Clinical trial NCT04486313
Conditions: COVID-19
Sponsor: Romark Laboratories L.C.
Start date: 2020-08-13; Completion date: 2021-02-08
Enrollment: 935 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Trial to Evaluate Efficacy and Safety of Nitazoxanide in the Treatment of Mild or Moderate COVID-19

Detailed description:
Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate Efficacy and Safety of Nitazoxanide in the Treatment of Mild or Moderate COVID-19

Arms: arm 1: Two nitazoxanide 300 mg tablets orally twice daily for 5 days arm 2: Two placebo tablets orally twice daily for 5 days
Interventions: intervention 1: Nitazoxanide intervention 2: Placebo intervention 3: Vitamin Super B-Complex
Intervention descriptions: intervention 1: Two nitazoxanide 300 mg tablets administered orally twice daily with food for 5 days intervention 2: Two placebo tablets administered orally twice daily with food for 5 days intervention 3: Vitamin Super B-Complex administered orally twice daily to maintain the blind

Protocol documents:
Prot_000.pdf: 


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CONFIDENTIAL 
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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TABLE OF CONTENTS 
STATEMENT OF COMPLIANCE .................................................................................................1 
INVESTIGATOR’S AGREEMENT ...............................................................................................2 
TABLE OF CONTENTS .................................................................................................................3 
1. 
PROTOCOL SUMMARY ............................................................................................6 
1.1. 
Synopsis ........................................................................................................................6 
1.2. 
Schedule of Assessments ............................................................................................10 
2. 
INTRODUCTION ......................................................................................................11 
2.1. 
Coronavirus Disease 2019 (COVID-19) ....................................................................11 
2.2. 
Nitazoxanide (NTZ) ....................................................................................................11 
2.2.1. 
NTZ Inhibits Viral Replication and Cytokine Secretion ............................................11 
2.2.2. 
Pharmacokinetics of NTZ in Humans ........................................................................13 
2.2.3. 
Overview of Clinical Experience with NTZ ...............................................................14 
2.2.4. 
Clinical Experience with NTZ in Treatment of Coronaviruses ..................................14 
2.3. 
Rationale for the Study ...............................................................................................15 
3. 
STUDY OBJECTIVES ..............................................................................................15 
4. 
STUDY DESIGN .......................................................................................................16 
4.1. 
Study Design Overview ..............................................................................................16 
4.2. 
Rationale for Important Issues in the Study Design ...................................................17 
4.2.1. 
Choice of NTZ Dose and Duration of Treatment .......................................................17 
4.2.2. 
Choice of Duration of Follow Up ...............................................................................17 
4.2.3. 
Choice of Control Group ............................................................................................17 
4.2.4. 
Choice of Patient Population ......................................................................................17 
4.2.5. 
Use of Vitamin B Complex Supplement ....................................................................19 
4.2.6. 
Choice of Patient-Reported Outcome Instrument .......................................................19 
4.2.7. 
Choice of Primary Endpoint .......................................................................................20 
5. 
STUDY POPULATION .............................................................................................20 
5.1. 
Inclusion Criteria ........................................................................................................20 
5.2. 
Exclusion Criteria .......................................................................................................21 
5.3. 
Study Population Diversity .........................................................................................22 
6. 
STUDY INTERVENTION ........................................................................................22 
6.1. 
Study Intervention(s) Administration .........................................................................22 


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6.1.1. 
Study Intervention Description ...................................................................................22 
6.1.2. 
Dosing and Administration .........................................................................................22 
6.2. 
Preparation, Handling, Storage and Accountability ...................................................23 
6.2.1. 
Acquisition and Accountability ..................................................................................23 
6.2.2. 
Packaging and Labeling ..............................................................................................23 
6.3. 
Randomization and Blinding ......................................................................................23 
6.4. 
Study Intervention Compliance ..................................................................................24 
6.5. 
Concomitant Therapy .................................................................................................24 
7. 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION ...............................................................................................24 
8. 
STUDY PROCEDURES ............................................................................................25 
8.1. 
Visit Procedures ..........................................................................................................25 
8.1.1. 
Informed Consent .......................................................................................................25 
8.1.2. 
Medical History ..........................................................................................................26 
8.1.3. 
Physical Examination .................................................................................................26 
8.1.4. 
Body Measurements and Resting Vital Signs ............................................................26 
8.1.5. 
Screening FLU-PRO ...................................................................................................26 
8.1.6. 
Randomization and Dispensing Study Medication .....................................................27 
8.1.7. 
Subject Instructions ....................................................................................................27 
8.1.8. 
Day 2-7 Subject Contact .............................................................................................28 
8.2. 
Laboratory Assessments .............................................................................................28 
8.2.1. 
Assessments in the Clinic ...........................................................................................28 
8.2.2. 
Central Laboratory Assessments ................................................................................28 
8.2.3. 
Pharmacokinetics Assessments ..................................................................................29 
8.2.4. 
Plan for Monitoring Viral Resistance .........................................................................29 
8.3. 
Subject Diary ..............................................................................................................29 
8.3.1. 
Subject Diary Completion ..........................................................................................29 
8.3.2. 
Subject Diary Compliance Monitoring .......................................................................30 
8.4. 
Adverse Events and Serious Adverse Events .............................................................30 
8.4.1. 
Definitions ..................................................................................................................30 
8.4.2. 
Recording and Follow Up of Adverse Events ............................................................31 
8.4.3. 
Reporting Requirement ...............................................................................................31 
8.4.4. 
Management of Subjects Requiring Hospitalization ..................................................32 


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8.4.5. 
Medication Errors .......................................................................................................32 
9. 
STATISTICAL CONSIDERATIONS .......................................................................32 
9.1. 
Sample Size Determination ........................................................................................32 
9.2. 
Efficacy Variables ......................................................................................................33 
9.3. 
Response Definitions ..................................................................................................34 
9.4. 
Statistical Methodology ..............................................................................................34 
9.4.1. 
Efficacy Analyses .......................................................................................................34 
9.4.2. 
Population Pharmacokinetics Analysis .......................................................................35 
9.4.3. 
Safety Analyses ..........................................................................................................35 
10. 
OPERATIONAL CONSIDERATIONS .....................................................................36 
10.1. 
Regulatory, Ethical and Study Oversight Considerations ..........................................36 
10.1.1. 
Ethics ..........................................................................................................................36 
10.1.2. 
Investigator Responsibilities .......................................................................................36 
10.1.3. 
Quality Assurance and Quality Control ......................................................................37 
10.1.4. 
Safety Oversight .........................................................................................................37 
10.1.5. 
Data Handling and Record Keeping ...........................................................................37 
10.1.6. 
Clinical Monitoring ....................................................................................................38 
10.1.7. 
Protocol Deviations ....................................................................................................38 
10.1.8. 
Study Discontinuation and Closure ............................................................................38 
10.1.9. 
Data and Report Requirements ...................................................................................38 
10.1.10. 
Confidentiality and Privacy ........................................................................................39 
10.1.11. 
Publication and Data Sharing .....................................................................................39 
10.1.12. 
Key Roles and Study Governance ..............................................................................39 
11. 
REFERENCES ...........................................................................................................40 
APPENDIX 1. PROTOCOL REVISION HISTORY .................................................................43 
APPENDIX 2. CONTACT INFORMATION ............................................................................49 
APPENDIX 3. LIST OF ESSENTIAL DOCUMENTS FOR THE SITE ..................................50 
APPENDIX 4. TOXICITY GRADING TABLES .....................................................................52 
APPENDIX 5. FLU-PRO DOMAIN/SUBDOMAIN STRUCTURE ........................................59 
 
 
 
 


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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Title of Study: 
A Phase 3, Randomized, Double-Blind, Placebo Controlled Trial to 
Evaluate the Efficacy and Safety of Nitazoxanide in the Treatment of Mild 
or Moderate COVID-19 
Name of Test Drug: 
Nitazoxanide 300 mg Tablets 
Name of Active Ingredient: Nitazoxanide 
Study Sponsor: 
The Romark Institute for Medical Research 
IND Number: 
149,166 
STUDY DETAILS 
Anticipated Study Period: 
July 2020 – January 2021 
Protocol & Amendments: 
Original Protocol, version 1.0: July 14, 2020 
Amendment 1, version 2.0: July 23, 2020 
Amendment 2, version 3.0: September 16, 2020 
Amendment 3, version 4.0: January 11, 2021 
Investigators: 
Multiple in the US. 
OBJECTIVES 
Primary Objective: 
To evaluate the effect of NTZ in reducing the time to Sustained Response 
compared to placebo in subjects with mild or moderate COVID-19 
Secondary Objectives: 
To evaluate the effect of NTZ in reducing the rate of progression to Severe 
COVID-19 Illness compared to placebo 
Exploratory Objectives: To evaluate: 
i. 
The proportion of subjects positive for SARS-CoV-2 by Aptima® SARS-CoV-
2 Assay  at each of Days 4 and 10 
ii. The change from baseline in quantitative SARS-CoV-2 RNA measured by 
RT-PCR at each of Days 4 and 10 
iii. The effect of NTZ in reducing the rate of hospitalization compared to placebo 
iv. The effect of NTZ in reducing the rate of mortality compared to placebo 
Safety Objectives: 
Safety will be assessed by analysis of adverse events. 
METHODOLOGY 
Study Design: 
Multicenter, randomized, double-blind trial  


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Treatments: 
Subjects will be randomized 1:1 to one of the following groups:  
Group 1 (NTZ): 
Two NTZ 300 mg tablets b.i.d. for 5 days 
administered orally with food. 
Group 2 (Placebo): Two placebo tablets b.i.d. for 5 days administered 
orally with food. 
Study Duration: 
Subjects will receive 2 tablets b.i.d. for 5 days (10 doses). The follow up 
period will extend through the end of study visit at study Day 28. 
SUBJECT POPULATION 
Number of Subjects Planned:  At least 350 up to 400 subjects with laboratory-confirmed SARS-CoV-2-
infection. This may require enrollment of up to 800 total subjects. 
Inclusion Criteria: 
1. Male or female at least 12 years of age 
2. [Criterion removed in protocol amendment 2. See Appendix 1 for revision history.] 
3. Presence of clinical signs and/or symptoms consistent with worsening or stable mild or moderate 
COVID-19 (one of the following is required): 
a. Presence of at least two respiratory symptom domains (head, throat, nose, chest, cough) with a 
score of ≥2 as determined by Screening FLU-PRO OR  
b. Presence of at least one respiratory symptom domain (head, throat, nose, chest, cough) with a 
score of ≥2 as determined by Screening FLU-PRO with pulse rate ≥90 OR  
c. Presence of at least one respiratory symptom domain (head, throat, nose, chest, cough) with a 
score of ≥2 as determined by Screening FLU-PRO with respiratory rate ≥16 
AND patient reported assessment that symptoms are present, the symptoms are not consistent with the 
subject’s usual health, the symptoms interfere with daily activities, and the symptoms have worsened 
or remained the same relative to the previous day, as confirmed by responses to questions in the 
Screening FLU-PRO. 
4. Onset of symptoms no more than 72 hours before enrollment in the trial. Onset of symptoms is 
defined as the earlier of the first time at which the subject experienced subjective fever or any 
respiratory symptom (headache/head congestion, throat symptoms, nasal symptoms, chest 
symptoms, cough). 
5. Willing and able to provide written informed consent (including assent by legal guardian if under 
18 years of age) and comply with the requirements of the protocol, including completion of the 
subject diary and all protocol procedures. 
Exclusion Criteria: 
1. Persons with any clinical sign or symptoms suggestive of severe systemic illness with COVID-19, 
including the following: 
a. shortness of breath at rest,  
b. resting pulse ≥125 beats per minute,  
c. resting respiratory rate ≥30 breaths per minute, or 
d. SpO2 ≤ 93% on room air at sea level. 


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2. Subjects who experienced a previous episode of acute upper respiratory tract infection, otitis, 
bronchitis or sinusitis or received antibiotics for these conditions within two weeks prior to and 
including study day 1. 
3. Severely immunodeficient persons including: 
a. Subjects with immunologic disorders or receiving immunosuppressive therapy (e.g., for organ 
or bone marrow transplants, immunomodulatory therapies for certain autoimmune diseases) 
b. Subjects with untreated HIV infection or treated HIV infection with a CD4 count below 350 
cells/mm3 in the last six months 
c. Subjects actively undergoing systemic chemotherapy or radiotherapy treatment for 
malignancy 
d. Subjects using steroids as maintenance therapy for a chronic condition 
4. Subjects with active respiratory allergies or subjects expected to require anti-allergy medications 
during the study period for respiratory allergies. 
5. Females of childbearing potential who are either pregnant or sexually active without the use of 
birth control.   
6. Subjects with a history of COVID-19 or known to have developed anti-SARS-CoV-2 antibodies. 
7. Subjects residing in the same household with another subject participating in the study. 
8. 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. 
9. Receipt of any dose of NTZ within seven days prior to screening. 
10. Known sensitivity to NTZ or any of the excipients comprising the study medication. 
11. Subjects unable to swallow oral tablets or capsules. 
12. Subjects with known severe heart, lung, neurological or other systemic disease that the 
Investigator believes could preclude safe participation. 
13. Subjects likely or expected to require hospitalization unrelated to COVID-19 during the study 
period. 
14. Subjects taking medications considered to be major CYP2C8 substrates. Refer to Table 5 in 
Section 6.5. 
15. 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. 
ASSESSMENTS 
Efficacy: 
 Subjects will complete a diary recording oral temperature twice daily and the FLU-PRO© 
patient reported outcomes instrument once daily in the evening for 21 days for efficacy 
evaluation.  
 Subjects will be contacted daily by site staff on study days 2-7 to screen for progression to 
severe illness or other complications. 


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Virology: Nasopharyngeal swab samples will be collected on each of study Days 1, 4, and 10 for analysis 
of virology endpoints. 
Safety: The safety of study drug administration will be monitored by assessment of adverse events from 
baseline through the Day 28 study exit, clinical laboratory testing at baseline and on Day 10, physical 
examinations and vital signs assessments at screening, Day 10 and Day 22 and telephone monitoring/at 
home visits during Day 2 through Day 7 and Day 28. 
Pharmacokinetics: On the morning of Day 4 prior to dosing, trough plasma samples will be collected.  
 


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1.2. 
Schedule of Assessments 
Table 1: 
Schedule of Assessments 
Assessment 
Screening 
Baseline 
Treatment 
Period 
Diary 
Period 
Follow-Up Visits 
Unscheduled  
Day 1 
Day 1 
Day 2-7 
Day 1-21 
Day 4±1 
Day 10±3 
Day 22+3 
Day 28+3 
As Needed 
Signed informed consent/assent1 
X 
 
 
 
 
 
 
 
 
Demographics, smoking & medical history2 
X 
 
 
 
 
 
 
 
 
Urine pregnancy test7 
X 
 
 
 
 
 
 
 
 
Physical examination3 
X 
 
 
 
X4 
X4 
X4 
 
X4 
Body weight and resting vital signs5 
X 
 
 
 
X 
X 
X 
 
X 
Complete Screening FLU-PRO6 
X 
 
 
 
 
 
 
 
 
Evaluate eligibility7 
X 
 
 
 
 
 
 
 
 
Collect nasopharyngeal swabs8 
 
X 
 
 
X 
X 
 
 
 
Collect blood sample for lab safety tests8 
 
X 
 
 
 
 
X 
 
X 
Collect blood sample for antibody tests8 
 
X 
 
 
 
 
X 
 
 
Collect blood sample for pharmacokinetics8 
 
 
 
 
X 
 
 
 
 
Collect urine sample for routine urinalysis8 
 
X 
 
 
 
 
X 
 
X 
Record concomitant medications 
 
X 
 
 
X 
X 
X 
 
X 
Randomize & dispense study medication9 
 
X 
 
 
 
 
 
 
 
First dose and practice diary in-office9,10 
 
X 
 
 
 
 
 
 
 
Review/record adverse events11 
 
X 
 
 
X 
X 
X 
 
X 
Instructions re: dosing, concomitant medications, diary 
completion, follow-up visits, and emergency care12 
 
X 
X 
 
X 
X 
X 
 
X 
Contact subject to screen for complications 
 
 
X13 
 
 
 
 
X14 
 
Complete diary (subject responsibility)10 
 
 
 
X 
 
 
 
 
 
Review subject diary entries (site responsibility)15 
 
 
 
X 
 
 
 
 
 
1 See Section 8.1.1 
2 See Section 8.1.2 
3 See Section 8.1.3 
4 Completed as necessary, see Section 8.1.3 
5 See Section 8.1.4 
6 See Section 8.1.5 
7 See Section 5.0 
 
8 See Section 8.2 
9 See Section 8.1.6 
10 See Section 8.3.1 
11 See Section 8.4 
12 See Section 8.1.7 
13 See Section 8.1.8  
14 See Section 8.1.9 
 15 See Section 8.3.2 


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2. 
INTRODUCTION 
2.1. 
Coronavirus Disease 2019 (COVID-19) 
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel betacoronavirus, was 
isolated in December 2019 from patients presenting with unidentified viral pneumonia (Zhu et al. 
2020). As of early June 2020, the virus resulted in more than 7 million infections and nearly 
500,000 deaths worldwide (Johns Hopkins Coronavirus Resource Center 2020).  
Infection with SARS-CoV-2 produces illness known as Coronavirus Disease 2019 or “COVID-
19”. Commonly reported symptoms include fever, chills, cough, shortness of breath, difficulty 
breathing, fatigue, muscle or body aches, headache, new loss of taste or smell, sore throat, 
congestion or runny nose, nausea, vomiting, and diarrhea (U.S. CDC 2020a). The severity of 
illness ranges from mild and self-limited to very severe or fatal, with the current U.S. 
hospitalization rate of 82 per 100,000 cases and 255 per 100,000 in those over 65 years of age 
(U.S. CDC 2020b). 
Seroprevalence studies conducted in U.S. metropolitan areas have estimated between 5% and 14% 
population-level exposure to SARS-CoV-2, indicating that a significant proportion of the 
population is still at risk for a first infection (Sood et al. 2020, Goldberg 2020). Continued social 
distancing and “safer at home” measures aimed at reducing transmission of the virus has resulted 
in record unemployment in the U.S., and the SARS-CoV-2 pandemic is expected to result in a 
more than 10% reduction in U.S. domestic GDP in 2020 (OECD 2020). 
Remdesivir for intravenous administration has received emergency use authorization in the U.S. 
for hospitalized patients with COVID-19, but no antiviral has been authorized or approved for 
mild or moderate illness. 
2.2. 
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). 
2.2.1. 
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, HCoV-229E, HCoV-OC43, HCoV-NL63, 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 


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(HIV) (Rossignol 2014, Rossignol 2016, Wang et al. 2020, Piacentini et al. 2018, Romark data on 
file).  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 viral respiratory infections (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 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. 


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2.2.2. 
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 
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 


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Table 3: 
Summary of Tizoxanide and Tizoxanide Glucuronide Trough Plasma 
Concentrations (µg/mL) by Study Day 
Analyte 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Tizoxanide 
0.709 
(139) 
1.55 
(100) 
2.36 
(101) 
3.24 
(100) 
3.80 
(146) 
3.26 
(119) 
3.02  
(99) 
Tizoxanide 
Glucuronide 
1.39  
(61) 
3.68  
(72) 
4.38 
(73) 
5.35 
(77) 
5.83 
(99) 
5.94 
(91) 
5.65 
(69) 
 
2.2.3. 
Overview of Clinical Experience with NTZ 
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, 
2,659 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 (NT-300 Investigators Brochure-COVID/VRI). 
2.2.4. 
Clinical Experience with NTZ in Treatment of Coronaviruses 
Fifty-two (52) coronavirus-infected subjects meeting the criteria proposed by this protocol were 
enrolled in study RM08-3004, a study of NTZ in the treatment of influenza. The FLU-PRO 
instrument was administered daily for 21 days. The NTZ group experienced a treatment benefit of 
101 hours at the median in Time to Sustained Response [Median (IQR): 101.3 (58-250) for the 
NTZ group and 201.8 (117->504) for the placebo group, p=0.0932]. See Figure 1 for Kaplan-
Meier curves of Time to Sustained Response for this population. 




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Safety Objectives: 
Safety will be assessed by analysis of adverse events. 
4. 
STUDY DESIGN 
4.1. 
Study Design Overview 
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 five days compared 
to a placebo for the treatment of mild or moderate COVID-19. 
Subjects will be stratified according to the following criteria: 
Severity of COVID-19 Illness: 
• 
Mild illness defined as baseline assessments of (1) at 
least one respiratory domain* with a baseline score 
≥2 and (2) resting pulse <90 beats per minute and (3) 
resting respiratory rate <20 breaths per minute. 
• 
Moderate illness defined as baseline assessments of 
(1) at least one respiratory domain* with a baseline 
score ≥2 and either (2) resting pulse ≥90 beats per 
minute or (3) resting respiratory rate ≥20 breaths per 
minute. 
* For this purpose, respiratory domains shall include the 
following 5 FLU-PRO domains/subdomains: chest, cough, 
nose, throat and head. 
Time from onset of symptoms to  
randomization:  
<36 hours/≥36 hours 
Risk of severe illness (per CDC):  
• 
At Increased Risk: Subjects with COPD, Type 2 
diabetes mellitus, obesity (BMI ≥30), chronic kidney 
disease, sickle cell disease, serious heart conditions 
(such as heart failure, coronary artery disease, or 
cardiomyopathies), asthma (moderate or severe), 
cerebrovascular disease, cystic fibrosis, hypertension 
or high blood pressure, immunocompromised state 
(due to immune deficiencies, HIV, use of 
corticosteroids, or use of other immune-weakening 
medications), neurologic conditions (e.g., dementia), 
liver disease, pulmonary fibrosis, past or present 
history of smoking, thalassemia, or type 1 diabetes 
mellitus. Subjects who are ≥65 years of age. 
• 
Not At Increased Risk: Subjects with none of the 
above conditions 
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 5 days 


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• Group 2 (Placebo): 
Two placebo tablets b.i.d. for 5 days 
The study is expected to take place from July 2020 through January 2021. 
We expect that a large number of subjects enrolled will be positive for Enterovirus/Rhinovirus 
(EV/RV). Efficacy and safety data for subjects who are positive for EV/RV at Baseline will be 
analyzed as part of concurrently enrolling study RM08-3009. 
4.2. 
Rationale for Important Issues in the Study Design 
4.2.1. 
Choice of NTZ Dose and Duration of Treatment 
The dose of NTZ used for this clinical trial (600 mg b.i.d. for 5 days) has been associated with 
reductions in durations of illness in subjects infected with influenza, Enterovirus/Rhinovirus, and 
coronavirus. Dose-range-finding study RM08-3001 in subjects with influenza infection 
demonstrated a dose-dependent efficacy response with a 300 mg b.i.d. group demonstrating a non-
significant improvement over placebo. 
In clinical trials involving 2,659 subjects, adverse events reported by subjects receiving 600 mg 
NTZ b.i.d. for 5 days were similar to those of subjects receiving the placebo, with the exception 
of a higher rate of chromaturia (10.8% compared to 0.8% for the placebo). Studies of NTZ at 
higher doses have shown dose-dependent increases in the frequency of reported diarrhea and other 
gastrointestinal side effects, therefore no higher dose is planned for this study. 
SARS-CoV-2 virus titer is believed to peak between the onset of symptoms and symptomatic day 
4 and is not able to be cultured after seven days of symptoms (Wölfel et al. 2020). Antiviral 
treatment will have a reduced magnitude of treatment benefit when the host immune response is 
effectively decreasing the infectious viral load. Further, a study of remdesivir comparing 5- and 
10-day courses of treatment found no difference between the two in patients with severe COVID-
19 (Goldman et al. 2020). Therefore, it is unlikely that a course of treatment beyond five days will 
confer any significant additional benefit.   
4.2.2. 
Choice of Duration of Follow Up 
A 28-day (+3 days) study duration is proposed, including five days on treatment and approximately 
23 days of safety and symptom follow-up. As previously described, SARS-CoV-2 virus titer is 
believed to peak between the onset of symptoms and symptomatic day 4 and is not able to be 
cultured after seven days of symptoms (Wölfel et al. 2020). Further, onset of Acute Respiratory 
Distress Syndrome (ARDS) in patients infected with SARS-CoV-2 is approximately 8-12 days (Li 
and Ma 2020). Therefore, 28 days is expected to be a sufficient period of time to capture resolution 
of viral shedding and any hospitalizations or severe complications of illness. Any adverse events 
ongoing at the time of the Day 28 visit will be followed to resolution. 
4.2.3. 
Choice of Control Group 
A placebo control is appropriate for the study due to lack of any approved active control. 
4.2.4. 
Choice of Patient Population 
The population to be studied includes adults and adolescents with mild or moderate illness 
consistent with SARS-CoV-2 infection. Because there are no approved antivirals for the treatment 


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of mild or moderate COVID-19 in outpatients, subjects will not be prevented from being 
prescribed rescue medication for complications if warranted. Therefore, participation in the study 
will not pose unreasonable risk to any eligible subject. Discussion of specific eligibility criteria is 
presented below. 
4.2.4.1. 
Choice of Signs and Symptoms Required for Inclusion 
Data from studies RM08-3004 and RM08-3005 indicate that, in subjects infected with influenza, 
EV/RV or seasonal coronavirus, subjects with low symptom scores for the head, throat, nose, chest 
and cough symptom domains in the absence of elevated pulse or respiratory rate, illness may be 
expected to resolve quickly. These subjects have less opportunity to benefit from antiviral 
treatment. Further, subjects who indicate that symptoms are already improving are also unlikely 
to benefit from treatment. Therefore, subjects will be required to have a score of ≥2 for two 
respiratory symptom domains (head, throat, nose, chest, or cough) or a score of ≥2 for one 
respiratory symptom domain in the presence of elevated vital signs (pulse ≥90 beats per minute or 
respiratory rate ≥16 breaths per minute). Subjects will be excluded if they report having no 
symptoms (global assessment), being at their usual health, that their symptoms do not interfere 
with their usual activities, or that their symptoms have improved since yesterday. Subjects 
presenting with signs or symptoms consistent with severe COVID-19 (resting shortness of breath, 
resting pulse ≥125, resting respiratory rate ≥30) will also be excluded from the study. 
4.2.4.2. 
Inclusion of Subjects At Least 12 Years of Age (No Upper Age Limit) 
The population to be studied includes adults and adolescents at least 12 years of age with mild or 
moderate COVID-19. This is a population similar to those selected for studies RM08-3001, RM08-
3002, RM08-3003, RM08-3004 and RM08-3005 of the NTZ 300 mg extended release tablets in 
more than 5,000 subjects with colds or influenza-like illness. No safety concerns have been 
identified from these clinical trials. Data from pharmacokinetics studies in healthy volunteers 12 
to 17 years of age or 18 to 65 years of age indicate that the pharmacokinetics of the major NTZ 
metabolites, tizoxanide and tizoxanide glucuronide, following oral administration of a NTZ 500 
mg tablet are similar for these age groups. Safety data is also similar for these age groups. 
Therefore, the adult dose is deemed appropriate for pediatric patients down to 12 years of age. 
Informed consent will be required for subject participation in this study (see Section 8.1.1). A 
signed assent form will be required for any minors enrolled (≤ 18 years of age or as local 
regulations apply) as well as signed parental/legal guardian consent by their parent/legal guardian 
allowing for the minor’s participation. 
4.2.4.3. 
Inclusion of Subjects with Underlying Conditions 
For the present study, some subjects (e.g., subjects >65 years of age, underlying asthma or COPD, 
diabetes mellitus, underlying cardiovascular disease, etc. – see Inclusion/Exclusion criteria) who 
are at higher risk of complications or exacerbations of underlying conditions will be allowed to 
participate if, in the judgment of the investigator, they are able to comply with protocol 
requirements and are not expected to require hospitalization. There is no approved antiviral for 
mild or moderate COVID-19, and subjects will not be prevented from being prescribed rescue 
medication for complications. Therefore, participation in the study will not pose unreasonable risk 
to any eligible subject.  


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The pharmacokinetics of the proposed dose of NTZ have been studied in subjects with renal and 
hepatic impairment and no dose adjustment is recommended in these populations. A thorough QTc 
study of NTZ at doses of 675 mg and 2700 mg found no prolongation of the QTc interval. 
CYP450 inhibition assays indicate that tizoxanide inhibits CYP2C8 with an IC50 of 4.3µM, but a 
mechanistic static model used for potential drug-drug interactions indicated that a clinical 
interaction stemming from CYP2C8 inhibition by tizoxanide is unlikely.  
While tizoxanide is more than 99.9% bound to plasma proteins, an in vivo drug-drug interaction 
study found no interaction between NTZ and warfarin. Tizoxanide inhibits the BCRP transporter 
and therefore may affect the pharmacokinetics of BCRP substrates, such as rosuvastatin. Co-
administration of NTZ and rosuvastatin for seven days led to a 40% increase in the Cmax of 
rosuvastatin and 80% and 70% increases of rosuvastatin AUC0-t and AUC0-∞, respectively. 
However, the short duration of treatment in this study is not anticipated to cause adverse effects 
related to co-administration of NTZ and rosuvastatin. 
For more detailed information, refer to the NT-300 Investigator’s Brochure-COVID/VRI. 
4.2.4.4. 
Exclusion of Subjects with Significant Immunodeficiency 
Individuals with significant immunodeficiency, such as patients undergoing chemotherapy, 
transplant recipients receiving immunosuppressive therapy, and HIV patients with very low CD4 
counts are more susceptible to longer durations of illness and more likely to experience 
complications due to viral respiratory infections. This is an important population in which to study 
antiviral drugs for the treatment of viral respiratory infections. Nonetheless, these subjects will be 
excluded from the present study due to (1) the likelihood of longer viral shedding necessitating 
longer courses or higher doses of treatment than what is proposed in this study, and (2) the 
likelihood that symptoms of illness may present differently in immunocompromised persons 
compared to immunocompetent persons due to reduced ability to produce the immune response 
that results in symptoms (van der Vries et al. 2013, St. Jude Children’s Research Hospital).  
4.2.5. 
Use of Vitamin B Complex Supplement 
All subjects will receive a vitamin B complex supplement (Super B-Complex™, Igennus 
Healthcare Nutrition, Cambridge, UK) one tablet twice a day with study medication. This dose 
follows the manufacturer’s labeled dosing. The purpose of the supplement is to help mask any 
chromaturia attributed to NTZ and aid in maintaining study blinding. The supplement will supply 
each subject with the following Percent Daily Values based on a 2,000 calorie diet: vitamin B1 
1,333%, vitamin B2 824%, vitamin B3 240%, vitamin B5 360%, vitamin B6 1000%, vitamin B7 
100%, vitamin B12 15,000%, folate 100%, and vitamin C 267%. Considering this supplement will 
provide well beyond the needed daily allowance of these water-soluble vitamins, excess amounts 
are expected to be excreted in the urine and provide discoloration.  
4.2.6. 
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 


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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). Data from Romark 
studies RM08-3004 and RM08-3005 also indicates validity and ability to detect change in patients 
infected with Enterovirus/Rhinovirus or seasonal coronavirus. 
4.2.7. 
Choice of Primary Endpoint 
The primary endpoint was developed using data collected from 1,467 subjects infected with 
influenza, Enterovirus/Rhinovirus or seasonal coronaviruses during Romark studies RM08-3004 
and RM08-3005. The endpoint defines a level of symptom improvement that constitutes a 
meaningful within-patient change in health status. The determination of meaningfulness was based 
on empiric evidence derived from the use of anchor questions. The endpoint requires (1) oral 
temperature <100.4 ºF, (2) reduction of total symptom severity score from the previous day, (3) 
the patient to provide confirmation that symptoms are at least somewhat better, and (4) no 
symptom domain increase except below background levels for the remainder of the study 
(sustained response). These background levels were derived based on symptom scores reported by 
patients at the time they also reported being at usual health. 
5. 
STUDY POPULATION 
5.1. 
Inclusion Criteria 
1. Male or female outpatients at least 12 years of age 
2. [Criterion removed in protocol amendment 2. See Appendix 1 for revision history.] 
3. Presence of clinical signs and/or symptoms consistent with worsening or stable mild or 
moderate COVID-19 (one of the following is required): 
a. Presence of at least two respiratory symptom domains (head, throat, nose, chest, cough) 
with a score of ≥2 as determined by Screening FLU-PRO OR  
b. Presence of at least one respiratory symptom domain (head, throat, nose, chest, cough) with 
a score of ≥2 as determined by Screening FLU-PRO with pulse rate ≥90 OR  
c. Presence of at least one respiratory symptom domain (head, throat, nose, chest, cough) with 
a score of ≥2 as determined by Screening FLU-PRO with respiratory rate ≥16 
AND patient reported assessment that symptoms are present, the symptoms are not consistent 
with the subject’s usual health, the symptoms interfere with daily activities, and the symptoms 
have worsened or remained the same relative to the previous day, as confirmed by responses 
to questions in the Screening FLU-PRO. 


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4. Onset of symptoms no more than 72 hours before enrollment in the trial. Onset of symptoms 
is defined as the earlier of the first time at which the subject experienced subjective fever or 
any respiratory symptom (head, throat, nose, chest, or cough symptoms). 
5. Willing and able to provide written informed consent (including assent by legal guardian if 
under 18 years of age) and comply with the requirements of the protocol, including completion 
of the subject diary and all protocol procedures. 
5.2. 
Exclusion Criteria 
1. Persons with any clinical sign or symptoms suggestive of severe systemic illness with COVID-
19, including the following: 
a. shortness of breath at rest,  
b. resting pulse ≥125 beats per minute,  
c. resting respiratory rate ≥30 breaths per minute, or 
d. SpO2 ≤ 93% on room air at sea level. 
2. Subjects who experienced a previous episode of acute upper respiratory tract infection, otitis, 
bronchitis or sinusitis or received antibiotics for these conditions within two weeks prior to 
and including study day 1. 
3. Severely immunodeficient persons including: 
a. Subjects with immunologic disorders or receiving immunosuppressive therapy (e.g., for 
organ or bone marrow transplants, immunomodulatory therapies for certain autoimmune 
diseases) 
b. Subjects with untreated HIV infection or treated HIV infection with a CD4 count below 
350 cells/mm3 in the last six months 
c. Subjects actively undergoing systemic chemotherapy or radiotherapy treatment for 
malignancy 
d. Subjects using steroids as maintenance therapy for chronic conditions 
4. Subjects with active respiratory allergies or subjects expected to require anti-allergy 
medications during the study period for respiratory allergies. 
5. 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 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. 
6. Subjects with a history of COVID-19 or known to have developed anti-SARS-CoV-2 
antibodies. 
7. Subjects residing in the same household with another subject participating in the study. 


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8. 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. 
9. Receipt of any dose of NTZ within seven days prior to screening. 
10. Known sensitivity to NTZ or any of the excipients comprising the study medication. 
11. Subjects unable to swallow oral tablets or capsules. 
12. Subjects with known severe heart, lung, neurological or other systemic disease that the 
Investigator believes could preclude safe participation. 
13. Subjects likely or expected to require hospitalization unrelated to COVID-19 during the study 
period. 
14. Subjects taking medications considered to be major CYP2C8 substrates. Refer to Table 5 in 
Section 6.5. 
15. 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. 
5.3. 
Study Population Diversity 
The Sponsor will select clinical sites to support recruitment of a diverse and representative 
population, including older individuals and racial and ethnic minorities. 
6. 
STUDY INTERVENTION 
6.1. 
Study Intervention(s) Administration 
6.1.1. 
Study Intervention Description 
NTZ 300 mg extended release tablets for use in this study are yellow, round, convex, film-coated, 
bi-layer tablets for oral administration, each tablet contains 300 mg of NTZ and the inactive 
ingredients. 
Placebo tablets will have the same appearance and inactive ingredients as the active NTZ 300 mg 
extended release tablet. 
The vitamin B complex supplement is Super B-Complex™ manufactured by Igennus Healthcare 
Nutrition, Cambridge, UK.  The supplement will supply each subject with the following Percent 
Daily Values based on a 2,000-calorie diet: vitamin B1 1,333%, vitamin B2 824%, vitamin B3 
240%, vitamin B5 360%, vitamin B6 1000%, vitamin B7 100%, vitamin B12 15,000%, folate 
100%, and vitamin C 267%. 
6.1.2. 
Dosing and Administration 
Group 1 (NTZ): 
Subjects will receive two NTZ 300 mg tablets b.i.d. with food (< 1 hour after 
food intake) and a B complex vitamin (Super B-Complex™, Igennus 
Healthcare Nutrition, Cambridge, UK) b.i.d. for 5 days 


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Group 2 (Placebo): Subjects will receive two placebo tablets b.i.d. with food (< 1 hour after food 
intake) and a B complex vitamin (Super B-Complex™, Igennus Healthcare 
Nutrition, Cambridge, UK) b.i.d. for 5 days 
The food prior to drug intake should preferably be a high-fat meal, but at minimum a cereal bar. 
All subjects will receive a vitamin B complex supplement one tablet twice a day (manufacturer’s 
labeled dosing) to help mask any potential chromaturia attributed to NTZ and aid in maintaining 
study blinding. 
6.2. 
Preparation, Handling, Storage and Accountability 
6.2.1. 
Acquisition and Accountability 
Study medication will be provided by the Sponsor to the Investigational Site for dispensing. 
Drug accountability will be tracked using an IWRS/IRT system as described in the study-specific 
Data Management Plan. Unused supplies must be returned to the Sponsor or destroyed in 
accordance with institutional procedures in effect at the study Site. 
6.2.2. 
Packaging and Labeling 
NTZ or placebo tablets will be packaged in white 30 cc HDPE bottles, each containing 20 tablets. 
The kits will be stored at room temperature and will bear labels with the following information: 
Table 4: 
Study Medication Label 
20 Tablets 
Study No. RM08-3008 
Treatment No: XXXX 
Lot No: XXXX 
 
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 
 
 
6.3. 
Randomization and Blinding 
Subjects will be randomized 1:1 to receive either NTZ or placebo.  An independent third party will 
prepare a master randomization list and maintain the masking of the study.  Subjects who qualify 
for the study will be assigned to treatment using 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. 


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6.4. 
Study Intervention Compliance 
Subject compliance with study medication will be checked by site staff daily during the treatment 
period. Subjects will return the treatment kit with any unused medication to the clinic at the Day 
10 visit. Subjects will be considered non-compliant (major protocol deviation) if they have missed 
more than two doses of the study medication during the first three days of the study. Non-
compliance will not be cause for discontinuation of subject participation in the study. 
6.5. 
Concomitant Therapy 
The following medications will not be allowed during the study: topical or systemic decongestants, 
nasal corticosteroids, and any prescription or non-prescription medications classified as (i) 
expectorants and cough preparations, (ii) analgesics and antipyretics, (iii) antihistamines 
(American Hospital Formulary Service (AHFS) classification) or (iv) medications considered 
major CYP2C8 substrates (see Table 5 below). As an exception to this rule, subjects will be 
allowed to use acetaminophen and/or dextromethorphan as necessary for disabling symptoms. 
Table 5: 
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, remdesivir, 
azithromycin  or lopinavir/ritonavir during the study except as standard-of-care rescue medication. 
Medications for pre-existing conditions that are not excluded (see exclusion criteria) should be 
continued as prescribed. Standard-of-care rescue medication is permitted for complications of 
COVID-19 illness. The use of such medication will be recorded in the EDC system. 
7. 
STUDY INTERVENTION DISCONTINUATION AND 
PARTICIPANT DISCONTINUATION 
Treatment will be discontinued for individual subjects for the following reasons: 
1. An allergic reaction occurs or is suspected. 


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2. Medical conditions that may require study medication 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. 
Subjects will be encouraged to complete all protocol-specified follow-up visits even if study drug 
is withdrawn. 
8. 
STUDY PROCEDURES 
8.1. 
Visit Procedures 
Study procedures to be completed at each visit are indicated in the Schedule of Assessments. 
Descriptions of selected procedures are outlined in the following sections. 
8.1.1. 
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 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. Only 
subjects who are fully able to understand the risks, benefits, and potential AEs of the study, and 
provide their consent voluntarily will be enrolled. 
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. 


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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.   
8.1.2. 
Medical History 
All relevant medical history should be entered in the EDC system at the Screening visit. Relevant 
medical history includes: 
1. Any disease, condition or surgery active at the time of the Screening visit; 
2. Any disease, condition or surgery ending within two months of the Screening visit; or 
3. Any other disease, condition or surgery relevant to the subject’s infection or clinical 
management. 
8.1.3. 
Physical Examination 
Physical examinations will include assessment of each body system including skin, head (eye, ear 
and nose), neck, mouth/throat, lymph nodes, cardiovascular, respiratory, gastrointestinal, 
neurological, and musculoskeletal systems as well as general appearance for abnormalities. 
The Investigator will complete a full physical examination at the Screening visit. Physical 
examinations should occur at follow-up and unscheduled visits as required by symptoms or 
adverse changes from baseline. 
8.1.4. 
Body Measurements and Resting Vital Signs 
Body measurements and resting vital signs will include assessment of the following: 
1. Height (Screening visit only) 
2. Weight 
3. Oral temperature 
4. Blood pressure 
5. Pulse rate 
6. Respiratory rate 
7. Oxygen saturation 
8.1.5. 
Screening FLU-PRO 
The FLU-PRO questionnaire will be administered during the Screening visit to confirm 
symptoms required for eligibility.  


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8.1.6. 
Randomization and Dispensing Study Medication 
Randomization and study medication kit assignment will be accomplished using an Interactive 
Randomization Tool (IRT) feature in the EDC system after all screening procedures have been 
completed and the subject has been determined to be eligible for the study. Site staff will witness 
the subject take the first dose of study medication in the clinic as soon as possible following 
randomization and record the date and time of medication intake in the EDC system.  
8.1.7. 
Subject Instructions 
At each subject contact, site staff will instruct the subject regarding: 
1. Administration of study medication. Subjects will be instructed to take the study medication 
(two tablets) twice daily with the morning and evening meals, approximately every 12 
hours (< 1 hour after food intake, preferably a high-fat meal but at a minimum a cereal bar) 
and a B complex vitamin (Super B-Complex™, Igennus Healthcare Nutrition, Cambridge, 
UK).   
2. Completion of subject diary.  Subjects will be reminded to complete the electronic diary 
and any questions will be answered. 
3. Use of birth control.  Female subjects of childbearing potential, if sexually active, will be 
instructed to continue an acceptable method of birth control for the duration of the study 
and for 1 month post-treatment.  Acceptable methods of birth control include a double 
barrier method, oral birth control pills, an IUD, or medroxyprogesterone acetate 
administered intramuscularly. 
4. Follow-up visits. Subjects will be reminded of the study schedule and of the next scheduled 
visit. 
5. Seeking emergency care or contacting the study physician or nurse. Subjects must be 
informed to seek emergency medical care or contact the study physician or nurse if they 
develop any of the following symptoms listed below at any point during the study. 
CONTACT STUDY PHYSICIAN IF YOU HAVE:  
• 
Trouble breathing including shortness of breath 
• 
Severe headache, stiff neck, confusion or excessive somnolence 
• 
If fever (≥99°F or ≥37.2°C) returns after being absent for 24 hours 
• 
Increased difficulty breathing 
• 
Wheezing develops 
• 
New pain develops or pain localizes to one area, such as an ear, the throat, the chest, 
or the sinuses 
• 
Symptoms become more severe or frequent 
• 
Symptoms recur or any difficulty breathing following 5-10 days resolution of illness 
• 
An allergic-like reaction occurs or is suspected 
• 
Abnormal behavior 


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8.1.8. 
Day 2-7 Subject Contact 
Site staff will contact each subject by telephone on study Days 2-7 to verify: 
1. Did the subject take all expected doses of study medication? 
2. Did the subject complete all expected electronic diaries? 
3. Does the subject have worsening symptoms or adverse events that warrant an 
unscheduled visit? 
4. Does the subject have shortness of breath at rest? If yes, instruct the subject to come to 
the clinic for an unscheduled visit to screen for progression of illness or refer to hospital 
as warranted. If the subject is referred to the hospital or emergency department, the 
Investigator will attempt to obtain hospital records indicating SpO2 or PaO2/FiO2 from 
the subject for the purposes of defining progression to severe COVID-19 illness. The 
SpO2 or PaO2/FiO2 obtained from hospital records will be entered on an Unscheduled 
Visit eCRF. 
If the subject has missed medication or electronic diaries, the site staff will re-train the subject on 
the importance of medication and diary compliance. 
This contact may occur at the Day 4 or unscheduled visit in lieu of telephone contact. 
8.1.9. 
Day 28 Subject Contact 
Site staff will contact each subject by telephone on study Day 28 to determine if the subject has 
experienced any new adverse events, developed severe COVID-19 illness, or required 
hospitalization for any reason. 
If warranted, the Day 28 subject contact may also occur in-person at the clinic or another 
location as agreed upon by the site and subject. 
8.2. 
Laboratory Assessments 
8.2.1. 
Assessments in the Clinic 
A urine pregnancy test will be performed in the clinic only for women of childbearing potential 
(post-menarche, pre-menopause, not surgically sterile) at the Screening visit. 
8.2.2. 
Central Laboratory Assessments 
A central laboratory will be used for safety, diagnostic virology, and serology testing. A laboratory 
manual will be provided to each clinical site with sample collection and handling details.  
8.2.2.1. 
Laboratory Safety Assessments 
Blood tests for safety monitoring 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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8.2.2.2. 
Diagnostic Virology Testing 
Diagnostic virology testing will be performed using nasopharyngeal swab samples collected at the 
Baseline, Day 4 and Day 10. The nasopharyngeal sample for virology testing will be collected 
using a single nasopharyngeal swab inserted into both nostrils in accordance with procedures 
detailed in the study-specific laboratory manual. 
The ePlex® Respiratory Pathogen Panel (“ePlex RPP”, GenMark, Carlsbad, CA) will be used 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 Aptima® SARS-CoV-2 Assay (Hologic, Inc, San Diego, CA) will be used to detect SARS-
CoV-2. 
All Baseline nasopharyngeal swabs will be tested by the ePlex RPP and Aptima® SARS-CoV-2 
assays. If the Baseline nasopharyngeal swab is positive for SARS-CoV-2, the Day 4 and 10 
nasopharyngeal swabs will be tested for SARS-CoV-2. If the Baseline nasopharyngeal swab is 
positive for EV/RV, the Day 4 and 10 nasopharyngeal swabs will be tested using the ePlex RPP. 
8.2.2.3. 
Quantitative Virology Testing 
Nasopharyngeal swab samples testing positive for SARS-CoV-2 will be subjected to quantitative 
RT-PCR for analysis of quantitative changes in viral RNA. 
8.2.2.4. 
Serology Testing 
Baseline and Day 22 blood samples will be tested for quantitative anti-SARS-CoV-2 antibodies. 
8.2.3. 
Pharmacokinetics Assessments 
Blood samples for pharmacokinetics analysis will be sent to the central laboratory by the site and 
shipped to a referral laboratory for analysis. Sample collection and handling details will be 
included in the central laboratory manual. 
8.2.4. 
Plan for Monitoring Viral Resistance 
If any Day 10 nasopharyngeal swab sample is positive for SARS-CoV-2 by the SARS-CoV-2 
assay or for EV/RV by the ePlex RPP, the Baseline and Day 10 nasopharyngeal swab samples for 
the subject will be tested for post-treatment reduced susceptibility to tizoxanide. 
8.3. 
Subject Diary 
The subject diary will be used to generate primary efficacy data. Therefore, diary compliance is of 
critical importance. 
8.3.1. 
Subject Diary Completion 
Subjects will complete a diary including: 
 Oral temperature taken using the study thermometer twice daily (morning and evening), 
and 


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 The FLU-PRO© symptoms questionnaire daily in the evening. 
The diary will be completed using the subject’s smartphone or provisioned device.  
Site staff will ensure subject access and ability to complete the diary during the Baseline visit. 
Subjects will complete the first post-Screening diary at home on the evening of study Day 1. 
Subjects will receive electronic reminders to complete the diary daily to ensure compliance. 
8.3.2. 
Subject Diary Compliance Monitoring 
It is the responsibility of the clinical site to ensure that subjects are completing the diary as directed. 
E-mail notifications will be sent to the site daily with a list of subjects who missed the previous 
day’s diary in order to direct follow-up contact with the subject to re-train on the importance of 
the diary. Site staff may also view a diary completion report at any time within the EDC system. 
8.4. 
Adverse Events and Serious Adverse Events 
8.4.1. 
Definitions 
The following definitions will apply to the reporting of adverse events: 
1. Adverse Event: 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 viral respiratory 
infections (VRIs) (cough, sore, throat, nasal obstruction, fatigue, headache, myalgia, or 
feverishness) will not be reported as adverse events. 
2. 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. 
3. Unexpected Adverse Event: Any adverse experience that is not identified in nature, 
severity, or frequency in the Investigator's Brochure for NTZ. 
4. Severity of adverse events will be assessed as mild, moderate, severe or potentially life-
threatening by the Investigator using the Toxicity Grading Scale Tables provided in 
Appendix 4 (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). 
5. Causality (relationship to treatment) will be assessed as follows: 


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• 
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. 
8.4.2. 
Recording and Follow Up of Adverse Events 
At the time of each visit, the subject will be questioned regarding the occurrence and nature of any 
adverse events and all events will be recorded in the subject’s 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. All adverse events must be followed until their 
resolution or stabilization even beyond the planned study period. 
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.   
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. 
8.4.3. 
Reporting Requirement 
The Principal Investigator is required to notify The Romark Institute for Medical Research 
(Sponsor) immediately (within 24 hours of the initial report) of any unexpected, fatal, or life-






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9.3. 
Response Definitions 
Sustained Response: 
A decrease in total FLU-PRO score from the 
previous diary with patient assessment that 
symptoms are at least “somewhat better than 
yesterday”, no oral temperature ≥100.4°F in the 
prior 24 hours, and no future increase in any of the 
FLU-PRO domains except within the following 
levels:  
FLU-PRO Domain* 
Background Level 
Body/Systemic 
0.56 
Throat 
0.67 
Eyes 
0.67 
Gastrointestinal 
2.00 
Head 
2.00 
Nose 
Score at time of response or 
0.75, whichever is greater 
Chest 
Score at time of response or 
0.00, whichever is greater 
Cough 
Score at time of response or 
1.75, whichever is greater 
 * A diagram of the FLU-PRO domain/subdomain 
structure is attached as Appendix 5. 
Time of Sustained Response: 
The time of the first diary at which all Sustained 
Response criteria are met. 
Time to Sustained Response: 
The time (hours) from the first dose of study 
medication and the Time of Sustained Response. 
Severe COVID-19 Illness: 
Subject must have (1) shortness of breath at rest 
and (2) SpO2≤93% on room air or PaO2/FiO2 <300. 
9.4. 
Statistical Methodology 
The statistical methodology is described briefly below and will be described in detail in the 
Statistical Analysis Plan. 
9.4.1. 
Efficacy Analyses 
Efficacy analyses will be based on a population consisting of all subjects randomized who receive 
at least one dose of study medication and are positive for SARS-CoV-2 by Aptima® SARS-CoV-
2 Assay at Baseline. For time-to-event analyses, a test of significance (as described in the 
following) will be performed with descriptive statistics provided, including the use of Kaplan-
Meier figures. 


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There will be one primary efficacy analysis: 
• 
Time to Sustained Response for the NTZ treatment group will be compared to that of the 
placebo treatment group using a stratified Gehan-Wilcoxon test (α=0.05) where 
stratification will follow that used for randomization. Subjects without a Sustained 
Response recorded will be treated as censored as of the last diary without a documented 
Sustained Response, except for subjects who are hospitalized or die during the study, who 
will be censored at Day 21 (hour 504). 
Sensitivity analyses for the primary efficacy analysis will be described in the Statistical Analysis 
Plan. 
If the primary analysis is significant at the 0.05 level, the key secondary efficacy analysis will be 
formally evaluated at the 0.05 level as follows: 
• 
Proportions of subjects progressing to Severe COVID-19 Illness will be compared between 
the treatment groups using a Cochran-Mantel-Haenszel (CMH) test stratified by the 
randomization strata. 
Exploratory analyses will be performed as follows: 
• 
Proportions of subjects positive for SARS-CoV-2 by Aptima® SARS-CoV-2 Assay at 
study Day 4 and Day 10 will be compared between the treatment groups using a Cochran-
Mantel-Haenszel (CMH) test stratified by the randomization strata. 
• 
Mean changes from baseline in quantitative SARS-CoV-2 RNA measured by RT-PCR at 
Day 4 and Day 10 will be compared using a t-test. 
• 
Proportions of subjects hospitalized due to COVID-19 or complications thereof will be 
compared across the treatment groups using a CMH test stratified by the randomization 
strata. 
• 
Proportions of subjects with mortality related to COVID-19 or complications thereof will 
be compared across the treatment groups using a CMH test stratified by the randomization 
strata. 
9.4.2. 
Population Pharmacokinetics Analysis 
On Day 4, plasma samples will be collected before the morning dose (at the trough) for 
determination of drug concentration.  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 NTZ-treated subjects except those positive for EV/RV at Baseline.  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. 
Pharmacokinetics data for subjects positive for EV/RV at Baseline will be analyzed as part of 
concurrently enrolling study RM08-3009. 
9.4.3. 
Safety Analyses 
All randomized subjects who receive at least one dose of study medication except those positive 
for EV/RV at Baseline will be evaluated for drug safety. Safety analyses will be done descriptively. 


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Safety data for subjects positive for EV/RV at Baseline will be analyzed as part of concurrently 
enrolling study RM08-3009. 
10. 
OPERATIONAL CONSIDERATIONS 
10.1. 
Regulatory, Ethical and Study Oversight Considerations 
10.1.1. 
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).   
Informed consent will be obtained from each subject as described in Section 8.1.1. 
Prior written approval of the study protocol and of the informed consent form will be obtained by 
the Sponsor from the appropriate central or local IRB.  
Prior to study initiation, the Investigator will provide the IRB with required documents for review 
and approval. See Appendix 3: List of Essential Documents for designation of documents that may 
be required by the IRB prior to study initiation or during the course of study conduct. No site will 
screen subjects until the IRB has given full approval of required documents and the data approval 
letter identifying the IRB and the documents approved is delivered to the study Sponsor. 
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. 
10.1.2. 
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. 


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10.1.3. 
Quality Assurance and Quality Control 
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 Investigator 
and associated personnel prior to the study, and by periodic monitoring visits by the Sponsor or 
Sponsor’s representatives (see Section 10.1.6). Written instructions will be provided for collection, 
preparation and shipment of biological samples. 
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. 
Quality oversight of study management will be accomplished according to the study-specific 
Integrated Quality and Risk Management Plan. 
10.1.4. 
Safety Oversight 
The Sponsor and Medical Monitor will be responsible for safety oversight of the study. Procedures 
for safety oversight are described in the study-specific Medical Monitoring Plan. 
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.   
10.1.5. 
Data Handling and Record Keeping 
10.1.5.1. Data Collection and Management Responsibilities 
Sponsor Data management will be responsible for oversight of data collection, cleaning and 
locking according to the study-specific Data Management Plan.  
Data will be collected on site-specific source data forms and transcribed into an electronic data 
capture (EDC) system by site staff. 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 monitors or 
data management personnel. The Investigator and/or designee will answer the queries and update 
the source data, as needed. 
10.1.5.2. Study Records Retention  
The Investigator/institution will maintain all CRFs, 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, and all study documents as specified by the applicable regulatory 
requirements for the duration required by applicable regulatory authorities or until the Sponsor 
informs the Investigator/institution that these documents are no longer needed.  


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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 will be responsible for maintaining the Trial Master File which is a clear 
documentation of the course of the study. 
10.1.6. 
Clinical Monitoring 
Clinical monitoring will be conducted by the Sponsor and/or a contract research organization 
(CRO) according to the study-specific 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. 
10.1.7. 
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. 
10.1.8. 
Study Discontinuation and Closure 
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 4). 
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 efficacy data will be 
submitted to the FDA in a timely manner. 
10.1.9. 
Data and Report Requirements 
See Appendix 3: List of Essential Documents for designation of documents required from the 
Investigator by the Sponsor prior to approval and initiation of the study and before the study can 
be considered complete and terminated. 


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10.1.10. 
Confidentiality and Privacy 
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 will 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 will 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. All reports and 
communications relating to the study subjects will identify subjects only by initials and subject 
identification number. 
Data generated for the study will 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.   
10.1.11. 
Publication and Data Sharing 
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. 
10.1.12. 
Key Roles and Study Governance  
See Appendix 2 for a list of key personnel and contact information. 
 


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11. 
REFERENCES 
ALINIA (nitazoxanide) prescribing information. Romark, L.C., Tampa, FL, June 2019. 
Anderson VR, Curran MP. NTZ: A review of its use in the treatment of gastrointestinal 
infections. Drugs 2007;67:1947-67. 
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 
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Cao J, Forrest JC, Zhang X. A screen of the NIH collection small molecule library identifies 
potential coronavirus. Antiviral Res 2015; 114:1-10. 
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COVIDView – Key Updates for Week 22, ending May 30, 2020.  
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required for efficient vaccinia virus production. J Biomed Sci 2009; 16:80. 
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Goldman JD et al. Remdesivir for 5 or 10 Day s in Patients with Severe COVID-19. NEJM 
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Hadad GM, Abdel Salam RA, Emara S. Validated and optimized high-performance liquid 
chromatographic determination of tizoxanide, the main active metabolite of nitazoxanide in 
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production in LPS-stimulated mouse macrophages and TG-injected mice. Int Immunopharmacol 
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Center. Accessed: 12 Jun 2020. Available at: https://coronavirus.jhu.edu/map.html 
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inflammatory and anti-inflammatory cytokines in adipose tissue with and without tissue 
expansion. Int J Obes 2017; 41:645-51. 
Li, X, Ma, X. Acute respiratory failure in COVID-19: is it “typical” ARDS?. Crit Care 24, 198 
(2020). https://doi.org/10.1186/s13054-020-02911-9 
Mirazimi A, Svensson L. ATP is required for correct folding and disulfide bond formation 
rotavirus VP7. J Virol 2000; 74:8048-52. 
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Piacentini S, La Frazia S, Riccio A, Pedersen JZ, Topai A, et al. Nitazoxanide inhibits 
paramyxovirus replication by targeting the Fusion protein folding: role of glycoprotein-specific 
thiol oxidoreductase ERp57. Sci Rep 2018; 8:10425. 
Powers JH, Bacci ED, Leidy NK, Poon JL, Stringer S, et al. Performance of the inFLUenza 
patient-reported outcome (FLU-PRO) diary in patients with influenza-like illness (ILI). PLoS 
ONE 2018 13(3):d0194180. 
Rossignol JF, La Frazia S, Chiappa L, Ciucci A, Santoro MG. Thiazolides, a new class of anti-
influenza molecules targeting viral hemagglutinin at the post-translational level. J Biol Chem 
2009; 284:29798-808. 
Rossignol JF, van Baalen C. Broad-spectrum antiviral nitazoxanide inhibits ATP-dependent 
replication of respiratory viruses and proinflammatory cytokines [Abstract]. Presented at the 2nd 
International Meeting on Respiratory Pathogens. Singapore, March 7-9, 2018. 
Rossignol JF. Nitazoxanide, a new drug candidate for the treatment of Middle East respiratory 
syndrome coronavirus. J Infect Public Health 2016; 9:227-30. 
Rossignol JF. Nitazoxanide: A first-in-class broad-spectrum antiviral agent. Antiviral Res 2014; 
110:94-103. 
Sag D, Carling D, Stout RD, Suttles J. AMP-activated protein kinase promotes macrophage 
polarization to an anti-inflammatory functional phenotype. J Immunol 2008; 181:8633-41. 


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Sleeman K, Mishin VP, Guo Z, Garten RJ, Balish A, et al. Antiviral susceptibility of variant 
influenza A(H3N2)v viruses isolated in the United States from 2011 to 2013. Antimicrob Agents 
Chemother 2014; 58:2045-51. 
Sood N, Simon P, Ebner P. Seroprevalence of SARS-CoV-2-Specific Antibodies Among Adults 
in Los Angeles County, California, on April 10-11, 2020. JAMA 2020. Published online May 
18, 2020. Available at: https://jamanetwork.com/journals/jama/fullarticle/2766367 
St. Jude Children’s Research Hospital. Infections in Immunocompromised Patients.  Accessed 
22 Jun 2020.  Available at: https://www.stjude.org/treatment/patient-resources/caregiver-
resources/infection-tips/infections-immunocompromised-patients.html 
Tilmanis D, van Baalen C, Oh DY, Rossignol J-F, Hurt AC. The susceptibility of circulating 
human influenza viruses to tizoxanide, the active metabolite of nitazoxanide. Antivir Res 2017; 
147:142-48. 
van der Vries E, Stittelaar KJ, van Amerongen G, et al. Prolonged influenza virus shedding and 
emergence of antiviral resistance in immunocompromised patients and ferrets. PLoS Pathog. 
2013;9(5):e1003343.  
Wang M, Cao R, Zhang L, Yang X, Liu J, et al. Remdesivir and chloroquine effectively inhibit 
the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 2020; 30:269-71. 
Wang W, Yang X, de Silanes IL, Carling D, Gorospe M. Increased AMP:ATP Ratio and AMP-
activated protein kinase activity during cellular senescence linked to reduced HuR function. J 
Biol Chem 2003; 278:27016-23. 
Wölfel, R., Corman, V.M., Guggemos, W. et al. Virological assessment of hospitalized patients 
with COVID-2019. Nature 581, 465–469 (2020). 
Yu J, Powers JH, Vallo D, Falloon J. Evaluation of efficacy endpoints for a phase IIb study of a 
respiratory syncytial virus vaccine in older adults using patient-reported outcomes with 
laboratory confirmation. Value Health 2020; 23:227-35. 
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2019. NEJM 2020; 382:727-733. 
 
 
 




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Summary of Changes 
Change 5: 
Page 25, Randomization and Dispensing Study Medication 
Updated “Site staff will witness the subject take the first dose of study medication in the clinic and record the date and time of 
medication intake in the EDC system” to “Site staff will witness the subject take the first dose of study medication in the clinic 
as soon as possible following randomization and record the date and time of medication intake in the EDC system.” 
Change 6: 
Page 27, Day 2-7 Contact 
Updated “4. Does the subject have shortness of breath at rest? If yes, instruct the subject to come to the clinic for an 
unscheduled visit to screen for progression of illness including determination of PaO2/FiO2.” to “4. Does the subject have 
shortness of breath at rest? If yes, instruct the subject to come to the clinic for an unscheduled visit to screen for progression 
of illness or refer to hospital as warranted. If the subject is referred to the hospital or emergency department, the Investigator 
will attempt to obtain hospital records indicating SpO2 or PaO2/FiO2 from the subject for the purposes of defining progression 
to severe COVID-19 illness. The SpO2 or PaO2/FiO2 obtained from hospital records will be entered on an Unscheduled Visit 
eCRF. 
Change 7: 
Page 27, Diagnostic Virology Testing 
Added: “The nasopharyngeal sample for virology testing will be collected using a single nasopharyngeal swab inserted into 
both nostrils in accordance with procedures detailed in the study-specific laboratory manual.” 
Replaced “Panther Fusion” with “Aptima®” 
Replaced: “Post-baseline samples (Days 4 and 10) will only be tested by the SARS-CoV-2 assay and will only be tested if the 
sample from the preceding timepoint was positive for SARS-CoV-2. For example, a subject who is positive for SARS-CoV-2 at 
Baseline will have the Day 4 sample tested by the SARS-CoV-2 assay. If the subjects’ Day 4 sample is negative for SARS-CoV-
2, the Day 10 sample will not be tested.” 
With: “If the Baseline nasopharyngeal swab is positive for SARS-CoV-2, the Day 4 and 10 nasopharyngeal swabs will be 
tested for SARS-CoV-2.” 
Change 8: 
Page 30: Management of Subjects Requiring Hospitalization 
Added: 
8.4.4 Management of Subjects Requiring Hospitalization 
Subjects requiring hospitalization for any reason during the course of the study will receive local standard of care under the 
supervision of the hospital’s attending physicians. The Investigator will attempt to follow up on the subject to obtain complete 
data for a narrative of the Serious Adverse Event and complete safety follow up procedures for the study as feasible. 




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Summary of Changes 
Change 2: 
Page 8, Synopsis 
Updated the following to reflect Day 28 contact: 
“The safety of study drug administration will be monitored by assessment of adverse events from baseline through the Day 28 
study exit, clinical laboratory testing at baseline and on Day 10, physical examinations and vital signs assessments at 
screening, Day 10 and Day 22 and telephone monitoring/at home visits during Day 2 through Day 7 and Day 28.” 
Page 9, Schedule of Assessments  
Added subject contact at Day 28 (+3 days). 
Page 27, 8.1.9 Day 28 Subject Contact 
Added section with text: “Site staff will contact each subject by telephone on study Day 28 to determine if the subject has 
experienced any new adverse events, developed severe COVID-19 illness, or required hospitalization for any reason. 
If warranted, the Day 28 subject contact may also occur in-person at the clinic or another location as agreed upon by the site 
and subject.” 
Change 3: 
Page 9, Schedule of Assessments 
Corrected Day 22 visit window from “±3” to “+3”. 
Change 4: 
Page 16, 4.1 Study Design Overview 
Added: “We expect that a large number of subjects enrolled will be positive for Enterovirus/Rhinovirus (EV/RV). Efficacy and 
safety data for subjects who are positive for EV/RV at Baseline will be analyzed as part of concurrently enrolling study RM08-
3009.” 
Page 28, 8.2.2.2 Diagnostic Virology Testing 
Added: “If the Baseline nasopharyngeal swab is positive for EV/RV, the Day 4 and 10 nasopharyngeal swabs will be tested using 
the ePlex RPP.” 
Page 28, 8.2.4 Plan for Monitoring Viral Resistance 
Added: “or for EV/RV by the ePlex RPP” 
Page 34, 9.4.2 Population Pharmacokinetics Analysis 
Updated text, “Trough plasma concentrations of tizoxanide and tizoxanide glucuronide will be summarized descriptively for 
NTZ-treated subjects” to add “except those positive for EV/RV at Baseline.” 




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Summary of Changes 
Change 4: 
Page 35, 9.4.1 Efficacy Analyses 
Updated:  
• 
Proportions of subjects positive for SARS-CoV-2 by TCID50 at study Day 4 and Day 10 will be compared between the 
treatment groups using a Cochran-Mantel-Haenszel (CMH) test stratified by the randomization strata. 
• 
Mean changes from baseline in SARS-CoV-2 TCID50 at Day 4 and Day 10 will be compared using a t-test. 
To: 
• 
Proportions of subjects positive for SARS-CoV-2 by Aptima® SARS-CoV-2 Assay at study Day 4 and Day 10 will be compared 
between the treatment groups using a Cochran-Mantel-Haenszel (CMH) test stratified by the randomization strata. 
• 
Mean changes from baseline in quantitative SARS-CoV-2 RNA measured by RT-PCR at Day 4 and Day 10 will be compared 
using a t-test. 
Change 5: 
Page 6, Synopsis & Page 17, Study Overview 
Updated anticipated end of enrollment from December 2020 to January 2021 
Change 6: 
Page 7, Synopsis & Page 17, Choice of Duration of Follow Up 
Corrected study duration from 22 days to 28 days 
Change 7: 
Page 49, Study Contact Information 
Updated Sponsor Project Management and Central Laboratory contact information 
 
 
 






















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APPENDIX 5. FLU-PRO DOMAIN/SUBDOMAIN STRUCTURE 
 

SAP_001.pdf: 






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Revision History 
 
Version 1.1 to 1.2 
 
• Updated the imputation rule for adverse event end dates to take into account the 
adverse event outcome in Section 2.3. 
• Added serology to Section 2.4.1.  
 
Version 1.0 to 1.1 
 
• Removed TCID50 and replaced it with either Aptima® SARS-CoV-2 Assay or 
quantitative RT-PCR, as appropriate. 
• Added Section 2.4.1 to describe the process for running a subset of the final 
TLFs prior to receiving final data from quantitative RT-PCR and/or PK testing.  
• Changed the units of the primary efficacy endpoint from hours to days.  Updates 
include edits to the text in Section 4.1.1 and Section 4.2.1.3. 
• Added subgroup analyses of the primary efficacy endpoint.  Updates include 
edits to the text in Section 2.2.2 and Section 4.2.1 and an additional table and 
figures in Section 8.0. 
• Added a sensitivity analysis of the primary efficacy endpoint using the log-rank 
test.  Updates include the addition of Section 4.2.1.1 (previous Section 4.2.1.1 
and 4.2.1.2 renumbered accordingly) and an additional table in Section 8.0. 
 
 
 


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Table of Contents 
Approval Page ............................................................................................................................. 2 
Revision History .......................................................................................................................... 4 
Abbreviations and Acronyms .................................................................................................... 7 
1.0 Synopsis of Study Design Procedures ............................................................................... 8 
1.1 Design and Treatment .......................................................................................................... 8 
1.2 Study Procedures ................................................................................................................. 9 
1.3 Sample Size ......................................................................................................................... 11 
2.0 Data Analysis Considerations ........................................................................................... 11 
2.1 Types of Analyses ............................................................................................................... 11 
2.2 Analysis Populations .......................................................................................................... 11 
2.3 Missing Data Conventions ................................................................................................. 12 
2.4 Interim Analyses ................................................................................................................. 13 
2.5 Study Center Considerations in the Data Analysis ......................................................... 14 
2.6 Documentation and Other Considerations....................................................................... 14 
3.0 Analysis of Baseline Subject Characteristics .................................................................. 14 
4.0 Analysis of Efficacy ............................................................................................................ 15 
4.1 Efficacy Variables ............................................................................................................... 15 
4.2 Efficacy Analysis ................................................................................................................. 16 
5.0 Analysis of Safety ............................................................................................................... 19 
5.1 Description of Safety Variables ......................................................................................... 19 
5.2 Description of Safety Analyses ......................................................................................... 20 
6.0 Other Relevant Data Analyses/Summaries ...................................................................... 21 
6.1 Subject Disposition ............................................................................................................. 21 
6.2 Protocol Deviations ............................................................................................................ 22 
6.3 Medical History and Concomitant Diseases .................................................................... 22 


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6.4 Prior and Concomitant Medications ................................................................................. 22 
6.5 Population Pharmacokinetics Analysis ............................................................................ 22 
6.6 Treatment Compliance ....................................................................................................... 22 
6.7 Anti-SARS-CoV-2 Antibodies ............................................................................................. 22 
7.0 References ........................................................................................................................... 23 
8.0 List of Analysis Tables, Figures and Listings .................................................................. 24 
 
 
 


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Abbreviations and Acronyms 
AE 
Adverse Event 
ARI 
Acute Respiratory Illness 
ATC 
Anatomic Therapeutic Chemical 
CDER 
Center for Drug Evaluation and Research 
COVID-19 
Novel Corona Virus Infectious Disease, 2019 
CMH 
Cochran-Mantel-Haenszel Chi-square Test 
FDA 
US Food and Drug Administration 
IAP 
Interim Analysis Plan 
LTCF 
Long Term Care Facility 
NTZ 
Nitazoxanide 
RT-PCR 
Reverse Transcriptase-Polymerase Chain Reaction 
SARS-CoV-2 
Severe Acute Respiratory Syndrome-Corona Virus 2, the pathogen 
causing COVID-19 
TEAE 
Treatment Emergent Adverse Event 
VRI 
Viral Respiratory Illness 
WHO 
World Health Organization 
 
 
 


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1.0 Synopsis of Study Design Procedures 
 
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 five days 
compared to a placebo for the treatment of mild or moderate COVID-19. 
 
The objectives of the study are: 
 
Primary Objective: To evaluate the effect of NTZ in reducing the time to Sustained 
Response compared to placebo in subjects with mild or moderate COVID-19 
 
Secondary Objective: To evaluate the effect of NTZ in reducing the rate of progression to 
Severe COVID-19 Illness compared to placebo 
 
Exploratory Objectives: To evaluate: 
i. 
The proportion of subjects positive for SARS-CoV-2 by Aptima® SARS-CoV-2 
Assay at each of Days 4 and 10 
ii. 
The change from baseline in quantitative SARS-CoV-2 RNA measured by RT-
PCR at each of Days 4 and 10 
iii. 
The effect of NTZ in reducing the rate of hospitalization compared to placebo 
iv. 
The effect of NTZ in reducing the rate of mortality compared to placebo 
 
Safety Objectives: Safety will be assessed by analysis of adverse events. 
 
1.1 Design and Treatment 
 
Subjects will be stratified according to the following criteria: 
 
• Severity of COVID-19 illness: mild, moderate 
• Time from onset of symptoms to randomization: < 36 hours, at least 36 hours 
• Risk of severe illness (per CDC): at increased risk, not at increased risk 
 
 Within strata, subjects will be randomized 1:1 to one of the following groups: 
• Group 1 (NTZ): Two 300 mg NTZ tablets b.i.d. (twice daily) for 5 days; 
• Group 2 (Placebo): Two placebo tablets b.i.d. for 5 days. 
 
All subjects will receive a vitamin B complex supplement one tablet twice a day 
(manufacturer’s labeled dosing) to help mask any potential chromaturia attributed to NTZ 
and aid in maintaining study blinding. 
 


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1.2 Study Procedures 
Screening 
Subjects will be screened on Study Day 1. After giving informed consent, the subject will 
be assigned a subject number and complete the following procedures:  
1. Collection of relevant medical history. 
2. Physical examination including body measurements and resting vital signs 
(blood pressure, pulse rate, respiratory rate, oxygen saturation, and oral 
temperature). 
3. Collection of demographic information and smoking history. 
4. Completion of the FLU-PRO questionnaire to confirm presence of symptoms 
required for eligibility. 
5. Evaluation according to eligibility (inclusion and exclusion) criteria. 
The information collected during the screening period must be current through the time 
of randomization. 
Baseline 
At Baseline (Study Day 1, the same day as the screening evaluation) the subject will be 
randomized and complete the following procedures: 
1. Collection of a nasopharyngeal swab sample for virology testing. 
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. Randomization and dispensing of study medication. Subjects will be considered 
enrolled in the study upon the randomized assignment to a treatment group. 
6. Administration of the first dose of study medication with food (< 1 hour after food 
intake) and a B complex vitamin (Super B-Complex™, Igennus Healthcare 
Nutrition, Cambridge, UK) under observation of Investigator or a member of 
Investigator’s staff, and entry in the medication administration record. 
7. Review/record adverse events. 
8. The subject will be instructed regarding the administration of study medication, 
completion of the electronic subject diary, use of birth control, follow-up visits at 
Study Days 4, 10, and 22, and on seeking emergency medical care or contacting 
the study physician or nurse under specific conditions, as listed in the protocol. 


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Treatment Period: Study Days 2 through 7 (Daily) 
Site staff will contact each subject by telephone on study Days 2-7 to verify whether the 
subject has: 
1. Completed all expected doses of study medications. 
2. Completed all expected electronic diaries. 
3. Worsening symptoms or adverse events warranting an unscheduled visit. 
4. Presence of shortness of breath at rest.  
Follow-up Visits 
Follow-up visits will occur on Day 4 + 1, Day 10 + 3, and Day 22 + 3. On Days 4 and 10 
the following assessments will be performed: 
1. Physical Examination, completed as necessary. 
2. Body weight and resting vital signs. 
3. Collect nasopharyngeal swab samples. 
4. Collect blood sample for pharmacokinetic analysis (Day 4 only). 
5. Record concomitant medications. 
6. Review and record adverse events. 
7. Review instructions re: dosing of study medication, concomitant medications, diary 
completion, follow-up visits, and emergency care. 
On Day 22 the following assessments will be performed: 
1. Physical Examination, completed as necessary. 
2. Body weight and resting vital signs. 
3. Collect blood sample for lab safety tests. 
4. Collect blood sample for antibody tests. 
5. Collect urine sample for routine urinalysis. 
6. Record concomitant medications. 
7. Review and record adverse events. 
8. Review instructions re: dosing of study medication, concomitant medications, diary 
completion, follow-up visits, and emergency care. 
Unscheduled Visits 
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: 


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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. 
4. Collection of urine sample for routine urinalysis. 
5. Review and recording of concomitant medications. 
6. Review and recording of adverse events. 
1.3 Sample Size 
The response definition planned for this study, the time from first dose to Sustained 
Response, was applied to data collected in Romark Institute for Medical Research studies 
RM08-3004 and RM08-3005, which evaluated the use of NTZ in the treatment of 
influenza (RM08-3004) and colds caused by Enterovirus/Rhinovirus (EV/RV) (RM08-
3005), respectively.  
For purposes of calculating sample size, we assume that the time to sustained response 
for SARS-CoV-2 infection is similar to influenza or colds caused by EV/RV. Based upon 
the influenza data, a sample of size 288 (144 per treatment group) would provide 90% 
power with  = 0.05 using the Gehan-Wilcoxon rank test. Based upon the EV/RV survival 
curves and the same testing parameters results in a required sample size of 312 subjects 
(156 per treatment group) to obtain 90% power. In order to ensure a robust dataset, a 
sample size of 350 subjects (175 per treatment group) was chosen including an allowance 
for approximately 10% of subjects to discontinue early or otherwise have missing data. If 
the pace of enrollment is high, the Sponsor will enroll up to 400 SARS-CoV-2 infected 
subjects.  
The Sponsor anticipates a SARS-CoV-2 positive rate between 50% and 75%, and hence 
enrolling 350-400 SARS-CoV-2 positive subjects may require enrolling 450 to 800 
subjects.  
2.0 Data Analysis Considerations 
 
2.1 Types of Analyses 
 
Data analyses will consist of analyzing subject characteristics and safety and efficacy 
data. 
 
2.2 Analysis Populations 
 
2.2.1 Population Definitions 
 
Subjects will be considered enrolled in the study upon completion of the baseline 
procedures. The following analysis populations will be used in the study. 


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• Intent-to-Treat (ITT) Population – the ITT population includes all subjects who 
are enrolled in the study and have received at least one dose of study medication 
(NTZ or placebo). 
• Intent-to-Treat Infected (ITTI) Population – the ITTI population includes all ITT 
subjects who are positive for SARS-CoV-2 by Aptima® SARS-CoV-2 assay at 
Baseline.  
• Per Protocol (PP) Population – the subset of the ITTI population with no major 
protocol deviations that may affect the integrity of the data or evaluation of 
effectiveness. Exclusion from the PP will be done before database lock. 
 
The ITT population will be used for all safety analyses. The ITTI population will be the 
primary population for all efficacy analyses.  
 
Data listings displaying the subjects excluded from each population will be created.  
These listings will be relative to all subjects enrolled in the study.  
 
2.2.2 Stratum and Subgroup Definitions 
 
Subjects will be stratified on the basis of Severity of COVID-19 illness (Mild or Moderate), 
Time from onset of symptoms to randomization (less than 36 hours or at least 36 hours), 
and Risk of severe illness per CDC guidelines (At increased risk or not at increased risk). 
There will be a total of 8 strata. 
 
The primary efficacy variable of the Time to Sustained Response will also be summarized 
by the following subgroups: 
 
• Risk of severe COVID-19 illness per CDC guidelines (At increased risk or not at 
increased risk) 
• Age (12-17, 18-64, ≥ 65) 
• Sex 
• Race (White/Non-white) 
 
Safety analyses will be grouped by treatment received.  
 
2.3 Missing Data Conventions 
 
Date variables with missing items will be imputed as shown in Table 2 below.  
 
Table 2. Imputation Rules for Missing Dates 
Data 
Handling Convention 
Adverse event onset 
date 
If onset date is completely missing, impute with the date of first dose. 
 
If year is missing, impute with the year of enrollment. 
 


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Data 
Handling Convention 
If only year or if year and day are present: 
• If year = year of first dose, then set month and day to the date of the first 
dose. 
• If year < year of first dose, then set month and day to December 31. 
• If year > year of first dose, then set month and day to January 1. 
 
If month and year are present, but day is missing: 
• If year = year of first dose and 
o If month = month of first dose, then set day to day of first dose. 
o If month < month of first dose, then set day to the last day of the month. 
o If month > month of first dose, then set day to the first day of the month. 
• If year < year of first dose, then set day to the last day of the month. 
• If year > year of first dose, then set day to the first day of the month. 
• For all other cases, set onset date to the date of first dose. 
Adverse event end date 
If the end date is partially or completely missing and AE outcome is not one 
of the following: RECOVERING/RESOLVING, NOT RECOVERED/NOT 
RESOLVED, UNKNOWN, or missing, then set to the last date the subject 
was known to be in the study.  Otherwise, if AE outcome is one of the 
following: RECOVERING/RESOLVING, NOT RECOVERED/NOT 
RESOLVED, UNKNOWN, or missing, then set the end date to missing. 
Concomitant medications 
start date 
If start date is completely missing, it will not be imputed. 
 
If only year or if year and day are present, set the month and day to 
January 1. 
 
If year and month are present and day is missing, set day to the first day of 
the month. 
Concomitant medications 
end date 
If end date is missing, frequency is “1X” and the medication is not listed as 
“ONGOING”, then end date should be set to equal the start date. 
 
If end date is completely missing, it will not be imputed. 
 
If only year or if year and day are present, set the month and day to 
December 31. 
 
If year and month are present and day is missing, set day to the last day of 
the month. 
 
2.4 Interim Analyses 
  
No interim analyses are planned. 
2.4.1 Analysis Timing Considerations 
It is anticipated that central lab data for the serology, quantitative SARS-CoV-2 RNA 
measured by RT-PCR, and the pharmacokinetics (PK) analysis of blood samples may be 
delayed at the end of the study, due to sample processing timelines.  These lab data will 
be transferred outside of the clinical database and will not impact the timing of database 
lock.  Further, these data have no impact on the primary and secondary efficacy 


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objectives of the study.  
At the Sponsor’s discretion, the final unblinded tables, listings, and figures (TLFs) using 
the locked database may be generated and shared with the Sponsor prior to completion 
of the serology, RT-PCR, and PK sample testing.   The central lab responsible for 
processing the serology, RT-PCR, and PK data will have no knowledge of the subjects’ 
treatment information nor any knowledge of the study outcomes while samples are being 
processed.  At the completion of sample processing, the central lab will transfer the 
serology, RT-PCR, and PK data directly to SCS to incorporate into the final study 
datasets.  The SAS programs used to generate the final study datasets will be re-run to 
include these new data files, and the final set of all TLFs will be generated.  This re-run 
of final TLFs will be conducted for the sole purpose of including the new central lab data; 
the TLFs generated prior to completion of serology, RT-PCR, and PK sample testing will 
remain unchanged.    
2.5 Study Center Considerations in the Data Analysis 
 
A study center is defined as a treatment administration site or group of treatment 
administration sites under the control and supervision of the same Principal Investigator 
(PI).  There will be no selective pooling of study centers – all sites will be pooled. The 
study is planned to be conducted at multiple sites. 
 
2.6 Documentation and Other Considerations 
 
The data analyses will be conducted using SAS Software, version 9.4 or later. 
 
3.0 Analysis of Baseline Subject Characteristics 
 
Baseline and demographic characteristics of the ITT and ITTI populations will be 
summarized. Continuous variables (age, baseline height, baseline weight) will be 
summarized via mean, standard deviation, minimum, median, maximum, interquartile 
range, and number of non-missing responses. Categorical variables (gender, race, and 
ethnicity) will be summarized via counts and percentages.   
 
A detailed listing of baseline data for each subject in the ITT population will also be 
provided. 


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4.0 Analysis of Efficacy 
 
4.1 Efficacy Variables 
 
4.1.1 Primary Efficacy Variable 
 
The primary efficacy variable is the Time to Sustained Response. This is defined as the 
time in days from the first dose of study medication to the time of the first diary entry 
meeting all the criteria for a sustained response (i.e., Time of Sustained Response). 
Sustained response to treatment is defined as a decrease in the total FLU-PRO score 
from the previous, subject assessment that symptoms are at least “somewhat better than 
yesterday”, no oral temperature > 100.4 F in the preceding 24 hours, and no future 
increase in any of the FLU-PRO domains except within the following levels: 
  
FLU-PRO Domain 
Background Level 
Body/Systemic 
0.56 
Throat 
0.67 
Eyes 
0.67 
Gastrointestinal 
2.00 
Head 
2.00 
Nose 
Larger of score at time of response or 0.75 
Chest 
Score at time of response  
Cough 
Larger of score at time of response or 1.75 
 
Subjects must have at least one diary following the time of sustained response in which 
there is no relapse, meaning that a subject cannot achieve sustained response at the 
last diary entry. 
 
Situation 
Censoring rule 
Has Time of Sustained Response 
Not censored. 
Hospitalized due to COVID-19 
Censored at Day 21 (i.e., hour 504). 
Died (any cause) 
Censored at Day 21 (i.e., hour 504). 
No Time of Sustained Response 
Censored at time of last diary entry 
without sustained response. 
 
4.1.2 Key Secondary and Exploratory Efficacy Variables 
 
The key secondary efficacy variable is Progression to Severe COVID-19 Illness. Any 
subject meeting both of the following criteria has advanced to Severe COVID-19 Illness: 
 
1. Shortness of breath at rest. 
2. SpO2 < 93% on room air, or PaO2/FiO2 < 300. 
 


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The exploratory efficacy variables are: 
 
1. Proportion of subjects positive for SARS-CoV-2 by Aptima® SARS-CoV-2 assay at 
Days 4 and 10. 
2. Change from baseline of quantitative SARS-CoV-2 RNA measured by RT-PCR at 
Days 4 and 10. 
3. Hospitalization due to COVID-19 or complications thereof. 
4. Mortality due to COVID-19 or complications thereof. 
 
4.2 Efficacy Analysis 
 
4.2.1 Primary Efficacy Analysis 
 
The Time to Sustained Response will be summarized with descriptive statistics (n, mean, 
standard deviation, minimum, maximum, median, and interquartile range) with censored 
values excluded from the descriptive statistics. 
 
The Time to Sustained Response will be tested for differences between the treatment 
groups using a stratified Gehan-Wilcoxon test at  = 0.05 using the stratification at 
randomization. Kaplan-Meier curves will be provided. The hypotheses being tested are 
 
H0: The survival curves of the NTZ Group and the Placebo Group are identical.
H1: The survival curves of the NTZ Group and the Placebo Group are different. 
 
The analysis table will include the Kaplan-Meier estimates of the mean and median for 
each treatment group. 
 
Subgroup analyses will be conducted on the subgroups specified in Section 2.2.2.  
Descriptive statistics and Kaplan-Meier estimates of the mean and median Time to 
Sustained Response will be provided by subgroup, but there will be no hypotheses tested 
in these subgroups.   
 
4.2.1.1 Sensitivity Analysis Using Log-rank Test 
 
The primary efficacy analysis will be repeated using a stratified log-rank test at  = 0.05 
using the stratification at randomization.  
 
4.2.1.2 Sensitivity Analysis for Major Protocol Deviations 
 
The primary efficacy analysis will be repeated for the PP population to assess the impact 
of subjects with major protocol deviations. 
 


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4.2.1.3 Sensitivity Analyses for Missing Data 
 
Our assumptions for missing data and subject discontinuation rates are based on 
observations from the approximately 2,800 subjects enrolled in studies RM08-3004 and 
RM08-3005. These studies enrolled a similar population to the one planned for this study, 
had a similar study design, and used the same diary requirements and strategies to 
minimize missing diary data. 
 
The majority of missing diary entries in RM08-3004 and RM08-3005 occurred after 
patient-reported return to usual health, which is consistent with findings in the validation 
study of FLU-PRO (Powers et al. 2018). Therefore, we expect that most missing data will 
not be informative regarding symptom course. Subjects missing a single diary entry after 
the time of Sustained Response had similar responses at the diary entries immediately 
before and after the missing entry.  
 
A sensitivity analysis will be performed assuming symptom worsening during all periods 
of potentially meaningful missing data. 
 
 
Situation 
Rule 
Subject discontinued study or was lost to 
follow up prior to achieving Sustained 
Response 
Censored at Day 21 (i.e., hour 504) 
Subject discontinued study or was lost to 
follow up after achieving Sustained 
Response 
Censored at Day 21 (i.e., hour 504) 
Subject missed at least two consecutive 
diary entries after achieving Sustained 
Response 
Assign the Time of Sustained Response 
to the next non-missing diary after the two 
consecutive missed diary entries 
 
4.2.2 Key Secondary and Exploratory Efficacy Analysis 
 
All key secondary and exploratory efficacy analyses will be performed for the ITTI 
population. 
 
4.2.2.1 Key Secondary Efficacy Analysis: Proportion of Subjects Progressing to 
Severe COVID-19 Illness 
 
The cross-tabulation (i.e., two-way table) of Progression to Severe COVID-19 illness 
versus treatment group will be provided, with conditional rates of progression for each 
treatment group. 
 
If the primary efficacy analysis is statistically significant at =0.05, the key secondary 
efficacy variable (Progression to Severe COVID-19 Illness) will be analyzed. The 
proportion of subjects in the NTZ and placebo groups experiencing progression to severe 


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COVID-19 illness will be analyzed using a CMH test stratified by randomization stratum 
with appropriate continuity correction at an unadjusted =0.05. The hypotheses tested 
are 
 
𝐻0: 𝑝𝑁𝑇𝑍= 𝑝𝐶𝑡𝑙
𝐻1: 𝑝𝑁𝑇𝑍≠𝑝𝐶𝑡𝑙, 
 
where pNTZ and pCtl respectively represent the rate at which NTZ subjects and placebo 
subjects progress to severe COVID-19 illness. The overall odds ratio and a 95% 
confidence interval for the odds ratio will be provided. 
 
4.2.2.2 Exploratory Analysis: Proportion of subjects Positive for SARS-CoV-2 by 
Aptima® SARS-CoV-2 Assay at Days 4 and 10 
 
Nasopharyngeal swabs for virology testing are scheduled to be taken on the Day 4 and 
Day 10 visits. The rates at which subject nasopharyngeal swabs test positive for SARS-
CoV-2 in the NTZ and placebo groups will be analyzed using a CMH test stratified by the 
randomization stratum with the appropriate continuity correction at an unadjusted  of 
0.05. The hypotheses tested are 
 
𝐻0: 𝑝𝑁𝑇𝑍= 𝑝𝐶𝑡𝑙
𝐻1: 𝑝𝑁𝑇𝑍≠𝑝𝐶𝑡𝑙, 
 
where pNTZ and pCtl respectively represent the rate at which NTZ subjects and placebo 
subjects test positive by the Aptima® SARS-CoV-2 assay. The overall odds ratio and a 
95% confidence interval for the odds ratio will be provided. The cross-tabulation of SARS-
CoV-2 status versus treatment group will be provided, with conditional rates for each 
treatment group. Day 4 and Day 10 data will be analyzed separately. 
 
4.2.2.3 Exploratory Analysis: Changes from Baseline in Quantitative SARS-CoV-
2 RNA Measured by RT-PCR 
 
Viral RNA levels will be determined for the Day 4 and Day 10 nasopharyngeal swabs by 
quantitative RT-PCR. The reported value will be transformed by log10(X+1), where X is 
the reported number of RNA copies/µL. The transformed values will be summarized with 
descriptive statistics (number of observations, mean, standard deviation, minimum, 
maximum, median) by treatment group. A Satterthwaite T-test will be used to test the 
hypotheses 
 
𝐻0: 𝜇𝑁𝑇𝑍= 𝜇𝐶𝑡𝑙
𝐻1: 𝜇𝑁𝑇𝑍≠𝜇𝐶𝑡𝑙, 
 
where NTZ and Ctl respectively represent the mean log10(RNA copies/µL) concentrations 
for the NTZ and placebo groups. A 95% confidence interval for the difference in means 
will be provided.  


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4.2.2.4 Exploratory Analysis: Proportion of Subjects Hospitalized Due to COVID-
19 or Complications Thereof 
 
The cross-tabulation of Hospitalization due to COVID-19 illness or complications thereof 
versus treatment group will be provided, with conditional rates for each treatment group. 
 
Hospitalization due to COVID-19 or complications thereof will be analyzed using a CMH 
test stratified by the randomization stratum with the appropriate continuity correction at 
an unadjusted  of 0.05. The hypotheses tested are 
 
𝐻0: 𝑝𝑁𝑇𝑍= 𝑝𝐶𝑡𝑙
𝐻1: 𝑝𝑁𝑇𝑍≠𝑝𝐶𝑡𝑙, 
 
where pNTZ and pCtl respectively represent the rate at which NTZ subjects and placebo 
subjects are hospitalized due to COVID-19 illness or its consequences. The overall odds 
ratio and a 95% confidence interval for the odds ratio will be provided. 
 
4.2.2.5 Exploratory Analysis: Proportion of Subjects with Mortality Due to COVID-
19 or Complications Thereof 
 
The cross-tabulation of Mortality due to COVID-19 illness or complications thereof versus 
treatment group will be provided, with conditional rates for each treatment group. 
 
Mortality due to COVID-19 or complications thereof will be analyzed using a CMH test 
stratified by the randomization stratum with the appropriate continuity correction at an 
unadjusted  of 0.05. The hypotheses tested are 
 
𝐻0: 𝑝𝑁𝑇𝑍= 𝑝𝐶𝑡𝑙
𝐻1: 𝑝𝑁𝑇𝑍≠𝑝𝐶𝑡𝑙, 
 
where pNTZ and pCtl respectively represent the rate at which NTZ subjects and placebo 
subjects die due to COVID-19 illness or its consequences. The overall odds ratio and a 
95% confidence interval for the odds ratio will be provided. 
 
5.0 Analysis of Safety  
 
5.1 Description of Safety Variables 
 
The safety analysis variables are defined as follows: 
 
• Adverse Events (AEs) 
• Clinical Laboratory Values (Hematology, Blood Chemistry, and Urinalysis) 
• Physical Exam 


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• Vital Signs 
 
The following describes the safety analyses to be performed for the study.  All safety 
analyses will be performed on the ITT population.  
  
5.2 Description of Safety Analyses 
 
Adverse Events  
Adverse events will be graded by the investigator according to the “Guidance for Industry: 
Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Trials” (FDA/CDER, 2007) as adapted in the Study Protocol. The 
investigator will also assess causality (relationship to treatment) as Definitely related, 
Probably related, Possibly related, and Unrelated. AEs will be coded using the Medical 
Dictionary for Regulatory Activities version 23.0 or higher (MedDRA®).  
 
Treatment-emergent AEs (TEAEs), defined as any AE that occurs after a subject receives 
the first dose of the assigned study treatment, will be summarized by the number and 
proportion of subjects reporting at least one occurrence of the AE.  Frequencies and rates 
of each TEAE will be summarized by MedDRA system organ class (SOC) and by 
preferred term within SOC, by severity grade, and relation to treatment for each treatment 
group.  The rate calculation will be based on the number of subjects in the ITT population 
for the relevant treatment group. 
 
Treatment emergent serious adverse events (TESAEs) will be summarized and displayed 
by frequency and rate by MedDRA SOC and by preferred term within SOC. 
 
A by-subject AE data listing of all adverse events including verbatim term, coded term, 
grade, and relation to treatment will be provided.   
 
Laboratory Tests  
Clinical laboratory tests will be performed at baseline and on Day 10. The following clinical 
laboratory tests will be performed:   
 
Hematology:  
Hemoglobin, hematocrit, complete white blood count (total and differential), 
platelet count, random blood glucose, total cholesterol, HDL, LDL, and 
triglycerides. 
Clinical Chemistry: 
Albumin, AST, ALT, GGT, alkaline phosphatase, bilirubin (total and direct), BUN, 
creatinine, sodium, potassium, and chloride. 
Urinalysis:  
Appearance, glucose, protein, and blood. 
 
Clinical laboratory results and the change from baseline (CFB, baseline defined as the 
value at the baseline visit) will be summarized for the ITT population with summary 


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statistics (mean, standard deviation, n, minimum, median, maximum) by visit for each 
treatment group.  
 
Clinical laboratory results will be classified according to the toxicity grading tables in the 
protocol Appendix 4 and will be summarized using a shift table from baseline according 
to these categories. 
 
All clinically significant abnormal laboratory findings will be reported as AEs. All AEs 
recorded will be listed. 
 
Physical Exam  
Physical exams (PEs) will be performed at baseline and at Days 4, 10 and 22 as needed 
due to symptoms or other changes from baseline.  All clinically significant abnormal PE 
findings will be recorded as AEs.  A shift table will be constructed to display changes in 
physical examination classification (Normal/Abnormal/Not Done) at each visit by body 
system for the ITT population.  All physical exam data will be listed. 
 
Vital Signs  
Vital signs will include weight, heart rate, respiratory rate, blood pressure (diastolic and 
systolic), temperature and oxygen saturation.  Vital signs will be taken at baseline, Day 
4, Day 10, and Day 22. If repeat vital signs are taken at a given time point, then the last 
measurement will be used for the analysis tables.   
 
Vital signs will be summarized for the ITT population with summary statistics (mean, 
standard deviation, n, minimum, median, maximum) by visit and treatment group for the 
raw and change from baseline values. All vital signs will be listed. 
 
6.0 Other Relevant Data Analyses/Summaries 
 
6.1 Subject Disposition  
 
Tables will be constructed with counts and percentages of subjects who complete or 
discontinue from the study and the mean (SD), median (IQR), and minimum and 
maximum number of days in the study.  The number of days in the study will be computed 
as the difference in the date of completion (or discontinuation) minus the date of 
randomization plus 1 day.  Disposition will be summarized for the ITT and ITTI 
populations.  
 
A data listing of all subjects’ completion status with withdrawal reasons will also be 
constructed. 
 


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6.2 Protocol Deviations  
 
Tables will be constructed with counts and percentages of subjects with protocol 
deviations by deviation classification (major or minor) and the common deviation term.  
Deviations will be summarized for the ITT and ITTI populations.  
 
A data listing of all reported protocol deviations will also be constructed. 
 
6.3 Medical History and Concomitant Diseases  
 
Medical history and concomitant diseases will be presented in data listings for the ITT 
population. Medical history and concomitant disease terms will be coded using the current 
version of MedDRA and summarized separately for the ITT and ITTI populations. 
 
6.4 Prior and Concomitant Medications  
 
Prior and concomitant medications will be listed for the ITT population. Prior and 
concomitant medications will be coded using the current version of the WHO Drug 
Dictionary and summarized separately for the ITT and ITTI populations. 
 
6.5 Population Pharmacokinetics Analysis 
 
On Day 4, plasma samples will be collected before the morning dose (at the trough) for 
determination of drug concentration. 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 NTZ-treated subjects. 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.   
 
6.6 Treatment Compliance 
 
Treatment compliance tables will summarize the total number of days on therapy and 
number of tablets taken using descriptive statistics for the ITT and ITTI populations. 
 
6.7 Anti-SARS-CoV-2 Antibodies 
 
Descriptive statistics of Anti-SARS-CoV-2 IgG and IgM titers (mean, standard deviation, 
minimum, median, maximum, and interquartile range, raw values and change from 
baseline) will be presented.  


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7.0 References 
FDA/CDER Guidance for Industry: Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials. US Department of 
Health and Human Services. September 2007. (Retrieved 28April2020 from 
https://www.fda.gov/media/73679/download). 
 
Powers JH 3rd, Bacci ED, Guerrero ML, et al. Reliability, Validity, and Responsiveness 
of InFLUenza Patient-Reported Outcome (FLU-PRO©) Scores in Influenza-Positive 
Patients. Value Health. 2018;21(2):210-218. 
 
 
 
 


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8.0 List of Analysis Tables, Figures and Listings 
 
Table No. 
Table Title 
14.1.1.1 
Subject Disposition Summary by Treatment and Overall (ITT Population) 
14.1.1.2 
Subject Disposition Summary by Treatment and Overall (ITTI Population) 
14.1.2.1 
Summary of Protocol Deviations (ITT Population) 
14.1.2.2 
Summary of Protocol Deviations (ITTI Population) 
14.1.3.1 
Summary of Baseline Demographic Characteristics (ITT Population) 
14.1.3.2 
Summary of Baseline Demographic Characteristics (ITTI Population) 
14.1.4.1 
Summary of Prior Medication (ITT Population) 
14.1.4.2 
Summary of Prior Medication (ITTI Population) 
14.1.5.1 
Summary of Concomitant Medication (ITT Population) 
14.1.5.2 
Summary of Concomitant Medication (ITTI Population) 
14.1.6.1 
Summary of Medical History (ITT Population) 
14.1.6.2 
Summary of Medical History (ITTI Population) 
14.1.7.1 
Summary of Concomitant Diseases (ITT Population) 
14.1.7.2 
Summary of Concomitant Diseases (ITTI Population) 
14.1.8.1 
Summary of Treatment Compliance (ITT Population) 
14.1.8.2 
Summary of Treatment Compliance (ITTI Population) 
14.2.1.1.1 
Analysis of Time to Sustained Response (ITTI Population) 
14.2.1.2.1 
Analysis of Time to Sustained Response by Subgroups (ITTI Population) 
14.2.2.1.1 
Sensitivity Analysis of Time to Sustained Response Using a Log-rank Test (ITTI 
Population) 
14.2.2.2.1 
Sensitivity Analysis of Time to Sustained Response for the Per Protocol Population (PP 
Population) 
14.2.2.3.1 
Sensitivity Analysis of Time to Sustained Response to Assess the Impact of Missing 
Data (ITTI Population) 
14.2.3 
Cochran-Mantel-Haenszel Test Results: Proportion of Subjects Progressing to Severe 
COVID-19 Illness (ITTI Population) 
14.2.4.1 
Cochran-Mantel-Haenszel Test Results: Proportion of Subjects Positive for SARS-CoV-
2 by Aptima SARS-CoV-2 Assay at Day 4 (ITTI Population) 
14.2.4.2 
Cochran-Mantel-Haenszel Test Results: Proportion of Subjects Positive for SARS-CoV-
2 by Aptima SARS-CoV-2 Assay at Day 10 (ITTI Population) 


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Table No. 
Table Title 
14.2.5.1 
Summary of Quantitative SARS-CoV-2 RNA Measured by RT-PCR by Treatment (ITTI 
Population) 
14.2.5.2 
Satterthwaite T-test Results: Change from Baseline in Quantitative SARS-CoV-2 RNA 
Measured by RT-PCR at Day 4 and Day 10 (ITTI Population) 
14.2.6 
Cochran-Mantel-Haenszel Test Results: Proportion of Subjects Hospitalized Due to 
COVID-19 or Complications Thereof (ITTI Population) 
14.2.7 
Cochran-Mantel-Haenszel Test Results: Proportion of Subjects with Death Due to 
COVID-19 or Complications Thereof (ITTI Population) 
14.2.8 
Summary of SARS-CoV-2 IgG and IgM Antibodies Raw and Change from Baseline 
Values (ITTI Population) 
14.2.9 
Analysis of Plasma Tizoxanide and Tizoxanide Glucuronide Concentrations (ITTI 
Population) 
14.3.1.1 
Summary of All Treatment Emergent Adverse Events (ITT Population) 
14.3.1.2 
Treatment Emergent Adverse Events by System Organ Class, Preferred Term, and 
Treatment (ITT Population) 
14.3.1.3 
Treatment Emergent Adverse Events by System Organ Class, Preferred Term, 
Treatment, and Severity (ITT Population) 
14.3.1.4 
Treatment Emergent Adverse Events by System Organ Class, Preferred Term, 
Treatment, and Relationship to Treatment (ITT Population) 
14.3.1.5 
Treatment Emergent Serious Adverse Events by System Organ Class, Preferred Term, 
and Treatment (ITT Population) 
14.3.2.1 
Clinical Laboratory Summary Statistics: Hematology by Treatment (ITT Population) 
14.3.2.2 
Clinical Laboratory Shift Tables: Hematology by Treatment (ITT Population) 
14.3.3.1 
Clinical Laboratory Summary Statistics: Clinical Chemistry by Treatment (ITT 
Population) 
14.3.3.2 
Clinical Laboratory Shift Tables: Clinical Chemistry by Treatment (ITT Population) 
14.3.4.1 
Clinical Laboratory Summary Statistics: Urinalysis by Treatment (ITT Population) 
14.3.4.2 
Clinical Laboratory Shift Tables: Urinalysis by Treatment (ITT Population) 
14.3.5 
Vital Signs Summary Statistics for Raw and Change from Baseline Values by Treatment 
(ITT Population) 
14.3.6 
Physical Examination Shift Tables by Treatment (ITT Population) 
 
 


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Listing No. 
 
Data Listing Title 
16.2.1 
Discontinued Subjects (ITT Population) 
16.2.2 
Protocol Deviations Listing (ITT Population) 
16.2.3 
Subjects Excluded from the ITTI and PP Populations (ITT Population) 
16.2.4.1 
Subject Demographics Listing (ITT Population) 
16.2.4.2 
Medical History Listing (ITT Population) 
16.2.4.3 
Prior and Concomitant Medications Listing (ITT Population) 
16.2.5.1 
Treatment Exposure Listing (ITT Population) 
16.2.5.2 
Plasma Tizoxanide and Tizoxanide Glucuronide Listing (ITT Population) 
16.2.6.1 
Subject Primary Efficacy and Sensitivity Analysis Variables Listing: Time to Sustained 
Response (ITTI Population) 
16.2.6.2 
Subject Secondary Efficacy Variables Listing: Progression to Severe COVID-19 Illness 
(ITTI Population) 
16.2.6.3 
Subject Exploratory Efficacy Variables Listing: Hospitalization Status, Mortality (ITTI 
Population) 
16.2.7.1 
Adverse Events Listing (ITT Population) 
16.2.7.2 
Serious Adverse Events Listing (ITT Population) 
16.2.7.3 
Subject Deaths Listing (ITT Population) 
16.2.8.1 
Virology Results Listing (ITT Population) 
16.2.8.2 
Serology Results Listing (ITT Population) 
16.2.8.3 
Hematology Listing (ITT Population) 
16.2.8.4 
Clinical Chemistry Listing (ITT Population) 
16.2.8.5 
Urinalysis Listing (ITT Population) 
16.2.9.1 
Physical Examination Listing (ITT Population) 
16.2.9.2 
Vital Signs Listing (ITT Population) 
 
 
 
Figure No. 
 
Figure Title 
14.2.1.1.2 
Kaplan-Meier Survival Curves for Time to Sustained Response (ITTI Population) 
14.2.1.2.2 
Kaplan-Meier Survival Curves for Time to Sustained Response – by Risk of Severe 
COVID-19 Illness (ITTI Population) 


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Figure No. 
 
Figure Title 
14.2.1.2.3 
Kaplan-Meier Survival Curves for Time to Sustained Response – by Age Category 
(ITTI Population) 
14.2.1.2.4 
Kaplan-Meier Survival Curves for Time to Sustained Response – by Sex (ITTI 
Population) 
14.2.1.2.5 
Kaplan-Meier Survival Curves for Time to Sustained Response – by Race (ITTI 
Population) 
14.2.2.2.2 
Kaplan-Meier Survival Curves for Sensitivity Analysis of Time to Sustained Response 
for the Per Protocol Population (PP Population) 
14.2.2.3.2 
Kaplan-Meier Survival Curves for Sensitivity Analysis of Time to Sustained Response 
to Assess the Impact of Missing Data (ITTI Population)