Phase 2, Double-blind, Randomized, Placebo-controlled Study of NasoVAX in the Prevention of Clinical Worsening in Patients With Early Coronavirus Infectious Disease 2019 (COVID-19)
Phase: PHASE2
Conditions: Coronavirus Infection
Sponsor: Altimmune, Inc.

 
Study Title Phase 2, Double-blind, Randomized, Placebo-controlled 
Study of NasoVAX in the Prevention of Clinical Worsening in 
Patients with Early Coronavirus Infectious Disease 2019 
(COVID-19) 
NCT Number NCT04442230 
Document  Study Protocol 
Document Date 04 January 2021 
 

 
 
Altimmune, Inc. 
910 Clopper Road, Suite 201 S 
Gaithersburg, MD 20878 
USA 
 
Clinical Study Protocol 
 
Study Title: 
Phase 2, Double-blind, Randomized, Placebo-controlled Study of 
NasoVAX in the Prevention of Clinical Worsening in Patients with 
Early Coronavirus Infectious Disease 2019 (COVID-19) 
Study Number: 
ALT-601-201 
Study Phase: 
Phase 2 
Test Product: 
NasoVAX  
Sponsor: 
Altimmune, Inc. 
910 Clopper Road, Suite 201-S 
Gaithersburg, MD  20878  
USA 
 
 
 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
The information in this document is confidential, and its contents are the property of 
Altimmune, Inc. and are confidential. Unauthorized copying, distribution, disclosure, or use is 
prohibited. 

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PROTOCOL ALT-601-201 
Phase 2, Double-blind, Randomized, Placebo-controlled Study of 
NasoVAX in the Prevention of Clinical Worsening in Patients 
with Early Coronavirus Infectious Disease 2019 (COVID-19) 
CONFIDENTIALITY AND INVESTIGATOR STATEMENT 
The information contained in this protocol and all other information relevant to 
NasoVAX are the confidential and proprietary information of Altimmune, Inc., and 
except as may be required by federal, state or local laws or regulation, may not be 
disclosed to others without prior written permission of Altimmune, Inc. 
I have read the protocol, including all appendices, and I agree that it contains all of the 
necessary information for me and my staff to conduct this study as described. I will 
conduct this study as outlined herein, in accordance with the regulations stated in the 
Federal Code of Regulations for Good Clinical Practice (GCP) and International Council 
for Harmonisation (ICH) guidelines and will make a reasonable effort to complete the 
study within the time designated. 
I will provide all study personnel under my supervision copies of the protocol and any 
amendments, and access to all information provided by Altimmune, Inc., or specified 
designees. I will discuss the material with them to ensure that they are fully informed 
about NasoVAX and the study. 
 
Principal Investigator Name (printed) 
Signature 
 
_________________________ 
 
_________________________ 
 
__ __ - __ __ __ - __ __ __ __ 
 
__ __ 
Date (dd-mmm-yyyy)  
 
 
Site Number 

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STUDY SUMMARY 
Sponsor: Altimmune, Inc. 
Study Title: Phase 2, Double-blind, Randomized, Placebo-controlled Study of NasoVAX in 
the Prevention of Clinical Worsening in Patients with Early Coronavirus Infectious Disease 
2019 (COVID-19) 
Study Number: ALT-601-201 
Study Phase: 2 
Study Centers: Up to 12 centers in the United States 
Number of Patients Planned: NasoVAX Approximately 96 patients with early COVID-19 
will be enrolled and randomized 1:1 to NasoVAX or placebo in 3 successive cohorts defined 
by age and risk factors for severe COVID-19 (Exclusion Criterion 5) (Cohort 1, ages 18-
49 years and risk factors disallowed; Cohort 2, ages 18 and above and risk factors 
disallowed; and Cohort 3, ages 18 and above and risk factors allowed) of approximately 20, 
28, and 48 patients, respectively, with patients randomized 1:1 to NasoVAX or placebo 
within each cohort. Cohort 2 will be stratified by age groups of 18-64 years and 65 years and 
above, whereas Cohort 3 will be stratified by age groups (ages 18-64 years, ages 65 and 
above) and co-morbidity (one or more risk factors present, no risk factors present).  
Duration of Patient Participation: Each patient will participate in the study up to 
approximately 4 weeks (28 days). Patients who remain hospitalized at the end of 28 days 
will be followed through Day 42 or death, whichever is sooner. 
Enrollment Period: Approximately 3 months 
Study Objectives: 
Efficacy 
Primary Objective: To assess the effectiveness of NasoVAX in preventing clinical worsening 
in patients with early COVID-19 
Secondary Objectives: 
• 
To assess the effects of NasoVAX on the severity of COVID-19, as indicated by changes 
in resting peripheral oxygen pulse saturation (SpO2) and resting pulse rate 
• 
To assess the effects of NasoVAX on rates hospital admission, oxygen supplementation 
and mechanical ventilation 

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Safety 
Primary Objective 
• 
To assess the safety and tolerability of NasoVAX in patients with early COVID-19 
Study Design: This is an exploratory Phase 2 clinical study to evaluate the protective effects 
of NasoVAX in patients with early COVID-19. Approximately 96 ambulatory patients with 
COVID-19, with one or more symptom(s) of fever, cough, and/or shortness of breath, onset 
of these symptoms within 72 hours of screening, and a diagnosis by a PCR-based or rapid 
antigen test diagnostic, will be enrolled in 3 successive cohorts defined by age and risk 
factors for severe COVID-19 (Exclusion Criterion 5) (Cohort 1, ages 18-49 years and risk 
factors disallowed; Cohort 2, ages 18 and above and risk factors disallowed; and Cohort 3, 
ages 18 and above and risk factors allowed) of approximately 20, 28, and 48 patients, 
respectively. The cohorts will be enrolled in ascending order, with Cohort 1 preceding 
Cohort 2, and Cohort 2 preceding Cohort 3. Patients in Cohort 2 will be stratified by age 
groups of 18-64 years and 65 years and above. Cohort 3 will be stratified by age groups 
(ages 18-64 years, ages 65 and above) and co-morbidity (one or more risk factors present, no 
risk factors present).  
Study conduct will be overseen by a Data Monitoring Committee (DMC), which will 
monitor the safety of study participants and review safety data real-time during the course of 
the study. If any of the Stopping Rules (Section 7.2) are met, enrollment and study drug 
treatment will be temporarily halted pending DMC review. 
Once a cohort is fully enrolled, enrollment will be paused until all patients either complete 
14 days of home assessments or they are determined to have been hospitalized. The DMC 
will then review the safety and tolerability data and make a recommendation regarding 
whether to progress to the next cohort. The DMC may unblind the data in conducting its 
assessments although treatment allocation will not be revealed to operational study 
personnel. 
Upon signing informed consent, patients will undergo Screening assessments at the study 
center, as per the Schedule of Events (Table 1). Within each cohort, patients who are 
determined to be eligible will be randomized that same day (Day 1) in a 1:1 ratio to receive 
either NasoVAX or placebo with approximately 10 and 14 patients in Cohorts 1 and 2, 
respectively, receiving NasoVAX and 10 and 14 receiving placebo in Cohorts 1 and 2, 
respectively. Approximately 24 patients will receive NasoVAX and 24 will receive placebo 
in Cohort 3.  
Study drug will be administered as a single intranasal dose of 0.5 mL (0.25 mL each nostril) 
in the supine position after which patients must remain in the supine position for 30 minutes. 
Patients will be observed for at least 2 hours post intranasal administration. Patients who are 
randomized will be considered enrolled in the study. 
No in-person visits are expected during the study after Day 1 unless a participant experiences 
a change in symptoms or adverse event (AE) that requires a visit for assessment. 
Prior to discharge from the study center on Day 1, patients will be provided with: 
• 
A fingertip pulse oximetry device connecting to a tablet that will be supplied to the 
patient to measure resting SpO2 and resting pulse rate remotely. Patients will be trained 
on the use of the device and tablet. 
• 
A digital thermometer for measurement of oral temperature 

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• 
Instructions regarding how to take the above measurements and access and complete a 
web-based electronic diary (eDiary) 
After discharge on Day 1, patients will return home for the duration of the study. Patients are 
to measure resting SpO2, resting pulse rate, and oral temperature twice daily at 09:00 hours 
and 16:00 hours, with a 1-hour window around each time point, and at any time they 
experience worsening symptoms until Day 14 or hospitalization, whichever comes first. 
Patients are to record COVID-19-related symptoms daily during this same time period. 
Study center personnel will contact patients daily by telephone during this period to 
document the patient’s clinical status, record concomitant medications and monitor for AEs. 
After Day 14, study center personnel will contact patients via telephone approximately every 
7±2 days for 14 additional days to determine if they were hospitalized and to follow AEs that 
were not resolved by Day 14. If the patient is hospitalized at any time, the dates and times of 
hospital admission/discharge, intensive care unit (ICU) admission/discharge, and ventilation 
requirement are to be recorded, as applicable. Patients who remain hospitalized at the end of 
28 days will be followed through Day 42 or death, whichever is sooner. 
Stopping Rules: 
Enrollment and study drug treatment will be temporarily halted pending DMC review for 
any of the following reasons: 
a. Any serious adverse event (SAE) considered possibly or probably related to study drug 
b. Any Grade 4 or Grade 5 (death) AE considered possibly or probably related to study drug 
c. Three or more subjects in the same cohort experience the same Grade 3 AE in the same 
Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class considered 
possibly or probably related to study drug 
d. Hospitalization rates in either treatment group in individual cohorts exceeding: 
• 
15% (Cohort 1 only) 
• 
20% (Cohort 2 only) 
• 
25% (Cohort 3 only) 
e. Mechanical ventilation rates in either treatment group in individual cohorts equal to or 
exceeding: 
• 
2 patients (Cohort 1 only) 
• 
3 patients (Cohort 2 only) 
• 
4 patients (Cohort 3 only) 
The DMC will be advised each time a patient dies or is hospitalized. The DMC may unblind 
individual patients for the assessment of the relationship of the event to study drug. The 
DMC may recommend resumption of dosing if subject safety is not considered to be at 
significant risk following analysis. 

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Inclusion Criteria: 
1. Able and willing to provide informed consent  
Patients themselves must provide written informed consent before the performance of 
any study-related procedures, and surrogate consent by family members, designated 
legal representatives or caregivers will not be permitted. 
2. Men and women 18 years of age and older 
3. Early COVID-19, defined as one or more symptom(s) of fever (oral temperature 
≥ 100.4oF), cough or shortness of breath, onset of these symptoms within 72 hours of 
screening, and confirmation of SARS-CoV-2 infection by a polymerase chain 
reaction (PCR)-based or rapid antigen test diagnostic 
4. Resting SpO2 ≥ 96.0% on room air on two successive measurements 
5. For women of childbearing potential (women who are not permanently sterile 
[documented hysterectomy, bilateral tubal ligation, salpingectomy, or oophorectomy] 
or postmenopausal [12 months with no menses without an alternative medical 
cause]) 
• 
Negative urine pregnancy test at Screening 
• 
Willingness to practice a highly effective method of contraception that includes, 
but is not limited to, abstinence, sex only with persons of the same sex, 
monogamous relationship with a postmenopausal partner, monogamous 
relationship with vasectomized partner, vasectomy, licensed hormonal methods, 
intrauterine device, or consistent use of a barrier method (eg, condom, 
diaphragm) with spermicide for 28 days after the last dose of study drug 
6. For men with sexual partners of childbearing potential, willingness to practice a 
highly effective method of contraception, as defined above, for 45 days after the last 
dose of study drug 
7. Ability and willingness to comply with all aspects of the study, including reliable 
internet access, through the entire study period 
Exclusion Criteria: 
1. Pregnant or lactating women or planning to conceive a child during the next 
3 months 
2. Resting respiratory rate >20 breaths/min on room air or resting pulse rate ≥ 125 
beats per minute 
3. A rapidly worsening course that in the opinion of the Investigator or treating medical 
practitioner would lead to hospitalization within the next 24-48 hours 
4. Any chronic pulmonary disease, including chronic obstructive pulmonary disease 
and asthma, or other respiratory diseases that could exacerbate independent of 
COVID-19 
5. The following risk factors for severe COVID-19 (Cohorts 1 and 2 only): 
a. Severe obesity, defined as body mass index ≥ 40 kg/m2 

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b. History of 
i. 
Severe cardiovascular disease, including but not limited to congestive heart 
failure, coronary artery disease, congenital heart disease, cardiomyopathies, 
or pulmonary hypertension 
ii. Diabetes mellitus 
iii. Chronic or current vaping or cigarette smoking 
iv. Chronic kidney disease requiring dialysis 
v. Chronic liver disease, including but not limited to chronic viral hepatitis, 
non-alcoholic steatohepatitis, or cirrhosis of any cause 
vi. Hemoglobin disorder, including sickle cell disease and thalassemia 
Based on ongoing review of efficacy and safety data, the DMC may remove part or 
all of these risk factors if preliminary data show no signal for adverse or paradoxical 
effects. 
6. History of Bell’s Palsy 
7. Nasal conditions that might affect the suitability of intranasal medication, such as a 
history of chronic rhinitis, nasal septal defect, cleft palate, nasal polyps, or nasal 
surgery other than cosmetic rhinoplasty.  
8. Use of hydroxychloroquine within the past 4 months, chloroquine with the past 
9 months, or other investigational agents for COVID-19 within the past 30 days 
9. History of conditions associated with immunocompromise, including but not limited 
to poorly controlled HIV, or treatments known to affect the immune system, 
including but not limited to oral or intravenous corticosteroids, alkylating drugs, 
antimetabolites, cytotoxic drugs, radiation, immune-modulating biologics (including 
interleukin [IL]-6, IL-12, Janus kinase inhibitors or antagonists), and cancer 
treatments, within 30 days of Screening, or anticipated use within 6 months 
following participation in this study  
10. Any medical, psychiatric, or social condition or occupational or other responsibility 
that in the judgment of the Investigator would interfere with or serve as a 
contraindication to protocol adherence, assessment of safety (including 
reactogenicity), or a patient’s ability to give informed consent 
Efficacy Endpoints: 
Primary Efficacy Endpoint: 
The primary endpoint is the proportion of patients with clinical worsening, defined as an 
absolute 4.0% decrease from Baseline in resting SpO2 by mobile pulse oximetry on two 
consecutive measurements during home follow-up, or hospitalization.  
Secondary Efficacy Endpoints: 
1. Maximal severity of COVID-19 after treatment, as assessed by the following: 
• 
average decrease in resting SpO2 from Baseline resting SpO2 at Screening 
during the 14 days of home follow-up or hospitalization 
• 
average increase in resting pulse rate from Baseline resting pulse rate at 
Screening during the 14 days of home follow-up or hospitalization 

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• 
proportion of patients requiring hospitalization through Day 42 according to 
maximal level of oxygen supplementation: 
- No oxygen supplementation 
- Oxygen supplementation with nasal cannula 
- Oxygen supplementation with high flow device or non-invasive ventilation 
- Mechanical ventilation 
2. All-cause mortality through Day 42 
Safety Endpoints 
• 
Incidence and severity of AEs 
• 
Oral temperatures 
• 
Use of antipyretics and bronchodilators 
• 
Hospital length of stay, and ICU length of stay 
Statistical Methods:  
Power and Sample Size Assumptions: 
The study is considered exploratory to assess the initial safety of NasoVAX in COVID-19 and 
response to treatment. The sample size chosen for this study was considered adequate to 
meet the study objectives and was selected without statistical significance considerations.  
Statistical Analysis: 
Population definitions: 
Safety Analysis Set: All patients who receive any study drug.  
Modified intent to treat (mITT): All randomized patients who receive any amount of study 
drug and have a Baseline and at least one post-Baseline resting SpO2 measurement. Patients 
will be analyzed according to the treatment that they receive.  
Per Protocol (PP): All randomized patients who receive any amount of study drug according 
to the correct treatment assignment and who have 80% of twice daily results from resting 
SpO2 measurements through Day 14 or hospitalization. 
General: 
Baseline is defined as data collected closest to randomization prior to any study drug dosing. 
For resting SpO2 and resting pulse rate, Baseline is defined as the average of the two 
measurements at Screening. All analyses and summary statistics will be presented by 
treatment group (NasoVAX, placebo) across cohorts, as well as by treatment group pooled 
across all cohorts. 
Descriptive statistics, including the numbers and percentages for categorical variables and 
the numbers, means, standard deviations, medians, minimums and maximums for continuous 
variables will be provided by treatment across cohorts. 
Patients will be randomized 1:1 to NasoVAX or placebo and proceed in 3 cohorts defined by 
age and risk factors for severe COVID-19 (Exclusion Criterion 5) (Cohort 1, ages 18-
49 years and risk factors disallowed; Cohort 2, ages 18 and above and risk factors 
disallowed; and Cohort 3, ages 18 and above and risk factors allowed) of approximately 20, 
28, and 48 patients, respectively. The cohorts will be enrolled in ascending order, with 
Cohort 1 preceding Cohort 2, and Cohort 2 preceding Cohort 3. Cohort 2 will be stratified by 

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age groups of 18-64 years and 65 years and above, whereas Cohort 3 will be stratified by age 
groups (ages 18-64 years, ages 65 and above) and co-morbidity (one or more risk factors 
present, no risk factors present). Patients in Cohorts 2 and 3 will be stratified first, and then 
randomized 1:1 to NasoVAX or placebo. Enrollment of patients ages 18-49 will not exceed 
approximately 30% of the randomized population of either treatment arm. In addition, a 
minimum of 40% of Cohort 3 will either be 65 years or above or have one or more risk 
factors for severe COVID-19. 
Efficacy Analyses: 
Descriptive statistics will be used to evaluate differences between Baseline and post-Baseline 
efficacy endpoints. The study is considered exploratory, and inferential statistics will be 
employed as appropriate. 
For the primary analysis, proportions of patients with clinical worsening, defined as a 4.0% 
decrease from Baseline in resting SpO2 on two consecutive measurements during the 14 days 
of home follow-up, or hospitalization, will be compared between NasoVAX and placebo 
groups using the Cochrane Mantel Haenszel test, while considering the stratification of age 
groups and risk factors, at a one-sided significance level of 0.025. The same approach will be 
applied for secondary or exploratory endpoints that are categorical in nature. Sensitivity 
analyses will be performed to assess the effect of site on the response to study drug. Linear 
and logistic regression will be employed to examine the effects of Baseline factors, such as 
age, sex, medications, and medical co-morbidities on response. 
Changes from Baseline in Severity of COVID-19, assessed by maximum decrease in resting 
SpO2 or increase in resting pulse rate by outpatient pulse oximetry and COVID-19 symptoms 
(eDiary) during home follow-up, will be analyzed using a mixed model for repeated 
measures. The model will include the fixed effects of treatment, week, and treatment-by-visit 
interaction as well as the continuous, covariate of Baseline level. The model will employ an 
unstructured within patient covariance matrix and a restricted maximum likelihood 
estimation method.  
A Kaplan-Meier method will be applied to compare changes between treatment groups in 
resting SpO2 over time.  
For the purpose of study efficacy endpoints, resting SpO2 and resting pulse rate will be 
assessed on observed data only; if data is missing, it will not be imputed. 
No multiplicity adjustments will be made for secondary or exploratory endpoints. 
Safety and Tolerability: 
Quantitative safety data, including the frequencies of AEs, oral temperatures, use of 
antipyretics and bronchodilators, and length of hospital and ICU stay, will be summarized 
using descriptive statistics and frequency distributions. Qualitative safety data will be 
summarized by frequencies and percentages. All summaries will be presented by treatment 
arms. AEs will be coded using MedDRA, and severity will be coded using the Common 
Terminology Criteria for Adverse Events (CTCAE), v.4.0.3. Concomitant medications will 
be coded using World Health Organization (WHO) drug dictionary. 
 

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TABLE OF CONTENTS 
CONFIDENTIALITY AND INVESTIGATOR STATEMENT ...................................3 
STUDY SUMMARY ..........................................................................................................4 
TABLE OF CONTENTS ................................................................................................11 
TABLE OF TABLES .......................................................................................................14 
TABLE OF FIGURES .....................................................................................................14 
LIST OF APPENDICES .................................................................................................14 
LIST OF ABBREVIATIONS .........................................................................................15 
1 
INTRODUCTION AND RATIONALE .................................................................17 
1.1 
Background ..........................................................................................................17 
1.1.1 
Nonclinical Data .............................................................................................18 
1.1.2 
Clinical Data ...................................................................................................19 
1.2 
Rationale for NasoVAX in COVID-19 ...............................................................19 
2 
STUDY OBJECTIVES ............................................................................................22 
2.1 
Efficacy..................................................................................................................22 
2.1.1 
Primary ...........................................................................................................22 
2.1.2 
Secondary........................................................................................................22 
2.2 
Safety .....................................................................................................................22 
3 
STUDY ENDPOINTS ..............................................................................................23 
3.1 
Primary Efficacy Endpoint .................................................................................23 
3.2 
Secondary Efficacy Endpoints ............................................................................23 
3.3 
Safety Endpoints ..................................................................................................23 
4 
STUDY PLAN ...........................................................................................................24 
4.1 
Study Design .........................................................................................................24 
4.2 
Rationale for Study Design .................................................................................25 
4.3 
Rationale for Study Population ..........................................................................26 
4.4 
Dose Rationale ......................................................................................................27 
4.5 
Schedule of Events ...............................................................................................27 
5 
POPULATION ..........................................................................................................30 
5.1 
Number of Patients ..............................................................................................30 
5.2 
Inclusion Criteria .................................................................................................30 
5.3 
Exclusion Criteria ................................................................................................31 
6 
STUDY DRUG ..........................................................................................................33 
6.1 
Description ............................................................................................................33 
6.1.1 
NasoVAX ........................................................................................................33 
6.1.2 
Placebo ............................................................................................................33 
6.1.3 
Packaging, Storage, and Handling ...............................................................33 
6.2 
Randomization .....................................................................................................34 
6.3 
Dose and Administration .....................................................................................34 
6.4 
Dosing Modifications ...........................................................................................34 
6.5 
Blinding and Unblinding .....................................................................................34 
6.6 
Accountability ......................................................................................................35 
6.7 
Prior and Concomitant Therapy ........................................................................35 
6.7.1 
Prohibited Prior and Concomitant Medications .........................................36 

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6.8 
Contraception .......................................................................................................36 
6.9 
Compliance ...........................................................................................................36 
7 
PREMATURE DISCONTINUATION ...................................................................37 
7.1 
Individual Patients ...............................................................................................37 
7.2 
Stopping Rules ......................................................................................................37 
7.3 
Study as a Whole ..................................................................................................38 
8 
DESCRIPTION OF STUDY PROCEDURES .......................................................39 
8.1 
Screening Assessments.........................................................................................39 
8.1.1 
Demographics .................................................................................................39 
8.1.2 
Medical History ..............................................................................................39 
8.1.3 
Pregnancy Testing (Females of Childbearing Potential Only) ..................39 
8.1.4 
Concomitant Medications .............................................................................39 
8.2 
Efficacy Assessments ...........................................................................................40 
8.2.1 
Pulse Oximetry, Pulse Rate, and Temperature ...........................................40 
8.2.2 
eDiary ..............................................................................................................41 
8.2.3 
Telephone calls ...............................................................................................41 
8.2.4 
Criteria for the Assessment of Severity of Illness in Patients with 
COVID-19 .......................................................................................................42 
8.2.5 
Additional Data Collection in Hospitalized Patients ..................................42 
8.2.6 
Vital Status .....................................................................................................43 
8.3 
Safety Assessments ...............................................................................................43 
8.3.1 
Height, Weight and Body Mass Index (BMI) ..............................................43 
8.3.2 
Physical Examination ....................................................................................43 
8.3.3 
Screening Vital Signs .....................................................................................43 
8.3.4 
Adverse Events ...............................................................................................43 
8.3.5 
Use of Antipyretics and Bronchodilators .....................................................43 
8.4 
Concomitant Care and Unscheduled Visits .......................................................44 
9 
ADVERSE EVENTS ................................................................................................45 
9.1 
Definitions .............................................................................................................45 
9.1.1 
Adverse Event.................................................................................................45 
9.1.2 
Unexpected Adverse Drug Experience .........................................................45 
9.1.3 
Serious Adverse Event ...................................................................................46 
9.2 
Reporting Responsibilities and Periods .............................................................46 
9.3 
Assessment of Adverse Events ............................................................................47 
9.3.1 
Severity............................................................................................................47 
9.3.2 
Relatedness (Causality) to Study Drug ........................................................48 
9.4 
Pregnancy .............................................................................................................48 
9.5 
Overdose ...............................................................................................................48 
9.6 
Procedures for Recording and Reporting Adverse Events ..............................49 
9.6.1 
Recording Adverse Events ............................................................................49 
9.6.2 
Reporting of Serious Adverse Events ...........................................................49 
9.6.3 
Special Reporting Situations .........................................................................50 
9.6.4 
Reporting Pregnancies...................................................................................51 
9.7 
Data Monitoring Committee ...............................................................................51 
9.8 
Medical Monitor...................................................................................................52 

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10 STATISTICS .............................................................................................................53 
10.1 
Sample Size ...........................................................................................................53 
10.2 
Analysis Sets .........................................................................................................53 
10.3 
Statistical Methods ...............................................................................................53 
10.3.1 
General Methods ............................................................................................53 
10.3.2 
Analysis of Efficacy ........................................................................................54 
10.3.3 
Analysis of Safety ...........................................................................................54 
10.3.4 
Demographic and Baseline Characteristics .................................................55 
10.4 
Statistical Analysis Plan (SAP) ...........................................................................55 
11 DATA QUALITY ASSURANCE ............................................................................56 
11.1 
Data Handling ......................................................................................................56 
11.2 
Computer Systems ...............................................................................................56 
11.3 
Data Entry ............................................................................................................56 
11.4 
Medical Information Coding ..............................................................................56 
11.5 
Data Validation ....................................................................................................56 
11.6 
Study Monitoring Requirements ........................................................................56 
11.7 
Source Document and Case Report Form Completion ....................................57 
11.8 
Record Retention .................................................................................................58 
12 ETHICS .....................................................................................................................59 
12.1 
Good Clinical Practice .........................................................................................59 
12.2 
Institutional Review Board .................................................................................59 
12.3 
Patient Information and Consent .......................................................................59 
12.4 
Patient Confidentiality.........................................................................................60 
12.5 
Protocol Compliance ............................................................................................60 
13 COMPENSATION, INSURANCE AND INDEMNITY .......................................61 
14 PUBLICATION POLICY ........................................................................................62 
15 CHANGES TO THE PROTOCOL ........................................................................63 
16 REFERENCES .........................................................................................................65 
 

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TABLE OF TABLES 
Table 1 
Schedule of Events – Screening and Treatment Periods ......................28 
 
TABLE OF FIGURES 
Figure 1 
Schematic Illustration of NasoVAX .......................................................17 
 
LIST OF APPENDICES 
Appendix A: Telephone Script, Days 2 through 14 .....................................................66 
Appendix B: Telephone Script, Day 21 and Day 28 ....................................................68 
Appendix C: Criteria for the Assessment of Severity of Illness in Patients with 
COVID-19 .................................................................................................69 
 
 

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LIST OF ABBREVIATIONS 
Abbreviation  
Definition 
BMI 
Body Mass Index 
CCL 
Chemokine [C-C motif] ligand 
COVID-19 
Coronavirus Infectious Disease 2019 
DMC 
Data Monitoring Committee 
eCRF 
Electronic case report form 
eDiary 
Electronic diary 
GCP 
Good Clinical Practice 
GMT 
Geometric mean titer 
HLA 
Human leukocyte antigen 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization 
ICU 
Intensive care unit 
IFN 
Interferon 
IND 
Investigational New Drug Application 
IP 
Investigational Product 
IRB 
Institutional Review Board 
IWRS 
Interactive Web Response System 
MedDRA 
Medical Dictionary for Regulatory Activities 
PCR 
Polymerase chain reaction 
RD-Ad5 
Replication-deficient adenovirus-5 
SAE 
Serious adverse event 

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Abbreviation  
Definition 
SAP 
Statistical analysis plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SpO2 
Peripheral oxygen pulse saturation 
TEAE 
Treatment-emergent adverse event 
WHO 
World Health Organization 
US 
United States 
vp 
Virus particles 
 

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1 INTRODUCTION AND RATIONALE 
1.1 
Background 
NasoVAX is being developed under IND 21210 for the prevention and treatment of 
Coronavirus Infectious Disease 2019 (COVID-19) caused by severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2). The RD-Ad5 vector that forms the basis of 
NasoVAX has been employed with genetic inserts against other pathogens in other vaccine 
products conducted under earlier INDs, including different strains of influenza (BB-IND 
8888, BB IND13575), tetanus (IND 10852), and anthrax (IND 017832, NasoShield). 
NasoVAX is also being developed under IND 017626 for the treatment of influenza A and 
B. Figure 1 provides a schematic diagram of the RD-Ad5 vector and identifies those 
sequences from the parent Ad5 genome that are retained in the vector. 
For the current study, NasoVAX is being developed for the prevention and treatment of 
clinical worsening in patients with early coronavirus disease 2019 (COVID-19) caused by 
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Administration of 
NasoVAX is by intranasal delivery. The rationale for investigating the use of NasoVAX in 
COVID-19 is based on observations, as described in Section 1.2, that the RD-Ad5 viral 
vector itself is protective against respiratory viruses independent of its influenza effects, 
because protection is afforded in the presence or absence of the influenza HA transgene. 
The collective safety experience with RD-Ad5 vectors suggests that NasoVAX will be safe 
in COVID-19 and that the HA transgene insert will not prevent the development of 
immunogenicity to the SARS-CoV-2 virus or alter the drug’s safety profile in patients with 
COVID-19. 
Figure 1 
Schematic Illustration of NasoVAX 
 
 

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1.1.1 
Nonclinical Data 

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Refer to the Investigator’s Brochure for additional information. 
1.1.2 
Clinical Data 
1.2 
Rationale for NasoVAX in COVID-19 

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The current exploratory Phase 2, double-blind, placebo-controlled study is designed to 
evaluate the potential of NasoVAX to decrease the progression of disease in ambulatory 
patients in early COVID-19. Nonclinical studies in support of this indication demonstrated 
a rapid and prolonged effect of intranasal administration of RD-Ad5 vectors, with 
protection from lethal challenge occurring within 2 days and lasting for as long as 47 days. 
In the context of the proposed clinical plan where patients with newly conformed 
COVID-19 will receive NasoVAX treatment, it is important to realize that the kinetics of 
virally induced death in the murine model (onset around 5-7 days post-challenge) is 
considerably faster than that observed in COVID-19 (median of 18.5 days) (Zhou 2020). 
Given the rapid (2 days) and prolonged (at least 47 days) protection treatment with 
RD-Ad5 vectors provides, the clinical development plan is supported by the nonclinical 
data. 

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2 STUDY OBJECTIVES 
2.1 
Efficacy 
2.1.1 
Primary 
The primary objective is to assess the effectiveness of NasoVAX in preventing clinical 
worsening in patients with early COVID-19. 
2.1.2 
Secondary 
The secondary objectives of the study are: 
• To assess the effects of NasoVAX on the severity of COVID-19, as indicated by 
changes in resting peripheral oxygen pulse saturation (SpO2) and resting pulse rate 
• To assess the effects of NasoVAX on rates hospital admission, oxygen supplementation 
and mechanical ventilation 
2.2 
Safety 
• To assess the safety and tolerability of NasoVAX in patients with early COVID-19 

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3 STUDY ENDPOINTS 
3.1 
Primary Efficacy Endpoint 
The primary endpoint is the proportion of patients with clinical worsening, defined as an 
absolute 4.0% decrease from Baseline in resting SpO2 on two consecutive measurements 
during home follow-up, or hospitalization. 
3.2 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints are: 
1. Maximal severity of COVID-19 after treatment, as assessed by the following: 
• average decrease in resting SpO2 from Baseline resting SpO2 at Screening 
during the 14 days of home follow-up or hospitalization 
• average increase in resting pulse rate from Baseline resting pulse rate at 
Screening during the 14 days of home follow-up or hospitalization 
• proportion of patients requiring hospitalization through Day 42 by maximal 
level of oxygen supplementation: 
- No oxygen supplementation 
- Oxygen supplementation with nasal cannula 
- Oxygen supplementation with high flow device or non-invasive ventilation 
- Mechanical ventilation 
2. All-cause mortality through Day 42 
3.3 
Safety Endpoints 
Safety endpoints are: 
• Incidence and severity of AEs 
• Oral temperatures 
• Use of antipyretics and bronchodilators 
• Hospital length of stay, and ICU length of stay 

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4 STUDY PLAN 
4.1 
Study Design 
This is an exploratory Phase 2 clinical study to evaluate the protective effects of NasoVAX 
in patients with early COVID-19. Approximately 96 ambulatory patients with COVID-19, 
with one or more symptom(s) of fever, cough, and/or shortness of breath, onset of these 
symptoms within 72 hours of screening, and a PCR-based or rapid antigen test diagnostic, 
will be enrolled in 3 successive cohorts defined by age and risk factors for severe COVID-
19 (Exclusion Criterion 5) (Cohort 1, ages 18-49 years and risk factors disallowed; Cohort 
2, ages 18 and above and risk factors disallowed; and Cohort 3, ages 18 and above and risk 
factors allowed) of approximately 20, 28, and 48 patients, respectively. The cohorts will be 
enrolled in ascending order, with Cohort 1 preceding Cohort 2, and Cohort 2 preceding 
Cohort 3. Cohort 2 will be stratified by age groups of 18-64 years and 65 years and above, 
whereas Cohort 3 will be stratified by age groups (ages 18-64 years, ages 65 and above) 
and co-morbidity (one or more risk factors present, no risk factors present).  
Study conduct will be overseen by a Data Monitoring Committee (DMC), which will 
monitor the safety of study participants and review safety data real-time during the course 
of the study. If any of the Stopping Rules (Section 7.2) are met, enrollment and study drug 
treatment will be temporarily halted pending DMC review. 
Once a cohort is fully enrolled, enrollment will be paused until all patients either complete 
14 days of home assessments or they are determined to have been hospitalized. The DMC 
will then review the safety and tolerability data and make a recommendation regarding 
whether to progress to the next cohort. The DMC may unblind the data in conducting its 
assessments although treatment allocation will not be revealed to operational study 
personnel. 
Upon signing informed consent, patients will undergo Screening assessments at the study 
center, as per the Schedule of Events (Table 1). Within each cohort, patients who are 
determined to be eligible will be randomized that same day (Day 1) in a 1:1 ratio to receive 
either NasoVAX or placebo with approximately 10 and 14 patients in Cohorts 1 and 2, 
respectively, receiving NasoVAX and 10 and 14 receiving placebo in Cohorts 1 and 2, 
respectively. Approximately 24 patients will receive NasoVAX and 24 will receive placebo 
in Cohort 3.  
Study drug will be administered as a single intranasal dose of 0.5 mL (0.25 mL each 
nostril) in the supine position after which patients must remain in the supine position for 
30 minutes. Patients will be observed for at least 2 hours post intranasal administration. 
Patients who are randomized will be considered enrolled in the study. 
No in-person visits are expected during the study after Day 1 unless a participant 
experiences a change in symptoms or AE that requires a visit for assessment. 

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Prior to discharge from the study center on Day 1, patients will be provided with: 
• A fingertip pulse oximetry device connecting to a tablet that will be supplied to the 
patient to measure resting SpO2 and resting pulse rate remotely. Patients will be trained 
on the use of the device and tablet 
• A digital thermometer for measurement of oral temperature 
• Instructions regarding how to take the above measurements and access and complete a 
web-based electronic diary (eDiary) 
After discharge on Day 1, patients will return home for the duration of the study. Patients 
are to measure resting SpO2, resting pulse rate and oral temperature twice daily at 09:00 
hours and 16:00 hours, with a 1-hour window around each time point, and at any time they 
experience worsening symptoms until Day 14 or hospitalization, whichever comes first. 
Patients are to record COVID-19-related symptoms daily during this same time period. 
Study center personnel will contact patients daily by telephone during this period to 
document the patient’s clinical status, record concomitant medications and monitor for 
AEs. 
After Day 14, study center personnel will contact patients via telephone approximately 
every 7±2 days for 14 additional days to determine if they were hospitalized and to follow 
AEs that were not resolved by Day 14. If the patient is hospitalized at any time, the dates 
and times of hospital admission/discharge, ICU admission/discharge, and ventilation 
requirement are to be recorded, as applicable. Patients who remain hospitalized at the end 
of 28 days will be followed through Day 42 or death, whichever is sooner. If a patient is 
discharged and then readmitted before Day 42, he/she will be followed until Day 42. 
4.2 
Rationale for Study Design 
Several design features are employed in the current study in an effort to minimize bias, 
including a double-blind design, with patients randomly assigned to NasoVax or placebo 
on a 1:1 basis. Random assignment of patients avoids bias and helps ensure that both 
known and unknown risk factors are distributed evenly between treatment groups. The use 
of placebo control permits prospective comparison between the active treatment group and 
the control group.  
In order to mitigate the risk of exposure to SARS-CoV-2 at the study center and reduce the 
use of personal protective equipment, all data after administration of study drug will be 
collected remotely, either electronically or via telephone; no in-person visits post-
vaccination are required unless a participant experiences a change in symptoms or AE that 
requires a visit for assessment. After study drug administration on Day 1, patients will be 
evaluated remotely.  
The study design adheres to the March 2020 FDA Guidance on the conduct of clinical trials 
during the COVID-19 pandemic (Centers for Disease Control and Prevention, Coronavirus 
Disease 2019 (COVID-19): Groups at Higher Risk for Severe Illness, Updated May 14, 

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2020 https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/groups-at-
higher-risk.html#serious-heart-conditions (last accessed June 7, 2020) 
United States Food and Drug Administration 2020). 
To ensure further the safety of participating patients, a DMC will review safety data after 
each cohort is enrolled and throughout the study. If any safety concerns are identified, the 
DMC will make a determination regarding continuation of the study; the DMC may be 
unblinded for this review. The DMC will oversee all aspects of the study to optimize the 
safety of study participants. Stopping Rules have also been developed for the further 
protection of patients. 
4.3 
Rationale for Study Population 
The model of lethal influenza challenge in mice recapitulates the key sequela associated 
with human infection with COVID-19 disease, including severe disease and death 
associated with massive lung inflammation and significant elevation in lung inflammatory 
cytokines. The ability of RD-Ad5 vectors to significantly decrease inflammatory cytokines, 
lung inflammation and morbidity following viral challenge in mice may be directly 
relevant to the treatment of COVID-19. 
Preclinical data show that intranasal administration of RD-Ad5 vectors, either harboring a 
transgene or not, can protect mice from lethal challenge with a respiratory pathogen when 
administered as a single intranasal dose within 2 days and up to 47 days before a lethal 
challenge with a respiratory pathogen. These observations support the use of NasoVAX or 
RD-Ad5 vectors in patients with recent or early COVID-19. 
To enhance the safety of study participants, the study will be enrolled in cohorts of 
increasing age and increasing risk for complications of COVID-19. Patients with risk 
factors for severe COVID-19 will be excluded from Cohort 1. Based on ongoing review of 
efficacy and safety data, the DMC may remove part or all of these risk factors if 
preliminary data show no signal for adverse or paradoxical effects. 
Because the cooperation of the patients is essential for the proper conduct of the study, 
patients themselves must provide written informed consent before the performance of any 
study-related procedures, and surrogate consent by family members, designated legal 
representatives, or caregivers will not be permitted. 
Hydroxychloroquine and chloroquine are excluded because these medications are known to 
acidify vesicles that may prohibit the entry of viruses like RD-Ad5 into respiratory mucosal 
cells. The half-lives of these agents are 22 and 55 days, respectively, and the periods of 
exclusion are based on 5 half-lives. The use of these agents is only permitted by the United 
States (US) Food and Drug Administration under Emergency Use Authorization in the 
hospital setting, so they are also not allowed in this study as rescue medications for patients 
with progressive symptoms in the outpatient setting. 

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While remdesivir use is not prohibited, it is not expected to interfere with study conduct, 
since it is an intravenous medication, the use of which would be restricted to hospitalized 
patients with severe forms of COVID-19. 
4.4 
Dose Rationale 
4.5 
Schedule of Events 
The schedule for study activities is presented in Table 1. 

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Table 1 
Schedule of Events – Screening and Treatment Periods 
Procedure 
Study Visit Type / Day 
Screening 
Study Drug 
Treatment 
Diary 
Completion/ 
Telephone 
Contact 
Telephone 
Contact 
Study Center Visit 
Remote Visit 
Day 1 
Pre-Dose 
Day 1 
Daily 
Days 1 to 14 
Days 21 and 28 
±2 days 
Informed consent 
X 
 
 
Eligibility criteria check 
X 
 
 
Demographics 
X 
 
 
 
Medical history 
X 
 
 
 
Focused cardiovascular and respiratory 
physical examination 
X 
 
 
 
Height and weight 
X 
 
 
 
Blood pressure and respiratory rate 
X 
 
 
 
Urine pregnancy testa 
X 
 
 
 
Randomization 
X 
 
 
 
Study drug administrationb 
 
X 
 
 
Resting SpO2c 
X 
 
Xd 
 
Resting pulse ratec 
X 
 
Xd 
 
Oral temperaturec 
X 
 
Xd 
 
Baseline/Concomitant medications 
X 
 
X 
X 
AEs 
 
 
X 
X 
eDiary completion for COVID-19 symptomse 
X 
 
X 
 
Criteria for the Assessment of Severity of Illness 
in Patients with COVID-19 f 
X 
 
 
X 
Daily telephone contact to document concomitant 
medications, clinical and hospitalization status 
and AEsg 
 
 
X 
 
Follow-up contact for hospitalization status, 
COVID-19 outcomes, and AEsh 
 
 
 
X 
a For women of child-bearing potential only. Results must be available and confirmed to be negative before study drug 
administration. 
b Study drug is to be administered with the patient in the supine position. The patient is to remain in the supine position 
for 30 minutes thereafter and be observed for at least 2 hours post intranasal administration. 
c To be measured remotely daily at 09:00 and 16:00 hours or at any time the patient experiences worsening symptoms 
using the study-supplied devices and recorded in the eDiary. Resting SpO2 and pulse are to be measured at rest for 
2 minutes. A ±1 hour window will be allowed. On Day 1, only the afternoon (16:00 hours) measurement is required 
and may be measured at the study center or remotely. 
d If the Screening visit occurs in the morning, the patient will be responsible for recording the 16:00 measurements at 
home later that day; if the visit occurs after 16:00, measurements will commence at home the following morning. 

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e The following symptoms will be recorded: fatigue, chills, headache, cough (with or without sputum production), 
myalgia, sore throat, shortness of breath, nasal congestion, diarrhea, and nausea or vomiting. 
f After Screening, the patient will be assessed at different timepoints over the course of the trial. The final determination 
will be made on Day 28 in patients who are not hospitalized and Day 42 in patients who are hospitalized. 
g Telephone calls to the patient will commence on Day 2. The script for these calls is provided in Appendix A. 
h The script for the Day 21 and Day 28 phone calls is provided in Appendix B. For hospitalized patients, the dates and 
times of hospital admission/discharge, date and time of intensive care unit admission/discharge, and ventilation 
requirement are to be recorded, as applicable. Patients who remain hospitalized at the end of 28 days will be followed 
through Day 42 or death, whichever is sooner.  
 
 

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5 POPULATION 
5.1 
Number of Patients 
Approximately 96 ambulatory patients with COVID-19, with one or more symptom(s) of 
fever, cough, or shortness of breath, onset of these symptoms within 72 hours of screening, 
and a confirmation of SARS-CoV-2 infection by a polymerase chain reaction (PCR)-based 
or rapid antigen test diagnostic, will be enrolled at up to 12 study centers in the US.  
5.2 
Inclusion Criteria 
Patients who meet all of the following criteria are eligible for participation in the study.  
1. Able and willing to provide informed consent 
Patients themselves must provide written informed consent before the performance of 
any study-related procedures, and surrogate consent by family members, designated 
legal representatives, or caregivers will not be permitted. 
2. Men and women 18 years of age and older 
3. Early COVID-19, defined as one or more symptom(s) of fever (oral temperature 
≥ 100.4oF), cough or shortness of breath, onset of these symptoms within 72 hours of 
screening, and confirmation of SARS-CoV-2 infection by a PCR-based or rapid antigen 
test diagnostic 
4. Resting SpO2 ≥ 96.0% on room air on two successive measurements 
5. For women of childbearing potential (women who are not permanently sterile 
[documented hysterectomy, bilateral tubal ligation, salpingectomy, or oophorectomy], 
postmenopausal [12 months with no menses without an alternative medical cause] or in 
monogamous same-sex relationships) 
• Negative urine pregnancy test at Screening 
• Willingness to practice a highly effective method of contraception that includes, 
but is not limited to, abstinence, sex only with persons of the same sex, 
monogamous relationship with a postmenopausal partner, monogamous 
relationship with vasectomized partner, vasectomy, licensed hormonal methods, 
intrauterine device, or consistent use of a barrier method (eg, condom, diaphragm) 
with spermicide for 28 days after the last dose of study drug 
6. For men with sexual partners of childbearing potential, willingness to practice a highly 
effective method of contraception, as defined above, for 45 days after the last dose of 
study drug 

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7. Ability and willingness to comply with all aspects of the study, including reliable 
internet access, through the entire study period 
5.3 
Exclusion Criteria 
Patients meeting any of the following criteria are not eligible for participation in the study: 
1. Pregnant or lactating women or planning to conceive a child during the next 3 months 
2. Resting respiratory rate >20 breaths/min on room air or resting pulse rate ≥ 125 beats 
per minute 
3. A rapidly worsening course that in the opinion of the Investigator of treating medical 
practitioner would lead to hospitalization within the next 24-48 hours 
4. Any chronic pulmonary disease, including chronic obstructive pulmonary disease and 
asthma, or other respiratory diseases that could exacerbate independent of COVID-19 
5. The following risk factors for severe COVID-19 (Cohorts 1 and 2 only) (Centers for 
Disease Control 2020): 
a. Severe obesity, defined as body mass index ≥ 40 kg/m2 
b. History of 
i. Severe cardiovascular disease, including but not limited to congestive heart 
failure, coronary artery disease, congenital heart disease, cardiomyopathies, 
or pulmonary hypertension 
ii. Diabetes mellitus 
iii. Chronic or current vaping or cigarette smoking 
iv. Chronic kidney disease requiring dialysis 
v. Chronic liver disease, including but not limited to chronic viral hepatitis, 
non-alcoholic steatohepatitis, or cirrhosis of any cause 
vi. Hemoglobin disorder, including sickle cell disease and thalassemia 
Based on ongoing review of efficacy and safety data, the DMC may remove part or 
all of these risk factors if preliminary data show no signal for adverse or paradoxical 
effects. 
6. History of Bell’s Palsy 

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7. Nasal conditions that might affect the suitability of intranasal medication, such as a 
history of chronic rhinitis, nasal septal defect, cleft palate, nasal polyps, or nasal 
surgery other than cosmetic rhinoplasty.  
8. Use of hydroxychloroquine within the past 4 months, chloroquine with the past 
9 months, or other investigational agents for COVID-19 within the past 30 days 
9. History of conditions associated with immunocompromise, including but not limited to 
poorly controlled HIV, or treatments known to affect the immune system, including but 
not limited to oral or intravenous corticosteroids, alkylating drugs, antimetabolites, 
cytotoxic drugs, radiation, immune-modulating biologics (including IL-6, IL-12, Janus 
kinase inhibitors or antagonists), and cancer treatments, within 30 days of Screening or 
anticipated use within 6 months following participation in this study 
10. Any medical, psychiatric, or social condition or occupational or other responsibility that 
in the judgment of the Investigator would interfere with or serve as a contraindication 
to protocol adherence, assessment of safety (including reactogenicity), or a patient’s 
ability to give informed consent 

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6 STUDY DRUG 
6.1 
Description 
6.1.1 
NasoVAX 
6.1.2 
Placebo 
Commercially available 0.9% Sodium Chloride injectable solution for intranasal 
administration will be supplied to the site pharmacy. The placebo will be prepared in 
syringes identical to those used for the NasoVAX dose. 
6.1.3 
Packaging, Storage, and Handling 

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Full preparation instructions are detailed in a separate pharmacy manual. 
6.2 
Randomization 
Following completion of the Screening activities, patients who meet all the inclusion and 
none of the exclusion criteria will be registered by the Interactive Web Response System 
(IWRS). Eligible patients will be randomly assigned in a 1:1 ratio to the NasoVAX or 
placebo group. Randomization will proceed in 3 cohorts defined by age and risk factors for 
severe COVID-19 (Exclusion Criterion 5) (Cohort 1, ages 18-49 years and risk factors 
disallowed; Cohort 2, ages 18 and above and risk factors disallowed; and Cohort 3, ages 18 
and above and risk factors allowed) of approximately 20, 28, and 48 patients, respectively. 
The cohorts will be enrolled in ascending order, with Cohort 1 preceding Cohort 2, and 
Cohort 2 preceding Cohort 3. Cohort 2 will be stratified by age groups of 18-64 years and 
65 years and above, whereas Cohort 3 will be stratified by age groups (ages 18-64 years, 
ages 65 and above) and co-morbidity (one or more risk factors present, no risk factors 
present). Patients in Cohorts 2 and 3 will be stratified first, and then randomized 1:1 to 
NasoVAX or placebo. Enrollment of patients ages 18-49 years will not exceed 
approximately 30% of the randomized population of either treatment arm.  In addition, a 
minimum of 40% of Cohort 3 will either be 65 years or above or have one or more risk 
factors for severe COVID-19. 
The randomization list will be generated by an independent unblinded statistician. 
6.3 
Dose and Administration 
NasoVAX or normal saline placebo will be administered as a single intranasal dose of 
0.5 mL (0.25 mL in each nostril) on Day 1 in the supine position followed by remaining in 
supine position for 30 minutes, according to the patient’s treatment assignment. Patients 
will be observed for at least 2 hours post intranasal administration. 
6.4 
Dosing Modifications 
As this is a single-dose study, no dose adjustments will be made on an individual patient 
basis.  
6.5 
Blinding and Unblinding 
The Pharmacy staff will be unblinded for the purpose of final drug preparation. The 
pharmacist will consult the unblinded study statistician for dose allocation and the 
Pharmacy staff will prepare each dose in compliance with the randomization list. 

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Due to the fact that formulations cannot be made to look identical, a blinded syringe will be 
used for administration. Study staff either preparing the syringes and/or administering the 
study drug will be independent and will not take part in any other activity of the study (eg, 
telephone contact).  
Knowledge of the randomization list will be limited to the persons responsible for creation 
of the randomization list, pharmacy staff who prepare the study drugs, and any unblinded 
study monitors or auditors, until all data collection and verification activities and 
assignment of patients to the analysis populations has been completed, the database has 
been locked, and the study formally unblinded. 
Data provided to the DMC may be unblinded, as required, for the assessment of safety. 
If unblinding is required in the interest of the safety of a patient, an Investigator will 
discuss the matter with the Sponsor before unblinding. In a medical emergency, the 
Investigator or delegate may unblind via the IWRS for that patient without prior 
consultation with the Sponsor. In that event, the Investigator or delegate will notify the 
Sponsor as soon as possible that the randomization code has been broken for the patient. If 
the blind is broken, the date, time, and reason must be recorded. 
Patients may also be unblinded for the assessment of Stopping Rules, DMC evaluations, 
expedited safety reports, and the emergency unblinding of individual patients, as detailed in 
a separate Safety Management Plan. 
6.6 
Accountability 
The Investigator (or designee) will maintain an accurate record of the receipt of each IP as 
shipped by the Sponsor (or designee), including the date received. In addition, an accurate 
IP disposition record will be kept, specifying the amount dispensed for each patient and the 
dates of dispensation and any returns. 
Sponsor approval is required for on-site destruction of all used IP and shipment of all 
unused IP back to the Sponsor at the completion of the study once all reconciliation has 
occurred. 
6.7 
Prior and Concomitant Therapy 
In the interests of patient safety and acceptable standards of medical care, both the 
Investigator and patient personal physician(s) will be permitted to prescribe additional 
treatment(s) at his/her discretion.  
Any medications that are ongoing at Screening are to be documented in the electronic case report 
form (eCRF). Thereafter, all concomitant medications, including supplemental oxygen, through 30 
days after study drug administration are to be documented in the eCRF. 
Concomitant medications, including supplemental oxygen, are to be recorded in the source 
documents and in the eCRF. 

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6.7.1 
Prohibited Prior and Concomitant Medications 
Prohibited prior and concomitant medications are as follows: 
• Hydroxychloroquine within 4 months or chloroquine within 9 months of Screening 
• Any treatment known to affect the immune system, including but not limited to oral or 
intravenous corticosteroids, alkylating drugs, antimetabolites, cytotoxic drugs, 
radiation, immune-modulating biologics, within 30 days of Screening 
• Live vaccines (such as live influenza vaccinations or live travel vaccinations) within 
30 days of Screening and through Day 14 post study drug administration 
• Receipt of any investigational drug or treatment within 30 days of Screening.  
The above medications are prohibited through Day 14 or hospitalization, and all other 
concomitant medications are permitted. If a patient is hospitalized due to COVID-19, there 
are no restrictions regarding concomitant medications. However, all medications 
administered, including antipyretics, bronchodilators, and supplemental oxygen 
requirements, are to be documented in the eCRF. 
6.8 
Contraception 
All female patients of childbearing potential must practice a highly effective method of 
contraception for 28 days after study drug administration. Male patients with partners of 
childbearing potential must practice a highly effective method of contraception for 45 days 
after study drug administration. 
Highly effective methods of contraception include, but are not limited to, abstinence, sex 
only with persons of the same sex, monogamous relationship with a postmenopausal 
partner, monogamous relationship with vasectomized partner, vasectomy, licensed 
hormonal methods, intrauterine device, or consistent use of a barrier method (eg, condom, 
diaphragm) with spermicide. 
6.9 
Compliance 
A single dose of study drug will be administered by study personnel and therefore 
compliance with study drug dosing is not a concern. The study personnel will be 
appropriately trained on study drug administration procedures and documentation 
requirements prior to study start. 
Non-compliance with study procedures will be reported to the Sponsor who will decide if 
persistent non-compliant patients should be withdrawn from continued study participation. 

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7 PREMATURE DISCONTINUATION 
7.1 
Individual Patients 
Patients can choose to discontinue study participation at any time, for any reason, without 
prejudice to their future medical care. Patients could be discontinued for any of the 
following reasons: 
• Patient request/withdrawal of consent 
• Noncompliance with study requirements 
• Loss to follow-up 
• Investigator discretion 
• Sponsor request, including termination of the study by the Sponsor 
For all patients who discontinue for reasons other than withdrawal of consent, a final 
telephone contact will be made by study center personnel to document final outcome and 
AEs. Serious adverse event (SAEs), hospital, and ICU lengths of stays, and mortality in 
hospitalized patients also will be documented. 
Eligible patients who are randomized and withdrawn before study drug administration will 
be replaced. Patients who receive study drug who are subsequently withdrawn from the 
study will not be replaced. 
To optimize the safety of study participants, once patients receive study drug, all efforts 
will be made to monitor their clinical courses according to study procedures. 
7.2 
Stopping Rules 
Enrollment and study drug treatment will be temporarily halted pending DMC review for 
any of the following reasons: 
• Any SAE considered possibly or probably related to study drug 
• Any Grade 4 or Grade 5 (death) AE considered possibly or probably related to 
study drug  
• Three or more subjects in the same cohort experience the same Grade 3 AE in the 
same Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class 
considered possibly or probably related to study drug 

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• Hospitalization rates in either treatment group in individual cohorts exceeding: 
- 15% (Cohort 1 only) 
- 20% (Cohort 2 only) 
- 25% (Cohort 3 only) 
• Mechanical ventilation rates in either treatment group in individual cohorts equal to 
or exceeding: 
- 2 patients (Cohort 1 only) 
- 3 patients (Cohort 2 only) 
- 4 patients (Cohort 3 only) 
The DMC will be advised each time a patient dies or is hospitalized. The DMC may 
unblind individual patients for the assessment of the relationship of the event to study drug. 
The DMC may recommend resumption of dosing if subject safety is not considered to be at 
significant risk following analysis. 
7.3 
Study as a Whole 
Both the Sponsor and the Investigator reserve the right to terminate the study at the 
Investigator’s site at any time. Should this be necessary, the Sponsor or a specified 
designee will inform the appropriate regulatory authorities of the termination of the study 
and the reasons for its termination, and the Investigator will inform the IRB of the same. In 
terminating the study, the Sponsor and the Investigator will assure that adequate 
consideration is given to the protection of the patients’ interests. 
Possible reasons for termination are: 
• Safety reasons –the incidence of AEs in this or any other study using the same 
investigational product(s) indicates a potential health risk for the patients 
• New scientific knowledge becomes known that makes the objectives of the study no 
longer feasible/valid 
• Unsatisfactory enrollment of patients 

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8 DESCRIPTION OF STUDY PROCEDURES 
Patients will be solicited from medical office, clinics, or hospitals where they seek care for 
COVID-19 symptoms and where COVID-19 test positivity is documented. All recruitment 
materials will be reviewed by the Institutional Review Board overseeing the study. Patients 
need not have a personal doctor to participate in the study. Patients themselves must 
provide written informed consent before the performance of any study-related procedures, 
and surrogate consent by family members, designated legal representatives, or caregivers 
will not be permitted. In the event that the patient progresses to hospitalization or is unable 
to complete the eDiary or telephone calls, designated legal representatives, family members 
or caregivers will be contacted, as provided by informed consent, for this information. 
8.1 
Screening Assessments 
8.1.1 
Demographics 
Demographic data (age, sex, race, ethnicity) will be recorded during Screening. The name 
and contact information for the patient’s family member(s) or caregiver(s) will also be 
obtained in the event that the eDiary (Section 8.2.2) is not completed patient does not 
respond to telephone calls (Section 8.2.3). The contact information for the patient’s 
personal doctor (s) will also be obtained.  
8.1.2 
Medical History 
A complete medical history, including diabetes, hypertension, and respiratory history, is to 
be documented during Screening. Smoking history of use of any inhalation products 
(eg, nicotine-containing products including e-cigarettes or e-vaporizers) is to be 
documented. 
The patient’s COVID-19 symptom history, including fever (temperature >100.4ºF 
[38.0ºC]), fatigue, chills, headache, cough (with or without sputum production), myalgia, 
sore throat, shortness of breath, nasal congestion, diarrhea, and nausea or vomiting is to be 
documented, including date of onset of symptoms, and any laboratory or radiological test 
results obtained. 
The date of initial SARS-CoV-2 positivity also is to be documented. 
8.1.3 
Pregnancy Testing (Females of Childbearing Potential Only) 
A urine pregnancy test is to be performed for female patients of childbearing potential at 
Screening. Results must be available and confirmed to be negative before study drug 
administration.  
8.1.4 
Concomitant Medications 
Concomitant medications will be documented, per Section 6.7. 

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8.2 
Efficacy Assessments 
8.2.1 
Pulse Oximetry, Pulse Rate, and Temperature 
After signing informed consent, patients will be provided with a fingertip pulse oximetry 
device that connects to a mobile device connecting to a tablet that will be supplied to the 
patient to measure resting SpO2 and resting pulse rate. Patients will be trained on the use of 
the device and tablet. This device will be used to determine study eligibility at Screening, 
and if the patient is eligible, he/she will return home with the device for remote monitoring 
of resting SpO2 and resting pulse rate for the duration of the study.  
8.2.1.1 
Screening 
Resting SpO2 and resting pulse rate will be measured twice at Screening, with each 
measurement being of 2 minutes duration. For the first measurement, the patient will be 
sitting and breathing room air for at least 5 minutes before the measurement is made. A 3- 
to 5-minute interval will transpire before the second measurement is commenced. The 
patient should continue to sit and breath room air through the time that the second 
measurement is completed. To ensure stabilization of resting SpO2, only the average of 
resting SpO2 and resting pulse rate in the second minute of each measurement will be used 
to determine study eligibility. To be eligible for the study, patients will be required to have 
an average resting SpO2 ≥ 96.0% and average resting pulse rate < 125 beats per minute on 
both measurements. Baseline for resting SpO2 and resting pulse rate will be defined as the 
mean of the two measurements. Oral temperature will also be recorded. 
8.2.1.2 
Home Monitoring 
Resting SpO2 and resting pulse rate will be measured remotely twice daily at 09:00 hours 
and 16:00 hours for 14 days, with each measurement being of 2 minutes duration and with 
a 1-hour window around each time point. They will also record resting SpO2 and resting 
pulse rate at any time they experience worsening symptoms. The patient will be sitting at 
rest and breathing room air for at least 5 minutes before these measurements are made and 
should continue to sit and breath room air through the time that the measurement is 
completed. To ensure stabilization of resting SpO2 and resting pulse measurements, only 
the averages of these parameters in the second minute of measurement will be analyzed. 
Similarly, patients will be provided with a digital thermometer to measure oral temperature 
at 09:00 hours and 16:00 hours twice daily, with a 1-hour window around each time point, 
and at any time they experience worsening symptoms through Day 14, with results 
recorded in the eDiary.  
Resting SpO2 and resting pulse rate measurements will automatically be captured in the 
mobile device, while oral temperature will be captured in the eDiary (Section 8.2.2). 
The Screening visit is defined as Day 1. If the visit occurs in the morning, the patient will 
be responsible for recording the 16:00-hour measurements at home later that day; if the 

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visit occurs after 16:00 hours, measurements will commence at home the following 
morning. 
8.2.2 
eDiary 
The eDiary will be completed by patient each day through Day 14. The following 
symptoms will be collected: 
• Fatigue 
• Chills 
• Headache 
• Cough (with or without sputum production) 
• Myalgia 
• Sore throat 
• Shortness of breath 
• Nasal congestion 
• Diarrhea 
• Nausea or vomiting  
For each of these symptoms, the patient will be asked to grade them by the following scale: 
• Not at all 
• A little bit 
• Somewhat 
• Quite a bit 
• Very much 
The patient will also record all temperatures in the eDiary. 
In the event that the patient progresses to hospitalization or is unable to complete the 
eDiary, family members, designated legal representatives or caregivers will be contacted, 
as provided by informed consent, to determine the status of the patient. 
8.2.3 
Telephone calls 
The patient will be called each day, Day 2 through Day 14. The telephone script is 
provided in Appendix A. 
After the completion of Day 14, the patient will be called weekly through Day 28. The 
telephone script is provided in Appendix B. 

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Based on the findings of telephone calls, an Unscheduled Visit with the Investigator or 
personal doctor may be scheduled (Section 8.4). 
In the event that the patient progresses to hospitalization or is unable to complete the 
telephone calls, family members or caregivers will be contacted, as provided by informed 
consent, to determine the status of the patient. 
8.2.4 
Criteria for the Assessment of Severity of Illness in Patients with COVID-19 
The criteria in Appendix C will be used to assess changes in the severity of COVID-19 in 
patients at different timepoints over the course of the trial. The final determination will be 
made on Day 28 in patients who are not hospitalized and Day 42 in patients who are 
hospitalized. 
8.2.5 
Additional Data Collection in Hospitalized Patients 
Additional data to be collected for patients hospitalized due to COVID-19 through Day 42 
to include the following: 
• Date and time of hospital admission and discharge 
• If transferred to ICU, date and time of ICU admission and discharge 
• Requirement for oxygen (yes/no), and if yes, method of oxygenation (mask/nasal 
prongs, non-invasive ventilation, or high-flow oxygen; intubation and mechanical 
ventilation 
- If required ventilation, start date and time of ventilation, method of ventilation 
including whether intubated (yes/no) 
• Change in ambulatory status 
• Death 
It is anticipated that most of this information will be obtained from the medical record. 
When necessary, a family member, designated legal representative or caregiver, as 
permitted by informed consent, will be contacted if the patient has expired or is too ill or 
otherwise unable to provide this information. 
The rate (liters/min) of oxygen administered is to be captured as a concomitant medication. 
If, in the Investigator’s opinion, a patient required a higher level of oxygenation, but did 
not receive due to resource availability, this should be documented. 

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Furthermore, if, in the Investigator’s opinion, the patient required a higher level of care 
(ie, admittance to the ICU) but did not receive due to resource availability, this should be 
documented. 
8.2.6 
Vital Status 
Vital status is to be documented at each study contact. If the patient died due to a reason 
other than COVID-19, the primary cause of death is to be recorded and reported as an SAE. 
Death due to worsening fever, cough, shortness of breath, resting SpO2, or resting pulse 
rate or COVID-19 symptoms that are reported at Screening (Section 8.1.2) is not 
considered to be an SAE in the context of this study although cause of death will be 
reviewed by the DMC in real time. 
8.3 
Safety Assessments 
8.3.1 
Height, Weight and Body Mass Index (BMI) 
Height (cm) and weight (kg) will be measured and recorded at Screening. BMI will be 
subsequently be calculated from these measurements. 
8.3.2 
Physical Examination 
A cardiovascular and respiratory-focused physical examination will be performed by 
trained medical personnel during Screening. 
8.3.3 
Screening Vital Signs 
Blood pressure and respiratory rate obtained after sitting at rest for at least 5 minutes will 
be recorded at Screening. The procedures for recording resting pulse rate and oral 
temperature are detailed in Section 8.2.1. 
8.3.4 
Adverse Events 
The AE reporting period is from the start of study drug administration on Day 1 through 
Day 14 or until time of hospitalization. AEs will be assessed by direct observation on 
Day 1 and then by web-based questionnaire and patient interview during daily telephone 
contact through Day 14 after study drug administration and then through telephone contact 
thereafter until resolved, stabilized, or transitioned to the patient’s main healthcare provider 
for follow up. 
Details on the definitions, reporting, and management of AEs are provided in Section 9. 
8.3.5 
Use of Antipyretics and Bronchodilators 
The use of antipyretics and bronchodilators will be considered study safety endpoints and 
should be collected with concomitant medications, per Section 6.7.1. 

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8.4 
Concomitant Care and Unscheduled Visits 
No study center visits are scheduled other than Screening. Patients will continue to follow 
with their personal doctors during the study and receive medications at their direction after 
Screening. The prescription and use of any prohibited medications through Day 14 will be 
recorded but will not result in the discontinuation of any study procedures. If it determined 
that the patient is in the need of an unscheduled clinic visit for further evaluation, an 
unscheduled visit with the personal doctor, or hospitalization, these arrangements will be 
made. The Investigator will assist in making these arrangements whenever possible. The 
decision to seek this unscheduled care will be at the discretion of the patient, the personal 
doctor, or Investigator. 

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9 ADVERSE EVENTS 
9.1 
Definitions 
9.1.1 
Adverse Event 
An AE is defined as any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. An AE can therefore be any unfavorable 
and unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of the investigational product whether or not related to 
the investigational product. An AE can be any sign, symptom, or diagnosis that appears or 
changes in intensity during the course of the study. 
Unchanged chronic conditions are not AEs and should not be recorded on the AE pages of 
the eCRF. These medical conditions should be adequately documented on the appropriate 
page of the eCRF (medical history or physical examination). However, medical conditions 
present on the first day of treatment that worsen in intensity or frequency during the 
treatment or post-treatment periods in a manner not consistent with natural disease 
progression should be reported and recorded as AEs. The Investigator will actively solicit 
this information and assess the event in terms of severity and relationship to the study 
treatment regimen.  
The objective of this study is to assess the effective and safety of NasoVAX in preventing 
clinical worsening of early COVID-19. The worsening of fever, cough, shortness of breath, 
resting SpO2 or resting pulse rate and symptoms of COVID-19 that are reported in the 
eDiary during Screening (Section 8.1.2) will be captured in aggregate in the eCRF and will 
not be reported as AEs.  
The term AE is used to include any AE whether serious or not serious. 
9.1.2 
Unexpected Adverse Drug Experience 
An unexpected adverse drug experience is defined as an adverse experience, the nature or 
severity of which is not consistent with the reference safety information in the 
Investigator’s Brochure.  
For the purpose of expedited reporting of IND-Safety Reports, only unexpected serious 
adverse events considered possibly or probably related to study medication by the Sponsor 
and unexpected serious AEs (SAEs [Section 9.1.3]) will be considered IND-Safety 
Reports. 

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9.1.3 
Serious Adverse Event 
An AE or suspected adverse reaction is considered serious (an SAE) if, in the view of 
either the Investigator or Sponsor, it results in any of the following outcomes: 
• Death 
• Life-threatening (An AE is considered life-threatening if, in the view of either the 
Investigator or Sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an AE that, had it occurred in a more severe form, might have 
caused death.) 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• A congenital anomaly/birth defect 
Life-threatening means that the patient or subject was at immediate risk of death at the time 
of the SAE; it does not refer to a serious AE that hypothetically might have caused death if 
it were more severe. Hospitalization does not include same day surgery, elective surgery, 
optional admission not associated with a precipitating AE (ie, elective cosmetic surgery), or 
hospitalization planned before the start of the study for a pre-existing condition that has not 
worsened. Persistent or significant disability or incapacity means that there is a substantial 
disruption of a person’s ability to carry out normal life functions. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical intervention 
to prevent one of the outcomes listed in this definition. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
9.2 
Reporting Responsibilities and Periods 
It is the responsibility of the Investigator to perform periodic assessment for AEs. AEs 
spontaneously reported by the patient or reported in response to an open question from the 
study personnel (eg, ‘Have you had any health problems since the previous visit/you were 
last asked?’) or revealed by observation will be recorded.  
AEs and concomitant medications will be recorded from the start of study drug 
administration on Day 1 through 14 or until the time of hospitalization. The AE term, date 
of AE onset, date of AE resolution (if applicable), severity, causality, action taken for the 
AE, outcome and whether or not the AE was serious will be recorded. 

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AEs must be monitored until they are resolved, stabilized or transferred to the patient’s 
main healthcare provider for follow up, are clearly determined to be due to a patient’s 
stable or chronic condition or intercurrent illness(es), the patient is hospitalized, or 
follow-up is no longer possible. Data describing AEs will be recorded in the patient’s 
medical record and as appropriate, an SAE report form. SAEs will be reported to the 
Sponsor as described in Section 9.6. 
Any SAE that the Investigator considers to be related to study drug and occurs at any time 
after completion of the study must be reported to the Sponsor or designee. If at the time the 
Investigator initially reports an SAE, the event has not resolved, the Investigator must 
provide a follow-up report as soon as it resolves (or upon receipt of significant information 
if the event is still ongoing).  
Note that for the purposes of this study, hospitalization due to worsening fever, cough or 
shortness of breath, resting SpO2 or resting pulse rate or symptoms of COVID-19 that are 
reported prior to treatment (Section 8.1.2) will not be considered an SAE.  
9.3 
Assessment of Adverse Events 
9.3.1 
Severity 
The Investigator should assess the severity of each AE. The AE will be recorded at its 
initial severity level. The initial AE will be considered ended and a new AE will be 
recorded if the event changes in severity.  
The severity of all AEs, both serious and non-serious, will be assessed by assigning a 
Grade of 1, 2, 3, 4, or 5 according to the CTCAE, v 4.03 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
When an AE cannot be graded by CTCAE, the following severity grading may be used: 
• Grade 1 (Mild): awareness of sign or symptom, but easily tolerated 
• Grade 2 (Moderate): discomfort enough to cause interference with usual activity 
• Grade 3 (Severe): incapacitating with inability to work or do usual activity 
• Grade 4 (Life-Threatening): refers to an event in which the patient was, in the view of 
the Investigator, at risk of death at the time of the event. (This category is not to be used 
for an event that hypothetically might have caused death if it were more severe.) 
• Grade 5 (Fatal): death related to AE 
An AE that is assessed as severe should not be confused with an SAE. Severity is a 
category for rating the intensity of an event, and both non-serious AEs and SAEs can be 

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assessed as severe. An event will be defined as serious when it meets one of the criteria 
described in Section 9.1.3. 
9.3.2 
Relatedness (Causality) to Study Drug 
The assessment of causality will be based on the information available and may be changed 
upon receipt of additional information. 
Causality should be assessed using the following categories: 
• Unrelated/Unlikely Related: clinical event with an incompatible time relationship to 
investigational agent administration, and that could be explained by underlying disease 
or other drugs or chemicals or is incontrovertibly not related to the investigational agent 
• Possibly related: clinical event with a reasonable time relationship to investigational 
agent administration, and that is unlikely to be attributed to concurrent disease or other 
drugs or chemicals 
• Probably related: clinical event with plausible time relationship to investigational agent 
administration, and that cannot be explained by concurrent disease or other drugs or 
chemicals 
9.4 
Pregnancy 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP may have 
interfered with the effectiveness of a contraceptive medication. Pregnancy in a patient’s 
partner is not considered an AE. Congenital abnormalities/birth defects and spontaneous 
miscarriages should be reported and handled as SAEs. Elective abortions without 
complications should not be handled as AEs. The outcome of a pregnancy will be 
followed-up and documented even if the patient was withdrawn from the study. See 
Section 9.6.4 for further information on reporting of pregnancy.  
An induced elective abortion to terminate a pregnancy without medical reason is not 
regarded as an AE. However, an induced therapeutic abortion to terminate a pregnancy 
because of complications or medical reasons must be reported as an SAE. The underlying 
medical diagnosis for this procedure should be reported as the SAE term. A spontaneous 
abortion in a study patient is always considered an SAE. 
9.5 
Overdose 
Any instance of overdose (suspected or confirmed and irrespective of whether or not it 
involved study drug must be communicated to the Sponsor or a specified designee within 
24 hours and be fully documented as an SAE. Details of any signs or symptoms and their 
management should be recorded including details of any antidote(s) administered. 

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An overdose of study drug is not expected to occur in this study, as a single dose is being 
administered intranasally. Should patients receive a higher dose than the allocated dose, 
this should be reported in the eCRF and the Sponsor should be informed. Any deviations 
from the assigned dose will be handled as a protocol deviation. 
9.6 
Procedures for Recording and Reporting Adverse Events 
9.6.1 
Recording Adverse Events 
To improve the quality and precision of AE data, Investigators should observe the 
following guidelines: 
• Whenever possible, use recognized medical terms when recording AEs on the AE page 
of the eCRF. Do not use colloquialisms, jargon, or abbreviations. 
• If known, record the diagnosis (ie, disease or syndrome) rather than component signs 
and symptoms on AE pages of the eCRF (eg, record “congestive heart failure” rather 
than “dyspnea”, “rales”, and “cyanosis”). However, signs and symptoms that are 
considered unrelated to an encountered syndrome or disease should be recorded as 
individual AEs on the eCRF page. For example, if congestive heart failure and severe 
headache are observed at the same time, each event should be recorded as an individual 
AE. 
• Adverse events occurring secondary to other events (ie, sequelae) should be identified 
by the primary cause. A primary AE, if clearly identifiable, generally represents the 
most accurate clinical term to record on the AE page of the eCRF. If a primary SAE is 
recorded on an AE eCRF page, events occurring secondary to the primary event should 
be described in the narrative description of the event. 
• Any laboratory abnormalities that are identified by the Investigator as clinically 
significant, as applicable, are to be considered AEs and recorded on the AE eCRF page. 
9.6.2 
Reporting of Serious Adverse Events 
Serious AEs require reporting to the Sponsor or designee within 24 hours, regardless of the 
relationship of the event to the study treatment regimen. Refer to Section 9.1.3 for the 
definition of an SAE. Procedures for recording and reporting SAEs will be detailed in a 
separate Safety Management Plan for processing SAEs, expedited safety reports, and the 
emergency unblinding of patients. 
Within 24 hours of the Investigator’s observation or learning of an SAE, the Investigator 
should notify 
 by completing the SAE forms as thoroughly as 
possible with all available details of the event, including a determination of causality (even 
if preliminary), and signing them. The Investigator should communicate with Pivotal 
Pharmacovigilance if input is needed to complete the SAE assessment. Investigator 

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causality determination and signature MUST be included for all SAEs. The completed SAE 
form and cover sheet should be sent by email or fax to 
 
If not all information regarding an SAE is initially available, the Investigator should not 
wait to receive additional information before completing the AE eCRF and SAE forms. For 
initial SAE reports, the Investigator should record all case details that can be garnered on 
the SAE form and the AE eCRF page. Relevant follow-up information is to be submitted 
on updated SAE forms as soon as it becomes available. 
If there are questions regarding reporting an SAE or if information needs to be transmitted 
that cannot be recorded on the SAE forms (eg, discharge summaries, laboratory reports), 
the Investigator should contact 
 
For unexpected serious adverse drug reactions (SUSARs), blinded reports will be 
disseminated and provided to Investigators at each study site. 
When required and according to local law and regulations, unblinded SUSARs or other 
SAEs will be reported by an unblinded designee to the IRB and regulatory authorities. 
9.6.3 
Special Reporting Situations 
Hospitalization or Death 
Hospitalization and death are outcomes of an event. The event that resulted in 
hospitalization or death should be recorded and reported on the SAE form and the AE 
eCRF page. 
As noted in Section 9.2 and Section 8.2.6, hospitalizations and deaths related to worsening 
fever, cough, shortness of breath, resting SpO2 or resting pulse rate or symptoms of 
COVID-19 at Screening (Section 8.1.2) will not be considered SAE, although narratives of 
the hospitalizations and causes of death will be reported to and reviewed by the DMC in 
real time. 
Surgical or Diagnostic Procedures 
The illness leading to a surgical or diagnostic procedure is to be recorded as an AE/SAE, 
not the procedure itself. The procedure is to be captured in the case narrative as part of the 
action taken in response to the illness. 

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9.6.4 
Reporting Pregnancies 
Pregnancy itself is not considered an AE. If a patient becomes pregnant during the study 
or within 1 month of discontinuing study drug or the partner of a patient participating in 
the study becomes pregnant during the study or within 3 months of discontinuing study 
drug, the Investigator should report the pregnancy on a separate pregnancy report form 
provided to the sites. Only pregnancies occurring from the time of first study drug dose 
administered to the patient will be reported and documented. 
The patient/partner should be followed by the Investigator until completion of the 
pregnancy. If the pregnancy ends for any reason before the anticipated date, the 
Investigator should notify the Sponsor. At the completion of the pregnancy, the 
Investigator will document the outcome of the pregnancy. 
This pregnancy report form must be completed and submitted, either by e-mail or fax, 
immediately but no later than 24 hours of the Investigator’s learning of the event to: 
However, any pregnancy complication, spontaneous or elective abortion, still birth, 
neonatal death, or congenital anomaly will be recorded as an AE or SAE, and reported, as 
applicable. 
9.7 
Data Monitoring Committee 
This study will be overseen by an independent DMC, which will have access to unblinded 
data, as needed, for the assessment of the efficacy, safety, and tolerability of study drug and 
make a recommendation regarding whether to progress to the next cohort. Real-time data 
on patient status, including hospitalization and death, will be provided for review. The 
DMC may unblind the data in conducting its assessments.  
To enhance the safety of study participants, patients with risk factors for severe COVID-19 
will be excluded from Cohort 1 (Exclusion Criterion 5). Following DMC review of the 
efficacy and safety data of each cohort, some or all of these may be removed if preliminary 
data show no signal for adverse or paradoxical effects.  
A charter describing the roles, responsibilities, and operating procedures of the DMC will 
be implemented prior to study initiation.  

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9.8 
Medical Monitor 
A Medical Monitor will provide 24-hour/7-day coverage for medical issues pertaining to 
this study. The contact information for the Medical Monitor is provided below: 

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10 STATISTICS 
10.1 
Sample Size 
The study is considered exploratory to assess the initial safety of NasoVAX in COVID-19 
and response to treatment. The sample size chosen for this study was considered adequate 
to meet the study objectives and was selected without statistical significance 
considerations.  
10.2 
Analysis Sets 
Safety Analysis Set: All patients who receive any study drug. Patients will be analyzed 
according to the treatment that they receive. 
Modified intent to treat (ITT) Analysis Set: All randomized patients who receive any 
amount of study drug, have a Baseline and at least one post-Baseline resting SpO2 
measurement. Patients will be analyzed according to the treatment that they receive. 
Patients will be analyzed according to the treatment that they receive. This analysis set will 
be used for primary and secondary analyses. 
Per Protocol (PP) Set: All randomized patients who receive any amount of study drug 
according to the correct treatment assignment and who have 80% of twice daily results 
from resting SpO2 measurements through Day 14 or hospitalization. 
10.3 
Statistical Methods 
10.3.1 
General Methods 
Baseline is defined as data collected closest to randomization prior to any study drug 
dosing. For resting SpO2 and resting pulse rate, Baseline is defined as the average of the 
two measurements at Screening. All analyses and summary statistics will be presented by 
treatment group (NasoVAX, placebo) across cohorts, as well as by treatment group pooled 
across all cohorts, for each analysis set separately.  
Descriptive statistics, including the numbers and percentages for categorical variables and 
the numbers, means, standard deviations, medians, minimums and maximums for 
continuous variables will be provided by treatment. The study is considered exploratory, 
and inferential statistics will be employed as appropriate across cohorts, as well as by 
treatment group pooled across all cohorts. 
Patients will be randomized 1:1 to NasoVAX or placebo and proceed in 3 cohorts defined 
by age and risk factors (Exclusion Criterion 5) for severe COVID-19 (Cohort 1, ages 18-
49 years and risk factors disallowed; Cohort 2, ages 18 and above and risk factors 
disallowed; and Cohort 3, ages 18 and above and risk factors allowed) of approximately 20, 
28 and 48 patients, respectively. The cohorts will be enrolled in ascending order, with 
Cohort 1 preceding Cohort 2, and Cohort 2 preceding Cohort 3. Cohort 2 will be stratified 

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by age groups of 18-64 years and 65 years and above, whereas Cohort 3 will be stratified 
by age groups (ages 18-64 years, ages 65 and above) and co-morbidity (one or more risk 
factors present, no risk factors present). Patients in Cohorts 2 and 3 will be stratified first, 
and then randomized 1:1 to NasoVAX or placebo. Enrollment of patients ages 18-49 years 
will not exceed approximately 30% of the randomized population of either treatment arm. 
In addition, a minimum of 40% of Cohort 3 will either be 65 years or above or have one or 
more risk factors for severe COVID-19. 
All descriptive and statistical analyses will be performed using SAS statistical software 
Version 9.2 or higher, unless otherwise noted. 
10.3.2 
Analysis of Efficacy 
For the primary analysis, the proportion of patients with clinical worsening, defined as a 
4.0% decrease from Baseline in resting SpO2 on two successive measurements during 
home follow-up or hospitalization, will be compared between NasoVAX and placebo 
groups using the Cochran-Mantel-Haenszel test, while considering the stratification of age 
groups and risk factors, at a one-sided significance level of 0.025. The same approach will 
be applied for secondary endpoints that are categorical in nature. Sensitivity analyses will 
be performed to assess the effect of site on the response to study drug. Linear and logistic 
regression will be employed to examine the effects of Baseline factors, such as age, sex, 
medications, and medical co-morbidities on response. 
Changes from Baseline in Severity of COVID-19, assessed by average decrease in resting 
SpO2, average increase in resting pulse rate by outpatient pulse oximetry and COVID-19 
symptoms (eDiary) during home follow-up, will be analyzed using a mixed model for 
repeated measures. The model will include the fixed effects of treatment, week, and 
treatment-by-visit interaction as well as the continuous, covariate of Baseline level. The 
model will employ an unstructured within patient covariance matrix and a restricted 
maximum likelihood estimation method.  
A Kaplan-Meier method will be applied to compare changes between treatment groups in 
resting SpO2 over time.  
For the purpose of study efficacy endpoints, resting SpO2 and resting pulse rate will be 
assessed on observed data only; if data is missing, it will not be imputed. 
No multiplicity adjustments will be made for secondary endpoints. 
10.3.3 
Analysis of Safety 
Quantitative safety data, including the frequencies of AEs, oral temperatures, use of 
antipyretics and bronchodilators, and length of hospital and ICU stay, will be summarized 
using descriptive statistics and frequency distributions. Qualitative safety data will be 
summarized by frequencies and percentages. All summaries will be presented by treatment 

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arms. AEs will be coded using MedDRA, Concomitant medications will be coded using 
World Health Organization (WHO) drug dictionary. 
10.3.4 
Demographic and Baseline Characteristics 
Demographic and Baseline characteristics (age, gender, race, ethnicity, body mass index) 
will be summarized by treatment group across cohorts and by treatment group pooled 
across all cohorts for each analysis set separately. 
10.4 
Statistical Analysis Plan (SAP) 
The SAP will be developed and finalized prior to the database lock and unblinding of treatment 
assignment. This plan will confirm the analysis sets used in the analysis, outline all data handling 
conventions, and specify all statistical methods to be used for all safety and efficacy analyses. The 
SAP will supersede the protocol with respect to analyses specified, although the primary analysis 
will remain the same. It is only anticipated that additional analyses may be desired to be pre-
specified in the SAP. 

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11 DATA QUALITY ASSURANCE 
Accurate, consistent, and reliable data will be ensured through the use of standard practices 
and procedures. These are described in the following sections. 
11.1 
Data Handling 
Data will be entered into an electronic database and reviewed by the Clinical Research 
Associate (CRA) remotely. All corrections or changes made to any study data must be 
appropriately tracked in an audit trail in the eCRF system. The eCRFs will be considered 
complete when all missing, incorrect, and/or inconsistent data have been accounted for. 
11.2 
Computer Systems 
Data will be processed using a validated computer system conforming to regulatory 
requirements. 
11.3 
Data Entry 
Data must be recorded using the eCRF system as the study is in progress. All study site 
personnel must log into the system using their secure user name and password in order to 
enter, review, or correct study data. These procedures must comply with 21 CFR Part 11 
and other appropriate international regulations. All passwords will be strictly confidential. 
11.4 
Medical Information Coding 
The latest version of the WHO Drug Dictionary and MedDRA will be used for coding of 
concomitant medications and AEs. 
11.5 
Data Validation 
Validation checks programmed within the eCRF system, as well as supplemental validation 
performed via review of the downloaded data, will be applied to the data in order to ensure 
accurate, consistent, and reliable data. Data identified as erroneous, or data that are 
missing, will be referred to the investigative site for resolution through data queries. 
The eCRFs must be reviewed and electronically signed by the Investigator who signed the 
protocol. 
11.6 
Study Monitoring Requirements 
It is the responsibility of the Investigator to ensure that the study is conducted in 
accordance with the protocol, Declaration of Helsinki, ICH GCP guidelines, and applicable 
regulatory requirements, and that valid data are entered into the eCRFs. 
The Investigator will permit the Sponsor or their designee to monitor the study as 
frequently as deemed necessary to determine that data recording and protocol adherence 

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are satisfactory. Monitoring will include review of the eCRFs for completeness and clarity, 
cross-checking with source documents, and clarification of administrative matters. The 
review of medical records will be performed in a manner to ensure that patient 
confidentiality is maintained. All monitoring activities will be reported and archived. In 
addition, monitoring visits will be documented by CRA signature and date on the study-
specific monitoring log and the completion of a detailed monitoring report. 
The CRA will ensure that the investigation is conducted according to protocol design and 
regulatory requirements by frequent communications with the investigational site 
(monitoring visits, letter, telephone, email, and fax). 
All unused study drug and other study materials are to be returned to the Sponsor or 
designee after the clinical phase of the study has been completed. 
Regulatory authorities, the IRB, and/or the Sponsor’s clinical quality assurance group may 
request access to all source documents, eCRFs, and other study documentation for on-site 
audit or inspection. Direct access to these documents must be guaranteed by the 
Investigator, who must provide support at all times for these activities. 
11.7 
Source Document and Case Report Form Completion 
Source data is defined as all information in original records and certified copies of original 
records of clinical findings, observations, or other activities in a clinical study necessary for 
the evaluation and reconstruction of the clinical study. Source data are contained in source 
documents (ie, original records or certified copies). Source documents and the eCRFs will 
be completed for each study patient. It is the Investigator’s responsibility to ensure the 
accuracy, completeness, and timeliness of the data reported in the patient’s source 
document/eCRF. The source document/eCRF should indicate the patient’s participation in 
the study and should document the dates and details of study procedures, AEs, and patient 
status. 
The Investigator, or designated representative, should complete the source document/eCRF 
as soon as possible after information is collected, preferably on the same day that a study 
patient is seen for an examination, treatment, or any other study procedure. Any 
outstanding entries must be completed immediately after the final examination. An 
explanation should be given for all missing data. 
The Investigator must sign and date the Investigator’s Statement at the end of the source 
document/eCRF to endorse the recorded data. 
The Investigator will retain all completed source documents. A site-specific eCRF archive 
and audit trail will be provided at the close of the study to each Investigator. The Sponsor 
or designee will retain the eCRF archive and audit trail for all investigative sites. 

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11.8 
Record Retention 
Records of patients, source documents, monitoring visit logs, eCRFs, inventories of study 
product, regulatory documents, and other correspondence pertaining to the study must be 
kept in the appropriate study files at the site. The Investigator will maintain all study 
records according to ICH GCP and applicable regulatory requirements. Records will be 
retained for at least 2 years after the last marketing application approval or 2 years after 
formal discontinuation of the clinical development of the investigational product or 
according to applicable regulatory requirements. If the Investigator withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person willing 
to accept the responsibility. The Sponsor must be notified in writing if a custodial change 
occurs. 

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12 ETHICS 
12.1 
Good Clinical Practice 
The study will be conducted in accordance with the protocol, GCP, the relevant ICH 
guidelines, the applicable regulatory requirements, and the ethical principles that have their 
origins in the Declaration of Helsinki. As required by US FDA (21 CFR 56) and the 
Declaration of Helsinki, the study protocol, amendments, and informed consent form will 
be reviewed and approved, according to 21 CFR Parts 50 and 56 (or similar local 
requirements, such as ICH E6, for ex-US sites), respectively, by each study center’s IRB or 
EC. 
12.2 
Institutional Review Board 
The IRB will review all appropriate study documentation in order to safeguard the rights, 
safety, and wellbeing of patients. Federal/local regulations and ICH GCP guidelines require 
that approval be obtained from an IRB prior to participation of patients in research studies. 
The study will only be conducted at sites where IRB approval has been obtained. The 
protocol, Investigator’s Brochure, informed consent form, advertisements (if applicable), 
written information given to the patients, safety updates, annual progress reports, and any 
revisions to these documents will be provided to the IRB by the Investigator. 
No study drug will be released to the site for dosing until written IRB authorization has 
been received by the Sponsor. 
12.3 
Patient Information and Consent 
The informed consent form and any changes to the informed consent form made during the 
course of the study must be agreed to by the Sponsor or their designee and the IRB/EC 
prior to its use and must be in compliance with FDA Regulations in 21 CFR Part 50, 
Department of Health & Human Service in 45 CFR Part 46 (if applicable), ICH GCP 
guidelines, local regulatory requirements, and legal requirements. 
The Investigator must ensure that each study patient or proxy is fully informed about the 
nature and objectives of the study and possible risks associated with participation and must 
ensure that the patient has been informed of his/her rights to privacy. The Investigator will 
obtain written informed consent from each patient or the patient’s legally authorized 
representative before any study-specific activity is performed and will document in the 
source documentation that consent was obtained prior to enrollment in the study. The 
original signed copy of the informed consent form must be maintained by the Investigator 
and is subject to inspection by the Sponsor, their representatives, auditors, the IRB, and/or 
regulatory agencies. A copy of the signed informed consent form will be given to the study 
patient or proxy. Whenever possible, patients who participate based on proxy consent will 
be re-consented once deemed capable by the Investigator of providing consent on their 
own. 

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If significant new findings are developed during the course of research which may affect 
the willingness of patients to continue study participation, the Sponsor will notify each 
Investigator of the findings via letter or telephone. 
12.4 
Patient Confidentiality 
In order to maintain patient privacy, all eCRFs, study drug accountability records, study 
reports and communications will identify the patient by initials and the assigned patient 
number. The Investigator will grant monitor(s) and auditor(s) from the Sponsor or its 
designee and regulatory authority(ies) access to the patient’s original medical records for 
verification of data gathered on the eCRFs and to audit the data collection process. The 
patient’s confidentiality will be maintained and will not be made publicly available to the 
extent permitted by the applicable laws and regulations. 
12.5 
Protocol Compliance 
The Investigator will conduct the study in compliance with the protocol provided by the 
Sponsor, the approval/favorable opinion of the IRB and the appropriate regulatory 
authority(ies). Modifications to the protocol should not be made without agreement of both 
the Investigator and the Sponsor. Changes to the protocol will require written IRB 
approval/favorable opinion prior to implementation, except when the modification is 
needed to eliminate an immediate hazard(s) to patients. The IRB may provide, if applicable 
regulatory authority(ies) permits, expedited review and approval/favorable opinion for 
minor change(s) in ongoing studies that have the approval/favorable opinion of the IRB. 
The Sponsor will submit all protocol modifications to the regulatory authority(ies) in 
accordance with the governing regulations. 
When immediate deviation from the protocol is required to eliminate an immediate 
hazard(s) to patients, the Investigator will contact the Sponsor, if circumstances permit, to 
discuss the planned course of action. Any departures from the protocol must be fully 
documented in the eCRF and source documentation and reported to the appropriate study 
monitor or staff in a timely fashion. 

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13 COMPENSATION, INSURANCE AND INDEMNITY 
The Sponsor has retained an insurance policy covering, in its terms and provisions, its legal 
liability for injuries caused to participating persons and arising out of this research 
performed strictly in accordance with the scientific protocol as well as with applicable law 
and professional standards. The patient will be appropriately treated or compensated, or 
both, for any health or other problems arising from participation in this study. 

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14 PUBLICATION POLICY 
All information provided regarding the study, as well as all information 
collected/documented during the course of the study, will be regarded as confidential. The 
Investigator agrees not to disclose such information in any way without prior written 
permission from the Sponsor. 
Any publication of the results, either in part or in total, including articles in journals or 
newspapers, oral presentations, or abstracts, by the Investigator(s) or their representative(s), 
shall require prior approval, notification, and review within a reasonable time frame by the 
Sponsor and cannot be made in violation of the Sponsor’s confidentiality restrictions or to 
the detriment of the Sponsor’s intellectual property rights. 
It is anticipated that the results of this study will be presented at scientific meetings and/or 
published in a peer reviewed scientific or medical journal. A Publications Committee, 
comprising the Investigators participating in the study and representatives from the 
Sponsor, as appropriate, will be formed to oversee the publication of the study results, 
which will reflect the experience of all participating study centers. Subsequently, individual 
Investigators may publish results from the study in compliance with their agreement with 
the Sponsor. A pre-publication manuscript is to be provided to the Sponsor at least 60 days 
prior to the submission of the manuscript to a publisher. Similarly, the Sponsor will provide 
any company prepared manuscript to the Investigators for review at least 30 days prior to 
submission to a publisher. 

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16 REFERENCES 
Centers for Disease Control and Prevention, Coronavirus Disease 2019 (COVID-19): 
Groups at Higher Risk for Severe Illness, Updated May 14, 2020 
https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/groups-at-higher-
risk.html#serious-heart-conditions (last accessed June 7, 2020) 
United States Food and Drug Administration, FDA Guidance on Conduct of Clinical Trials 
of Medical Products during COVID-19 Pandemic, March 2020. 
Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients 
with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020; 395:1054-62. 
 

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Appendix A: Telephone Script, Days 2 through 14 
Greeting 
Question about general health and adverse events experienced by the patient.  
“Have you had any changes in your health since our last phone call? If so, please 
describe.” 
“If you have a personal doctor, have you been in contact with your doctor about 
these changes in your health, and what did your doctor recommend to you?” 
Question about symptoms [only for patients who are unable to complete the eDiary]: 
“Have you had any of the following symptoms? If so, were they mild, moderate, or 
severe?” 
• Fatigue 
• Chills 
• Headache 
• Cough (with or without sputum production) 
• Myalgia 
• Sore throat 
• Shortness of breath 
• Nasal congestion 
• Diarrhea 
• Nausea or vomiting  
For each of these symptoms, the patient will be asked to grade them by the following 
scale: 
• Not at all 
• A little bit 
• Somewhat 
• Quite a bit 
• Very much 
Question about concomitant medications: 

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• “Have you taken any medications, including any new medications, changed the 
dose of any medications, or stopped any medications since our last phone call?” 
Question about the need for a clinic or hospital visit: 
• Do you feel that you will need to make a visit to see us, your personal doctor, or the 
hospital? If so, I will call your doctor or the hospital and let them know you will be 
arriving soon [or time provided by patient].” 
• If the Investigator (or delegate) feels that the patient should have a clinic or hospital 
visit, he/she will make that recommendation. 
If the patient cannot be reached, the designated family member or caregiver will be 
contacted for a determination of the patient’s status. The patient’s doctor may also be 
contacted for additional information identified during the telephone call. 

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Appendix B: Telephone Script, Day 21 and Day 28 
Greeting 
Question on current health: 
• “I am calling to check on the status of your health since you completed the first 
14 days in the study. Were you admitted to the hospital at any time? If so, please 
provide the details of the hospital and dates.” 
• Have you had any changes to your health that have required a doctor’s visit?  
If the answer to either of these questions is yes, the doctor or hospital will be contacted for 
further details. 
If the patient cannot be reached, the designated family member or caregiver will be 
contacted for this information. 

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Appendix C: 
Criteria for the Assessment of Severity of Illness in Patients with COVID-19 
SARS-CoV-2 infection without symptoms 
• 
Positive testing by standard reverse transcription polymerase chain reaction (RTPCR) assay 
or equivalent test 
• 
No symptoms 
Mild COVID-19 
• 
Positive testing by standard RT-PCR assay or equivalent test 
• 
Symptoms of mild illness that could include fever, cough, sore throat, malaise, headache, 
muscle pain, gastrointestinal symptoms 
• 
No clinical signs indicative of Moderate, Severe, or Critical Severity 
Moderate COVID-19 
• 
Positive testing by standard RT-PCR assay or equivalent testing 
• 
Symptoms of moderate illness with COVID-19, which could include any symptom 
of mild illness or shortness of breath with exertion 
• 
Clinical signs suggestive of moderate illness with COVID-19, such as RR ≥ 20, 
HR ≥ 90, or requires ≤2L oxygen by nasal cannula in order maintain SaO2 ≥93% 
• 
No clinical signs indicative of Severe or Critical Illness Severity 
Severe COVID-19 
• 
Positive testing by standard RT-PCR assay or an equivalent test 
• 
Symptoms suggestive of severe systemic illness with COVID-19, which could 
include any symptom of moderate illness or shortness of breath at rest, or 
respiratory distress 
• 
Clinical signs indicative of severe systemic illness with COVID-19, such as RR ≥ 30, HR ≥ 
125, requires > 2L oxygen by nasal cannula in order maintain SaO2 ≥93%, or PaO2/FiO2 
<300 
• 
No criteria for Critical Severity 
Critical COVID-19 
• 
Positive testing by standard RT-PCR assay or equivalent test 
• 
Evidence of critical illness, defined by at least one of the following: 
– 
Respiratory failure defined based on resource utilization requiring at least one of 
the following: 

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 
Endotracheal intubation and mechanical ventilation, oxygen delivered by 
high-flow nasal cannula (heated, humidified, oxygen delivered via 
reinforced nasal cannula at flow rates >20 L/min with fraction of delivered 
oxygen ≥0.5), noninvasive positive pressure ventilation, ECMO, or clinical 
diagnosis of respiratory failure (ie, clinical need for one of the preceding 
therapies, but preceding therapies not able to be administered in setting 
of resource limitation) 
– 
Shock (defined by SBP < 90 mm Hg, or Diastolic BP < 60 mm Hg or requiring 
vasopressors) 
– Multi-organ dysfunction/failure