Conditions: COVID-19 Viral Respiratory Illnesses
Keywords: COVID-19 Viral Respiratory Illnesses
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1407
Healthy volunteers: no

Brief summary:
Trial to Evaluate the Efficacy and Safety of Nitazoxanide (NTZ) for Pre- and Post Exposure Prophylaxis of COVID-19 and Other Viral Respiratory Illnesses (VRI) in Healthcare Workers and Others at Increased Risk of SARS-CoV-2 Infection

Detailed description:
Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate the Efficacy and Safety of Nitazoxanide (NTZ) for Pre- and Post Exposure Prophylaxis of COVID-19 and Other Viral Respiratory Illnesses (VRI) in Healthcare Workers and Others at Increased Risk of SARS-CoV-2 Infection

Arms:
arm 1: Two NTZ 300 mg tablets orally twice daily for 6 weeks. arm 2: Two placebo tablets orally twice daily for 6 weeks.

Interventions: intervention 1: Nitazoxanide intervention 2: Placebo intervention 3: Vitamin Super B-Complex
Intervention descriptions: intervention 1: Nitazoxanide 600 mg administered orally twice daily for six weeks intervention 2: Placebo administered orally twice daily for six weeks intervention 3: Vitamin Super B-Complex administered orally twice daily to maintain the blind

Protocol document:
Prot_000.pdf: 
Protocol RM08-3007 Prophylaxis v5.0 
 
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CONFIDENTIAL 
 
 
 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO CONTROLLED TRIAL 
TO EVALUATE THE EFFICACY AND SAFETY OF NITAZOXANIDE 
(NTZ) FOR PRE- AND POST-EXPOSURE PROPHYLAXIS OF COVID-19 
AND OTHER VIRAL RESPIRATORY ILLNESSES (VRI) IN 
HEALTHCARE WORKERS AND OTHERS AT INCREASED RISK OF 
SARS-COV-2 INFECTION 
 
PROTOCOL NO. RM08-3007 
 
Study Sponsor: 
 
The Romark Institute for Medical Research 
 
 
 
 
Version: FINAL v5.0 
 
October 26, 2020 
 
 


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TABLE OF CONTENTS 
PROTOCOL NO. RM08-3007 ........................................................................................................1 
INVESTIGATOR’S AGREEMENT ...............................................................................................6 
SYNOPSIS ......................................................................................................................................7 
1. 
INTRODUCTION ......................................................................................................10 
1.1. 
Viral Respiratory Infections .......................................................................................10 
1.1.1. 
Antivirals Studied for Chemoprophylaxis of Viral Respiratory Infections ................11 
1.2. 
Nitazoxanide (NTZ) ....................................................................................................11 
1.2.1. 
NTZ Inhibits Viral Replication and Cytokine Secretion ............................................12 
1.2.2. 
Pharmacokinetics of NTZ in Humans ........................................................................13 
1.2.3. 
Clinical Experience with Geriatric Subjects (≥65 Years of Age) Exposed to 
NTZ 300 mg Extended Release Tablets in Clinical Trials .........................................14 
1.2.4. 
Overview of Other Experience in Clinical Trials and Post-marketing 
Surveillance ................................................................................................................15 
1.3. 
Rationale for the Study ...............................................................................................15 
2. 
STUDY OBJECTIVES ..............................................................................................16 
3. 
STUDY DESIGN .......................................................................................................16 
4. 
SUBJECT SELECTION .............................................................................................18 
4.1. 
Inclusion Criteria ........................................................................................................18 
4.2. 
Exclusion Criteria .......................................................................................................19 
5. 
STUDY PROCEDURES ............................................................................................20 
5.1. 
Screening Evaluation (Day -30 to Day 1) ...................................................................20 
5.2. 
Baseline (Day 1, may be same day as screening evaluation) .....................................20 
5.3. 
Daily Day 1 through Week 6 ......................................................................................22 
5.4. 
Suspected ARI Visit ...................................................................................................22 
5.5. 
Week 3 (±7 days) and Week 6 Evaluations (±2 days) ................................................23 
5.6. 
Week 8 Evaluation (+7 days) .....................................................................................24 
5.7. 
Unscheduled Visit .......................................................................................................24 
5.8. 
Study Discontinuation ................................................................................................24 
5.9. 
Plan for Laboratory Safety Tests ................................................................................24 
5.10. 
Plan for Virology Testing and Monitoring Resistance ...............................................25 
6. 
RANDOMIZATION ..................................................................................................25 
7. 
DATA MANAGEMENT ...........................................................................................26 


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7.1. 
Electronic Data Entry .................................................................................................26 
7.2. 
Protocol Deviations ....................................................................................................26 
7.3. 
Data Quality Assurance ..............................................................................................26 
8. 
STATISTICAL CONSIDERATIONS .......................................................................27 
8.1. 
Sample Size Calculations ...........................................................................................27 
8.2. 
Efficacy Variables ......................................................................................................28 
8.3. 
Response Definitions ..................................................................................................28 
8.4. 
Statistical Methodology ..............................................................................................28 
8.4.1. 
Efficacy Analyses .......................................................................................................28 
8.4.2. 
Population Pharmacokinetics Analysis .......................................................................29 
8.4.3. 
Safety Analyses ..........................................................................................................29 
9. 
INVESTIGATIONAL PRODUCTS ..........................................................................30 
9.1. 
Drug Regimens, Administration and Duration ...........................................................30 
9.2. 
Identity of Investigational Products ............................................................................30 
9.3. 
Packaging and Labeling ..............................................................................................30 
9.4. 
Drug Accountability ...................................................................................................31 
9.5. 
Subject Compliance ....................................................................................................31 
9.6. 
Disallowed Medication ...............................................................................................31 
10. 
ADVERSE EVENTS..................................................................................................32 
10.1. 
Definitions ..................................................................................................................32 
10.2. 
Clinical Adverse Events .............................................................................................33 
10.3. 
Reporting Requirement ...............................................................................................34 
10.4. 
Medication Modification/Withdrawal Due to an Adverse Event ...............................34 
10.5. 
Medication Errors .......................................................................................................35 
11. 
DISCONTINUATION ...............................................................................................35 
11.1. 
Study Discontinuation ................................................................................................35 
11.2. 
Subject Discontinuation ..............................................................................................35 
12. 
ELECTRONIC DATA COLLECTION (EDC) SYSTEM .........................................35 
13. 
RETENTION OF RECORDS ....................................................................................36 
14. 
MONITORING THE STUDY ...................................................................................36 
15. 
INFORMED CONSENT ............................................................................................36 
16. 
ETHICS ......................................................................................................................37 
16.1. 
Study-Specific Design Considerations .......................................................................37 


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16.2. 
Investigator Responsibilities .......................................................................................38 
16.3. 
Institutional Review Board (IRB) ...............................................................................38 
16.4. 
Privacy of Personal Data ............................................................................................39 
17. 
DATA CONFIDENTIALITY, DISCLOSURE OF DATA, AND 
PUBLICATION ..........................................................................................................40 
18. 
DATA AND REPORT REQUIREMENTS ...............................................................40 
19. 
CONTACT INFORMATION ....................................................................................42 
20. 
LIST OF REFERENCES ............................................................................................43 
21. 
APPENDICES ............................................................................................................46 
21.1. 
Appendix I: Study Schedule .......................................................................................47 
21.2. 
Appendix II: Toxicity Grading for Adverse Events ...................................................48 
21.3. 
Appendix III: List of Essential Documents for the Investigative Site ........................55 
21.4. 
Appendix IV: Protocol Revision History ...................................................................57 
21.5. 
Appendix V: Declaration of Helsinki .........................................................................63 
 


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LIST OF TABLES 
Table 1: 
List of Abbreviations ....................................................................................................9 
Table 2: 
Summary of Tizoxanide and Tizoxanide Glucuronide Pharmacokinetics 
Parameters ...................................................................................................................13 
Table 3: 
Summary of Tizoxanide and Tizoxanide Glucuronide Trough Plasma 
Concentrations ............................................................................................................14 
Table 4: 
Population Pharmacokinetics, Trough Data, for Geriatric Subjects ≥65 Years 
of Age from Phase 2b/3 and Phase 3 Clinical Trials ..................................................15 
Table 5: 
Clinical Illness Required for Diagnosis of ARI1 (adapted from Yu et al. 
2020) ...........................................................................................................................22 
Table 6: 
Study Medication Labels ............................................................................................31 
Table 7: 
Major CYP2C8 Substrates ..........................................................................................32 
Table 8: 
Contact Information ....................................................................................................42 
Table 9: 
Schedule of Assessments ............................................................................................47 
Table 10: Table for Clinical Abnormalities: Vital Signs ............................................................48 
Table 11: Table for Clinical Abnormalities: Systemic (General) ...............................................49 
Table 12: Table for Clinical Abnormalities: Systemic Illness ....................................................49 
Table 13: Table for Laboratory Abnormalities: Serum ..............................................................50 
Table 14: Table for Laboratory Abnormalities: Hematology .....................................................53 
Table 15: Table for Laboratory Abnormalities: Urine ................................................................54 
Table 16: List of Essential Documents for the Investigative Site ...............................................55 
Table 17: Protocol Revision History...........................................................................................57 
 
 


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INVESTIGATOR’S AGREEMENT 
CONFIDENTIALITY 
The information in this protocol is provided to you, as an Investigator or consultant, for review by 
you, your staff, and an applicable institutional review committee.  By accepting this document, 
you agree that information contained herein will be considered confidential and will not be 
disclosed to others, without written authority from The Romark Institute for Medical Research, 
except to the extent necessary to obtain:  (a) Institutional Review Board approval and (b) informed 
consent from those persons to whom the investigational medicinal product will be administered. 
 
APPROVAL OF FINAL PROTOCOL 
My signature below constitutes agreement with this protocol.  I am providing the necessary 
assurances that this study will be conducted by me and my staff according to all stipulations of the 
protocol, including all statements regarding confidentiality, and in complete accordance with all 
applicable regulations including current Good Clinical Practice guidelines and the ethical 
guidelines set by the World Medical Assembly (Declaration of Helsinki, last amendment in 
Fortaleza, Brazil October 2013).  Furthermore, my signature below indicates that source 
documents will be available for review by the Sponsor or their designated representative. 
 
Principal Investigator Signature: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Principal Investigator  
 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
Print name:  
 
 
 
 
 
 
 
 
 
 
With the signature below, the Sponsor approves of this protocol. 
 
 
Sponsor Signature: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The Romark Institute for Medical Research  
 
 
 
 
 
 
Date 
 
Print name:  
 
 
 
 
 
 
 
 
 




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Secondary Efficacy Parameters: 
i. 
Mortality due to COVID-19 or complications thereof. 
 
ii. 
The proportion of subjects (with or without symptoms) 
testing positive for antibodies to SARS-CoV-2 at 
either of the Week 6 or Week 8 visits. 
Exploratory Efficacy Parameters: 
Proportion of subjects hospitalized due to viral respiratory 
illness (VRI) or complications thereof; mortality due to 
VRI or complications thereof; proportion of subjects 
experiencing acute respiratory illness (ARI); proportion of 
subjects hospitalized due to ARI or complications thereof;  
mortality due to ARI or complications thereof. 
Safety Parameters: 
Adverse events 
Biological Samples: 
Blood and urine samples for safety will be collected for all 
subjects at baseline, Week 3 and Week 6.  Blood samples 
for pharmacokinetics will be collected at the Week 3 and 
Week 6 visits.  Blood tests for anti-SARS-CoV-2 
antibodies will be collected at Baseline, Week 6 and Week 
8.  Nasopharyngeal swabs will be collected at baseline for 
all subjects.  Additional nasopharyngeal swabs and fecal 
specimens will be collected by the Investigator at visits for 
COVID-19/VRI symptoms. 
Study Centers: 
Multicenter, USA  
Trial Duration: 
April 2020 – April 2021 
 
 


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Table 1: 
List of Abbreviations 
Abbreviation 
Term 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ARI 
Acute Respiratory Illness 
AST 
Aspartate Aminotransferase 
ATP 
Adenosine Triphosphate 
b.i.d. 
Twice Daily 
BUN 
Blood Urea Nitrogen 
CMH 
Cochran-Mantel-Haenszel 
COPD 
Chronic Obstructive Pulmonary Disease 
COVID-19 
Coronavirus Disease 2019 (caused by SARS-CoV-2) 
CRF 
Case Report Form 
EC50 
50% Effective Concentration 
EDC 
Electronic Data Collection 
EV/RV 
Rhinovirus/Enteroviruses 
FDA 
Food and Drug Administration 
FLU-PRO 
InFLUenza Patient-Reported Outcome Questionnaire  
GCP 
Good Clinical Practice 
GGT 
Gamma Glutamyl Transferase 
HDL 
High Density Lipoprotein 
HIV 
Human Immunodeficiency Virus 
hMPV 
Human Metapneumovirus 
IC50 
50% Inhibitory Concentration 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IL 
Interleukin 
IRB 
Institutional Review Board 
LDL 
Low Density Lipoprotein 
MDCK 
Madin-Darby Canine Kidney 
NTZ 
Nitazoxanide 
RSV 
Respiratory Syncytial Virus 
RT-PCR 
Reverse Transcription Polymerase Chain Reaction 
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus 2 
VRI 
Viral Respiratory Illness 


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1. 
INTRODUCTION 
1.1. Viral Respiratory Infections  
Respiratory infections are the leading cause of disease globally.  There are more than 500 
million non-influenza viral respiratory infections or “common colds” each year in the United 
States, with adults experiencing as many as 2-6 illnesses per year and children experiencing 
6-8 (Fendrick et al. 2003, Turner 1997, Worrall 2011).  Colds have been reported to account 
for as much as 40% of time lost from work in the employed population and 30% of school 
absences (Kirkpatrick 1996).  In a study conducted from November of 2000 to February of 
2001, the total economic impact of non-influenza viral respiratory tract infections was nearly 
$40 billion (Fendrick et al. 2003).  Adjusted for inflation (February 2001 to January 2018), 
the economic impact today would exceed $56 billion (USDOL Bureau of Labor Statistics 
2018).  Epidemic outbreaks of VRIs, like SARS-CoV-2, can diminish entire economies and 
have cost impacts of trillions of dollars. 
Common respiratory viral pathogens include adenovirus, human coronavirus, hMPV, 
EV/RV, influenza, parainfluenza and RSV.  In most cases, respiratory viral infections are 
self-limiting and confined to the upper airways, where they evoke relatively mild symptoms 
such as sneezing and a runny nose.  However, in susceptible individuals, such as newborns, 
those with pre-existing lung disease, and the elderly, the symptoms can impact on the lower 
airways, resulting in wheeze, shortness of breath, bronchiolitis or pneumonia (Troy and 
Bosco 2016).   
The EPIC study (Etiology of Pneumonia in the Community) conducted by researchers at the 
Centers for Disease Control and Prevention was a large multicenter population-based 
surveillance study conducted in the United States, which used rigorous microbiologic testing 
in 2259 hospitalized adults with community acquired pneumonia.  In this study respiratory 
viruses were the most common pathogen identified in adults hospitalized with pneumonia 
accounting for 23% of all pneumonia admissions.  Rhinovirus (9%) was the most common 
pathogen identified followed by influenza A/B (6%), S. pneumoniae (5%), hMPV (4%), and 
RSV (3%).  Overall, of the individual organisms identified, viruses accounted for 6 of the 7 
most common single as well as co-pathogens.  The data further indicated serious VRIs can 
occur year-round with some intra-virus seasonality (Jain et al. 2015).   
Aside from the seasonal prevalence of typical respiratory viruses, outbreaks can occur with 
these as well as novel strains like SARS-CoV-2 and MERS-CoV.  Rhinoviruses have been 
associated with as much as 59% of outbreaks in long-term care facilities as well as seasonal 
strains of coronavirus, both leading to severe disease (Longtin et al. 2010, Hand et al. 2018).  
RSV and hMPV are widely reported to circulate during an influenza season, with RSV 
infections occurring at 4 times the rate of the general population in the elderly (Ursic et al. 
2016, Thompson et al. 2003).      
Influenza is the only respiratory virus for which a vaccine exists.  Moreover, vaccine efficacy 
is variable with each season and has demonstrated diminished vaccine responses in the 
elderly (Centers for Disease Control and Prevention 2019, Goodwin et al. 2006).  Despite 
widespread vaccine availability and uptake, influenza outbreaks are still quite common.  For 
instance, as much as 90% of those residing in long-term care facilities are vaccinated for 
influenza, yet at least half of these facilities report outbreaks every year (McGeer et al. 2000).  


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The Infectious Diseases Society of America recommends chemoprophylaxis for institutional 
outbreaks and in certain situations involving patients at high-risk for complications or 
unvaccinated personnel in close contact with high-risk patients (Uyeki et al. 2018).  
However, these recommendations are limited to influenza since there are no available agents 
for the chemoprophylaxis of other respiratory viruses.  Considering the lack of vaccine and 
chemoprophylaxis availability for most pathogens, inefficacy of influenza vaccination, 
enhanced rate of spread in certain settings and emergence of novel viral respiratory 
pathogens a novel broad-spectrum chemoprophylaxis strategy is of paramount importance. 
1.1.1. 
Antivirals Studied for Chemoprophylaxis of Viral Respiratory Infections 
The only drugs approved for chemoprophylaxis in this population, for any respiratory 
virus, are oseltamivir and zanamivir which are only for influenza A and B infections.   
In a pooled analysis of two seasonal chemoprophylaxis trials in healthy unvaccinated 
adults (aged 18 to 65 years), oseltamivir 75 mg once daily taken for 42 days during a 
community outbreak reduced the incidence of laboratory-confirmed clinical influenza 
from 5% (25/519) for the placebo group to 1% (6/520) for the oseltamivir group. 
(TAMIFLU® Prescribing Information 2019, Hayden et al. 1999) 
Two seasonal prophylaxis trials assessed zanamivir 10 mg inhaled once daily versus 
placebo inhaled once daily for 28 days during community outbreaks.  The first trial 
enrolled subjects aged 18 years or older (mean age: 29 years) from 2 university 
communities.  In this trial, the incidence of symptomatic laboratory-confirmed influenza 
was reduced from 6.1% (34 of 554) for the placebo group to 2.0% (11 of 553) for the 
group receiving zanamivir.  The second seasonal prophylaxis trial enrolled subjects aged 
12 to 94 years (mean age: 60 years) with 56% of them older than 65 years.  In this trial, 
the incidence of symptomatic laboratory-confirmed influenza was reduced from 1.4% 
(23 of 1,685) for the placebo group to 0.2% (4 of 1,678) for the group receiving zanamivir 
(RELENZA® Prescribing Information 2018).   
There are no drugs approved for the treatment or chemoprophylaxis of viral respiratory 
infections caused by other common respiratory pathogens like coronavirus, RSV, 
rhinovirus, hMPV, and parainfluenza in this population.  
1.2. Nitazoxanide (NTZ) 
NTZ is a thiazolide anti-infective with in vitro activity against parasites, anaerobic bacteria, 
and viruses (Anderson and Curran 2007). 
ALINIA® (NTZ) for Oral Suspension (patients 1 year of age and older) and ALINIA (NTZ) 
Tablets (patients 12 years and older) are marketed in the United States for the treatment of 
diarrhea caused by Giardia lamblia or Cryptosporidium parvum.  ALINIA for Oral 
Suspension and ALINIA Tablets have not been shown to be superior to placebo for the 
treatment of diarrhea caused by Cryptosporidium parvum in HIV-infected or 
immunodeficient patients (ALINIA Prescribing Information 2019). 


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1.2.1. 
NTZ Inhibits Viral Replication and Cytokine Secretion 
Tizoxanide, the active circulating metabolite of NTZ, has been shown to possess antiviral 
activity in cell culture against a broad range of viruses including influenza A and B 
viruses, coronaviruses (SARS-CoV-2, MERS-CoV, canine CoV S-378, murine 
coronavirus, mouse hepatitis virus strain A59 (MHV-A59)), parainfluenza (Sendai) 
virus, RSV A-2, rotavirus, norovirus, hepatitis C virus genotypes 1a and 1b, Japanese 
encephalitis virus, dengue fever virus-2, yellow fever virus, hepatitis B virus, and human 
immunodeficiency virus (HIV) (Rossignol 2014, Rossignol 2016, Wang et al. 2020, 
Piacentini et al. 2018).  Experiments in HeLa R19 cells have shown that NTZ inhibits 
replication of rhinovirus A serotypes 2 and 16 (Romark Study Report RM01-0434).  
Concentrations of tizoxanide required to inhibit replication of these viruses by 50% 
(EC50s) were generally between 0.2 and 3 µM depending upon the test conditions.    
The anti-influenza activity of nitazoxanide and its circulating metabolite, tizoxanide, has 
been investigated in human (Monocytic U937, T-lymphocytic Jurkat, and Alveolar type 
II-like A549) and canine (MDCK) cells after infection with multiple different strains of 
influenza A virus including oseltamivir-resistant and amantadine-resistant strains 
(Rossignol et al. 2009, Ashton et al. 2010, Sleeman et al. 2014).  In a study of the 
susceptibility of 210 circulating seasonal influenza viruses to tizoxanide demonstrated 
median EC50 values (±IQR) of 0.48 μM (0.33-0.71), 0.62 μM (0.56-0.75), 0.66 μM (0.62-
0.69), and 0.60 μM (0.51-0.67) for A(H1N1)pdm09, A(H3N2), B(Victoria lineage) and 
B(Yamagata lineage), respectively (Tilmanis et al. 2017). 
Laboratory studies to evaluate the potential for resistance of influenza A virus to 
tizoxanide have been unable to select for resistant virus (Romark Study Report RM01-
0417).  These studies suggest a low potential for resistance. 
Studies in peripheral blood mononuclear cells have also shown tizoxanide suppresses 
secretion of pro-inflammatory cytokines that are upregulated by VRIs.  Concentrations 
required to suppress cytokine secretion by 50% for IL-2, IL-4, IL-5, IL-6, IL-8, IL-10 
and TNF-α ranged from 2.0 to 9.8 µM (Rossignol and van Baalen 2018, Romark Study 
Report 9264).  Nitazoxanide has also been shown to suppress IL-6 production in 
thioglycollate broth-injected mice (Hong et al. 2012). 
Ongoing studies of the mechanism of action of NTZ have shown NTZ and tizoxanide 
modulate mitochondrial function by uncoupling oxidative phosphorylation.  Studies 
indicate tizoxanide decreases cellular ATP in a dose-dependent manner in MDCK cells 
and in MDCK cells infected with influenza viruses.  Maximum inhibition of ATP in 
influenza-infected or uninfected MDCK cells reaches up to 45% after 24 hours of 
exposure to 100 µM tizoxanide.  In these experiments, a 10% reduction of ATP achieved 
by adding less than 10 µM tizoxanide is sufficient to inhibit influenza virus replication 
by approximately 90%.  The decrease in cellular ATP does not affect cell viability and is 
reversible after eliminating tizoxanide from the culture (Rossignol and van Baalen 2018).  
Studies of a number of different viruses have shown viral replication is ATP-dependent 
(Braakman et al. 1992, Braakman et al. 1991, Doms et al. 1987, Chang et al. 2009, 
Mirazimi and Svensson 2000).  In the case of NTZ, key viral proteins like hemagglutinin 
(influenza), F-protein (RSV and parainfluenza), and N protein (coronavirus) have been 
identified as potential end targets of this mechanism (Rossignol et al. 2009, Piacentini et 


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al. 2018, Cao et al. 2015).  In addition, inhibition of ATP and its downstream effect on 
AMP-activated protein kinase activation has been shown to suppress secretion of pro-
inflammatory cytokines (Lee et al. 2017, Sag et al. 2008, Wang et al. 2003). 
The activity of NTZ in inhibiting replication of a broad range of respiratory viruses as 
well as the secretion of pro-inflammatory cytokines upregulated during respiratory virus 
infection has prompted clinical development of NTZ for treatment or prophylaxis of 
respiratory illness caused by VRIs. 
1.2.2. 
Pharmacokinetics of NTZ in Humans 
NTZ is not detectable in the plasma following oral administration of the drug.  The main 
metabolites of NTZ in humans are tizoxanide and tizoxanide glucuronide.  Tizoxanide is 
highly bound to plasma proteins (>99%).  The absorption of NTZ in immediate release 
tablets is significantly enhanced (Cmax and AUC of tizoxanide and tizoxanide glucuronide 
in plasma are more than doubled) when it is administered with food.  In fasted human 
volunteers receiving a single 500 mg dose of 14C NTZ, approximately one-third of the 
dose was excreted in urine as tizoxanide and tizoxanide glucuronide, and two-thirds was 
excreted in feces as tizoxanide.  No other significant metabolites were detected (NTZ 
300 mg Tablets Investigators Brochure). 
The pharmacokinetics of tizoxanide and tizoxanide glucuronide during repeated oral 
dosing of NTZ 300 mg extended release tablets administered 600 mg twice daily with 
food were evaluated in healthy volunteers.  Twelve (12) subjects received two NTZ 
controlled release tablets twice daily with food for 7 days.  The pharmacokinetics were 
studied in plasma up to 12 hours post-dose after the morning dose on Day 1 and Day 7, 
and before the morning dose on Day 2-6.  Based on mixed effect analysis of variance, 
the steady state tizoxanide and tizoxanide glucuronide plasma concentrations was 
reached by Day 2, after one day of treatment with NTZ at 600 mg b.i.d.  The main 
pharmacokinetics parameters of tizoxanide and tizoxanide glucuronide are summarized 
in the table below: 
Table 2: Summary of Tizoxanide and Tizoxanide Glucuronide Pharmacokinetics 
Parameters 
PK Parameter (unit) 
Tizoxanide 
Tizoxanide Glucuronide 
 
Day 1 
N=12 
Day 7 
N=12 
Day 1 
N=12 
Day 7 
N=12 
Cmax (µg/mL) 
5.23 ± 2.71 
8.16 ± 4.16 
4.88 ±1.72 
8.96 ±3.48 
tmax (h) 
6.00 (4.00-9.00) 
5.00 (3.00-8.00) 
6.00 (5.00-11.00) 
5.50 (0.00-7.02) 
tlag (h) 
0.00 (0.00-2.00) 
0.00 (0.00-0.00) 
0.50 (0.00-2.00) 
0.00 (0.00-0.00) 
AUC0-t (µg.h/mL) 
26.9  ± 16.1 
52.5 ± 33.7 
29.5  ± 12.1 
75.0 ± 37.8 
AUC0- Τ (µg.h/mL) 
28.6  ± 16.3a 
48.3 ± 31.9b 
30.5  ± 12.2c 
75.2 ± 37.9 
C Τ (µg/mL) 
0.709 ± 0.987 
1.72 ± 2.04 
1.39 ± 0.846 
3.89 ± 2.88 
AUC0-∞ (µg.h/mL) 
27.8 ± 17.8b 
52.3 ± 35.6b 
35.3 ± 16.5d 
62.1 ± 24.2e 
t1/2 (h) 
1.66 ± 0.408b 
2.19 ± 0.485b 
2.70 ± 0.848c 
4.99 ± 5.20 
λz (1/h) 
0.441 ± 0.106b 
0.331 ± 0.0733b 
0.282 ± 0.0902c 
0.201 ± 0.0813 
Cavg (µg/mL) 
NA 
4.02 ± 2.66b 
NA 
6.27 ± 3.16 
Cmin (µg/mL) 
NA 
1.50 ± 1.83 
NA 
3.63 ± 3.00 


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PK Parameter (unit) 
Tizoxanide 
Tizoxanide Glucuronide 
 
Day 1 
N=12 
Day 7 
N=12 
Day 1 
N=12 
Day 7 
N=12 
PTF (%) 
NA 
193 ± 39.1b 
NA 
101 ± 40.7 
Swing (%) 
NA 
1039 ± 656 
NA 
268 ± 194 
Values are arithmetic mean ± SD, except median (range) for tmax and tlag 
N = number of subjects with data; NA = not applicable 
a N=10; b N=11; c N=11; d N=8; e N=7 
Table 3: Summary of Tizoxanide and Tizoxanide Glucuronide Trough Plasma 
Concentrations 
PK Parameter (unit) 
Trough Concentrations (µg/mL 
Mean (CV%) 
Dose Group 
Nitazoxanide 
Day 
 
1 (a) 
2 
3 
4 
5 
6 
7 (b) 
Tizoxanide 
0.709 
(139) 
1.55 
(100) 
2.36 
(101) 
3.24 
(99.7) 
3.80 
(146) 
3.26 
(119) 
3.02 
(98.6) 
Tizoxanide 
Glucuronide 
1.39 
(61.0) 
3.68 
(72.3) 
4.38 
(72.8) 
5.35 
(77.2) 
5.83 
(98.8) 
5.94 
(91.2) 
5.65 
(68.7) 
1.2.3. 
Clinical Experience with Geriatric Subjects (≥65 Years of Age) Exposed to NTZ 
300 mg Extended Release Tablets in Clinical Trials 
Of the 3,147 subjects exposed to NTZ 300 mg extended release tablets in clinical trials, 
89 were elderly adults aged 65 years and older.  Fourteen (14) of these subjects received 
a single 600 mg dose in a pharmacokinetic study, while 75 subjects were enrolled in 
Phase 3 clinical trials for the treatment of influenza and common cold due to 
enterovirus/rhinovirus.  In the Phase 3 trials, all were treated with nitazoxanide 600 mg 
twice daily for 5 days, two of which received nitazoxanide in combination with 
oseltamivir.  
Overall, the type and severity of AEs reported in this population were similar to the total 
population and the known adverse event profile for the drug.  In the pharmacokinetic 
study only two adverse events were reported in two subjects (headache and diarrhea), 
both were mild in nature and not considered to be related to nitazoxanide.  In Phase 2b/3 
and Phase 3 clinical trials, two subjects experienced serious adverse events unrelated to 
study medication, but rather related to a pre-existing history of a concurrent condition.  
One of the subjects experienced an exacerbation of congestive heart failure was 
hospitalized and subsequently recovered.  The other subject had a history of severe back 
and neck pain and was hospitalized for musculoskeletal pain.  This subject also 
recovered.  The other adverse events experienced by geriatric subjects were mild to 
moderate in nature.  The most commonly reported AEs (at least 2%) for geriatric subjects 
receiving nitazoxanide in Phase 3 studies (n = 75) regardless of causality assessment 
were: diarrhea (9.3%), chromaturia (6.7%), nausea (2.7%), and headache (2.7%).  The 
rates of occurrence of AEs did not differ significantly from those of the placebo.   
Population pharmacokinetic data for tizoxanide and tizoxanide glucuronide troughs 
(prior to next dose) from geriatric subjects receiving nitazoxanide 600 mg twice daily for 


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5 days is available for 50 subjects enrolled Phase 2b/3 and Phase 3 clinical trials.  A 
comparison of this data to the adult population (18 to 64 years of age) from these studies 
is presented in the following table (NTZ 300 mg Tablets Investigators Brochure). 
Table 4: 
Population Pharmacokinetics, Trough Data, for Geriatric Subjects ≥65 Years 
of Age from Phase 2b/3 and Phase 3 Clinical Trials 
Metabolite 
Trough Data 
Subjects 12 to 17 years 
Trough Data 
Subjects 18 to 64 years 
Tizoxanide 
0.86 μg/mL (n = 50) 
0.81 μg/mL (n = 1305) 
Tizoxanide glucuronide 
3.08 μg/mL (n = 50) 
2.34 μg/mL (n = 1314) 
1.2.4. 
Overview of Other Experience in Clinical Trials and Post-marketing Surveillance 
NTZ has been marketed for diarrheal disease caused by Giardia or Cryptosporidium in 
the United States since 2003 and in Latin America since 1996.  It is estimated that more 
than 350 million patients have been exposed to NTZ worldwide.  No drug-related serious 
adverse events have been reported during post-marketing experience with NTZ. 
Over 7,500 subjects have been treated with NTZ in clinical trials, including 3,147 
subjects 12 years of age and older who have been exposed to the NTZ 300 mg extended 
release tablets (as monotherapy, n = 2,659, or in combination with oseltamivir, n = 488).  
Of the 3,147 subjects, 2,686 were given a dose of 600 mg twice daily for 5 days.  The 
most commonly (at least 2% of treated subjects) reported adverse events (AEs) regardless 
of causality assessment were: chromaturia (10.8%), diarrhea (6.3%), abdominal 
pain/abdominal pain upper/abdominal pain lower (2.8%), bronchitis (2.8%), nausea 
(2.7%), and headache (2.3%).  In the placebo-controlled trials, the rates of occurrence of 
AEs did not differ significantly from those of placebo except for chromaturia (10.8% 
compared to 0.8% for placebo).  Less than 1% of subjects discontinued therapy because 
of AEs (NTZ 300 mg Tablets Investigators Brochure). 
1.3. Rationale for the Study 
There is an important need for therapies to prevent VRIs, especially in outbreak situations, 
and particularly in healthcare workers caring for seriously ill patients.  VRIs are a critical 
health concern especially in those at risk for complications.  Of the most common viruses 
associated with VRI, chemoprophylaxis therapies and vaccines are only commercially 
available for influenza.       
NTZ’s broad-spectrum of activity against respiratory viruses makes it a good candidate for 
chemoprophylaxis as it has demonstrated activity against the common pathogens associated 
with VRI.  Importantly, previous studies have demonstrated NTZ has a favorable safety 
profile and low risk for developing viral resistance. 
This study will be conducted during a time when COVID-19 (caused by SARS-CoV-2) is 
circulating and posing significant risk.  There is an important need for an oral medication 
that could be administered as chemoprophylaxis of COVID-19. 
This study is a multicenter randomized, double-blind, placebo-controlled trial designed to 
evaluate efficacy and safety of NTZ 600 mg administered orally twice daily for 6 weeks 


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compared to a placebo for pre- and post-exposure prophylaxis of COVID-19 and other VRIs 
in healthcare workers and others at high risk of contracting SARS-CoV-2 infection. 
2. 
STUDY OBJECTIVES 
The primary objectives of this study are to evaluate the effect of NTZ administered orally 
600 mg twice daily for 6 weeks in preventing symptomatic laboratory-confirmed COVID-
19 and other VRIs in healthcare workers and others at high risk of contracting SARS-CoV-
2 infection compared to that of a placebo. 
The secondary objectives of this study are to evaluate the effect of NTZ administered orally 
600 mg twice daily for 6 weeks in (i) preventing mortality due to COVID-19 or complications 
thereof, and (ii) reducing the proportion of subjects (with or without symptoms) testing 
positive for antibodies to SARS-CoV-2 at either of the Week 6 or Week 8 visits. 
Exploratory objectives include (i) hospitalization due to VRI or complications thereof, (ii) 
mortality due to VRI or complications thereof, (iii) proportions of subjects experiencing 
acute respiratory illness (ARI), (iv) hospitalization due to ARI or complications thereof, and 
(v) mortality due to ARI or complications thereof.     
Other important objectives include evaluation of the safety of NTZ by analysis of adverse 
events and evaluation of relationships between pharmacokinetics and clinical or virologic 
responses. 
3. 
STUDY DESIGN 
The study will be a multicenter, stratified, randomized, double-blind, placebo-controlled trial 
to evaluate the efficacy and safety of NTZ for pre- and post-exposure prophylaxis of COVID-
19 and other VRIs.  
Subjects will be stratified according to their most likely location of exposure, which is a 
proxy for exposure to SARS-CoV-2 and other VRIs. The strata are: 
 Emergency Department 
 Intensive Care Unit 
 COVID-specific Care Unit 
 Walk-in Clinic 
 Paramedics and other first responders (e.g., firefighter/EMT) 
 Social Activities (3-5 per week) 
 Social Activities (>5 per week) 
Within strata, subjects will be randomized 1:1 to one of the following groups:  
 Group 1 (NTZ): 
Two NTZ 300 mg tablets b.i.d. for 6 weeks 
 Group 2 (Placebo): Two placebo tablets b.i.d. for 6 weeks 
This study is expected to run from April 2020 through April 2021. 




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daily allowance of these water-soluble vitamins, excess amounts are expected to be 
excreted in the urine and provide discoloration. 
 Choice of Patient-Reported Outcome Instrument.  This clinical trial will use the 
InFLUenza Patient-Reported Outcome Questionnaire (FLU-PRO©).  
FLU-PRO© was developed with the support of the U.S. Department of Health and 
Human Services through the National Cancer Institute and the National Institutes of 
Allergy and Infectious Diseases, National Institutes of Health, in response to the need 
for improved metrics to evaluate treatment effect in clinical trials of drugs for the 
treatment of influenza and other respiratory tract viral diseases.  It was developed and 
validated in accordance with FDA’s guidance, “Patient-Reported Outcome Measures: 
Use in Medical Product Development to Support Labeling Claims.”  It has also been 
validated for use on an electronic device as part of an electronic diary (“eDiary”) that 
can time stamp diary entries to ensure timely recording, thereby mitigating risks of 
recall bias.  We will use an electronic diary for this clinical trial.  FLU-PRO© was 
separately validated for use in a population with non-influenza like illness and also has 
recently been used in vaccine studies with older adults for the prevention of RSV 
(Powers et al. 2018, Yu et al. 2020). 
 Choice of ARI Definition.  The primary endpoint of this trial requires a determination 
that an ARI has occurred.  We have defined ARI as “≥0.5 increase from baseline in 
mean symptom score for the chest/respiratory FLU-PRO domain or  ≥0.5 increase from 
baseline in mean symptom score for at least two of the following FLU-PRO© domains: 
body/systemic, nose, throat.”  In arriving at this definition, we reviewed published 
mean FLU-PRO© symptom score data over the course of RSV illness (Yu et al. 2020) 
as well as data from recently completed clinical trials in approximately 3,000 subjects 
with colds and influenza (Romark, data on file).  The ARI definition requires an 
increase in symptom scores from baseline, although the magnitude of the required 
increase (≥0.5) in mean domain scores is low, and we are requiring that the increase in 
mean score be achieved for only one or two of the four domains.   
4. 
SUBJECT SELECTION 
The criteria for inclusion and exclusion are defined below: 
4.1. Inclusion Criteria 
1. Males and females at least 18 years of age or of legal consenting age based on local 
requirements. 
2. Persons at increased risk of contracting COVID-19, including: 
a. Healthcare workers with known direct occupational exposure to COVID-19 within 
7 days prior to enrollment. A qualifying person (i) provides healthcare to patients 
and/or (ii) typically positions themselves within 6 feet of patients (“close contact”) 
and (iii) is a full-time employee (average of ≥ 24 hrs/week) in a high contact area 
(Emergency Department, Intensive Care Unit, COVID-specific Care Unit, Walk-in 
Clinic, Paramedic/First Responder). 


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b. Persons participating in social activities without the practice of generally accepted 
social distancing practices at least three times per week. Qualifying activities 
include the presence of at least 10 people in close (<6 feet) proximity to each other 
without masks or other personal protective equipment (e.g., socializing at bars or 
community/social centers, in-home social gatherings, classes or trainings, etc.). 
These subjects must have engaged in such activities at least three times in the past 
7 days and plan to continue these activities during the study. 
3. Must have a smartphone, tablet, computer, or other qualifying internet-enabled device 
and daily internet access. 
4. Occupational exposure to a person infected with SAR-CoV-2 within 7 days prior to 
enrollment or social interaction as defined in criterion 2(b). 
5. Willing and able to provide written informed consent and comply with the requirements 
of the protocol, including completion of the subject diary. 
4.2. Exclusion Criteria 
1. Subjects not at increased risk of contracting SARS-CoV-2 from occupational or social 
behaviors. 
2. Subjects with known severe heart, lung, neurological or other systemic disease that the 
Investigator believes could preclude safe participation. 
3. Subjects with a history of COVID-19 or known to have developed anti-SARS-CoV-2 
antibodies or received a SARS-CoV-2 vaccine. 
4. Subjects who experienced a previous episode of acute upper respiratory tract infection, 
otitis, bronchitis or sinusitis or received antibiotics for these conditions or antiviral 
therapy for influenza within two weeks prior to and including study day 1. 
5. Subjects residing in the same household with another family member currently 
participating in the study. 
6. Receipt of any dose of NTZ within 7 days prior to screening. 
7. Treatment with any investigational drug or vaccine therapy within 30 days prior to 
screening and willing to avoid them during the course of the study. 
8. Known sensitivity to NTZ or any of the excipients comprising the study medication. 
9. Subjects unable to swallow oral tablets or capsules. 
10. Females of childbearing potential who are either pregnant or sexually active without the 
use of birth control.  Female subjects of child-bearing potential that are sexually active 
must have a negative baseline pregnancy test and must agree to continue an acceptable 
method of birth control for the duration of the study and for 1 month post-treatment.  A 
double barrier method, oral birth control pills administered for at least 2 monthly cycles 
prior to study drug administration, an IUD, or medroxyprogesterone acetate administered 
intramuscularly for a minimum of one month prior to study drug administration are 
acceptable methods of birth control for inclusion into the study.  Female subjects are 
considered of childbearing potential unless they are postmenopausal (absence of 


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menstrual bleeding for 1 year - or 6 months if laboratory confirmation of hormonal 
status), or have had a hysterectomy, bilateral tubular ligation or bilateral oophorectomy. 
11. Females who are breastfeeding. 
12. Subjects with active respiratory allergies or subjects expected to require anti-allergy 
medications during the study period for respiratory allergies. 
13. Subjects taking medications considered to be major CYP2C8 substrates, refer to Table 7. 
14. Subjects who, in the judgment of the Investigator, will be unlikely to comply with the 
requirements of this protocol including completion of the subject diary. 
5. 
STUDY PROCEDURES 
5.1. Screening Evaluation (Day -30 to Day 1) 
Before screening, subjects will be informed of the nature of study, and written consent 
must be obtained prior to participation.  After giving informed consent, the subject will be 
assigned a subject number, and the following procedures will be carried out: 
1. Survey of COVID-19 exposure. 
2. Complete medical history. 
3. Physical examination including body weight and vital signs (blood pressure, pulse, 
respiratory rate and body temperature). 
4. Collection of demographic information and smoking history. 
5. Urine pregnancy test for all females of childbearing potential (must be performed Day 
1). 
6. Evaluation according to eligibility (inclusion and exclusion) criteria. 
The information collected during the screening period must be current through the time of 
randomization. 
5.2. Baseline (Day 1, may be same day as screening evaluation) 
At baseline, the following procedures will be carried out: 
1. Collection of a nasopharyngeal swab sample using a single nylon flocked dry swab 
inserted into both nostrils for RT-PCR. 
2. Collection of blood sample for laboratory safety tests and anti-SARs-CoV-2 antibodies. 
3. Collection of a urine sample for routine urinalysis (appearance, glucose, protein and 
blood). 
4. Review and recording of any concomitant medications. 
5. Provision of an electronic symptom diary to subject and subject completion of baseline 
electronic diary under supervision and instruction of study site personnel. 




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5.3. Daily Day 1 through Week 6 
Subjects will keep a daily diary to chart study medication and answer the question, “do you 
feel like you have symptoms of a cold or flu?”  If the subject responds “yes”, they will be 
prompted to complete a full symptom diary questionnaire (FLU-PRO©) and contact the 
Investigator.  A study physician, nurse or other designated site personnel will review each 
subject’s electronic diary entries daily to ensure compliance with collection of diary data.  If 
a subject has not completed his/her diary or if errors are suspected, the study personnel will 
contact the subject to implement appropriate corrective actions. 
If the subject reports (i) at least one of the Lower Respiratory Symptoms presented in Table 5 
below or (ii) at least one symptom from each of the Upper Respiratory Symptoms and 
Systemic Symptoms categories presented in Table 5 below, the subject will then contact the 
study physician to complete a “Suspected ARI Visit” with the procedures provided below. 
All subjects meeting this criteria will complete a “Suspected ARI Visit” as soon as possible, 
but in any event within 5 days of the first diary at which these criteria are met for each episode 
of suspected ARI regardless of patient or physician assessment of illness nature or severity. 
Table 5: 
Clinical Illness Required for Diagnosis of ARI1 (adapted from Yu et al. 2020) 
Upper Respiratory Symptoms 
Lower Respiratory Symptoms 
Systemic Symptoms 
 Nasal congestion/rhinorrhea 
(runny or dripping nose, 
congested or stuffy nose, head 
congestion, sinus pressure) 2 
 Sore throat (sore or painful 
throat) 2 
 Cough (coughing, chest 
congestion, chest tightness, 
dry or hacking cough, wet or 
loose cough) 2 
 Dyspnea (shortness of breath) 
2 
 Sputum (coughing up sputum 
or phlegm) 2 
 Wheezing 
 Myalgias or arthralgias (body 
aches or pains) 2 
 Fatigue (weak or tired, 
sleeping more than usual) 2 
 Headache 
 Decreased appetite (lack of 
appetite, did not feel like 
eating) 2 
 Feverishness (felt hot, chills or 
shivering, felt cold, sweating) 2 
1 Suspected ARI requires self-reporting of any Lower Respiratory Symptom, or at least one Upper 
Respiratory Symptom together with one Systemic Symptom. 
2  Lay language used in the FLU-PRO© questionnaire is presented in parentheses. 
5.4. Suspected ARI Visit 
Subjects requiring Suspected ARI Visit will be evaluated as follows: 
1. Physical examination as warranted by the Investigator for any change from baseline. 
2. Body weight and collection of vital signs to include blood pressure, pulse, respiratory rate 
and body temperature. 


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3. Collect a nasopharyngeal swab sample using a single nylon flocked dry swab inserted into 
both nostrils for RT-PCR at the Suspected ARI Visit, 24 to 36 hours later, and then again 
4 to 5 days later. 
4. Collect a fecal specimen for RT-PCR at the Suspected ARI Visit, 24 to 36 hours later, and 
then again 4 to 5 days later. 
5. The subject will complete a FLU-PRO© symptom diary daily until he/she responds “yes” 
to the FLU-PRO© question, “Have you returned to your usual health?” for 3 consecutive 
days or until the Week 8 Visit, whichever occurs first.  The daily FLU-PRO© diary will be 
completed between 7:00 pm and 11:00 pm.   
6. Review and recording of concomitant medications. 
7. Review and recording of adverse events/side effects. 
8. Laboratory investigations for safety may be performed as warranted based upon the 
Investigator’s judgment.   
9. If a subject tests positive for a respiratory virus by RT-PCR, that subject may receive 
standard of care as clinically warranted by the Investigator.   
Regardless of symptoms or laboratory data, the subject will continue treatment until the 6-
week treatment period has ended.   
5.5. Week 3 (±7 days) and Week 6 Evaluations (±2 days) 
Subjects will attend in-clinic visits at Week 3 and Week 6, and the following procedures will 
be performed: 
1. Physical examination as warranted by the Investigator for any change from baseline. 
2. Body weight and collection of vital signs to include blood pressure, pulse, respiratory 
rate and body temperature. 
3. Collection of blood sample for laboratory safety tests, pharmacokinetics (pre-dose, at 
least six hours after the most recent previous dose) and anti-SARs-CoV-2 antibodies 
(antibody testing at Week 6 visit only). 
4. Collection of urine sample for routine urinalysis. 
5. Review of compliance with study medication, collection of medication bottle with any 
unused medications (Week 6 visit only), and completion of the pill count log form. 
6. Review and recording of concomitant medications. 
7. Review and recording of adverse events/side effects and complications. Note that all 
adverse events and complications must be followed until their resolution or stabilization 
even beyond the 8-week study period. 
8. Review of number and type of social activities. 
9. Advise subjects to follow local public health guidelines for SARS-CoV-2 infection 
control. 


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5.6. Week 8 Evaluation (+7 days) 
Subjects will attend in-clinic visits at Week 8 and the following procedures will be 
performed: 
1. Physical examination as warranted by the Investigator for any change from baseline. 
2. Collection of blood sample for anti-SARs-CoV-2 antibodies. 
3. Review and recording of concomitant medications. 
4. Review and recording of adverse events/side effects and complications.  Note that all 
adverse events and complications must be followed until their resolution or stabilization 
even beyond the 8-week study period. 
5. Document any infections diagnosed during the follow-up period. 
5.7. Unscheduled Visit 
Subjects requiring an unscheduled visit due to worsening symptoms or adverse events will 
be evaluated at the discretion of the Investigator as is medically warranted.  Tests and/ or 
procedures performed at this visit may include, but are not limited to, the following: 
1. Physical examination as warranted by the Investigator for any change from baseline. 
2. Body weight and collection of vital signs to include blood pressure, pulse, respiratory 
rate and body temperature. 
3. Collection of a nasopharyngeal swab sample using a single nylon flocked dry swab 
inserted into both nostrils for RT-PCR. 
4. Collection of blood sample for laboratory safety tests. 
5. Collection of urine sample for routine urinalysis. 
6. Review of compliance with study medication. 
7. Review and recording of concomitant medications. 
8. Review and recording of adverse events/side effects. 
5.8. Study Discontinuation 
Rules for discontinuation of a subject or for discontinuing the study are provided in 
Section 11.2. All subjects discontinued from the study before Week 6 will be evaluated at 
study discontinuation using the procedures described above for the Week 6 evaluation.  
Those discontinued after Week 6 will be evaluated as warranted by the Investigator. 
5.9. Plan for Laboratory Safety Tests 
A central laboratory will be used for laboratory safety testing.  Blood tests will include 
hemoglobin, hematocrit, complete blood count (total and differential), platelet count, random 
blood sugar, total cholesterol, HDL, LDL, triglycerides, albumin, AST, ALT, GGT, alkaline 
phosphatase, bilirubin (total/direct), BUN, creatinine, sodium, potassium, chloride.  Routine 
urinalysis will include appearance, glucose, protein, and blood. 


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5.10. Plan for Virology Testing and Monitoring Resistance 
Blood samples collected at Baseline, Week 6 and Week 8 will be tested for anti-SARS-CoV-
2 antibodies at a central laboratory using a validated assay (when such become available). 
Virology testing of nasopharyngeal swab samples will be conducted as described below. 
1. Collection of samples: 
Two nasopharyngeal swabs will be collected from each subject at Baseline (Day 1), at 
each Suspected ARI Visit, 24 to 36 hours after each Suspected ARI Visit, 4 to 5 days 
after each Suspected ARI Visit, and as warranted by the Investigator. 
A fecal specimen will be collected from each subject at each Suspected ARI Visit, 24 to 
36 hours after each Suspected ARI Visit, and 4 to 5 days after each Suspected ARI Visit.  
2. Testing of biological samples: 
Each nasopharyngeal swab sample will be subjected to RT-PCR using the 
 
 to detect influenza A (non-
specific as to subtype); influenza A H1, H1N1 (2009), H3 subtypes; influenza B; RSV A 
and B; parainfluenza 1, 2, 3 and 4; hMPV; adenovirus; human EV/RV; coronavirus 
NL63, HKU1, 229E and OC43; Chlamydophila pneumoniae; and Mycoplasma 
pneumoniae.  The 
 
 will be 
used to test for SARS-CoV-2.  
Each fecal sample will be subjected to RT-PCR using the 
 
 
 will be used to test for SARS-CoV-2. 
3. Drug susceptibility testing: 
If any Suspected ARI Visit nasopharyngeal swab sample is positive for a VRI, the virus 
will be isolated (if possible) and tested for susceptibility to tizoxanide.   
4. Storage of samples:  All samples collected during the study will be stored for at least 2 
years for potential future testing. 
5. Clinical virology laboratory for diagnostic testing:   
  
 
 
6. Clinical virology laboratory for drug susceptibility testing: 
 
 
 
6. 
RANDOMIZATION 
Subjects will be randomized 1:1 to receive either NTZ or placebo.  An independent third 
party will prepare master randomization lists for each of the strata and maintain the masking 
of the study.  Subjects who qualify for the study will be assigned to treatment using 


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centralized randomization procedures.  The treatment numbers will appear on the bottles 
containing the masked study medication.  The randomization list will be masked to study 
participants including Sponsor, Investigators, study monitors, statisticians, subjects and 
laboratory personnel.  Unmasking procedures will be detailed in the Medical Monitoring 
Plan and Investigators will be provided instructions for unmasking. 
7. 
DATA MANAGEMENT 
7.1. Electronic Data Entry 
Data will be transcribed from source documents into an electronic data capture (EDC) 
system. 
The responsible study monitor(s) will verify data according to the Clinical Monitoring Plan, 
either remotely or at the clinical study site.  The Investigator will ensure that the data recorded 
are accurate and complete.  
Queries emerging during data cleaning will be generated within the EDC system by data 
management or clinical research associates. The Investigator or his/her designee will answer 
the queries and update the source data, if needed.  
Adverse events and comorbid conditions will be coded by data management using the latest 
version of the Medical Dictionary for Regulatory Activities (MedDRA).  Medications will 
be coded by data management using the World Health Organization (WHO) Drug 
Dictionary. 
After the last subject’s last visit has taken place, the database will be cleaned as necessary.  
As soon as the database is considered clean, it will be locked.  The locked database will be 
used in the final statistical analysis for study reporting.  Measures will be undertaken to 
protect subject data handled during inspections against disclosure to unauthorized third 
parties.  Subject confidentiality will be maintained at all times. 
7.2. Protocol Deviations 
Protocol deviations will be documented by the Investigator, reported to the institutional 
review board (IRB) as appropriate, and also reviewed by the assigned clinical research 
associate.  Deviations will be reported in the clinical trial management system or applicable 
EDC.  Each deviation will be classified as major or minor according to the following 
definitions: 
Major protocol deviation: 
A deviation that has an impact on subject safety, may 
substantially alter risks to subjects, may have an effect on the 
integrity of the study data, or may affect the subject’s 
willingness to participate in the study  
Minor protocol deviation: 
All other protocol deviations. 
7.3. Data Quality Assurance 
The accuracy and reliability of the study data will be assured by the selection of qualified 
Investigators and appropriate study centers, review of protocol procedures with the 


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Investigator and associated personnel prior to the study, and by periodic monitoring visits by 
the Sponsor or Sponsor’s representatives.  Written instructions will be provided for 
collection, preparation, and shipment of samples. 
The monitor will review the source data for accuracy and completeness, and any 
discrepancies will be resolved with the Investigator or designee, as appropriate.  
The Sponsor will be entitled to inspect and audit the facilities used in the clinical and 
laboratory parts of the study, as well as to make anonymized copies of all the data files 
pertaining to the study.  Similar procedures may also be conducted by agents of any 
regulatory body, either as part of a national GCP compliance program or to review the results 
of this study in support of a regulatory submission.  The Investigator should immediately 
notify the Sponsor if they have been contacted by a regulatory agency concerning an 
upcoming inspection. 
8. 
STATISTICAL CONSIDERATIONS 
8.1. Sample Size Calculations 
For purposes of calculating our sample size, we assume that the proportion of subjects 
experiencing COVID-19 over a 6-week period is 1% and that the proportion of subjects 
experiencing any VRI is 2%. Current illness rates in the trial are approximately 1.2% for 
COVID-19 and 2.8% for VRIs. We further assume that effective prophylaxis will result in 
80% reduction of the illness rate. Influenza prophylaxis studies of oseltamivir have resulted 
in approximately 80% reduction of influenza illness (see Tamiflu® prescribing information). 
Using these assumptions, a Cox proportional hazards regression model (fitting the strata and 
treatment arm as a set of indicator variables) can be used to generate the number of events 
(COVID-19 cases) needed for 90% power to detect a hazard ratio of 0.8 versus a hazard ratio 
of 1. This number is 17 events. Earlier iterations of this protocol were sized on the assumption 
of a 3% overall rate for COVID-19 cases. Because the infection rate is much lower than 
anticipated, the Sponsor has decided to power the trial based on event counts. The intent is 
to keep the Cochran-Mantel-Haenszel (CMH) analysis previously planned. The expected 
sample size was generated from the event count required and the current illness rate 
approximating 1%. The power of the CMH analysis was then evaluated. 
The expected sample size is 2842 subjects assigned equally to strata and to treatment arm 
within strata. This (fixed) sample size has 80.6% power for a CMH test of equal illness rates 
in the two treatment arms. When determining the fixed sample size necessary for 90% power 
for the CMH test under the current rates and effect size, a sample size of approximately 4000 
is required. Under current assumptions this results in 23 expected events in the study – very 
near the number of events originally hypothesized based upon 800 total subjects and a 
blended illness rate of 3% for the two treatment arms. 
A study-wide event count of 24 COVID-19 cases was chosen. This proposed event count 
results in power for the VRI endpoint (at the expected sample size) of 98.2%. 


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8.2. Efficacy Variables 
Primary Efficacy Parameters:   
i. The proportion of subjects with symptomatic 
laboratory-confirmed COVID-19 identified after 
start of treatment and before the end of the 6-week 
treatment period 
 
ii. The proportion of subjects with symptomatic 
laboratory-confirmed VRI identified after start of 
treatment and before the end of the 6-week 
treatment period 
Secondary Efficacy Parameters:   
i. Mortality due to COVID-19 or complications 
thereof 
 
ii. The proportion of subjects (with or without 
symptoms) testing positive for antibodies to 
SARS-CoV-2 at either of the Week 6 or Week 8 
visits 
Exploratory Efficacy Parameters: 
Hospitalization due to VRI or complications thereof, 
mortality due to VRI or complications thereof, 
proportions 
of 
subjects 
experiencing 
acute 
respiratory illness (ARI), hospitalization due to ARI 
or complications thereof, mortality due to ARI or 
complications thereof. 
8.3. Response Definitions 
ARI: 
≥0.5 increase from baseline in mean symptom score for the 
chest/respiratory FLU-PRO domain or ≥0.5 increase from baseline 
in mean symptom score for at least two of the following FLU-
PRO© domains: body/systemic, nose, throat.   
COVID-19: 
ARI after start of treatment and before the end of the 6-week 
treatment period associated with detection of SARS-CoV-2 by RT-
PCR assay of nasopharyngeal swab. 
VRI: 
ARI after start of treatment and before the end of the 6-week 
treatment period associated with detection of any respiratory virus 
by RT-PCR assay of nasopharyngeal swab. 
8.4. Statistical Methodology 
The statistical methodology is described briefly below and will be described in detail in the 
Statistical Analysis Plan. 
8.4.1. 
Efficacy Analyses 
Efficacy analyses will be based on a population consisting of all subjects randomized 
without a laboratory-detected viral respiratory infection at the baseline visit (intention-


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to-treat or ITT population).  All chi-square analyses will be calculated with appropriate 
continuity corrections. 
There will be two primary efficacy analyses: 
 The proportion of subjects experiencing COVID-19 in the NTZ treatment group will 
be compared to that of the placebo treatment group using a two-sided Cochran-
Mantel-Haenszel (CMH) chi-square test (α =0.049).  
 The proportion of subjects experiencing VRI in the NTZ treatment group will be 
compared to that of the placebo treatment group using a two-sided CMH chi-square 
test (α =0.001). 
Secondary analyses will be performed as follows: 
 The proportion of subjects experiencing COVID-19 or VRI for treatment vs control 
will be tested within strata using Pearson chi-square tests at an unadjusted  = 0.05. 
 Confidence intervals (95% confidence level) will be produced for the overall odds 
ratio and for the odds ratios for NTZ vs placebo for each stratum. 
 Proportions of subjects experiencing mortality due to COVID-19 or complications 
thereof will be compared by treatment group using a two-sided Pearson chi-square 
test (unadjusted α =0.05). 
 Proportions of subjects (with or without symptoms) testing positive for antibodies 
to SARS-CoV-2 at either of the Week 6 or Week 8 visits will be compared by 
treatment group using a two-sided Pearson chi-square test (unadjusted α =0.05). 
Exploratory analyses will be performed as follows: 
 Proportions of subjects experiencing each of the following will be compared by 
treatment group using a two-sided Pearson chi-square test (unadjusted α =0.05): (i) 
hospitalization due to VRI or complications thereof, (ii) mortality due to VRI or 
complications thereof, (iii) proportions of subjects experiencing acute respiratory 
illness (ARI), (vi) hospitalization due to ARI or complications thereof, (v) mortality 
due to ARI or complications thereof.   
8.4.2. 
Population Pharmacokinetics Analysis 
On Week 3 and 6, the plasma samples will be collected before the morning dose (at the 
trough).  These data will allow for analysis of relationships between trough plasma 
concentrations and clinical and virologic response.   
Trough plasma concentrations of tizoxanide and tizoxanide glucuronide will be 
summarized descriptively for each of the treatment groups.  Exploratory analyses will be 
conducted to evaluate the relationships between plasma concentrations and age, race, 
gender, body weight, body mass index, VRI and adverse events. 
8.4.3. 
Safety Analyses 
All randomized subjects who receive the study medication will be evaluated for drug 
safety.  Safety analyses will be done descriptively. 




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Table 6: 
Study Medication Labels 
External Box Label 
Principal Investigator: 
9 Bottles (20 Tablets Each) 
180 Tablets Total 
Study N° RM08-3007 
Treatment N°: XXXX  
Lot: 
 
 
Take 2 Tablets by Mouth with Food Twice Daily 
Caution: New Drug-Limited by Federal Law to Investigational Use 
STORE AT ROOM TEMPERATURE • DO NOT USE BEYOND END OF STUDY 
KEEP OUT OF REACH OF CHILDREN 
Study Sponsor: The Romark Institute for Medical Research 
 
 
Individual Bottle Label 
20 Tablets 
Study N° RM08-3007 
Treatment N°: XXXX  
Lot: 
 
 
Take 2 Tablets by Mouth with Food Twice Daily 
Caution: New Drug-Limited by Federal Law to Investigational Use 
STORE AT ROOM TEMPERATURE • DO NOT USE BEYOND END OF STUDY 
KEEP OUT OF REACH OF CHILDREN 
Study Sponsor: The Romark Institute for Medical Research 
 
9.4. Drug Accountability 
Medication will be dispensed at baseline.  Medication compliance will be reviewed with each 
subject at each scheduled and unscheduled visit, subjects will be asked to return the bottles 
in which the medication was dispensed along with any unused medication.  
The Investigator or designee is required to maintain adequate records of the disposition of 
all study drug, including dates, quantity and use by subject.  Unused supplies must be 
returned to the Sponsor. 
9.5. Subject Compliance 
Subject compliance with the protocol will be checked by the Investigator and recorded in the 
EDC system at each visit. 
Subjects will be considered non-compliant if they have missed more than 20% of the doses 
of the study medication (major protocol violation).  Non-compliance will not be cause for 
discontinuation of subject participation in the study. 
9.6. Disallowed Medication 
During the active treatment course of the study, concomitant use of medications considered 
major CYP2C8 substrates are prohibited, see below. 


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Table 7: 
Major CYP2C8 Substrates 
Generic Name 
Brand Name(s) 
Therapeutic Use and/or 
Drug Class 
Amodiaquine 
BASOQUIN, CAMOQUIN, 
FLAVOQUIN 
Antimalarial 
Daprodustat (GSK1278863) 
* 
Antianemic, prolyl 
hydroxylase inhibitor 
Dasabuvir (ABT-333) 
EXVIERA 
Antiviral, NSB5 inhibitor 
Enzalutamide 
XTANDI 
Anticancer, antiandrogen 
Montelukast 
SINGULAIR 
Antiasthmatic, LTRA 
Pioglitazone 
ACTOS 
Antidiabetic, PPAR-γ agonist 
Repaglinide 
NOVONORM, PRANDIN 
Antidiabetic, meglitinide 
analog 
Source: Backman et al. 2016. 
*Currently listed as investigational only and not yet granted a trade name by the manufacturer. 
Subjects are also prohibited from taking hydroxychloroquine, chloroquine, NTZ (except as 
the blinded investigational medication) or any other investigational medication or vaccine 
during the study.  Since tizoxanide is highly protein-bound and may compete with plasma 
protein binding sites, co-administration of NTZ and warfarin should be avoided if reasonably 
possible.  If co-administration of NTZ and warfarin cannot be avoided, the investigator must 
monitor prothrombin time and international normalized ratio (PT/INR) in subjects taking 
warfarin as clinically warranted. 
Medications for pre-existing conditions that are not excluded (see exclusion criteria) should 
be continued as prescribed.  The use of such medication will be recorded in the EDC system. 
10. ADVERSE EVENTS 
The term “adverse event” is defined for purposes of this study as any unwanted physical, 
psychological or behavioral change experienced by a subject during the course of the study 
and after taking the first dose of study medication regardless of its severity or relation to the 
study.  Adverse events may include symptoms, signs, unexpected worsening of pre-existing 
conditions, clinically significant changes in laboratory values, diseases and syndromes, and 
significant and unexpected failures of pharmacological action of other medications.  
Symptoms of VRIs (cough, sore throat, nasal obstruction, fatigue, headache, myalgia, 
feverishness) and complications of VRIs will not be reported as adverse events. 
Adverse events will be recorded on the appropriate EDC forms throughout the study, and the 
severity of each adverse event will be graded on a four-point scale: mild, moderate, severe, 
or life-threatening (See Appendix II).  The duration of the adverse event and relationship to 
the study drug will also be recorded.  All adverse events must be followed until their 
resolution or stabilization even beyond the planned study period. 
10.1. Definitions 
The following definitions will apply to the reporting of adverse events: 


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1. Serious Adverse Event: Any adverse experience occurring at any dose that is fatal or 
life threatening; requires in-patient hospitalization or prolongation of an existing 
hospitalization; is a persistent significant disability/incapacity; is a congenital anomaly 
or birth defect; or is an important medical event that may not result in death, be life-
threatening, or require hospitalization but, based upon appropriate medical judgment, 
may jeopardize the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed above. 
2. Unexpected Adverse Event: Any adverse experience that is not identified in nature, 
severity, or frequency in the Investigator's Brochure for NTZ. 
3. Severity of adverse events will be assessed by the Investigator using the Toxicity 
Grading Scale Tables provided in Appendix II (derived and adapted from “Guidance for 
Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled 
in Preventive Vaccine Clinical Trials”, US Dept. of HHS, FDA, CDER, September 2007 
and the National Institutes of Health, National Cancer Institute Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0). 
4. Causality (relationship to treatment) will be assessed as follows: 
 Definitely Related: The adverse event is clearly related to the investigational 
agent(s) or research intervention: the adverse event has a temporal relationship to 
the administration of the investigational agent(s) or research intervention, follows 
a known pattern of response, and no alternative cause is present. 
 Probably Related: The adverse event is likely related to the investigational agent(s) 
or intervention: the adverse event has a temporal relationship to the administration 
of the investigational agent(s) or research intervention, follows a known or 
suspected pattern of response, but an alternative cause may be present. 
 Possibly Related: There is a reasonable possibility that the event may have been 
caused by or is linked in a significant way to the research; the adverse event has a 
temporal relationship to the administration of the investigational agent(s) or 
research intervention, follows a suspected pattern of response, but an alternative 
cause is present. 
 Unrelated (or Not Related): The adverse event is clearly NOT related to the 
investigational agent(s) or intervention: the adverse event has no temporal 
relationship to the administration of the investigational agent(s) or research 
intervention, follows no known or suspected pattern of response, and an alternative 
cause is present. 
Under double-blind treatment conditions, it should be assumed that all subjects are taking 
the test drug. 
10.2. Clinical Adverse Events 
At the time of each return visit, the subject will be questioned regarding the occurrence and 
nature of any adverse events.  All events must be recorded in the subjects' medical records 
and in the EDC system.  Any subject affected will be examined by the Investigator as deemed 
necessary to ascertain the course of the event and any residual effects.  


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All moderate and severe adverse events will be reviewed by the Principal Investigator who 
will determine using his/her best clinical judgment whether they warrant the subject to be 
discontinued from the study.  The Sponsor will be notified immediately if a subject is 
discontinued from the study.  For all adverse events that require the subject to be discontinued 
from the study, relevant clinical assessments and laboratory tests will be repeated as 
clinically indicated until final resolution or stabilization of the event(s). 
All subjects will be instructed to contact the Investigator, Investigator's assistants, or clinical 
personnel should the subject have any serious adverse experiences.  Serious adverse events, 
including death regardless of the cause, must be reported to the Sponsor immediately (within 
24 hours of the initial report). 
A serious event requiring immediate notification by telephone is an event that: 
 results in death 
 is life threatening  
 requires inpatient hospitalization or prolongation of an existing hospitalization 
 is a persistent or significant disability/incapacity 
 is a congenital anomaly/birth defect 
 an important medical event that may not result in death, be life-threatening, or require 
hospitalization but, based upon appropriate medical judgment, may jeopardize the 
subject and may require medical or surgical intervention to prevent one of the outcomes 
listed above. 
An overdose is defined as any intentional or unintentional consumption of the drug by any 
route that exceeds the highest dose stated in the Investigator's Brochure or in an 
investigational protocol, whichever dose is larger.  Overdoses without an associated adverse 
event should be recorded, but not reported as an adverse event. 
10.3. Reporting Requirement 
The Principal Investigator is required to notify The Romark Institute for Medical Research 
(Sponsor) immediately of any unexpected, fatal, or life-threatening experience and all 
unusual, alarming, or serious reactions to medication regardless of any opinions as to the 
cause/effect relationship.  All serious adverse events will also be reported to the IRB.  
Adverse events should be reported to: 
The Romark Institute for Medical Research  
Medical Affairs 
  
  
 
 
10.4. Medication Modification/Withdrawal Due to an Adverse Event 
If a severe adverse reaction develops during therapy, the study medication should be 
discontinued, and the subject should be withdrawn from the study. 


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10.5. Medication Errors 
A medication error is defined as any preventable event related to dosing instructions, product 
labeling, or packaging that causes or leads to inappropriate medication use or subject harm 
while the medication is in the control of the investigative site or subject.  Medication errors 
which result in adverse events should be recorded and reported as adverse events.  All other 
medication errors should be reported to the study Sponsor through the Medical Affairs 
department within 7 days of identification by the site. 
11. DISCONTINUATION 
11.1. Study Discontinuation 
The study may be discontinued under the following circumstances: 
1. The Sponsor reserves the right to discontinue the study at any time.  
2. Adverse event listings will be produced for safety monitoring at least once every two 
weeks during recruitment.  The data will be tested to determine if there are greater than 
20% of the subjects who have had ≥ Grade 3 adverse events considered by the 
Investigator to be possibly, probably or definitely related to the study drug (defined by 
the Toxicity Grading Scale Tables provided in Appendix II). 
If greater than 20% of the subjects have at least one Grade 3 or Grade 4 adverse event 
considered to be possibly, probably or definitely related to the study drug by the study 
Medical Monitor, then the study must be stopped and the Institutional Review Boards, 
and FDA’s Division of Anti-Infectives will be notified.  All safety and activity data will 
be submitted to the FDA in a timely manner. 
11.2. Subject Discontinuation 
Treatment will be discontinued for individual subjects for the following reasons: 
1. An allergic reaction occurs or is suspected. 
2. Medical conditions that may require study discontinuation in the Investigator’s 
judgment. 
3. Subject desire to discontinue participation. 
In the case of an allergic reaction or other medical condition requiring subject 
discontinuation, appropriate treatment will be instituted by the Investigator. 
12. ELECTRONIC DATA COLLECTION (EDC) SYSTEM 
An EDC system will be used for this study.  Prior to study initiation, site staff and authorized 
Romark personnel will be trained to use this system.  
All source forms are to be filled out completely by the examining site staff and reviewed and 
signed off on by the Investigator(s).   


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13. RETENTION OF RECORDS 
Essential Documents are documents that individually and collectively permit evaluation of 
the conduct of a trial and quality of the data produced.  They demonstrate the compliance of 
the Investigator, Sponsor, and monitor with the GCP standards and with all applicable 
regulatory requirements. 
In compliance with the ICH/GCP guidelines, the Investigator/institution will maintain all 
CRFs and all EDC source forms and source documents that support the data collected from 
each subject, as well as all study documents as specified in ICH/GCP Section 8, Essential 
Documents for the Conduct of a Clinical Trial, and all study documents as specified by the 
applicable regulatory requirement(s).  A list of these documents is found in Appendix III: 
List of Essential Document for the Investigative Site.  The Investigator/institution will take 
measures to prevent accidental or premature destruction of these documents. 
Essential documents listed in Appendix III must be retained for the duration required by 
applicable regulatory authorities or until the Sponsor informs the Investigator/institution 
these documents are no longer needed. 
If it becomes necessary for the Sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the Investigator must permit access to such reports. 
The Sponsor is responsible for organizing and maintaining the Trial Master File which is a 
clear documentation of the course of the study. 
14. MONITORING THE STUDY 
Monitoring will be conducted by the Sponsor and/or a contract research organization 
according to standard operating procedures.  Site visits will be conducted on-site or remotely 
by the Sponsor or their representatives at regular intervals to conduct inspections. 
A full description of the monitoring procedures for this study will be detailed in the Clinical 
Monitoring Plan.   
The Investigator will grant representatives of the Sponsor's clinical operations team and 
quality team, as well as regulatory agencies and ethical committees access to inspect facilities 
and records (including subject charts) relevant to this study and agrees to assist the monitors 
in their activities, if requested. 
An Independent Data Monitoring Committee (IDMC) will be organized to monitor safety 
and futility for this study.  A full description of the IDMC procedures for this study will be 
detailed in the Medical Monitoring (Safety) Plan and IDMC Charter.   
15. INFORMED CONSENT 
Each subject must give written consent according to local requirements after the nature of 
the study has been fully explained.  The informed consent form (ICF) must be signed before 
performance of any study-related activity.  The informed consent form will be approved by 
both the Sponsor and by the reviewing IRB.  They will be in accordance with principles that 


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originated in the Declaration of Helsinki, current ICH and GCP guidelines, applicable 
regulatory requirements, and Sponsor policy. 
Before enrollment in the study, the Investigator or an authorized member of the 
investigational staff must explain to potential subjects the aims, methods, reasonably 
anticipated benefits, and potential hazards of the study, and any discomfort participation in 
the study may entail.  Subjects will be informed that their participation is voluntary and that 
they may withdraw consent to participate at any time.  They will be informed that choosing 
not to participate will not affect the care he/she will receive.  Finally, they will be told that 
the Investigator will maintain a subject identification register for the purposes of long-term 
follow-up if needed and that their records may be accessed by health authorities and 
authorized Sponsor staff without violating the confidentiality of the subject, to the extent 
permitted by the applicable law(s) or regulations.  By signing the ICF the subject is 
authorizing such access, and agrees to allow his or her study physician to re-contact the 
subject for the purpose of obtaining consent for additional safety evaluations, if needed. 
The subject will be given sufficient time to read the ICF and the opportunity to ask questions.  
After this explanation and before entry into the study, consent should be appropriately 
recorded by means of the subject's personally dated signature.  After having obtained the 
consent, a copy of the ICF must be given to the subject. 
If the subject is unable to read or write, an impartial witness should be present for the entire 
informed consent process (which includes reading and explaining all written information) 
and should personally date and sign the ICF after the oral consent of the subject is obtained, 
if permitted by local law. 
Assent from any minor (≤ 18 years of age or as local regulations apply) enrolled into the 
study will be obtained along with documented consent from their parent/legal guardian to 
allow the minor to participate in the study.  The assent and consent forms must be signed 
prior to the performance of any study related activity.   
Signed ICFs must remain in the subject's file(s) and be available for verification by 
representatives of Romark, the IRB, and FDA/relevant regulatory agencies at any time.   
16. ETHICS 
The clinical trial will be performed in accordance with the guidelines set by the World 
Medical Assembly (Declaration of Helsinki, last amendment in Fortaleza, Brazil, October 
2013).  Prior written approval of the study protocol and of the informed consent form will be 
obtained from the appropriate local Medical Ethics Review Board. 
16.1. Study-Specific Design Considerations 
Potential subjects will be fully informed of the risks and requirements of the study and during 
the study subjects will be given any new information that may affect their decision to 
continue participation.  They will be told that their consent to participate in the study is 
voluntary and may be withdrawn at any time with no reason given and without penalty or 
loss of benefits to which they would otherwise be entitled.  Only subjects who are fully able 


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to understand the risks, benefits, and potential AEs of the study, and provide their consent 
voluntarily will be enrolled. 
16.2. Investigator Responsibilities 
The Investigator is responsible for ensuring that the clinical study is performed in accordance 
with the protocol, current International Conference on Harmonization (ICH) guidelines on 
Good Clinical Practice (GCP), and applicable regulatory and country specific requirements. 
Good Clinical Practice is an international ethical and scientific quality standard for 
designing, conducting, recording, and reporting studies that involve the participation of 
human subjects.  Compliance with this standard provides public assurance that the rights, 
safety, and wellbeing of study subjects are protected, consistent with the principles that 
originated in the Declaration of Helsinki, and that the clinical study data are credible. 
16.3. Institutional Review Board (IRB) 
Before the start of the study, the Investigator (or Sponsor where required) will provide the 
IRB with current and complete copies of the following documents: 
 Final protocol and, if applicable, amendments 
 Sponsor-approved ICF (and any other written materials to be provided to the subjects) 
 Investigator’s Brochure (or equivalent information) and addenda 
 Sponsor-approved subject recruiting materials 
 Information on compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable 
 Investigator’s curriculum vitae or equivalent information (unless not required, as 
documented by IRB) 
 Information regarding funding, name of the Sponsor, institutional affiliations, other 
potential conflicts of interest, and incentives for subjects 
 Any other documents that the IRB requests to fulfill its obligation 
This study will be undertaken only after the IRB has given full approval of the final protocol, 
amendments (if any), the ICF, applicable recruiting materials, and subject compensation 
programs, and the Sponsor has received a copy of this approval.  This approval letter must 
be dated and must clearly identify the IRB and the documents being approved. 
During the study, the Investigator (or Sponsor where required) will send the following 
documents and updates to the IRB for their review and approval, where appropriate:  
 Protocol amendments 
 Revision(s) to ICF and any other written materials to be provided to subjects 
 If applicable, new or revised subject recruiting materials approved by the Sponsor 
 Revisions to compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable 


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 Investigator’s Brochure addenda or new edition(s) 
 Summaries of the status of the study at intervals stipulated in guidelines of the IRB (at 
least annually) 
 Reports of AEs that are serious, unlisted, and associated with the investigational drug 
 New information that may adversely affect the safety of the subjects or the conduct of 
the study 
 Deviations from or changes to the protocol to eliminate immediate hazards to the subjects 
 Report of deaths of subjects under the Investigator’s care 
 Notification if a new Investigator is responsible for the study at the site 
 Annual IND Update Report, Short Term Study Specific Safety Summary and Line 
Listings, where applicable 
 Any other requirements of the IRB 
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the amendment and applicable informed 
consent form and assent form revisions must be submitted promptly to the IRB for review 
and approval before implementation of the change(s), except when necessary to eliminate 
immediate hazard to the study subjects.  If a deviation from, or a change to the protocol was 
implemented to eliminate an immediate hazard to study subjects, then the implemented 
deviation or change, the reasons for it, and, if appropriate, the protocol amendment should 
be submitted to the IRB as soon as possible. 
The re-approval of the clinical study by the IRB should be documented in writing. 
At the end of the study, the Investigator (or Sponsor where required) will notify the IRB 
about the study completion. 
16.4. Privacy of Personal Data 
The collection and processing of personal data from subjects enrolled in this study will be 
limited to those data that are necessary to investigate the safety, quality, and utility of the 
investigational study drug(s) used in this study. 
These data must be collected and processed with adequate precautions to ensure 
confidentiality and compliance with applicable data privacy protection laws and regulations.  
Appropriate technical and organizational measures to protect the personal data against 
unauthorized disclosures or access, accidental or unlawful destruction, or accidental loss or 
alteration must be put in place.  Sponsor personnel whose responsibilities require access to 
personal data agree to keep the identity of study subjects confidential. 
The informed consent obtained from the subject includes explicit consent for the processing 
of personal data and for the Investigator to allow direct access to his or her original medical 
records for study-related monitoring, audit, IRB review, and regulatory inspection.  This 
consent also addresses the transfer of the data to other entities and to other countries. 


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17. DATA CONFIDENTIALITY, DISCLOSURE OF DATA, AND PUBLICATION 
Data generated for the study should be stored by the Investigator in a limited-access file area 
and be accessible only to representatives of the study site, Romark, the IRB, and 
FDA/relevant regulatory agencies.  Medical information resulting from a subject’s 
participation in this study may be given to the subject’s personal physician or to the 
appropriate medical personnel responsible for the subject’s welfare.   
No information that can be related to a specific individual subject may be released or used in 
any fashion without the signed written consent of that subject.  All reports and 
communications relating to study subjects will identify subjects only by initials and subject 
identification number.  The Investigator will keep complete subject identification for 
purposes of long-term follow-up, if needed.  This information will be treated with strict 
adherence to professional standards of confidentiality. 
Site personnel will enter data relating to each subject’s participation in the study into the 
EDC system provided by the Sponsor.  In the EDC system, identification numbers and initials 
will be used to identify subjects.  Subject names will not be used in the CRFs.  Management 
of data from the EDC system and the production of the clinical study report will be the 
responsibility of the Sponsor.  Access to the database will be restricted to employees who 
have been trained to use the system.  Access to the EDC system and study report will be 
limited to the IRB, FDA or other regulatory agencies and the Sponsor. 
Presentation and/or publication of the results of the study is encouraged provided that The 
Romark Institute for Medical Research is notified in advance of the author's intent and is 
given the opportunity to review the manuscript or abstract 45 days prior to its submission for 
presentation at a scientific meeting or for publication in a scientific journal.  The 
Investigators will have complete autonomy regarding the content and wording of any 
abstracts, presentations, and scientific publications arising from this study, including the 
decision of whether or not to publish.  
18. DATA AND REPORT REQUIREMENTS 
Data required by The Romark Institute for Medical Research prior to approval and initiation 
of the study are as follows: 
1. Curriculum vitae of the Principal Investigator and all Co-Investigators.  
2. Copy of the IRB-approved Informed Consent and subject information forms.  
3. Copy of the IRB approval for the conduct of the study.  
Data and materials required by The Romark Institute for Medical Research before the study 
can be considered complete and terminated are as follows:  
1. Pre- and post-treatment history, physical examination and subject evaluations.  
2. Pre- as well as interim and post-treatment laboratory findings and all special test results. 
3. EDC forms properly completed and signed by the Principal Investigator.  
4. Drug Inventory Logs indicating drug dispensed and return of the unused supplies to the 
Sponsor or destruction by study site.  


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5. Signed Informed Consent/Assent from each subject. 




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20. LIST OF REFERENCES 
Anderson VR, Curran MP. NTZ: A review of its use in the treatment of gastrointestinal infections. 
Drugs 2007;67:1947-67. 
ALINIA (nitazoxanide) prescribing information. Romark, L.C., Tampa, FL, June 2019. 
Ashton LV, Callan RL, Rao S, Landolt GA. In vitro susceptibility of canine influenza A (H3N8) 
virus to nitazoxanide and tizoxanide. Vet Med Int 2010; 2010:891010. 
Backman JT, Filppula AM, Niemi M, Neuvonen PJ. Role of cytochrome P450 2C8 in drug 
metabolism and interactions. Pharmacol Rev 2016; 68:168-241. 
Braakman I, Helenius J, Helenius A. Role of ATP and disulphide bonds during protein folding in 
the endoplasmic reticulum. Nature 1992; 356:260-62. 
Braakman I, Hoover-Litty H, Wagner KR, Helenius A. Folding of influenza hemagglutinin in the 
endoplasmic reticulum J Cell Biol 1991; 114:401-11. 
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21. APPENDICES 
Appendix I: 
Study Schedule  
Appendix II: 
Toxicity Grading for Adverse Events 
Appendix III:  List of Essential Documents for the Investigative Site 
Appendix IV: Protocol Revision History 
Appendix V: 
Declaration of Helsinki 
 
 


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21.1. Appendix I: Study Schedule 
Table 9: 
Schedule of Assessments 
 
Screening 
(Day -30 to 
Day 1) 
Baseline 
(Day 1) 
Day 1-
Week 6 
Weeks 
3, 6 
Week 
8 
Suspected 
ARI Visit 
Unscheduled 
Visit 
Signed informed consent/assent 
X 
 
 
 
 
 
 
Complete medical history 
X 
 
 
 
 
 
 
Physical examination 
X 
 
 
X1 
X1 
X1 
X 
Body weight/vital signs2 
X 
 
 
X 
 
X 
X 
Demographics/smoking history 
X 
 
 
 
 
 
 
Urine pregnancy test (Day 1) 
X 
 
 
 
 
 
 
Record body temperature 
X 
 
 
X 
 
X 
X 
Evaluate according to inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
Review number and type of social 
activities9 
X 
 
 
X 
 
 
 
Collect nasopharyngeal swabs  
 
X 
 
 
 
X3 
X 
Collect fecal specimen 
 
 
 
 
 
X3 
 
Blood sample for pharmacokinetics4 
 
 
 
X 
 
 
 
Blood sample for laboratory safety tests5 
 
X 
 
X 
 
 
X 
Blood sample for anti-SARS-CoV-2 Ab 
 
X 
 
X6 
X 
 
 
Urine sample for routine urinalysis5 
 
X 
 
X 
 
 
X 
Record concomitant medications 
 
X 
X 
X 
X 
X 
X 
Complete symptom diary 
 
X 
X7 
 
 
 
 
Randomization/dispense study 
medication 
 
X 
 
 
 
 
 
First dose, then study medication twice 
daily for 6 weeks  
 
X 
X 
 
 
 
 
Instructions re: dosing, swab collection 
concomitant medications, subject diary, 
follow-up visits, seeking emergency care 
and local public health guidelines 
 
X 
 
X 
 
 
X 
Review/record adverse events 
 
X 
 
X 
X 
X 
X 
Review electronic subject diary entries 
 
 
 
 
 
X8 
X8 
Review compliance with study 
medication, collect container with unused 
medication, complete pill count log form 
 
 
 
X 
 
 
 
Document any infections diagnosed 
during follow-up period 
 
 
 
 
X 
 
 
1  Physical examination as warranted by the Investigator for any change from Baseline. 
2  Body weight and collection of vital signs to include blood pressure, pulse, respiratory rate and body temperature. 
3 Nasopharyngeal swabs and a fecal specimen are to be collected at a Suspected ARI Visit and then again 24 to 36 hours and 4 to 5 days later. 
4 Blood sample to be collected pre-dose. 
5  Laboratory safety tests include hemoglobin, hematocrit, complete blood count (total and differential), platelet count, random blood sugar, total 
cholesterol, HDL, LDL, triglycerides, albumin, AST, ALT, GGT, alkaline phosphatase, bilirubin (total/direct), BUN, creatinine, sodium, 
potassium, chloride and routine urinalysis (appearance, glucose, proteins and blood). 
6 Blood samples for anti-SARS-CoV-2 antibodies are to be collected at Baseline, Week 6 and Week 8 only. 
7 If the subject meets the criteria for a Suspected ARI, then he/she will be asked to complete a symptom diary, and then continue daily with the 
symptom diary between 7 pm and 11 pm each day until the subject returns to usual health for 3 consecutive days or until the Week 8 Visit, 
whichever comes first.   
8 Site staff will contact subjects as needed during study to ensure timely completion of electronic diary. 
9  Subjects who qualify for the study based upon social risk only. 
 
 






















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Summary of Changes 
Change 1 
Pages 1 & 7 
Updated title of the study from “A Randomized, Double-Blind, Placebo Controlled Trial to Evaluate the Efficacy and Safety of 
Nitazoxanide (NTZ) for Post-exposure Prophylaxis of COVID-19 and Other Viral Respiratory Illnesses (VRI) in Healthcare 
Workers” to “A Randomized, Double-Blind, Placebo Controlled Trial to Evaluate the Efficacy and Safety of Nitazoxanide 
(NTZ) for Pre- and Post-exposure Prophylaxis of COVID-19 and Other Viral Respiratory Illnesses (VRI) in Healthcare 
Workers and Others at Increased Risk of SARS-CoV-2 Infection” 
Change 2 
Page 7, Synopsis 
 Updated indication from “Post-exposure prophylaxis” to “Pre- and post-exposure prophylaxis” 
 Updated population from “Healthcare workers at increased risk of occupational exposure to COVID-19” to “Healthcare 
workers and others at increased risk of contracting SARS-CoV-2 
 Updated trial duration from “April 2020 – August 2020” to “April 2020 – December 2020” 
Change 3 
Page 16, 1.3 Rationale for the Study 
Updated “post-exposure prophylaxis of COVID-19 and other VRIs in healthcare workers at high risk of occupational 
exposure to SARS-CoV-2” to “pre- and post-exposure prophylaxis of COVID-19 and other VRIs in healthcare workers and 
others at high risk of contracting SARS-CoV-2 infection” 
Change 4 
Page 16, 2. Study Objectives 
Updated “healthcare workers at high risk of occupational exposure” to “healthcare workers and others at high risk of 
contracting SARS-CoV-2 infection” 
Change 5 
Page 16, 3. Study Design 
 Updated “post-exposure” to “pre- and post-exposure” 
 Updated “Subjects will be stratified according to their workspace” to “Subjects will be stratified according to their most 
likely location of exposure” 
 Added “Social Activities” stratum 
 Updated expected end month from August to December 
Change 6 
Page 17, Choice of Patient Population 
 Updated “healthcare workers at high risk of occupational exposure to COVID-19” to “healthcare workers and others at 
high risk of contracting SARS-CoV-2 and other respiratory virus infections” 


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CONFIDENTIAL 
Summary of Changes 
 Updated “subjects will be excluded if they reside in a household with another subject enrolled as a participant in the study” 
to “subjects will be excluded if they reside in a household with a family member currently enrolled as a participant in the 
study” 
Change 7 
Pages 18 & 19, 4.1 Inclusion Criteria 
 Updated “Males and females at least 18 years of age” to “Males and females at least 18 years of age or of legal consenting 
age based on local requirements” 
 Updated Inclusion Criteria 2 from: 
2. Healthcare workers at increased risk for direct occupational exposure to COVID-19.  
a. Subject meets the definition of “healthcare worker”  
 
Provides healthcare to patients and/or  
 
Typically positions themselves within 6 feet of patients (“close contact”) and  
 
Is a full-time employee (average of ≥ 24 hrs/week) in a high contact area (Emergency Department, Intensive 
Care Unit, COVID-specific Care Unit, Walk-in Clinic, Paramedic/First Responder) 
To: 
6. Persons at increased risk of contracting COVID-19, including: 
a. Healthcare workers with known direct occupational exposure to COVID-19 within 7 days prior to enrollment. 
A qualifying person (i) provides healthcare to patients and/or (ii) typically positions themselves within 6 feet of 
patients (“close contact”) and (iii) is a full-time employee (average of ≥ 24 hrs/week) in a high contact area 
(Emergency Department, Intensive Care Unit, COVID-specific Care Unit, Walk-in Clinic, Paramedic/First 
Responder). 
b. Persons participating in social activities without the practice of generally accepted social distancing practices 
at least three times per week. Qualifying activities include the presence of at least 10 people in close (<6 feet) 
proximity to each other without masks or other personal protective equipment (e.g., socializing at bars or 
community/social centers, in-home social gatherings, classes or trainings, etc.). These subjects must have 
engaged in such activities at least three times in the past 7 days and plan to continue these activities during the 
study. 
 Added “or social interaction as defined in criterion 2(b)” to Inclusion Criteria 4 






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CONFIDENTIAL 
Summary of Changes 
Change 1: 
Page 7, Synopsis 
Updated Number of Subjects from 800 to “≥800 up to 4,000 as required to obtain 24 COVID-19 illnesses” 
Page 27, 8.1 Sample Size Calculation 
Updated description of the sample size calculation using an event-based approach to require 24 COVID-19 illnesses. 
Change 2: 
Page 8, Synopsis & Page 16, Study Design 
Updated expected trial duration from “April 2020-December 2020” to “April 2020-April 2021” 
Change 3: 
Page 19, Exclusion Criteria 
Added “or received a SARS-CoV-2 vaccine” to exclusion criterion #3 
Change 4: 
Page 22, 5.3 Daily Day 1 through Week 6 
Updated: “All subjects meeting this criteria will complete a “Suspected ARI Visit” regardless of patient or physician 
assessment of illness nature or severity.”  
to: “All subjects meeting this criteria will complete a “Suspected ARI Visit”as soon as possible, but in any event within 5 days 
of the first diary at which these criteria are met for each episode of suspected ARI regardless of patient or physician 
assessment of illness nature or severity.” 
Change 5: 
Page 23, 5.5 Week 3 (±7 days) and Week 6 Evaluations (±2 days) 
Added: “at least six hours after the most recent previous dose” to instructions for the pre-dose pharmacokinetics blood 
sample. 
 


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CONFIDENTIAL 
21.5. 
Appendix V: Declaration of Helsinki 




Copyright 2013 American Medical Association. All rights reserved.
13. Groups that are underrepresented in medical research should
be provided appropriate access to participation in research.
14. Physicians who combine medical research with medical care
should involve their patients in research only to the extent that
this is justified by its potential preventive, diagnostic or thera-
peuticvalueandifthephysicianhasgoodreasontobelievethat
participation in the research study will not adversely affect the
health of the patients who serve as research subjects.
15. Appropriate compensation and treatment for subjects who are
harmed as a result of participating in research must be en-
sured.
Risks, Burdens and Benefits
16. Inmedicalpracticeandinmedicalresearch,mostinterventions
involve risks and burdens.
Medical research involving human subjects may only be con-
ductediftheimportanceoftheobjectiveoutweighstherisksand
burdens to the research subjects.
17. All medical research involving human subjects must be pre-
ceded by careful assessment of predictable risks and burdens
to the individuals and groups involved in the research in com-
parisonwithforeseeablebenefitstothemandtootherindividu-
als or groups affected by the condition under investigation.
Measurestominimisetherisksmustbeimplemented.Therisks
mustbecontinuouslymonitored,assessedanddocumentedby
the researcher.
18. Physiciansmaynotbeinvolvedinaresearchstudyinvolvinghu-
mansubjectsunlesstheyareconfidentthattheriskshavebeen
adequately assessed and can be satisfactorily managed.
When the risks are found to outweigh the potential benefits or
when there is conclusive proof of definitive outcomes, physi-
cians must assess whether to continue, modify or immediately
stop the study.
Vulnerable Groups and Individuals
19. Somegroupsandindividualsareparticularlyvulnerableandmay
haveanincreasedlikelihoodofbeingwrongedorofincurringad-
ditional harm.
All vulnerable groups and individuals should receive specifi-
cally considered protection.
20. Medical research with a vulnerable group is only justified if the
research is responsive to the health needs or priorities of this
group and the research cannot be carried out in a non-
vulnerable group. In addition, this group should stand to ben-
efit from the knowledge, practices or interventions that result
from the research.
Scientific Requirements and Research Protocols
21. Medicalresearchinvolvinghumansubjectsmustconformtogen-
erally accepted scientific principles, be based on a thorough
knowledge of the scientific literature, other relevant sources of
information, and adequate laboratory and, as appropriate, ani-
mal experimentation. The welfare of animals used for research
must be respected.
22. The design and performance of each research study involving
human subjects must be clearly described and justified in a re-
search protocol.
The protocol should contain a statement of the ethical consid-
erations involved and should indicate how the principles in this
Declaration have been addressed. The protocol should include
information regarding funding, sponsors, institutional affilia-
tions, potential conflicts of interest, incentives for subjects and
information regarding provisions for treating and/or compen-
sating subjects who are harmed as a consequence of participa-
tion in the research study.
In clinical trials, the protocol must also describe appropriate ar-
rangements for post-trial provisions.
Research Ethics Committees
23. Theresearchprotocolmustbesubmittedforconsideration,com-
ment, guidance and approval to the concerned research ethics
committee before the study begins. This committee must be
transparent in its functioning, must be independent of the re-
searcher, the sponsor and any other undue influence and must
be duly qualified. It must take into consideration the laws and
regulations of the country or countries in which the research is
to be performed as well as applicable international norms and
standardsbutthesemustnotbeallowedtoreduceoreliminate
anyoftheprotectionsforresearchsubjectssetforthinthisDec-
laration.
The committee must have the right to monitor ongoing stud-
ies.Theresearchermustprovidemonitoringinformationtothe
committee, especially information about any serious adverse
events. No amendment to the protocol may be made without
consideration and approval by the committee. After the end of
thestudy,theresearchersmustsubmitafinalreporttothecom-
mittee containing a summary of the study’s findings and con-
clusions.
Privacy and Confidentiality
24. Every precaution must be taken to protect the privacy of re-
search subjects and the confidentiality of their personal infor-
mation.
Informed Consent
25. Participation by individuals capable of giving informed consent
as subjects in medical research must be voluntary. Although it
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may be appropriate to consult family members or community
leaders, no individual capable of giving informed consent may
be enrolled in a research study unless he or she freely agrees.
26. In medical research involving human subjects capable of giving
informed consent, each potential subject must be adequately
informed of the aims, methods, sources of funding, any pos-
sible conflicts of interest, institutional affiliations of the re-
searcher,theanticipatedbenefitsandpotentialrisksofthestudy
and the discomfort it may entail, post-study provisions and any
other relevant aspects of the study. The potential subject must
be informed of the right to refuse to participate in the study or
to withdraw consent to participate at any time without repri-
sal. Special attention should be given to the specific informa-
tionneedsofindividualpotentialsubjectsaswellastothemeth-
ods used to deliver the information.
Afterensuringthatthepotentialsubjecthasunderstoodthein-
formation, the physician or another appropriately qualified in-
dividual must then seek the potential subject’s freely-given in-
formed consent, preferably in writing. If the consent cannot be
expressedinwriting,thenon-writtenconsentmustbeformally
documented and witnessed.
Allmedicalresearchsubjectsshouldbegiventheoptionofbeing
informed about the general outcome and results of the study.
27. When seeking informed consent for participation in a research
study the physician must be particularly cautious if the poten-
tial subject is in a dependent relationship with the physician or
mayconsentunderduress.Insuchsituationstheinformedcon-
sentmustbesoughtbyanappropriatelyqualifiedindividualwho
is completely independent of this relationship.
28. For a potential research subject who is incapable of giving in-
formedconsent,thephysicianmustseekinformedconsentfrom
thelegallyauthorisedrepresentative.Theseindividualsmustnot
be included in a research study that has no likelihood of benefit
forthemunlessitisintendedtopromotethehealthofthegroup
represented by the potential subject, the research cannot in-
stead be performed with persons capable of providing in-
formed consent, and the research entails only minimal risk and
minimal burden.
29. When a potential research subject who is deemed incapable of
givinginformedconsentisabletogiveassenttodecisionsabout
participationinresearch,thephysicianmustseekthatassentin
addition to the consent of the legally authorised representa-
tive. The potential subject’s dissent should be respected.
30. Research involving subjects who are physically or mentally in-
capable of giving consent, for example, unconscious patients,
may be done only if the physical or mental condition that pre-
ventsgivinginformedconsentisanecessarycharacteristicofthe
research group. In such circumstances the physician must seek
informedconsentfromthelegallyauthorisedrepresentative.If
nosuchrepresentativeisavailableandiftheresearchcannotbe
delayed,thestudymayproceedwithoutinformedconsentpro-
videdthatthespecificreasonsforinvolvingsubjectswithacon-
dition that renders them unable to give informed consent have
beenstatedintheresearchprotocolandthestudyhasbeenap-
provedbyaresearchethicscommittee.Consenttoremaininthe
researchmustbeobtainedassoonaspossiblefromthesubject
or a legally authorised representative.
31. Thephysicianmustfullyinformthepatientwhichaspectsoftheir
care are related to the research. The refusal of a patient to par-
ticipateinastudyorthepatient’sdecisiontowithdrawfromthe
study must never adversely affect the patient-physician rela-
tionship.
32. For medical research using identifiable human material or data,
such as research on material or data contained in biobanks or
similarrepositories,physiciansmustseekinformedconsentfor
its collection, storage and/or reuse. There may be exceptional
situations where consent would be impossible or impracti-
cable to obtain for such research. In such situations the re-
search may be done only after consideration and approval of a
research ethics committee.
Use of Placebo
33. The benefits, risks, burdens and effectiveness of a new inter-
vention must be tested against those of the best proven inter-
vention(s), except in the following circumstances:
Where no proven intervention exists, the use of placebo, or no
intervention, is acceptable; or
Where for compelling and scientifically sound methodological
reasons the use of any intervention less effective than the best
proven one, the use of placebo, or no intervention is necessary
to determine the efficacy or safety of an intervention
andthepatientswhoreceiveanyinterventionlesseffectivethan
thebestprovenone,placebo,ornointerventionwillnotbesub-
ject to additional risks of serious or irreversible harm as a result
of not receiving the best proven intervention.
Extreme care must be taken to avoid abuse of this option.
Post-Trial Provisions
34. Inadvanceofaclinicaltrial,sponsors,researchersandhostcoun-
trygovernmentsshouldmakeprovisionsforpost-trialaccessfor
all participants who still need an intervention identified as ben-
eficialinthetrial.Thisinformationmustalsobedisclosedtopar-
ticipants during the informed consent process.
Research Registration and Publication and Dissemination
of Results
35. Every research study involving human subjects must be regis-
teredinapubliclyaccessibledatabasebeforerecruitmentofthe
first subject.
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Special Communication Clinical Review & Education
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36. Researchers, authors, sponsors, editors and publishers all have
ethical obligations with regard to the publication and dissemi-
nationoftheresultsofresearch.Researchershaveadutytomake
publicly available the results of their research on human sub-
jectsandareaccountableforthecompletenessandaccuracyof
their reports. All parties should adhere to accepted guidelines
for ethical reporting. Negative and inconclusive as well as posi-
tiveresultsmustbepublishedorotherwisemadepubliclyavail-
able. Sources of funding, institutional affiliations and conflicts
of interest must be declared in the publication. Reports of re-
search not in accordance with the principles of this Declaration
should not be accepted for publication.
Unproven Interventions in Clinical Practice
37. In the treatment of an individual patient, where proven inter-
ventions do not exist or other known interventions have been
ineffective, the physician, after seeking expert advice, with in-
formed consent from the patient or a legally authorised repre-
sentative, may use an unproven intervention if in the physi-
cian's judgement it offers hope of saving life, re-establishing
health or alleviating suffering. This intervention should subse-
quently be made the object of research, designed to evaluate
its safety and efficacy. In all cases, new information must be re-
corded and, where appropriate, made publicly available.
ARTICLE INFORMATION
Corresponding Author: World Medical
Association, 13, ch. du Levant, CIB - Bâtiment A,
01210 Ferney-Voltaire, France; wma@wma.net.
Published Online: October 19, 2013.
doi:10.1001/jama.2013.281053.
Disclaimer: ©2013 World Medical Association, Inc.
All Rights Reserved. All intellectual property rights
in the Declaration of Helsinki are vested in the
World Medical Association. The WMA has granted
JAMA exclusive rights to publish the
English-language version of the Declaration
through December 31, 2013.
Online-Only Content: Audio podcast is available at
www.jama.com.
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SAP_001.pdf: 




St ati sti c al  A n al y si s  Pl a n  
R M 0 8 -3 0 0 7  
 
 
P a g e   3 of  2 4  
 
R o m ar k  I n stit ut e f or M e di c al  R e s e ar c h  
V er si o n  1. 3  
                                                A pril  2 6,  2 0 2 4  
 
R e vi si o n  Hi st or y  
 
V er si o n  1. 2  t o 1. 3  
1.   U p d at e d  pl a n n e d   s oft w ar e fr o m  S A S t o  P yt h o n a n d  r el at e d  st ati sti c al  p a c k a g e s 
( s e cti o n 2. 6) . 
2.   U p d at e d   d o c u m e nt  o w n er s hi p fr o m 
 t o  R o m ar k I n stit ut e 
f or  M e di c al  R e s e ar c h. 
 
V er si o n  1. 1  t o 1. 2  
1.   C h a n g e d  t h e a ut h or  a n d  i nt er n al r e vi e w er.  
2.     A d d e d t er m s t o li st of   a b br e vi ati o n s. 
3.     A d d e d  m et h o d s t o h a n dl e   mi s si n g d at a  i n t h e  pri m ar y  a n al y si s. 
4.     A d d e d f urt h er d et ail s  t o t h e i nt eri m  a n al y si s  d e s cri pti o n. 
5.   U p d at e d  t h e  d e m o gr a p hi c a n d   b a s eli n e  c h ar a ct eri sti c  v ari a bl e s i n  S e cti o n 3. 0.  
6.     Cl arifi e d t h e d efi niti o n  of  a n   A RI t o i n cl u d e t h e  S u s p e ct e d  A RI  Vi sit r e q uir e m e nt s. 
7.     M o difi e d t h e  pri m ar y  a n al y si s  d e s cri pti o n t o  c o m p ut e t h e  c o m m o n r el ati v e ri s k i n 
pl a c e  of  t h e ri s k  diff er e n c e. 
8.     R e n a m e d T a bl e  1 4. 2. 1. 9,  a d d e d  T a bl e  1 4. 2. 1. 1 0,  a n d  r e n u m b er e d  s u b s e q u e nt 
1 4. 2. 1. x  t a bl e s. 
9.   T h e  f oll o wi n g u p d at e s   w er e  m a d e t o ali g n  wit h   Pr ot o c ol  V er si o n 3. 0,  d at e d  2 7  
A u g u st  2 0 2 0 : 
a.     St u d y titl e 
b.     A d d e d ‘ s o ci al  a cti viti e s’ a s   a  str at u m f or  m o st li k el y l o c ati o n of   e x p o s ur e 
c.  C h a n g e d  t h e  n a s o p h ar y n g e al  s w a b  s a m pl e d et ail s  
d.   C h a n g e d   d e s cri pti o n of  W e e k   3 a n d   8  E v al u ati o n s t o  st at e t h at  s u bj e ct s 
will  att e n d  i n- cli ni c  vi sit s 
e.     M o difi e d  s a m pl e  si z e  d e s cri pti o n t o  a c c o u nt f or  6  str at a 
1 0.  T h e  f oll o wi n g u p d at e s   w er e  m a d e t o ali g n  wit h   Pr ot o c ol  V er si o n  4. 0, d at e d   2 8 
S e pt e m b er  2 0 2 0 : 
a.   U p d at e d  t h e  str at a  s o t h at ‘ s o ci al  a cti viti e s’  str at u m i s n o w   di vi d e d i nt o 
s o ci al  a cti viti e s ( 3- 5  p er   w e e k) a n d   s o ci al  a cti viti e s ( >  5 p er   w e e k), 
r e s ulti n g i n  a t ot al of   7  str at a i n t h e  st u d y. 
1 1.  T h e  f oll o wi n g u p d at e s   w er e  m a d e t o ali g n  wit h   Pr ot o c ol  V er si o n 5. 0,  d at e d  2 6  
O ct o b er  2 0 2 0 : 
a.     M o difi e d  s a m pl e  si z e j u stifi c ati o n t o r efl e ct a n   e v e nt- dri v e  a p pr o a c h 
 
V er si o n  1. 0  t o 1. 1  
1.     Ri s k  diff er e n c e s a d d e d  t o  pri m ar y  effi c a c y e n d p oi nt.  
2.     S e cti o n 2. 2. 2   S e x,  A g e, a n d   R a c e  s u b gr o u p  a n al y s e s f or  pri m ar y  effi c a c y 
e n d p oi nt  a d d e d.  
3.     S e n siti vit y  a n al y s e s a d d e d  f or  mi s si n g  v al u e s of   pri m ar y  effi c a c y  v ari a bl e s. 
 
 


St ati sti c al  A n al y si s  Pl a n  
R M 0 8 -3 0 0 7  
 
 
P a g e   4 of  2 4  
 
R o m ar k  I n stit ut e f or M e di c al  R e s e ar c h  
V er si o n  1. 3  
                                                A pril  2 6,  2 0 2 4  
 
T a bl e  of  C o nt e nt s 
A p pr o v al  P a g e  ............................................................................................................................ 2 
R e vi si o n  Hi st or y  ......................................................................................................................... 3 
A b br e vi ati o n s  a n d  a cr o n y m s  .................................................................................................... 5 
1. 0  S y n o p si s  of  St u d y  D e si g n  Pr o c e d ur e s  .............................................................................. 6 
1. 1  D e si g n  a n d  Tr e at m e nt  .......................................................................................................... 6 
1. 2  St u d y  Pr o c e d ur e s  ................................................................................................................. 6 
T a bl e  1:  Cli ni c al  Ill n e s s R e q uir e d  f or Di a g n o si s  of  A RI 1  ( a d a pt e d fr o m Y u  et  al.  2 0 2 0)  ...... 8 
1. 3  S a m pl e  Si z e  ......................................................................................................................... 1 1  
2. 0  D at a  A n al y si s  C o n si d er ati o n s  ........................................................................................... 1 1  
2. 1  T y p e s  of  A n al y s e s  .............................................................................................................. 1 1  
2. 2  A n al y si s  P o p ul ati o n s  ......................................................................................................... 1 2  
2. 3  Mi s si n g  D at a  C o n v e nti o n s  ................................................................................................. 1 2  
T a bl e  2.  I m p ut ati o n r ul e s f or mi s si n g  d at e s.  ......................................................................... 1 2  
2. 4  I nt eri m A n al y s e s  ................................................................................................................. 1 3  
2. 5  St u d y  C e nt er  C o n si d er ati o n s  i n t h e D at a  A n al y si s  ......................................................... 1 4  
2. 6  D o c u m e nt ati o n  a n d  Ot h er  C o n si d er ati o n s  ...................................................................... 1 4  
3. 0  A n al y si s  of  B a s eli n e  P ati e nt  C h ar a ct eri sti c s  ................................................................... 1 4  
4. 0  A n al y si s  of  Effi c a c y  ............................................................................................................ 1 5  
4. 1  Effi c a c y  V ari a bl e s  ............................................................................................................... 1 5  
4. 2  Effi c a c y  A n al y si s  ................................................................................................................ 1 6  
5. 0  A n al y si s  of  S af et y  ............................................................................................................... 1 8  
5. 1  D e s cri pti o n  of  S af et y  V ari a bl e s  ......................................................................................... 1 8  
5. 2  D e s cri pti o n  of  S af et y  A n al y s e s  ......................................................................................... 1 8  
6. 0  Ot h er  R el e v a nt  D at a  A n al y s e s/ S u m m ari e s  ...................................................................... 1 9  
6. 1  P ati e nt  C o m pl eti o n  ............................................................................................................. 1 9  
6. 2  Pri or  a n d  C o n c o mit a nt  M e d i c ati o n s ................................................................................. 2 0  
6. 3  D e at h  R e p ort  ....................................................................................................................... 2 0  
6. 4  A d diti o n al  B a s eli n e  D at a  ................................................................................................... 2 0  
6. 5  Pr ot o c ol  D e vi ati o n s  ............................................................................................................ 2 0  
6. 6  Tr e at m e nt  C o m pli a n c e  a n d  A d mi ni str ati o n  ..................................................................... 2 0  
7. 0  R ef er e n c e s  .......................................................................................................................... 2 1  
8. 0  Li st  of  A n al y si s  T a bl e s,  Fi g ur e s  a n d  Li sti n g s  ................................................................. 2 2  
 
 
 


St ati sti c al  A n al y si s  Pl a n  
R M 0 8 -3 0 0 7  
 
 
P a g e   5 of  2 4  
 
R o m ar k  I n stit ut e f or M e di c al  R e s e ar c h  
V er si o n  1. 3  
                                                A pril  2 6,  2 0 2 4  
 
A b br e vi ati o n s  a n d  a cr o n y m s  
 
T er m   
D efi niti o n  
A E 
A d v er s e  E v e nt 
A RI  
A c ut e  R e s pir at or y  Ill n e s s 
A T C 
A n at o mi c  T h er a p e uti c  C h e mi c al 
C D E R   
C e nt er  f or Dr u g  E v al u ati o n  a n d  R e s e ar c h  
C F B   
C h a n g e  fr o m  b a s eli n e 
C M H   
C o c hr a n -M a nt el -H a e n s z el  C hi -s q u ar e  T e st  
C O VI D- 1 9   
C or o n a  Vir u s  Di s e a s e,  2 0 1 9  
C S  
Cli ni c all y  si g nifi c a nt  
F D A   
U S  F o o d  a n d   Dr u g  A d mi ni str ati o n 
I A P 
I nt eri m A n al y si s  Pl a n  
I D M C  
I n d e p e n d e nt D at a   M o nit ori n g  C o m mitt e e 
I T T 
Int e nti o n -t o-tr e at 
M e d D R A  
M e di c al  Di cti o n ar y  f or  R e g ul at or y  A cti viti e s 
N C S   
N ot  cli ni c all y  si g nifi c a nt  
N T Z   
Nit a z o x a ni d e 
P E  
P h y si c al  e x a m  
PI 
Pri n ci p al I n v e sti g at or 
R T -P C R   
R e v er s e -Tr a n s cri pt a s e  P ol y m er a s e  C h ai n  R e a cti o n  
S A R S- C o V - 2  S e v er e  A c ut e  R e s pir at or y  S y n dr o m e- C or o n a  Vir u s  2 (t h e  p at h o g e n  
r e s p o n si bl e f or C O VI D -1 9)  
S O C 
S y st e m  or g a n  cl a s s 
T E( S) A E   
Tr e at m e nt  E m er g e nt  ( S eri o u s) A d v er s e  E v e nt  
V RI 
Vir al  R e s pir at or y Ill n e s s 
W H O   
W orl d  H e alt h  Or g a ni z ati o n  
 
 
 


St ati sti c al  A n al y si s  Pl a n  
R M 0 8 -3 0 0 7  
 
 
P a g e   6 of  2 4  
 
R o m ar k  I n stit ut e f or M e di c al  R e s e ar c h  
V er si o n  1. 3  
                                                A pril  2 6,  2 0 2 4  
 
1. 0  S y n o p si s  of  St u d y  D e si g n  Pr o c e d ur e s  
 
1. 1  D e si g n  a n d   Tr e at m e nt 
 
T hi s  i s  a  m ulti- c e nt er, r a n d o mi z e d, d o u bl e -bli n d,   pl a c e b o- c o ntr oll e d  st u d y t o  a s s e s s t h e 
s af et y  a n d   effi c a c y of   Nit a z o x a ni d e  ( N T Z) f or  p o st- e x p o s ur e  pr o p h yl a xi s of   C O VI D-1 9,  
t h e  vir al r e s pir at or y  di s e a s e  c a u s e d b y  t h e  n o v el  c or o n a vir u s  S A R S-C o V - 2 a n d  ot h er   vir al 
r e s pir at or y ill n e s s e s  ( V RI s)  i n  h e alt h c ar e  w or k er s a n d   ot h er s at  hi g h   ri s k of   c o ntr a cti n g 
S A R S- C o V - 2 i nf e cti o n. T h e   st u d y i s  a  str atifi e d t w o- ar m  st u d y. T h e   m o st li k el y l o c ati o n of  
e x p o s ur e  i s b ei n g   u s e d a s   a  pr o x y f or  S A R S-C o V - 2  e x p o s ur e. T h e   s e v e n  str at a  ar e: 
•     E m er g e n c y  D e p art m e nt  
•    I nt e n si v e  C ar e U nit   
•     C O VI D- s p e cifi c  C ar e U nit   
•   W al k -i n Cli ni c   
•     P ar a m e di c s a n d   Fir st  R e s p o n d er s 
•     S o ci al  A cti viti e s ( 3- 5 p er   w e e k) 
•     S o ci al  A cti viti e s ( >  5 p er   w e e k) 
 
  P arti ci p a nt s will  b e  r a n d o mi z e d wit hi n   str at a ( 1: 1) t o o n e  of  
•     Gr o u p I ( N T Z) —T w o  3 0 0   m g N T Z  t a bl et s  or all y b.i. d.  (t wi c e  d ail y) f or  si x  w e e k s. 
•     Gr o u p II ( Pl a c e b o) —T w o   pl a c e b o t a bl et s b.i. d.  (t wi c e  d ail y) f or  si x  w e e k s. 
 
All  p arti ci p a nt s  will  r e c ei v e  a  B- c o m pl e x  vit a mi n (
 
)  t wi c e  d ail y   t o    m a s k  p ot e nti al    c hr o m at uri a  t h at    m a y  b e  
a s s o ci at e d  wit h  N T Z.  
 
1. 2   St u d y  Pr o c e d ur e s 
 
S cr e e ni n g 
P ati e nt s  will   b e   s cr e e n e d  fr o m    St u d y  D a y   -3 0   t o    St u d y  D a y   1.     Aft er  gi vi n g  i nf or m e d 
c o n s e nt,  t h e  s u bj e ct  will   b e    a s si g n e d   a  s u bj e ct   n u m b er  a n d   c o m pl et e  t h e  f oll o wi n g 
pr o c e d ur e s: 
1.     S ur v e y  of  C O VI D- 1 9  e x p o s ur e. 
2.     C o m pl et e  m e di c al  hi st or y. 
3.     P h y si c al  e x a mi n ati o n  i n cl u di n g  b o d y   w ei g ht  a n d  vit al  si g n s  ( bl o o d  pr e s s ur e, 
p ul s e, r e s pir at or y r at e,  a n d  b o d y t e m p er at ur e). 
4.     C oll e cti o n  of  d e m o gr a p hi c i nf or m ati o n  a n d  s m o ki n g  hi st or y. 
5.     Uri n e  pr e g n a n c y t e st f or  all f e m al e s  of  c hil d b e ari n g  p ot e nti al ( m u st  b e 
p erf or m e d  D a y  1). 
6.     E v al u ati o n  a c c or di n g t o  eli gi bilit y (i n cl u si o n  a n d  e x cl u si o n)  crit eri a. 


St ati sti c al  A n al y si s  Pl a n  
R M 0 8 -3 0 0 7  
 
 
P a g e   7 of  2 4  
 
R o m ar k  I n stit ut e f or M e di c al  R e s e ar c h  
V er si o n  1. 3  
                                                A pril  2 6,  2 0 2 4  
 
T h e i nf or m ati o n  c oll e ct e d  d uri n g t h e  s cr e e ni n g  p eri o d  m u st  b e  c urr e nt t hr o u g h t h e ti m e 
of r a n d o mi z ati o n. 
B a s eli n e  
At  B a s eli n e ( St u d y  D a y  1,  w hi c h  m a y  b e t h e  s a m e  d a y  a s t h e  s cr e e ni n g  e v al u ati o n) t h e 
s u bj e ct  will  b e r a n d o mi z e d t o  Gr o u p I  or  Gr o u p II  a n d  c o m pl et e t h e f oll o wi n g 
pr o c e d ur e s: 
1.   C oll e cti o n  of  a  n a s o p h ar y n g e al  s w a b  s a m pl e  u si n g  a  si n gl e  n yl o n  fl o c k e d  dr y 
s w a b i n s ert e d i nt o  b ot h  n o stril s f or  R T- P C R. 
2.   C oll e cti o n  of  bl o o d  s a m pl e  f or  l a b or at or y  s af et y  t e st s  a n d  a nti- S A R S-C o V -2 
a nti b o di e s. 
3.   C oll e cti o n  of  a  uri n e  s a m pl e f or r o uti n e  uri n al y si s ( a p p e ar a n c e,  gl u c o s e,  pr ot ei n, 
a n d  bl o o d). 
4.   R e vi e w  a n d r e c or di n g  of  a n y  c o n c o mit a nt  m e di c ati o n s. 
5.   Pr o vi si o n  of  a n  el e ctr o ni c  s y m pt o m  di ar y  t o  s u bj e ct  a n d  s u bj e ct  c o m pl eti o n  of 
b a s eli n e   el e ctr o ni c   di ar y   u n d er   s u p er vi si o n   a n d   i n str u cti o n   of   st u d y   sit e 
p er s o n n el. 
6.   R a n d o mi z ati o n   a n d   di s p e n si n g   of  st u d y    m e di c ati o n  ( m e di c ati o n   a s si g n e d  i n 
s e q u e nti al  or d er).  S u bj e ct s  ar e  e nr oll e d i n t h e  st u d y  at t hi s  p oi nt. 
7.   A d mi ni str ati o n  of t h e fir st  d o s e  of  st u d y  m e di c ati o n  wit h f o o d ( <  1  h o ur  aft er f o o d 
i nt a k e)   a n d   a    B   c o m pl e x   vit a mi n  (
 
)  u n d er  o b s er v ati o n  of  I n v e sti g at or  or  a    m e m b er  of 
I n v e sti g at or’ s  st aff,  a n d  e ntr y i n t h e  m e di c ati o n  a d mi ni str ati o n r e c or d. 
8.   T h e  s u bj e ct  will  b e i n str u ct e d r e g ar di n g t h e  a d mi ni str ati o n  of  st u d y  m e di c ati o n, 
c o m pl eti o n  of t h e  el e ctr o ni c  s u bj e ct  di ar y,  u s e  of  birt h  c o ntr ol, f oll o w- u p  vi sit s  at 
w e e k s  3,  6,  8,  a n d  o n  s e e ki n g  e m er g e n c y  m e di c al  c ar e  or  c o nt a cti n g t h e  st u d y 
p h y si ci a n  or  n ur s e  u n d er  s p e cifi c  c o n diti o n s. 
C O N T A C T  S T U D Y  P H Y SI CI A N, I F:  
•     Tr o u bl e  br e at hi n g i n cl u di n g  s h ort n e s s  of  br e at h. 
•     S e v er e  h e a d a c h e,  stiff  n e c k,  c o nf u si o n  or  e x c e s si v e  s o m n ol e n c e. 
•    If f e v er ( ≥ 9 9° F  or  ≥ 3 7. 2° C) r et ur n s  aft er  b ei n g  a b s e nt f or  2 4  h o ur s. 
•    I n cr e a s e d  diffi c ult y  br e at hi n g. 
•     W h e e zi n g  d e v el o p s. 
•     N e w  p ai n  d e v el o p s  or  p ai n l o c ali z e s t o  o n e  ar e a,  s u c h  a s  a n  e ar, t h e 
t hr o at, t h e  c h e st,  or t h e  si n u s e s. 
•     S y m pt o m s  b e c o m e  m or e  s e v er e  or fr e q u e nt. 


St ati sti c al  A n al y si s  Pl a n  
R M 0 8 -3 0 0 7  
 
 
P a g e   8 of  2 4  
 
R o m ar k  I n stit ut e f or M e di c al  R e s e ar c h  
V er si o n  1. 3  
                                                A pril  2 6,  2 0 2 4  
 
•     S y m pt o m s r e c ur  or  a n y  diffi c ult y  br e at hi n g f oll o wi n g  5- 1 0  d a y s r e s ol uti o n 
of ill n e s s. 
•     A n  all er gi c-li k e r e a cti o n  o c c ur s  or i s  s u s p e ct e d. 
•     A b n or m al  b e h a vi or. 
St u d y  W e e k s  1 t hr o u g h  6 ( D ail y)  
S u bj e ct s  will  k e e p  a  d ail y  di ar y t o  c h art  st u d y  m e di c ati o n  a n d  a n s w er t h e  q u e sti o n, “ d o 
y o u f e el li k e  y o u  h a v e  s y m pt o m s  of  a  c ol d  or fl u ?”  If t h e  s u bj e ct r e s p o n d s “ y e s”, t h e y  will 
b e  pr o m pt e d t o  c o m pl et e  a f ull  s y m pt o m  di ar y  q u e sti o n n air e ( F L U- P R O © )  a n d  c o nt a ct t h e 
I n v e sti g at or.   A  st u d y  p h y si ci a n,  n ur s e  or  ot h er  d e si g n at e d  sit e  p er s o n n el  will r e vi e w  e a c h 
s u bj e ct’ s  el e ctr o ni c  di ar y  e ntri e s  d ail y t o  e n s ur e  c o m pli a n c e  wit h  c oll e cti o n  of  di ar y  d at a.  
If  a  s u bj e ct  h a s  n ot  c o m pl et e d  hi s/ h er  di ar y  or if  err or s  ar e  s u s p e ct e d, t h e  st u d y  p er s o n n el 
will  c o nt a ct t h e  s u bj e ct t o i m pl e m e nt  a p pr o pri at e  c orr e cti v e  a cti o n s. 
If t h e  s u bj e ct  r e p ort s  (i)  at l e a st  o n e  of t h e  L o w er  R e s pir at or y  S y m pt o m s  pr e s e nt e d i n 
T e xt   T a bl e  1   b el o w  or   (ii)  at  l e a st  o n e  s y m pt o m  fr o m  e a c h  of  t h e    U p p er    R e s pir at or y 
S y m pt o m s  a n d   S y st e mi c   S y m pt o m s  c at e g ori e s  pr e s e nt e d  i n   T e xt   T a bl e  1   b el o w,  t h e 
s u bj e ct  will t h e n  c o nt a ct t h e  st u d y  p h y si ci a n t o  c o m pl et e  a “ S u s p e ct e d  A RI  Vi sit”  wit h t h e 
pr o c e d ur e s  pr o vi d e d  b el o w.  
T a bl e  1:  Cli ni c al  Ill n e s s R e q uir e d  f or Di a g n o si s  of  A RI 1  ( a d a pt e d fr o m  Y u et  al.  
2 0 2 0 ) 
U p p er  R e s pir at or y  S y m pt o m s   
L o w er  R e s pir at or y  S y m pt o m s   
S y st e mi c  S y m pt o m s  
•   N a s al  c o n g e sti o n/r hi n orr h e a 
(r u n n y  or  dri p pi n g  n o s e, 
c o n g e st e d  or  st uff y  n o s e, 
h e a d  c o n g e sti o n,  si n u s 
pr e s s ur e)   2 
•   S or e t hr o at ( s or e  or  p ai nf ul 
t hr o at)  2 
•   C o u g h ( c o u g hi n g,  c h e st 
c o n g e sti o n,  c h e st ti g ht n e s s,  dr y 
or  h a c ki n g  c o u g h,  w et  or  l o o s e 
c o u g h)   2 
•   D y s p n e a ( s h ort n e s s  of  br e at h)   2 
•   S p ut u m ( c o u g hi n g  u p  s p ut u m  or 
p hl e g m)   2 
•   W h e e zi n g  
•   M y al gi a s  or  art hr al gi a s ( b o d y 
a c h e s  or  p ai n s)   2 
•   F ati g u e ( w e a k  or tir e d, 
sl e e pi n g  m or e t h a n  u s u al)   2 
•   H e a d a c h e  
•   D e cr e a s e d  a p p etit e (l a c k  of 
a p p etit e,  di d  n ot f e el li k e 
e ati n g)   2 
•   F e v eri s h n e s s (f elt  h ot,  c hill s  or 
s hi v eri n g, f elt  c ol d,  s w e ati n g)   2 
1 S u s p e ct e d  A RI r e q uir e s  s elf -r e p orti n g  of  a n y  L o w er  R e s pir at or y  S y m pt o m,  or  at l e a st  o n e  U p p er 
R e s pir at or y  S y m pt o m t o g et h er  wit h  o n e  S y st e mi c  S y m pt o m.  
2 L a y l a n g u a g e  u s e d i n t h e  F L U -P R O ©  q u e sti o n n air e i s  pr e s e nt e d i n  p ar e nt h e s e s.  


St ati sti c al  A n al y si s  Pl a n  
R M 0 8 -3 0 0 7  
 
 
P a g e   9 of  2 4  
 
R o m ar k  I n stit ut e f or M e di c al  R e s e ar c h  
V er si o n  1. 3  
                                                A pril  2 6,  2 0 2 4  
 
S u s p e ct e d  A RI  Vi sit  
S u bj e ct s  r e p orti n g   a n y  l o w er  r e s pir at or y  s y m pt o m   or   at  l e a st   o n e   u p p er  r e s pir at or y 
s y m pt o m   a n d   o n e   s y st e mi c   s y m pt o m   ar e   c o n si d er e d  t o   h a v e   a   s u s p e ct e d   a c ut e 
r e s pir at or y ill n e s s  ( A RI)  a n d  will  c o m pl et e t h e f oll o wi n g  pr o c e d ur e s  at  a n  u n s c h e d ul e d 
S u s p e ct e d  A RI  Vi sit. 
1.     P h y si c al  e x a mi n ati o n  a s    w arr a nt e d  b y  t h e  I n v e sti g at or  f or  a n y  c h a n g e  fr o m 
b a s eli n e. 
2.     B o d y  w ei g ht  a n d  c oll e cti o n  of  vit al  si g n s t o i n cl u d e  bl o o d  pr e s s ur e,  p ul s e, 
r e s pir at or y r at e,  a n d  b o d y t e m p er at ur e. 
3.     C oll e ct  a  n a s o p h ar y n g e al  s w a b  s a m pl e  u si n g  a  si n gl e  n yl o n fl o c k e d  dr y  s w a b 
i n s ert e d i nt o  b ot h  n o stril s f or  R T- P C R  at t h e  S u s p e ct e d  A RI  Vi sit,  2 4 t o  3 6  h o ur s 
l at er,  a n d t h e n  a g ai n  4 t o  5  d a y s l at er. 
4.     C oll e ct  a f e c al  s p e ci m e n f or  R T- P C R  at t h e  S u s p e ct e d  A RI  Vi sit,  2 4 t o  3 6  h o ur s 
l at er,  a n d t h e n  a g ai n  4 t o  5  d a y s l at er. 
5.     T h e   s u bj e ct    will   c o m pl et e   a    F L U- P R O©    s y m pt o m   di ar y   d ail y   u ntil   h e/ s h e 
r e s p o n d s  “ y e s”  t o  t h e   F L U- P R O©   q u e sti o n,  “ H a v e  y o u  r et ur n e d  t o  y o ur  u s u al 
h e alt h ?” f or  3  c o n s e c uti v e  d a y s  or  u ntil t h e  W e e k  6  Vi sit,  w hi c h e v er  o c c ur s fir st.  
T h e  d ail y  F L U- P R O ©   di ar y  will  b e  c o m pl et e d  b et w e e n  7: 0 0  p m  a n d  1 1: 0 0  p m.   
6.     R e vi e w  a n d r e c or di n g  of  c o n c o mit a nt  m e di c ati o n s. 
7.     R e vi e w  a n d r e c or di n g  of  a d v er s e  e v e nt s/ si d e  eff e ct s. 
8.    L a b or at or y i n v e sti g ati o n s f or  s af et y  m a y  b e  p erf or m e d  a s  w arr a nt e d  b a s e d  u p o n 
t h e I n v e sti g at or’ s j u d g m e nt.   
9.     S u bj e ct s t e sti n g  p o siti v e f or  a r e s pir at or y  vir u s  b y  R T- P C R  m a y r e c ei v e  st a n d ar d 
of  c ar e  a s  cli ni c all y  w arr a nt e d  b y t h e I n v e sti g at or.   
R e g ar dl e s s  of  s y m pt o m s  or l a b or at or y  d at a, t h e  s u bj e ct  will  c o nti n u e tr e at m e nt  u ntil t h e 
6- w e e k tr e at m e nt  p eri o d  h a s  e n d e d.   
W e e k  3 ( +  7  d a y s)  a n d  W e e k  6 ( +  2  d a y s)  E v al u ati o n s  
S u bj e ct s    will  att e n d  i n- cli ni c  vi sit s  at    W e e k  3  a n d    W e e k  6  a n d  p erf or m  t h e  f oll o wi n g 
pr o c e d ur e s: 
1.     P h y si c al    E x a mi n ati o n  a s    w arr a nt e d  b y  t h e  I n v e sti g at or  f or  a n y  c h a n g e  fr o m 
b a s eli n e. 
2.     B o d y    w ei g ht   a n d   c oll e cti o n   of   vit al   si g n s  t o  i n cl u d e   bl o o d   pr e s s ur e,   p ul s e, 
r e s pir at or y r at e,  a n d  b o d y t e m p er at ur e. 
3.     C oll e cti o n  of  bl o o d  s a m pl e  f or  l a b or at or y  s af et y  t e st s,  p h ar m a c o ki n eti c s  ( pr e-
d o s e)  a n d  a nti- S A R s- C o V - 2  a nti b o di e s ( a nti b o d y t e sti n g  at  W e e k  6  vi sit  o nl y). 
4.     C oll e cti o n  of  uri n e  s a m pl e f or r o uti n e  uri n al y si s. 


St ati sti c al  A n al y si s  Pl a n  
R M 0 8 -3 0 0 7  
 
 
P a g e  1 0  of  2 4  
 
R o m ar k  I n stit ut e f or M e di c al  R e s e ar c h  
V er si o n  1. 3  
                                                A pril  2 6,  2 0 2 4  
 
5.     R e vi e w  of  c o m pli a n c e  wit h  st u d y  m e di c ati o n,  c oll e cti o n  of  m e di c ati o n  b ottl e  wit h 
a n y  u n u s e d  m e di c ati o n s ( W e e k  6  vi sit  o nl y),  a n d  c o m pl eti o n  of t h e  pill  c o u nt l o g 
f or m. 
6.     R e vi e w  a n d r e c or di n g  of  c o n c o mit a nt  m e di c ati o n s. 
7.     R e vi e w  a n d r e c or di n g  of  a d v er s e  e v e nt s/ si d e  eff e ct s  a n d  c o m pli c ati o n s.  N ot e 
t h at  all  a d v er s e  e v e nt s  a n d  c o m pli c ati o n s  m u st  b e f oll o w e d  u ntil t h eir r e s ol uti o n 
or  st a bili z ati o n  e v e n  b e y o n d t h e  8- w e e k  st u d y  p eri o d. 
W e e k  8  E v al u ati o n ( +  7  d a y s)  
S u bj e ct s    will  att e n d  i n- cli ni c  vi sit s  at    W e e k  3  a n d    W e e k  6  a n d  p erf or m  t h e  f oll o wi n g 
pr o c e d ur e s: 
1.     P h y si c al  e x a mi n ati o n  a s    w arr a nt e d  b y  t h e  I n v e sti g at or  f or  a n y  c h a n g e  fr o m 
b a s eli n e. 
2.     C oll e cti o n  of  bl o o d  s a m pl e f or  a nti- S A R s-C o V -2  a nti b o di e s . 
3.     R e vi e w  a n d r e c or di n g  of  c o n c o mit a nt  m e di c ati o n s. 
4.     R e vi e w  a n d  r e c or di n g  of  a d v er s e  e v e nt s/ si d e  eff e ct s  a n d  c o m pli c ati o n s.   N ot e 
t h at  all  a d v er s e  e v e nt s  a n d  c o m pli c ati o n s  m u st  b e f oll o w e d  u ntil t h eir r e s ol uti o n 
or  st a bili z ati o n  e v e n  b e y o n d t h e  8- w e e k  st u d y  p eri o d. 
5.     D o c u m e nt  a n y i nf e cti o n s  di a g n o s e d  d uri n g t h e f oll o w- u p  p eri o d. 
Ot h er  U n s c h e d ul e d  Vi sit s  
S u bj e ct s r e q uiri n g  a n  u n s c h e d ul e d  vi sit  d u e t o  w or s e ni n g  s y m pt o m s  or  a d v er s e  e v e nt s 
will  b e  e v al u at e d  at t h e  di s cr eti o n  of t h e I n v e sti g at or  a s i s  m e di c all y  w arr a nt e d.   T e st s 
a n d/  or  pr o c e d ur e s  p erf or m e d  at t hi s  vi sit  m a y i n cl u d e,  b ut  ar e  n ot li mit e d t o, t h e f oll o wi n g:  
1.     P h y si c al  e x a mi n ati o n  a s  w arr a nt e d  b y t h e I n v e sti g at or f or  a n y  c h a n g e fr o m 
b a s eli n e. 
2.     B o d y    w ei g ht   a n d   c oll e cti o n   of   vit al   si g n s  t o  i n cl u d e   bl o o d   pr e s s ur e,   p ul s e, 
r e s pir at or y r at e,  a n d  b o d y t e m p er at ur e. 
3.     C oll e cti o n  of  a  n a s o p h ar y n g e al  s w a b  s a m pl e  u si n g  a  si n gl e  n yl o n  fl o c k e d  dr y 
s w a b i n s ert e d i nt o  b ot h  n o stril s f or  R T- P C R. 
4.     C oll e cti o n  of  bl o o d  s a m pl e f or l a b or at or y  s af et y t e st s. 
5.     C oll e cti o n  of  uri n e  s a m pl e f or r o uti n e  uri n al y si s. 
6.     R e vi e w  of  c o m pli a n c e  wit h  st u d y  m e di c ati o n. 
7.     R e vi e w  a n d r e c or di n g  of  c o n c o mit a nt  m e di c ati o n s. 
8.     R e vi e w  a n d r e c or di n g  of  a d v er s e  e v e nt s/ si d e  eff e ct s. 
 


St ati sti c al  A n al y si s  Pl a n  
R M 0 8 -3 0 0 7  
 
 
P a g e  1 1  of  2 4  
 
R o m ar k  I n stit ut e f or M e di c al  R e s e ar c h  
V er si o n  1. 3  
                                                A pril  2 6,  2 0 2 4  
 
1. 3   S a m pl e  Si z e 
 
F or  p ur p o s e s  of  c al c ul ati n g  s a m pl e  si z e,  it  i s  a s s u m e d  t h at  t h e  pr o p orti o n  of  s u bj e ct s 
e x p eri e n ci n g  C O VI D- 1 9  di s e a s e  o v er  a  6- w e e k  p eri o d i s  1 %  a n d t h at t h e  pr o p orti o n  of 
s u bj e ct s  e x p eri e n ci n g  a n y   V RI  i s  2 %.   At  t h e  ti m e  pr ot o c ol   V er si o n  5. 0    w a s  fi n ali z e d, 
c urr e nt ill n e s s r at e s i n t h e tri al  b a s e d  u p o n  bli n d e d  p o ol e d  d at a  w e r e  a p pr o xi m at el y  1. 2 % 
f or  C O VI D- 1 9  a n d  2. 8 % f or  V RI s. It i s f urt h er  a s s u m e d t h at  eff e cti v e  pr o p h yl a xi s  will r e s ult 
i n  8 0 %  r e d u cti o n  of  t h e  ill n e s s  r at e.  I nfl u e n z a  pr o p h yl a xi s  st u di e s  of  o s elt a mi vir  h a v e 
r e s ult e d  i n  a p pr o xi m at el y  8 0 %  r e d u cti o n  of  i nfl u e n z a  ill n e s s  ( s e e   T a mifl u ®  pr e s cri bi n g 
i nf or m ati o n). 
 
U si n g t h e s e  a s s u m pti o n s,  a  C o x  pr o p orti o n al  h a z ar d s r e gr e s si o n  m o d el (fitti n g t h e  str at a 
a n d  tr e at m e nt  ar m  a s  a  s et  of i n di c at or  v ari a bl e s) w a s   u s e d t o  g e n er at e t h e  n u m b er  of 
e v e nt s ( C O VI D- 1 9  c a s e s)  n e e d e d f or  9 0 %  p o w er t o  d et e ct  a  h a z ar d r ati o  of  0. 8  v er s u s  a 
h a z ar d r ati o  of  1 ,  a s  p art  of  a  bli n d e d  s a m pl e  si z e r e- e sti m ati o n.  T hi s  n u m b er i s  1 7  e v e nt s. 
E arli er it er ati o n s  of t h e  pr ot o c ol  w er e  si z e d  o n t h e  a s s u m pti o n  of  a  3 %  o v er all ( p o ol e d) 
r at e f or  C O VI D- 1 9  c a s e s.  B e c a u s e t h e i nf e cti o n r at e i s  m u c h l o w er t h a n  a nti ci p at e d, t h e 
S p o n s or  h a s  d e ci d e d t o  p o w er t h e tri al  b a s e d  o n  e v e nt  c o u nt s.  T h e i nt e nt i s t o  k e e p t h e 
C o c hr a n- M a nt el- H a e n s z el ( C M H)  a n al y si s  pr e vi o u sl y  pl a n n e d.  T h e  e x p e ct e d  s a m pl e  si z e 
w a s  g e n er at e d  fr o m  t h e  e v e nt  c o u nt  r e q uir e d  a n d  t h e  c urr e nt,  st u d y- wi d e   ill n e s s  r at e 
a p pr o xi m ati n g  1 %.  T h e  p o w er  of t h e  C M H  a n al y si s  w a s t h e n  e v al u at e d. 
T h e  e x p e ct e d  s a m pl e  si z e i s  2 8 4 2  s u bj e ct s  a s si g n e d  e q u all y t o  str at a  a n d t o tr e at m e nt 
ar m  wit hi n  str at a.  T hi s (fi x e d)  s a m pl e  si z e  h a s  8 0. 6 %  p o w er f or  a  C M H t e st  of  e q u al ill n e s s 
r at e s i n t h e t w o tr e at m e nt  ar m s.  W h e n  d et er mi ni n g t h e fi x e d  s a m pl e  si z e  n e c e s s ar y f or 
9 0 %  p o w er  f or t h e  C M H t e st  u n d er t h e  c urr e nt  r at e s  a n d  eff e ct  si z e,  a  s a m pl e  si z e  of 
a p pr o xi m at el y  4 0 0 0 i s  r e q uir e d.  U n d er  c urr e nt  a s s u m pti o n s t hi s  r e s ult s i n  2 3  e x p e ct e d 
e v e nt s i n t h e  st u d y  –  v er y  n e ar t h e  n u m b er  of  e v e nt s  ori gi n all y  h y p ot h e si z e d  b a s e d  u p o n 
8 0 0 t ot al  s u bj e ct s  a n d  a  p o ol e d ill n e s s r at e  of  3 % f or t h e t w o tr e at m e nt  ar m s. 
A  st u d y- wi d e  e v e nt  c o u nt  of  2 4  C O VI D- 1 9  c a s e s  w a s  c h o s e n.  T hi s  pr o p o s e d  e v e nt  c o u nt 
r e s ult s i n  p o w er f or t h e  V RI  e n d p oi nt ( at t h e  e x p e ct e d  s a m pl e  si z e)  of  9 8. 2 %. 
2. 0  D at a  A n al y si s  C o n si d er ati o n s  
 
2. 1  T y p e s  of  A n al y s e s  
 
D at a   a n al y s e s will   c o n si st of   a n al y zi n g p ati e nt   c h ar a ct eri sti c s,  s af et y, a n d   effi c a c y d at a.  
 


St ati sti c al  A n al y si s  Pl a n  
R M 0 8 -3 0 0 7  
 
 
P a g e  1 2  of  2 4  
 
R o m ar k  I n stit ut e f or M e di c al  R e s e ar c h  
V er si o n  1. 3  
                                                A pril  2 6,  2 0 2 4  
 
2. 2  A n al y si s   P o p ul ati o n s 
 
2. 2. 1   P o p ul ati o n  D efi niti o n s 
 
S u bj e ct s  will  b e   c o n si d er e d  e nr oll e d i n t h e  st u d y u p o n   c o m pl eti o n of  t h e  b a s eli n e 
pr o c e d ur e s.  T h e  f oll o wi n g  a n al y si s p o p ul ati o n s  will  b e   u s e d i n t h e  st u d y. 
 
•   S af et y  P o p ul ati o n   – t h e  saf et y   po p ul ati o n  i n cl u d e s all  p ati e nt s  w h o   ar e  e nr oll e d 
i n t h e  st u d y a n d  t h at  h a v e  r e c ei v e d at  l e a st o n e   d o s e of  t h e  a s si g n e d tr e at m e nt 
ar m ( N T Z  or   pl a c e b o). 
•   I nt e nti o n-t o-Tr e at   P o p ul ati o n (I T T)  – t h e I T T p o p ul ati o n  i n cl u d e s all  p ati e nt s  i n 
t h e  s af et y  p o p ul ati o n   w h o   di d   n ot   h a v e  a  l a b or at or y  d et e ct e d  r e s pir at or y  vir u s 
i nf e cti o n at  t h e  b a s eli n e  vi sit. 
 
T h e   saf et y   po p ul ati o n  will  b e   u s e d f or all   s af et y  a n al y s e s. T h e  I T T p o p ul ati o n  will  b e  t h e 
pri m ar y  p o p ul ati o n  f or all   effi c a c y  a n al y s e s.  
 
A  d at a  li sti n g  di s pl a yi n g t h e p ati e nt s  e x cl u d e d fr o m  t h e I T T p o p ul ati o n  will  b e   cr e at e d, a s  
s h o w n  i n t h e T a bl e   R e q uir e m e nt s  D o c u m e nt.  T hi s  li sti n g will  b e  r el ati v e t o all  p ati e nt s  i n 
t h e  s af et y p o p ul ati o n .  
 
2. 2. 2   S u b gr o u p  D efi niti o n s 
 
C ert ai n  effi c a c y  a n al y s e s  will  b e   c o n d u ct e d o n  t h e  v ari o u s  st u d y  str at a.  Effi c a c y  a n al y s e s 
f or t h e  pri m ar y e n d p oi nt s  will  b e   p erf or m e d b y   s e x ( m al e/f e m al e), r a c e ( w hit e/n o n -w hit e ), 
a n d  a g e   gr o u p ( 1 8- 3 4   y e ar s, 3 5 - 6 4   y e ar s, a n d  6 5   y e ar or   ol d er).  S af et y  a n al y s e s will  b e  
gr o u p e d  b y  tr e at m e nt r e c ei v e d. 
 
2. 3   Mi s si n g  D at a  C o n v e nti o n s 
 
D at e   v ari a bl e s wit h   mi s si n g it e m s will  b e  i m p ut e d a s   s h o w n i n T a bl e   2 b el o w . 
 
T a bl e  2.  I m p ut ati o n r ul e s f or mi s si n g   d at e s. 
D at a  
H a n dli n g  C o n v e nti o n  
A d v er s e  e v e nt  o n s et  
d at e  
If o n s et  d at e  i s c o m pl et el y  mi s si n g,  i m p ut e wit h  t h e d at e  of  fir st d o s e.  
 
If y e ar  i s mi s si n g,  i m p ut e wit h  t h e y e ar  of  e nr oll m e nt.  
 
If o nl y  y e ar  or  if y e ar  a n d  d a y  ar e  pr e s e nt:  
•   If y e ar   = y e ar  of  fir st d o s e,  t h e n s et  m o nt h  a n d  d a y  t o t h e d at e  of  t h e fir st 
d o s e.  
•   If y e ar   < y e ar  of  fir st d o s e,  t h e n s et  m o nt h  a n d  d a y  t o D e c e m b er  3 1.  
•   If y e ar   > y e ar  of  fir st d o s e,  t h e n s et  m o nt h  a n d  d a y  t o J a n u ar y  1.  
 
If m o nt h  a n d  y e ar  ar e  pr e s e nt,  b ut  d a y  i s mi s si n g:  
•  If y e ar   = y e ar  of  fir st d o s e  a n d  
o  If m o nt h   = m o nt h  of  fir st d o s e,  t h e n s et  d a y  t o d a y  of  fir st d o s e.  


St ati sti c al  A n al y si s  Pl a n  
R M 0 8 -3 0 0 7  
 
 
P a g e  1 3  of  2 4  
 
R o m ar k  I n stit ut e f or M e di c al  R e s e ar c h  
V er si o n  1. 3  
                                                A pril  2 6,  2 0 2 4  
 
D at a  
H a n dli n g  C o n v e nti o n  
o  If m o nt h   < m o nt h  of  fir st d o s e,  t h e n s et  d a y  t o t h e l a st d a y  of  t h e m o nt h.  
o  If m o nt h   > m o nt h  of  fir st d o s e,  t h e n s et  d a y  t o t h e fir st d a y  of  t h e m o nt h.  
•  If y e ar   < y e ar  of  fir st d o s e,  t h e n s et  d a y  t o t h e l a st d a y  of  t h e m o nt h.  
•  If y e ar   > y e ar  of  fir st d o s e,  t h e n s et  d a y  t o t h e fir st d a y  of  t h e m o nt h.  
•  F or  all  ot h er  c a s e s,  s et  o n s et  d at e  t o t h e d at e  of  fir st d o s e.  
A d v er s e  e v e nt  e n d  d at e   
If t h e e n d  d at e  i s p arti all y  or  c o m pl et el y  mi s si n g,  s et  t o t h e l a st d at e  t h e 
s u bj e ct  w a s  k n o w n  t o b e  i n t h e st u d y.  
C o n c o mit a nt  m e di c ati o n s  
st art  d at e  
If st art  d at e  i s c o m pl et el y  mi s si n g,  it will  n ot  b e  i m p ut e d. 
 
If o nl y  y e ar  or  if y e ar  a n d  d a y  ar e  pr e s e nt,  s et  t h e m o nt h  a n d  d a y  t o 
J a n u ar y  1.  
 
If y e ar  a n d  m o nt h  ar e  pr e s e nt  a n d  d a y  i s mi s si n g,  s et  d a y  t o t h e fir st d a y  of  
t h e m o nt h.  
C o n c o mit a nt  m e di c ati o n s  
e n d  d at e  
If e n d  d at e  i s mi s si n g,  fr e q u e n c y i s “ 1 X” a n d  t h e m e di c ati o n  i s n ot  li st e d a s  
“ O N G OI N G”, t h e n e n d  d at e  s h o ul d  b e  s et  t o e q u al  t h e st art  d at e.  
 
If e n d  d at e  i s c o m pl et el y  mi s si n g,  it will  n ot  b e  i m p ut e d. 
 
If o nl y  y e ar  or  if y e ar  a n d  d a y  ar e  pr e s e nt,  s et  t h e m o nt h  a n d  d a y  t o 
D e c e m b er  3 1.  
 
If y e ar  a n d  m o nt h  ar e  pr e s e nt  a n d  d a y  i s mi s si n g,  s et  d a y  t o t h e l a st d a y  of  
t h e m o nt h.  
 
W hil e   e v er y  eff ort will  b e   m a d e t o  c o m pil e t h e d at a  i n  a c c or d a n c e wit h  i nt e nt-t o-tr e at, it i s 
li k el y t h at  s o m e  s u bj e ct s will   h a v e  mi s si n g  e n d p oi nt s.  S u bj e ct s  wit h   a  c o m pl et el y  mi s si n g 
b a s eli n e  F L U - P R O©  will   h a v e t h eir  s y m pt o m s  i m p ut e d wit h   a  s c or e of  0.   A d diti o n all y, 
s u bj e ct s  w h o   o nl y   p arti all y  c o m pl et e  a  F L U - P R O©   at   a n y   vi sit  will   h a v e  t h eir    mi s si n g 
s c or e s i m p ut e d  wit h   a 0.   N ot e  t h at  c o m pl et el y  mi s si n g F L U - P R O©   q u e sti o n n air e s at   p o st-
b a s eli n e  vi sit s  will  n ot  b e  i m p ut e d.  
 
Aft er t a ki n g  i nt o  a c c o u nt t h e i m p ut ati o n of   mi s si n g F L U - P R O©   s c or e s a s   d e s cri b e d  a b o v e, 
s u bj e ct s  wit h   mi s si n g  pri m ar y e n d p oi nt s  will  b e  i m p ut e d a s   u ni nf e ct e d.  T h at  i s,  s u bj e ct s 
i n b ot h  tr e at m e nt  ar m s will   h a v e t h eir  mi s si n g  pri m ar y e n d p oi nt  d at a  i m p ut e d a s   a b s e n c e 
of   s y m pt o m ati c  C O VI D-1 9   di s e a s e a n d   a b s e n c e of   s y m pt o m ati c  V RI. 
 
S e n siti vit y  a n al y s e s  will  b e   p erf or m e d t o  a s s e s s t h e i nfl u e n c e  mi s si n g  pri m ar y e n d p oi nt s  
m a y  h a v e  o n   t h e  st u d y’ s  c o n cl u si o n s.  T h e   fir st  a n al y si s  will   b e   a  b e st- c a s e  a n al y si s, 
a s si g ni n g i nf e ct e d  st at u s  t o all   mi s si n g  C O VI D-1 9   di s e a s e a n d   V RI  st at u s i n t h e  pl a c e b o 
ar m  a n d  n o n -i nf e ct e d  st at u s  t o t h e s e  v ari a bl e s i n t h e N T Z   ar m. T h e   s e c o n d  s e n siti vit y 
a n al y si s  will  b e   a  w or st- c a s e  a n al y si s. T hi s   a n al y si s will   a s si g n i nf e ct e d  st at u s f or  C O VI D-
1 9   di s e a s e  a n d    V RI  t o    mi s si n g  v al u e s  i n  t h e  N T Z   ar m  a n d   n o n -i nf e ct e d  st at u s  t o  t h e 
mi s si n g  v al u e s  i n  t h e  pl a c e b o  ar m.   Fi n all y,  a  ti p pi n g  p oi nt   a n al y si s  will   u s e    m ulti pl e 
i m p ut ati o n    m et h o d s t o  d et er mi n e  t h e  all o c ati o n  of   i nf e ct e d  a n d   n o n -i nf e ct e d  st at u s  t o 
mi s si n g  v al u e s  i n t h e N T Z   ar m  w hi c h  c h a n g e s t h e  st u d y  c o n cl u si o n s. 
 


St ati sti c al  A n al y si s  Pl a n  
R M 0 8 -3 0 0 7  
 
 
P a g e  1 4  of  2 4  
 
R o m ar k  I n stit ut e f or M e di c al  R e s e ar c h  
V er si o n  1. 3  
                                                A pril  2 6,  2 0 2 4  
 
2. 4  I nt eri m A n al y s e s  
 
T w o   i nt eri m  d at a   r e vi e w s  a n d   a n al y s e s  will   b e   s c h e d ul e d  a n d   h el d   pr o m ptl y  aft er   t h e 
p erti n e nt    mil e st o n e  h a s   b e e n   r e a c h e d.  T h e   fir st  a n al y si s  will   o c c ur  w h e n   2 5 %  of   t h e 
s u bj e ct s  h a v e  c o m pl et e d  w e e k  3.   T h e  fir st i nt eri m  a n al y si s will  b e   a bli n d e d   a n al y si s f or 
dr u g  s af et y  o nl y.   
T h e   s e c o n d  a n al y si s will   o c c ur w h e n  5 0 %  of  t h e pl a n n e d   2 4  C O VI D- 1 9  c a s e s  h a v e  b e e n 
r e p ort e d (i. e.,  aft er  1 2  C O VI D- 1 9  c a s e s  ar e r e p ort e d). T h e   s e c o n d i nt eri m a n a l y si s will  b e  
f or  s af et y a n d  p ot e nti all y   st o p pi n g t h e tri al f or f utilit y. T h e  I nt eri m D at a   R e vi e w  Pl a n will  
b e  i n cl u d e d i n t h e I n d e p e n d e nt D at a   M o nit ori n g  C o m mitt e e (I D M C)  c h art er. 
F utilit y  will  b e   a s s e s s e d  vi a t h e  effi c a c y of  N T Z  f or t h e  C O VI D-1 9  e n d p oi nt.  T h e  I D M C will  
r e c o m m e n d  st o p pi n g  f or  f utilit y  if  t h e    C M H  t e st  st ati sti c  f or  c o m p ari n g  t h e  tr e at m e nt 
gr o u p s  o n  t h e  C O VI D-1 9  e n d p oi nt  i s l e s s t h a n 0. 1 7 9  (i. e.,  a p - v al u e  gr e at er t h a n  0. 3 2 7 8).  
T h e   C M H t e st will  b e   c o n d u ct e d f or t h e  s ol e  p ur p o s e of   e v al u ati n g f utilit y; t h er e will  b e  n o  
e arl y  st o p pi n g  f or  effi c a c y.  T hi s  b o u n d  w a s   s et  u si n g  O’ Bri e n- Fl e mi n g b o u n d s  f or f utilit y 
wit h   o v er all a   = 0. 0 4 9.  
T h e  I D M C will   c o n d u ct t h e  m e eti n g s i n  a c c or d a n c e wit h  t h e I D M C  c h art er. N o   effi c a c y 
a n al y si s  i s pl a n n e d  a n d  n o   all o c ati o n of  a  t o t h e i nt eri m  a n al y si s i s  n e c e s s ar y. 
2. 5   St u d y  C e nt er  C o n si d er ati o n s i n t h e  D at a A n al y si s  
 
A   st u d y   c e nt er  i s  d efi n e d   a s    a  tr e at m e nt   a d mi ni str ati o n   sit e  or    gr o u p  of   tr e at m e nt 
a d mi ni str ati o n  sit e s  u n d er  t h e  c o ntr ol a n d   s u p er vi si o n of  t h e  s a m e  Pri n ci p al I n v e sti g at or 
( PI).  T h er e  will  b e  n o   s el e cti v e p o oli n g  of   st u d y  c e nt er s  – all   sit e s will  b e  p o ol e d.  T h e  
st u d y  i s pl a n n e d  t o b e   c o n d u ct e d at   m ulti pl e  sit e s. 
 
2. 6   D o c u m e nt ati o n a n d   Ot h er  C o n si d er ati o n s 
 
T h e  d at a   a n al y s e s will  b e   c o n d u ct e d  u si n g  P yt h o n a n d   s u p p ort e d  st ati sti c al  p a c k a g e s. 
 
3. 0  A n al y si s  of  B a s eli n e  P ati e nt  C h ar a ct eri sti c s  
 
B a s eli n e  a n d   d e m o gr a p hi c  c h ar a ct eri sti c s of  t h e  saf et y  p o p ul ati o n  will  b e   s u m m ari z e d. 
C o nti n u o u s   v ari a bl e s ( a g e a n d   b a s eli n e w ei g ht ) will  b e   s u m m ari z e d  vi a  m e a n,  st a n d ar d 
d e vi ati o n,    mi ni m u m,    m e di a n,    m a xi m u m,  a n d    n u m b er  of   n o n - mi s si n g   r e s p o n s e s. 
C at e g ori c al  v ari a bl e s ( g e n d er, r a c e  et h ni cit y,  a n d  t o b a c c o  u s e ( b y  pr o d u ct t y p e)) will  b e  
s u m m ari z e d  vi a  c o u nt s  a n d   p er c e nt a g e s.   
 
A  d et ail e d  li sti n g of   b a s eli n e d at a  f or  e a c h p ati e nt  i n t h e  s af et y p o p ul ati o n  will   al s o b e  
pr o vi d e d  a s   s h o w n i n  A p p e n di x  B. 
 


St ati sti c al  A n al y si s  Pl a n  
R M 0 8 -3 0 0 7  
 
 
P a g e  1 5  of  2 4  
 
R o m ar k  I n stit ut e f or M e di c al  R e s e ar c h  
V er si o n  1. 3  
                                                A pril  2 6,  2 0 2 4  
 
 4. 0  A n al y si s  of  Effi c a c y  
 
4. 1   Effi c a c y  V ari a bl e s 
 
All  t h e  effi c a c y  v ari a bl e s  ar e  c at e g ori c al i n  n at ur e: t h e  pr e s e n c e or   a b s e n c e of   an y   V RI, 
A RI,  or   C O VI D-1 9   d uri n g t h e  st u d y  p eri o d.  Si mil arl y,  h o s pit ali z ati o n ( a n d it s  c a u s e) a n d  
d e at h  ( a n d it s  c a u s e)  ar e  c at e g ori c al. 
 
Pri m ar y  Effi c a c y  V ari a bl e s  
T h e r e  ar e t w o  pri m ar y  effi c a c y  v ari a bl e s:  
1.   T h e   pr e s e n c e or   a b s e n c e of   s y m pt o m ati c  C O VI D-1 9   di s e a s e i d e ntifi e d aft er  t h e 
st art  of  tr e at m e nt a n d   b ef or e t h e e n d  of  t h e  6-w e e k  tr e at m e nt  p eri o d. 
2.   T h e   pr e s e n c e or   a b s e n c e of   s y m pt o m ati c  V RI (i n cl u di n g  C O VI D-1 9)  i d e ntifi e d aft er  
t h e  st art of  tr e at m e nt a n d   b ef or e t h e e n d  of  t h e  6-w e e k  tr e at m e nt  p eri o d. 
S y m pt o m ati c  C O VI D- 1 9  i s d efi n e d  a s  a n   A RI aft er   st art of  tr e at m e nt a n d   b ef or e t h e e n d  
of  t h e  6-w e e k   tr e at m e nt  p eri o d  a s s o ci at e d  wit h   d et e cti o n  of    S A R S-C o V - 2  b y  R T - P C R 
a s s a y  of   n a s o p h ar y n g e al  s w a b.  
S y m pt o m ati c  V RI  i s d efi n e d  a s  a n   A RI aft er   st art of  tr e at m e nt a n d   b ef or e t h e e n d  of  t h e 
6- w e e k  tr e at m e nt  p eri o d  a s s o ci at e d wit h   d et e cti o n of  a n y   r e s pir at or y  vir u s b y  R T - P C R 
a s s a y  of   n a s o p h ar y n g e al  s w a b.  
A  s u bj e ct  will  b e   c o n si d er e d t o  h a v e  m et t h e  crit eri a f or a n   A RI if: 
1.   T h e   s u bj e ct    m e et s t h e  crit eri a t h at tri g g er t h e  S u s p e ct e d   A RI  Vi sit  ( s e e   S e cti o n 
1. 2) ; 
A N D 
2.   T h e   s u bj e ct  s ati sfi e s t h e f oll o wi n g  A RI d efi niti o n:   A RI i s d efi n e d  a s  ≥ 0. 5  i n cr e a s e 
fr o m  b a s eli n e i n  m e a n  s y m pt o m  s c or e f or t h e F L U - P R O©   c h e st/r e s pir at or y  d o m ai n 
al o n e;  or   a  > 0. 5  i n cr e a s e fr o m  b a s eli n e i n  m e a n  s y m pt o m  s c or e f or at  l e a st t w o of  
t h e f oll o wi n g F L U - P R O©   d o m ai n s:  b o d y/ s y st e mi c,  n o s e, t hr o at. 
S e c o n d ar y  Effi c a c y  V ari a bl e s 
T h e   s e c o n d ar y  effi c a c y  v ari a bl e s  ar e: 
 
1.     M ort alit y d u e  t o  C O VI D-1 9  or   c o m pli c ati o n s t h er e of. 
2.   T h e   pr e s e n c e or   a b s e n c e of  a nti - S A R S-C o V - 2 a nti b o di e s  at  eit h er  of  t h e W e e k   6 
or  W e e k   8  vi sit s. 
 
E x pl or at or y  Effi c a c y  V ari a bl e s 
T h e   e x pl or at or y  effi c a c y  v ari a bl e s  ar e: 


St ati sti c al  A n al y si s  Pl a n  
R M 0 8 -3 0 0 7  
 
 
P a g e  1 6  of  2 4  
 
R o m ar k  I n stit ut e f or M e di c al  R e s e ar c h  
V er si o n  1. 3  
                                                A pril  2 6,  2 0 2 4  
 
 
1.     H o s pit ali z ati o n d u e  t o  V RI or   c o m pli c ati o n s t h er e of. 
2.     M ort alit y d u e  t o  V RI or   c o m pli c ati o n s t h er e of. 
3.     Pr e s e n c e or   a b s e n c e of  a n   A RI. 
4.     H o s pit ali z ati o n d u e  t o  A RI or   c o m pli c ati o n s t h er e of. 
5.     M ort alit y d u e  t o  A RI or   c o m pli c ati o n s t h er e of. 
 
4. 2   Effi c a c y A n al y si s  
 
4. 2. 1   Pri m ar y  Effi c a c y  V ari a bl e s 
 
T hi s   st u d y h a s  t w o  pri m ar y  e n d p oi nt s:  s y m pt o m ati c  C O VI D-1 9   di s e a s e a n d   s y m pt o m ati c 
V RI.  T h e   st u d y- wi s e  T y p e I  err or r at e i s 0. 0 5,   all o c at e d a   = 0. 0 4 9  t o  C O VI D-1 9   di s e a s e 
a n d  a   = 0. 0 0 1  t o all   V RI. I n  e a c h  c a s e t h e  h y p ot h e s e s t o b e  t e st e d  ar e 
 
H ! : 𝑝" = 𝑝#
H " : 𝑝" ≠ 𝑝# , 
 
w h er e  p 1   r e pr e s e nt s  t h e   C O VI D-1 9   di s e a s e  r at e  ( or   V RI  r at e)  i n  t h e  N T Z   ar m  a n d   p 2  
r e pr e s e nt s t h e  C O VI D-1 9   di s e a s e r at e ( or  V RI r at e) i n t h e  pl a c e b o  ar m. 
 
Pri m ar y  A n al y si s  
T h e   pr o p orti o n  of   s u bj e ct s  e x p eri e n ci n g  s y m pt o m ati c    C O VI D-1 9   di s e a s e  i n  t h e  N T Z  
tr e at m e nt  gr o u p will  b e   c o m p ar e d t o t h e  si mil ar  pr o p orti o n i n t h e  pl a c e b o  gr o u p  u si n g  a 
t w o- si d e d  C M H t e st wit h   c o nti n uit y  c orr e cti o n at  a = 0. 0 4 9.  T h e   c o nti n g e n c y t a bl e s will  b e  
pr o vi d e d  wit h  r at e s r el ati v e t o t h e tr e at m e nt  m ar gi n s. T h e   c o m m o n r el ati v e ri s k a n d  t h e 
o d d s   r ati o  b et w e e n   t h e  tr e at m e nt   gr o u p s  a n d   9 5 %    c o nfi d e n c e  i nt er v al s  f or  t h e s e 
p ar a m et er s  will  b e   pr o vi d e d. T h e   a n al y si s will  b e  r e p e at e d b y   s e x of   s u bj e ct (f e m al e or  
m al e),  a g e   gr o u p of   s u bj e ct s ( 1 8- 3 4   y e ar s, 3 5 - 6 4   y e ar s, 6 5   y e ar s a n d   ol d er), a n d  r a c e 
of   s u bj e ct (w hit e  or  n o n -w hit e ). 
 
T h e   pr o p orti o n of   s u bj e ct s  e x p eri e n ci n g  s y m pt o m ati c  V RI i nf e cti o n s i n t h e N T Z  tr e at m e nt 
gr o u p  will  b e   c o m p ar e d t o t h e  si mil ar  pr o p orti o n i n t h e  pl a c e b o  gr o u p  u si n g  a t w o- si d e d 
C M H  C hi - s q u ar e t e st wit h   c o nti n uit y  c orr e cti o n at  a = 0. 0 0 1 . T h e   c o nti n g e n c y t a bl e s will  
b e   pr o vi d e d wit h   r at e s  r el ati v e t o t h e tr e at m e nt  m ar gi n s. T h e   c o m m o n  r el ati v e  ri s k a n d  
t h e  o d d s   r ati o  b et w e e n   t h e  tr e at m e nt  gr o u p s  a n d   9 5 %   c o nfi d e n c e  i nt er v al s  f or  t h e s e 
p ar a m et er s  will  b e   pr o vi d e d. T h e   a n al y si s will  b e  r e p e at e d b y   s e x of   s u bj e ct (f e m al e or  
m al e),  a g e   gr o u p of   s u bj e ct s ( 1 8- 3 4   y e ar s, 3 5 - 6 4   y e ar s, 6 5   y e ar s a n d   ol d er), a n d  r a c e 
of   s u bj e ct (w hit e  or  n o n -w hit e ). 
 
W hil e   e v er y  eff ort will  b e   m a d e t o  c o m pil e t h e d at a  i n  a c c or d a n c e wit h  i nt e nt-t o-tr e at, it i s 
li k el y t h at  s o m e  s u bj e ct s will   h a v e  mi s si n g  e n d p oi nt s.  S u bj e ct s wit h   mi s si n g  o ut c o m e s 
d at a  will  b e   i n cl u d e d i n t h e  pri m ar y  a n al y si s. T h e   pri m ar y  a n al y si s will   i m p ut e    mi s si n g 
d at a  a s   u ni nf e ct e d i n  e a c h tr e at m e nt  ar m.  B e st- c a s e  a n d   w or st- c a s e  s e n siti vit y  a n al y s e s 
will  b e   p erf or m e d a s  o utli n e d  i n  S e cti o n 2. 3   a b o v e. I n a d diti o n,   a ti p pi n g p oi nt   a n al y si s will  


St ati sti c al  A n al y si s  Pl a n  
R M 0 8 -3 0 0 7  
 
 
P a g e  1 7  of  2 4  
 
R o m ar k  I n stit ut e f or M e di c al  R e s e ar c h  
V er si o n  1. 3  
                                                A pril  2 6,  2 0 2 4  
 
b e   p erf or m e d,  i m p uti n g  v ari o u s  l e v el s  of   C O VI D-1 9  a n d    V RI i nf e cti o n  r at e s t o    mi s si n g 
v al u e s  i n  t h e  N T Z   ar m  t o  d et er mi n e  t h e  i nf e cti o n  r at e  at    w hi c h  t h e  st u d y  c o n cl u si o n s 
c h a n g e. 
 
S e c o n d ar y  A n al y si s  
S e c o n d ar y   a n al y s e s  of   t h e   pri m ar y  e n d p oi nt s    i n cl u d e   th e    pr o p orti o n  of    s u bj e ct s 
e x p eri e n ci n g  s y m pt o m ati c  C O VI D- 1 9  i n t h e N T Z  tr e at m e nt  gr o u p will  b e   c o m p ar e d wit h  
t h e  si mil ar  pr o p orti o n i n t h e  pl a c e b o  gr o u p f or  e a c h  str at u m  u si n g  a  P e ar s o n C hi - s q u ar e 
t e st  wit h    c o nti n uit y   c orr e cti o n.    A  9 5 %     Wil s o n   c o nfi d e n c e  i nt er v al   ( wit h   c o nti n uit y 
c orr e cti o n)  will  b e   pr o d u c e d f or t h e  s y m pt o m ati c  C O VI D-1 9  i nf e cti o n i n  e a c h  gr o u p wit hi n  
e a c h  str at u m.   A  9 5 %   c o nfi d e n c e  i nt er v al  f or  t h e  o d d s -r ati o  of   s y m pt o m ati c   C O VI D-1 9  
i nf e cti o n  r at e  i n  t h e  N T Z   v s  pl a c e b o  gr o u p s  will   b e   pr o d u c e d  f or  e a c h  str at u m.  T h e  
c o nti n g e n c y  t a bl e s will  b e   pr o vi d e d wit h  r at e s r el ati v e t o t h e tr e at m e nt  m ar gi n s. 
 
4. 2. 2   S e c o n d ar y  Effi c a c y  V ari a bl e s 
 
St ati sti c al t e st s  f or t h e  s e c o n d ar y  effi c a c y  v ari a bl e s will  b e   p erf or m e d o nl y  if t h e  pri m ar y 
a n al y s e s  of   pri m ar y  effi c a c y  v ari a bl e s b ot h  r ej e ct t h e n ull   h y p ot h e si s.  T h e s e t e st s  a ct a s  
g at e k e e p er s  t o  t h e   s e c o n d ar y   effi c a c y  t e st s.  N o    all o c ati o n  of    st u d y- wi s e  a   t o  t h e 
s e c o n d ar y t e st s  i s  n e c e s s ar y.  
 
T h e   m ort alit y r at e s d u e  t o  C O VI D-1 9  or   c o m pli c ati o n s will  b e  c o m p ar e d  b y   str at u m wit h  
a  P e ar s o n  C hi - s q u ar e t e st. T h e   o v er all  m ort alit y r at e d u e  t o  C O VI D-1 9  or   c o m pli c ati o n s 
i n t h e t w o  tr e at m e nt  gr o u p s will   e a c h b e   c o m p ar e d  u si n g  a   C M H  C hi - s q u ar e  t e st  wit h  
c o nti n uit y  c orr e cti o n  at  a = 0. 0 5.  A  9 5 %   c o nfi d e n c e i nt er v al f or t h e p o ol e d  o d d s -r ati o will  
b e   pr o vi d e d. 
 
T h e   pr o p orti o n of   s u bj e ct s t e sti n g  p o siti v e f or  S A R S-C o V - 2 a nti b o di e s  at  eit h er  W e e k   6 
or  W e e k   8 will  b e   c o m p ar e d  u si n g  P e ar s o n C hi - s q u ar e t e st s wit h   c o nti n uit y  c orr e cti o n i n 
e a c h  str at u m.  T h e   c o nti n g e n c y t a bl e s will  b e   pr o vi d e d wit h  r at e s r el ati v e t o t h e tr e at m e nt 
m ar gi n s.  T h e   o v er all  p o siti v e  r at e s i n t h e tr e at m e nt s will  b e   a n al y z e d wit h   a  C M H  Chi -
s q u ar e t e st. 
 
4. 2. 3   E x pl or at or y  Effi c a c y  V ari a bl e s 
 
H o s pit ali z ati o n  d u e  t o  V RI or   c o m pli c ati o n t h er e of,  m ort alit y d u e  t o  V RI or   c o m pli c ati o n s 
t h er e of,  pr e s e n c e  of   a n    A RI,  h o s pit ali z ati o n  d u e   t o   A RI  or   c o m pli c ati o n s  t h er e of,  a n d  
m ort alit y  d u e  t o   A RI or   c o m pli c ati o n s  t h er e of  will   e a c h  b e   s u m m ari z e d  i n  a  t hr e e-w a y  
c o nti n g e n c y  t a bl e ( Str at u m* Tr e at m e nt* V ari a bl e) wit h   c o u nt s a n d   p er c e nt a g e s r el ati v e t o 
t h e t a bl e r o w  m ar gi n s.  P e ar s o n  c hi- s q u ar e t e st r e s ult s p er   str at u m will  b e   pr o vi d e d a s  will  
a  C M H  C hi - s q u ar e t e st of  tr e at m e nt  eff e ct s a n d   a 9 5 %   c o nfi d e n c e i nt er v al f or t h e p o ol e d  
o d d s  r ati o f or t h e N T Z   v s  pl a c e b o  gr o u p. 


St ati sti c al  A n al y si s  Pl a n  
R M 0 8 -3 0 0 7  
 
 
P a g e  1 8  of  2 4  
 
R o m ar k  I n stit ut e f or M e di c al  R e s e ar c h  
V er si o n  1. 3  
                                                A pril  2 6,  2 0 2 4  
 
 
5. 0  A n al y si s  of  S af et y   
 
5. 1   D e s cri pti o n of   S af et y  V ari a bl e s 
 
T h e   s af et y  a n al y si s  v ari a bl e s  ar e d efi n e d  a s  f oll o w s: 
•     A d v er s e  E v e nt s ( A E s). 
•     Cli ni c al  L a b or at or y  V al u e s ( H e m at ol o g y,  Bl o o d  C h e mi str y, a n d   Uri n al y si s). 
•     P h y si c al  E x a m. 
•     Vit al  Si g n s.    
 
T h e  f oll o wi n g  d e s cri b e s  t h e  s af et y  a n al y s e s  t o b e   p erf or m e d  f or t h e  st u d y.   All  s af et y 
a n al y s e s  will  b e   p erf or m e d o n  t h e  s af et y p o p ul ati o n.   
  
5. 2  D e s cri pti o n  of   S af et y A n al y s e s  
 
A d v er s e   E v e nt s  
A d v er s e  e v e nt s  will  b e   gr a d e d b y  t h e i n v e sti g at or  a c c or di n g t o t h e “ G ui d a n c e f or I n d u str y: 
T o xi cit y    Gr a di n g    S c al e  f or  H e alt h y     A d ult  a n d     A d ol e s c e nt    V ol u nt e er s    E nr oll e d  i n 
Pr e v e nti v e   V a c ci n e   Tri al s”  a s  a d a pt e d  i n t h e  St u d y  Pr ot o c ol. T h e  i n v e sti g at or will   al s o 
a s s e s s   c a u s alit y  (r el ati o n s hi p  t o  tr e at m e nt)  a s   D efi nit el y   r el at e d,    Pr o b a bl y  r el at e d, 
P o s si bl y r el at e d,  a n d  U nr el at e d.   A E s will   al s o b e   c o d e d  u si n g t h e  M e di c al  Di cti o n ar y f or 
R e g ul at or y    A cti viti e s   v er si o n  2 3   or   hi g h er    ( M e d D R A® ).       Tr e at m e nt- e m er g e nt    A E s 
( T E A E s),  d efi n e d   a s   a n y    A E  t h at  o c c ur s  aft er   a  p ati e nt   r e c ei v e s  t h e  fir st  d o s e  of   t h e 
a s si g n e d  st u d y tr e at m e nt,  will  b e   s u m m ari z e d b y  t h e  n u m b er a n d   pr o p orti o n of  p ati e nt s 
r e p orti n g at  l e a st o n e   o c c urr e n c e of  t h e  A E.  Fr e q u e n ci e s  a n d  r at e s of   e a c h  T E A E will  b e  
s u m m ari z e d  b y     M e d D R A  pr ef err e d  t er m  wit hi n   s y st e m  or g a n  cl a s s  ( S O C),  b y   s e v erit y 
gr a d e,  a n d   r el ati o n t o  tr e at m e nt f or  e a c h  tr e at m e nt  gr o u p  T h e   r at e  c al c ul ati o n will  b e  
b a s e d  o n  t h e  n u m b er of  p ati e nt s  i n t h e  S af et y  po p ul ati o n  f or t h e r el e v a nt tr e at m e nt  gr o u p. 
 
Tr e at m e nt  e m er g e nt  s eri o u s  a d v er s e  e v e nt s ( T E S A E s)  will  b e   s u m m ari z e d a n d   di s pl a y e d 
b y  fr e q u e n c y a n d  r at e b y   M e d D R A  pr ef err e d t er m wit hi n   S O C. 
 
A  b y -p ati e nt   A E d at a  li sti n g of  all   a d v er s e  e v e nt s i n cl u di n g  v er b ati m t er m,  c o d e d t er m, 
gr a d e,  a n d  r el ati o n t o  st u d y tr e at m e nt will  b e   pr o vi d e d.   
 
L a b or at or y  T e st s  
Cli ni c al  l a b or at or y  t e st s  will  b e   p erf or m e d  at  t h e  ti m e s  pr e s cri b e d  i n t h e  pr ot o c ol.  T h e  
f oll o wi n g  cli ni c al l a b or at or y t e st s will  b e   a n al y z e d:   
 


St ati sti c al  A n al y si s  Pl a n  
R M 0 8 -3 0 0 7  
 
 
P a g e  1 9  of  2 4  
 
R o m ar k  I n stit ut e f or M e di c al  R e s e ar c h  
V er si o n  1. 3  
                                                A pril  2 6,  2 0 2 4  
 
H e m at ol o g y:   
H e m o gl o bi n,   h e m at o crit,   c o m pl et e  w hit e   bl o o d    c o u nt   (t ot al  a n d    diff er e nti al), 
pl at el et    c o u nt,   r a n d o m  bl o o d    gl u c o s e,  t ot al   c h ol e st er ol,  H D L,   L D L,   a n d  
tri gl y c eri d e s. 
Cli ni c al   C h e mi str y: 
A S T,  A L T,  G G T,   al k ali n e  p h o s p h at a s e,  bilir u bi n (t ot al a n d   dir e ct),  B U N,  cr e ati ni n e, 
s o di u m,  p ot a s si u m,  a n d   c hl ori d e. 
Uri n al y si s:   
A p p e ar a n c e,  gl u c o s e,  pr ot ei n,  a n d  bl o o d . 
 
Cli ni c al l a b or at or y  r e s ult s  a n d  t h e  c h a n g e fr o m  b a s eli n e  ( C F B,  b a s eli n e d efi n e d  a s  t h e 
v al u e  at  t h e  b a s eli n e  vi sit) will  b e   s u m m ari z e d f or t h e  S af et y  po p ul ati o n  wit h   s u m m ar y 
st ati sti c s  ( m e a n,  st a n d ar d  d e vi ati o n,  n,     mi ni m u m,    m e di a n,    m a xi m u m)  b y   ti m e p oi nt  f or 
e a c h  tr e at m e nt   gr o u p.    Cli ni c al  l a b or at or y  r e s ult s  will   b e    cl a s sifi e d  a s   “ N or m al”,  or  
“ A b n or m al”; “ A b n or m al” r e s ult s will  b e  f urt h er  cl a s sifi e d b y  t h e  PI a s  “ Cli ni c all y  si g nifi c a nt” 
( C S) or  “ N ot  cli ni c all y  si g nifi c a nt” ( N C S).  Cli ni c al l a b or at or y r e s ult s will  b e   s u m m ari z e d b y  
a  s hift  t a bl e fr o m  b a s eli n e wit h   c at e g ori e s  “ N or m al”,  “ A b n or m al  ( N C S)”, a n d   “ A b n or m al 
( C S)”. 
 
All  cli ni c all y  si g nifi c a nt  a b n or m al  l a b or at or y  fi n di n g s  will   b e   r e p ort e d  a s    A E s.   All   A E s 
r e c or d e d will  b e  li st e d. 
 
P h y si c al  E x a m  
P h y si c al  e x a m s ( P E s)  will  b e   p erf or m e d a s  o utli n e d  i n t h e  pr ot o c ol.  All  cli ni c all y  si g nifi c a nt 
a b n or m al  P E  fi n di n g s will  b e  r e c or d e d a s   A E s.  All  p h y si c al  e x a m  d at a  will  b e  li st e d a s  
s h o w n  i n  A p p e n di x  B. 
 
Vit al  Si g n s  
Vit al s  si g n s  will  i n cl u d e w ei g ht,   h e art r at e, r e s pir at or y r at e, bl o o d   pr e s s ur e ( di a st oli c a n d  
s y st oli c),  a n d   t e m p er at ur e.    Vit al  si g n s  will   b e   t a k e n  a s   o utli n e d   i n  t h e  pr ot o c ol.  T h e  
b a s eli n e  vi sit  vit al  si g n s  will  b e   u s e d f or  b a s eli n e f or  c h a n g e s at  t h e W e e k   3 a n d  W e e k   6 
f oll o w-u p    vi sit s.  If  r e p e at   vit al   si g n s   ar e  t a k e n  at    a   gi v e n  ti m e  p oi nt,   t h e n  t h e  l a st 
m e a s ur e m e nt  will  b e   u s e d f or t h e  a n al y si s t a bl e s.   
 
Vit al  si g n s  a n d  C F B  will  b e   s u m m ari z e d f or t h e  saf et y   po p ul ati o n  wit h   s u m m ar y  st ati sti c s 
( m e a n,  st a n d ar d  d e vi ati o n, n,   mi ni m u m,  m e di a n,  m a xi m u m) b y  ti m e p oi nt  a n d  tr e at m e nt 
gr o u p.  All  vit al  si g n s  will  b e  li st e d. 
 
6. 0  Ot h er  R el e v a nt  D at a  A n al y s e s/ S u m m ari e s  
 
6. 1   P ati e nt  C o m pl eti o n  
 
A  t a bl e  will   b e   c o n str u ct e d  wit h   c o u nt s  a n d   p er c e nt a g e s  b y   tr e at m e nt  a s si g n m e nt  of  
s u bj e ct s’  di s p o siti o n  st at u s,  i n cl u di n g  t h e  r e a s o n  f or    wit h dr a w al  f or  all   s u bj e ct s  w h o  


St ati sti c al  A n al y si s  Pl a n  
R M 0 8 -3 0 0 7  
 
 
P a g e  2 0  of  2 4  
 
R o m ar k  I n stit ut e f or M e di c al  R e s e ar c h  
V er si o n  1. 3  
                                                A pril  2 6,  2 0 2 4  
 
wit h dr e w.  P er c e nt a g e s  will  b e   c o m p ut e d r el ati v e t o t h e  n u m b er of   s u bj e ct s r a n d o mi z e d 
t o  e a c h tr e at m e nt. 
 
6. 2  Pri or  a n d   C o n c o mit a nt  M e di c ati o n s 
 
All  pri or/ c o n c o mit a nt  m e di c ati o n s t a k e n  b y  or   a d mi ni st er e d t o  a p ati e nt  will  b e   c oll e ct e d 
fr o m  t h e  3 0    d a y s   pri or  t o  tr e at m e nt  t hr o u g h  t h e   c o m pl eti o n  of   t h e  f oll o w-u p    vi sit. 
C o n c o mit a nt  m e di c ati o n s  will  b e   c o d e d  u si n g t h e  m o st r e c e nt  v er si o n of  t h e W H O   Dr u g 
Di cti o n ar y.  A  d at a  li sti n g f or  c o n c o mit a nt  m e di c ati o n s i n cl u di n g  A T C  L e v el s I a n d  I V will  
b e   pr o vi d e d.   
 
6. 3  D e at h  R e p ort  
 
T h e   n u m b er a n d   p er c e nt a g e of  d e at h s   fr o m all   c a u s e s will  b e   c o m p ut e d b y   tr e at m e nt 
gr o u p  f or t h e  s af et y p o p ul ati o n.   All  d e at h  r e p ort d at a  will  b e  li st e d. 
 
6. 4  A d diti o n al  B a s eli n e   D at a 
 
M e di c al  hi st or y  will  b e   pr e s e nt e d i n d at a  li sti n g s f or t h e  s af et y p o p ul ati o n.   Hi st or y  e v e nt s 
will  b e   c o d e d  u si n g t h e  c urr e nt  v er si o n of   M e d D R A ( v er si o n 2 3  or  hi g h er ). 
 
6. 5   Pr ot o c ol  D e vi ati o n s 
 
T a bl e s  will  b e   c o n str u ct e d t o  s u m m ari z e  m aj or a n d   mi n or  pr ot o c ol  d e vi ati o n s b y  tr e at m e nt 
gr o u p  f or t h e  s af et y p o p ul ati o n.   All  pr ot o c ol  d e vi ati o n s  will  b e  li st e d. 
 
6. 6   Tr e at m e nt C o m pli a n c e  a n d   A d mi ni str ati o n 
 
Tr e at m e nt   c o m pli a n c e  d at a   will   b e    s u m m ari z e d  b y   tr e at m e nt   gr o u p  f or  t h e   s af et y 
p o p ul ati o n.   All tr e at m e nt  c o m pli a n c e  a n d   a d mi ni str ati o n d at a  will  b e  li st e d. 
 
 
 


St ati sti c al  A n al y si s  Pl a n  
R M 0 8 -3 0 0 7  
 
 
P a g e  2 1  of  2 4  
 
R o m ar k  I n stit ut e f or M e di c al  R e s e ar c h  
V er si o n  1. 3  
                                                A pril  2 6,  2 0 2 4  
 
7. 0  R ef er e n c e s  
F D A/ C D E R    G ui d a n c e   f or   I n d u str y:    T o xi cit y    Gr a di n g    S c al e   f or    H e alt h y    A d ult   a n d 
A d ol e s c e nt  V ol u nt e er s  E nr oll e d i n  Pr e v e nti v e  V a c ci n e  Cli ni c al  Tri al s.  U S  D e p art m e nt  of 
H e alt h   a n d    H u m a n    S er vi c e s.    S e pt e m b er   2 0 0 7.   ( R etri e v e d   2 8 A pril 2 0 2 0   fr o m 
htt p s:// w w w.f d a. g o v/ m e di a/ 7 3 6 7 9/ d o w nl o a d ). 
Y u  J,  P o w er s  J H,  V all o  D,  F all o o n  J.  E v al u ati o n  of  effi c a c y  e n d p oi nt s f or  a  p h a s e II b  st u d y 
of  a  r e s pir at or y  s y n c yti al  vir u s  v a c ci n e i n  ol d er  a d ult s  u si n g  p ati e nt-r e p ort e d  o ut c o m e s 
wit h l a b or at or y  c o nfir m ati o n.  V al u e  H e alt h  2 0 2 0;  2 3: 2 2 7 -3 5.
 


St ati sti c al  A n al y si s  Pl a n  
R M 0 8 -3 0 0 7  
 
 
P a g e  2 2  of  2 4  
 
R o m ar k  I n stit ut e f or M e di c al  R e s e ar c h  
V er si o n  1. 3  
                                                A pril  2 6,  2 0 2 4  
 
8 . 0 Li st  of  A n al y si s  T a bl e s,  Fi g ur e s  a n d  Li sti n g s  
 
 
T a bl e  N o.  
 
 
T a bl e  Titl e  
1 4. 1. 1. 1   
S u bj e ct  Di s p o siti o n  S u m m ar y  b y  Tr e at m e nt  a n d  O v er all  ( All S u bj e ct s)  
1 4. 1. 2. 1   
S u m m ar y  of  M aj or  Pr ot o c ol  D e vi ati o n s  ( S af et y P o p ul ati o n)  
1 4. 1. 2. 2   
S u m m ar y  of  Mi n or  Pr ot o c ol  D e vi ati o n s  ( S af et y P o p ul ati o n)  
1 4. 1. 3. 1   
S u m m ar y  of  D e m o gr a p hi c  C at e g ori c al  V ari a bl e s  b y  Tr e at m e nt  a n d  Str at u m  ( S af et y 
P o p ul ati o n)  
1 4. 1. 3. 2   
S u m m ar y  of  D e m o gr a p hi c  Q u a ntit ati v e  V ari a bl e s  b y  Tr e at m e nt  a n d  Str at u m  ( S af et y 
P o p ul ati o n)  
1 4. 1. 4   
S u m m ar y  of  Tr e at m e nt  C o m pli a n c e  ( S af et y P o p ul ati o n)  
1 4. 2. 1. 1   
C o c hr a n -M a nt el -H a e n s z el  T e st  R e s ult s:  C O VI D -1 9  St at u s  (I T T P o p ul ati o n)  
1 4. 2. 1. 2   
C o c hr a n -M a nt el -H a e n s z el  T e st  R e s ult s : S y m pt o m ati c  C O VI D -1 9  S u bj e ct  St at u s  wit h  
B e st -C a s e  a n d  W or st -C a s e  A n al y si s  of  Mi s si n g  D at a  (I T T P o p ul ati o n)  
1 4. 2. 1. 3   
C o c hr a n -M a nt el -H a e n s z el  T e st  R e s ult s  b y  S e x:  S y m pt o m ati c  C O VI D -1 9  S u bj e ct  St at u s  
wit h  Ti p pi n g  P oi nt  A n al y si s  of  Mi s si n g  D at a  (I T T P o p ul ati o n)  
1 4. 2. 1. 4   
C o c hr a n -M a nt el -H a e n s z el  T e st  R e s ult s  b y  S e x:  S y m pt o m ati c  C O VI D -1 9  S u bj e ct  St at u s  
(I T T P o p ul ati o n)  
1 4. 2. 1. 5  
C o c hr a n -M a nt el -H a e n s z el  T e st  R e s ult s  b y  A g e  Gr o u p:  S y m pt o m ati c  C O VI D -1 9  S u bj e ct  
St at u s  (I T T P o p ul ati o n)  
1 4. 2. 1. 6  
C o c hr a n -M a nt el -H a e n s z el  T e st  R e s ult s  b y  R a c e:  S y m pt o m ati c  C O VI D -1 9  S u bj e ct  
St at u s  (I T T P o p ul ati o n)  
1 4. 2. 1. 7  
P e ar s o n  C hi -s q u ar e  T e st  R e s ult s  b y  Str at u m:  C O VI D -1 9  St at u s  (I T T P o p ul ati o n)  
1 4. 2. 1. 8  
C o c hr a n -M a nt el -H a e n s z el  T e st  R e s ult s:  V RI  St at u s  (I T T P o p ul ati o n)  
1 4. 2. 1. 9  
C o c hr a n -M a nt el -H a e n s z el  T e st  R e s ult s : S y m pt o m ati c  V RI  S u bj e ct  St at u s  wit h  B e st -
C a s e  a n d  W or st -C a s e  A n al y si s  of  Mi s si n g  D at a  (I T T P o p ul ati o n)  
1 4. 2. 1. 1 0   
C o c hr a n -M a nt el -H a e n s z el  T e st  R e s ult s:  S y m pt o m ati c  V RI  S u bj e ct  St at u s  wit h  Ti p pi n g  
P oi nt  A n al y si s  of  Mi s si n g  D at a  (I T T P o p ul ati o n)  
1 4. 2. 1. 1 1   
C o c hr a n -M a nt el -H a e n s z el  T e st  R e s ult s  b y  S e x:  S y m pt o m ati c  V RI  S u bj e ct  St at u s  (I T T 
P o p ul ati o n)  
1 4. 2. 1. 1 2   
C o c hr a n -M a nt el -H a e n s z el  T e st  R e s ult s  b y  A g e  Gr o u p:  S y m pt o m ati c  V RI  S u bj e ct  St at u s  
(I T T P o p ul ati o n)  
1 4. 2. 1. 1 3   
C o c hr a n -M a nt el -H a e n s z el  T e st  R e s ult s  b y  R a c e:  S y m pt o m ati c  V RI  S u bj e ct  St at u s  (I T T 
P o p ul ati o n)  
1 4. 2. 1. 1 4   
P e ar s o n  C hi -s q u ar e  T e st  R e s ult s  b y  Str at u m:  V RI  St at u s  (I T T P o p ul ati o n)  


St ati sti c al  A n al y si s  Pl a n  
R M 0 8 -3 0 0 7  
 
 
P a g e  2 3  of  2 4  
 
R o m ar k  I n stit ut e f or M e di c al  R e s e ar c h  
V er si o n  1. 3  
                                                A pril  2 6,  2 0 2 4  
 
 
T a bl e  N o.  
 
 
T a bl e  Titl e  
1 4. 2. 2. 1  
C o c hr a n -M a nt el -H a e n s z el  T e st  R e s ult s:  C O VI D -1 9  R el at e d  M ort alit y  St at u s  (I T T 
P o p ul ati o n)  
1 4. 2. 2. 2  
P e ar s o n  C hi -s q u ar e  T e st  R e s ult s  b y  Str at u m : C O VI D -1 9  R el at e d  M ort alit y  St at u s  (I T T 
P o p ul ati o n)  
1 4. 2. 3. 1  
C o c hr a n -M a nt el -H a e n s z el  T e st  R e s ult s:  C O VI D -1 9  A nti b o d y  T e st  St at u s  (I T T 
P o p ul ati o n)  
1 4. 2. 3. 2  
P e ar s o n  C hi -s q u ar e  T e st  R e s ult s  b y  Str at u m:  C O VI D -1 9  A nti b o d y  T e st  St at u s  (I T T 
P o p ul ati o n)  
1 4. 2. 3. 3  
C o c hr a n -M a nt el -H a e n s z el  T e st  R e s ult s:  V RI  R el at e d  H o s pit ali z ati o n  St at u s  (I T T 
P o p ul ati o n)  
1 4. 2. 3. 4   
P e ar s o n  C hi -s q u ar e  T e st  R e s ult s  b y  Str at u m:  V RI  R el at e d  H o s pit ali z ati o n  St at u s  (I T T 
P o p ul ati o n  
1 4. 2. 3. 5   
C o c hr a n -M a nt el -H a e n s z el  T e st  R e s ult s:  V RI  R el at e d  M ort alit y  St at u s  (I T T P o p ul ati o n)  
1 4. 2. 3. 6   
P e ar s o n  C hi -s q u ar e  T e st  R e s ult s  b y  Str at u m:  V RI  R el at e d  M ort alit y  St at u s  (I T T 
P o p ul ati o n)  
1 4. 2 . 3. 7  
C o c hr a n -M a nt el -H a e n s z el  T e st  R e s ult s:  A RI  I n ci d e n c e St at u s  (I T T P o p ul ati o n)  
1 4. 2. 3. 8   
P e ar s o n  C hi -s q u ar e  T e st  R e s ult s  b y  Str at u m:  A RI  I n ci d e n c e St at u s  (I T T P o p ul ati o n)  
1 4. 2. 3. 9   
C o c hr a n -M a nt el -H a e n s z el  T e st  R e s ult s:  A RI  R el at e d  H o s pit ali z ati o n  St at u s  (I T T 
P o p ul ati o n)  
1 4. 2. 3. 1 0   
P e ar s o n  C hi -s q u ar e  T e st  R e s ult s  b y  Str at u m:  A RI  R el at e d  H o s pit ali z ati o n  St at u s  (I T T 
P o p ul ati o n)  
1 4. 2. 3. 1 1   
C o c hr a n -M a nt el -H a e n s z el  T e st  R e s ult s:  A RI  R el at e d  M ort alit y  St at u s  (I T T P o p ul ati o n)  
1 4. 2. 3. 1 2   
P e ar s o n  C hi -s q u ar e  T e st  R e s ult s  b y  Str at u m:  A RI  R el at e d  M ort alit y  St at u s  (I T T 
P o p ul ati o n)  
1 4. 3. 1. 1   
Tr e at m e nt  E m er g e nt  A d v er s e  E v e nt s  S u m m ar y:  T ot al  A E,  T o xi cit y  Gr a d e,  R el ati o n s hi p  
t o Tr e at m e nt,  S eri o u s  A E s  b y  Tr e at m e nt  ( S af et y P o p ul ati o n)  
1 4. 3. 1. 2   
Tr e at m e nt  E m er g e nt  A d v er s e  E v e nt s  b y  S y st e m  Or g a n  Cl a s s,  Pr ef err e d  T er m,  a n d  
Tr e at m e nt  ( S af et y P o p ul ati o n)  
1 4. 3. 1. 3   
Tr e at m e nt  E m er g e nt  A d v er s e  E v e nt s  b y  S y st e m  Or g a n  Cl a s s,  Pr ef err e d  T er m,  
Tr e at m e nt,  a n d  T o xi cit y  Gr a d e  ( S af et y P o p ul ati o n)  
1 4. 3. 1. 4   
Tr e at m e nt  E m er g e nt  A d v er s e  E v e nt s  b y  S y st e m  Or g a n  Cl a s s,  Pr ef err e d  T er m,  
Tr e at m e nt,  a n d  R el ati o n s hi p  t o Tr e at m e nt  ( S af et y P o p ul ati o n)  
1 4. 3. 1. 5   
Tr e at m e nt  E m er g e nt  S eri o u s  A d v er s e  E v e nt s  b y  S y st e m  Or g a n  Cl a s s,  Pr ef err e d  T er m,  
a n d  Tr e at m e nt  ( S af et y P o p ul ati o n)  
1 4. 3. 2. 1   
Cli ni c al  L a b or at or y  S u m m ar y  St ati sti c s:  H e m at ol o g y  ( S af et y P o p ul ati o n)  


St ati sti c al  A n al y si s  Pl a n  
R M 0 8 -3 0 0 7  
 
 
P a g e  2 4  of  2 4  
 
R o m ar k  I n stit ut e f or M e di c al  R e s e ar c h  
V er si o n  1. 3  
                                                A pril  2 6,  2 0 2 4  
 
 
T a bl e  N o.  
 
 
T a bl e  Titl e  
1 4. 3. 2 . 2  
Cli ni c al  L a b or at or y  S hift  T a bl e s:  H e m at ol o g y  ( S af et y P o p ul ati o n)  
1 4. 3. 3. 1   
Cli ni c al  L a b or at or y  S u m m ar y  St ati sti c s:  Cli ni c al  C h e mi str y  ( S af et y P o p ul ati o n)  
1 4. 3. 3. 2   
Cli ni c al  L a b or at or y  S hift  T a bl e s:  Cli ni c al  C h e mi str y  ( S af et y P o p ul ati o n)  
1 4. 3. 4. 1   
Cli ni c al  L a b or at or y  S u m m ar y  St ati sti c s:  Uri n al y si s  ( S af et y P o p ul ati o n)  
1 4. 3. 4. 2   
Cli ni c al  L a b or at or y  S hift  T a bl e s:  Uri n al y si s  ( S af et y P o p ul ati o n)  
1 4. 3. 5. 1   
Vit al  Si g n s  S u m m ar y  St ati sti c s  ( S af et y P o p ul ati o n)  
 
 
Li sti n g  N o.  
 
 
D at a  Li sti n g  Titl e  
1 6. 2 . 1  
S u bj e ct  Di s p o siti o n  Li sti n g  ( All r e c or d s) 
1 6. 2. 2   
Pr ot o c ol  D e vi ati o n s  Li sti n g  ( S af et y P o p ul ati o n)  
1 6. 2. 3   
P ati e nt s  E x cl u d e d  fr o m t h e Effi c a c y  A n al y si s  ( S af et y P o p ul ati o n)  
1 6. 2. 4. 1   
S u bj e ct  D e m o gr a p hi c s  Li sti n g  ( S af et y P o p ul ati o n)  
1 6. 2. 4. 2  
M e di c al  Hi st or y  Li sti n g  ( S af et y P o p ul ati o n)  
1 6. 2. 4. 3  
C o n c o mit a nt  M e di c ati o n s  Li sti n g  ( S af et y P o p ul ati o n)  
1 6. 2. 5. 1   
Tr e at m e nt  C o m pli a n c e  Li sti n g  ( S af et y P o p ul ati o n)  
1 6. 2. 5. 2   
Dr u g  C o n c e ntr ati o n  D at a  Li sti n g  ( S af et y P o p ul ati o n)  
1 6. 2. 6. 1   
S u bj e ct  Pri m ar y  Effi c a c y  V ari a bl e s  Li sti n g:  C O VI D -1 9  St at u s,  V RI  St at u s  ( S af et y 
P o p ul ati o n)  
1 6. 2. 6. 2   
S u bj e ct  S e c o n d ar y  Effi c a c y  V ari a bl e s  Li sti n g:  A RI  St at u s,  H o s pit ali z ati o n  St at u s  
( S af et y P o p ul ati o n)  
1 6. 2. 6. 3   
S A R S -C o V - 2 A nti b o d y  St at u s  ( S af et y P o p ul ati o n)  
1 6. 2. 7 . 1  
A d v er s e  E v e nt s  Li sti n g  ( S af et y P o p ul ati o n)  
1 6. 2. 7. 2   
S u bj e ct  D e at h s  Li sti n g  ( S af et y P o p ul ati o n)  
1 6. 2. 8. 1   
H e m at ol o g y  Li sti n g  ( S af et y P o p ul ati o n)  
1 6. 2. 8. 2   
Cli ni c al  C h e mi str y  Li sti n g  ( S af et y P o p ul ati o n)  
1 6. 2. 8. 3   
Uri n al y si s  Li sti n g  ( S af et y P o p ul ati o n)  
1 6. 2. 9. 1   
P h y si c al  E x a mi n ati o n  Li sti n g  ( S af et y P o p ul ati o n)  
1 6. 2. 9. 2   
Vit al  Si g n s  Li sti n g  ( S af et y P o p ul ati o n)