for worsening respiratory 
illness will be determined as a percentage of those subjects self-reporting these events compared to the 
total cohort following seven days of follow-up. A physician office visit or hospitalization for worsening 
respiratory illness will be categorically expressed as a single endpoint with incidence rates expressed as 
percentages. Difference in need to seek medical care will be compared using Chi-squared tests. Analysis 
will be performed based on intention-to-treat. Missing data will be handled by last observation carried 
forward based on most recent self-reported medical visit (or lack thereof). 
 
9.4.4 SAFETY ANALYSES 
 
Rates of adverse events including, nausea, vomiting, indigestion, worsening of shortness of breath or 
difficulty breathing, allergic reaction (skin rash, hives, swelling of lips or tongue), and hospitalized or 
physician visit will be included in secondary analysis as out outlined in Section 9.4.3. Unsolicited adverse 
events recorded will be categorized as “other adverse events” and will be described as a incidence rate 
expressed as a percentage. Each adverse event recorded will be only counted once for any given study 
subject during the study follow-up period.   The 10th revision of the International Statistical 
Classification of Diseases and Related Health Problems (ICD-10) codes will be used to code adverse 
events where appropriate. Severity of adverse events will be classified as follows: 
• 
MILD: Awareness of signs or symptoms, but easily tolerated and are of minor irritant type 
causing no loss of time from normal activities. Symptoms do not require therapy or a 
medical evaluation; signs and symptoms are transient. 
• 
MODERATE: Events introduce a low level of inconvenience or concern to the participant and 
may interfere with daily activities, but are usually improved by simple therapeutic measures; 
moderate experiences may cause some interference with functioning 
• 
SEVERE:  Events interrupt the participant’s normal daily activities and generally require 
systemic drug therapy or other treatment; they are usually incapacitating 
Expectedness of adverse events will be determined as follows: 
• 
UNEXPECTED - nature or severity of the event is not consistent with information about the 
condition under study or intervention in the protocol, consent form, product brochure, or 
investigator brochure. 
• 
EXPECTED - event is known to be associated with the intervention or condition under study.   
Relatedness of adverse events will be determined as follows: 


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• 
DEFINITELY RELATED:  The adverse event is clearly related to the investigational 
agent/procedure – i.e. an event that follows a reasonable temporal sequence from 
administration of the study intervention, follows a known or expected response pattern to 
the suspected intervention, that is confirmed by improvement on stopping and 
reappearance of the event on repeated exposure and that could not be reasonably 
explained by the known characteristics of the subject’s clinical state. 
• 
POSSIBLY RELATED:  An adverse event that follows a reasonable temporal sequence from 
administration of the study intervention follows a known or expected response pattern to 
the suspected intervention, but that could readily have been produced by a number of other 
factors. 
• 
NOT RELATED:  The adverse event is clearly not related to the investigational 
agent/procedure - i.e. another cause of the event is most plausible; and/or a clinically 
plausible temporal sequence is inconsistent with the onset of the event and the study 
intervention and/or a causal relationship is considered biologically implausible.  
Dates of adverse events self-reported by study participants will be recorded, and any adverse event 
leading to premature discontinuation from the study including serious treatment-emergent AEs will be 
listed.  
 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
 
Baseline characteristics planned to be collected include the following: 
• 
age 
• 
sex 
• 
height 
• 
weight 
• 
ethnicity 
• 
history of asthma 
• 
history of chronic obstructive pulmonary disease (COPD) 
• 
history of diabetes 
• 
COVID-19 status 
• 
history of hospitalization for respiratory condition within the past year 
 
9.4.6 PLANNED INTERIM ANALYSES  
 
N/A 
 
9.4.7 SUB-GROUP ANALYSES 
 
Sub-group analysis based on patient demographic variables (e.g. age, sex, race/ethnicity) will not be 
performed.  
 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
 


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Study subject data will be tabulated by measure and time point through the study follow-up period.  
 
9.4.9 EXPLORATORY ANALYSES 
 
The impact of combination supplementation against placebo on symptom duration and severity in the 
COVID-19 positive subgroup of enrolled patients will be assessed as an exploratory endpoint. This 
outcome will be determined from observing the proportion of COVID-19 positive patients (expressed as 
percentage) recovered from cold and flu-like symptoms (defined as scoring 0 or 1 daily total symptom 
severity score) following seven days of follow-up. Recovery from cold and flu-like symptoms will be 
categorically assessed as a single endpoint. The difference in recovery rates between study drug and 
placebo will be compared using Chi-squared test and be expressed with 95% confidence intervals. 
Analysis will be performed based on intention-to-treat. Missing data will be handled by last observation 
carried forward based on most recent self-reported total daily symptom severity score.  
 
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 
 
Consent forms describing in detail the study intervention, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to starting 
intervention/administering study intervention.  The following consent materials are provided separately 
from this protocol: 
 
 
Consent for randomized control trial 
 
Consent for separate blood sample study  
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
 
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. Consent forms will be Institutional 
Review Board (IRB)-approved and the participant will be asked to read and review the document. The 
investigator will explain the research study to the participant and answer any questions that may arise. 
A verbal explanation will be provided in terms suited to the participant’s comprehension of the 
purposes, procedures, and potential risks of the study and of their rights as research participants.  
Participants will have the opportunity to carefully review the written consent form and ask questions 
prior to signing. The participants should have the opportunity to discuss the study with their family or 
surrogates or think about it prior to agreeing to participate. The participant will sign the informed 
consent document prior to any procedures being done specifically for the study. Participants must be 


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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 in the source document (including the 
date), and the form signed, before the participant undergoes any study-specific procedures. 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. Non-English-
speaking patients will be offered language interpreting services for purposes of consenting. Patients not 
able to make sound decisions for themselves will not be approached for consent and study enrollment.  
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, investigators, and regulatory 
authorities.  If the study is prematurely terminated or suspended, the Principal Investigator (PI) will 
promptly inform study participants, the Institutional Review Board (IRB), and Independent Safety 
Monitor 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 
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination of futility 
 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the 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 and their 
staff. This confidentiality is extended to cover testing of biological samples and genetic tests in addition 
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 
primary investigator.  
 
All research activities will be conducted in as private a setting as possible. 
 
The study monitor, other authorized representatives of the primary investigator, representatives of the 
Institutional Review Board (IRB), and 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. 
 


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The study participant’s contact information will be securely stored at each clinical site 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 and Institutional policies. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be transmitted to and stored at University of Missouri Health Care. This will not include the participant’s 
contact or identifying information. Rather, individual participants and their research data will be 
identified by a unique study identification number. Given the ubiquitous nature of cold and flu-like 
illness, including COVID-19, deidentified information including patient demographic data such as age, 
ethnicity, sex, etc. is not expected to make any individual or group of individuals identifiable.  The key 
for identifying patients with their unique study number will be kept with the Investigational Drug Service 
(IDS) pharmacist for the duration of the study period, and it will be stored under lock and key in the IDS 
pharmacy or password protected in a dedicated IDS database folder located at University of Missouri 
Health Care for digital storage. The study data entry and study management systems used by clinical 
sites and by University of Missouri Health Care research staff will be secured and password protected. 
Sharing unidentified data will occur as necessary amongst research team members as well as the study 
monitor for such reasons as to review adverse events including assessment of severity, expectedness, 
and relatedness.   At the end of the study, all study databases will be de-identified and archived at 
University of Missouri Health Care. 
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
Specimens collected as part of this study will not be kept for future studies. Specimens obtained will be 
discarded in accordance with each laboratory’s policy and procedures upon completion of their 
respective analyses. Any specimens not destroyed at time of study end will be discarded in accordance 
to the respective laboratory’s policy and procedures.  
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
 
 
10.1.6 SAFETY OVERSIGHT 
 
Safety oversight will be under the direction of an Independent Safety Monitor (ISM) composed of an 
individual with expertise in Infectious Disease.  Members of the ISM should be independent from the 
study conduct and free of conflict of interest, or measures should be in place to minimize perceived 
Principal Investigator 
Medical Monitor 
Syed Naqvi, MD 
Associate Professor of Clinical Medicine 
Division Director, Hospital Medicine 
Associate Chief Medical Officer, MU Health Care 
 
Taylor Nelson, MD 
Medical Director, General Infectious Disease Clinic 
Director of Social Media Outreach 
Assistant Professor of Clinical Medicine 
University of Missouri. Health Care  
University of Missouri. Health Care  
1 Hospital Dr, Columbia, MO 65212 
1 Hospital Dr, Columbia, MO 65212 
573 884 9066 
573 882 8788 
naqvis@health.missouri.edu 
nelsontb@health.missouri.edu 


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conflict of interest.  The ISM will meet regularly at enrollment intervals of 25%, 50%, 75%, and 100% of 
target to assess safety data on each arm of the study. The ISM will provide its input to the primary 
investigator and Institutional Review Board. 
 
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 
Conference on Harmonization Good Clinical Practice (ICH GCP), and with applicable regulatory 
requirement(s).  
 
• 
The Independent Safety Monitor (ISM) will conduct clinical monitoring, on-site, at enrollment 
intervals of 25%, 50%, 75%, and 100% of target throughout the study period. Safety data 
including adverse events, events necessitating unblinding, and the ongoing dropout rate will be 
comprehensively reviewed.  Reports of data monitored will be provided to the primary 
investigator and Institutional Review Board as necessary. Serious adverse events or events 
leading to unblinding procedures will be reported to the ISM and primary investigator within 24 
hours for review.  
 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
 
Each clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion.  Quality management for specimens collected will 
be in accordance to each laboratory’s established quality assurance procedures. Tracking logs and digital 
communication records will be used to ensure reception and completed analysis of specimens collected.  
 
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. 
 
The study investigators will verify that the clinical trial is conducted and data are generated and 
biological specimens are collected, documented (recorded), and reported in compliance with the 
protocol, International Conference on Harmonization Good Clinical Practice (ICH GCP), and applicable 
regulatory requirements (e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)).  
 
The investigational site will provide direct access to all trial related sites, 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  
 


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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. 
 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation 
of data.  Source documents will include hardcopy case report forms that will include baseline 
characteristic information as described in Section 9.4.5 of this protocol, data elements relevant to 
primary and secondary endpoints as described in Sections 8.1 and 8.2 of this protocol, unsolicited 
adverse events, date of serious adverse event occurrence, severity, estimated expectedness, and 
relatedness of adverse events, and information pertinent to patients discontinued from study 
participation as outline in Section 7.3 of this protocol. A separate case report form will be used to collect 
laboratory data as described in Section 8.3.8 of this protocol.  
 
Hardcopies of the study visit case report forms will be provided for use as source document worksheets 
for recording data for each participant enrolled in the study.  Data recorded in the electronic case report 
form (eCRF) derived from source documents should be consistent with the data recorded on the source 
documents. Study team members will transmit study subject hardcopy visit worksheets into 
corresponding electronic case report forms within one week of completing the hard copy worksheet on 
an ongoing bases throughout the study period. Electronic case report forms will be kept centrally in a 
secured manner including password protection at University of Missouri Health Care and be used to 
capture the ongoing dropout rate, serious adverse events, and events leading to unblinding; these 
reports will be used by the Independent Safety Monitor for review. Findings necessitating reporting to 
the appropriate regulatory bodies such as the IRB will be generated from this data collection procedure. 
Serious adverse events or events necessitating unblinding will be recorded using hardcopy case report 
forms upon initial collection/identification. Although the electronic version of the data is to be captured 
within one week of completing hardcopy case report forms, direct communication via telephone and/or 
email to the primary investigator and the Independent Safety Monitor upon discovering one of these 
events will occur with 24 hours as described in this protocol. 
 
Laboratory data associated with study procedures as described in Section 8.3.8 will be kept in 
accordance with each laboratory’s local practices and policies. These data will not be retained for future 
use once the study has completed and thus retention of records will be in accordance with each 
laboratory’s local practices and policies. Transmission of data from the respective laboratories will occur 
electronically using the University of Missouri Health Care electronic health record system where 
feasible, otherwise information will be collected securely through encrypted electronic communications 
on an ongoing basis throughout the study period.  
 
Clinical data and clinical laboratory data obtained as part of routine care captured during study 
enrollment will be entered into University of Missouri Health Care electronic health record system, 
Cerner Millennium PowerChart, provided by Cerner Corp. This platform is not certified as it relates to 21 
CFR Part 11 as records kept for patient care purposes are not applicable. However, these records are 
maintained in accordance to other state and federal requirements including HIPPA Privacy and Security 
Rules.  This platform is certified for the purposes of the Meaningful Use incentive program.  
 
10.1.9.2 STUDY RECORDS RETENTION  


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It is the investigators responsibility to maintain adequate documentation of research 
procedures/process/data in printed form or electronically. Retention of all study related data will be 
kept for at least seven years after conclusion of the study in accordance with local policies and 
regulations set forth by the Investigational Review Board.  
 
10.1.10 
PROTOCOL DEVIATIONS  
 
A protocol deviation is any noncompliance with the clinical trial protocol, International Conference on 
Harmonization 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 14 working days of identification of the protocol deviation, or within 14 working days 
of the scheduled protocol-required activity.  All deviations must be addressed in study source 
documents, reported to the primary investigator and Institutional Review Board.  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 
 
Publication will be decided amongst the study investigative team based on contribution to study design 
and development, execution, and role in securing funding for study related costs.   
 
This study will be conducted in accordance with the following publication and data sharing policies and 
regulations: 
 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access to the 
published results of NIH funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for 
publication. 
 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded 
Clinical Trial Information and 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 peer-
reviewed journals. 
 


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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 managed in a 
way that is appropriate to their participation in the design and conduct of this trial.  The study 
leadership in conjunction with University of Missouri Health Care has established policies and 
procedures for all study group members to disclose all conflicts of interest and will establish a 
mechanism for the management of all reported dualities of interest. 
 
10.2 ADDITIONAL CONSIDERATIONS 
 
None 
 
10.3 ABBREVIATIONS 
The list below includes abbreviations utilized in this template.  However, this list should be customized for 
each protocol (i.e., abbreviations not used should be removed and new abbreviations used should be 
added to this list). 
 
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 
CRF 
Case Report Form 
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 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
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 Harmonization  
ICMJE 
International Committee of Medical Journal Editors 


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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 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
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 
The table below is intended to capture changes of IRB-approved versions of the protocol, including a 
description of the change and rationale. A Summary of Changes table for the current amendment is 
located in the Protocol Title Page.  
 
Version 
Date 
Description of Change  
Brief Rationale 
1.2 
November 24, 2021 
Changed study dates 
Delay in funding; planned award 
release in December 2021 
1.3 
April 12, 2022 
Changed study dates 
 
 
Capsules used will be white and 
opaque 
Delay in funding; planned award 
release in April 2022 
 
Changing capsule manufacture 
(for entire study) due to supply 
issues with original capsule 
1.4 
August 11, 2022 
Changed dosing instructions and 
the mg weight of each study 
component per capsule.  
Zinc citrate product corrected to 
be 32% elemental zinc by 
weight 
Changed dosing instructions to 
reflect three (3) capsules taken 
twice daily as capsule fill 
capability was limited; 
importantly the total daily 
exposure of each study 
component has NOT changed 
1.4 
August 11, 2022 
Added legend at bottom of 
chart 
Updated activities to include 
daily telephone visits and 
removed biochemical pregnancy 
test 
IRB review feedback to include 
definition of superscript letter(s) 
and to indicate which activities 
are a part of routine care 
Include telephone visits as part of 
the schedule of activities table to 
better capture full study 
procedures in the table; removed 
pregnancy test as this status will 
be obtained verbally 
1.4 
August 11, 2022 
Updated to account for new 
COVID-19 treatments 
IRB review feedback to address 
context of newer COVID-19 
treatments as it relates to this 
study protocol 
1.4 
August 11, 2022 
Updated to include use of 
advertisements 
Using advertisements to increase 
awareness of study activities 
1.4 
August 11, 2022 
Updated to clarify that study 
subjects undergoing blood 
sampling procedures will not be 
randomized or assigned to 
placebo 
IRB review feedback requested 
clarification 
1.4 
August 11, 2022 
Updated to clarify that study 
subject undergoing blood 
IRB review feedback requested 
clarification 


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sampling procedures will not be 
contacted via daily telephone 
visits for collection of efficacy 
and pre-defined safety 
assessments 
1.4 
August 11, 2022 
Updated to include medical 
monitor 
Medical monitor identified and 
added to protocol 
1.4 
August 11, 2022 
Updated history of changes 
made to IRB approved versions 
of the protocol 
IRB feedback requested this 
update 
1.4 
August 11, 2022 
Added legend at bottom of 
chart 
Updated activities to include 
daily telephone visits and 
removed biochemical pregnancy 
test 
IRB review feedback to include 
definition of superscript letter(s) 
and to indicate which activities 
are a part of routine care 
Include telephone visits as part of 
the schedule of activities table to 
better capture full study 
procedures in the table; removed 
pregnancy test as this status will 
be obtained verbally 
1.5 
November 14, 2022 
Changed inclusion criterion 
from ≤ 36 hours to 
< 72 hours 
Current symptom duration 
criterion is 
demonstrating to be too 
restrictive and 
impairing enrollment. Increase 
time to < 72 
hours to help with enrollment 
efforts. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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8. Read SA, Obeid S, Ahlenstiel C, Ahlenstiel G. The Role of Zinc in Antiviral Immunity. Adv Nutr. 2019 
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9. Wessels I, Rolles B, Rink L. The Potential Impact of Zinc Supplementation on COVID-19 Pathogenesis. 
Front Immunol. 2020 Jul 10;11:1712. doi: 10.3389/fimmu.2020.01712. PMID: 32754164; PMCID: 
PMC7365891. 
10. Doboszewska U, Wlaź P, Nowak G, Młyniec K. Targeting zinc metalloenzymes in coronavirus disease 
2019. Br J Pharmacol. 2020 Jul 15:10.1111/bph.15199. doi: 10.1111/bph.15199. Epub ahead of 
print. PMID: 32671829; PMCID: PMC7405164. 
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20471814. 
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PMID: 25050823. 


ZiPhenol Study 
Version 1.6 
Protocol #1 
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NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017 
 
47 
 
15. Derwand R, Scholz M. Does zinc supplementation enhance the clinical efficacy of 
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19. Zhen-Yu Chen, Qin Yan Zhu, Yeun Fan Wong, Zesheng Zhang, and Hau Yin Chung. Stabilizing Effect of 
Ascorbic Acid on Green Tea Catechins. Journal of Agricultural and Food Chemistry 1998 46 (7), 2512-
2516. DOI: 10.1021/jf971022g 
20. Green RJ, Murphy AS, Schulz B, Watkins BA, Ferruzzi MG. Common tea formulations modulate in 
vitro digestive recovery of green tea catechins. Mol Nutr Food Res. 2007 Sep;51(9):1152-62. doi: 
10.1002/mnfr.200700086. PMID: 17688297. 
21. Peters CM, Green RJ, Janle EM, Ferruzzi MG. Formulation with ascorbic acid and sucrose modulates 
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10.1016/j.foodres.2009.08.016. PMID: 20161530; PMCID: PMC2802066. 
22. Chen L, Wang W, Zhang J, Cui H, Ni D, Jiang H. Dual effects of ascorbic acid on the stability of EGCG 
by the oxidation product dehydroascorbic acid promoting the oxidation and inhibiting the hydrolysis 
pathway. Food Chem. 2020 Jul 24;337:127639. doi: 10.1016/j.foodchem.2020.127639. Epub ahead 
of print. PMID: 32799157. 
23. Mereles D, Hunstein W. Epigallocatechin-3-gallate (EGCG) for clinical trials: more pitfalls than 
promises? Int J Mol Sci. 2011;12(9):5592-603. doi: 10.3390/ijms12095592. Epub 2011 Aug 31. PMID: 
22016611; PMCID: PMC3189735. 
24. Dostal AM, Samavat H, Bedell S, Torkelson C, Wang R, Swenson K, Le C, Wu AH, Ursin G, Yuan JM, 
Kurzer MS. The safety of green tea extract supplementation in postmenopausal women at risk for 
breast cancer: results of the Minnesota Green Tea Trial. Food Chem Toxicol. 2015 Sep;83:26-35. doi: 
10.1016/j.fct.2015.05.019. Epub 2015 Jun 5. PMID: 26051348; PMCID: PMC4540665. 
25. EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS), Younes M, Aggett P, 
Aguilar F, Crebelli R, Dusemund B, Filipič M, Frutos MJ, Galtier P, Gott D, Gundert-Remy U, Lambré C, 
Leblanc JC, Lillegaard IT, Moldeus P, Mortensen A, Oskarsson A, Stankovic I, Waalkens-Berendsen I, 
Woutersen RA, Andrade RJ, Fortes C, Mosesso P, Restani P, Arcella D, Pizzo F, Smeraldi C, Wright M. 
Scientific opinion on the safety of green tea catechins. EFSA J. 2018 Apr 18;16(4):e05239. doi: 
10.2903/j.efsa.2018.5239. PMID: 32625874; PMCID: PMC7009618. 
26. Oketch-Rabah HA, Roe AL, Rider CV, Bonkovsky HL, Giancaspro GI, Navarro V, Paine MF, Betz JM, 
Marles RJ, Casper S, Gurley B, Jordan SA, He K, Kapoor MP, Rao TP, Sherker AH, Fontana RJ, Rossi S, 
Vuppalanchi R, Seeff LB, Stolz A, Ahmad J, Koh C, Serrano J, Low Dog T, Ko R. United States 


ZiPhenol Study 
Version 1.6 
Protocol #1 
 23 February 2023 
 
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017 
 
48 
 
Pharmacopeia (USP) comprehensive review of the hepatotoxicity of green tea extracts. Toxicol Rep. 
2020 Feb 15;7:386-402. doi: 10.1016/j.toxrep.2020.02.008. PMID: 32140423; PMCID: PMC7044683. 
27. Lewis MR, Kokan L. Zinc gluconate: acute ingestion. J Toxicol Clin Toxicol. 1998;36(1-2):99-101. doi: 
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28. Eby GA, Davis DR, Halcomb WW. Reduction in duration of common colds by zinc gluconate lozenges 
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29. Natural Medicines. (2020, July 17). Vitamin C 
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30. Zinc, Serum. Mayo Clinic Laboratories website. Accessed September 15, 2020. 
31. Hemilä H. Zinc lozenges may shorten the duration of colds: a systematic review. Open Respir Med J. 
2011;5:51-8. doi: 10.2174/1874306401105010051. Epub 2011 Jun 23. PMID: 21769305; PMCID: 
PMC3136969. 
32. Al-Nakib W, Higgins PG, Barrow I, Batstone G, Tyrrell DA. Prophylaxis and treatment of rhinovirus 
colds with zinc gluconate lozenges. J Antimicrob Chemother. 1987 Dec;20(6):893-901. doi: 
10.1093/jac/20.6.893. PMID: 3440773; PMCID: PMC7110079. 
33. Hemilä H. Zinc lozenges and the common cold: a meta-analysis comparing zinc acetate and zinc 
gluconate, and the role of zinc dosage. JRSM Open. 2017 May 2;8(5):2054270417694291. doi: 
10.1177/2054270417694291. PMID: 28515951; PMCID: PMC5418896. 
34. Hemilä H, Haukka J, Alho M, Vahtera J, Kivimäki M. Zinc acetate lozenges for the treatment of the 
common cold: a randomised controlled trial. BMJ Open. 2020 Jan 23;10(1):e031662. doi: 
10.1136/bmjopen-2019-031662. PMID: 31980506; PMCID: PMC7045205. 
35. Nève J, Hanocq M, Peretz A, Khalil FA, Pelen F. Absorption and metabolism of oral zinc gluconate in 
humans in fasting state, during, and after a meal. Biol Trace Elem Res. 1992 Jan-Mar;32:201-12. doi: 
10.1007/BF02784604. PMID: 1375057. 
36. Jothimani D, Kailasam E, Danielraj S, Nallathambi B, Ramachandran H, Sekar P, Manoharan S, 
Ramani V, Narasimhan G, Kaliamoorthy I, Rela M. COVID-19: Poor outcomes in patients with Zinc 
deficiency. Int J Infect Dis. 2020 Sep 10:S1201-9712(20)30730-X. doi: 10.1016/j.ijid.2020.09.014. 
Epub ahead of print. PMID: 32920234. 
37. Wegmüller R, Tay F, Zeder C, Brnic M, Hurrell RF. Zinc absorption by young adults from 
supplemental zinc citrate is comparable with that from zinc gluconate and higher than from zinc 
oxide. J Nutr. 2014 Feb;144(2):132-6. doi: 10.3945/jn.113.181487. Epub 2013 Nov 20. PMID: 
24259556; PMCID: PMC3901420. 
38. Natural Medicines. (2020, August 19). Zinc 
[monograph]. http://naturalmedicines.therapeuticresearch.com 
39. Stanclift M. Antiviral and Anti-Inflammatory Effects of Green Tea Extract (ECGC). Metagenics 
Institute website. Accessed August 26, 2020. 
40. Natural medicines. (2020, August 5). Green Tea 
[monograph]. http://naturalmedicines.therapeuticresearch.com 
41. Chow HH, Hakim IA, Vining DR, Crowell JA, Cordova CA, Chew WM, Xu MJ, Hsu CH, Ranger-Moore J, 
Alberts DS. Effects of repeated green tea catechin administration on human cytochrome P450 
activity. Cancer Epidemiol Biomarkers Prev. 2006 Dec;15(12):2473-6. doi: 10.1158/1055-9965.EPI-
06-0365. PMID: 17164372. 
42. Chow HH, Hakim IA, Vining DR, Crowell JA, Ranger-Moore J, Chew WM, Celaya CA, Rodney SR, Hara 
Y, Alberts DS. Effects of dosing condition on the oral bioavailability of green tea catechins after 


ZiPhenol Study 
Version 1.6 
Protocol #1 
 23 February 2023 
 
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017 
 
49 
 
single-dose administration of Polyphenon E in healthy individuals. Clin Cancer Res. 2005 Jun 
15;11(12):4627-33. doi: 10.1158/1078-0432.CCR-04-2549. PMID: 15958649. 
43. Chow HH, Cai Y, Hakim IA, Crowell JA, Shahi F, Brooks CA, Dorr RT, Hara Y, Alberts DS. 
Pharmacokinetics and safety of green tea polyphenols after multiple-dose administration of 
epigallocatechin gallate and polyphenon E in healthy individuals. Clin Cancer Res. 2003 Aug 
15;9(9):3312-9. PMID: 12960117. 
 
44. EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS), Younes M, Aggett P, 
Aguilar F, Crebelli R, Dusemund B, Filipič M, Frutos MJ, Galtier P, Gott D, Gundert-Remy U, Lambré C, 
Leblanc JC, Lillegaard IT, Moldeus P, Mortensen A, Oskarsson A, Stankovic I, Waalkens-Berendsen I, 
Woutersen RA, Andrade RJ, Fortes C, Mosesso P, Restani P, Arcella D, Pizzo F, Smeraldi C, Wright M. 
Scientific opinion on the safety of green tea catechins. EFSA J. 2018 Apr 18;16(4):e05239. doi: 
10.2903/j.efsa.2018.5239. PMID: 32625874; PMCID: PMC7009618. 
45. Oketch-Rabah HA, Roe AL, Rider CV, Bonkovsky HL, Giancaspro GI, Navarro V, Paine MF, Betz JM, 
Marles RJ, Casper S, Gurley B, Jordan SA, He K, Kapoor MP, Rao TP, Sherker AH, Fontana RJ, Rossi S, 
Vuppalanchi R, Seeff LB, Stolz A, Ahmad J, Koh C, Serrano J, Low Dog T, Ko R. United States 
Pharmacopeia (USP) comprehensive review of the hepatotoxicity of green tea extracts. Toxicol Rep. 
2020 Feb 15;7:386-402. doi: 10.1016/j.toxrep.2020.02.008. PMID: 32140423; PMCID: PMC7044683. 
46. Dostal AM, Samavat H, Bedell S, Torkelson C, Wang R, Swenson K, Le C, Wu AH, Ursin G, Yuan JM, 
Kurzer MS. The safety of green tea extract supplementation in postmenopausal women at risk for 
breast cancer: results of the Minnesota Green Tea Trial. Food Chem Toxicol. 2015 Sep;83:26-35. doi: 
10.1016/j.fct.2015.05.019. Epub 2015 Jun 5. PMID: 26051348; PMCID: PMC4540665. 
47. Zhen-Yu Chen, Qin Yan Zhu, Yeun Fan Wong, Zesheng Zhang, and Hau Yin Chung. Stabilizing Effect of 
Ascorbic Acid on Green Tea Catechins. Journal of Agricultural and Food Chemistry 1998 46 (7), 2512-
2516. DOI: 10.1021/jf971022g 
48. Green RJ, Murphy AS, Schulz B, Watkins BA, Ferruzzi MG. Common tea formulations modulate in 
vitro digestive recovery of green tea catechins. Mol Nutr Food Res. 2007 Sep;51(9):1152-62. doi: 
10.1002/mnfr.200700086. PMID: 17688297. 
49. Peters CM, Green RJ, Janle EM, Ferruzzi MG. Formulation with ascorbic acid and sucrose modulates 
catechin bioavailability from green tea. Food Res Int. 2010 Jan 1;43(1):95-102. doi: 
10.1016/j.foodres.2009.08.016. PMID: 20161530; PMCID: PMC2802066. 
50. Chen L, Wang W, Zhang J, Cui H, Ni D, Jiang H. Dual effects of ascorbic acid on the stability of EGCG 
by the oxidation product dehydroascorbic acid promoting the oxidation and inhibiting the hydrolysis 
pathway. Food Chem. 2020 Jul 24;337:127639. doi: 10.1016/j.foodchem.2020.127639. Epub ahead 
of print. PMID: 32799157. 
51. Mereles D, Hunstein W. Epigallocatechin-3-gallate (EGCG) for clinical trials: more pitfalls than 
promises? Int J Mol Sci. 2011;12(9):5592-603. doi: 10.3390/ijms12095592. Epub 2011 Aug 31. PMID: 
22016611; PMCID: PMC3189735. 
52. Natural Medicines. (2020, July 17). Vitamin C 
[monograph]. http://naturalmedicines.therapeuticresearch.com 
53. Zinc Sulfate. Package Insert. American Regent, Inc; 2020. 
54. Veregen. Package Insert. Fougera Pharmaceuticals, Inc; 2018. 
55. Ascor. Package Insert. McGuff Pharmaceuticals, Inc; 2017. 


ZiPhenol Study 
Version 1.6 
Protocol #1 
 23 February 2023 
 
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017 
 
50 
 
single-dose administration of Polyphenon E in healthy individuals. Clin Cancer Res. 2005 Jun 
15;11(12):4627-33. doi: 10.1158/1078-0432.CCR-04-2549. PMID: 15958649. 
43. Chow HH, Cai Y, Hakim IA, Crowell JA, Shahi F, Brooks CA, Dorr RT, Hara Y, Alberts DS. 
Pharmacokinetics and safety of green tea polyphenols after multiple-dose administration of 
epigallocatechin gallate and polyphenon E in healthy individuals. Clin Cancer Res. 2003 Aug 
15;9(9):3312-9. PMID: 12960117. 
 
44. EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS), Younes M, Aggett P, 
Aguilar F, Crebelli R, Dusemund B, Filipič M, Frutos MJ, Galtier P, Gott D, Gundert-Remy U, Lambré C, 
Leblanc JC, Lillegaard IT, Moldeus P, Mortensen A, Oskarsson A, Stankovic I, Waalkens-Berendsen I, 
Woutersen RA, Andrade RJ, Fortes C, Mosesso P, Restani P, Arcella D, Pizzo F, Smeraldi C, Wright M. 
Scientific opinion on the safety of green tea catechins. EFSA J. 2018 Apr 18;16(4):e05239. doi: 
10.2903/j.efsa.2018.5239. PMID: 32625874; PMCID: PMC7009618. 
45. Oketch-Rabah HA, Roe AL, Rider CV, Bonkovsky HL, Giancaspro GI, Navarro V, Paine MF, Betz JM, 
Marles RJ, Casper S, Gurley B, Jordan SA, He K, Kapoor MP, Rao TP, Sherker AH, Fontana RJ, Rossi S, 
Vuppalanchi R, Seeff LB, Stolz A, Ahmad J, Koh C, Serrano J, Low Dog T, Ko R. United States 
Pharmacopeia (USP) comprehensive review of the hepatotoxicity of green tea extracts. Toxicol Rep. 
2020 Feb 15;7:386-402. doi: 10.1016/j.toxrep.2020.02.008. PMID: 32140423; PMCID: PMC7044683. 
46. Dostal AM, Samavat H, Bedell S, Torkelson C, Wang R, Swenson K, Le C, Wu AH, Ursin G, Yuan JM, 
Kurzer MS. The safety of green tea extract supplementation in postmenopausal women at risk for 
breast cancer: results of the Minnesota Green Tea Trial. Food Chem Toxicol. 2015 Sep;83:26-35. doi: 
10.1016/j.fct.2015.05.019. Epub 2015 Jun 5. PMID: 26051348; PMCID: PMC4540665. 
47. Zhen-Yu Chen, Qin Yan Zhu, Yeun Fan Wong, Zesheng Zhang, and Hau Yin Chung. Stabilizing Effect of 
Ascorbic Acid on Green Tea Catechins. Journal of Agricultural and Food Chemistry 1998 46 (7), 2512-
2516. DOI: 10.1021/jf971022g 
48. Green RJ, Murphy AS, Schulz B, Watkins BA, Ferruzzi MG. Common tea formulations modulate in 
vitro digestive recovery of green tea catechins. Mol Nutr Food Res. 2007 Sep;51(9):1152-62. doi: 
10.1002/mnfr.200700086. PMID: 17688297. 
49. Peters CM, Green RJ, Janle EM, Ferruzzi MG. Formulation with ascorbic acid and sucrose modulates 
catechin bioavailability from green tea. Food Res Int. 2010 Jan 1;43(1):95-102. doi: 
10.1016/j.foodres.2009.08.016. PMID: 20161530; PMCID: PMC2802066. 
50. Chen L, Wang W, Zhang J, Cui H, Ni D, Jiang H. Dual effects of ascorbic acid on the stability of EGCG 
by the oxidation product dehydroascorbic acid promoting the oxidation and inhibiting the hydrolysis 
pathway. Food Chem. 2020 Jul 24;337:127639. doi: 10.1016/j.foodchem.2020.127639. Epub ahead 
of print. PMID: 32799157. 
51. Mereles D, Hunstein W. Epigallocatechin-3-gallate (EGCG) for clinical trials: more pitfalls than 
promises? Int J Mol Sci. 2011;12(9):5592-603. doi: 10.3390/ijms12095592. Epub 2011 Aug 31. PMID: 
22016611; PMCID: PMC3189735. 
52. Natural Medicines. (2020, July 17). Vitamin C 
[monograph]. http://naturalmedicines.therapeuticresearch.com 
53. Zinc Sulfate. Package Insert. American Regent, Inc; 2020. 
54. Veregen. Package Insert. Fougera Pharmaceuticals, Inc; 2018. 
55. Ascor. Package Insert. McGuff Pharmaceuticals, Inc; 2017. 


ZiPhenol Study 
Version 1.6 
Protocol #1 
       23 February 2023 
 
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Addendum A 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




 
Hard Eight Nutrition, LLC 
7511 Eastgate Road, Henderson, NV 89011 USA |   Telephone: 702-293-0222  
 
SAFETY DATA SHEET 
Section 1: Identification 
Product Name: Zinc Citrate 
Chemical Name/Synonyms:  Zinc citratetribasicdihydrate Citric acidzinc salt 
Company: Hard Eight Nutrition, LLC Dba BulkSupplements.com  
                     7511 Eastgate Road, Henderson, NV 89011 USA    Telephone: 702-293-0222 
 
In emergency call 911. 
For information about this SDS, use this department contact phone#:  702-293-0222 
   
Section 2: Hazard(s) Identification 
Classification of the substance or mixture  
Not a hazardous substance or mixture. 
GHS Label elements, including precautionary statements 
Not a hazardous substance or mixture.  
Hazards not otherwise classified (HNOC) or not covered by GHS - none 
Section 3: Composition/ Information on Ingredients 
 
Chemical Name 
Chemical formula 
CAS# 
Conc. 
Zinc citratetribasicdihydrate Citric 
acidzinc salt 
C12H10O14Zn3.2H2O 
5990-32-9 
≤100% 
 
 
Section 4: First-Aid Measures 
After skin contact:  Wash off with soap and plenty of water. Consult a physician. 
After eye contact:  Rinse with plenty of water for at least 15 minutes and consult a physician. 
After inhalation:  Move to fresh air. If not breathing, give artificial respiration. Consult a physician.  
After swallowing:  Never give anything by mouth to an unconscious person. Rinse mouth with water. 
Consult a physician.  
 
Section 5: Fire-Fighting Measures 
Suitable extinguishing agents: Water spray, alcohol-resistant foam, dry chemical, or carbon dioxide.  
Special Remarks on Explosion Hazards: No data available 
Special protective equipment for firefighters:  Use self-contained breathing apparatus for firefighting if 
necessary.  
Section 6: Accidental Release Measures 
Personal precautions: Use personal protective equipment. Avoid dust formation. Ensure adequate 
ventilation. 
Measures for environmental protection: Do not let product enter drains 
Measures for cleaning/collecting: Sweep or shovel into a closed container for disposal. 


2 
 
Section 7: Handling and Storage 
Handling:  Avoid contact with skin and eyes. Avoid formation of dust. Provide exhaust ventilation at places 
where dust is formed.  
Storage:  Keep container closed in a dry, well ventilated place.   
 
Section 8: Exposure Controls/Personal Protection 
Engineering Controls: Handle in accordance with good industrial hygiene and safety practice. Wash hands 
frequently. 
General protective and hygienic measures:  Follow good industrial hygiene. 
Breathing equipment:  Wear a type P95 or type P1 respirator.  
Protection of hands:  Wear suitable gloves prior to handling.  
Eye protection:  Wear suitable eye protection.  
 
Section 9: Physical and Chemical Properties 
Form: Solid 
Color:  White 
Odor:  Odorless 
Odor threshold:  No data available 
pH:  No data available 
Melting point/melting range:  No data available 
Boiling point/boiling range:  No data available 
Flash point:  No data available 
Evaporation rate:  No data available 
Flammability:  No data available 
Upper/lower flammability or explosive limits:  No data available 
Auto ignition temperature:  No data available 
Danger of explosion: No data available 
Vapor pressure:  No data available  
Vapor density:  No data available 
Relative density:  No data available 
Solubility in/Miscibility with water:  No data available 
 
Section 10: Stability and Reactivity 
Stability: Stable under recommended storage conditions 
Materials to avoid: Avoid moisture.  
Incompatibility: Strong oxidizers.  
Section 11: Toxicological Information 
Skin: No data available 
Eyes: No data available 
Inhalation: No data available 
Ingestion: No data available 
Section 12: Ecological Information (non-mandatory) 
Ecotoxicity: Very toxic to aquatic life with long lasting effects. 
BOD5 and COD: No data available 
Products of Biodegradation: No data available 
Toxicity of the Products of Biodegradation: No data available 
Special Remarks on the Products of Biodegradation: No data available 


3 
 
Section 13: Disposal Considerations (non-mandatory) 
Product 
Offer surplus and non-recyclable solutions to a licensed disposal company 
Contaminated packaging  
Dispose of as unused product. 
Section 14: Transport Information (non-mandatory) 
Not dangerous goods 
Section 15: Regulatory Information (non-mandatory) 
SARA 302 Components 
No chemicals in this material are subject to the reporting requirements of SARA Title III, 
Section 302. 
SARA 313 Components 
The following components are subject to reporting levels established by SARA Title III, Section 313 
SARA 311/312 Hazards 
No SARA hazards 
Section 16: Other Information 
The information provided in this safety data sheet is the best of our knowledge, information and belief at 
the date of its publication. The information given is designed only as a guidance for safe handling, use, 
processing, storage, transportation, disposal and release and is not to be considered a warranty or quality 
specification. The information relates only to the specific material designated and may not be valid for such 
material used in combination with any other materials or in any process, unless specified in the text. 
 
SDS date of preparation/update:  7/23/2020 
 




ZiPhenol Study 
Version 1.6 
Protocol #1 
       23 February 2023 
 
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Addendum B 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




 
Hard Eight Nutrition, LLC 
7511 Eastgate Road, Henderson, NV 89011 USA |   Telephone: 702-293-0222  
 
SAFETY DATA SHEET 
Section 1: Identification 
Product Name: Green Tea Extract (50% EGCG)  
Chemical Name/Synonyms:  N/A 
Company: Hard Eight Nutrition, LLC Dba BulkSupplements.com  
                     7511 Eastgate Road, Henderson, NV 89011 USA    Telephone: 702-293-0222 
 
In emergency call 911. 
For information about this SDS, use this department contact phone#:  702-293-0222 
   
Section 2: Hazard(s) Identification 
Hazard Classification:  Not a hazardous substance 
Signal Word(s): N/A 
Hazard Statements:  N/A 
Pictograms: N/A  
 
Precautionary Statements:  N/A 
Description of other hazards: None 
 
Section 3: Composition/ Information on Ingredients 
 
Chemical Name 
Chemical formula 
CAS# 
Conc. 
Green Tea Extract (50% EGCG) 
N/A 
84650-60-2 
N/A 
 
 
Section 4: First-Aid Measures 
 
After skin contact:  Flush skin with soap and water for at least 30 minutes. Remove contaminated clothing. 
If symptoms develop, contact a physician.  
After eye contact:  Flush eyes with water for 15 minutes. Contact a physician.  
After inhalation:  Remove from exposure and move to fresh air immediately. Give artificial respiration if 
not breathing. Call a physician.  
After swallowing:  If conscious and alert, give 2-4 cups of water or milk. Never give anything by mouth to 
an unconscious person. Call a physician.  
 
Section 5: Fire-Fighting Measures 
 
Suitable extinguishing agents: Foam, dry powder, CO2, water spray jet. 
Special Remarks on Fire Hazards: None 
Special Remarks on Explosion Hazards: None 


2 
 
Special protective equipment for firefighters:  Use personal protective equipment as required.  
Section 6: Accidental Release Measures 
 
Personal precautions: Ensure adequate ventilation, especially in confined areas. Avoid causing dust. Wear 
protective clothing. 
Measures for environmental protection: N/A 
Measures for cleaning/collecting: Take up mechanically. Rinse residues with water. Dispose of material in 
accordance with safety regulations. 
 
Section 7: Handling and Storage 
 
Handling:  Wash thoroughly after handling. Minimize dust generation and accumulation.  
Storage:  Store under normal warehouse conditions. Store in a cool, dry place away from direct sunlight 
and heat.  
 
Section 8: Exposure Controls/Personal Protection 
 
 
Chemical Name 
OSHA PEL 
OSHA PEL (ceiling) 
ACGIH OEL (TWA) 
ACGIH OEL (STEL) 
Green Tea Extract 
(50% EGCG) 
None 
None 
None 
None 
 
General protective and hygienic measures:  Minimize dust generation and accumulation. Avoid contact 
with eyes, skin, and clothing. Avoid ingestion and inhalation.  
Breathing equipment:  Wear a respirator that meets OHOA’S 29 CFE 1910.134 and ANSI Z88.2 
requirements. 
Protection of hands:  Wear appropriate gloves. 
Eye protection:  Wear appropriate eyewear.  
 
Section 9: Physical and Chemical Properties 
 
Form:  Powder 
Odor:  Characteristic 
Odor threshold:  No data available 
pH:  No Data Available 
Melting point/melting range:  No Data Available 
Boiling point/boiling range:  No Data Available 
Flash point:  No Data Available 
Evaporation rate:  No Data Available 
Flammability:  No Data Available 
Upper/lower flammability or explosive limits:  No Data Available 
Auto ignition temperature:  No Data Available 
Danger of explosion:  No Data Available 
Vapor pressure:  No Data Available 
Vapor density:  No Data Available 


3 
 
Relative density:  No Data Available 
Solubility in/Miscibility with water:  No Data Available 
 
Section 10: Stability and Reactivity 
 
Stability: Normally stable  
Instability Temperature: No Data Available 
Conditions of Instability: No Data Available 
Incompatibility with various substances: No Data Available 
Special Remarks on Reactivity: No Data Available 
Special Remarks on Corrosivity: No Data Available 
Polymerization: No Data Available 
Section 11: Toxicological Information 
 
Skin: No Data Available 
Eyes: No Data Available 
Inhalation: No Data Available 
Ingestion: No Data Available 
Chronic Potential Health Effects: No Data Available 
Section 12: Ecological Information (non-mandatory) 
 
Ecotoxicity: No Data Available 
BOD5 and COD: No Data Available 
Products of Biodegradation: No Data Available 
Toxicity of the Products of Biodegradation: No Data Available 
Special Remarks on the Products of Biodegradation: No Data Available 
 
Section 13: Disposal Considerations (non-mandatory) 
Chemical waste generators must determine whether a discarded chemical is classified as hazardous waste. 
US EPA guideline for the classification determination are listed in 40 CFR Parts 261.3. Additionally, waste 
generators must consult state and local hazardous waste regulations to ensure complete and accurate 
classification.  
Section 14: Transport Information (non-mandatory) 
 
DOT Classification: None 
• 
Hazard class:  No Data Available 
• 
Land transport ADR/RID (cross-border):  No Data Available 
• 
ADR/RID class:  No Data Available 
• 
Maritime transport IMDG:  No Data Available 
Air transport ICAO-TI and IATA-DGR:  No Data Available 
• 
ICAO/IATA Class:  No Data Available 
 
Section 15: Regulatory Information (non-mandatory) 
 
US Federal Regulations 
SARA Section 355 (extremely hazardous substances):  No Data Available 
SARA Section 313 (specific toxic chemical listings):  No Data Available 


4 
 
Clean Air Act, Section 112 Hazardous Air Pollutants (HAPs):  No Data Available 
TSCA (Toxic Substances Control Act):  No Data Available 
 
Section 16: Other Information 
 
The information provided in this safety data sheet is the best of our knowledge, information and belief at 
the date of its publication. The information given is designed only as a guidance for safe handling, use, 
processing, storage, transportation, disposal and release and is not to be considered a warranty or quality 
specification. The information relates only to the specific material designated and may not be valid for such 
material used in combination with any other materials or in any process, unless specified in the text. 
 
SDS date of preparation/update:  5/3/2020 
 


 
7511 Eastgate Road, Henderson, NV 89011 USA  |  Telephone: 702-293-0222  |  Email: Cs@Bulksupplements.com  
 
 
Certificate of Analysis 
Product: 
Green Tea Extract 50% EGCG 
Latin Name: 
Camellia sinensis L. 
Part Used: 
Leaf 
Lot Number: 
1904408 
 
 
Manufacture Date: 
8/22/2019 
Expiration Date: 
8/30/2022 
 
  
 
 
Signature ________________________________________   Date __________________ 
Item 
Specification 
Results 
Characteristics 
Appearance 
Red brown powder 
Conforms 
Identity 
FTIR 
Conforms 
Test 
Loss on drying 
NMT 5.0% 
4.21% 
Particle size 
80 mesh 
Conforms 
Bulk Density 
Report 
0.46g/ml 
Heavy Metals 
Arsenic (As) 
NMT 5.0 ppm 
Conforms 
Cadmium (Cd) 
NMT 1.0 ppm 
Conforms 
Lead (Pb) 
NMT 5.0 ppm 
Conforms 
Mercury (Hg) 
NMT 0.2 ppm 
Conforms 
Microbial 
Total Plate Count 
NMT 10000 cfu/g 
Conforms 
Yeast & Mold 
NMT 1000 cfu/g 
Conforms 
Coliforms 
Negative 
Conforms 
E Coli 
Negative 
Conforms 
Salmonella 
Negative 
Conforms 
Enterobacteriaceae 
Negative 
Conforms 
 Storage 
Store in tight, light resistant containers. Avoid exposures to direct sunlight, moisture and 
excessive heat. 
11/20/2019


ZiPhenol Study 
Version 1.6 
Protocol #1 
       23 February 2023 
 
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Addendum C 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




 
Hard Eight Nutrition, LLC 
7511 Eastgate Road, Henderson, NV 89011 USA |   Telephone: 702-293-0222  
 
SAFETY DATA SHEET 
Section 1: Identification 
Product Name: L-Ascorbic acid  
Chemical Name/Synonyms:  Vitamin C  
Company: Hard Eight Nutrition, LLC Dba BulkSupplements.com  
                     7511 Eastgate Road, Henderson, NV 89011 USA    Telephone: 702-293-0222 
 
In emergency call 911. 
For information about this SDS, use this department contact phone#:  702-293-0222 
   
Section 2: Hazard(s) Identification 
 
Signal Word(s): Not a hazardous substance or mixture 
Hazard Statements:  N/A 
Pictograms: N/A  
Precautionary Statements:  N/A 
Section 3: Composition/ Information on Ingredients 
 
Chemical Name 
Chemical formula 
CAS# 
Conc. 
L-Ascorbic acid 
C6H8O6 
50-81-7 
≤ 100% 
 
 
Section 4: First-Aid Measures 
After skin contact:  Wash off with soap and water. 
After eye contact:  Flush eyes with water. 
After inhalation:  Move to fresh air. If not breathing, give artificial respiration.  
After swallowing:  Never give anything by mouth to an unconscious person. Rinse mouth with water. 
 
Section 5: Fire-Fighting Measures 
Suitable extinguishing agents: Water spray, alcohol-resistant foam, dry chemical, or carbon dioxide.  
Special Remarks on Fire Hazards: No data available 
Special Remarks on Explosion Hazards: No data available 
Special protective equipment for firefighters:  Wear self-contained breathing apparatus for firefighting if 
necessary. 
Section 6: Accidental Release Measures 
Personal precautions: Avoid dust formation. Avoid breathing vapors, mist, or gas.  
Measures for environmental protection: No precautions required. 
Measures for cleaning/collecting: Sweep or shovel into closed containers for disposal.  


2 
 
Section 7: Handling and Storage 
Handling:  Provide appropriate exhaust ventilation at places where dust is formed. 
Storage:  Keep tightly closed in a dry and well-ventilated place.  Light sensitive.  
 
Section 8: Exposure Controls/Personal Protection 
Engineering Controls: No data available 
General protective and hygienic measures:  use general industrial hygiene practice. 
Breathing equipment:  Wear suitable type N95 or type P1 dust masks. 
Protection of hands:  Use gloves prior to handling.  
Eye protection:  use suitable eye protection.  
 
Section 9: Physical and Chemical Properties 
Form: Solid 
Color:  White or clear 
Odor:  No data available 
Odor threshold:  No data available 
pH:  1.0 – 2.5 
Melting point/melting range:  190-194 °C (374-381 °F) 
Boiling point/boiling range:  No data available 
Flash point:  No data available 
Evaporation rate:  No data available 
Flammability:  No data available 
Upper/lower flammability or explosive limits: No data available  
Auto ignition temperature:  No data available 
Danger of explosion: No data available 
Vapor pressure:  No data available 
Vapor density:  No data available 
Relative density:  No data available 
Solubility in/Miscibility with water:  176 g/l at 20 °C (68 °F) 
 
Section 10: Stability and Reactivity 
Stability: Stable under recommended storage conditions 
Materials to avoid: Strong oxidizing agents, Extremely strong light.  
Hazardous Decomposition Products: Carbon oxides 
Incompatibility: Strong oxidizing agents, extremely strong light.  
Section 11: Toxicological Information 
 
Skin: No data available 
Eyes: No data available 
Inhalation: No data available 
Ingestion: No data available 
Section 12: Ecological Information (non-mandatory) 
Ecotoxicity: No data available 
BOD5 and COD: No data available 
Products of Biodegradation: No data available 
Toxicity of the Products of Biodegradation: No data available 
Special Remarks on the Products of Biodegradation: No data available 


3 
 
Section 13: Disposal Considerations (non-mandatory) 
Product 
Offer surplus and non-recyclable solutions to a licensed disposal company. 
Section 14: Transport Information (non-mandatory) 
 
DOT (US) 
Not dangerous goods 
IMDG 
Not dangerous goods 
IATA 
Not dangerous goods 
 
Section 15: Regulatory Information (non-mandatory) 
SARA 302 Components 
No chemicals in this material are subject to the reporting requirements of SARA Title III, 
Section 302. 
SARA 313 Components 
This material does not contain any chemical components with known CAS numbers that 
exceed the threshold (De Minimis) reporting levels established by SARA Title III, Section 
313. 
 
Section 16: Other Information 
The information provided in this safety data sheet is the best of our knowledge, information and belief at 
the date of its publication. The information given is designed only as a guidance for safe handling, use, 
processing, storage, transportation, disposal and release and is not to be considered a warranty or quality 
specification. The information relates only to the specific material designated and may not be valid for such 
material used in combination with any other materials or in any process, unless specified in the text. 
 
SDS date of preparation/update:  5/3/2020 
 




ZiPhenol Study 
Version 1.6 
Protocol #1 
       23 February 2023 
 
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Addendum D 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Page
1
Total aerobic 
microbial count
<= 1000
Conforms
cfu/g
Microbial Enumeration Tests 
<61>
Total yeasts and 
molds count
<= 100
Conforms
cfu/g
Microbial Enumeration Tests 
<61>
Tests for specified 
organisms
Staphylococcus aureus
Conforms
Tests for Specified 
Microorganisms <62>
Bulk density
0.27 - 0.34
0.31
g/mL
USP Monograph
Water-soluble 
substances
<= 0.25
0.16
%
USP Monograph
Ether-soluble 
substances
<= 0.05
0.02
%
USP Monograph
Tests for specified 
organisms
Pseudomonas aeruginosa
Conforms
Tests for Specified 
Microorganisms <62>
Residual solvents
Conforms
Conforms
Residual Solvents <467>
Test for specific 
organisms
E.Coli
Conforms
Tests for Specified 
Microorganisms <62>
Tests for specified 
organisms
Salmonella
Conforms
Tests for Specified 
Microorganisms <62>
Elemental Impurities
Conforms
Conforms
<232>, <233>
pH
5.0 - 7.5
6.5
<791>
Identification A
Conforms
Conforms
USP, Iodinated zinc chloride 
solution
Identification B
Conforms
Conforms
Degree of polymerization
Description
Fine, white or almost white powder
Conforms
Fagron US
Loss on drying
<= 7.0
4.3
%
Loss on Drying <731>
Conductivity
<= 75
56
µS/cm
USP Monograph
Solubility
Insoluble in water
Conforms
Fagron US
Degree of 
polymerization
<= 350
237
units
Viscosity - Capillary Methods 
<911>
Residue on ignition
<= 0.1
0.1
%
Residue on Ignition <281>
Productname:
Expiration Date
Batchnumber:
Inspection Report No.
Analyzed according to:
5/15/25
Cellulose Microcryst PH-102
20G31-U01-009671
INS12041
NF
Quantity:
1 KG
Tests
Requirement
Result
Unit
Standard remark
Certificate of Analysis


Page
2
Release:
Julie Lentz
Quality Assurance 
Technician
Conclusion Date:
3/17/21
Conclusion: APPROVED
This document has been produced electronically from our quality system and is valid without signature.
Tests
Requirement
Result
Unit
Standard remark
Productname:
Expiration Date
Batchnumber:
Inspection Report No.
Analyzed according to:
5/15/25
Cellulose Microcryst PH-102
20G31-U01-009671
INS12041
NF
Quantity:
1 KG
Certificate of Analysis

ICF_001.pdf: 
 
 
 
 
 
 
1 of 15
 
CONSENT FORM AND HIPAA AUTHORIZATION FOR PARTICIPATION IN A RESEARCH 
STUDY 
 
INVESTIGATOR’S NAME: SYED NAQVI, MD 
 
 
PROJECT IRB #:  2035652 
 
STUDY TITLE: EVALUATION OF ZINC AND GREEN TEA EXTRACT 
SUPPLEMENTATION ON REDUCTION IN SYMPTOM DURATION AND SEVERITY 
ASSOCIATED WITH COMMUNITY RESPIRATORY VIRAL INFECTIONS: A RANDOMIZED 
CONTROL TRIAL (ZIPHENOL STUDY) 
 
We invite you to take part in this research study. This consent form tells you why we are doing 
the study, what will happen if you join the study, and other important information about the 
study. 
 
Please take as much time as you need to read this consent form. You can discuss it with your 
family, friends, or personal doctor. If there is anything you do not understand, please ask us to 
explain. Then you can decide if you want to take part in the study or not.  
 
The Principal Investigator (also called the study doctor) is Dr. Syed Naqvi. The people working 
with Dr. Syed Naqvi on this study are called the study team. 
University of Missouri School of Medicine (called the sponsor in this form) is paying for this 
study. 
 
WHAT SHOULD I KNOW BEFORE I DECIDE WHETHER TO TAKE PART IN THIS 
STUDY?  
• Research studies help us to learn new things and test new ideas about treating certain 
conditions/diseases.  
• Taking part in a research study is voluntary. You decide if you want to take part, and you 
can stop taking part at any time. Your regular medical care at the University of Missouri 
Hospitals and Clinics will not be affected now or in the future if you decide you do not 
want to be in this study. 
IRB Approval Date: May 10, 2023; Written Consent with HIPAA Authorization ID #641312; Annual Update ID #392016


 
 
 
 
 
 
2 of 15
• We hope to learn if taking a dietary supplement can speed up the recovery from cold and 
flu like symptoms, including those caused by COVID-19. Other potential benefits such as 
fewer missed days from work or school will also be studied. 
• We invite you to take part in this study because you came to the Emergency Department 
for concerns about a viral respiratory infection.  
• About 100 people will take part in this study at the University of Missouri. 
• If you take part in this study, you will be discharged from your Emergency Department 
Visit with a supplement to take twice a day.  We will be calling you every day to check 
on your symptoms for seven days.   We will explain these procedures in this form. 
• If you join this study, you will have to stop any supplements or products that contain 
zinc, green tea, or ascorbic acid (vitamin C) for as long as you are in the study. 
• The total amount of time you could be in this study is about 8 days (including today).   
• Taking part in this study may or may not make your health better. We hope that the 
information we learn from this study will help in the future treatment of people with cold 
and flu like illness including COVID-19.  There is no guarantee that taking part in 
this research will result in any improvement in your condition. 
• As with any research study, there are risks that we know about and there may be some we 
don’t know about. We will explain these risks in this form. 
• We will only include you in this study if you give us your permission first by signing this 
consent form. 
 
Why Are The Researchers Doing This Study? 
In this study, we want to find out if a dietary supplement containing Zinc, Vitamin C, and Green 
Tea extract (also called the study drug in this form), works better than a placebo.  A placebo is 
something that looks like the study drug, but does not contain any active dietary supplements.  
To do this, we will compare study drug and the placebo in people with viral respiratory illness 
and see which one is more effective at reducing the time it takes to feel better.  The dietary 
supplement is not approved by the U.S. Food and Drug Administration (FDA), but these 
ingredients are commonly used by people as over the counter supplements. 
 
IRB Approval Date: May 10, 2023; Written Consent with HIPAA Authorization ID #641312; Annual Update ID #392016


 
 
 
 
 
 
3 of 15
We don’t know if this study will help you. Your condition may get better, but it could stay the 
same or even get worse. We hope the information we get from this study will help us to develop 
better treatment for respiratory illness in the future. 
 
What will happen if I take part in this study? 
Screening Tests 
If you decide to join this study, you will sign this form and then you will have some screening 
tests to see if you qualify to be in the study. These are the screening tests: 
• Physical Exam: You will have a physical exam, similar to what happens during regular 
doctor visits. 
• Medical Chart Review: The study doctors will review your medical chart. 
 
If the results of these tests show that you can be in the study, you will start in the study today. If 
you do not qualify to be in the study, the study doctor will discuss other options with you and/or 
refer you back to your regular doctor. 
 
 
Research Study Groups 
To find out if study drug works better than placebo for cold and flu like illness including 
COVID-19, this study has 2 groups. One group will take study drug, and the other group will 
take placebo. A placebo is a pill that looks like study drug but does not contain any real 
medicine. We will check the symptoms of everyone in the groups in 1 day and every day 
thereafter for 6 days and compare the results. 
 
Because we don’t know which of the supplements is best, we will “randomize” you into one of 
the 2 study groups.  “Randomize” means putting you into a group by chance.  It is like flipping a 
coin or pulling a number from a hat. You will have an equal chance of being placed in either 
group. A computer program chooses which group you go in. You and the study doctor cannot 
choose which group you go into.  
 
IRB Approval Date: May 10, 2023; Written Consent with HIPAA Authorization ID #641312; Annual Update ID #392016


 
 
 
 
 
 
4 of 15
This study is “blinded”, which means that you and the study team will not know which study 
drug you are getting until the end of the study. This way, no one’s expectations of what will 
happen in the study will affect the results.  
In an emergency, the study doctor can find out which study drug you are getting.  
 
Study Tests and Procedures 
If you take part in this study, you will have the following tests and procedures for study purposes 
only: 
• At discharge from your Emergency Department visit, you will receive enough 
supplement or placebo to take for five days with the following directions: 
o Take three (3) capsules by mouth two (2) hours following a meal twice daily for 
five (5) days  
• You will need to be available for one telephone visit lasting 15-20 minutes in duration 
from University of Missouri Healthcare Emergency Department personnel anytime 
during the hours of 8:00am – 8:00pm every day starting tomorrow and everyday 
thereafter for six days. Please inform study personnel of a preferred time of day (e.g. 
morning or afternoon) to be contacted. During each telephone visit you will be asked the 
following questions: 
o You will be asked to rate the severity of 12 different symptoms using a simple 
scale ranging from 0 to 3 points. 
o You be asked if you are experiencing any side effects such as nausea or skin rash 
o You will be asked how many days you may have missed from work or school due 
to being sick 
o You will be asked if you required any medical treatment such as going to your 
doctor or being admitted to the hospital  
o You will be asked about any missed doses of study drug or placebo 
o You will be asked about taking any over-the-counter (OTC) products including 
product name(s) and number of doses taken. If may be helpful to use a diary to 
record use of these products, but it is not required. 
 
IRB Approval Date: May 10, 2023; Written Consent with HIPAA Authorization ID #641312; Annual Update ID #392016


 
 
 
 
 
 
5 of 15
We will keep the information we collect from you for this study without asking for your consent 
again. Information that could identify you will be removed from your research data so no one 
will know that they belong to you. 
 
Your information may be used by the investigator to develop new treatments that may be sold 
commercially for profit. You will not share in these profits. 
 
Results of research testing will be given to your doctor only if it is needed to treat you for an 
unexpected side effect suspected to be due from taking study drug.  
 
 
How Long Will I Be in the Study? 
You will be in this study for about 8 days (including today). 
You will take the study drug or placebo for 5 days. 
A study team member will call you every day for seven days starting tomorrow to check on your 
symptoms and other study related events of interest. 
 
 
CAN I STOP BEING IN THE STUDY? 
You can stop being in the study at any time without giving a reason. If you stop being in the 
study, your regular medical care will not change. Leaving the study will not affect your future 
medical care at the University of Missouri.  
 
There is no penalty to you if you do not join the study or if you leave it early. You will not 
lose any benefits you are entitled to if you leave the study. 
 
If you decide to stop participating in the study, you should discuss your decision with the study 
doctor. If you still want to stop participating in the study after talking to the study doctor then 
you can bring back any remaining study drug or placebo to the University of Missouri 
Healthcare Emergency Department for disposal or you can place your study drug or placebo 
IRB Approval Date: May 10, 2023; Written Consent with HIPAA Authorization ID #641312; Annual Update ID #392016


 
 
 
 
 
 
6 of 15
bottle with unused capsules in a sealed container such as a Ziplock bag and dispose in the trash 
in an area away from children or pets.  
 
The study doctor may decide to take you off this study at any time, even if you want to stay in 
the study. The study doctor will tell you the reason why you need to stop being in the study. 
These reasons may be: 
• If it is in your best medical interest 
• Your condition gets worse 
• You are hospitalized for any reason 
• You become pregnant 
• You do not follow the study rules 
• The whole study is stopped 
 
If necessary, the study doctor will arrange for you to continue your medical care with your 
regular doctor. 
 
What health risks or problems can I expect from the Study? 
There are risks to taking part in any research study. There is a risk that you may get a study drug 
that does not help your condition or makes it worse. There may also be problems (also called 
side effects) we do not know about yet. If we learn about new important risks and side effects, 
we will tell you. We will tell you about any new information we learn that may affect your 
decision to continue taking part in the study. 
 
Dietary supplements can affect people in different ways. Not everyone gets the same side effects. 
Side effects may be mild or very serious. Many go away soon after you stop taking the drug. 
Some side effects can last a long time or never go away. You may receive other drugs to make 
side effects less severe and uncomfortable.  Complications of some of the side effects listed 
below may lead to life-threatening events such as liver injury or a severe allergic reaction. 
 
We will closely watch everyone in the study for side effects. You need to tell the study doctor 
immediately if you have any problems, side effects, or changes in your health. Dr. Syed Naqvi, 
MD telephone number is 573-884-9066. 
IRB Approval Date: May 10, 2023; Written Consent with HIPAA Authorization ID #641312; Annual Update ID #392016


 
 
 
 
 
 
7 of 15
In other studies, the side effects that other people have experienced so far with study drug are: 
• Nausea 
o This can occur in up to 10-15% of patients. 
o Taking study drug two (2) hours after a meal can help reduce the risk of nausea. 
o Do not take study drug on an empty stomach. 
• Skin rash 
o This can occur in up to 3.4% of patients. 
• Elevations in liver function tests such as ALT, which could indicate liver injury 
o This can occur in up to 6.7% of patients. 
o Severe elevations of ALT that may require medical treatment can occur in up to 
1.3% of patients. 
o In patients for which ALT elevations occurred all recovered an average of one 
month after stopping treatment.  
 
• Randomization risks: You will be put into a group by chance. The supplement you 
receive may turn out to be less effective or have more side effects than that in the other 
groups. It may also be less effective and have more side effects than other supplements 
taken for respiratory illness.   While you are in this study, we will not know which 
supplement you are getting. If your condition gets worse during the study and we need to 
know which you are getting, there will be a way for us to find out.  
• Placebo risks: If you are in the placebo group, you will go without study treatment for 
your condition for 5 days, however, use of over-the-counter medications to treat cold and 
flu-like symptoms will be permitted so long as they do not contain any of the ingredients 
of the study drug.  
 
• Unknown risks: The experimental supplement in this study may have side effects that no 
one knows about yet. The study team will tell you if they learn anything that might make 
you change your mind about being in the study. 
 
 
Are There Benefits to Taking Part in the Study? 
IRB Approval Date: May 10, 2023; Written Consent with HIPAA Authorization ID #641312; Annual Update ID #392016


 
 
 
 
 
 
8 of 15
We don’t know if this study will help you. Your condition may get better, but it could stay the 
same or even get worse. We hope that this study will help us to learn more about the study drug, 
and to develop new treatments for cold and flu like illness including COVID-19 in the future. 
 
What Other Choices Do I Have? 
You do not have to take part in this study. You are free to say yes or no. If you do not want to 
join this study, your doctor will discuss other choices with you. The study doctor can discuss the 
possible benefits and risks of the other options available to you. 
 
What about Privacy And Confidentiality? 
 
The study team needs to use some of your health/personal information. This information comes 
from questions we ask you, forms you fill out, and your medical record. One risk of taking part 
in a research study is that more people will handle your personal health information. We are 
committed to respecting your privacy and to keeping your personal information confidential. The 
study team will make every effort to protect your information and keep it confidential to the 
extent allowed by law. However, it is possible that an unauthorized person will see it.  
 
State and federal privacy laws (HIPAA) protect the use and release of your health information. If 
you decide to take part in this study, you also give us your permission to use your private health 
information, including the health information in your medical records and information that can 
identify you.  
You have the right to refuse to give us your permission for us to use your health information. 
However, doing so would mean that you could not take part in this study.  
 
The following identifiers will be obtained from your health records: 
Name 
 
 
 
 
 
Address 
Dates related to you 
 
 
 
Telephone number(s) 
Fax Number 
 
 
 
 
Email Address 
Social Security Number 
 
 
 
Medical Record Number 
Health Plan Beneficiary Number  
 
Account Numbers 
Certificate or License Numbers 
 
 
Any vehicle or device serial number 
Web Address (URL) 
 
 
 
Internet Protocol (IP) Address(es) 
IRB Approval Date: May 10, 2023; Written Consent with HIPAA Authorization ID #641312; Annual Update ID #392016


 
 
 
 
 
 
9 of 15
Biometric Identifiers (finger/voice print)  
Photographic images 
Any other characteristic that could identify you 
 
The following is the type of protected health information that will be used in the study: 
Radiology Images  
 
 
 
Discharge Summaries 
Radiology Reports  
 
 
 
Health Care Billing or Financial Records 
EKG Recordings/Reports  
 
 
Consultations 
Progress Notes 
 
 
 
 
Medications 
History and Physical Exams 
 
 
Emergency Medicine Reports 
Operative Reports  
 
 
 
Dental Records 
Pathology Reports  
 
 
 
Demographics (age, race, etc.) 
Laboratory Reports 
 
 
 
Questionnaires, Surveys, Diaries 
Photographs/Video Recordings 
 
 
Audio Recordings 
Social Security Number (This is only collected for billing/payment purposes and will not be 
shared with the study sponsor) 
Other 
 
We may share any of this information with the following: 
• Authorized members and staff of the University of Missouri Institutional Review Board 
(IRB).  
• Laboratories and other individuals and organizations that may need to see your health  
information in connection with this study. 
• Study monitors and auditors who make sure that the study is being done properly.  
• Government agencies and public health authorities, such as the Food and Drug  
Administration (FDA), the Department of Health and Human Services (DHHS), and the 
Office for Human Research Protections (OHRP) 
 
Any research information shared with outside entities will not contain your name, address, 
telephone or social security number, or any other personal identifier unless it is necessary for 
review or required by law. 
 
IRB Approval Date: May 10, 2023; Written Consent with HIPAA Authorization ID #641312; Annual Update ID #392016


 
 
 
 
 
 
10 of 15
We will keep the information we collect from you for this study to use in future research/to share 
with other investigators to use in future studies without asking for your consent again. 
Information that could identify you will be removed from your research data so no one will know 
that they belong to you. 
 
The people who get your health information may not be required by Federal privacy laws (such 
as the HIPAA Privacy Rule) to protect it. Some of those people may be able to share your 
information with others without your separate permission. 
 
Your permission for us to use and/or release your information will last until the end of the study 
unless you cancel your permission. 
 
You can cancel your permission at any time by writing to: 
Investigator’s Name: Syed Naqvi, MD 
Institution: University of Missouri Health Care 
Department: Medicine 
Address: One Hospital Drive, DC043.00 
 
Columbia, MO 65212 
 
The information we have already collected may still be used for this research study, but we will 
not collect any more information after we receive your letter.  
 
You will not be allowed to access your protected health information that is obtained or created 
during this research project until the end of the study. 
 
If you have not already received a copy of the University of Missouri Healthcare Privacy Notice, 
you may request one. If you have any questions or concerns about your privacy rights, you may 
contact the Privacy Officer at 573-882-9054. 
 
 
We will scan a copy of this consent form into your medical record. We may also record your 
research information, including the results of tests and procedures, in your medical record. The 
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medical information produced by this study will become part of your hospital medical record, 
and people allowed to look at your medical records may see this research information.  
 
Information that does not become part of your medical record will be stored in the investigator’s 
electronic/computer or paper files. Computer files are protected with a password and the 
computer is in a locked office that only study team members can open. Paper files are kept in a 
locked drawer in a locked office that only study team members can open. 
 
Your records will be given a code number and will not contain your name or other information 
that could identify you.  The code number that connects your name to your information will be 
kept in a separate, secure location.  Information that may identify you may not be given to 
anyone who is not working on this study without your written consent, or if required by law.   
 
The people who may use and/or release your research information include: 
• Those working on the study team at University of Missouri Health Care 
• The members of the University of Missouri Institutional Review Board (IRB) 
• Those who check on research activities to make sure it is being done correctly and safely  
• The FDA  
• Other government or inspection agencies  
We may present the results of this study in public talks or written articles, but we will not use 
information that can identify you.   
 
CAN I SEE MY RESEARCH RECORDS?  
If you join this study, you will be given one of the study supplements without knowing exactly 
which one. This is called a “blinded” study. This is a way of doing research when we want to 
compare drugs and we don’t want people’s feelings about the drug to affect the results.  
 
If you ask to see your health records during this blinded study, the study team cannot tell you 
which study drug you are getting. This is because the study team is also blinded to which study 
drug you are getting. You would have to wait until all participants have completed the study.  
 
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If we need the blinded information to treat you for an emergency, the study doctor will be able to 
find out. 
 
Are There Any Costs To Being In The Study? 
There is no cost to you for taking part in this study. 
 
The sponsor will provide the study drug to you free of charge while you are in this study. 
 
Some tests and procedures are done for your routine health care, and you would get them even if 
you weren’t in this study. You and/or your health plan/insurance will be billed for the tests and 
procedures you need for your routine health care while you are in this study. 
 
Some health plans/insurance companies will not pay for these costs for people who are in 
research studies. Check with your health plan/insurance company to find out what they will pay 
for. If you have any questions about which tests/procedures will be billed to you and/or your 
health plan/insurance, please ask us. 
 
 
Will I be Paid for Taking Part in this Study? 
There is no payment to you for taking part in this study. 
 
 
What Happens If I am Injured During The Study?  
It is not the policy of the University of Missouri to compensate human subjects in the event the 
research results in injury.  The University of Missouri, in fulfilling its public responsibility, has 
provided medical, professional and general liability insurance coverage for any injury in the event 
such injury is caused by the negligence of the University of Missouri, its faculty and staff.   
The University of Missouri also will provide, within the limitations of the laws of the State of 
Missouri, facilities and medical attention to subjects who suffer injuries while participating in the 
research projects of the University of Missouri.   
 
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In the event you have suffered injury as the result of participation in this research program, you are 
to contact the Risk Management Officer, telephone number (573) 882-1181, at the Health Sciences 
Center, who can review the matter and provide further information.   
This statement is not to be construed as an admission of liability. 
 
 
What Are My Rights as a Study Participant? 
Taking part in this study is voluntary.  You do not have to take part.  Your present or future 
medical care will not be affected if you decide not to take part.   
 
If you do decide to take part, you can change your mind and drop out of the study at any time. 
This will not affect your current or future care at the University of Missouri Hospitals and 
Clinics. There is no penalty for leaving the study and you will not lose any benefits that you are 
entitled to receive. 
 
If the study investigator decides to take you off the study, he will explain the reasons and help 
arrange for your continued care by your own doctor, if needed.   
 
An Independent Safety Monitor, an independent group of experts, will review the data collected 
during this study. We will tell you about any new information discovered during this study that 
might affect your health, welfare, or change your mind about taking part. 
 
Where Can I Get More Information About This Study? 
 
A description of this clinical trial will be available on www.ClinicalTrials.gov, as required by 
U.S. law. This Web site will not include information that can identify you. At most, the Web site 
will include a summary of the results. You can search this Web site at any time. 
 
Who Can Answer My Questions About The Study? 
If you have more questions about this study at any time, you can call Dr. Syed Naqvi at 573-884-
9066. 
You may also contact the University of Missouri Institutional Review Board (IRB) if you: 
• Have any questions about your rights as a study participant; 
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• Want to report any problems or complaints; or 
• Feel under any pressure to take part or stay in this study.  
 
The IRB is a group of people who review research studies to make sure the rights of participants 
are protected. Their phone number is 573- 882-3181, and email is muresearchirb@missouri.edu.  
 
If you want to talk privately about your rights or any issues related to your participation in this 
study, you can contact University of Missouri Research Participant Advocacy by calling 888-
280-5002 (a free call), or emailing MUResearchRPA@missouri.edu. 
 
We will give you a copy of this consent form. Please keep it where you can find it easily. It will 
help you to remember what we discussed today. 
 
 
 
 
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SIGNATURE OF STUDY PARTICIPANT  
 
Consent to Participate in Research 
 
By signing my name below, I confirm the following: 
• I have read/had read to me this entire consent form. 
• All of my questions were answered to my satisfaction. 
• The study’s purpose, procedures, risks and possible benefits were explained to me. 
• I voluntarily agree to take part in this research study. I have been told that I can stop at 
any time. 
 
 
 
 
Subject’s Signature 
Date  
 
 
 
 
 
 
 
*A witness is required when a participant is competent to provide consent but is blind, or cannot 
read or write. 
 
SIGNATURE OF PERSON AUTHORIZED TO OBTAIN CONSENT*  
I have explained the purpose of the research, the study procedures (identifying those that are 
investigational), the possible risks and discomforts and potential benefits of the study, and have 
answered questions regarding the study to the best of my ability. 
 
 
 
 
 
*This signature is required for FDA regulated research and/or research that involves any 
medical procedure or surgical treatment. 
 
 
 
 
Signature of Witness (if applicable)* 
Date  
 
 
 
Signature of Person Authorized to Obtain Consent 
Date  
IRB Approval Date: May 10, 2023; Written Consent with HIPAA Authorization ID #641312; Annual Update ID #392016