A Multicenter, Randomized, Double-blinded, Placebo-controlled, Phase 3 Clinical Efficacy Study Evaluating Nitric Oxide Nasal Spray (NONS) as Prevention for Treatment of Individuals at Risk of Exposure to COVID-19 Infection
Phase: PHASE3
Conditions: SARS-CoV-2 Infection
Sponsor: Sanotize Research and Development corp.

Clinical Trial Protocol: COVID-NONS-04 
TITLE PAGE 
Study Title: 
Multicenter, randomized, double-blinded, placebo-controlled, phase 3 
clinical efficacy study evaluating nitric oxide nasal spray (NONS) as 
prevention for treatment of individuals at risk of exposure to COVID-
19 infection 
Study Number: 
COVID-NONS-04 [NCT05109611] 
Study Phase: 
3 
Product Name: 
NONS (nitric oxide nasal spray) 
Control 
Number: 
Health Canada NOL c252244 
EudraCT 
Number: 
2021-004394-31 
Indication: 
Prevention of COVID-19 infection 
Investigators: 
Multicenter 
Sponsor: 
SaNOtize Research and Development Corporation 
8755 Ash Street, Suite 1  
Vancouver, BC, V6P 6T3 (Canada) 
Sponsor  
Contact: 
SaNOtize Research and Development Corporation 
Chris Miller, PhD, CSO 
Medical  
Monitor: 
Keith Moore, PharmD, FCCP, BCPS (Sponsor’s Designee) 
CSO, ICIOMICS Life Sciences, LLC 
759 Wessel Drive, Suite 1 
Fairfield, Ohio 45014 (USA) 
+1 513-226-5801 
Original  
Protocol: 
12 May 2021 
Revised 
Protocol: 
08 December 2021 (Version 1.2) 
 
 
Confidentiality Statement 
The confidential information in the following document is provided to you as an 
Investigator, potential Investigator, or consultant for review by you, your staff, and 
applicable Institutional Review Board (IRB)/Independent Ethics Committee (EC) or 
regulatory Health Authority. The information contained herein should not be 
disclosed to others, without written authorization from SaNOtize.  
 

NONS (nitric oxide nasal spray) 
 
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Clinical Trial Protocol: COVID-NONS-04 Prevention  
08 December 2021 
 
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TABLE OF CONTENTS 
TITLE PAGE .............................................................................................................................1 
TABLE OF CONTENTS ...........................................................................................................2 
LIST OF TABLES .....................................................................................................................5 
LIST OF FIGURES ...................................................................................................................6 
LIST OF APPENDICES ............................................................................................................6 
SYNOPSIS .................................................................................................................................7 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................12 
1 
INTRODUCTION ...........................................................................................................14 
1.1 
Nitric Oxide as a Therapeutic Agent .....................................................................14 
1.1.1 
Nitric Oxide Viricidal Properties .................................................................14 
1.1.2 
Nitric Oxide Antiviral Properties .................................................................14 
1.1.3 
Angiotensin Converting Enzyme-2 Inhibition .............................................15 
1.2 
Nitric Oxide Mechanism of Action ........................................................................15 
1.3 
Nitric Oxide Releasing Solution (NORS) ..............................................................15 
1.4 
Nitric Oxide Nasal Spray Effect on SARS-CoV-2 Clinical Isolates .....................16 
1.5 
Nitric Oxide Nasal Spray Effects in Humans ........................................................17 
1.5.1 
Nitric Oxide Nasal Spray (NONS) for the Treatment of Mild COVID-
19 Infection Trial .........................................................................................17 
1.5.2 
Nitric Oxide Nasal Spray COVID-19 Prevention Trial ...............................18 
1.5.3 
Nitric Oxide Nasal Spray Background ........................................................18 
2 
STUDY OBJECTIVES AND ENDPOINTS ...................................................................19 
2.1 
Primary Objective and Endpoint ............................................................................19 
2.2 
Secondary Objectives and Endpoints.....................................................................19 
3 
INVESTIGATIONAL PLAN ..........................................................................................20 
3.1 
Overall Study Design and Plan ..............................................................................20 
3.2 
Rationale for Study Design and Control Group .....................................................21 
3.2.1 
Rationale for Use of Nitric Oxide for COVID-19 Therapy .........................21 
3.2.2 
Rationale for use of a Nitric Oxide Releasing Solution Spray (NONS) 
Formulation ..................................................................................................21 
3.2.3 
Rationale for Multicenter Trial Design ........................................................21 
3.3 
Study Duration and Dates ......................................................................................22 
3.3.1 
End of Study Definition ...............................................................................22 
4 
STUDY POPULATION SELECTION ...........................................................................23 
4.1 
Study Population ....................................................................................................23 
4.2 
Inclusion Criteria ...................................................................................................23 
4.3 
Exclusion Criteria ..................................................................................................24 
5 
STUDY TREATMENT ...................................................................................................25 

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5.1 
Description of Treatment .......................................................................................25 
5.2 
Treatments Administered .......................................................................................25 
5.3 
Selection and Timing of Dose for Each Participant ...............................................26 
5.4 
Method of Assigning Participants to Treatment Groups .......................................26 
5.5 
Blinding..................................................................................................................27 
5.6 
Concomitant Therapy.............................................................................................28 
5.7 
Lifestyle Considerations ........................................................................................28 
5.7.1 
Prior Therapy ...............................................................................................28 
5.7.2 
Fluid and Food Intake Considerations .........................................................28 
5.7.3 
Patient Activity Restrictions ........................................................................28 
5.8 
Screen Failures .......................................................................................................28 
5.9 
Treatment Compliance ...........................................................................................29 
6 
STUDY PROCEDURES .................................................................................................30 
6.1 
Informed Consent...................................................................................................30 
6.1.1 
Emergency Contact Informed Consent ........................................................30 
6.2 
Screening Assessment ............................................................................................30 
6.3 
Demographics, Medical History, and Physical Examination ................................30 
6.4 
Clinical Laboratory Assessments ...........................................................................31 
6.4.1 
Urine Pregnancy Test ...................................................................................31 
6.5 
Dispensing Study Drug ..........................................................................................31 
6.6 
Efficacy Assessments.............................................................................................32 
6.6.1 
Daily Treatment Diary and Questionnaire (eCRF) ......................................32 
6.6.2 
In-Person On-Site/Telephone Contact .........................................................32 
6.6.3 
Remote Video Conferencing........................................................................33 
6.6.4 
COVID-19 Symptoms List ..........................................................................33 
6.6.5 
Early Termination Assessment ....................................................................33 
7 
ADVERSE EVENTS ASSESSMENTS ..........................................................................34 
7.1 
Adverse Event Definition ......................................................................................34 
7.2 
Method of Detecting AEs and SAEs .....................................................................34 
7.3 
Performing Adverse Events Assessments ..............................................................35 
7.4 
Timing ....................................................................................................................35 
7.4.1 
Reportability ................................................................................................35 
7.4.2 
Severity ........................................................................................................36 
7.4.3 
Relationship between Adverse Event and Study Drug ................................36 
7.4.4 
Adverse Drug Events ...................................................................................37 
7.4.5 
Expectedness ................................................................................................37 
7.5 
Adverse Event and Concomitant Mediations Coding ............................................37 
7.6 
Reporting Serious Adverse Events and COVID-19 Reporting..............................37 

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7.6.1 
Serious Adverse Event and Suspected Unexpected Serious Adverse 
Reaction Reporting ......................................................................................37 
7.6.2 
Study Sponsor Notification of Adverse Event Outcome by Investigator ....38 
7.6.3 
Institutional Review Board/ Independent Ethics Committee Notification ..38 
7.6.4 
Regulatory Reporting Requirements for Serious Adverse Events ...............38 
7.6.5 
COVID-19 Health Authority Notification ...................................................39 
7.7 
Treatment-Emergent Adverse Events ....................................................................39 
7.8 
Adverse Events of Special Interest ........................................................................39 
7.9 
Adverse Event, Serious Adverse Event, and Adverse Events of Special 
Interest Follow-Up .................................................................................................39 
7.10 
Pregnancy Reporting ..............................................................................................39 
7.11 
Concomitant Medication Assessments ..................................................................40 
7.12 
Safety Follow-Up ...................................................................................................40 
7.12.1 
Removal of Participants from the Trial or Study Treatment .......................40 
 
Discontinuation from Study Drug Treatment ....................................40 
 
Discontinuation from Study ...............................................................41 
 
Data Collection and Follow Up for Withdrawn Participants .............41 
7.12.2 
Participant Replacement ..............................................................................42 
7.12.3 
Lost to Follow-Up ........................................................................................42 
7.13 
Study Stopping Rules .............................................................................................42 
7.14 
Appropriateness of Measurements .........................................................................42 
8 
CLINICAL TRIAL MATERIALS ..................................................................................43 
8.1 
Study Treatment Supplies ......................................................................................43 
8.1.1 
Nitric Oxide Nasal Spray and Placebo.........................................................43 
8.2 
Packaging and Labeling .........................................................................................43 
8.3 
Distribution and Supply Management ...................................................................43 
8.4 
Storage and Accountability ....................................................................................43 
8.4.1 
Study Treatment Storage..............................................................................43 
8.4.2 
Study Treatment Accountability ..................................................................44 
8.5 
Investigational Product Retention at Sponsor ........................................................44 
8.6 
Preparation of Study Treatment .............................................................................44 
8.7 
Use of the Spray Bottle ..........................................................................................44 
9 
PLANNED STATISTICAL METHODS ........................................................................45 
9.1 
General Considerations ..........................................................................................45 
9.2 
Determination of Sample Size ...............................................................................45 
9.3 
Analysis Populations ..............................................................................................46 
9.4 
Demographics and Baseline Characteristics ..........................................................47 
9.5 
Analysis of Efficacy ...............................................................................................47 
9.5.1 
Primary Efficacy Analysis ...........................................................................47 

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9.5.2 
Secondary Efficacy Analysis .......................................................................48 
9.5.3 
Exploratory Analysis ...................................................................................49 
9.5.4 
Analysis of Safety ........................................................................................49 
9.6 
Interim Analysis .....................................................................................................49 
10 QUALITY CONTROL AND ASSURANCE .................................................................50 
10.1 
Regulatory and Ethical Considerations ..................................................................50 
10.1.1 
Data Protection.............................................................................................51 
10.1.2 
Dissemination of Clinical Study Data..........................................................51 
10.1.3 
Auditing and Inspecting ...............................................................................51 
11 ADMINISTRATIVE CONSIDERATIONS ....................................................................53 
11.1 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) 
Approval ................................................................................................................53 
11.2 
Ethical Conduct of the Study .................................................................................53 
11.3 
Participant Information and Consent .....................................................................53 
11.4 
Patient Confidentiality ...........................................................................................54 
11.5 
Study Monitoring ...................................................................................................54 
11.6 
Case Report Forms and Study Records .................................................................55 
11.7 
Data Monitoring Committee ..................................................................................55 
11.8 
Protocol Violations/Deviations ..............................................................................55 
11.9 
Access to Source Documentation ..........................................................................55 
11.10 Principal Investigator Sign-Off on Electronic Case Report Forms .......................56 
11.11 Data Generation and Analysis ...............................................................................56 
11.12 Retention of Data ...................................................................................................56 
11.13 Financial Disclosure...............................................................................................56 
11.14 Publication and Disclosure Policy .........................................................................56 
12 REFERENCE LIST .........................................................................................................58 
13 APPENDICES .................................................................................................................61 
Centers for Disease Control COVID-19 Symptoms List .............................................64 
Health Canada COVID-19 Symptoms List..................................................................64 
 
LIST OF TABLES 
Table 1 
 Identity of Investigational Product............................................................43 
Table 2 
 Daily COVID-19 Counts ..........................................................................46 
Table 3 
 Populations for Analysis ...........................................................................47 
Table 4  
Schedule of Events .....................................................................................62 
 

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LIST OF FIGURES 
Figure 1 
 Nitric Oxide Mechanisms of Action Against SARS-CoV-2 ....................15 
Figure 2 
 Virucidal Effect of Nitric Oxide Spray .....................................................17 
Figure 3 
 Nitric Oxide Nasal Spray ..........................................................................25 
Figure 4 
 Study Schema............................................................................................26 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Events .....................................................................................62 
Appendix 2 
COVID-19 Symptoms List ........................................................................64 
Appendix 3 
Electronic Patient-Reported Outcomes Survey .........................................65 
Appendix 4 
Sponsor Signatures.....................................................................................68 
Appendix 5 
Investigator’s Signature .............................................................................69 
 
 

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SYNOPSIS 
Sponsor: 
SaNOtize Research and Development Corporation 
Name of Finished Product: 
NONS (nitric oxide nasal spray)  
Name of Active Ingredient: 
NONS (nitric oxide nasal spray) 
Study Title: 
Multicenter, randomized, double-blinded, placebo-controlled, phase 3 clinical efficacy 
study evaluating nitric oxide nasal spray (NONS) as prevention for treatment of 
individuals at risk of exposure to COVID-19 infection 
Study Number: 
COVID-NONS-04 
Study Centers: 
This is a multicenter trial; however regional study centers will be established to facilitate 
study assessments and distribution of study treatment to participants 
Study Phase: 3 
Primary Objective(s):  
To assess the efficacy of nitric oxide nasal spray (NONS) in the reduction of risk of 
coronavirus disease-19 (COVID-19) infection. 
Secondary Objective(s): 
To assess the efficacy of NONS in reduction of risk of the need for medical intervention 
resulting from COVID-19. 
Assess tolerability of NONS in participants with COVID-19. 
Study Design: 
This is a multicenter, randomized, double blinded, placebo controlled, Phase 3 clinical 
efficacy study evaluating NONS in healthy adult volunteers as a prevention treatment for 
individuals at risk from COVID-19 infection. Participants aged 18 or over with no known 
history of SARS-CoV-2 infection will be enrolled into one of two cohorts of this study in a 
ratio of 1:1 (Treatment: Placebo Control). Participants with or without underlying medical 
conditions will be eligible to enroll. 
Participants will self-administer a nasal spray three (3) times per day, morning, noon, and 
night containing either blinded study treatment or placebo (herein called study treatment). 
Nitric oxide nasal spray will be delivered from manual pump nasal spray bottle (containing 
25 mL of solution) with each nasal spray dispensing approximately 130-150 µL of 
solution. Each treatment will require two sprays per nostril (1 spray per nostril, repeated 
once), or about 0.56 mL per treatment (4 sprays total per dose). 
The primary endpoint is to assess the efficacy of NONS in the prevention of COVID-19 
infection as determined by a positive COVID-19 test (antigen or reverse-transcriptase 

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polymerase chain reaction [RT-PCR]). Positive test results obtained within 48 hours of 
randomization will be considered infected at randomization and not counted as events. 
The secondary endpoints are to determine the proportion for participants requiring 
hospitalization or emergency room (ER/emergency department [ED]) visits for COVID-19 
or flu-like symptoms by Day 28 and assess the safety/tolerability of the use of NONS in 
participants for the prevention of COVID-19. 
This study will be a multicenter trial, allowing remote and in-person on-site visits, 
including telephone contact, as applicable per respective country regulatory legislation. All 
data collection and monitoring to be performed remotely where possible. Screening and 
enrollment will take place through an online portal and through telehealth assessments, 
unless in a region that does not accept an eICF, in which case the consenting procedure 
will occur in-person on-site (screening and baseline procedures may also be performed in- 
person on-site). Participants will receive study treatment shipped directly to their homes 
unless in a region (European Union [EU]) or other location where the participant must 
receive the study product directly from the sites’ staff/physician. Participants in the EU 
will have three in-person visits (screening visit, baseline visit [unless screening and 
baseline can occur on the same day] and a post-treatment visit). Participants will enter their 
study treatment dates and times and describe any symptoms in an online questionnaire (or 
paper diary cards if required). 
Study Population:  
The study population will consist of healthy volunteer males and females of any ethnic 
background aged at least 18 years of age with no prior history of a COVID-19 infection, or 
current SARS-CoV-2 infection.  
Inclusion Criteria:  
Each participant must meet the following criteria to be enrolled in this study. 
1. At least aged 18 years old at the time of consent. 
2. If female, be surgically sterile or post-menopausal (no menses for at least 12 months), 
or if of child-bearing potential, must be using an acceptable method of contraception 
such as a combination estrogen/progestin hormonal contraceptive (oral or injected) for 
at least 1 month prior to Day 1, or such items as an intrauterine device (IUD), 
intrauterine system (IUS), transdermal hormonal implant, vaginal hormonal ring, or 
two forms of the following: diaphragm, cervical cap, patch, condom, spermicide, or 
sponge. Total abstinence is permitted. If local regulations deviate from the previously 
listed contraception methods to prevent pregnancy, local requirements will apply. In 
addition, females of child-bearing potential must agree to continue to use their method 
of birth control for the duration of the study and 12 weeks following discharge from the 
study. 
3. If male, be surgically sterile, or agree to use appropriate contraception (latex condom 
with spermicide) when engaging in sexual activity and agree to not donate sperm for 
the duration of the study and 12 weeks following discharge from the study. 
4. Be in good health (ie, no acute illnesses or hospitalizations within 30 days of the study 
start, no planned procedures during study participation, and no newly diagnosed 
chronic illnesses that are not deemed stable by the participant’s primary care 

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physician), in the opinion of the Investigator, based on medical history (ie, absence of 
any clinically relevant abnormality) during Screening. 
5. Be able to understand and provide written, informed consent. 
6. Access to a telephone, the internet, a device that reliability connects to the internet, and 
able to dial into Telehealth checkups and study related assessments is required; 
however, if access to the internet precludes involvement, then paper diaries may be 
completed and promptly entered into the data capture system at the study centers as 
part of regular follow-up visits. 
7. Must be able to receive study product shipments directly to their home (ie, no Post 
Office Boxes), unless in a region (EU) or other location where the participant must 
receive the study product directly from the sites’ staff/physician.  
 
Exclusion Criteria:  
Participants who meet any of the following criteria will be excluded from the study. 
1. Participants with acute illnesses or hospitalizations within 30 days of the study start, 
and/or planned procedures during study participation, and/or newly diagnosed chronic 
illnesses that are not deemed stable by the participant’s primary care physician), based 
on Investigator assessment of medical history during Screening. 
2. Participants with any respiratory infection, flu-like symptoms, or unexplained fever or 
chills during the week prior to Screening. 
3. Participants with any prior history of SARS-CoV-2 infection. 
4. Participants who use intranasally dosed drugs, prescriptions or over-the-counter 
medications such as fluticasone within the last 7 days. 
5. Participants who underwent a previous tracheostomy. 
6. Participants who are receiving any form of oxygen therapy. 
7. Females who are breastfeeding, pregnant, or attempting to become pregnant. 
8. Participants who have any other condition that, in the opinion of the Investigator, 
would interfere with a participant’s ability to adhere to the protocol (eg, participants 
whom are mentally or neurologically disabled and whom are considered not fit to their 
participation in the study), interfere with assessment of the investigational product, or 
compromise the safety of the participant or the quality of the data. 
 
Planned Number of Participants: 13,000 to be randomized with a maximum of 11,480 
participants initiating study treatment. 
Test Product, Dose, and Mode of Administration: The test product is nitric oxide (NO) 
releasing solution delivered in the form of a nasal spray which will be self-administered 
three (3) times per day, morning, noon, and night for 28 days.  
The comparator is a placebo of saline solution to be self-administered as the test product. 
Duration of Treatment: Participants will be on study for 5 weeks (to include 1 week of 
screening/baseline, 4 weeks of treatment, 1 week of Follow-Up). 

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Efficacy Assessments: Participants will self-assess COVID-19-related symptoms, report if 
they have tested positive for COVID-19, and report if they need hospitalization or an ER 
visit. A positive COVID-19 test can be either by antigen or SARS-CoV-2 RT-PCR.    
Safety Assessments: Adverse events (AEs) and discontinuations of treatment will be 
collected, and the number of participants that are hospitalized or visit the ED or ER for 
COVID-19/flu-like symptoms. 
Study Endpoints: Primary Endpoint: Confirmed positive COVID-19 test (Both antigen 
and SARS-CoV-2 RT-PCR are acceptable) by Day 28. 
Secondary Endpoint: Hospitalization or ER/ED visits for COVID-19/flu-like symptoms 
by Day 28. 
Safety Endpoint: AEs and discontinuation of treatment. 
Statistical Methods:  
Determination of Sample Size: For an annualized infection rate of 3% in the placebo arm 
(daily incidence = 0.000075), and assuming a true hazard ratio of 0.15 implying protective 
effect of NONS equivalent to a vaccine efficacy of 85%, a sample size of 11,480 
participants randomized 1:1 (NONS:Placebo) and available in the modified intent-to-treat 
(mITT) population will provide 90% power to demonstrate superiority of NONS to 
placebo in preventing COVID-19 infections reported through 28 days, based on Cox 
regression model and a 2-sided 0.05-level test. The expected number of events in the two 
arms is 2 and 10 for the NONS and placebo groups respectively. This further assumes 25% 
censoring during the 28-day period (1.05% loss per day).  
Analysis Populations: Randomized participant, mITT, Per-Protocol, and the Safety 
population (all participants receiving any dose of treatment), the Per-Protocol population 
(received drug and had no major documented protocol violations). 
Primary Efficacy Analysis: The primary efficacy objective is to demonstrate that NONS 
product reduces the risk of COVID-19 infection. The associated null hypothesis is that the 
hazard ratio (HR) of NONS relative to placebo is greater than 1, or H0: HR ≥ 1, or 
equivalently in terms of a vaccine efficacy, H0: VE ≥ 0 where vaccine efficacy is 
calculated as VE = 100% x (1-HR). The HR will be estimated using a Cox proportional 
hazard regression model with a fixed effect only for treatment arm.  
The estimand of the primary analysis is a treatment policy strategy and will consider 
intercurrent events as censored.  
Secondary Endpoint Analysis: For the secondary objective of prevention of medical 
intervention for COVID-19, the secondary endpoint will be executed similarly to the 
primary efficacy analysis.  
Safety Analysis: All safety analyses will be performed in the Safety Population. The 
primary analysis of safety will include counts and proportions of participants with AEs and 
SAEs summarized by Medical Dictionary of Regulatory Activities (MedDRA) System 
Organ Class (SOC) and Preferred Term (PT) and cross-tabulated by severity, relationship 
to study treatment, treatment received, and overall. Exact Clopper-Pearson 95% confidence 
intervals for proportions may be constructed. All AEs and SAEs will be reported in a 
listing and events of interest will be itemized and listed separately. 

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Interim Analysis: Given the small number of expected events, there will be no interim 
analysis for efficacy. Participant enrollment may be closed before 11,480 subjects have 
entered the mITT population if 18 cases are accumulated, but this will be considered the 
final analysis, not an interim analysis. 
Date of Original Approved Protocol: 12 May 2021 
 
Document History Summary 
 
Version / Date 
Summary of Revisions 
1.0 / 12 May 2021 
Original Protocol 
1.1 / 11 Aug 2021 
Modification to a Multicenter trial from a decentralized trial. 
Expanded language to be globally relevant. 
Study product administration details added for clarity. 
Daily use population analysis added. 
EudraCT Number added. 
Administrative updates. 
1.2 / 08 Dec 2021 
Eligibility, updated to include an allowance of prior COVID-19 vaccination. 
Expanded option for paper-based questionnaire collection. 
Removal of antibody testing requirements. 
Relationship between Adverse Event and Study Drug, updated. 
Administrative updates. 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ACE 
Angiotensin converting enzyme 
AE 
Adverse event 
CCID50 
Cell culture infectious dose 50% 
CFR 
Code of federal regulations 
CI 
Confidence interval 
DMC/DSMC 
Data monitoring committee/Data Safety and Monitoring Committee 
eCRF 
Electronic case report form 
ePRO 
Electronic patient-reported outcomes 
CRO 
Clinical Research Organization  
ER/ED 
Emergency room/emergency department  
GCP 
Good Clinical Practice 
HC 
Health Canada 
HR 
Hazard ratio 
ICH 
International Council for Harmonisation  
ICF 
Informed consent form 
ICMJE 
International Committee of Medical Journal Editors 
IEC 
Independent ethics committee 
IOP 
Internal Operating Procedures 
IND 
Investigational new drug  
IRB 
Institutional review board 
IWRS 
Interactive web response system 
MedDRA 
Medical dictionary for regulatory activities 
MOP 
Manual of procedures 
mITT 
modified intent-to-treat 
NO 
Nitric Oxide 
NONS 
Nitric oxide nasal spray 
NORS 
Nitric oxide releasing solution 

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PCR 
Polymerase chain reaction  
PP 
per protocol 
RT-PCR 
Real-time polymerase chain reaction 
SAE 
Serious adverse event 
SD 
Standard deviation 
SDV 
Source data verification  
SUSAR 
Suspected unexpected serious adverse reaction 
VE 
Vaccine efficacy 
WHO 
World Health Organization  

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1 
INTRODUCTION 
1.1 
Nitric Oxide as a Therapeutic Agent 
Nitric oxide (NO) is a naturally occurring endogenously produced nano-molecule in most 
mammals, shown to possess a wide variety of biochemical characteristics that play a role in 
innate immunity, mammalian host defense against infection, modulation of wound healing, 
vasodilation, neurotransmission, and angiogenesis (Moncada, Palmer et al. 1991, Fang 1997) 
Nitric oxide properties such as antimicrobial, immunoregulatory, ciliary motility, and biofilm 
dispersal have utility in the treatment of a wide range of infections (Moncada, Palmer et al. 
1991, Balijepalli, Comstock et al. 2015, Barraud, Kelso et al. 2015, Sheridan, Regev-
Shoshani et al. 2016). Nitric oxide was approved as a selective pulmonary vasodilator used to 
treat “blue baby” syndrome over two decades ago (The Neonatal Inhaled Nitric Oxide Study 
Group 1997). Nitric oxide is widely recognized as a primary signaling molecule in biological 
systems and these effects are likely dose dependent (Schairer, Chouake et al. 2012). Despite 
these characteristics, NO has yet to be commercialized as an antimicrobial drug due to 
complex challenges with gaseous administration outside a hospital environment. 
1.1.1 
Nitric Oxide Viricidal Properties 
Nitric Oxide is well-known to be an efficient broad-spectrum anti-infective agent. It has been 
reported to have antimicrobial activity against bacteria, yeast, fungi, and viruses both in vitro 
and in vivo animal studies (Rimmelzwaan, Baars et al. 1999, Ghaffari, Neil et al. 2005, 
Ghaffari, Miller et al. 2006, Regev-Shoshani, Ko et al. 2010, Regev-Shoshani, Church et al. 
2013, Regev-Shoshani, Vimalanathan et al. 2013, Akaberi, Krambrich et al. 2020). Nitric 
oxide has been shown to have a direct effect on virions prior to infection and host cells 
already infected by viruses (Miller C 2008, Regev-Shoshani, Church et al. 2013, Regev-
Shoshani, Vimalanathan et al. 2013).Nitric oxide, after nitrosylating cysteine moieties, 
causes conformational changes on surface glycoproteins. Nitric oxide also binds and block 
essential viral receptor sites on the host cell (Akerström, Gunalan et al. 2009). These 
conformational changes interfere with host cell fusion, preventing infection and release of 
virions from already infected host cells, and likely act similar to neuraminidase inhibitors 
(Akaberi, Krambrich et al. 2020).  
1.1.2 
Nitric Oxide Antiviral Properties 
Within infected cells, NO interferes with messenger RNA (mRNA) transcription and 
replication by either inhibiting viral ribonucleotide (Croen 1993, Akarid, Sinet et al. 1995, 
Lin, Huang et al. 1997) or through inhibition of viral RNA synthesis (Sungnak, Huang et al. 
2020). Other direct mechanisms could also account for the antiviral effects through viral 
DNA deamination or hydroxyl radical injury (Wink and Mitchell 1998). These effects were 
once attributed to peroxynitrite rather than NO, but this has since been disproven (Akerström, 
Gunalan et al. 2009). Nitric oxide was also shown to covalently bind and inhibit proteases 
and thus mitigate replication of the virus (Fang 1997). For this reason, a recently reported 
study concluded “given that nasal carriage is likely to be a key feature of transmission, 
drugs/vaccines administered intranasally could be highly effective in limiting spread of 
COVID-19 infection”(Sungnak, Huang et al. 2020). 

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1.1.3 
Angiotensin Converting Enzyme-2 Inhibition  
The dual antiviral and angiotensin converting enzyme 2 (ACE-2) inhibition action of NO 
makes nitric oxide releasing solution (NORS) an attractive therapeutic to treat and prevent 
the spread of COVID-19 infection. NO has been shown to act as an ACE2 inhibitor which is 
highly expressed in the upper respiratory tract epithelial cells and the primary entry point of 
SARS-CoV-2 virus (Akerström, Gunalan et al. 2009). Infection of epithelial cells by the 
SARS-CoV-2 virus depends on ACE-2 as a receptor for cellular entry which is highly 
expressed in the nose (Li, Moore et al. 2003, Hoffmann, Kleine-Weber et al. 2020). The 
binding affinity of the viral Spike protein and ACE-2 was found to be a major determinant of 
SARS-CoV-2 replication rate and disease severity (Matsuyama, Nagata et al. 2010).  
1.2 
Nitric Oxide Mechanism of Action 
Nitric oxide causes nitrosylation of surface glycoproteins resulting in structural changes of 
the virion particle. Nitric oxide binds to the ACE-2 receptor on epithelial tract cells 
preventing fusion between SARS-CoV-2 virus and the host cell, and NO bind to proteases 
mitigating viral replication (Figure 1). 
Figure 1  
Nitric Oxide Mechanisms of Action Against SARS-CoV-2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nitric Oxide Mechanisms of Action Against SARS-CoV-2, 1) nitrosylation of surface glycoproteins resulting 
structural changes of the virion; 2) NO binds to ACE-2 receptor preventing fusion between SARS-CoV-2 virus 
and host cell, and 3) NO bind to proteases mitigating viral replication. 
Abbreviations: ACE-2= angiotensin converting enzyme-2; NO= nitric oxide. 
 
1.3 
Nitric Oxide Releasing Solution (NORS) 
SaNOtize has developed an innovative approach to deliver NO at doses that are lethal to 
microbes but safe to humans. SaNOtize’s issued patent (US 9,730,956) describes the method 
and composition of NORS. This method combines the right formulation to produce an 
effective NO dose. NORS allows the delivery of varying amounts of NO, required to be an 
effective antimicrobial, for a wide range of indications. These characteristics enable NORS to 
Picture demonstrating  
1) nitrosylation of surface glycoproteins resulting structural changes of the virion;  
2) NO binds to ACE-2 receptor preventing fusion between SARS-CoV-2 virus and host cell, and  
3) NO bind to proteases mitigating viral replication. 

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be a truly innovative platform technology for a variety of medical indications to eradicate 
multiple species of bacteria, fungi and viruses, including drug resistant organisms, as well as 
to reduce inflammation and increase wound healing. The development of NORS by 
SaNOtize was based on the antimicrobial data from pressurized NO gas studies. The 
effective antimicrobial NO dose was identified to be in the 120-200ppm per min range to 
eradicate a wide range of bacteria suspended in saline (See Investigator’s Brochure Version 
1.0). SaNOtize created a liquid, using two compounds abundantly used within the food 
industry, which contains an equivalent NO concertation as free gas to eradicate microbes. 
The active drug used in this study is nitric oxide (NO). It is delivered within a saline-based 
liquid. The Sponsor proposes the use of an in situ activated, nitric oxide generating 
formulation that provides the same antimicrobial chemical characteristics in a solution as that 
of an exposure of 160 ppm NO gas to bacterial suspension in saline for 4 to 6 hours. This 
initial liquid with its specific chemical content is referred to by the Sponsor as Nitric Oxide 
Releasing Solution (NORS). 
Nitric oxide nasal spray will be self-administered throughout the day. The intervention 
solution will be delivered in a manual pump nasal spray container (containing a dual chamber 
designed by the Sponsor) with 25 mL of solution. Each spray will dispense approximately 
130-150µL of solution. Topical delivery of NONS will be performed with 4 nasal sprays at a 
time (two in each nostril) three (3) times daily, morning, noon, and night. The intervention 
solution will be delivered in a proprietary dual chambered (USP63/079,277) nasal spray 
container custom designed under cGMP for the Sponsor. The device is manufactured and 
formulated, filled/finished and packaged in by Nextar Chempharma Solutions (Nee Ziona, 
Israel). Each container holds 12.5 mL of liquid formulation and when activated by a manual 
pump, will mix equally the solutions in the head of the container to create NONS. When 
manually actuated, mixed NONS will be dispensed in a spray volume of approximately 130-
150µL. The droplet size is greater than 5 µm to avoid droplets entering the lung field and 
maximize bulk application throughout the nasal cavity. Topical delivery of NONS will be 
performed with 4 nasal sprays at a time (two in each nostril) 3 times daily, morning, noon, 
and night.  
1.4 
Nitric Oxide Nasal Spray Effect on SARS-CoV-2 Clinical Isolates 
In vitro tests conducted early in March 2020, by the Institute for Antiviral Research at Utah 
State University confirmed that NORS inactivated more than 99.9% of SARS-CoV-2 (below 
limit of detection) <0.7 cell culture infectious dose 50% (CCID50) per 0.1 mL (>99.9%), 
within 2 minutes in laboratory tests using recent clinical isolates at titers of 104 PFU/ml 
(Figure 2). Testing was performed to determine if NORS samples inactivate viruses when 
exposed for a contact time of 2 minutes or 8 minutes.  
After a 2-minute contact time, Dose B (similar NO release profile as NONS) reduced virus 
by from 3.9 to 1.8 log CCID50 per 0.1 mL (>99%). After 8 minutes, Dose B reduced virus 
below the limit of detection, <0.7 CCID50 per 0.1 mL (>99.9%). After the 2-minute and 8-
minute contact time, Dose C (double NO release profile as NONS) reduced virus below the 
limit of detection of 0.7 CCID50 per 0.1 mL (>99.9%).  

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Figure 2  
Virucidal Effect of Nitric Oxide Spray 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Viricidal activity of two NORS doses against SARS-CoV-2 after two contact periods. CCID50/well (log10) was 
measured. Dotted line represents the limit of detection. Water was used as positive control. N=3. P<0.0001 as 
measured by one-way ANOVA with Dunnett’s multiple comparison test.  
Abbreviations: ANOVA= one-way analysis of variance; NORS= nitric oxide releasing solution. 
 
1.5 
Nitric Oxide Nasal Spray Effects in Humans 
The Sponsor has conducted Phase 1 and Phase 2 clinical trials to help establish the safety of 
NORS as a localized topical antimicrobial and further demonstrate the lack of a systemic 
toxicity signal as measured by methemoglobin. These trials also provide environmental 
safety data demonstrating that nitrogen dioxide (NO2) levels remain below detection limits 
and far below Occupational Safety & Health Administration (OSHA) guidelines. 
1.5.1 
Nitric Oxide Nasal Spray (NONS) for the Treatment of Mild COVID-19 
Infection Trial 
In 2020, the Sponsor conducted a double-blinded, placebo-controlled trial that involved 79 
adults diagnosed with mild COVID-19 in the community (confirmed by polymerase chain 
reaction [PCR]). Participants were randomly assigned to treatment with NONS or placebo 
(saline solution) at day 1. Nasal and throat swabs were collected at presentation for baseline 
followed by collection at Days 2, 4 and 6 which were 1, 3 and 5 days after starting treatment, 
respectively. Quantitative real-time reverse-transcriptase polymerase chain reaction (qRT-
PCR) was performed to determine SARS-CoV-2 RNA. Nitric oxide nasal spray, started on or 
before day 5 of symptom onset, was independently associated with a significantly accelerated 
decrease in SARS-CoV-2 RNA concentration of -1.21 log10 copies/ml on both Days 2 and 4, 
as compared to placebo. Therefore, the mean SARS-CoV-2 RNA concentration was lower 
for NONS, as compared to placebo, by a factor of 16 at both Days 2 and 4. Day 6 equated to 
at least 10 days since symptom onset and significant reduction of SARS-CoV-2 with or 
Graph depicts log 6 SARS-CoV-2 viral concentrations (log pu/mL) at baseline, followed by different 
doses (A, B, C) with viral growth measured at 30, 60 and 180 seconds.  
No growth is demonstrated at all three timepoints for doses B & C. 
No growth id demonstrated at 180 seconds for dose A, with log 2 growth shown at 60 seconds and 
log 3.5 growth at 30 seconds dose NORS/NONS. 
 
 
Proprietary (Information) 
 

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without treatment was expected. Nevertheless, the SARS-CoV-2 RNA concentration was still 
lower on NONS at Day 6. The primary endpoint was a reduction of viral load from Day 1 
through Day 6 (measured as area under the curve). Analysis revealed a mean difference of -
5.22 log10 copies/ml between NONS and placebo. This difference was shown to be 
significant with a P value of 0.0096. The average viral log reduction in the first 24 hours, in 
treatment arm was -1.362 which correlates to about 95%, while the average viral log 
reduction in the control (saline) arm was -0.15 which correlates to about 30% In addition, the 
majority of patients in this study were positive for SARS-CoV-2 variants of concern 
(VOC202012/01) also commonly known as the UK variant (European Medicines Agency 
2020). 
1.5.2 
Nitric Oxide Nasal Spray COVID-19 Prevention Trial 
In 2020, the Sponsor closed enrollment of a Health Canada (HC) trial (NCT04337918) to 
evaluate the safety and efficacy of NORS to prevent infection from SARS-CoV-2. In total, 
143 participants were enrolled, and 103 participants received the NORS interventions in the 
form of NONS. Over 7,000 doses of NONS were administered in this trial and there were no 
reports of serious adverse events (SAEs) or significant adverse reactions (ARs) related to 
NONS specifically. Some participants reported adverse events (AEs) of mild nasal irritation 
which quickly resolved. None of the participants in the intervention arm (N=103) tested 
positive for COVID-19 during the study. However, no participants in the control arm (N=40) 
tested positive either so efficacy was not shown. 
1.5.3 
Nitric Oxide Nasal Spray Background 
The NORS formulation is manipulated to achieve a safe dose that is microbicidal within 
minutes to viral and bacterial pathogens. Specific to pathogens related to sinusitis, it is called 
Nitric Oxide Nasopharyngeal Irrigation (NONI) or Nitric Oxide Gargle (NOG) or Nitric 
Oxide Nasal Spray (NONS). Based on scientific data (see Investigator Brochure Version 1,0 
for details) the NO releasing capability of these products, should act as a nitrosative viricidal 
agent, may have beneficial restorative mucociliary and anti-inflammatory effects in 
participants with Flu/COVID-19.  
Prevention is essential in controlling the spread of COVID-19. The Sponsor’s nitric oxide 
nasal spray (NONS) would provide a new daily preventative measure as an easy-to-use 
prophylaxis. Nitric oxide nasal spray aims to initially reduce the pathogen load in the nasal 
passages where viruses first enter and reside and then blocks viral entry before they can 
penetrate the cells lining the nose.  
Nitric oxide nasal spray will be self-administered throughout the day. The intervention 
solution will be delivered in a manual pump nasal spray container with 25 mL of solution. 
Each spray will dispense approximately 130-150µL of solution. Topical delivery of NONS 
will be performed after the individual blows their nose, with 4 nasal sprays at a time (two in 
each nostril) 3 times per day.  
 

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2 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Primary Objective and Endpoint 
Objective 
Endpoint 
To assess the efficacy of NONS 
in the reduction of risk of 
COVID-19 infection 
Confirmed positive COVID-19 test (Both antigen and 
SARS-CoV-2 RT-PCR are acceptable) by Day 28.  
Positive test results based on sample collection within 
48 hours of randomization will be considered infected 
at randomization and not counted as events. 
Abbreviations: NONS=nitric oxide nasal spray; RT-PCR=real-time polymerase chain reaction. 
 
2.2 
Secondary Objectives and Endpoints 
Objective 
Endpoint 
To assess the efficacy of NONS 
in prevention of severe 
COVID-19 
Hospitalization or ER/ED visits for COVID-19/flu-like 
symptoms by Day 28  
 
Assess tolerability of NONS in 
participants with all 
participants including those 
with COVID-19 
AEs and discontinuation of treatment 
Abbreviations: AE=adverse events; ER/ED=emergency room, emergency department NONS=nitric oxide nasal 
spray. 
 

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3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan  
This is a multicenter, randomized, double-blinded, placebo controlled, Phase 3 clinical 
efficacy study evaluating NONS in healthy adult volunteers as a prevention treatment for 
individuals at risk from COVID-19 infection.  
Up to 13,000 adult participants aged 18 or over with no known history of SARS-CoV-2 
infection will be randomized into one of two cohorts of this study in a ratio of 1:1 
(Treatment: Placebo Control). Participants with or without underlying medical conditions 
will be eligible to enroll. The NONS formulation proposed for use in this COVID-19 clinical 
study will be self-administered at a maximum of 3 times per day, morning, noon, and night 
for 28 days. Participants will be on study for 4 weeks of treatment (to include 5 days of 
Screening, 1 week of Follow-Up, participants will be followed for a total of approximately 5 
weeks) as a viricidal Investigational Medical Product. 
Participants will self-administer a nasal spray containing either blinded study treatment or 
placebo (herein called study treatment). Nitric oxide nasal spray (NONS) will be delivered 
from manual pump nasal spray container with 25 mL of solution with each nasal spray 
dispensing approximately 130-150 µL of solution. After the subject blows their nose, each 
treatment will require two sprays per nostril, or about 0.5 mL per treatment.  
The primary endpoint is to assess the efficacy of NONS in the prevention of COVID-19 
infection as determined by a positive COVID-19 test (antigen or reverse-transcriptase 
polymerase chain reaction [RT-PCR]),  
The secondary endpoints are to determine the proportion for participants requiring 
hospitalization or emergency room (ER/emergency department [ED]) visits for COVID-19 or 
flu-like symptoms by Day 28 and assess the safety and tolerability of use of NONS in 
participants with COVID-19. 
This study will be a multicenter trial, allowing remote and in-person on-site visits, including 
telephone contact, as applicable per respective country regulatory legislation. All data 
collection and monitoring to be primarily performed remotely (Clinical Trials 
Transformation Initiative 2018). Screening and enrollment will take place through an online 
portal and through telehealth assessments, unless in a region that does not accept an eICF, in 
which case the consenting procedure will occur in-person on-site (screening and baseline 
procedures may also be performed in-person on-site). Participants will receive study 
treatment shipped directly to their homes as described in Section 6.5., unless in a region (EU) 
where the participant must receive the study product directly from the sites’ staff/physician. 
Participants in the EU will have three in-person visits (screening visit, baseline visit [unless 
screening and baseline can occur on the same day] and a post-treatment visit). Participants 
will enter their study treatment dates and times and describe any symptoms in an online 
questionnaire (Table 4), or paper diary if necessary. Study sites will maintain contact with all 
enrolled participants and regularly collect paper diaries to ensure timely data entry. 

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3.2 
Rationale for Study Design and Control Group 
3.2.1 
Rationale for Use of Nitric Oxide for COVID-19 Therapy 
SARS-CoV-2 is a novel, human-infecting coronavirus, termed COVID-19. COVID-19 is 
highly contagious, with a high virulence, and on March 11, 2020 it was declared by the 
World Health Organization a global pandemic. A study treating individuals with a viricidal 
agent like NORS could be advantageous for many reasons. This treatment could be used 
either for infection prevention or at the time of diagnosis when the virus is the most 
susceptible because it is still in the nose or in upper airways. This approach could prevent the 
population in viral outbreak areas from getting infected, mitigate the progression of the viral 
infection and spread of the disease from those who are infected already to others. Obtaining 
an early diagnosis when the patient has mild to moderate disease and treating them while 
spontaneously breathing, could translate in the reduction of morbidity and mortality. Thus, it 
could lower the burden on already limited healthcare resources. 
3.2.2 
Rationale for use of a Nitric Oxide Releasing Solution Spray (NONS) 
Formulation 
It is hypothesized that a NORS formulation, delivered prophylactically or at early stages of 
COVID-19 exposure, will be well tolerated, and may have other beneficial secondary 
outcomes. In addition, due to nitric oxide’s broad spectrum, non-specific antimicrobial 
(specifically viricidal) characteristics and its fundamental basic biochemical action, microbial 
drug resistance may even be avoided. This is especially important with the emergence of 
variants that reduce the effectiveness of vaccines. 
Nitric oxide releasing solution will be delivered in a nasal spray formulation, referred to 
herein as nitric oxide nasal spray (NONS). Given the severity and persistence of the 
complications associated with COVID-19 infection, the Sponsor hypothesizes that nitric 
oxide delivered via NONS may prevent COVID-19 infection.  
While there have been only minimal reported side-effects from the topical application of 
gaseous nitric oxide, there have been reported adverse side effects of nitric oxide releasing 
compounds. Specifically, the adverse effects associated with topical nitrate/nitrite application 
include skin rash, burning sensation, sensitivity and staining of the skin and are mostly 
associated with the carrier or the acid required for NO donor release (Weller, Price et al. 
1997). 
The dose for the NONS is based on preliminary in-vitro dosing studies, using H1N1 and 
H3N2 and SARS-CoV-2 viruses, and based on the highest tolerated dose in volunteers in 
previous clinical trials conducted by the Sponsor.  
3.2.3 
Rationale for Multicenter Trial Design 
The study will be conducted in a blinded fashion in conjunction with a placebo control to 
remove evaluation biased by the expected effects of the study treatment. 

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If allowed by applicable legislation in the respective country, all data collection and 
monitoring will be remote through telehealth assessments and phone calls without 
performing on-person visits. This allows for broader geographic reach and rapid response, for 
easy access to areas that present with a higher prevalence of the COVID-19 infection. 
In countries where only remote visits are applicable, all participant interactions with the 
Investigator will occur through telehealth assessments in the participant’s home (see Section 
6.6.2 and Section 6.6.3 for more details on telehealth assessments). The participant will 
receive study treatment directly to their home, unless in a region (EU) or other location 
where the participant must receive the study product directly from the sites’ staff/physician. 
All study treatments will be self-administered. A completely remote option trial design 
allows for potentially faster and more diverse participant recruitment, improved participant 
retention, which may reduce missing data, and provides the participant with greater control, 
convenience, and comfort performing treatments in the home. The administration of 
treatments in the home may also be more representative of real-world administration and use 
of the study treatment post-approval. 
3.3 
Study Duration and Dates 
Actual overall study duration or participant recruitment period may vary. The proposed study 
start is Q4 2021. A participant’s time on the study is expected to last 5 weeks from 
enrollment. Subject participation will consist of 5 days of Screening/Baseline, and 28 days 
study treatment, followed by 7 days of Follow-Up for safety assessments. Participants should 
complete the study on Day 35. 
For participants that test positive for COVID-19, Health Canada (HC)/FDA, or other applic-
able relevant local/national regulatory health authorities should be notified as applicable to 
the regional area. Participants that test positive for COVID-19 will be encouraged to 
complete early termination assessments and record their symptoms using the COVID-19 
symptom list. 
3.3.1 
End of Study Definition 
A participant is considered to have completed the study if they have completed all phases of 
the study including Follow-up (Day 35), or they/their emergency contact completes the early 
termination assessment questionnaire after the last treatment. The end of the study is defined 
as the date of the last assessment of the last participant. 

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4 
STUDY POPULATION SELECTION 
4.1 
Study Population 
The study population will consist of healthy volunteer males and females of any ethnic 
background aged at least 18 years of age with no prior history of a COVID-19 infection, or 
current SARS-CoV-2 infection. 
If allowed by local regulations, participants will be recruited through public announcements 
and social media as approved by the ethics review board(s). Ideally, cooperation with Public 
Health Officials will aid in identifying “hotspots” where focused advertising for recruitment 
will be targeted. A study website may be set up to support initial interest and screening 
efforts. Additional efforts to support study visibility and broaden recruitment areas to more 
remote locations, will be assessed throughout the course of the study such as television or 
radio advertising. Local/national regulations regarding recruitment of participants for clinical 
research will be applied in each country. 
Participants may be recruited in multiple countries, starting in Sri Lanka, using a multicenter 
method, it is estimated that up to 13,000 participants will be randomized with an anticipated 
11,480 participants initiating study treatment. A screened participant is defined as someone 
who has expressed interest in the study but has not completed the consent and randomization 
process. 
4.2 
Inclusion Criteria 
Each participant must meet the following criteria to be enrolled in this study. 
1. At least aged 18 years old at the time of consent. 
2. If female, be surgically sterile or post-menopausal (no menses for at least 12 months), or 
if of child-bearing potential, must be using an acceptable method of contraception such as 
a combination estrogen/progestin hormonal contraceptive (oral or injected) for at least 1 
month prior to Day 1, or such items as an intrauterine device (IUD), intrauterine system 
(IUS), transdermal hormonal implant, vaginal hormonal ring, or two forms of the 
following: diaphragm, cervical cap, patch, condom, spermicide, or sponge. Total 
abstinence is permitted. If local regulations deviate from the previously listed 
contraception methods to prevent pregnancy, local requirements will apply. In addition, 
females of child-bearing potential must agree to continue to use their method of birth 
control for the duration of the study and 12 weeks following discharge from the study. 
3. If male, be surgically sterile, or agree to use appropriate contraception (latex condom 
with spermicide) when engaging in sexual activity and agree to not donate sperm for the 
duration of the study and 12 weeks following discharge from the study. 
4. Be in good health (ie, no acute illnesses or hospitalizations within 30 days of the study 
start, no planned procedures during study participation, and no newly diagnosed chronic 
illnesses that are not deemed stable by the participant’s primary care physician), in the 
opinion of the Investigator, based on medical history (ie, absence of any clinically 
relevant abnormality) during Screening. 

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5. Be able to understand and provide written, informed consent. 
6. Access to a telephone, the internet, a device that reliability connects to the internet, and 
able to dial into Telehealth checkups and study related assessments. If access to the 
internet precludes involvement, then paper diaries may be completed and promptly 
entered into the data capture system at the study centers as part of the regular follow-up 
visits. 
7. Must be able to receive study product shipments directly to their home (ie, no Post Office 
Boxes), unless in a region (EU) or other location where the participant must receive the 
study product directly from the sites’ staff/physician. 
 
4.3 
Exclusion Criteria 
Participants who meet any of the following criteria will be excluded from the study. 
1. Participants with acute illnesses or hospitalizations within 30 days of the study start, 
and/or planned procedures during study participation, and/or newly diagnosed chronic 
illnesses that are not deemed stable by the participant’s primary care physician), based on 
Investigator assessment of medical history during Screening. 
2. Participants with any respiratory infection, flu-like symptoms, or unexplained fever or 
chills during the week prior to Screening (see Section 6.6.2). 
3. Participants with any prior history of SARS-CoV-2 infection. 
4. Participants who use intranasally dosed drugs, prescriptions or over-the-counter 
medications such as fluticasone within the last 7 days. 
5. Participants who underwent a previous tracheostomy. 
6. Participants who are receiving any form of oxygen therapy. 
7. Females who are breastfeeding, pregnant, or attempting to become pregnant. 
8. Participants who have any other condition that, in the opinion of the Investigator, would 
interfere with a participant’s ability to adhere to the protocol (eg, participants whom are 
mentally or neurologically disabled and whom are considered not fit to their participation 
in the study), interfere with assessment of the investigational product, or compromise the 
safety of the participant or the quality of the data. 

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5 
STUDY TREATMENT 
5.1 
Description of Treatment 
The Sponsor designed a dual chamber nasal spray bottle for NONS administration. 
Components are mixed from two chambers to create the final NO-producing formulation. 
The liquid contains NO at 0.11 ppm*hour, which acts as a viricidal agent (Figure 3). 
Instructions for storing, preparing, and administering the study treatment will be provided to 
participants. 
Figure 3  
Nitric Oxide Nasal Spray  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: hr= hour; NO= nitric oxide, ppm= parts per million 
 
5.2 
Treatments Administered 
Nitric oxide nasal spray or placebo will be self-administered by the participant three (3) times 
throughout the day, at approximately in the morning, noon, and night (or about every 8 
hours) for 28 days. The intervention solution will be delivered in a manual nasal spray pump 
bottle container with 25 mL of solution. Each spray will dispense approximately 130-150 µL 
of solution and each treatment or dose requires 4 total sprays (delivered as 1 spray in each 
nostril, and then repeated as 1 spray in each nostril). Total exposure to study intervention will 
be a maximum of 84 treatments totaling 50 mL (three 25 mL spray bottles will be dispensed 
to ensure enough solution volume is available to participants, including coverage for priming 
the bottles, malfunctioning bottles and/or misplaced/lost bottles). All participants will be 
monitored for 7 days post-last treatment dose (to Day 35) as shown in Figure 4. Refer also to 
the Dosing Instructions for Participants. 
 
 
Picture of two compartment nasal spray bottle. 
Each compartment contains Solution A or Solution B. 
When tip of bottle actuated, the two solution combine as released from the bottle producing nitric oxide (NO). 
 
 
 
 
Proprietary (Information) 

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Figure 4  
Study Schema 
 
 
 
 
 
 
 
 
 
 
IP: in-person on-site visit 
 
5.3 
Selection and Timing of Dose for Each Participant 
After screening has been completed, participants will be randomized by an interactive web 
response system (IWRS) into one of two groups, one group of 6,500 for the NONS treatment 
and one group of 6,500 for placebo treatments. Following randomization, study treatment 
will be dispensed during the in-person on-site visit (as required by local/national regulations) 
or shipped directly to participants for immediate use and confirmation on the appropriate 
eCRF. Participants will be instructed to treat themselves 3 times daily, morning, noon, and 
night (or approximately every 8 hours) with the nasal spray for 28 consecutive days.  
5.4 
Method of Assigning Participants to Treatment Groups 
Participants will be randomized 1:1 to receive either NONS or placebo. Randomization will 
be in a double-blinded manner using an IWRS with pre-generated randomization lists. When 
participants performing remote visits (only) are confirmed as eligible, the IWRS system will 
provide the participant’s contact information and randomized assignment to the regional drug 
distribution center who will compile the kit with the appropriate 3 bottles of test articles 
(NONS or placebo) and ship them directly to the participant. 
Participants may only enroll on the study once. During eligibility screening, data will be 
collected verifying identity (date of birth and partial postcode) to prevent participants from 
attempting to enroll the study again. 
Schema available upon request 

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Randomization will be stratified based on age and COVID-19 risk factors. There will be 
three strata: 
1. ≥ 65 years of age 
2. < 65 years of age and at increased risk 
3. < 65 years of age and not at increased risk 
Participants will be considered ‘at increased risk’ if they report having at least one of the 
following risk factors during Screening: 
• Cancer 
• Chronic lung disease (eg: emphysema and chronic bronchitis, idiopathic pulmonary 
fibrosis and cystic fibrosis) or moderate to severe asthma 
• Significant cardiac disease (eg: heart failure, coronary artery disease, congenital heart 
disease, cardiomyopathies, and pulmonary hypertension) 
• Down Syndrome 
• Immunocompromised following immunosuppressive therapies (e.g. post-transplant 
procedures, chemotherapies, treatments with biologics/biosimilars) 
• COPD (chronic obstructive pulmonary disease) 
• Obesity (body mass index [BMI] ≥ 30 kg/m2) 
• Diabetes (Type 1, Type 2 or gestational) 
• Liver disease 
• HIV infection 
 
5.5 
Blinding 
Following confirmation of eligibility and baseline data collection, participants will be 
enrolled and randomized.  
If an in-person on-site visit is performed, blinded kits will be delivered to, or prepared at, the 
sites. A subject number will be assigned to each randomized participant. Site staff/physician 
will then dispense kit labeled with the authorization number generated during randomization 
to the individual participant. 
For participants performing remote visits, each authorization number/code will be associated 
with a specific treatment assignment, within stratum, from a pre-generated list. The 
authorization number/code will be provided to the regional study drug distribution center(s) 
who will select the appropriate treatment assignment, compile a blinded kit, and distribute 
directly to the participant. In addition to the necessary staff at the study drug distribution 
center, unblinded staff at the study contract research organization (CRO) will be the only 
study personnel with access to unblinded treatment assignments.  
If the Investigator, or any medical caregiver, determines that unblinding is warranted to 
manage a medical condition, AE, or other purpose, they should follow the specified contact 

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procedure in the study Safety Monitoring Plan – contact information will be available to 
study participants to provide to physicians or other medical caregivers who may be providing 
care to the subject. Safety must always be the first consideration in making a determination to 
unmask. The requestor should believe that knowledge of the participant’s randomized study 
treatment would influence the participant’s care or their treatment decisions. Upon approval 
by the Sponsor, or in the case of urgent medical need, the unblinding information will be 
provided with notification to the Sponsor and documentation of the unblinding event in the 
study file. 
5.6 
Concomitant Therapy 
If possible, participants should be maintained on stable medications and dosing throughout 
the entire study period, as medically feasible. Concomitant medications (including COVID-
19 vaccination) other than naturopathic products will be recorded for the duration of the 
study. 
The use of standard delivery nasal sprays including over-the-counter medications and generic 
formulations such as fluticasone are prohibited whilst the participant is on the study. This 
includes all forms of nasal therapy (e.g. nasal lavage of any kind, steam inhalation of any 
kind, or any other homeopathic nasal treatments) that could interfere with study outcomes. 
Participants requiring an initiation of new medications or treatment for COVID-19 at any 
point will contact the appropriate study staff personnel, i.e., investigator/study coordinator, at 
the regional site/office. 
5.7 
Lifestyle Considerations 
5.7.1 
Prior Therapy 
The Investigator or qualified designee will review prior medication use with the participant 
and record the use of any prescription or non-prescription drugs taken by the participant 
within 14 days before Day 1. 
5.7.2 
Fluid and Food Intake Considerations 
Participants should maintain their usual diet.  
5.7.3 
Patient Activity Restrictions 
Participants should maintain their usual levels of activity.  
5.8 
Screen Failures 
For participants who are Screen failures and do not receive any study treatment, their 
demographics and the reason for Screening failure will be recorded. The same information 
will be recorded for participants that pass Screening but subsequently are not randomized and 
do not receive any study treatment. 

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5.9 
Treatment Compliance 
As participants are self-administering the study treatment at home, compliance with study 
treatment will be reviewed at each contact with the participant (including telehealth 
assessments) and the eCRF treatment diaries or paper diaries. Participants will complete a 
treatment diary at home for the dosing days. Any safety issues noted on the electronic 
treatment diary or paper diary will be recorded in the eCRF and reviewed by the regional 
Investigator. Participants that do not confirm use of the treatments on the appropriate eCRF 
may be terminated early at the discretion of the investigator. 
If a participant develops clinical symptoms of COVID-19, they should document these in a 
COVID-19 symptoms diary (Appendix 2).  
Refer to the Manual of Procedures (MOP), Internal Operating Procedures (IOP) or supply 
management plan for study treatment accountability and returns. 

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6 
STUDY PROCEDURES 
Details of the timing of study procedures are provided in Table 4. 
6.1 
Informed Consent 
Potential participants will be offered participation in the study. The informed consent will be 
obtained as per applicable legislation in the respective country. Potential participants will be 
invited to the site where they will receive the Informed Consent Form document and the 
investigator will explain the study and answer any questions related to the study. Potential 
participant will be given as much time as needed to decide if they are willing to participate. 
In countries where Informed Consent Form is allowed to be obtained remotely as per 
applicable legislation, the informed consent document will then be sent electronically to the 
potential participant, whom will be given as much time as possible to review and ask 
questions by telephone or virtual meeting as institutional standards allow with research ethics 
board approval. Once the participant has signed the form, he or she will receive an electronic 
copy. The Investigator can then access the signed consent in a secure manner and print it or 
transfer the file electronically (Table 4). Electronic signature collection software will comply 
with 21 CRF part 11 (Part 11).  
6.1.1 
Emergency Contact Informed Consent 
Participants will be asked to designate an emergency contact person and alternate contact 
telephone number during consent. The emergency contact will be asked to provide written, 
informed consent to perform these duties as per local regulations. 
The emergency contact will be contacted in the event the participant is hospitalized and is 
unable to complete their daily electronic diary. Emergency contacts are encouraged to submit 
study data on behalf of the participant (as applicable). 
6.2 
Screening Assessment 
Screening will be performed on-site unless specific geographic jurisdiction allows remote 
screening procedures. Remotely consented participants will be referred to a regional study 
center for a telehealth evaluation by a principal or sub-Investigator who is a medical provider 
qualified to order testing and prescribe medication for a specific geographic jurisdiction. 
Screening procedures will be performed as described in the Schedule of Events (Table 4). 
Participants will be enrolled on the study if determined eligible and assigned a randomization 
number.  
6.3 
Demographics, Medical History, and Physical Examination  
Demographic information (month and year of birth, sex, ethnicity, and race) will be collected 
as described in the Schedule of Events (Table 4).  
Concomitant medication information will be collected as described in the Schedule of Events 
(Table 4). 

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The investigator (qualified medical provider if remote screening is allowed) will complete a 
pertinent medical history and current concomitant medications (refer to the MOP/IOP) and 
physical examination (remotely if applicable), including an assessment of any flu-like 
symptoms (see Section 6.6.2) as described in the Schedule of Events (Table 4).  
All medical history findings that have been present/active within the 3 years prior to 
enrollment will be recorded regardless of clinical relevance or presence at study start. 
Medical history findings that have not been present/active within the 3 years prior to 
enrollment will be recorded if deemed clinically relevant by the Investigator to the conduct of 
the study. The medical history should include any history of allergic reactions to drugs. 
6.4 
Clinical Laboratory Assessments 
6.4.1 
Urine Pregnancy Test 
A urine pregnancy test will be required from female participants of childbearing potential as 
described in the Schedule of Events (Table 4). Self-reported urine pregnancy test will be used 
if remote screening is applicable. 
A negative urine pregnancy test is required prior to enrolling the participant in the study. The 
negative pregnancy test will be confirmed during Screening and prior to dosing as described 
in the Manual of Procedures (MOP) or Internal Operating Procedures (IOP). 
6.5 
Dispensing Study Drug 
Study drug will be dispensed during the baseline on-site visit per applicable local/national 
legislation. Remotely enrolled participants will be sent overnight, a direct to participant 
temperature-controlled and monitored package which will contain a 28-day supply of study 
treatment and instructional materials as described in the MOP/IOP. The instructional 
materials will consist of study treatment administration, contact information for reporting 
safety concerns, and what to do if they are diagnosed with COVID-19.  
Three nasal spray bottles will be provided. Participants are to self-administer study treatment 
at 3 times (doses) per day for 28 consecutive days. Participants will record in their diaries the 
dosing date and time when they administer each study treatment. 
There are no preparation steps for the nasal spray bottle (after it is primed). Each dose will be 
4 sprays in total. The technique for spraying will be to first blow the nose to clear mucous 
debris. The tip of the bottle should be barely placed in the opening of the nostril. Begin with 
a single spray to the lateral inside of the nose of each nostril (1 spray in each nostril). Then 
proceed with a single spray directly into the nose of each nostril (1 spray in each nostril, for a 
total of 4 sprays per dose) while breathing in (note that this maneuver may cause a slight 
astringent sensation). 
The participants will be instructed on nasal spray technique and instructed the day before 
dosing to ensure consistency with understanding and technique (an online video link will be 
provided).  

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6.6 
Efficacy Assessments 
Participants will self-assess COVID-19-related symptoms (Section 6.6.2), report if they have 
tested positive for COVID-19, and report if they need hospitalization or an ER/ED visit as 
described in the Schedule of Events (Table 4). A positive COVID-19 test can be either by 
antigen or SARS-CoV-2 RT-PCR. 
6.6.1 
Daily Treatment Diary and Questionnaire (eCRF) 
The questionnaire and electronic treatment diary will record the compliance of treatments 
administered or missed. It will also ask if treatments were tolerated and report any side 
effects or other comments. There is also a discomfort/pain scale if needed. Refer to Section 
8.7 for action to be taken in the event of the spray bottle malfunctioning. Paper diaries with 
comparable information and instructions will be available as backup for all participants or as 
primary collection instruments for participants without sufficient access to devices or internet 
connectivity. 
All participants will be asked to fill out an online (or paper if required) daily treatment 
questionnaire and COVID-19 symptoms diary as described in the Schedule of Events 
(Table 4). The complete language and content of all of the questions is described in the 
Manual of Procedures.  
Participants must have access to the internet and a device that reliability connects to the 
internet and is able to dial into telehealth assessment. In the event of an inability to access the 
electronic PRO, the process described in the MOP/IOP will be followed for completion of 
paper records. 
If a participant develops clinical symptoms of COVID-19 (see Section 6.6.4), they/their 
emergency contact should make every effort to document these in a COVID-19 symptoms 
list (Appendix 2). 
Participants who enroll in the study could be asymptomatic for COVID-19 at time of 
randomization; in which case, if the participant tests positive for COVID-19 within < 2 days 
(48hrs) of the baseline visit they will be considered unevaluable for the study endpoint and 
will be discontinued. 
 
 
6.6.2 
In-Person On-Site/Telephone Contact 
Study staff for sites requiring on-site visits will contact participants via telephone on Day 7 
and 28 (all others performing remote monitoring will contact participants on Day 7, 28, and 
35) as described in the Schedule of Events (Table 4) and confirm participants’ current health 
status including presence of any COVID-19 symptoms (Appendix 2; Appendix 3), in 
addition to any ER or hospital visits that might have occurred as a result of COVID-19. 
Participants will also be asked about any challenges with administration or any AEs they may 
have experienced.  

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Participants who are hospitalized for any reason and are unable to attend their on-site visit / 
telehealth assessment or complete their daily diary should have their emergency contact 
notify study staff as soon as possible. Participants that are hospitalized for COVID-19 only 
are considered treatment failures. Participants that are hospitalized for any other reason may 
stay on the study at the discretion of the Investigator. 
Follow-up visits (end of study and early termination assessments) will be performed 
preferably on-site (in countries where remote only conduct is not allowed), but if the 
participant is hospitalized, in quarantine or unable to visit the site in-person for any 
reasonable cause as per investigators’ judgement, these visits may be performed remotely 
and will not be considered a protocol deviation. Follow-up of all adverse events must be 
completed as described in the protocol Section 7. 
6.6.3 
Remote Video Conferencing 
All study staff who will be conducting remote telehealth assessments should be trained on 
how to conduct real-time video conferencing assessments. Procedures will be put in place to 
maintain participant privacy as in an in-person visit. Both the Investigator and the participant 
should confirm their identities to one another before engaging in a real-time video conference 
assessment (National Insttitue of Standard and Technology (NIST) Digital Identity 
Guidelines 2017, Royal College of Physicians and Surgeons of Canada 2020, Food and Drug 
Administration 2021). 
6.6.4 
COVID-19 Symptoms List 
Health Canada COVID-19 symptoms list: https://www.canada.ca/en/public-
health/services/diseases/2019-novel-coronavirus-infection/symptoms.html 
Center for Disease Control (CDC) COVID-19 symptoms list: 
https://www.cdc.gov/coronavirus/2019-ncov/symptoms-testing/symptoms.html  
6.6.5 
Early Termination Assessment 
Participants that discontinue the study early due to COVID-19 infection or are hospitalized 
for any reason are encouraged to attend the early termination assessment to the best of their 
ability. If the participant is unable to complete the treatment diary or attend the early 
termination assessment, the designated emergency contact is encouraged to submit this 
information on behalf of the participant to the best of their ability. 
Protocol deviations to be recorded for this study include visit/phone/telehealth procedure 
deviations and noncompliance; PRO noncompliance; study medication dosing 
noncompliance; and dispensing deviations. A special emphasis will be placed on dosing 
errors, lack of completion of the required daily PRO reporting, and the incomplete return of 
study medication at the conclusion of the study. 
Study medication noncompliance is defined as less than 80% of expected doses administered 
while on possible study treatment. PRO noncompliance is defined as less than 70% of 
possible reporting days of data recorded, eg. before a hospitalization, or an early termination.

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7 
ADVERSE EVENTS ASSESSMENTS 
7.1 
Adverse Event Definition 
As per Good clinical Practice (GCP) guidelines, an AE is any untoward medical occurrence 
in a patient or clinical investigation participant administered a pharmaceutical product and 
which does not necessarily have to have a causal relationship with this treatment. An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not related to the medicinal (investigational) product. 
AEs will include (1) any new medical condition (sign/symptom/disease) that occurs during 
the AE reporting period, or (2) any preexisting condition that worsens in severity or 
frequency or changes in character during the AE reporting period. 
An SAE is defined as an AE that, in the view of either the Investigator or Sponsor, meets any 
of the following criteria: 
• Results in death 
• Is a life-threatening AE 
- 
A life-threatening AE is defined as an AE that in the view of either the Investigator or 
Sponsor, places the patient or participant at immediate risk of death. It does not 
include an AE that, had it occurred in a more severe form, might have caused death. 
• Requires inpatient hospitalization or prolongation of existing hospitalization (except 
hospitalization for elective procedures for a pre-existing condition that has not worsened, 
admission to a nursing home or rehabilitation facility, or social admissions) 
• Results in persistent or significant disability or incapacity (substantial disruption of the 
ability to conduct normal life functions; it does not include experiences of relatively 
minor medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, or accidental trauma [eg, sprained ankle] that may interfere or prevent 
everyday life functions but do not constitute a substantial disruption) 
• Is a congenital anomaly or birth defect (ie, an adverse outcome in a child or fetus of a 
female participant exposed to the study product) 
• Important medical events that do not meet any of the above criteria may be considered 
serious when, based upon appropriate medical judgment, they jeopardize the participant 
and may require intervention to prevent one of the other outcomes listed in this definition 
7.2 
Method of Detecting AEs and SAEs 
Recording, evaluating, and assessing causality of AE and SAE methods and the procedures 
for completing and transmitting SAE reports are provided in Section 11. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences. 

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7.3 
Performing Adverse Events Assessments 
The Investigator is responsible for monitoring of participants for AEs/SAEs over the 
assessment period as specified in the Schedule of Events (Table 4). Each AE/SAE will be 
evaluated as described in Section 7.4.1 and Section 7.4.3. Treatment of any AE/SAE will be 
managed by the participant’s healthcare provider. If any aspect of evaluation or treatment of 
an AE/SAE is performed by a physician who is not part of the study team, the Investigator 
will ensure that the appropriate party is contacted as promptly as possible to collect the 
relevant information and documentation to complete the protocol-required assessment of 
each AE/SAE. 
7.4 
Timing 
The Sponsor’s medical monitor will have read-only access to the AEs recorded within the 
eCRF. All SAEs must be reported within 24 hours of disclosure/discovery. All SAEs will be 
recorded and reported to the Sponsor or designee immediately via automatic notification 
procedures from the eCRF and under no circumstance should this not exceed 24 hours. The 
Investigator will submit any updated SAE data to the Sponsor within 24 hours of it being 
available. 
Adverse events and SAEs will be collected from the start of study treatment until the Follow-
Up assessment as specified in the Schedule of Events (Table 4). Medical occurrences that 
begin before the start of study intervention but after obtaining informed consent will be 
recorded on the Medical History/Current Medical Conditions section of eCRF, not on the AE 
section. 
Investigators are not obligated to actively seek AEs or SAEs after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, at any time 
after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the Investigator must 
promptly notify the Sponsor. 
7.4.1 
Reportability 
The Investigator, CRO medical monitor and Sponsor’s medical monitor are responsible for 
determining whether an event should be classified as serious. If in the opinion of the 
Investigator, the AE meets the criteria of an SAE, the SAE is to be reported to the Sponsor or 
Sponsor’s medical monitor designee. All SAEs, regardless of causality, must be reported. 
SAEs must be reported from the time the Informed Consent Form (ICF) is signed until 
30 days after the last dose of study drug. SAEs considered related to study drug that occur 
after the specified Follow-up period should also be reported.  
For expedited reporting purposes, SAEs assessed as Definitely Related, Probably Related or 
Possibly Related by the Investigator will be considered as "Related" events, while those 
assessed as Not Related will be considered as "Not related" events. These processes will be 
delineated in the CRO prepared, Safety/Medical Monitoring Plan, in consultation with 
sponsor’s medical monitor prior to study. 

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7.4.2 
Severity 
The intensity (severity) of each AE will be assessed using the guidelines below: 
• Mild: Does not interfere with usual activities, easily tolerated, requires no treatment. 
• Moderate: Somewhat interferes with usual activities, may cause discomfort, may require 
treatment. 
• Severe: Significantly interferes with usual daily activities, may be incapacitating, may 
require treatment. 
Severity of an event is not the same as seriousness. Regardless of severity rating, an AE is 
considered serious if it meets the criteria for an SAE. 
7.4.3 
Relationship between Adverse Event and Study Drug 
The relationship between the AE and study drugs (ie, separate assessments for relationship to 
study treatment) will be determined as one of the following:  
• Definitely Related 
• Probably Related 
• Possibly Related 
• Not Related 
For analysis purposes, AEs assessed as Definitely Related, Probably Related or Possibly 
Related by the Investigator will be considered as "Related" events, while those Not Related 
will be considered as "Not related" events.  
Causality will be determined based on clinical judgment and the following guidelines: 
Definitely Related: 
The event followed a reasonable temporal sequence from the time of study medication 
administration and/or followed a known response pattern to the study medication and could 
not have been produced by other factors such as the subject’s clinical state, therapeutic 
intervention, or concomitant therapy and either occurred immediately following study 
medication administration or improved on stopping the medication. 
Probably Related: 
The event was reasonably temporally related to study medication administration, was 
consistent with known effects of the study medication, improved upon withdrawal of the 
study medication, and was unlikely explained by another etiology. 
Possibly Related: 
The event was reasonably temporally related to study medication administration which 
follows a known or expected pattern of the suspected medication but could be explained by 
another etiology. 
 

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Not Related: 
The event was clearly due to extraneous causes (e.g., diseases, environment), which was to 
be specified if known; or the event was most likely produced by other factors such as the 
subject’s clinical state, therapeutic interventions, or concomitant therapy and did not follow a 
known response pattern to the study medication. 
The CRO Medical Monitor will review the Investigator’s assessment of causality and may 
agree or disagree. Both the Investigator’s and CRO Medical Monitor’s assessments will be 
recorded. The CRO Medical Monitor will have the final say in determining the causality. 
7.4.4 
Adverse Drug Events 
Adverse drug events (ADE) may be expected to be generally associated with irritation of the 
nasal mucous membranes in both NONS and placebo treated participants. These events may 
include headache, pharyngitis, epistaxis, nasal burning/nasal irritation, nausea/vomiting, 
asthma symptoms, and cough. 
7.4.5 
Expectedness 
An unexpected AE is one of a type not identified in nature, severity or frequency in the 
current Investigator’s brochure. Expected events may include upper respiratory irritation-like 
symptoms due to use of the nasal spray. 
7.5 
Adverse Event and Concomitant Mediations Coding 
Adverse events will be coded using the current MedDRA dictionary and Concomitant 
Medications using the current WHODrug dictionary. 
7.6 
Reporting Serious Adverse Events and COVID-19 Reporting 
7.6.1 
Serious Adverse Event and Suspected Unexpected Serious Adverse Reaction 
Reporting  
All SAEs that occur from the time of participant enrollment until the end of the study 
(whether drug related or not) will be documented on an initial SAE form. All SAEs will be 
reviewed by the Investigator and reported to within 24 hours or specified by regulatory and 
IRB for SAE reporting. 
If only a partial SAE report is available, preliminary information will be documented on an 
SAE form, reviewed by the Investigator, and reported within 24 hours or specified by 
regulatory and IRB for SAE reporting. When additional relevant information is available, this 
information will be submitted on a new SAE form within 24 hours. 
Refer to the Safety Management Plan for SAE reporting methods. 
 
 

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Reporting of SAEs to the IRB/IEC will be performed by the Investigator in accordance with 
the standard operating procedures and policies of the IRB/IEC.  
The Sponsor will report SUSARs ([serious adverse drug reactions] that are not identified in 
nature, severity or frequency in the risk information set out in the Investigator’s brochure or 
on the label of the drug) to the Regulatory Authorities (eg, HC/FDA, or other applicable 
relevant local/national regulatory authorities) in accordance with regulations (e.g., 
C.05.014(1)) and related guidance.  
7.6.2 
Study Sponsor Notification of Adverse Event Outcome by Investigator 
Any SAEs, regardless of causality, must be reported to the Sponsor or Sponsor’s designee 
within 24 hours of the Investigator or any staff’s knowledge of the event.  
Within 24 hours after receipt of additional relevant information, the Investigator must 
provide Follow-up information on the SAE along with any additional relevant documentation 
(eg, test results, physician narrative, discharge summary, autopsy findings) that will assist in 
the understanding of the event.  
7.6.3 
Institutional Review Board/ Independent Ethics Committee Notification 
The Investigator must report all SAEs (including Follow-up information) to the 
IRB/independent ethics committee (IEC) in accordance with IRB/IEC requirements. Copies 
of each report and documentation of IRB/IEC notification and receipt will be kept in the 
local Regulatory files. 
7.6.4 
Regulatory Reporting Requirements for Serious Adverse Events 
• Prompt notification by the Investigator to the Sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met. 
• The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards (IRB)/ 
IEC, and Investigators. 
• For all studies, except those utilizing medical devices Investigator safety reports, must be 
prepared for SUSAR according to local regulatory requirements and Sponsor policy and 
forwarded to Investigators as necessary. 
• An Investigator who receives an Investigator safety report, describing a SAE or other 
specific safety information (e.g., summary or listing of SAEs), from the Sponsor, will 
review and then file it along with the Investigator’s Brochure. He or she will then notify 
the IRB/IEC, if appropriate according to local requirements. 
 

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7.6.5 
COVID-19 Health Authority Notification 
Health Canada/FDA, and other relevant local/national regulatory authorities must be notified 
of any participant who contracts COVID-19 during the study (if applicable).  
7.7 
Treatment-Emergent Adverse Events 
Information regarding the occurrence of treatment-emergent AEs (TEAEs) will be captured 
throughout the study and verified at each telehealth assessment. A description of the AE, 
duration (start and stop dates and times), severity, outcome, treatment and relation to study 
medication will be collected. 
7.8 
Adverse Events of Special Interest 
• COVID-19 related symptoms or diagnosis 
• Non-compliance for any reason 
• Complaints or unanticipated problems associated with the manual pump and spray bottle 
or use of these, especially malfunction of the manual pump spraying apparatus or a 
deterioration in its effectiveness, or inadequacy of the directions for use 
 
7.9 
Adverse Event, Serious Adverse Event, and Adverse Events of Special 
Interest Follow-Up 
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent assessments/contacts. All SAEs, and AEs of special interest will be 
followed until resolution, stabilization, the event is otherwise explained, or the participant is 
lost to Follow-Up (Section 7.12.3).  
7.10 Pregnancy Reporting 
Should a female participant or female partner of a male participant become pregnant at any 
time during the study, the Investigator must notify the Sponsor within 24 hours after learning 
about the pregnancy. The Sponsor will request Follow-up information regarding the course 
of the pregnancy and its outcome. Voluntary consent must be obtained from a female 
participant or female partner of a male participant (and/or legally authorized representative if 
the participant is mentally incompetent or physically incapacitated) before any pregnancy-
related follow-up is obtained. 
Pregnancy, in and of itself, is not considered an AE, unless there is suspicion that the study 
product may have interfered with the effectiveness of a contraceptive medication or method. 
However, any pregnancy complication or elective termination of a pregnancy for medical 
reasons will be recorded as an AE or SAE and will be followed accordingly. A spontaneous 
abortion is considered to be an SAE. 

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7.11 Concomitant Medication Assessments 
Concomitant medication usage for a participant will be recorded for the period starting on 
Day 1 and continuing throughout the study, including medications administered for 
management of any AEs as described in Table 4. 
Concomitant medications to be recorded include prescription and non-prescription drugs, 
including vaccines (including all previous SARS-CoV-2 vaccine doses), vitamins, herbal 
supplements, and recreational drugs. 
Non-pharmacologic therapies should be recorded if relevant to a reported AE. 
7.12 Safety Follow-Up  
Safety Follow Up will be conducted on-site or by the qualified medical provider by 
telephone, as described in the Schedule of Events (Table 4).  
7.12.1 
Removal of Participants from the Trial or Study Treatment 
The Investigator may withdraw a participant from the study for any of the following reasons: 
• A protocol violation occurs, 
• A serious or intolerable adverse event occurs, 
• A clinically significant change in a laboratory parameter occurs,  
• The Sponsor or Investigator terminates the study, or 
• The participant requests to be discontinued from the study. 
A participant may choose to discontinue study treatment and/or withdraw from the study at 
any time. Participants who become pregnant during the study are to be withdrawn from study 
treatment. In the absence of a medical contraindication, every effort should be made by the 
Investigator to encourage participants who prematurely discontinue treatment to remain in 
the study as appropriate and, at a minimum, follow the participant for safety data collection. 
 
Discontinuation from Study Drug Treatment 
Participants may discontinue for the following reasons: any study drug related AEs that in the 
opinion of the Investigator, makes it unsafe for the participant to continue; any study drug 
related AE that repeats upon re-challenge. 
A participant may be discontinued prematurely from study drug treatment for the following 
reasons: 
• AE (including hospitalization for COVID-19/sequalae) 
• Withdrawal by participant (specify reason in the eCRF) 
• Lost to Follow-up 
• Pregnancy 

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• Physician decision (ie, Investigator decision – specify reason in the eCRF) 
• Sponsor decision (specify reason in the eCRF) 
• Noncompliance with study protocol 
• Other (specify reason in the eCRF) 
 
 
Discontinuation from Study 
A participant may be discontinued prematurely from the study (in its entirety) for the 
following reasons: 
• AE (including hospitalization for COVID-19/sequalae) 
• Withdrawal by participant (specify reason in the eCRF) 
• Lost to Follow-up 
• Death 
• Physician decision (ie, Investigator decision – specify reason in the eCRF) 
• Sponsor decision (specify reason in the eCRF) 
• Noncompliance with study protocol 
• Other (specify reason in the eCRF) 
If a participant is withdrawn because of an adverse experience, the participant will be 
followed and treated by their health care provider (with documented follow-up) until the 
abnormal parameter or symptom has resolved or stabilized. 
If, for any reason, a participant does not complete the study, the reason will be entered on the 
eCRF. All participants are free to withdraw from participation at any time, for any reason, 
specified or unspecified, and without prejudice. The Investigator must record the reason for 
the early termination and document it in the eCRF. 
 
Data Collection and Follow Up for Withdrawn Participants 
If a participant is discontinued prematurely from treatment or from the study, the reason for 
discontinuation will be collected in the eCRF. 
For participants who discontinue from the study for reasons other than withdrawal of 
consent, lost to Follow up, or death, a reasonable effort should be made to complete certain 
study procedures at or near the time of discontinuation. 
Any AEs that are present at the time of discontinuation/withdrawal should be followed in 
accordance with the safety requirements. 
If a participant is lost to Follow-up, every reasonable effort must be made by the study site 
personnel to contact the participant and determine the reason for discontinuation/withdrawal. 
 

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7.12.2 
Participant Replacement 
Participants who withdraw from the study will not be replaced. 
Participants who are withdrawn due to a positive COVID-19 infection prior to completing <2 
days (48hrs) on study may be replaced at the discretion of the investigator. 
 
7.12.3 
Lost to Follow-Up 
A participant will be considered lost to Follow-Up if they repeatedly fail to attend scheduled 
visits/contacts/telehealth assessments and are unable to be contacted by the study site. 
The following actions will be taken if a participant fails to attend a scheduled 
visit/contact/telehealth assessment: 
• The investigator/site/regional center must attempt to contact the participant and 
reschedule the missed assessment(s) as soon as possible. They must counsel the 
participant on the importance of maintaining the assigned assessment schedule and 
ascertain whether or not the participant wishes to and/or should continue in the study. 
• Before a participant is deemed lost to Follow-Up, the Investigator or designee (i.e. 
regional call center) must make every effort to regain contact with the 
participant/emergency contact (where possible, 3 telephone calls and, if necessary, a 
certified letter to the participant’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the participant’s medical 
record. 
• Should the participant continue to be unreachable, they will be considered to have 
withdrawn from the study. 
 
7.13 Study Stopping Rules 
A formal plan for interim data monitoring for futility will be established. Review of serious, 
unexpected, and related AEs by the CRO Medical Monitor, Data Safety Monitoring Board 
(DSMB), IRB, or HC/ FDA or applicable relevant local/national regulatory authorities may 
also result in suspension of further study agent administration. Health Canada/FDA/IRB/or 
local/national regulatory authority and study Sponsor(s) retain the authority to suspend 
additional enrollment and study agent for the entire study, as applicable.  
7.14 Appropriateness of Measurements 
All assessments used in the study are considered standard (ie, widely used and generally 
recognized as reliable, accurate, and relevant). 

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8 
CLINICAL TRIAL MATERIALS 
8.1 
Study Treatment Supplies 
8.1.1 
Nitric Oxide Nasal Spray and Placebo 
Supplies of NONS and placebo are described in Table 1. 
Table 1 
 
Identity of Investigational Product 
Study Drug 
Formulation 
Nitric oxide spray (supplied by the Sponsor) 
12.5 mL formula A in saline in one chamber, 
and 12.5 mL formula B in saline in the other 
chamber of the dual chamber nasal spray device 
which delivers a metered dose 
Placebo (supplied by the Sponsor) 
Sterile 0.9% Sodium Chloride, USP 
 
8.2 
Packaging and Labeling 
The drug will be prepared and packaged in an ISO 13485 and GMP registered facility. The 
NONS solution will be prepared in three 25 mL bottles of manual pump nasal spray bottles 
with the labeled statement according to local regulatory guidelines for labeling “for 
investigational use only” with minimally the lot/batch number, expiry date, and storage 
conditions.  
8.3 
Distribution and Supply Management  
Regional distribution and supply management is a critical piece to the overall success of the 
study. Distribution and supply management following participants’ randomization will be 
completed in accordance with the Supply Management Plan. The Sponsor in conjunction 
with support vendors, as applicable, will detail how study supplies are received, shipped and 
returned to sites for both remote and on-site enrolled participants. The Sponsor or designee 
(ie, CRO or supply management and support vendor(s)) will be responsible for maintaining 
this document throughout the course of the study. 
For more details, refer to the Supply Management Plan. 
8.4 
Storage and Accountability 
8.4.1 
Study Treatment Storage 
Study treatment provided to participants will be stored, dispensed, and recorded in 
accordance with this protocol, Pharmacy Manual, Supply Management Plan and other 
multicenter operational procedures document for this study including participant instructions. 
Only participants enrolled in the study may receive study treatment. 

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All study treatment should be stored at temperatures ranging from 2°C to 40°C (35°F to 
104°F) and protected from flames and combustible materials. Study medication should be 
kept out of the reach of children. 
8.4.2 
Study Treatment Accountability  
The Investigator or his/her designee will maintain accurate records of the receipt of all study 
treatment. In addition, accurate records will be kept regarding when and how much of each 
study treatment is dispensed, used and unused by each study participant and documented in 
the eCRF. 
8.5 
Investigational Product Retention at Sponsor 
At the conclusion of the study, any unused or opened study treatment bottles will be returned 
to the Sponsor or designee for accountability tracking (refer to the Supply Management 
Plan). The Sponsor should not dispose of any used or unused study drug until drug 
accountability is performed by the Sponsor or its designee.  
8.6 
Preparation of Study Treatment 
There is no preparation of the study treatment required.  
8.7 
Use of the Spray Bottle 
In the event of a malfunction of the spray bottle, or the participants misplace the spray bottle, 
participants should contact the regional study center for further instructions. 
At the end of the study, or at the time of participant discontinuation or early termination, 
nasal spray bottles will be returned to the Sponsor as described in the MOP/IOP. 
Participants will complete the spray bottle PRO on Day 1 and Day 5, documenting their 
perception of the ease of use of the spray bottle (Appendix 3). 

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9 
PLANNED STATISTICAL METHODS 
9.1 
General Considerations 
A detailed statistical analysis plan will be developed separately and finalized prior to 
randomization of the first participant. Deviations from the protocol-planned analyses will be 
noted.  
The statistical analysis of the data obtained from this study will be performed using SAS® 
Version 9.4 or higher. All statistical tests will be performed at the 0.05 (two-sided) 
significance level, unless otherwise noted. 
The data collected in this study will be documented using summary tables and participant 
data listings. Continuous variables will be summarized using descriptive statistics, 
specifically the number of observations, mean, median, standard deviation, minimum and 
maximum. Categorical variables will be summarized by frequencies and percentages. The 
analysis of both efficacy and safety parameters will be conducted for each treatment group 
separately. Active treatment will be compared against placebo. 
Baseline characteristics will be summarized using descriptive statistics or frequencies and 
percentages, as appropriate. No statistical hypothesis tests will be performed on these 
characteristics. 
9.2 
Determination of Sample Size 
For an annualized infection rate of 3% in the placebo arm (daily incidence = 0.000075), and 
assuming a true hazard ratio of 0.15 implying protective effect of NONS equivalent to a 
vaccine efficacy of 85%, a sample size of 11,480 participants randomized 1:1 
(NONS:Placebo) and available in the modified intent-to-treat (mITT) population will provide 
90% power to demonstrate superiority of NONS to placebo in preventing COVID-19 
infections reported through 28 days, based on Cox regression model and a 2-sided 0.05-level 
test (Schoenfeld 1983). The expected number of events in the two arms is 2 and 10 for the 
NONS and placebo groups respectively. This further assumes 25% censoring during the 28-
day period (1.05% loss per day).  
Sample size calculations conducted under version 1.0 of the protocol (dated April 27, 2021) 
used estimates of annualized case rates as listed in Table 2. At that time, the recent estimated 
annualized infection rate based on confirmed cases ranged from 2.2 through 3.9% in select 
Canadian provinces, though there was considerable variability, and these rates underestimate 
the true infection rates considering those untested. The US and other nations may have 
substantially higher infection rates and require fewer subjects to be randomized.  
In particular, for the Czech Republic, Slovakia, and Sri Lanka, the reported annualized rates 
are between 0.14% and 8.23%, 0.07% and 7.27%, and 1.48% and 6.18% respectively over 
the period of May 1, 2021, to July 31, 2021. We are therefore likely to have sufficient power 
to conduct this study in those countries.  

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The maximum number of participants who will be randomized is 13,000, in order to achieve 
a maximum of 11,480 participants initiating their randomized treatment assignment and 
entering the mITT population. If the infection rate is higher than assumed here, enrollment 
and randomization will be closed if the total number of COVID-19 events in the mITT 
population exceeds 18 cases, 50% more than the number expected for 90% power. This 
inflation accounts for the increased infection rate and the consequent increased risk of 
infection between the time of randomization and time of initiation of study treatment due 
shipping times. 
Table 2 
 
Daily COVID-19 Counts  
Population 
Estimated 
annualized rate 
in February 2021 
(through 
25FEB2021 
Equivalent daily counts 
based on study assumption 
in control arm  
Days Daily Confirmed 
case counts exceeded 3% / 
4% annualized rate 
1FEB-25FEB2021 
3% 
annualized 
rate 
4% 
annualized 
rate 
Manitoba 
2.2% 
104 
138 
4 / 0 Days  
Alberta 
2.8% 
328 
437 
12 / 1 Days 
British 
Columbia 
3.2% 
380 
507 
21 / 3 Days  
Quebec 
3.9% 
637 
849 
25 / 15 day 
Ontario 
2.9% 
1101 
1468 
11 / 4 days  
Canada (all 
provinces) 
3.0% 
2819 
3759 
20 / 2 days  
United States 
> 4% 
24,615 
32,820 
25 days  
Source: https://www.canada.ca/en/public-health/services/diseases/2019-novel-coronavirus-infection.html  
 
9.3 
Analysis Populations  
Analysis populations are Randomized participant, mITT, Per-Protocol (PP), and the Safety 
population (all participants receiving any dose of treatment), the Per Protocol population 
(received drug and had no major documented protocol violations), defined as in  
Table 3. 
 
 

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Table 3 
 
Populations for Analysis 
Population 
Description 
Randomized 
All participants randomized regardless of adherence to treatment or 
study status, analyzed as randomized. 
mITT 
All participants in the Randomized population who received at least 
one dose of the test article (NONS or placebo), analyzed as 
randomized. 
Daily Use 
All participants in the mITT set who documented at least one self-
administered NONS dose per day on at least 25 of 28 expected 
dosing days or 90% of days while on study treatment. Analyzed as 
treated 
Per Protocol 
All participants in the mITT set who documented self-administered 
NONS on at least 25 of 28 expected dosing days or 90% of days and 
80% of expected doses while on study treatment. Analyzed as 
treated. 
Safety 
All randomized participants who receive at least 1 dose of the study 
intervention. 
Abbreviations: mITT=modified intent-to-treat; NONS=nitric oxide nasal spray. 
 
9.4 
Demographics and Baseline Characteristics 
Demographic data will be provided in listings and summary tables with descriptive statistics. 
No statistical hypothesis tests will be performed on these characteristics. 
9.5 
Analysis of Efficacy 
9.5.1 
Primary Efficacy Analysis 
The primary efficacy objective is to demonstrate that NONS product reduces the risk of 
COVID-19 infection. The associated null hypothesis is that the hazard ratio (HR) of NONS 
relative to placebo is greater than 1, or H0: HR ≥ 1, or equivalently in terms of a vaccine 
efficacy, H0: VE ≥ 0 where vaccine efficacy is calculated as VE = 100% x (1-HR). The HR 
will be estimated using a Cox proportional hazard regression model with a fixed effect only 
for treatment arm. Due to the small, expected event rate (see the Section 9.2), incorporation 
of additional fixed effects may not be possible. However, as a sensitivity analysis, a stratified 
Cox model using randomization strata (≥ 65, <65 at increased risk, < not at increased risk) 
will also be fit. Similarly, age-group (≥/<65) and region-specific models will be fit, 
aggregating adjacent provinces, states, or larger geographies to enable model convergence 
and evaluate, to the extent possible, whether differences exist. 
The primary analysis will be executed in the mITT data set and count all cases occurring 
starting from the day after participants begin administering study treatment.  

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For all models, a 2-sided score-based 95% confidence interval (CI) and 2-sided p-value for 
the effect of NONS will be calculated.  
The estimand of the primary analysis is a treatment policy strategy and will consider 
intercurrent events as censored. Specifically, participants who stop administering NONS for 
any reason, stop submitting data to the electronic patient-reported outcomes (ePRO) system, 
do not submit paper diaries, or are unreachable by telephone contact, will be censored on the 
day of their last ePRO clinical status submission or last available documented day on paper 
diary (ie, the last day confirming no positive COVID-19 test). Participants who submit 
COVID-19 test results following Day 28, will be censored at Day 28. Participants submitting 
a COVID-19 test result on or prior to Day 28 will be considered to have reached the primary 
endpoint on the day that the specimen (ie, nasal swab) is collected, not the date of the test. 
Positive test results obtained within 48 hours of randomization will be considered infected at 
randomization and not counted as events. 
The Cox model will be fit to the following sets (if different) as sensitivity analyses: 
• mITT set counting all cases after randomization, 
• PP set counting cases after first administration, 
• PP set counting all cases after randomization, and 
• Randomized set counting all cases after randomization 
The primary analysis will be repeated in the following subgroups: 
• Subjects unvaccinated against SARS-CoV-2 prior to randomization 
• Subjects partially vaccinated against SARS-CoV-2 prior to randomization 
• Subjects fully vaccinated against SARS-CoV-2 prior to randomization 
• Subjects who are fully vaccinated and have received a booster shot against SARS-CoV-2 
prior to randomization 
• Subjects who become partially vaccinated against SARS-CoV-2 during the course of the 
study 
• Subjects who become fully vaccinated against SARS-CoV-2 during the course of the 
study 
• Subjects who receive a booster vaccine against SARS-CoV-2 during the course of the 
study 
Specific procedures to account for missing data, unused or spurious data and criteria for 
termination will be delineated in the SAP. Procedures for reporting any deviation(s) from the 
original statistical plan will be described in the SAP and justified (if needed) in the final 
clinical study report. 
9.5.2 
Secondary Efficacy Analysis 
For the secondary objective of prevention of medical intervention for COVID-19, the 
secondary endpoint will be executed similarly to the primary efficacy analysis above.  

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Participants who are hospitalized for COVID-19-related symptoms, but who test negative for 
COVID-19 will not be considered to have met the endpoint. The time of the endpoint will be 
considered the study day at which the participant was hospitalized or the day at which the 
ER/ED visit occurred even if a COVID-19 positive result was obtained before or after the 
day of the event. 
9.5.3 
Exploratory Analysis 
Device use questions to support the human factors study of the delivery device will be 
performed as an exploratory analysis as described in the SAP. Any AEs, protocol deviations, 
or compliance issues identified in this study will be included in the primary analysis of this 
study and will be detailed in the main SAP. 
9.5.4 
Analysis of Safety 
All safety analyses will be performed in the Safety Population. 
The primary analysis of safety will include counts and proportions of participants with Aes 
and SAEs summarized by MedDRA System Organ Class (SOC) and Preferred Term (PT) 
and cross-tabulated by severity, relationship to study treatment, treatment received, and 
overall. Exact Clopper-Pearson 95% confidence intervals for proportions may be constructed. 
All AEs and SAEs will be reported in a listing and events of interest will be itemized and 
listed separately. 
9.6 
Interim Analysis 
Given the small number of expected events, there will be no interim analysis for efficacy. As 
described in Section 9.2, the enrollment may be closed when 18 cases are accumulated, but 
this will be considered the final analysis, not an interim analysis. 
After every approximately 2,000 participants from the mITT cohort complete the study, the 
aggregated COVID case-rate will be used to calculate the projected number of cases for the 
full sample size of 11,480. The study may be considered futile if fewer than 10 cases are 
projected to be observed for the full sample size. 

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10 QUALITY CONTROL AND ASSURANCE 
10.1 Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines 
• Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans – TCPS 2 
(2018)  
• International Council for Harmonisation (ICH) E6 (R2) Guideline for Good Clinical 
Practice 
• Food and Drug Regulations Part C, Division 5 Drugs for Clinical Trials Involving Human 
Participants 
• Health Canada ‘s Management of clinical trials during the COVID-19 pandemic: Notice 
to clinical trial Sponsors 
• Regulations of all other jurisdiction where the trial is undertaken, eg, with respect to the 
EU, all applicable laws and regulations of a member state where the trials is undertaken, 
especially those transposing and implementing Directive 2001/20/EC of the European 
Parliament and of the Council of 4 April 2001 on the approximation of the laws, 
regulations and administrative provisions of the Member States relating to the 
implementation of good clinical practice in the conduct of clinical trials on medicinal 
products for human use. Or the Regulation EU No 536/2014 of the European Parliament 
and of the Council on clinical trials on medicinal products for human use should it 
become effective in term of the present Agreement. Plus the Regulation (EU) 2016/679 
on the protection of natural persons with regard to the processing of personal data and on 
the free movement of such data, and repealing Directive 95/46/EC (General Data 
Protection Regulation), and if in the United States, regulations 21 Code of Federal 
Regulations (CFR) 50, 56 and 312. 
• The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (e.g., advertisements) must be submitted to an IRB/IEC by the Investigator 
and reviewed and approved by the IRB/IEC before the study is initiated. 
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants. 
 
The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC 
• Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 

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Providing oversight of the conduct of the study at the site and adherence to requirements of 
Food and Drug Regulations Part C, Division 5 Drugs for Clinical Trials Involving Human 
Participants, in particular the undertakings and practices described in: C.05.012(3)(f) 
(Qualified Investigator Undertaking) and C.05.010 concerning Good Clinical Practices. 
Therapeutic Product’s Directorate Guideline for Good Clinical Studies, Guidance Document: 
Part C, Division 5 of the Food and Drug Regulations “Drugs for Clinical Trials Involving 
Human Participants” (GUI-0100) – Summary or all other applicable local regulations e.g. US 
regulations 21 CFR 312. 60-68. 
10.1.1 
Data Protection 
• Participants will be assigned a unique study number. Any participant records or datasets 
that are transferred to the Sponsor will contain the identifier only; participant names or 
any information which would make the participant identifiable will not be transferred. 
• Only participant data will be analyzed during the study.  
• The following emergency contact data will be collected: informed consent, name, and 
telephone number. 
• The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure must 
also be explained to the participant who will be required to give consent for their data to 
be used as described in the ICF.  
• The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
10.1.2 
Dissemination of Clinical Study Data 
Following completion of the study, the data may be considered for publication in a scientific 
journal or for reporting at a scientific meeting. The Investigator is obligated to keep data 
pertaining to the study confidential. Archiving per country specific requirements (eg, 25 
years in Canada). 
10.1.3 
Auditing and Inspecting 
The study may be evaluated by representatives of the Health Canada, and where applicable, 
other government agencies, national health agencies, and national health authorities, who 
also will be allowed access to study documents. The Investigator and regional centers should 
promptly notify the Sponsor when any inspections are scheduled, as well as providing the 
results of any unscheduled investigations performed by any regulatory authorities. 
The Investigator and regional centers will permit study related monitoring, audits, and 
inspections by the IRB/EC, the Sponsor, government regulatory bodies, and compliance and 
quality assurance groups of all study related documents (eg, source documents, regulatory 

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documents, data collection instruments, study data, etc.). The Investigator will ensure the 
capability for inspections of applicable study-related facilities. All authorized personnel, 
including health authority inspector(s), Sponsor and designees, Study/CRO Medical 
Monitor(s), Data Monitoring Committee (DMC) members, and auditor(s) will be given direct 
access to source data and documentation (eg, medical records, laboratory results, etc.) for 
source data verification, provided that participant confidentiality is maintained in accordance 
with local requirements. 
Participation as an Investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable compliance and quality assurance offices. 

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11 ADMINISTRATIVE CONSIDERATIONS 
11.1 Institutional Review Board (IRB) or Independent Ethics Committee (IEC) 
Approval 
The Investigator, sub-Investigator, and regional centers will provide the ethics review board 
(eg, IRB or IEC) with the study protocol, the ICF, all written materials for the participant, 
and all advertisements used for participant recruitment. No participants are to be enrolled in 
the study until the IRB/IEC provides written approval of the protocol and the ICF, and not 
until approval documents have been sent to the Investigator and copies received by the 
Sponsor. All reviews will be in accordance with GCP. The IRB will be notified of any SAEs 
reported on the study. Appropriate reports on the progress of the study will be made by the 
Investigator to the IRB/IEC and to the Sponsor in accordance with the applicable government 
regulations, and in agreement with the policy established by the Sponsor. 
11.2 Ethical Conduct of the Study 
The study will be conducted in accordance with GCP requirements as described in the 
current revision of the International Council for Harmonisation (ICH) of Technical 
Requirements for Pharmaceuticals for Human Use guidelines and all applicable regulations, 
including the current Canadian Food and Drug Regulations Part C, Division 5 in particular 
C.05.010, US Code of Federal Regulations (CFR), Title 21, Parts 50, 54, 56, and 312, and 
Title 45, Part 164. Compliance with these regulations and guidelines will also constitute 
compliance with the ethical principles that have their basis in the Declaration of Helsinki and 
as outlined in the Tri-Council Policy Statement: Ethical Conduct for Research Involving 
Humans – TCPS 2 (2018). This study will also be carried out in accordance with local legal 
requirements in each participating country. 
11.3 Participant Information and Consent 
Each participant will be provided a written ICF (electronic or hard copy), describing this 
study and providing sufficient information to make an informed decision about participation 
in this study. The participant will be given opportunities to discuss and review the study 
requirements with a regional representative for their location. Copies of completed consents, 
will be provided back to the participant (digitally or hard copy) based on the email address 
provided by the participant or in-person during the on-site visit. 
A copy of the proposed ICF must be submitted to the Sponsor and/or designee for review 
prior to submission to the reviewing IRB/EC. The ICF must be approved by the IRB/EC and 
must contain all elements required by federal, provincial, state, local, and institutional 
regulations or requirements. Canadian institutions must comply with all applicable federal 
and provincial privacy legislation (see Section 11.5). 
Institutions in the US must be in compliance with Health Insurance Portability and 
Accountability Act of 1996 with regard to obtaining authorizations for use and disclosure of 
Protected Health Information. Local privacy regulations must be followed, including the 

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General Protection Data Regulation (GDPR) applicable in the EU. For Canada, see Section 
11.4 regarding legal obligations for privacy and confidentiality of personal information. 
The study, including its goals, methods, expected benefits, and potential hazards will be 
completely explained to each prospective study participant. It will also be explained to 
participants that they are free to refuse entry or to withdraw from the study at any time 
without prejudice to future treatment. Voluntary informed consent must be obtained from 
each eligible participant (and/or legally authorized representative if the participant is 
mentally incompetent or physically incapacitated) before any protocol-defined procedures 
are performed. 
The participant’s willingness to participate in this study will be documented on the IRB/EC 
approved ICF which must be signed and dated by the participant or legally acceptable 
surrogate, and the physician Investigator (Principal or sub-Investigator). The Investigator will 
keep the original ICF, and a copy will be given to the participant. The process for obtaining 
informed consent should also be noted in the participant’s source documentation. 
11.4 Patient Confidentiality 
The Investigator, sub-Investigator, and regional centers must assure that the privacy of the 
participants, including their identity and all personal medical information, will be maintained 
at all times. In the eCRFs and other documents (eg, laboratory reports, etc.) submitted to the 
Sponsor, participants will not be identified by name, but by an identification code (eg, 
participant identification numbers). Remote monitoring may involve either a redacted source 
document or remote review of unredacted source document, per CRO and/or institutional 
polices. All Non-Canadian institutions must comply with all applicable national and regional 
privacy legislation. Canadian institutions must comply with all applicable federal (Personal 
Information Protection and Electronic Documents Act) and provincial privacy legislation eg,: 
• BC Personal Information Protection Act, Freedom of Information and Protection of 
Privacy Regulations, BC eHealth Act,  
• Alberta Personal Information Protection Act 
• Ontario Personal Health Information Protection Act  
• Quebec Loi sur la protection des renseignements personnels dans le secteur privé 
Personal medical information may be reviewed for the purpose of verifying data recorded in 
the CRF by the Study/CRO Medical Monitor, Sponsor or designee, or regulatory authorities. 
Personal medical information will always be treated as confidential. Personal data is also 
protected in accordance with the personal data privacy legislation in each participating 
country, per the General Protection Data Regulation (GDPR) applicable in the EU. 
11.5 Study Monitoring 
The Investigator/regional Principal Investigator will allocate adequate time for remote study 
monitoring activities. The regional Investigator will also ensure that the Study Monitor, or 

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other compliance or quality assurance reviewer, is given access to all study-related 
documents and study related facilities. 
The Study Monitor will review ICFs and eCRFs and compare them with source documents to 
verify adherence to the protocol, and to ensure complete, accurate, consistent, and timely 
collection of data. The Investigator will be asked to provide any missing information or to 
clarify any discrepancies found by the Study Monitor. 
In addition to source document verification of CRFs and ICFs, the Study Monitor will review 
the Clinical Site Regulatory Binder that is to be maintained by the Principal Investigator. 
Refer to the Study Monitoring Plan for source data verification (SDV) and remote 
monitoring requirements and frequency. 
11.6 Case Report Forms and Study Records 
All eCRFs will be completed according to eCRF completion guidelines. The Principal 
Investigator must electronically sign and date a declaration on the eCRF attesting to his/her 
responsibility for the quality of all data recorded and that the data represent a complete and 
accurate record of each participant’s participation in the study. An electronic copy of the 
completed eCRF will then be sent to the Investigator to be retained for their records. 
11.7 Data Monitoring Committee 
The DMC will review participant safety data regularly (meeting at least biannually), and after 
1,000 participants have completed 5 weeks of Follow-Up. The composition and policies of 
the DMC are described in the DMC Charter. If any safety concerns arise, these data will be 
conveyed to the DMC expeditiously. After review of the data, the DMC will make any 
recommendations regarding study conduct. 
11.8 Protocol Violations/Deviations 
Except for a change intended to eliminate an immediate hazard to a study participant, the 
protocol shall be conducted as described without any changes or deviations. Any change 
must be reported immediately to the Sponsor and to the IRB/EC and/or regulatory authority 
as required by guidelines or regulation.  
11.9 Access to Source Documentation 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents including web-based documentation are to 
be filed at the regional centers. 
Data reported entered in the eCRF that are transcribed from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
Investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available for all data collected in the eCRF. 

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 Refer to the Monitoring Plan for SDV review and requirements.  
11.10 Principal Investigator Sign-Off on Electronic Case Report Forms 
Whomever completes the medical assessment and initial consent for the participant is 
responsible for reviewing and signing off on the eCRF at the end of the study. 
11.11 Data Generation and Analysis 
All participant data relating to the study will be recorded directly into the eCRFs.  
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRFs. 
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), 
methods, responsibilities and requirements, including handling of noncompliance issues and 
remote monitoring techniques are provided in the Monitoring Plan.  
11.12 Retention of Data 
Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained subject to applicable local regulations after study completion, eg, in Canada 25 
years. No records may be destroyed during the retention period without the written approval 
of the Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor. 
11.13 Financial Disclosure 
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate 
financial information as requested to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities, e.g. 
US regulation 21 CFR Part 54, which also covers the spouse and each dependent child of the 
Investigator. Investigators are responsible for providing information on financial interests 
during the course of the study and for 1 year after completion of the study. 
11.14 Publication and Disclosure Policy 
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before 
submission. This allows the Sponsor to protect proprietary information and to provide 
comments. 
The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 

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publication of multicenter studies only in their entirety and not as individual site data. In this 
case, a coordinating Investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors (ICMJE) authorship requirements.  
The Sponsor will adhere to the trials registration policy adopted by the ICMJE member 
journal. This policy requires that all clinical trials be registered in a public trials registry such 
as ClinicalTrials.gov, which is Sponsored by the National Library of Medicine. 

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Akaberi, D., J. Krambrich, J. Ling, C. Luni, G. Hedenstierna, J. D. Järhult, J. Lennerstrand 
and Å. Lundkvist (2020). "Mitigation of the replication of SARS-CoV-2 by nitric oxide in 
vitro." Redox Biol 37: 101734. 
Akarid, K., M. Sinet, B. Desforges and M. A. Gougerot-Pocidalo (1995). "Inhibitory effect 
of nitric oxide on the replication of a murine retrovirus in vitro and in vivo." J Virol 69(11): 
7001-7005. 
Akerström, S., V. Gunalan, C. T. Keng, Y. J. Tan and A. Mirazimi (2009). "Dual effect of 
nitric oxide on SARS-CoV replication: viral RNA production and palmitoylation of the S 
protein are affected." Virology 395(1): 1-9. 
Balijepalli, A. S., A. T. Comstock, X. Wang, G. C. Jensen, M. B. Hershenson, M. A. 
Zacharek, U. S. Sajjan and M. E. Meyerhoff (2015). "Enhancement of Inducible Nitric Oxide 
Synthase Activity by Low Molecular Weight Peptides Derived from Protamine: A Potential 
Therapy for Chronic Rhinosinusitis." Mol Pharm 12(7): 2396-2405. 
Barraud, N., M. J. Kelso, S. A. Rice and S. Kjelleberg (2015). "Nitric oxide: a key mediator 
of biofilm dispersal with applications in infectious diseases." Curr Pharm Des 21(1): 31-42. 
Centers for Disease Control and Prevention. (2021, 22 February). "Symptoms of 
Coronavirus."   Retrieved 04 March 2021, from https://www.cdc.gov/coronavirus/2019-
ncov/symptoms-testing/symptoms.html. 
Clinical Trials Transformation Initiative (2018) "CTTI Reccomendations: Decentralized 
Clinical Trials." 
Croen, K. D. (1993). "Evidence for antiviral effect of nitric oxide. Inhibition of herpes 
simplex virus type 1 replication." J Clin Invest 91(6): 2446-2452. 
European Medicines Agency. (2020). "EU Clinical Trials Register, EudraCT Number 2020-
00494-27, Clinical Efficacy of Nitric Oxide Nasal Spray (NONS) for the Treatment of Mild 
COVID-19 Infection."   Retrieved 05 March, 2021, from 
https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-004994-27/GB. 
Fang, F. C. (1997). "Perspectives series: host/pathogen interactions. Mechanisms of nitric 
oxide-related antimicrobial activity." J Clin Invest 99(12): 2818-2825. 
Fang, F. C. (1997). "Perspectives series: host/pathogen interactions. Mechanisms of nitric 
oxide-related antimicrobial activity." The Journal of clinical investigation 99(12): 2818-2825. 
Food and Drug Administration (2021). Conduct of Clincial Trials During-COVID 19 Public 
Health Emergency Guidance for Industry. US Department of Health and Human Services. 
Ghaffari, A., C. C. Miller, B. McMullin and A. Ghahary (2006). "Potential application of 
gaseous nitric oxide as a topical antimicrobial agent." Nitric Oxide 14(1): 21-29. 

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Ghaffari, A., D. H. Neil, A. Ardakani, J. Road, A. Ghahary and C. C. Miller (2005). "A direct 
nitric oxide gas delivery system for bacterial and mammalian cell cultures." Nitric Oxide 
12(3): 129-140. 
Health Canada. (2021, 25 February ). "Coronavirus disease (COVID-19): Symptoms and 
treatment."   Retrieved 05 March, 2021, from https://www.canada.ca/en/public-
health/services/diseases/2019-novel-coronavirus-infection/symptoms.html. 
Hoffmann, M., H. Kleine-Weber, S. Schroeder, N. Krüger, T. Herrler, S. Erichsen, T. S. 
Schiergens, G. Herrler, N. H. Wu, A. Nitsche, M. A. Müller, C. Drosten and S. Pöhlmann 
(2020). "SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a 
Clinically Proven Protease Inhibitor." Cell 181(2): 271-280.e278. 
Infection rates (COVID-19 annualized) for Czech Republic, https://onemocneni-
aktualne.mzcr.cz/covid-19. 
Infection rates (COVID-19 annualized) for Slovakia, 
https://www.ecdc.europa.eu/en/publications-data/data-daily-new-cases-covid-19-eueea-
country. 
Infection rates (COVID-19 annualized) for Sri Lanka, 
http://www.epid.gov.lk/web/index.php?option=com_content&view=article&id=225&lang=e
n. 
Li, W., M. J. Moore, N. Vasilieva, J. Sui, S. K. Wong, M. A. Berne, M. Somasundaran, J. L. 
Sullivan, K. Luzuriaga, T. C. Greenough, H. Choe and M. Farzan (2003). "Angiotensin-
converting enzyme 2 is a functional receptor for the SARS coronavirus." Nature 426(6965): 
450-454. 
Lin, Y. L., Y. L. Huang, S. H. Ma, C. T. Yeh, S. Y. Chiou, L. K. Chen and C. L. Liao (1997). 
"Inhibition of Japanese encephalitis virus infection by nitric oxide: antiviral effect of nitric 
oxide on RNA virus replication." J Virol 71(7): 5227-5235. 
Matsuyama, S., N. Nagata, K. Shirato, M. Kawase, M. Takeda and F. Taguchi (2010). 
"Efficient activation of the severe acute respiratory syndrome coronavirus spike protein by 
the transmembrane protease TMPRSS2." J Virol 84(24): 12658-12664. 
Miller C, M. B., Road J.A.G.Y., (2008). Nitric Oxide Gas is an Effective Anti-Viral Agent in 
a Bovine Inoculation Model. Canada Meeting Sixth  International Consortium on Anti-Virals 
Symposium, Peterborough and Toronto, Canada. 
Moncada, S., R. M. Palmer and E. A. Higgs (1991). "Nitric oxide: physiology, 
pathophysiology, and pharmacology." Pharmacol Rev 43(2): 109-142. 
National Insttitue of Standard and Technology (NIST) Digital Identity Guidelines. (2017). 
"Special Publication 800-63A- Enrollment and Identity Proofing Requirements When 
Developing and Identity Verification Plan."   Retrieved 25 February 2021, from 
https://pages.nist.gov/800-63-3/sp800-63a.html. 

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Regev-Shoshani, G., J. S. Church, N. J. Cook, A. L. Schaefer and C. Miller (2013). 
"Prophylactic nitric oxide treatment reduces incidence of bovine respiratory disease complex 
in beef cattle arriving at a feedlot." Res Vet Sci 95(2): 606-611. 
Regev-Shoshani, G., M. Ko, C. Miller and Y. Av-Gay (2010). "Slow release of nitric oxide 
from charged catheters and its effect on biofilm formation by Escherichia coli." Antimicrob 
Agents Chemother 54(1): 273-279. 
Regev-Shoshani, G., S. Vimalanathan, B. McMullin, J. Road, Y. Av-Gay and C. Miller 
(2013). "Gaseous nitric oxide reduces influenza infectivity in vitro." Nitric Oxide 31: 48-53. 
Rimmelzwaan, G. F., M. M. Baars, P. de Lijster, R. A. Fouchier and A. D. Osterhaus (1999). 
"Inhibition of influenza virus replication by nitric oxide." J Virol 73(10): 8880-8883. 
Royal College of Physicians and Surgeons of Canada. (2020). "Telemedicine and virtual care 
guidelines (and other clinical resources for COVID-19)."   Retrieved 04 March, 2021, from 
https://www.royalcollege.ca/rcsite/documents/about/covid-19-resources-telemedicine-virtual-
care-e. 
Schairer, D. O., J. S. Chouake, J. D. Nosanchuk and A. J. Friedman (2012). "The potential of 
nitric oxide releasing therapies as antimicrobial agents." Virulence 3(3): 271-279. 
Schoenfeld, D. A. (1983). "Sample-size formula for the proportional-hazards regression 
model." Biometrics 39(2): 499-503. 
Sheridan, M. P., G. Regev-Shoshani, J. Martins, S. Vimalanathan and C. Miller (2016). 
"Nitric oxide modulates the immunological response of bovine PBMCs in an in vitro BRDc 
infection model." Res Vet Sci 109: 21-28. 
Sungnak, W., N. Huang, C. Bécavin, M. Berg, R. Queen, M. Litvinukova, C. Talavera-
López, H. Maatz, D. Reichart, F. Sampaziotis, K. B. Worlock, M. Yoshida and J. L. Barnes 
(2020). "SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together 
with innate immune genes." Nat Med 26(5): 681-687. 
The Neonatal Inhaled Nitric Oxide Study Group (1997). "Inhaled Nitric Oxide in Full-Term 
and Nearly Full-Term Infants with Hypoxic Respiratory Failure." New England Journal of 
Medicine 336(9): 597-604. 
Weller, R., R. Price, A. Ormerod, N. Benjamin and C. Leifert (1997). "Antimicrobial effects 
of acidified nitrite on skin commensals and pathogens." Br J Dermatol 136: 464. 
Wink, D. A. and J. B. Mitchell (1998). "Chemical biology of nitric oxide: Insights into 
regulatory, cytotoxic, and cytoprotective mechanisms of nitric oxide." Free Radic Biol Med 
25(4-5): 434-456. 
 
 

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13 APPENDICES

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Appendix 1 
Schedule of Events 
Table 4  Schedule of Events 
 
Assessments 
Screening a 
Baseline 
Daily on 
TX  
Early TX 
Day 
Last Tx Day 
Post-Tx Follow-up 
 
 
Phone 
Assessment 
1 
Phone 
Assessment 
2 
Phone 
Assessment 
3 
ET 
Visit Type (per specific country regulatory legislation) 
Remotely  
or  
On-Site 
Remotely 
Remotely 
Remotely 
Remotely  
or  
On-Site 
Remotely  
or  
On-Site 
Study Day 
-7 to 1  
1-35d 
7+3 
28 +2 
End of 
Study 35±3 
 
Participant Informed Consent (Virtual, if applicable/respective country) b 
X 
 
 
 
 
 
Demographics (Virtual, if applicable/respective country) 
X 
 
 
 
 
 
Medical History (Virtual, if applicable/respective country) 
X 
 
 
 
 
 
Clinical Exam including Vitals (Virtual, if applicable/respective country) 
X 
 
 
 
X 
X 
Pregnancy Test (Urine) c 
X 
 
 
 
X 
X 
Concomitant Medications d 
X 
X 
X 
X 
X 
X 
Randomization 
X 
 
 
 
 
 
Study treatment instructions e 
X 
 
X 
 
 
 
COVID related symptom assessment f 
 
 
X 
X 
X 
X 
NONS Self Administration g 
 
X 
X 
X 
 
 
Questionnaire (online/paper) h 
 
 Xi 
X 
X 
X 
X 
Adverse Events  
 
X 
X 
X 
X 
X 
Study Drug Accountability/Compliance 
 
X 
X 
X 
 
X 
Report if tested positive for COVID-19 infection 
 
X 
X 
X 
X 
X 
Report need for Hospitalization/ER Visit for COVID-19 related sequelae 
 
X 
X 
X 
X 
X 
Abbreviations: ER=emergency room; ET= early termination; NONS= nitric oxide nasal spray; Tx=treatment. 

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a 
Screening and baseline are to be taken within 7 days but may be taken at the same assessment.  Post-Treatment Follow-up visits (end of study and ET) may be 
performed remotely. For countries requiring an in-person visit, these will be performed on-site, unless the participant is hospitalized, in quarantine or unable to visit the 
site for any reasonable cause as per the investigators’ judgement; these visits may then be performed remotely and will not be considered a protocol deviation. Follow-
up of all adverse events must be completed as described in the protocol Section 7. 
b 
Participants will be asked to designate an emergency contact who will also sign informed consent. In the event the participant is hospitalized and cannot complete their 
treatment diary or questionnaire emergency contacts will be encouraged to provide symptoms on behalf of a participant in a COVID-19 symptoms list Diary 
(Appendix 2). 
c 
Pregnancy test to be self-reported if remote visit is allowed per respective country regulatory legislation; however, results must be confirmed at Screening prior to 
enrolling the participant on the study. 
d 
Excludes naturopathic products. 
e 
For remote visits per respective country regulatory legislation, instructions on administering the study treatment will be provided via videocall on Day 1 and a check in 
call to confirm comfort with administration of the study treatment. For in-person visits, instructions will be given by the sites’ staff with a confirmation of the 
participants’ comfort with administration of the study treatment. 
f 
Assessment for COVID-19 symptoms will be performed using the COVID-19 symptoms list (Appendix 2; Appendix 3). 
g 
Dosing should start within 2 days of the baseline assessment. 
h 
For the Spray Bottle Use Perception Questionnaire PRO, participants will only provide their feedback on the usage of the spray bottle on Day 1 and Day 5 (Appendix 
3).  

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Appendix 2 
COVID-19 Symptoms List 
Centers for Disease Control COVID-19 Symptoms List 
People with COVID-19 have had a wide range of symptoms reported – ranging from mild 
symptoms to severe illness. Symptoms may appear 2-14 days after exposure to the virus. 
People with these symptoms may have COVID-19: 
• Fever or chills 
• Cough 
• Shortness of breath or difficulty breathing 
• Fatigue 
• Muscle or body aches 
• Headache 
• New loss of taste or smell 
• Sore throat 
• Congestion or runny nose 
• Nausea or vomiting 
• Diarrhea 
This list does not include all possible symptoms. Centers for Disease Control (CDC) will 
continue to update this list as we learn more about COVID-19 (Centers for Disease Control 
and Prevention 2021). 
Health Canada COVID-19 Symptoms List 
Symptoms of COVID-19 can vary from person to person. They may also vary in different 
age groups. The more commonly reported Health Canada COVID-19 symptoms are similar  
to those reported in the Centers for Disease Control COVID-19 symptoms list. Children tend 
to have abdominal symptoms and skin changes or rashes. Symptoms may take up to 14 days 
to appear after exposure to COVID-19 (Health Canada 2021). 
 

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Appendix 3 
Electronic Patient-Reported Outcomes Survey 
COVID-NONS – 04 
The complete language and content of all treatment (diary) and COVID-19 symptoms 
associated PRO questions are described in the Manual of Procedures (eCRF Section).  
The daily questions address the participants’ study medication dosing compliance (doses 
administered, bottle number in use, spray bottle mishaps/malfunction, etc.), treatment 
emergent adverse events (TEAE), changes to concomitant medications, and other general 
health-related changes. The specific daily symptoms and spray bottle use perception (Day 1 
& 5 only) questions, include:  
I. COVID-19 Symptom PRO Assessments (reported each day).  
Over the last 24 hours did you have any of the following symptoms; if so, what 
was the severity of the symptom at its worst (Check best box/button for the 
symptom)?  
 
1. Stuffy or Runny Nose 
 
None 
Mild 
Moderate 
Severe 
 
6. Muscle or body aches 
 
None 
Mild 
Moderate 
Severe 
 
 
 
 
 
 
2. Sore throat 
 
None 
Mild 
Moderate 
Severe 
 
7. Headache 
 
None 
Mild 
Moderate 
Severe 
 
 
 
 
 
 
3. Shortness of breath or 
difficulty breathing 
 
None 
Mild 
Moderate 
Severe 
 8. Chills or shivering 
 
None 
Mild 
Moderate 
Severe 
 
 
 
 
 
 
4. Cough 
 
None 
Mild 
Moderate 
 9. Feeling hot or feverish 
 
None 
Mild 
Moderate 
 
 
 
 

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Severe 
 
Severe 
5. Low energy or 
tiredness 
 
None 
Mild 
Moderate 
Severe 
 
10. Nausea, or feeling 
like you wanted to 
throw up 
 
 
None 
Mild 
Moderate 
Severe 
 
 
 
 
 
 
 
How often did you have the following 2 symptoms in the last 24 hours 
(Check best box/ button for the number of times having the symptom)? 
 
11. How many times did 
you vomit (throw up) 
 
None 
1 to 2 times 
3 to 4 times 
5 or more 
 
12. How many times did 
you have diarrhea 
(loose or watery 
stools)  
 
None 
1 to 2 times 
3 to 4 times 
5 or more 
 
 
 
 
 
 
 
Rate your sense of smell and taste in the last 24 hours (Check best box/ 
button for the symptom)?  
13. Sense of smell  
 
Same 
Less 
Smell Lost 
 
14. Sense of taste 
 
Same 
Less 
Taste Lost 
 
 
 
 
 
 
 

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II. Spray Bottle Use Perception Questionnaire (Day 1 and Day 5 only) 
 
Spray bottle ‘experience’ questions will be included on Day 1 (i.e. after one or more doses) and 
Day 5. The four-point Likert rating response options should be coded as -3, -1, 1, and 3 (most 
negative to most positive). 
Spray Bottle Use Perception Questionnaire 
Please answer the following questions about your experience with using the spray bottle 
(strongly disagree to strongly agree); 
1. The spray bottle was easy to operate? Strongly Disagree; Disagree;  Agree; Strongly 
Agree 
2. The tip of the spray bottle in the nose was comfortable? Strongly Disagree; Disagree;  
Agree; Strongly Agree 
3. The smell of the spray was mild to none? Strongly Disagree; Disagree;  Agree; 
Strongly Agree 
4. The aftertaste of the spray was mild to none? Strongly Disagree; Disagree;  Agree; 
Strongly Agree 
5. The spray mist was gentle? Strongly Disagree; Disagree;  Agree; Strongly Agree 
6. The nasal irritation was minimal to none? Strongly Disagree; Disagree;  Agree; 
Strongly Agree 
7. The amount of spray that leaked out of the nose was minimal to none? Strongly 
Disagree; Disagree;  Agree; Strongly Agree 
 

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Appendix 4 
Sponsor Signatures 
Study Title: 
Multicenter, randomized, double-blinded, placebo-controlled, 
phase 3 clinical efficacy study evaluating nitric oxide nasal spray 
(NONS) as prevention for treatment of individuals at risk of 
exposure to COVID-19 infection  
Study Number: 
COVID-NONS-04 
Final Date: 
08 December 2021 
 
This clinical study protocol was subject to critical review and has been approved by the 
Sponsor. The following personnel contributed to writing and/or approving this protocol: 
 
Signed: 
 
 
Date:  
 
Christopher Miller, PhD, BA, RT 
Chief Science Officer 
SaNOtize Research and Development Corporation 
 
 
Signed: 
 
 
Date:  
 
Gilly Regev, PhD 
Chief Executive Officer 
SaNOtize Research and Development Corporation 
 

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Appendix 5 
Site Physician Investigator’s Signature 
Study Title: 
Multicenter, randomized, double-blinded, placebo-controlled, 
phase 3 clinical efficacy study evaluating nitric oxide nasal spray 
(NONS) as prevention for treatment of individuals at risk of 
exposure to COVID-19 infection  
Study Number: 
COVID-NONS-04 
Final Date: 
08 December 2021 
 
I have read the protocol described above. I agree to comply with all applicable regulations 
and to conduct the study as described in the protocol.  
 
 
 
 
Name (Print):  
_________________________________________ 
Title:  
 
 
_________________________________________ 
Address:  
 
_________________________________________ 
 
 
 
 
 
_________________________________________ 
Telephone #:  
_________________________________________ 
 
 
Signed: 
 
 
Date: