Clinical trial NCT04405570
Conditions: SARS-CoV-2 Infection, COVID-19
Sponsor: Ridgeback Biotherapeutics, LP
Start date: 2020-06-19; Completion date: 2021-02-21
Enrollment: 204 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This was a phase IIa, double-blind, placebo-controlled, randomized trial, designed to compare the safety, tolerability, and antiviral activity of EIDD-2801 (molnupiravir) versus placebo as measured by SARS-CoV-2 viral RNA detection in symptomatic adult outpatients with COVID-19.

Detailed description:
This was a phase IIa, double-blind, placebo-controlled, randomized trial, designed to compare the safety, tolerability, and antiviral activity of molnupiravir versus placebo as measured by SARS-CoV-2 viral RNA detection in symptomatic adult outpatients with COVID-19. The study was a multicenter trial that was conducted in the United States.

In this study, 204 participants were randomized and 202 received molnupiravir or placebo orally twice a day (BID) for 5 days. The study enrolled participants in 5 parts with each part evaluating molnupiravir doses of either 200 mg BID, 400 mg BID, or 800 mg BID. Doses were chosen based on emerging virology and safety data from this and ongoing studies. New dose groups were started after the selected dose had been studied for safety in a Phase 1 study.

Arms: arm 1: Molnupiravir 200 mg, twice daily (BID) for 5 days arm 2: Molnupiravir 400 mg, twice daily (BID) for 5 days arm 3: Molnupiravir 800 mg, twice daily (BID) for 5 days arm 4: None
Interventions: intervention 1: Molnupiravir 200 mg intervention 2: Molnupiravir 400 mg intervention 3: Molnupiravir 800 mg intervention 4: Placebo (PBO)
Intervention descriptions: intervention 1: Oral capsule of molnupiravir intervention 2: Oral capsule of molnupiravir intervention 3: Oral capsule of molnupiravir intervention 4: placebo oral capsule

Protocol documents:
Prot_003.pdf: 
1
CLINICAL TRIAL PROTOCOL 
A Phase IIa, Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate the Safety, 
Tolerability, and Efficacy of EIDD-2801 to Eliminate SARS-CoV-2 Viral RNA Detection in 
Persons with COVID-19 
Protocol No:  EIDD-2801-2003 
Protocol Version – 5.0 
Date: 15 November 2020 
Sponsor: 
Ridgeback Biotherapeutics, LP 
3162 Commodore Plaza 
Miami, FL 
Sponsor’s e-mail address: 
 
Principal Investigator:  
 
Medical Monitor:  
 
Medical Director, CPS 
Phone: 
 
e-mail:  
 
Confidential Information:  The information contained in this document is the property of 
Ridgeback Biotherapeutics LP and may not be reproduced, published, or disclosed to others 
without written authorization from Ridgeback Biotherapeutics LP. 


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TABLE OF CONTENTS 
CLINICAL TRIAL PROTOCOL ................................................................................................1 
TABLE OF CONTENTS .................................................................................................................2 
SPONSOR APPROVAL .................................................................................................................6 
SIGNATURE PAGE .......................................................................................................................7 
SITES PARTICIPATING IN THIS STUDY ..................................................................................8 
PROTOCOL TEAM ROSTER ........................................................................................................9 
GLOSSARY OF PROTOCOL-SPECIFIC TERMS .....................................................................11 
SCHEMA  ....................................................................................................................................14 
1. 
HYPOTHESIS AND STUDY OBJECTIVES ...........................................................16 
1.1. 
Hypotheses ..................................................................................................................16 
1.2. 
Primary Objectives .....................................................................................................16 
1.3. 
Secondary Objectives .................................................................................................16 
1.4. 
Exploratory Objectives ...............................................................................................17 
2. 
INTRODUCTION ......................................................................................................18 
2.1. 
Background .................................................................................................................18 
2.2. 
Rationale .....................................................................................................................21 
2.3. 
Preclinical Data ...........................................................................................................21 
2.4. 
Evidence in Humans ...................................................................................................24 
2.5. 
Potential Risks and Benefits .......................................................................................24 
2.6. 
Justification for Dose ..................................................................................................26 
2.7. 
Justification for the Control Arm ................................................................................27 
2.8. 
Justification for Placebo-Controlled Design ...............................................................27 
2.9. 
Justification for Age Restriction .................................................................................27 
2.10. 
Justification for Including Women of Childbearing Potential ....................................28 
2.11. 
Justification for Not Performing Urinalysis ...............................................................28 
3. 
STUDY DESIGN .......................................................................................................29 
3.1. 
Recruitment .................................................................................................................30 
3.2. 
Study Visits .................................................................................................................30 
3.3. 
Isolation Procedures ....................................................................................................31 


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4. 
SELECTION AND ENROLLMENT OF PARTICIPANTS .....................................32 
4.1. 
Inclusion Criteria ........................................................................................................32 
4.2. 
Exclusion Criteria .......................................................................................................34 
4.3. 
Study Enrollment Procedures .....................................................................................35 
4.4. 
Co-enrollment Guidelines ...........................................................................................35 
5. 
STUDY TREATMENT ..............................................................................................36 
5.1. 
Regimens, Administration, and Duration ...................................................................36 
5.2. 
Study Product Formulation and Preparation ...............................................................37 
5.3. 
Pharmacy: Product Supply, Distribution, and Accountability ....................................37 
5.4. 
Concomitant Medications ...........................................................................................37 
6. 
SCHEDULE OF EVENTS .........................................................................................38 
6.1. 
Timing of Evaluations ................................................................................................40 
6.2. 
Instructions for Evaluations ........................................................................................41 
7. 
ADVERSE EVENTS AND STUDY MONITORING ...............................................49 
7.1. 
Definition of Adverse Events .....................................................................................49 
7.2. 
Adverse Event Collection Requirements for This Protocol .......................................49 
7.3. 
Reporting Requirements for this Study ......................................................................50 
7.4. 
Study Monitoring ........................................................................................................52 
8. 
CLINICAL MANAGEMENT ISSUES .....................................................................53 
8.1. 
Toxicity .......................................................................................................................53 
8.2. 
Management of Side Effects of EIDD-2801 ..............................................................53 
8.3. 
Grade 1 or 2 ................................................................................................................53 
8.4. 
Grade 3 ........................................................................................................................53 
8.5. 
Grade 4 ........................................................................................................................54 
8.6. 
Pregnancy ...................................................................................................................54 
8.7. 
Breastfeeding ..............................................................................................................54 
9. 
CRITERIA FOR DISCONTINUATION ...................................................................55 
9.1. 
Permanent and Premature Treatment Discontinuation ...............................................55 
9.2. 
Premature Study Discontinuation ...............................................................................55 
10. 
STATISTICAL CONSIDERATIONS .......................................................................56 
10.1. 
General Design Issues .................................................................................................56 
10.2. 
Outcome Measures .....................................................................................................56 
10.3. 
Objectives and Endpoints ...........................................................................................56 


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10.4. 
Randomization and Stratification ...............................................................................58 
10.5. 
Sample Size and Accrual ............................................................................................59 
10.6. 
Populations for Analyses ............................................................................................61 
10.7. 
Statistical Analyses .....................................................................................................61 
10.8. 
Pooled Analyses ..........................................................................................................65 
10.9. 
Interim Analysis ..........................................................................................................66 
10.10. 
Unblinding ..................................................................................................................67 
11. 
DATA COLLECTION AND MONITORING ...........................................................68 
11.1. 
Reporting Protocol Deviations ...................................................................................68 
11.2. 
Records to Be Kept .....................................................................................................68 
11.3. 
Role of Data Management ..........................................................................................68 
11.4. 
Clinical Site Monitoring and Record Availability ......................................................68 
12. 
PARTICIPANTS ........................................................................................................70 
12.1. 
Institutional Review Board (IRB) Review and Informed Consent .............................70 
12.2. 
Participant Confidentiality ..........................................................................................70 
12.3. 
Study Discontinuation ................................................................................................70 
13. 
PUBLICATION OF RESEARCH FINDINGS ..........................................................71 
14. 
BIOHAZARD CONTAINMENT ..............................................................................72 
15. 
REFERENCES ...........................................................................................................73 
16. 
APPENDICES ............................................................................................................75 
16.1. 
Appendix 1: Health Organization Ordinal Scale for Clinical Improvement of 
COVID-19 Disease .....................................................................................................75 
16.2. 
Appendix 2:  Contraceptive Guidance ........................................................................76 
 
 
 


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LIST OF FIGURES 
Figure 1: SARS-CoV-2 viral load in throat and nasal swabs 1 ......................................................18 
Figure 2: Prolonged viral RNA detection in patients with critical illness .....................................18 
Figure 3: Prolonged viral RNA detection in saliva and endotracheal aspirates 3. .........................20 
Figure 4: Virus isolation from throat and nasopharyngeal swabs5 ................................................21 
Figure 5: Antiviral activity and cytotoxicity of EIDD-2801 in Vero E6 cells infected 
with SARS-CoV-2 .................................................................................................22 
Figure 6: Reduction in infectious SARS-CoV-2 production in primary human airway 
epithelial cells. .......................................................................................................23 
 
 
Figure 8.  Probability of SARS-CoV-2 viral RNA detection assumed in 
power/sample size determination ...........................................................................60 
Figure 9: .... Probability of detectable SARS-CoV-2 assumed in power/sample size 
determination .........................................................................................................64 
 
 


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Protocol EIDD-2801-2003
A Phase IIa, Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate the Safety, 
Tolerability, and Efficacy of EIDD-2801 to Eliminate SARS-CoV-2 Viral RNA Detection in 
Persons with COVID-19
SPONSOR APPROVAL
I have read the protocol and approve it:
Date
 Biotherapeutics LP
Date
 LP




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Protocol EIDD-2801-2003
A Phase IIa, Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate the Safety, 
Tolerability, and Efficacy of EIDD-2801 to Eliminate SARS-CoV-2 Viral RNA Detection in 
Persons with COVID-19
SIGNATURE PAGE
I will conduct the study in accordance with the provisions of this protocol and all applicable 
protocol-related documents. I agree to conduct this study in compliance with United States (US) 
Health and Human Service regulations (45 CFR part 46); applicable US Food and Drug 
Administration regulations; standards of the International Council on Harmonisation Guideline for 
Good Clinical Practice (E6); Institutional Review Board/Ethics Committee determinations; all 
applicable in-country, state, and local laws and regulations; and other applicable requirements 
(e.g., US National Institutes of Health, Division of AIDS) and institutional policies.
Principal Investigator: _______________________________________________
Print/Type
Signed:
_____ Date: _____________



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SITES PARTICIPATING IN THIS STUDY 
EIDD-2801-2003 is a multicenter study that will be initially limited to and conducted at the 
University of North Carolina Clinical Trials Unit (CTU).  Up to 15 additional sites, including 
Wake Forest University CTU, may be added based on the local incidence of COVID-19.   
 
 


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PROTOCOL TEAM ROSTER 
Principal Investigator, University of North Carolina at Chapel Hill 
(Other Study Sites Will Each Have Their Own Principal Investigator) 
 
Division of Pulmonary and Critical Care Medicine 
 
University of North Carolina School of Medicine 
CB#7020 
130 Mason Farm Road 
Chapel Hill, NC 27599 
Email: 
 
Co-Investigators: 
 
Chapel Hill CRS 
Suite 2100, Bioinformatics Building 
130 Mason Farm Road 
Chapel Hill, NC 27514 
Phone: 
 
Fax: 
 
E-mail: 
 
 
Chapel Hill CRS 
Suite 2100, Bioinformatics Building 
130 Mason Farm Road 
Chapel Hill, NC 27514 
Phone: 
 
Fax: 
 
E-mail: 
 
 
Chapel Hill CRS 
Suite 2100, Bioinformatics Building 
130 Mason Farm Road 
Chapel Hill, NC 27514 
Phone: 
 
Fax: 
 
 
 
Gillings School of Global Public Health 
3304 Michael Hooker Research Building 
CB#7435 
Chapel Hill, NC 27599 
 
 
Wake Forest University 
 
 
 
Medical Center Boulevard  \  Winston-Salem, 
NC 27157-1042 
 
   \  WakeHealth.edu 
 
Gillings School of Global Public Health 
3304 Michael Hooker Research Building 
CB#7435 
Chapel Hill, NC 27599 
 


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Statisticians 
 
 
University of North Carolina School of 
Medicine 
Chapel Hill, NC USA 27599 
 
 
 
Gillings School of Global Public Health 
Chapel Hill, NC USA 27599 
 
 
 
Gillings School of Global Public Health 
Chapel Hill, NC USA 27599 
Email:  
u 
 
 
Laboratory Specialist 
 
 
University of North Carolina Global HIV  
Prevention and Treatment CTU 
Bioinformatics Building 
130 Mason Farm Road, Suite 2144  
Chapel Hill, NC 27599-7215 
Phone: 
 
E-mail: 
 
 
 
 
 
Safety Monitoring Committee: 
 
 
Ridgeback Representative 
 
UNC Clinical and Research Laboratories 
 
 
 
 
 
 
 
 
 


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GLOSSARY OF PROTOCOL-SPECIFIC TERMS 
AE  
 
Adverse Event  
AIDS  
Acquired Immune Deficiency Syndrome 
ALT 
 
Alanine Aminotransferase 
ARDS  
Acute Respiratory Distress Syndrome 
AST 
 
Aspartate Aminotransferase 
BID 
 
Twice Daily 
BMI 
 
Body Mass Index 
CFR   
Code of Federal Regulations  
CI  
 
Confidence interval  
CLIA   
Clinical Laboratory Improvement Amendments  
COVID-19 
Coronavirus Disease 2019 
CQMP  
Clinical Quality Management Plan  
CRS 
 
Cytokine Release Syndrome 
DAIDS 
Division of AIDS 
DMT  
Data Management Team 
DSS 
 
Drug Safety Services (Covance) 
EC 
 
Ethics Committee  
eCRF  
Electronic Case Report Form  
EUA  
Emergency Use Authorization 
FDA  
Food and Drug Administration  
FSH 
 
Follicle Stimulating Hormone 
GCP 
 
Good Clinical Practice 
HAE  
Human airway epithelial cell culture  
HIV 
 
Human Immunodeficiency Virus 
HTN  
Hypertension 
HRT  
Hormone Replacement Therapy 
IB  
 
Investigator Brochure  
ICU 
 
Intensive Care Unit 
ICF  
 
Informed Consent Form  
ID 
 
Identification 


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IL 
 
Interleukin 
IND   
Investigational New Drug Application  
IRB  
 
Institutional Review Board  
IUD 
 
Intrauterine device 
IUS 
 
Intrauterine hormone releasing system 
IV  
 
Intravenous  
MOPS  
Manual of Procedures 
MERS-CoV 
Middle East Respiratory Syndrome coronavirus 
m-ITT  
Modified Intention-To-Treat 
NIH   
National Institutes of Health  
NP 
 
Nasopharyngeal 
NPI 
 
Nonpharmacologic Intervention 
OHRP  
Office for Human Research Protections  
OP 
 
Oropharyngeal 
PD 
 
Pharmacodynamic 
PHI  
 
Protected Health Information  
PI  
 
Principal Investigator  
PK 
 
Pharmacokinetic 
 
 
 
PSS 
 
Patient Safety Solutions (Covance) 
  
 
RT-PCR 
Reverse Transcription Polymerase Chain Reaction 
SAE   
Serious Adverse Event  
SAP   
Statistical Analysis Plan  
SARS-CoV 
Severe Acute Respiratory Syndrome coronavirus 
SARS-CoV-2  Severe Acute Respiratory Syndrome coronavirus 2  
SMC   
Safety Monitoring Committee  
SOE 
 
Schedule of Evaluations 
SOP   
Standard Operating Procedure  
SUSAR  
Suspected Unexpected Serious Adverse Reaction  
ULN  
Upper Limit of Normal 


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UNC  
University of North Carolina 
WHO  
World Health Organization 
 


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SCHEMA 
 
 
EIDD-2801-2003 
 
A Phase IIa, Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate the Safety, 
Tolerability, and Efficacy of EIDD-2801 to Eliminate SARS-CoV-2 Viral RNA Detection in 
Persons with COVID-19 
 
 
DESIGN  
This is a Phase IIa, double-blind, placebo-controlled, randomized trial 
designed to compare the safety, tolerability, and antiviral activity of EIDD-
2801 (also known as MK-4482) versus placebo as measured by viral RNA 
detection in symptomatic adult outpatients with coronavirus disease-2019 
(COVID-19). 
 
 
DURATION  
28 days. Treatment will be for 5 days with 23 days of post-treatment follow-
up.  
 
 
SAMPLE SIZE  
This study will enroll up to approximately 172 fully evaluable participants  
in multiple study parts. If participants in a dose group drop out or otherwise 
have missing or unevaluable primary or key secondary virology endpoint 
data, additional participants may be enrolled to ensure adequate data at each 
dose level. The total number of participants to be enrolled will not exceed 
204. 
Part 1:   
• Arm A (EIDD-2801 200 mg): up to approximately 22 participants 
• Arm B (placebo): up to approximately 22 participants 
Parts 2-4 (Optional): 
• Arms C (Part 2), E (Part 3), G (Part 4) (EIDD-2801 up to 800 mg): 
up to approximately 12 participants per part 
• Arms D (Part 2), F (Part 3), H (Part 4) (placebo): up to 
approximately 4 participants per part 
Parts 5-9 (Optional):  
• Arms I, K, M, O, Q (EIDD-2801 up to 800 mg): up to approximately 
12 participants per part 
• Arms J, L, N, P, R (placebo): up to approximately 4 participants per 
part 
 
The dose of EIDD-2801 evaluated in Part 1 will be 200 mg BID.  Doses 
selected for subsequent study parts  may be the same, higher or lower than 
doses studied in previous Part(s), and will not exceed 800 mg BID. Doses 


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will be chosen based on emerging virology and safety data from this study 
and other ongoing clinical studies. Selected doses will be communicated in 
an official memo/protocol clarification letter. The maximum number of 
participants enrolled will be 204. Participants who are randomized but do 
not start study treatment will be replaced. All study part sizes are 
approximate. Study parts may be combined for randomization purposes if 
the same dose is planned for more than one part. Study parts enrolling at the 
same dose level may be enrolled simultaneously. 
 
Sample Treatment Assignment Table (Fully Evaluable Participants) 
(doses and order of progression subject to change) 
Study Part 
 
Treatment Arm 
(n) 
Placebo Arm 
(n) 
Total Subjects 
Projected Dose 
Level 
1 
A (22) 
B (22) 
44 
200 mg 
2 
C (12) 
D (4) 
16 
400 mg 
3 
E (12) 
F (4) 
16 
400 mg 
4 
G (12) 
H (4) 
16 
400 mg 
5 
I (12) 
J (4) 
16 
TBD or 800 mg 
6 
K (12) 
L (4) 
16 
TBD or 800 mg 
7 
M (12) 
N (4) 
16 
TBD or 800 mg 
8 
O (12) 
P (4) 
16 
TBD or 200 mg 
9 
Q (12) 
R (4) 
16 
TBD or 400 mg 
Total: 
118 
54 
172 
 
 
POPULATION  
Symptomatic, outpatient (at baseline), adults (aged ≥18 years) with severe 
acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection within 
7 days of symptom onset. 
 
REGIMEN  
In Part 1 of the study, participants will be randomized 1:1 
into Arms A and B to receive active/placebo study treatment as follows: 
EIDD-2801 200 mg or placebo orally BID for 5 days. Enrollment for Arms 
A and B may be considered full when at least 24 and up to approximately 
44 participants are enrolled.  Enrollment in Part 1 may be interrupted to 
initiate enrollment in a different study Part, and may resume at a later time 
point. In subsequent optional study parts, participants will be randomized 
3:1 to receive treatment as follows: EIDD-2801 up to 800 mg or placebo 
orally BID for 5 days. 
 


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1. 
HYPOTHESIS AND STUDY OBJECTIVES 
1.1. 
Hypotheses 
1.1.1. 
EIDD-2801 treatment will decrease the time to clearance of SARS-CoV-2 virus in 
NP specimens from symptomatic SARS-CoV-2 infected adults compared to 
placebo. 
1.1.2. 
EIDD-2801 will be safe and well tolerated in persons with symptomatic SARS-
CoV-2 infection. 
1.2. 
Primary Objectives 
1.2.1. 
Primary Efficacy Objective To determine if EIDD-2801 reduces the time to viral 
RNA negativity. Viral RNA negativity will be determined by reverse-transcriptase 
polymerase chain reaction (RT-PCR) of NP \swabs. 
1.2.2. 
Primary Safety Objective To determine the safety and tolerability of EIDD-2801 
including 1) any adverse events (AEs) leading to early discontinuation of 
treatment, 2) study drug-related discontinuation of treatment, 3) new grade 3 or 
higher AEs (not already present at baseline), and 4) study drug-related new grade 
3 or higher AEs. 
1.3. 
Secondary Objectives 
1.3.1. 
To determine if EIDD-2801 reduces the time (days) to negativity of infectious 
virus isolation in NP swabs from SARS-CoV-2-infected adults. Infectious virus 
isolation is determined by isolation in Vero cell line culture.  
1.3.2. 
To compare the incidence of grade 2 or higher AEs and drug-related AEs between 
treatment arms.  
1.3.3. 
To determine if EIDD-2801 reduces the shedding of SARS-CoV-2 RNA in NP 
swabs compared to placebo as measured by median change in RNA at Treatment 
Days 3, 5, 7, 14, and 28 as determined by quantitative RT-PCR.   
1.3.4. 
To determine if EIDD-2801 increases viral RNA mutation rate.  RNA mutation 
rate is measured by Next Generation sequencing. 
1.3.5. 
To determine if EIDD-2801 changes the severity and duration of self-reported 
symptoms of COVID-19. 
1.3.6. 
To determine if EIDD-2801 treatment reduces the proportion of participants who 
are hospitalized for COVID-19 related illness by Day 28.  
1.3.7. 
To characterize the PK of EIDD-2801/EIDD-1931 in patients with COVID-19 
following administration of study regimen. 


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1.3.8. 
To determine the relationship between drug exposure and viral elimination 
dynamics including time to clearance. 
 
1.4. 
Exploratory Objectives 
1.4.1. 
To determine if EIDD-2801 will prevent the composite endpoint of 
hospitalization, oxygen desaturation, oxygen requirement, mechanical ventilation, 
or death by 28 days after study entry. Hospitalization is defined as ≥24 hours of 
acute care. Oxygen desaturation will be measured using pulse oximetry. Oxygen 
requirement will be measured using the World Health Organization (WHO) 
ordinal scale (see Appendix 1) 
1.4.2. 
To determine the comparability between site-collected NP and available OP swabs 
and available self-collected nasal mid-turbinate swabs for the quantification of 
SARS-CoV-2 RNA or quantitative culture  
1.4.3. 
To determine comparability between viral RNA detection and virus isolation from 
site-collected NP swabs. 
 
 


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2. 
INTRODUCTION 
2.1. 
Background 
2.1.1. 
Public Health Emergency of International Concern 
On December 31, 2019, China reported a cluster of cases of severe pneumonia of unknown 
etiology in the city of Wuhan to the WHO.  The China Centers for Disease Control and Prevention 
(China CDC) rapidly identified a novel betacoronavirus, SARS-CoV-2, as the etiologic agent with 
approximately 70% genetic homology with Severe Acute Respiratory Syndrome Coronavirus 
(SARS-CoV) and 50% homology with Middle Eastern Respiratory Syndrome Coronavirus 
(MERS-CoV). In the ensuing 4 months, this virus has infected more than 5 million individuals 
globally with over 345,000 deaths as of the date of this protocol, leading the WHO to declare the 
COVID-19 outbreak a Public Health Emergency of International Concern6. 
In the absence of currently approved therapies for SARS-CoV-2 infection and given the rapid 
spread of this virus with a marked increase in mortality, the identification of an effective 
therapeutic represents an urgent public health need. As a result, global efforts to identify 
therapeutic interventions with antiviral or immunomodulatory activity have intensified.   
 
 
  
 
 
After an incubation period of between 2 and 14 days from exposure, approximately 81% of patients 
develop uncomplicated illness characterized by variable appearance of non-specific symptoms 
including fever, non-productive cough, dyspnea and myalgias 1,7-12. Approximately, 14% of 
symptomatic patients develop severe illness often defined by a respiratory rate >30 breaths per minute, 
oxygen saturation <93%, a partial pressure of arterial oxygen:percentage of inspired oxygen 
Figure 1: SARS-CoV-2 viral load in throat and 
nasal swabs 1 
Figure 2: Prolonged viral RNA detection in patients 
with critical illness 


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(PaO2:FiO2) ratio <300, or greater than 50% lung involvement on chest imaging 7. An additional 5% 
of patients become critically ill with respiratory failure, shock and multi-organ dysfunction 7. Although 
asymptomatic infection has been described, the relative proportion of patients who never develop 
symptoms is not known13,14. 
Risk factors for severe disease include older age, male sex, and metabolic syndrome comorbidities 
including hypertension, diabetes mellitus, and obesity.  Markers of a systemic inflammatory 
response have been reported in association with disease progression and death including D-Dimer, 
lactate dehydrogenase (LDH) and C-reactive protein (CRP) 2,8-11,15,16.  Additionally, cytokine 
levels including interleukin (IL)1β, IL1RA, IL7, IL8, IL9, granulocyte-colony stimulating factor 
(GCSF), granulocyte-macrophage colony-stimulating factor (GMCSF), interferon gamma (IFNγ), 
inducible protein-10 (IP-10), monocyte chemoattractant protein-1 (MCP1), macrophage 
inflammatory protein 1 alpha (MIP1α), macrophage inflammatory protein 1 beta (MIP1β), tumor 
necrosis factor alpha (TNFα), platelet-derived growth factor (PDGF) and vascular endothelial 
growth factor (VEGF) levels were increased among patients admitted to the intensive care unit 
(ICU) compared with non-ICU patients and healthy adults 9. Though low overall relative to acute 
respiratory distress syndrome (ARDS) and bacterial sepsis, IL-6 is also increased among non-
survivors of COVID-19 15. 
Despite limited data on viral replication dynamics, there is evidence of virus replication in both 
the upper and lower respiratory tract.  Most studies suggest that viral loads are highest in the first 
week of illness (Figure 1) with long-term viral RNA persistence potentially associated with 
severity of illness (Figure 2) 1,3,5,16,17.  The median time to viral RNA clearance is approximately 
11 days for mild disease and 21 days in patients with severe or critical illness (Figure 2) 2,17. 
Increased viral loads in addition to prolonged virus replication in patients with severe illness 
suggest that viral loads maybe a useful surrogate for assessing severity in COVID-19.  
Viral RNA detection is also dependent upon sample type, with evidence of prolonged viral RNA 
detection in lower respiratory tract samples including saliva and sputum compared with 
nasopharyngeal swab samples (Figure 1 and Figure 3) 1-3,5,16,17. Daily sampling of the upper and 
lower respiratory tract reveal that, in general, viral RNA in OP swabs are elevated in initial samples 
and already on the decline at the time of presentation whereas sputum samples peak during the 
first week of symptoms and decline more slowly 5. 
 


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Datapoints denote the mean; error bars indicate SD; slope represents best fit line. The number of patients who provided 
a sample on each day is shown in the table below the plot. D=days after symptom onset. S=saliva. E=endotracheal 
aspirate 
Less is known about shedding of infectious virus. While infectious virus was readily isolated from 
clinical samples in a single study, it was again dependent on sample type, viral load, and timing. 
In the only study to date to evaluate infectious virus kinetics, infectious virus was successfully 
isolated from 17% of OP swabs and from 83% of sputum samples but only from samples collected 
within the first week from symptom onset and only in those that contained >106 viral RNA 
copies/mL (Figure 4). No infectious virus was isolated beyond Day 8 from symptom onset despite 
elevated viral loads 5.  
The persistence of infectious virus in the upper respiratory tract has important implications for 
both transmission and infection prevention and control strategies.  SARS-CoV-2 is thought to be 
transmitted primarily through droplet and contact routes during close unprotected contact between 
an infected and susceptible individual 18.  Although viral RNA has been detected in air samples  
within airborne isolation rooms, airborne transmission is not believed to be a major driver of 
transmission based on current evidence 19. Recent reports indicate that human-to-human 
transmission in China is largely driven by familial transmission with secondary attack rates of 
3-11%14,18,20.  Among 344 clusters including 1308 of 1836 reported cases in Guangdong, 
approximately 78-85% occurred within families 18. Identification of interventions to interrupt 
household and community transmission could have a profound impact on the pandemic at large as 
well as slow the surge of patients requiring hospitalization and critical care. 
Figure 3: Prolonged viral RNA detection in saliva and endotracheal 
aspirates 3. 


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2.2. 
Rationale 
Antiviral therapeutic interventions that reduce infectious virus production could play a key role in 
decreasing community transmission, decreasing surge on healthcare facilities, and potentially 
reduce clinical complications of infection. This “treatment as prevention” approach has the 
potential to reduce the burden of COVID-19 illness and mitigate ongoing transmission.  Given the 
current therapeutic landscape and limitations, there is an urgent need for an orally available direct 
acting antiviral. 
 
 
 EIDD-2801 is the 5’-isobutyrate prodrug of the broadly active, direct acting antiviral 
ribonucleoside analogue EIDD-1931, which inhibits replication of multiple viral pathogens from 
multiple RNA families. Further clinical information is needed to determine safety, tolerability, and 
antiviral activity in humans.   
2.3. 
Preclinical Data 
2.3.1. 
Mechanism of Action 
The primary mechanism of action of EIDD-2801 is inhibition of viral RNA replication by 
incorporation of the EIDD-1931-5’-monophosphate metabolite into the viral RNA genome 
resulting in induction of viral error catastrophe.  Upon incorporation into nascent chain RNA, 
EIDD-1931-5’-monophosphate induces increased mutational frequency in the viral genome 
resulting in the production of non-viable virus. Following oral delivery, EIDD-2801 is rapidly 
hydrolyzed by circulating esterases to produce high circulating plasma levels of EIDD-1931 which 
is in turn phosphorylated into a tri-phosphate (EIDD-2601) that can pair with either guanosine or 
adenosine and can substitute for either CTP or UTP, respectively,  resulting in an accumulation of 
Figure 4: Virus isolation from throat and nasopharyngeal swabs5 


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mutations that increase with each cycle of viral replication 21. Additionally, the active metabolite, 
EIDD-1931-5’-triphosphate, may act as a chain terminator and arrest viral replication via a next 
nucleoside effect.  Given this dual mechanism of action, it is anticipated that there will be a high 
barrier to the development of resistance. 
 
 
2.3.2. 
In Vitro Evidence 
Antiviral activity of EIDD-2801 against coronaviruses including MERS-CoV, SARS-CoV, 
SARS-CoV-2, and related zoonotic group 2b or 2c Bat-CoVs has been demonstrated in a number 
of different tissue culture cell lines including primary human airway epithelial cell cultures4.  Using 
a clinical isolate of SARS-CoV-2, EIDD-1931 exhibited an average half-maximum inhibitory 
concentration (IC50) of 0.3µM and a 50% cytotoxic concentration (CC50) of >10 µM (Figure 5) 4. 
A dose-dependent reduction in infectious virus titers was observed during treatment in a human 
lung epithelial cell line, Calu-3 cells infected with SARS-CoV-2 with an IC50 of 0.09 µM. A dose-
dependent reduction in SARS-CoV-2 infectious virus production was also found for EIDD-1931 
in primary HAE cell cultures without appreciable alteration of host gene expression at doses up to 
100 µM (Figure 6)4. Similar results were found for MERS-CoV- and SARS-CoV-infected cell 
lines and primary HAEs 4.   
Figure 5: Antiviral activity and cytotoxicity of EIDD-2801 in 
Vero E6 cells infected with SARS-CoV-2 


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Figure 6: Reduction in infectious SARS-
CoV-2 production in primary 
human airway epithelial cells. 


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2.4. 
Evidence in Humans 
EIDD-2801 has not been used prophylactically or therapeutically in patients with COVID-19; 
however, EIDD-2801 has been studied in a single and multiple ascending dose study in healthy 
volunteers (Study EIDD-2801-1001). Preliminary data from this study showed that doses of 
200 mg produce plasma levels of EIDD-1931 that are predicted to show antiviral activity in 
humans. A brief summary of safety information from Study EIDD-2801-1001 is provided in 
Section 2.6. 
2.5. 
Potential Risks and Benefits 
There remains unmet medical need for the treatment of COVID-19, particularly in outpatients 
where intravenous administration of antiviral therapy is difficult. Participants in this study will be 
monitored throughout the 5-day treatment course and follow-up period with surveillance for and 
reporting of all AEs.   
2.5.1. 
Risks Associated with EIDD-2801 
Novel therapies can lead to unexpected, incidental findings that could have a potential effect on 
the participant’s health.   
Enrollment in a Phase I study of EIDD-2801 (Study EIDD-2801-1001) in 130 healthy volunteers 
has completed. No serious AEs were reported and no trends of increased frequency or severity of 
AEs with higher doses of EIDD-2801 were observed. No clinically significant findings or dose-
related trends were observed in clinical laboratory, vital signs, or electrocardiogram (ECG) data. 
 
 
 Further details for EIDD-2801-1001 are provided in Section 2.6. 


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Ongoing surveillance for AEs will be conducted throughout the present study and other ongoing 
studies, and in the event of confirmation of a potential health effect, the study team will notify 
participants and will advise appropriate medical follow up when indicated.  
EIDD-2801 and EIDD-1931 were shown to be mutagenic (Ames positive) in a bacterial 
mutagenesis assay with and without metabolic activation.
 
 
Given the anticipated short-duration of treatment for COVID-19 (eg, 
5 days), EIDD-2801 is considered to have a benefit/risk profile that supports further clinical 
development. 
2.5.2. 
Risks of Nasopharyngeal Sampling 
This procedure will be nurse-administered on Days 1, 3, 5, 7, 14, and 28. Temporary discomfort 
is associated with this routine medical diagnostic procedure with no reported risk. 
2.5.3. 
Risks of Self-Nasal Mid-Turbinate Swab Sampling 
For participants enrolled at applicable sites only, this optional procedure may be self-administered 
on Days 1, 3, 5, 7, 14, and 28.  No reported risks are associated with this procedure. 
2.5.4. 
Risks of Oropharyngeal Sampling 
For participants enrolled at applicable sites only, this optional procedure may be nurse-
administered on Days 1, 3, 5, 7, 14, and 28.  Temporary discomfort is associated with this routine 
medical diagnostic procedure with no reported risk. 
2.5.5. 
Risk of Blood Collection 
Blood collection may cause pain, bruising, and occasionally a feeling of lightheadedness or 
fainting.  Rarely, it may be associated with an infection at the site of blood drawing. 
2.5.6. 
Risks of Pregnancy and Use in Nursing Women 
Treatment with EIDD-2801 is contraindicated in women who are pregnant or nursing and in the 
male partners of women who are pregnant. Extreme care must be taken to avoid pregnancy during 
the study and for 50 days after completion of EIDD-2801 dosing in female participants and for 
100 days after completion of EIDD-2801 dosing in female partners of male participants.
 
 
2.5.7. 
Risk of Exposure to COVID-19 
There is the potential risk for increased transmission of SARS-CoV-2 to study team members. 
Precautions will be taken to prevent this. Home visits will be carried out by highly trained study 
nurses equipped with proper personal protective equipment (gown, gloves, N95 respirator, face 
shield). Wherever possible, single use testing supplies will be used, and other testing equipment 
will be wiped down with hospital-approved disinfectant between each use. The nurse will perform 
study procedures with each participant on an individual basis in a separate room. Study participants 
will be encouraged to use their own devices to complete online questionnaires and symptom 


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diaries, or through interview with the study nurse, so that tablets are not passed between 
individuals. Specimens will be stored in individual biohazard bags following the same protocols 
used in the clinical care setting. 
2.5.8. 
Risks of Breach of Confidentiality  
Data gathered on study participants will include their age, sex, medical history, concomitant 
medications, and symptom status. The study team will also collect home address and contact 
information in order to carry out study procedures, but this information will not be used as study 
data (it will not be entered into the study database). In the early phase of the epidemic, a COVID-19 
diagnosis may carry significant stigma. The study nurse will use discretion when carrying out 
home visits, calling ahead and arranging appointment times and using an unmarked vehicle. 
2.5.9. 
Potential Benefits 
The study will have generalizable benefits by improving our understanding of whether EIDD-2801 
has antiviral effects against SARS-CoV-2 that could make it useful for treatment and/or prevention 
of COVID-19.  
In the absence of an approved therapeutic to reduce progression of illness in COVID-19 and 
transmission of SARS-CoV-2, new antiviral therapeutics represent an urgent public health need. 
 
 
  
2.6. 
Justification for Dose 
In a recent Phase I safety study (Study EIDD-2801-1001) a total of 130 healthy volunteers were 
enrolled. Sixty-four participants received a single dose of between 50 and 1600 mg EIDD-2801 or 
placebo; 56 participants received multiple dose of between 50 and 800 mg EIDD-2801 or placebo 
BID for 5.5 days; and 10 participants received a single dose of 200 mg EIDD-2801 in the fed state 
followed by a single dose of 200 mg EIDD-2801 in the fasted state after a washout period of 14 
days, or vice versa.  
Among participants who received single doses of EIDD-1801 or placebo, a greater proportion of 
participants reported AEs following administration of placebo (43.8%) than following 
administration of EIDD-2801 (35.4%). One moderate AE (headache) was reported by 1 participant 
following administration of EIDD-2801 at the 400-mg dose level, and 2 moderate AEs (nausea 
and headache) were reported by 1 participant following administration of placebo. No severe AEs 
were reported. The most frequently reported AE was headache, which was reported by 18.8% of 
participants who were administered placebo and 12.5% of participants who were administered 
EIDD-2801.  
Among participants who received multiple ascending doses of EIDD-2801 or placebo BID over 
5.5 days, a greater proportion reported AEs following administration of placebo (50.0%) than 
following administration of EIDD-2801 (42.9%). With the exception of 1 participant in the 200-mg 
BID group who reported moderate AEs of sore throat, aching limbs, and flu-like symptoms, all 
other AEs were mild in severity. The most frequently reported AE was diarrhea, which was 
reported by 7.1% of participants who were administered EIDD-2801 and 7.1% of participants who 


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were administered placebo. One participant had an AE of mild, truncal, maculopapular, pruritic 
rash following multiple doses of 800-mg EIDD-2801, which was considered by the investigator to 
be related to the study drug; this AE resulted in early discontinuation of the study drug dosing on 
Day 3. The participant was administered a topical steroid and anti-histamines, and the AE resolved 
after 18 days.  
Among participants in the food-effect evaluation, 3 participants reported 1 AE each, all of which 
were mild in severity.   
There were no serious AEs reported in this study and there were no trends of increased frequency 
or severity of AEs with higher doses of EIDD-2801.  
There were no clinically significant findings in clinical laboratory, vital signs, or ECG data.  
 
no 
clinically significant changes in hematological parameters were seen in the Phase 1 study.  
In the Phase 1 study EIDD-2801-1001, dose escalations were discontinued before a maximum 
tolerated dose was reached because plasma exposures that were expected to be efficacious based 
on scaling from animal models of seasonal and pandemic influenza were exceeded.   
 
The 200-mg dose is selected for Part 1 of 
this study. To allow for variability in PK including intracellular half-life of the EIDD-1931- 5’-
triphosphate and to account for uncertainty in scaling assumptions, doses of up to 800 mg are 
considered appropriate to explore a range of potentially efficacious doses. Based on safety and PK 
data from a Phase 1 study, doses up to 800 mg BID may be selected for evaluation in subsequent 
study parts . The subsequent optional study parts may explore different doses, or the same dose 
used in one part may be repeated in a different Part. 
2.7. 
Justification for the Control Arm 
In light of the variability of viral replication kinetics and disease progression in individuals with 
COVID-19, the inclusion of a control group is essential to evaluate if EIDD-2801 has an antiviral 
effect.  To this end, this trial will include a double-blinded placebo control arm to determine the 
efficacy, safety, and tolerability of EIDD-2801 in the outpatient setting for individuals with 
COVID-19. 
2.8. 
Justification for Placebo-Controlled Design 
In the absence of efficacy data and in light of potential risks, a placebo-controlled trial will provide 
the best opportunity to rigorously evaluate the safety, tolerability, and efficacy of EIDD-2801. No 
approved therapy is available to treat COVID-19 in outpatients. 
2.9. 
Justification for Age Restriction 
Children, adolescents, and adults under the age of 18 will not be included in this trial.  Initial 
epidemiologic information indicates that while children and adolescents under the age of 18 are 
able to be infected, the overwhelming burden of severe disease occurs among adults, particularly 
older adults.  Given the low incidence of disease in children, and in consideration that the Phase I 


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data for EIDD-2801 are limited to adults, the risk/benefit analysis does not warrant inclusion of 
this population at this time. 
2.10. 
Justification for Including Women of Childbearing Potential  
There is no safety data currently available in pregnant women or those who are breastfeeding.
 
 
pregnant women or those who are nursing will not be eligible for 
this study. However, in the recently published study of remdesivir, which demonstrated a 
significant reduction in the duration of illness compared with placebo, the greatest recovery rate 
ratio occurred in individuals between the ages of 18 and 40. Given the patient population that may 
benefit the most, there is a now a clear rationale for including women of child-bearing age into 
this Phase 2 study.  
Women of childbearing potential (as defined in Appendix 2) will therefore be eligible for 
enrollment only if they meet Inclusion Criterion 4.1.10, including the following:  
1. Have a negative highly sensitive pregnancy test at Screening 
2. Agree to undergo a follow-up pregnancy test on Study Day 28  
3. Comply with the contraception guidelines provided in Appendix 2  
In addition, male participants must refrain from donating sperm during the study and for 100 days 
after dosing of the study drug is complete.  Male participants with female partners must also 
comply with the contraception guidelines provided in Appendix 2.  
2.11. 
Justification for Not Performing Urinalysis 
This study is being conducted in part at the
 
in an outdoor testing facility designed specifically 
for patients who have COVID-19.  This center does not have facilities for urine collection, and 
therefore, urine cannot be collected at clinic visits.   
Review of preliminary, blinded urinalysis data from Phase I study EIDD-2801-1001 has not 
revealed any safety concerns.  Safety data from the ongoing Phase I study and other studies that 
are initiated will be reviewed by the sponsor on an ongoing basis.  If there are any safety signals 
that suggest that urinalysis testing is needed, this protocol will be reviewed and if warranted, 
amended to address this issue.   
 
 


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3. 
STUDY DESIGN 
This is a Phase IIa, double-blind, placebo-controlled, randomized trial, designed to compare the 
safety, tolerability, and antiviral activity of EIDD-2801 versus placebo as measured by viral RNA 
detection in symptomatic adult outpatients with COVID-19.  The study is a multicenter trial.  
This study will enroll up to approximately 172 fully evaluable participants in multiple study parts. 
If participants in a dose group drop out or otherwise have missing or unevaluable primary or key 
secondary virology endpoint data, additional participants may be enrolled to ensure adequate data 
at each dose level. The total number of participants to be enrolled will not exceed 204.  
In Part 1 of this study, up to approximately 44 participants will be randomized 1:1 to receive 
EIDD-2801 200 mg BID (Arm A) or placebo (Arm B) orally BID for 5 days. Enrollment in Part 1 
may be interrupted to initiate enrollment in a different cohort, and may resume at a later time point.  
The study may continue to enroll the following optional study parts: 
• In Parts 2--4, up to approximately16 participants per part will be randomized 3:1 into 
Arms C and D (Part 2), Arms E and F (Part 3) and Arms G and H (Part 4) to receive 
treatment as follows: EIDD-2801 up to 800 mg or placebo orally BID for 5 days.  
• In Parts 5--9, up to approximately 16 participants per part will be randomized 3:1 into 
Arms I and J (Part 5), Arms K and L (Part 6), Arms M and N (Part 7), Arms O and P 
(Part 8), and Arms Q and R (Part 9) to receive treatment as follows: EIDD-2801 up to 
800 mg or placebo orally BID for 5 days. 
The dose of EIDD-2801 evaluated in Part 1 will be 200 mg BID. The doses selected for subsequent 
study parts may be the same, higher or lower than the dose(s) studied in previous study parts, and 
will not exceed 800 mg BID. Doses will be chosen based on emerging virology and safety data 
from this and other ongoing studies. Selected doses will be communicated in an official 
memo/protocol clarification letter. The maximum number of participants enrolled will be 204 .   
All study part sizes are approximate. Study parts may be combined for randomization purposes if 
the same dose is planned for more than one part. Study parts enrolling at the same dose level may 
be enrolled simultaneously.  
 
Sample Treatment Assignment Table (Fully Evaluable Participants) 
(doses and order of progression subject to change) 
Study Part 
 
Treatment Arm 
(n) 
Placebo Arm 
(n) 
Total Subjects 
Projected Dose 
Level 
1 
A (22) 
B (22) 
44 
200 mg 
2 
C (12) 
D (4) 
16 
400 mg 
3 
E (12) 
F (4) 
16 
400 mg 
4 
G (12) 
H (4) 
16 
400 mg 
5 
I (12) 
J (4) 
16 
TBD or 800 mg 
6 
K (12) 
L (4) 
16 
TBD or 800 mg 
7 
M (12) 
N (4) 
16 
TBD or 800 mg 
8 
O (12) 
P (4) 
16 
TBD or 200 mg 
9 
Q (12) 
R (4) 
16 
TBD or 400 mg 
Total: 
118 
54 
172 
 
 


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All participants will be followed for 5 days on treatment and an additional 23 days off treatment.  
Participants who do not start study treatment will be replaced.  
In Part 1, randomization will be stratified by time (days) from symptom onset – “early” versus 
“late” presentation, where “early” and “late” presentation are defined by: 
• Early presentation: enrollment (i.e., randomization date and time) 0 to ≤60 hours from 
symptom onset  
• Late presentation: enrollment (i.e., randomization date and time)  >60 to <168 hours from 
symptom onset  
Randomization will not be stratified in subsequent study parts. 
3.1. 
Recruitment 
Participants will be recruited through active outpatient surveillance programs including the 
 
, screening centers at the Wake Forest School of Medicine, local emergency departments, 
additional study sites, and public health surveillance programs actively conducting outbreak 
investigations among others including nursing homes. Primary recruitment will begin at UNC, and 
UNC-affiliated satellite clinics, and will be conducted in partnership with the 
  At the 
time of testing, participants who present to the 
 are approached for a global consent to 
be contacted for research studies. Those who test positive will be approached for enrollment into 
this study at the time they are notified of their diagnosis. Participants identified in the emergency 
department will be referred to the study immediately upon SARS-CoV-2 diagnosis by ordering 
providers and study coordinators who receive test results.   
3.2. 
Study Visits 
The informed consent process will be performed in person or remotely in compliance with 
institutional and regulatory requirements. At Study Entry (Day 1), all consented participants will 
have an in-person study visit. Blood will be obtained for safety labs, inflammatory markers, 
immunoglobulins, and pregnancy testing if indicated, and if participants meet all of the inclusion 
criteria and none of the exclusion criteria, they will be randomized. Participants will provide 
medical and medication histories and contact information for themselves including their home 
address and cell phone numbers and that for persons who can be contacted to help locate the study 
participant in case study staff cannot reach the participant. Participants will be dispensed study 
treatment and contact numbers for the study staff.  
The participant’s first symptom(s) associated with COVID-19 and when it/they occurred will be 
recorded.  
Either in-clinic visits or in-home visits will continue on Days 3, 5, 7, 14, and 28.   
On Days 3, 7, and 14, study staff will contact participants per the Schedule of Evaluations (SOE), 
and in-home or in-clinic visits will occur for respiratory sampling including NP swabs, and blood 
samples will be obtained for safety labs, inflammatory markers, and immunoglobulins. 
Participants will also be assessed for their symptoms, temperature, oxygen saturation, medication 
adherence, and major events such as medical visits and hospitalizations. If participants cannot be 
reached after 2 attempts 24 hours apart, then their alternative contact person(s) will be called. 


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On Day 5, participants will have an in-clinic visit. Respiratory samples including NP swab, OP 
swab (at UNC at Chapel Hill only) and self-collected nasal mid-turbinate swab (at UNC at Chapel 
Hill only) will be collected.  Blood will also be obtained for safety labs, inflammatory markers, 
and immunoglobulins. At sites that are able to process PK samples, single day sparse PK sampling 
will be collected on Day 5. 
On Day 28 (the End-of-Study [EOS] visit), participants will have an in-clinic visit. Blood samples 
will be obtained for safety labs, pregnancy testing if indicated, inflammatory markers, and 
immunoglobulins.  Respiratory samples including NP swab, OP swab (UNC at Chapel Hill only), 
and self-collected nasal mid-turbinate swab (UNC at Chapel Hill only) will be collected.  At these 
visits, study staff will record any hospitalizations or outpatient medical visits (including 
telemedicine visits) that occurred since the last visit. 
Participants will be instructed to contact study staff immediately if they seek medical help at 
any time during the study. 
3.3. 
Isolation Procedures 
Given that SARS-CoV-2 is spread through respiratory droplets, each site must develop procedures 
to protect study staff and participants of other trials from infectious exposure. Each site will have 
a plan for maximal protection by providing personal protective equipment (PPE), setting up 
isolation rooms or outside areas, providing special access points or contact with study participants. 
Each site will develop their own set of procedures for such participant contact. 


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4. 
SELECTION AND ENROLLMENT OF PARTICIPANTS 
4.1. 
Inclusion Criteria 
4.1.1. 
Able to provide informed consent prior to initiation of any study procedures. 
4.1.2. 
≥18 years of age at Screening. 
4.1.3. 
Study treatment is expected to begin within ≤168 hours from first symptom onset. 
4.1.4. 
Ability to swallow pills 
4.1.5. 
Documentation of confirmed active SARS-CoV2 infection, as determined by a 
molecular or non-molecular (“rapid”) test conducted at any clinic or laboratory 
that has a Clinical Laboratory Improvement Amendments (CLIA) certification or 
its equivalent from a sample collected ≤96 hours prior to study entry.   
4.1.6. 
Experiencing at least one of the following SARS-CoV-2 infection symptoms at 
the time of enrollment: fever (can be subjective including feeling feverish or 
having chills) OR signs/symptoms of respiratory illness (including but not limited 
to upper respiratory congestion, loss of sense of smell or taste, sore throat OR 
lower respiratory illness – cough, shortness of breath). 
4.1.7. 
Agrees to not participate in another interventional clinical trial for the treatment of 
SARS-CoV-2 during the study period (28 days) unless hospitalized.  
4.1.8. 
Agrees to not obtain investigational medications outside of the EIDD-2801 study. 
4.1.9. 
Agrees to the sampling detailed in the SOE and to comply with study requirements 
including contraception requirements.  


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4.1.10. 
A female participant is eligible to participate if she is not pregnant or breastfeeding 
and at least one of the following conditions applies:  
• 
Is not a woman of childbearing potential (WOCBP) 
OR 
• 
Is a WOCBP and using a contraceptive method that is highly effective (a low user 
dependency method OR a user-dependent method in combination with a barrier 
method), or be abstinent from heterosexual intercourse as their preferred and 
usual lifestyle (abstinent on a long-term and persistent basis), as described in 
Appendix 2 during the intervention period and for at least 50 days after the last 
dose of study intervention. The investigator should evaluate the potential for 
contraceptive method failure (ie, noncompliance, recently initiated) in 
relationship to the first dose of study intervention. 
• 
A WOCBP must have a negative highly sensitive pregnancy test (serum or urine) 
within 24 hours before the first dose of study intervention. 
• 
Additional requirements for pregnancy testing during and after study intervention 
are located in Section 6.2.15. 
• 
The investigator is responsible for review of medical history, menstrual history, 
and recent sexual activity to decrease the risk for inclusion of a woman with an 
early undetected pregnancy. 
• 
Contraceptive use by women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies. 
• 
Given the elevated risk of venous thrombotic events in patients hospitalized with 
COVID-1922,23, estrogen-containing contraceptives must not be started to fulfill 
the contraceptive requirement of this study at any time during participant’s 
hospitalization. If contraceptives are interrupted as standard of care management 
of COVID-19 patients and resumed at a later time point, such as at hospital 
discharge, then abstinence must be practiced for the defined period of back-up 
contraception per the contraceptive product labeling. After this period, 
contraceptive use must adhere to Appendix 2.   
4.1.11. 
Male participants are eligible to participate if they agree to the following during 
the intervention period and for at least 100 days after the last dose of study 
intervention:  
• 
Refrain from donating sperm  
PLUS either:  
• 
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent 
OR 
• 
Must agree to use contraception unless confirmed to be azoospermic 
(vasectomized or secondary to medical cause [Appendix 2]) as detailed below: 
Agree to use a male condom plus partner use of an additional contraceptive 


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method when having penile-vaginal intercourse with a WOCBP who is not 
currently pregnant. Note: Men with a pregnant or breastfeeding partner must 
agree to remain abstinent from penile-vaginal intercourse or use a male condom 
during each episode of penile-vaginal penetration. 
• 
Contraceptive use by men should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies. 
4.2. 
Exclusion Criteria 
4.2.1. 
Need for hospitalization or immediate medical attention in the clinical opinion of 
the study investigator. 
4.2.2. 
Hemoglobin <10 g/dL in men and <9 g/dL in women 
4.2.3. 
Platelet count <100,000/ µL or received a platelet transfusion within 5 days prior 
to enrollment 
4.2.4. 
Is on dialysis or has an estimated Glomerular Filtration Rate (eGFR) 
<30 mL/min/1.73 m2 
4.2.5. 
Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) >3x the upper 
limit of normal (ULN) 
4.2.6. 
History of or current hospitalization for COVID-19. NOTE: Individuals 
hospitalized and then discharged, even if only hospitalized for 1 day, are excluded. 
4.2.7. 
History of kidney disease  as evidenced by estimated creatinine clearance value 
<30 mL/min.  
4.2.8. 
History of significant liver disease in the opinion of the site investigator or active 
hepatitis B or active hepatitis C. Human immunodeficiency virus (HIV) that is 
advanced (CD4 <200/mm3) and/or on treatment with nucleos(t)ide analogues. 
4.2.9. 
Use of therapeutic interventions with possible anti-SARS-CoV-2 activity within 
30 days prior to study entry, e.g., remdesivir, lopinavir/ritonavir fixed dose 
combination, ribavirin, chloroquine, hydroxychloroquine, and convalescent 
plasma, or participation in a clinical trial involving any of these drugs whether for 
treatment or prophylaxis. 
4.2.10. 
Receipt of a SARS-CoV-2 vaccination prior to study entry.  
4.2.11. 
Known allergy/sensitivity or any hypersensitivity to components of EIDD-2801 
or its formulation. 
4.2.12. 
Active drug or alcohol use or dependence that, in the opinion of the site 
investigator, would interfere with adherence to study requirements. 


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4.2.13. 
History of recent (within the past 3 months) hemorrhagic cerebrovascular accident 
(CVA) or major bleed. 
4.2.14. 
Presence of a condition, that in the opinion of the investigator, would place the 
subject at increased risk from study participation. 
4.3. 
Study Enrollment Procedures 
Prior to implementation of this protocol, and any subsequent full version amendments, each site 
must have the protocol and the protocol consent form(s) approved, as appropriate, by the 
institutional review board (IRB)/ethics committee (EC) and any other applicable regulatory entity 
(RE) responsible for oversight of the study.  
Upon receiving final IRB/EC and any other applicable RE approvals for an amendment, sites 
should implement the amendment immediately.  
Once a candidate for study entry has been identified, details will be carefully discussed with the 
participant. The participant will be asked to read and sign the approved protocol consent form.  
Participants from whom a signed informed consent has been obtained may be screened and 
enrolled, if they otherwise qualify.   
4.3.1. 
Randomization/Participant Registration 
For participants from whom informed consent has been obtained, but who are deemed ineligible 
or who do not enroll into the initial protocol step, a Screening Failure Results form must be 
completed and keyed into the database. Participants who meet the enrollment criteria will be 
registered to the study according to standard procedures.  
4.4. 
Co-enrollment Guidelines 
For specific questions and approval for co-enrollment in other studies, sites should first contact 
the protocol team via e-mail. 


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5. 
STUDY TREATMENT  
5.1. 
Regimens, Administration, and Duration 
Doses of EIDD-2801 and matching placebo will be formed from combinations of 
 
.  In Part 1 of the study, participants will be randomized 1:1 to receive one of the 
following two regimens: 
• ARM A: 
Day 1-5: 
EIDD-2801 200 mg  orally BID for 5 days.  
• ARM B: 
Days 1-5: 
Placebo for EIDD-2801 orally BID for 5 days.   
An optional Part 2 may be initiated in which patients will be randomized 3:1 (active:placebo) to 
receive one of the following two regimens:  
• ARM C: 
Day 1-5: 
EIDD-2801 up to 800 mg orally BID for 5 days.  
• ARM D: 
Days 1-5: 
Placebo for EIDD-2801 orally BID for 5 days.   
An optional Part 3 may be initiated in which patients will be randomized 3:1 (active:placebo) to 
receive one of the following two regimens:  
• ARM E: 
Day 1-5: 
EIDD-2801 up to 800 mg orally BID for 5 days.  
• ARM F: 
Days 1-5: 
Placebo for EIDD-2801 orally BID for 5 days.   
An optional Part 4 may be initiated in which patients will be randomized 3:1 (active:placebo) to 
receive one of the following two regimens:  
• ARM G: 
Day 1-5: 
EIDD-2801 up to 800 mg orally BID for 5 days.  
• ARM H: 
Days 1-5: 
Placebo for EIDD-2801 orally BID for 5 days.   
Additional optional Parts 5-9 may be initiated in which patients will be randomized 3:1 
(active:placebo) to receive one of the following two regimens:  
• ARM I (Part 5), K (Part 6), M (Part 7), O (Part 8), Q (Part 9): 
Day 1-5: 
EIDD-2801 up to 800 mg orally BID for 5 days.  
• ARM J (Part 5), L (Part 6), N (Part 7), P (Part 8), R (Part 9): 
Days 1-5: 
Placebo for EIDD-2801 orally BID for 5 days.   
 
Each participant will begin study treatment dosing with the first dose on Day 1 and the second 
dose at least 4 hours later on Day 1. If the first dose on Day 1 is a late evening dose, the second 
dose may be taken on the morning of Day 2, in which case the final dose will be taken on the 
morning of Day 6.  In addition, if a participant misses up to 2 doses during Days 1 to 5, dosing 
may be extended into Day 6.  


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5.2. 
Study Product Formulation and Preparation 
 
  
5.3. 
Pharmacy: Product Supply, Distribution, and Accountability 
5.3.1. 
Study Product Acquisition/Distribution 
 
 will be supplied as 
 for 
oral administration, along with the batch/lot numbers and Certificates of Analysis.  
EIDD-2801 and matching placebo 
are supplied by Ridgeback Biotherapeutics. 
5.3.2. 
Study Product Accountability 
The site pharmacist is required to maintain complete records of all study products received from 
Ridgeback Biotherapeutics and subsequently dispensed. All unused study products at the sites 
must be returned to Ridgeback Biotherapeutics (or as otherwise directed by the sponsor) after the 
study is completed or terminated.  
5.4. 
Concomitant Medications 
Whenever a concomitant medication or study agent is initiated or a dose changed, investigators 
must review the concomitant medication’s and study agent’s most recent package insert, or 
Investigator’s Brochure to obtain the most current information on drug interactions, 
contraindications, and precautions. 
 


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6. 
SCHEDULE OF EVENTS 
SCHEDULE OF EVENTS 
Screening 
(in person 
or by 
phone) 
Study Entry /  
Enrollment 
Post-Entry Evaluations 
Premature 
Study 
Discontin-
uation 
Day 1 
Day 3 
Day 5 
Day 7 
Day 14 
Day 28 
(EOS) 
 
Visit Windows (days) 
Pre 
dose 
First 
Dose 
 
 
(±1 day) 
(±4 days) 
 
 
In-Clinic or In-Home Visit 
 
 
 
X 
X 1 
X 
 
X 
X 
In-Clinic Visit  
 
X 
 
 
 
 
X 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Documentation of Positive SARS-
CoV-2 Molecular Test2 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical history & COVID-19 
Symptom Screen 
X 
X 
 
 
 
 
 
X 
 
Vital signs 3 
 
X 
 
X 
X 
X 
X 
 
X 
Review inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
X 
 
Pregnancy Test in Women of 
Childbearing Potential 4 
 
X 
 
 
 
 
X 
 
X 
Study Kit and Study Diary 
Dispensed 5 
 
X 
 
 
 
 
 
 
 
EIDD-2801 or Placebo BID Daily 
Days 1-5 6 
 
 
X 
X 
X 
 
 
X 
 
Review of Study Daily Diary7 
 
 
 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
 
X 
X 
X 
X 
X 
X 
Study Endpoint Determination 
 
 
 
X 
X 
X 
X 
X 
X 
Nasopharyngeal (NP) Swab 8 
 
X 
 
X 
X 
X 
X 
X 
X 
Oropharyngeal (OP) Swab 9 
 
X 
 
X 
X 
X 
X 
X 
X 
Self-Collected Nasal Mid-turbinate 
Swab 9 
 
X 
 
X 
X 
X 
X 
X 
X 
Safety labs 10  
X 
X 
 
X 
X 
X 
X 
X 
X 
Inflammatory Markers  
 
X 
 
X 
X 
X 
X 
X 
X 
Plasma for Immune Responses  
 
X 
 
X 
X 
X 
X 
X 
X 
Plasma for Immunoglobulin Assay 
 
X 
 
 
 
X 
X 
 
X 
Pharmacokinetics (Sparse) 11 
 
 
 
 
X 
 
 
 
 
Vital Status Follow-up  
 
 
 
 
 
 
 
 
X 


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1. The Day 5 visit will be in-clinic for sites that are able to process PK samples, and may be in-home for other sites.  
2. Test to be performed within 96 hours of study entry.  Rapid tests are acceptable for confirming infection. 
3. Assessment includes measurements of temperature, blood pressure, respiratory rate, heart rate, and oxygen saturation. Height and 
weight should be recorded and may be obtained by participant’s self-report. 
4. High sensitivity pregnancy tests are required at Screening (urine or serum) within 24 hours of the first dose of study drug and on 
Day 28 (serum).  Additional serum or urine pregnancy tests may be performed, as determined necessary by the investigator or 
required by local regulation, to establish the absence of pregnancy at any time during the subject's participation in the study. 
5. Activities will include the collection of secondary contact information. 
6. First Dose will be administered in the morning of Day 1, if possible. Dosing is twice daily through Day 5 (inclusive).  If the first 
dose on Day 1 is a late evening dose, the second dose may be taken on the morning of Day 2, in which case the final dose will be 
taken on the morning of Day 6.  In addition, if a participant misses up to 2 doses  during Days 1 to 5, dosing may be extended into 
Day 6. 
7. Study treatment adherence will be assessed by review of the treatment adherence portion of the study diary and counting returned 
study drug and containers. 
8. The site at which virology testing will be performed (UNC at Chapel Hill) will collect 1 NP swab per timepoint and will divide 
the sample in preparation for analysis by infectivity versus PCR assay. All other study sites will collect 2 NP swabs (one per 
nostril) at each timepoint and 1 swab each will be prepared and shipped for analysis by infectivity versus PCR assay.   
9. Participants enrolled at the site at which virology testing will be performed (UNC at Chapel Hill) will have OP and nasal mid-
turbinate swabs collected at the timepoints indicated. OP and nasal mid-turbinate swabs are not collected at all other study sites.  
10. Hematology and chemistry:  Results from hematology and chemistry will be evaluated before assessing a participant’s eligibility. 
Lab results obtained within 48 hours of enrollment (i.e., randomization date and time)  are acceptable.  When screening and 
enrollment visits are combined, a single blood draw may be performed for both screening and baseline laboratory assessments. 
11. At all sites that are able to process PK samples, PK samples will be obtained immediately before the morning dose on Day 5 and at 
approximately 1 hour and 2 hours after the morning dose, where possible.  When possible, participants should fast overnight before 
their Day 5 visit (i.e. participants should arrive at the Day 5 visit having had no food or drink intake except for water in the previous 
8 hours). 
 
 
 


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6.1. 
Timing of Evaluations 
6.1.1. 
Screening Evaluations  
Screening evaluations must occur prior to the participant starting any study medications, 
treatments, or interventions. 
Screening evaluations to determine eligibility may be completed remotely or in-person. Screening 
and enrollment (i.e., randomization; Day 1) visits may occur on the same day. 
In addition to data being collected on participants who enroll into the study, demographic and 
available clinical and laboratory data on screening failures will be captured in a Screening Failure 
Results form and entered into the Study database or other applicable site-specific database.  
6.1.2. 
Enrollment and Study Entry 
Screening and enrollment visits may be combined whenever possible to ensure the shortest 
possible time between symptom onset and dosing of study drug. The study enrollment (i.e., 
randomization; Day 1) visit is an in-person visit as safety labs must be performed prior to initial 
dosing. Participants must begin study treatment within 168 hours of symptom onset. The first dose 
of study treatment should be the first of two doses on Day 1. 
When screening and enrollment visits are combined, a single blood draw may be performed for 
both screening and baseline laboratory assessments. Participants must have the NP swab(s) and 
blood collected prior to receiving the first treatment dose.  Optional OP and self-collected nasal 
mid-turbinate swabs, if performed, should also be collected prior to receiving the first treatment 
dose. 
6.1.3. 
On-Treatment Evaluations  
Participants will undergo an in-clinic or in-home visit on Days 3 and 5 as outlined in the SOE.  For 
sites that are able to process PK samples, Day 5 visits will be in-clinic, as needed.  
During these visits, participants will undergo NP swabs, blood collection, and other clinical 
evaluations as indicated in the SOE. Optional OP and self-collected nasal mid-turbinate swabs 
may also be collected at applicable study sites.   
6.1.4. 
Post-Treatment Evaluations  
Participants will undergo post-treatment evaluations at either in-home or in-clinic study visits on 
Days 7 and 14 as outlined in the SOE.  
6.1.5. 
End of Study Evaluations  
Participants will undergo an in-clinic evaluation on Day 28 for an End of Study visit. 


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6.1.6. 
Discontinuation Evaluations 
6.1.6.1. 
Evaluations for Participants Who Do Not Start Study Treatment 
Participants who are randomized but do not take the first (confirmed) dose of study treatment do 
not need to be followed. A study discontinuation electronic case report form (eCRF) must be 
completed to record this and any evaluations completed for these participants should also be 
recorded on the Day 1 eCRFs.   
6.1.6.2. 
Premature Treatment Discontinuation Evaluations  
Participants who discontinue study treatment early should remain on study and all evaluations 
should be performed as outlined in the SOE. 
6.1.6.3. 
Premature Study Discontinuation Evaluations  
Participants who discontinue study participation should undergo premature study discontinuation 
evaluations, as outlined in the SOE, within 7 days of study discontinuation. If study discontinuation 
occurs on or prior to Day 5, all procedures should be performed as described in the SOE for 
premature study discontinuation evaluations. If study discontinuation occurs on or between Day 5 
and Day 28 all evaluations EXCEPT treatment adherence should be performed. If study 
discontinuation occurs after Day 5, all evaluations including site-collected NP swab(s) and blood 
collection should be performed.  
For participants who prematurely discontinue from the study for reasons other than withdrawal of 
consent, sites will attempt to obtain information regarding vital status and endpoints per the SOE. 
6.2. 
Instructions for Evaluations 
All clinical and laboratory information required by this protocol is to be present in the source 
documents.  
All stated evaluations are to be recorded on the eCRF unless otherwise specified. Refer to 
Section 7.3 for information on the DAIDS AE Grading Table and requirements for reporting of 
AEs. 
6.2.1. 
Informed Consent  
Participants will review and provide informed consent to participate in the study either over the 
telephone or in person.  
6.2.2. 
Documentation of Positive SARS CoV-2 Infection 
Active SARS CoV-2 infection documentation is recorded on the eCRF. If a viral load level is 
available, it should be recorded as well. 
6.2.3. 
COVID-19 Symptom Screen 
Participants will be asked about their first symptoms related to COVID-19 and their current 
symptoms, to document eligibility. This will include when and what symptoms the participant 


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noticed having. The date of first symptom onset will be recorded and used to establish the 
randomization stratum. 
6.2.4. 
Medical History 
The medical history must include all signs and symptoms regardless of grade and all diagnoses 
identified for clinical events and other diagnoses regardless of grade within the past 14 days. In 
addition, the following diagnoses should be recorded regardless of when the diagnosis was made:  
• Hypertension 
• Chronic obstructive pulmonary disease 
• Obesity (body mass index [BMI] >30) 
• “Severe Obesity” (BMI >40) 
• Immunosuppressive conditions 
• Reactive airway disease, asthma 
• Autoimmune disease 
• Acquired Immune Deficiency Syndrome (AIDS)-defining conditions 
• HIV infection 
• Coronary heart disease 
• Heart failure 
• Myocarditis 
• Arrhythmias 
• Valvular heart disease 
• Stroke 
• Cancer (exclusive of basal/squamous cell skin cancer) 
• Diabetes 
• Tuberculosis 
• Chronic hepatitis C 
• Chronic hepatitis B 
• Pregnancy history 
• If known by participant, if they have been diagnosed with an acute viral respiratory 
infection (influenza, parainfluenza, respiratory syncytial virus, rhinovirus) within the 
previous 14 days. 
A Smoking Status questionnaire will be completed at the Day 1 visit as part of medical history and 
recorded on the eCRF.  
Any allergies to any medications and their formulations must also be documented.  


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6.2.5. 
Medication History 
A medication history must be present, including start and stop dates. The table below lists the 
medications that must be included in the history at screening.  
 
Medication Category 
Complete History or Timeframe 
All prescription drugs 
Last 7 days 
All over the counter drugs 
Last 7 days 
Prescription drugs for high blood pressure 
Last 3 months  
Prescription drugs for diabetes and pre-diabetes 
Last 3 months  
Prescription drugs for lung disease 
Last 3 months  
Prescription drugs for heart disease 
Last 3 months  
Prescription drugs for autoimmune disease 
Last 3 months  
Cancer chemotherapy 
Complete history 
Antiretroviral therapy 
Last 3 months 
Immune-based therapy 
Last 3 months 
Blinded study treatment 
Last 12 months  
CoV-related vaccines 
Complete history 
Alternative therapies  
Last 3 months  
Dietary supplements  
Last 3 months  
  
6.2.6. 
Clinical Assessments 
No physical exams will be conducted.  
Clinical investigators will perform a clinical assessment at enrollment including vital signs 
(temperature, blood pressure, heart rate, respiratory rate, and oxygen saturation). Height and 
weight should be recorded and may be obtained by participant’s self-report. In their clinical 
judgement, they may identify some participants who are ill enough to warrant further clinical 
evaluation, which may result in hospitalization. They will then refer these participants for such 
evaluation. These participants will not start study treatment and will not be included in the 
analyses. While clinical judgement may not be standard across sites, the blinding process should 
balance site variation. 
Refer to Section 7.2 for AE collection requirements.  


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6.2.6.1. 
Concomitant Medications 
At entry and post-entry, the following new and discontinued concomitant medications must be 
recorded: 
• High blood pressure medications 
• Steroids or other immunosuppressive or immunomodulatory medication 
• Non-steroidal anti-inflammatory drugs (NSAIDS) 
• Chemotherapy 
• Antibiotics, antifungals, and antivirals (including antiretrovirals) 
• Hydroxychloroquine or chloroquine or any agent felt to have potential COVID-19 
activity 
• Inhalers 
6.2.6.2. 
Study Treatment (Intervention) Modifications 
Record any modification to treatment, treatment interruption, and permanent discontinuation of 
treatment, and the reason for the modification, interruption, or discontinuation.  
6.2.7. 
Secondary Contact 
At enrollment, secondary contact information for 2 individuals whom the clinical research team 
can contact if the participant cannot be reached (e.g., spouse, friend, neighbor, etc.) will be 
collected. Clinical research teams will also request contact information for participants’ health care 
provider(s) and the names of hospitals that the participant is likely to go to if they get sick. Contact 
information for secondary contacts or health care provider will not be recorded on any eCRF. If 
participants cannot be reached after 2 attempts 24 hours apart, then their listed secondary contact 
person(s) or health care provider will be called. At study entry only, the participant’s home address 
will be recorded in site records (it will not be reported on the eCRF).  
6.2.8. 
Study Kit Dispensed  
The kit will include: 
• Copy of informed consent (if not provided electronically) 
• Study Diary (if not completed electronically) 
• Study medications  
• Pocket/wallet card with site staff contact information 
• Instructions on what to do if they have worsening symptoms/become hospitalized 
6.2.9. 
Dispensing of Study Drug, Confirmation of First Dose, and Counseling 
Study treatment will be dispensed at study entry. Study staff will confirm the first dose taken by 
the participant and record this confirmation on an eCRF. Participants who do not start study 
treatment will be discontinued from the study. 


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Adherence counseling must be performed prior to the time the first dose of study treatment is 
taken. This counseling should include review of the timing of the first dose and the timing for the 
2 subsequent doses.  
6.2.10. 
Study Diary  
Distribution of Study Diary 
Participants will be provided a study diary at study entry (either electronic or paper).  
Participants will be asked to keep a log of symptoms, temperature (if possible), medications they 
are taking, presence of feverishness, chills, myalgias, headache, sore throat, loss of sense of smell, 
loss of sense of taste, cough, shortness of breath, and major events such as urgent visit to an 
emergency room or clinic (including telemedicine) and hospitalization in their study diary. At 
study entry, study diary information will be recorded prior to study treatment initiation. Starting 
on Day 2, participants will be asked to complete the diary in the evening.  
Review of Study Diary  
The study diary will be reviewed by study staff with each participant at the in-person (in-clinic 
and in-home) visits described in the SOE and the participant’s entries will be recorded in the 
Participant Study Diary eCRF. If feasible, prior to or during the remote study visits, sites will 
request that the participant send images of each of their study diary entries to be reviewed at the 
next study contact. 
Participants who report worsening illness from any cause during the trial may be referred to their 
health care provider or closest emergency room. Such instances will be recorded at the time of the 
notification, and during follow-up to assess study endpoints, (e.g., hospitalization or death). 
Review of Treatment Adherence 
The treatment adherence diary will be reviewed by study staff with each participant at the in-
person (in-clinic and in-home) visits, as described in the SOE. The participant’s answers regarding 
doses taken will be recorded in the Adherence Assessment eCRF. If any doses are missed, the 
reason for the missed dose will be recorded.  
Collection of Study Diary 
The study diary will be reviewed per the SOE. 
6.2.11. 
Study Endpoint Determination 
Study endpoints will be collected per the SOE. These will be recorded on the eCRF. Information 
about AEs, hospitalizations, or death should be keyed on the eCRF within 72 hours of a site 
becoming aware of an AE, hospitalization, or death. 
6.2.12. 
Vital Status Follow-up 
For participants who prematurely discontinue from the study for reasons other than withdrawal of 
consent, clinical research personnel will attempt to obtain information regarding vital status 
(including date last seen alive, hospitalization, date of death, and primary cause of death) from the 
participant or other sources (such as family members, other designated contacts, or clinic records) 


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per the SOE. Information about hospitalizations and deaths should be keyed on the eCRF within 
72 hours of a site becoming aware of a hospitalization or death. 
6.2.13. 
Virologic Studies 
Detailed instructions for preparation and shipment of virologic samples will be provided in a 
separate document. 
Nasopharyngeal (NP) Swab 
NP swabs are required to be collected at all sites at the times indicated in the SOE.  The site at 
which virology testing will be performed (UNC at Chapel Hill) will collect 1 NP swab per 
timepoint and will divide the sample in preparation for analysis by infectivity versus PCR assay. 
All other study sites will collect 2 NP swabs (1 per nostril) at each timepoint and 1 swab each will 
be prepared and shipped for analysis by infectivity versus PCR assay.   
At study entry (Day 1), the sample should be collected prior to the first dose of study treatment. 
Oropharyngeal (OP) Swab (Optional) 
Participants enrolled at the site at which virology testing will be performed (UNC at Chapel Hill) 
will have an OP swab collected per the SOE. At study entry (Day 1), if performed, the sample 
should be collected prior to the first dose of study treatment. Participants enrolled at other sites 
will not have OP swabs collected.  
Self-collected Nasal Mid-turbinate Swab (Optional) 
Participants enrolled at the site at which virology testing will be performed (UNC at Chapel Hill) 
will have a nasal mid-turbinate swab collected per the SOE. At study entry (Day 1), if performed, 
the sample should be collected prior to the first dose of study treatment.  Participants enrolled at 
other sites will not have mid-turbinate swabs collected. 
Samples collected for viral assessment may be evaluated for the emergence of antiviral resistance 
at a future date.  
6.2.14. 
Laboratory Evaluations 
Laboratory evaluations will be performed on participants prior to study drug administration per 
SOE. At study entry (Day 1), blood samples should be collected prior to the first dose of study 
treatment and results will be available for assessment of the participant’s eligibility. If the 
participant has lab study results available from within 48 hours of enrollment (i.e., within 48 hours 
of randomization date and time), these will be acceptable for baseline values.  
Hematology 
Per the SOE, participants will have a blood draw for complete blood cell count (CBC) with 
automated differential and platelet count. These tests will be performed in real-time at the local 
clinic laboratory. 
Chemistry 
Per the SOE, participants will have a blood draw for liver function tests (ALT, alkaline 
phosphatase [ALP], AST, Total Bilirubin, Direct Bilirubin, and Total Protein) and renal function 


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tests (blood urea nitrogen [BUN], Creatinine, Potassium, Glucose, and Sodium). A creatinine 
clearance will be recorded. These tests will be performed in real-time at the local clinic laboratory. 
Inflammatory Markers 
Per the SOE, participants will have a blood draw for LDH, CRP, ferritin and D-dimer. These tests 
will be performed in real-time at the local clinic laboratory. 
Plasma  
Per the SOE, blood plasma will be collected and tested for immune responses.  Analytes to be 
tested may include, but may not be limited to, IL8, IL6, TNFα, IFNγ, GMCSF, interferon alpha 
(IFNα), C-X-C Motif Chemokine Ligand 10 (CXCL10), C-C Motif Chemokine Ligand 2 (CCL2), 
C-C Motif Chemokine Ligand 3 CCL3, soluble receptor for advanced glycation end products 
(RAGE), IL-2RApk35, and soluble IL-6Rpk35. Immunoglobulin M (IgM) and immunoglobulin 
G (IgG) will be tested from samples collected at the times indicated in the SOE. 
6.2.15. 
Pregnancy Testing 
Pregnancy testing: 
• Pregnancy testing requirements for study inclusion are described in Section 4.1. 
• High sensitivity pregnancy testing should be conducted at screening (serum or urine) 
within 24 hours of the first dose of study drug and on Day 28 (serum) approximately 23 
days after the last dose of study intervention. 
• Additional serum or urine pregnancy tests may be performed, as determined necessary by 
the investigator or required by local regulation, to establish the absence of pregnancy at 
any time during the subject's participation in the study. 
6.2.16. 
Pharmacokinetics  
Per the SOE, sparse PK sampling will be collected at sites that are able to obtain and process PK 
samples. Day 5 blood collection may be used to measure drug levels to assess the relationship 
between drug exposure and viral elimination dynamics including time to clearance. 
When possible, participants should fast overnight before their Day 5 visit (i.e., participants should 
arrive at the Day 5 visit having had no food or drink intake except for water in the previous 
8 hours).  
Specifically, blood will be collected for sparse PK measurements at the following timepoints, 
where possible: 
• Just prior to the morning dose on Day 5 (trough) 
• Approximately 1-hour post morning dose on Day 5 
• Approximately 2-hours post morning dose on Day 5 (if possible) 
The timing of the post-dose samples may be adjusted for individual participants to increase the 
range of timepoints for PK evaluation.  No participant will have more than 3 PK samples taken. 
The approximate time of the 3 doses preceding the PK sampling, the exact time of the dose 


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immediately preceding the PK sample, the time of the most recent meal, and the exact time of each 
PK sample collection should be recorded.   
If it is determined that sufficient PK samples have been collected to characterize the PK profile in 
this patient population, PK sample collection may be discontinued by the Sponsor at any time. 


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7. 
ADVERSE EVENTS AND STUDY MONITORING 
7.1. 
Definition of Adverse Events 
An AE is any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or diagnosis that occurs in a study participant during the conduct of the study 
REGARDLESS of the attribution (i.e., relationship of event to medical treatment/study 
product/device or procedure/intervention). This includes any occurrence that is new in onset or 
aggravated in severity or frequency from the baseline condition. The principal investigator (PI) 
and medical monitor will review all AEs on a weekly basis to determine which are treatment-
related AEs. 
7.2. 
Adverse Event Collection Requirements for This Protocol 
Post-entry, all AEs must be recorded on the eCRFs within 72 hours if any of the following criteria 
have been met: 
• All Grade ≥2 AEs 
• All AEs that led to a change in study treatment/intervention regardless of grade 
The PI or clinical site personnel should notify Covance Patient Safety Solutions (PSS) of all SAEs, 
regardless of relationship to the investigational drug, within 24 hours of clinical site personnel 
becoming aware of the event. The PI (or designee) will provide the initial notification by sending 
a completed SAE form which must include the PI’s (or designee’s) assessment of the relationship 
of the event to investigational drug and must be signed by the PI. Follow-up information, or new 
information regarding an ongoing SAE, must be provided promptly to Covance Drug Safety 
Services (DSS) at SAEIntake@Covance.com or via fax.  
The SAE Form will collect data surrounding the event (e.g., the nature of the symptom[s], time of 
onset in relation to initiation of therapy, duration, intensity, and whether or not therapy was 
interrupted or discontinued). The Investigator’s assessment of the probable cause of the event will 
also be included. In addition, relevant medical history, concomitant medications, laboratory and 
diagnostic tests reports, and procedures as well as all pertinent medical information related to the 
event will also be collected. 
All AEs that are reported must have their severity graded. To grade AEs, sites must refer to the 
DAIDS AE Grading Table, corrected Version 2.1, July 2017, which can be found on the DAIDS 
RSC website at https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-grading-
tables. 
Serious Adverse Events (SAEs) 
An SAE is defined as any untoward medical occurrence that: 
• Results in death 
• Is life-threatening illness 
• Requires inpatient hospitalization or prolongation of existing hospitalization.  
• Results in persistent or significant disability/incapacity. 


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• Is a congenital anomaly/birth defect, or 
• Is an important medical event that may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the patient or may require intervention to 
prevent one of the other outcomes listed in the definition above). 
7.3. 
Reporting Requirements for this Study 
The PI or clinical site personnel should notify Covance PSS of all SAEs, regardless of relationship 
to the investigational drug, within 24 hours of clinical site personnel becoming aware of the event. 
The PI (or designee) will provide the initial notification by sending a completed SAE form which 
must include the PI’s (or designee’s) assessment of the relationship of the event to investigational 
drug and must be signed by the PI. Follow-up information, or new information regarding an 
ongoing SAE, must be provided promptly to Covance DSS at 
 or via 
fax. The study agents for which expedited reporting are required are:  
• EIDD-2801 or Placebo for EIDD-2801 
The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or 
other clinical information. Whenever possible, the diagnosis (not the individual signs/symptoms) 
will be documented as the AE/SAE. 
Additionally, all reported pregnancies from the day of randomization through 50 days (for female 
participants) or 100 days (for female partners of male participants) after the last dose of study 
intervention must be reported to the sponsor by the investigator. 
7.3.1. 
Laboratory Test Abnormalities 
Laboratory abnormalities present at the screening visit will be recorded as pre-treatment signs and 
symptoms. After study treatment administration, a clinical laboratory abnormality should be 
reported as an AE only if it is considered clinically significant by the investigator.  
In addition, the following laboratory abnormalities should also be captured on the AE CRF page 
as appropriate: 
• Any laboratory test result that is clinically significant or meets the definition of an SAE 
• Any laboratory abnormality that required the participant to have the investigational product 
discontinued or interrupted 
• Any laboratory abnormality that required the participant to receive specific corrective 
therapy 
It is expected that wherever possible, the clinical diagnosis would be used by the reporting 
investigator (e.g., anemia versus low hemoglobin value). 
7.3.2. 
Grading Severity of Events 
The DAIDS AE Grading Table, corrected Version 2.1, July 2017, must be used and is available 
on the DAIDS RSC website at https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-
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When changes in severity of an AE occur, the maximum severity for the experience should be 
noted.   
7.3.3. 
Relationship 
The relationship of an AE to the administration of the study drug is to be assessed by the 
investigator according to the following definitions: 
• No (unrelated, not related, no relation): The time course between the administration of 
study drug and the occurrence or worsening of the AE rules out a causal relationship and 
another cause (concomitant drugs, therapies, complications, etc.) is suspected. 
• Yes (related): The time course between the administration of study drug and the occurrence 
or worsening of the AE is consistent with a causal relationship and no other cause 
(concomitant drugs, therapies, complications, etc.) can be identified. 
The following factors should also be considered: 
• The temporal sequence from study drug administration - The event should occur after the 
study drug is given. The length of time from study drug exposure to event should be 
evaluated in the clinical context of the event. 
• Underlying, concomitant, intercurrent diseases - Each report should be evaluated in the 
context of the natural history and course of the disease being treated and any other disease 
the participant may have. 
• Concomitant medication - The other medications the participant is taking or the treatment 
the participant receives should be examined to determine whether any of them might be 
recognized to cause the event in question. 
• Known response pattern for this class of study drug - Clinical and/or preclinical data may 
indicate whether a particular response is likely to be a class effect. 
• Exposure to physical and/or mental stresses - The exposure to stress might induce adverse 
changes in the recipient and provide a logical and better explanation for the event. 
• The pharmacology and pharmacokinetics of the study drug - The known pharmacologic 
properties (absorption, distribution, metabolism, and excretion) of the study drug should 
be considered. 
7.3.4. 
Expedited AE Reporting Period 
• Any medical condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE. However, if any pre-existing medical 
condition increases in severity after starting study treatment, it should be recorded as an 
AE. 
• Although disease progression including hospitalization for COVID-19 will be collected 
as AEs, SAEs of disease progression will be considered expected for EIDD-2801 in this 
protocol and will not be reported as SUSARs. 


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7.3.5. 
Pregnancy and Exposure During Breastfeeding 
If a pregnancy is reported, the investigator will record pregnancy information on the appropriate 
form and submit it to the sponsor within 24 hours of learning of the pregnancy in a female 
participant or female partner of male participant (after obtaining the necessary signed informed 
consent from the female partner). 
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to the 
investigator or their designee), including the pregnancy of a male participant’s female partner, that 
occurs during the study are reportable to the Sponsor as described in Section 7.3. 
All reported pregnancies must be followed to the completion/termination of the pregnancy.  
Any pregnancy complication will be reported as an AE or SAE. 
The medical reason (example: maternal health or fetal disease) for an elective termination of a 
pregnancy will be reported as an AE or SAE. Prenatal testing showing a fetus will be born with 
severe abnormalities/congenital anomalies that leads to an elective termination of a pregnancy will 
be reported as an SAE for the fetus. 
Pregnancy outcomes of ectopic pregnancy, spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth must 
be reported as serious events (Important Medical Events). If the pregnancy continues to term, the 
outcome (health of infant) must also be reported. 
7.4. 
Study Monitoring 
7.4.1. 
Adverse Events 
The UNC Safety Monitoring Committee (SMC) will review and assess select expedited adverse 
events (EAE) reports for potential impact on the study participant safety and protocol conduct as 
per, guidance documents, and standard operating procedures (SOPs) as applicable. Summary 
reports of AEs will be shared weekly with the medical monitor(s). SAEs will be reported through 
the Covance SAE reporting protocol within 24 hours to the medical monitor(s). The EIDD-2801 
principal investigator, co-investigators, and Ridgeback medical officer will review all deaths on a 
weekly basis in a blinded fashion. 
7.4.2. 
Interim Review 
The protocol team will monitor the conduct of the study via regular summaries of screening, 
accrual, study and study treatment discontinuation, and data and specimen completeness. The UNC 
SMC will monitor safety regularly.  
Detailed plans for study monitoring are outlined in a Study Progress, Data, and Safety Monitoring 
Plan (SPSMP) developed prior to enrollment of the first participant. 


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8. 
CLINICAL MANAGEMENT ISSUES 
8.1. 
Toxicity  
Criteria for participant management, dose interruptions, dose adjustments and discontinuation, or 
changes in treatment will be described only for toxicities attributable to the study drug. The grading 
system for drug toxicities is located in the DAIDS AE Grading Table (see Section 7.3.2).  
NOTE: The study team must be notified via e-mail within 72 hours regarding toxicities that result 
in a change in study regimen. 
It is possible that some participants will experience transient or prolonged AEs during the study. 
For any concerning AEs that are felt to require clinical intervention, participants should be 
instructed to contact their health care provider or seek urgent or emergent care, or 911 should be 
called, as appropriate.  
8.2. 
Management of Side Effects of EIDD-2801 
Only toxicities related to study medications provided through this study will be considered in the 
toxicity management section. The grading system is located in the Division of AIDS Table for 
Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), 
Version 2.1, March 2017: http://rsc.tech-res.com/clinical-research-sites/safety-reporting/daids-
grading-tables.   
8.3. 
Grade 1 or 2 
Participants who develop a Grade 1 or 2 AE or toxicity may continue study medications without 
alteration of the dosage, except as stated in sections below. For participants experiencing Grade 1 
or 2 AEs who choose to discontinue all study medications, the site investigator should complete 
premature discontinuation of study therapy evaluations, contact the study leadership team, and the 
participant should be encouraged to complete follow-up protocol study evaluations. 
NOTE: If participants discontinue study medications due to experiencing Grade 1 or 2 AEs, this 
should be noted in the eCRF as the reason for discontinuation.  
8.4. 
Grade 3 
If the investigator (in consultation with the medical monitor at the investigator’s discretion) has 
evidence that the AE has NOT been caused by study medications, dosing may continue. 
Participants who develop a Grade 3 AE or toxicity thought to be related to a study medication, 
except as stated in section below, should have their study medication discontinued. The participant 
should be reevaluated daily until the AE resolves or returns to baseline. The study leadership team 
must be notified and the relevant eCRF completed. Participants experiencing Grade 3 AEs 
requiring permanent discontinuation of all study medications should be followed daily until 
resolution of the AE and encouraged to complete the premature discontinuation of study therapy 
and follow-up protocol study evaluations. 


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8.5. 
Grade 4  
Participants who develop a Grade 4 symptomatic AE or toxicity related to study product, will have 
the study medication permanently discontinued, except as stated below. Participants experiencing 
Grade 4 AEs requiring permanent discontinuation of all study medications should be followed 
daily until resolution of the AE and encouraged to complete the premature discontinuation of study 
therapy and follow-up protocol study evaluations. 
Situations where study product does not need to be discontinued:  
• Participants with Grade 3 or 4 asymptomatic creatine kinase (CK) elevation may continue 
study medication if the investigator has evidence that the CK elevation is not suspected to 
be related to the study medications.  
• Participants with new Grade 3 or 4 AEs that are considered to be COVID-19 related and 
not study product related may continue study product following discussion with one of the 
study team leads. 
8.6. 
Pregnancy  
The study products may not be given in pregnancy.  
8.7. 
Breastfeeding 
The study products may not be given to women who are breastfeeding.  


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9.
CRITERIA FOR DISCONTINUATION
The investigator, in consultation with the Sponsor, may decide to discontinue a subject from 
dosing or from the study based on their clinical judgement and/or in consultation with the Safety 
Monitoring Committee.   
9.1. 
Permanent and Premature Treatment Discontinuation 
Participants may have study treatment discontinued for reasons including, but not limited to, the 
following: 
•
Drug-related toxicity (see Section 8 CLINICAL MANAGEMENT ISSUES).
•
Participant experiencing an SAE that is considered at least possibly related to study
drug.
•
Request by participant to terminate treatment.
•
If platelet count drops below 75,000/mm3 treatment will be discontinued
•
NOTE: The reason for treatment discontinuation should be documented (e.g., concern
for AE, lack of efficacy, or other reason).
•
Clinical reasons believed life threatening by the physician, even if not addressed in the
toxicity section (Section 8.1) of the protocol.
•
Pregnancy.
9.2. 
Premature Study Discontinuation
Participants may be discontinued from the study for reasons including, but not limited to, the 
following: 
•
Request by the participant to withdraw consent.
•
Request of the health care provider if she or he thinks the study is no longer in the best
interest of the participant.
•
At the discretion of the IRB/EC, FDA, Office for Human Research Protections
(OHRP), other government agencies as part of their duties, investigator, or sponsor.
In the event that a participant prematurely discontinues from the study, unless they have withdrawn 
consent, sites will attempt to obtain information regarding vital status (including date last seen 
alive, hospitalization, date of death, and primary cause of death) from other sources (such as family 
members, other designated contacts, or clinic records). 


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10. 
STATISTICAL CONSIDERATIONS 
10.1. 
General Design Issues 
This is a phase IIa, double-blind, placebo-controlled trial to evaluate the safety, tolerability and 
antiviral activity of EIDD-2801 as measured by viral RNA detection in symptomatic adult 
outpatients with COVID-19.  
10.2. 
Outcome Measures 
Primary and secondary outcome measures listed below will be addressed in the study’s primary 
Statistical Analysis Plan, which will define the content of the Primary Analysis Report. This report 
will form the basis for the primary study manuscript and results reporting to ClinicalTrials.gov.  
10.3. 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
To determine if EIDD-2801 reduces the time to 
viral RNA negativity.  Viral RNA negativity will 
be determined by RT-PCR of NP swabs. 
 
• 
Qualitative RT-PCR 
To determine the safety and tolerability of 
EIDD-2801 including 1) any adverse events (AEs) 
leading to early discontinuation of treatment,  
2) study drug-related discontinuation of treatment, 
3) new grade 3 or higher AE (not already present at 
baseline), and 4) study drug-related new grade 3 or 
higher AE. 
• 
All AEs leading to early discontinuation of 
treatment 
• 
Study drug-related discontinuation of 
treatment 
• 
New grade 3 or higher AE 
• 
Study drug-related new grade 3 or higher AE 
 
 


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Secondary 
Safety Objective: To compare the incidence of 
grade 2 or higher AEs and drug-related AEs 
between treatment arms.  
• 
Grade 2 or higher AEs 
• 
Drug-related AEs 
Virologic Objectives:   
• 
To determine if EIDD-2801 reduces the time 
(days) to negativity of infectious virus isolation 
in NP swabs from SARS-CoV-2-infected 
adults. Infectious virus isolation is determined 
by isolation in Vero cell line cultures.  
 
• 
To determine if EIDD-2801 reduces the 
shedding of SARS-CoV-2 RNA in NP swabs 
compared to placebo as measured by median 
change in RNA at Treatment Days 3,  5, 7,  
14, and 28 as determined by quantitative RT-
PCR. 
 
• 
To determine if EIDD-2801 increases viral 
RNA mutation rate.  RNA mutation rate is 
measured by Next Generation sequencing. 
 
• 
Infectious virus detection in NP swab samples 
cultured on Vero-cell cultures 
• 
 Infectious virus detection by microfoci assay 
of NP swab samples cultured on Vero-cell 
cultures 
 
• 
Quantitative RT-PCR 
 
 
 
 
• 
Comparison of spike and RNA dependent 
RNA polymerase gene sequences using Next 
Generation sequencing 
Clinical Objectives:  
• 
To determine if EIDD-2801 changes the 
severity and duration of self-reported 
symptoms of COVID-19 
 
 
 
 
 
 
 
• 
To determine if EIDD-2801 treatment reduces 
the proportion of participants who are 
hospitalized for COVID-19 related illness by 
Day 28. 
• 
Patient reported symptoms 
• 
Time to improvement of new or worsened 
symptoms (including feverishness, chills, 
myalgias, headache, sore throat, loss of sense 
of smell, loss of sense of taste, cough, and 
difficulty breathing) as measured by a 
decrease in all of these symptoms from  
severe/moderate severity to mild/absent or a 
decrease in mild severity to absent in 
symptom diary (Absent or returned to pre-
COVID-19 level = 0, Mild =1, Moderate =2, 
Severe =3). 
• 
WHO 9-point ordinal scale (see Appendix 1): 
 


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Pharmacokinetic Objective: 
• 
To characterize the PK of EIDD-2801/EIDD-
1931 in patients with COVID-19 following 
administration of study regimen 
• 
To determine the relationship between drug 
exposure and viral elimination dynamics 
including time to clearance. 
 
• 
Concentrations of EIDD-2801 and EIDD-
1931 in blood and levels of viral RNA in 
respiratory and oral samples 
Exploratory 
Exploratory Clinical Objective 
• 
To determine if EIDD-2801 will prevent the 
composite endpoint of hospitalization, oxygen 
desaturation, oxygen requirement, mechanical 
ventilation, or death by 28 days after study 
entry. Hospitalization is defined as ≥24 hours 
of acute care. Oxygen desaturation will be 
measured using pulse oximetry.  Oxygen 
requirement will be measured using the WHO 
ordinal scale (see Appendix 1) 
 
• 
WHO 9-point ordinal scale (see Appendix 1) 
 
Exploratory Diagnostic Objective 
• 
To determine the comparability between site-
collected NP swabs and available OP swabs 
and available self-collected nasal mid-
turbinate swabs for the quantification of 
SARS-CoV-2 RNA or quantitative culture  
• 
To determine comparability between RNA 
detection and virus isolation from 
site-collected NP swabs  
 
• 
RT-PCR of site collected NP swabs and 
available OP swabs 
 
 
• 
RT-PCR swabs and RT-PCR of NP samples 
 
10.4. 
Randomization and Stratification 
In Part 1 of the study, eligible participants will be randomized using a 1:1 ratio to Arm A or B using 
permuted blocks. In all subsequent study parts, eligible participants will be randomized using a 
3:1 ratio (EIDD-2801:placebo) to Arm C or D (Part 2), Arm E or F (Part 3), Arm G or H (Part 4), 
Arm I or J (Part 5), Arm K or L (Part 6), Arm M or N (Part 7), Arm O or P (Part 8), or Arm Q or 
R (Part 9).   
In Part 1, randomization will be stratified by “early” versus “late” time from symptom onset, where 
“early” time from symptom onset is defined by enrollment (i.e., randomization date and time) 0 to 
≤60 hours from symptom onset and “late” is enrollment (i.e., randomization date and time) >60 to 
≤168 hours from symptom onset.  In subsequent study parts, randomization will not be stratified 
due to lack of availability of subjects in the “early” time from symptom onset.  


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10.5. 
Sample Size and Accrual 
The proposed total sample size for the study is up to approximately 172 fully evaluable 
participants. If participants in a dose group drop out or otherwise have missing or unevaluable 
primary or key secondary virology endpoint data, additional participants may be enrolled to ensure 
adequate data at each dose level. The total number of participants to be enrolled will not exceed 
204.  
For Part 1 of the study, the planned sample size is approximately 44 participants who take the first 
(confirmed) dose of study treatment (approximately 22 each in Arms A and B).   
In subsequent, optional study parts, the sample size for each part will include approximately 
16 participants who take the first (confirmed) dose of study treatment (approximately 
12 participants randomized to an active EIDD-2801 arm and 4 randomized to placebo). 
Participants who are randomized but do not take the first (confirmed) dose of study treatment will 
not be followed and will be replaced. 
This study is designed to evaluate the antiviral activity of EIDD-2801 by estimating the time (days) 
until elimination of viral RNA detection in NP swabs in people who receive EIDD-2801 compared 
to those who receive a blinded placebo. Kaplan-Meier estimation will be used with a corresponding 
exact, stratified log-rank test (for Part 1) and median time (days) until first non-detectable SARS-
Cov-2 NP swabs will be estimated in each trial arm.  
Power/Sample Size for Part 1: 
The distribution of days until SARS-CoV-2 viral RNA is not detectable (i.e., below the limit of 
quantification in NP swabs) can be compared between the 2 trial arms (drug vs placebo) using an 
exact log-rank test. At a 0.10 type I error probability and under the assumptions in Figure 8 and 
the corresponding table below, there is >85% power to detect a difference (Drug - Placebo) of at 
least 30% if the evaluable sample size is 19 individuals per arm.   
Anticipating up to 10% missing data, enrolling n=44 participants total (approximately 22 per arm) 
in Part 1 will provide 88% power for the primary endpoint.  Power was calculated empirically in 
R version 3.6.2 using 5000 simulated datasets. 
•
The power to detect a risk difference (RD) (Drug - Placebo) of -30% is 0.88.
•
The power to detect a RD (Drug - Placebo) of -40% is 0.98.
•
The power to detect a RD (Drug - Placebo) of -50% is >0.99
The table below contains the assumed data for the viral RNA detection simulations. This assumes 
collection of NP swabs from all enrolled individuals on Study Days 1, 3, 5, 7, 14, and 28. 


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Cumulative probability of viral RNA isolation 
 
Abbreviations:  D = Day; NP = nasopharyngeal;  Rx = treatment; Y = yes. 
 
Power/Sample Size for Parts 2 to 9:  
For Parts 2 to 9, no formal statistical hypotheses will be tested. In consideration of analysis of 
secondary virology endpoints in these dose range finding cohorts, separate power calculations 
were done for Parts 2 to 9.  For Parts 2 to 9, sample size sensitivity was estimated based on the 
combined study parts to compare the change from baseline in viral RNA between participants 
treated with EIDD-2801 versus participants treated with placebo. A total 96 participants in the 
Figure 8.  Probability of SARS-CoV-2 viral RNA detection assumed in power/sample 
size determination  


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active group and 32 participants in the placebo group will achieve 83% power to detect a between 
group difference of at least 0.6 SD in SARS-CoV-2 viral RNA change from baseline with a 
significance level of 0.05 using a two-sided test. 
Participants who receive placebo will be pooled in the final analyses.  The between group 
comparisons assessment of dose and exposure response will be evaluated based on endpoints of 
time to undetectable SARS-CoV-2 viral RNA and change in viral RNA over time (including 
viral RNA baseline-normalized AUC through Day 28), and number (%) of subjects with 1, 2 or 
≥3 log10 viral RNA decline over time.  
10.6. 
Populations for Analyses 
Statistical analyses will be performed on the following populations: 
• Modified Intent-to-Treat (mITT): All subjects who are randomized into the study and 
have baseline and at least 1 post baseline viral RNA assessment. Subjects will be analyzed 
according to the treatment they actually received. 
• Safety: All subjects who are randomized and take at least 1 dose of study drug. Subjects 
will be analyzed according to the treatment they actually received. 
• PK: Subjects in the safety population with at least 1 PK concentration value. 
• Per Protocol (PP): Subjects in the safety population who had no major protocol deviations 
and completed the Day 28 follow-up Visit.  
10.7. 
Statistical Analyses 
The efficacy, PK, and safety variables and associated analyses are described in this section. 
Additional details will be described in a statistical analysis plan (SAP) that will be prepared and 
finalized before database lock. Should the analyses specified in the SAP differ from those 
described in the protocol, the methodology in the SAP will prevail. General methodology will 
include descriptive tabular and/or graphical summarizations by treatment group and visit. 
Continuous variables will be presented using descriptive statistics: number of observations (n), 
mean, standard deviation, median, minimum, and maximum values. Categorical values will be 
summarized with counts and percentages. All collected data will be presented in listings. 
10.7.1. 
Demographic and Other Baseline Characteristics 
Descriptive statistical methods will be used to tabulate and summarize demographics and baseline 
characteristics. 
10.7.2. 
Pharmacokinetic and Pharmacokinetic-Pharmacodynamic Analyses 
Plasma concentrations of EIDD-2801 and EIDD-1931 will be listed and summarized by treatment 
and scheduled time point. A PK-pharmacodynamic (PD) model will also be developed to examine 
the relationship between EIDD-2801/EIDD-1931 PK, viral load reduction, and clinical outcomes. 
Details of PK and PK-PD analyses will be provided in the SAP. 


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10.7.3. 
Part 1 Analyses 
Part 1 will be analyzed separately as an a priori powered study. A Statistical Analysis Plan will be 
developed that describes the analyses to address the study’s primary, secondary, and exploratory 
objectives. 
The following provides an outline of the methods for the main comparisons between randomized 
arms, particularly for the primary outcome measure.   
Analyses involving randomized comparisons will include all randomized participants who 
received the first (confirmed) dose of study treatment, according to a modified intention-to-treat 
(m-ITT) approach. Participants who do not receive the first (confirmed) dose will be replaced. 
Unless stated otherwise, the date of randomization will be the time origin for analysis (Day 1). 
Additional per-protocol analyses may be performed, particularly for virology efficacy endpoints. 
Missing data are expected to be uncommon (<5 to 10% of participants). Losses to follow-up will 
be assumed non-informative and complete-case analyses will be conducted. 
This is a virology proof-of-principle study, as such a type I error probability of 10% (α=0.10) will 
be used throughout, with no planned adjustments for multiplicity or primary or secondary 
endpoints. Throughout, all statistical tests will be two-sided and “exact” statistical procedures that 
do not rely on large sample assumptions will be applied where computationally feasible.  
10.7.3.1. Primary Outcome Measures 
Virologic Efficacy: The distribution of days until first non-detectable SARS-CoV-2 viral RNA in 
NP swabs will be estimated for each randomized arm (drug versus placebo), using Kaplan-Meier 
methods with a corresponding exact stratified log-rank test (Part 1 only: to account for the “early” 
versus “late” time from symptom onset randomization strata). “Non detectable” will be defined as 
a viral load below the limit of quantification (BLOQ). Two consecutive non-detectable viral RNAs 
in NP swabs (or one negative with no further follow-up) will be required to achieve the event. The 
date of the first non-detectable will be the event date. Participants who prematurely discontinue 
the study before achieving non-detectable results will have follow-up for efficacy endpoints 
censored at the date of last measurement. Losses to follow-up will be assumed non-informative. 
Safety and Tolerability: In order to measure the safety and tolerability of EIDD-2801, we will 
estimate by randomization arm the probability of 1) any AEs leading to early discontinuation of 
blinded treatment (active or placebo), 2) study drug-related discontinuation of treatment, 3) new 
grade 3 or higher AE (not already present at baseline), and 4) study drug-related new grade 3 or 
higher AE. The cumulative probability (i.e., risk) of each safety and each tolerability endpoint 
(4 endpoints) will be estimated using the Kaplan-Meier approach and stratified log-rank test will 
be employed for between trial arm comparisons (as outlined for the primary efficacy outcome). 
Follow-up will be right censored at the date of last known status and event times will be the date 
of first onset of the given endpoint (e.g., time to first AE leading to early discontinuation of 
blinded treatment). 
The safety and tolerability profile of EIDD-2801 in humans is currently not fully characterized 
and descriptive participant-level listings of safety and tolerability events will be summarized. We 
will estimate 28-day risk function of each safety and tolerability endpoint with a corresponding 
2-sided 90% confidence interval, with focus on the upper confidence limit for interpretation of 
results. To inform the design of future larger trials we will estimate the difference in probabilities 


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(i.e., a risk difference) between randomization arms of each safety and tolerability endpoint with 
a corresponding 90% confidence interval. A risk ratio may also be estimated for comparison to 
other studies, although a risk difference is of greater public health relevance. 
Endpoints (1) and (2) above may be composited to assess tolerability as any AE leading to early 
discontinuation of blinded study treatment or any discontinuation of study treatment (active or 
placebo) deemed related to study drug. 
Additionally, we will describe and estimate mortality from any cause or hospitalization during 
the 28-day period from and including the day of the first (confirmed) dose of study treatment. 
Hospitalization is defined as requiring at least 24 hours of acute care in a hospital or similar 
acute care facility, including Emergency Rooms or temporary facilities instituted to address 
needs during the COVID-19 pandemic. Evaluation at a hospital or similar facility with less than 
24 hours of acute care is not considered a hospitalization. The Kaplan-Meier approach described 
above will be applied to the endpoint of days until death or first hospitalization and the 28-day 
risk function will be estimated as described for the primary safety endpoints. 
10.7.3.2. Secondary Outcomes 
Safety: Occurrence of Grade 2 or higher AEs and drug related AEs will be evaluated using the 
same approach as outlined for the primary safety analysis in Section 10.7.3.1. We will 
describe and estimate all-cause mortality and hospitalization during the 28-day period from and 
including the day of the first (confirmed) dose of study treatment. The Kaplan-Meier approach 
described above will be applied to the endpoint of days until first hospitalization or death, and 
the 28-day risk function will be estimated as described for the primary safety endpoints. 
Duration of fever, duration of symptoms, and duration of time to self-reported return to usual 
health will be summarized with descriptive statistics. Participant-specific durations of fever and 
symptoms will be compared between study arms using a stratified Wilcoxon rank-sum test. The 
distribution of days until improvement of all new or worsened COVID-19 symptoms will be 
compared between study arms using Kaplan-Meier methods with a corresponding exact stratified 
log-rank test (to account for the “early” versus “late” time from symptom onset randomization 
strata). New or worsened symptoms of COVID-19 may include feverishness, chills, myalgias, 
headache, sore throat, loss of sense of smell, loss of sense of taste, cough, and difficulty breathing. 
Improvement in these symptoms is defined as a decrease in all new or worsened symptoms (i.e., 
from severe/moderate severity to mild/absent/pre-COVID-19 severity, or a decrease in mild 
severity to absent). Participants who do not have complete symptom diaries due to hospitalization 
or death will be ranked in these analyses as having poorer outcomes than participants who survived 
without hospitalization. 
Analyses for the additional objectives will be described in the SAP. 
Virologic: The distribution of days until first non-detectable SARS-CoV-2 in NP swabs (i.e., 
infectious virus measurement) will also be estimated for each randomized arm (drug versus 
placebo), using Kaplan-Meier methods with a corresponding exact stratified log-rank test (to 
account for the “early” versus “late” time from symptom onset randomization strata). Participants 
who prematurely discontinue the study before achieving nondetectable results will have follow-up 
for efficacy endpoints censored at the date of last measurement.  Losses to follow-up will be 
assumed non-informative. 


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The distribution of days until SARS-CoV-2 is not detectable can be compared between the two 
trial arms (drug vs. placebo) using an exact stratified log-rank test.  At 0.10 (10%) type I error 
probability and under the assumptions in Figure 9 and the corresponding table below, there is 90% 
power if the evaluable sample size is 19 individuals per arm in Part 1.  In Part 1, anticipating up to 
10% missing data, enrolling n=44 participants (approximately 22 per arm) will provide 90% power 
for the secondary virologic endpoint of time to non-detectable SARS-CoV-2 in NP swabs.  Power 
was calculated empirically in R version 3.6.2 using 5000 simulated datasets. 
 
Figure 9: 
Probability of detectable SARS-CoV-2 assumed in power/sample size determination 
 
Cumulative probability of infectious virus isolation* 
 
D1 
D2 
D3 
D4 
D5 
D7 
D10 
NP swab 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
Placebo 
arm 
100% 
85% 
70% 
55% 
40% 
10% 
0% 
EIDD-
2801 Rx 
arm 
100% 
50% 
35% 
20% 
5% 
0% 
0% 
Abbreviations:  D = Day; NP = nasopharyngeal;  Rx = treatment; Y = yes. 
 Assumes treatment starts 3 to 4 days (i.e., 72 to 96 hours) after symptom onset. NP=nasopharyngeal. 
*Extrapolated from Wolfel, R et al. Nature 2020 
 
Reductions in shedding of SARS-CoV-2 RNA in NP swabs at Treatment Days  3, 5, 7, 14, and 
28 will also be compared between arms via stratified Wilcoxon rank-sum tests.  


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Mutation rate (number of mutations in the viral genome) will be assessed using next generation 
deep genome sequencing (NGS).  Mutation rates will be summarized with descriptive statistics 
and compared between study arms (drug versus placebo). 
10.8. 
Pooled Analyses 
For the final analyses, the demographic, baseline characteristics, and study disposition data will 
be summarized separately by study part and for the pooled analyses.   
Safety and efficacy data will be provided both based on the pooled analyses, as well as per cohort 
analyses.  For the pooled analyses, data across all study parts will be combined.  Subjects that 
received the same dose (i.e., placebo) across study parts will be combined into the same dose 
group.  All analyses will be performed based on the safety population (defined as subjects who 
received at least 1 dose of randomized study drug as treated) by dose group.  Data from the active 
treatment arms (e.g., Arms A, C, E, G, I, K, M, O, and Q) may be combined for analysis, when 
appropriate, in comparison with the pooled placebo group. No formal hypothesis tests will be 
performed for the pooled analyses. An estimation approach will provide the estimated between-
group differences and associated 95% confidence intervals. P-values for between-group 
comparisons may be included as descriptive statistics. 
The following provides an outline of the key methods for the efficacy and safety analyses: 
Virology Endpoints 
The time to response (i.e., time to BLOQ in viral RNA) will be analyzed using Kaplan-Meier 
methods. The median time to event and associated 95% confidence interval will be provided by 
dose group. The cumulative probability of BLOQ and associated 95% confidence intervals over 
time will also be provided by dose group. P-values for between-group comparison will be included 
as descriptive statistics using a log rank test.  
Responder endpoints (i.e., proportion of viral RNA below BLOQ) will be provided descriptively 
over time by dose group.  P-values for between-group comparison will be included as descriptive 
statistics using a 2-sample binomial test or Fisher’s exact test.  
Continuous endpoints (actual, change from baseline, percent change from baseline, adjusted AUC 
on treatment or during study) will be summarized over time by treatment group.  The between-
group differences and associated 95% confidence intervals will be estimated using an ANCOVA 
model, where dose group will be included as a fixed effect and baseline and days since infection 
will be included as covariates. Additional statistical models will be explored and details will be 
provided in the SAP.   
Analyses for the exploratory virologic objectives will be described in the SAP. 
Clinical Outcome Analyses 
Participant Symptom Diary 
Symptom diary data will be listed and individual symptom scores will be summarized by treatment 
and visit. The worst severity at each visit from the individual symptoms will also be summarized 
by treatment group.   


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The time to improvement (defined as symptoms becoming 0=absent or 1=mild; if baseline is mild, 
then improvement is defined as symptoms becoming absent) in all items and by individual item 
will be summarized using the Kaplan-Meier method and compared between randomization arms 
using a log-rank test. The median time to improvement and the cumulative probability of 
improvement over time with 95% confidence intervals will be provided by treatment group. 
Additional statistical models will be explored to assess the between group difference. Details will 
be provided in the SAP. 
WHO 9-Point Ordinal Scale and COVID-19 Related Medical Visits 
Ordinal Scale Clinical Improvement data will be listed and summarized by treatment. If data 
permit, the time to hospitalization/death will also be derived and summarized using the Kaplan-
Meyer method. 
The proportion of participants who require additional medical visits (including telemedicine visits 
and hospitalization) related to COVID-19 will be summarized by treatment group and compared 
between active drug versus placebo using a risk difference and corresponding 95% CI. 
Safety 
All safety data will be provided descriptively by dose group and scheduled time of assessment 
where appropriate.  Adverse events will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA). An AE is considered treatment-emergent if it begins or worsens in severity 
after the first dose of randomized study drug. The number and percentage of subjects with 
treatment-emergent AEs will be tabulated by system organ class (SOC) and preferred term. 
Additional AE summaries will be provided by severity, drug related AEs, AEs leading to study 
drug discontinuation, and serious AEs.  
Observed values and changes from baseline in laboratory and vital sign test results will be 
summarized by dose group at each scheduled visit. Laboratory abnormalities will be graded 
according to the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events 
Corrected Version 2.1, if applicable. Any graded abnormality that occurs following the initiation of 
study drug and represents at least a 1-grade increase from the baseline assessment is defined as 
treatment-emergent. The number and percentage of subjects experiencing treatment-emergent 
graded laboratory abnormalities will be summarized. Laboratory abnormality shifts from baseline 
to worst post-baseline assessments will also be summarized for the treatment emergent 
abnormality.    
Additional details will be described in a statistical analysis plan (SAP) and finalized before 
database lock. Should the analyses specified in the SAP differ from those described in the protocol; 
the methodology in the SAP will prevail. 
10.9. 
Interim Analysis 
No formal interim analysis is planned. 
An interim virology data monitoring report may be prepared after approximately the tenth 
participant in selected study parts (Parts 1 to 9) have data available through study Day 7. Blinded 
data listings and pooled descriptive interim summaries of viral RNA and infectious virus may be 
reviewed to verify assumptions made for sizing this proof-of-concept study, to determine whether 


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to enroll subsequent dose parts and determine doses to be evaluated in subsequent parts. In 
addition, the sponsor may choose to review pooled, blinded virology data summaries periodically 
during enrollment.   
A sponsor-designated Data Review Group comprised of a limited number of sponsor personnel 
may also review unblinded virology data from ongoing cohorts if a sufficient number of subjects 
have been enrolled. Site personnel will remain blinded until the database is locked at the end of 
the study. These data may be shared with the IND sponsor. 
After completion of each study part, unblinded virology data and safety data may be reviewed to 
determine the dose(s) for the subsequent parts.  
10.10. 
Unblinding 
For unblinding requests, including emergency unblinding, refer to 
 
, or other similar site-specific standard operating 
procedure.  
In the event that emergency disclosure of treatment assignment is thought to be required, the site 
investigator must follow 
, or other similar site-specific 
standard operating procedure. 
Unblinding will not occur to allow replacement of participants (see Section 6.2.4).  
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a participants’ study drug assignment is warranted. Participant safety must always be the first 
consideration in making such a determination. If the investigator decides that unblinding is 
warranted, the investigator should make every effort to contact the sponsor prior to unblinding a 
participant’s study drug assignment unless this could delay emergency treatment of the participant. 
If a participant’s study drug assignment is unblinded, the sponsor must be notified within 24 hours 
after breaking the blind. The date and reason that the blind was broken must be recorded in the 
source documentation and case report form, as applicable. 
If treatment assignment is unblinded, this information should only be shared with the physicians 
responsible for the management of the participant on a need-to-know basis. Treatment assignment 
should not be shared with others. This includes not sharing treatment assignment with the study 
team. 
All site e-mails to the team should be carefully worded to prevent unblinding the team. 
Unblinding of all study participants will take place after the last participant has completed the 
study, all data have been entered into the database, cleaned for primary and secondary outcome 
measures, and locked. For details, please refer to 
. 


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11. 
DATA COLLECTION AND MONITORING  
11.1. 
Reporting Protocol Deviations 
A protocol deviation is any change, divergence, or departure from the study design or procedures 
defined in the protocol. Important protocol deviations are a subset of protocol deviations that may 
significantly impact the accuracy, and/or reliability of the study data or that may significantly 
affect a participant's rights, safety, or well-being (ICH E3). The site principal investigator and 
personnel are responsible for identifying and reporting important deviations. Once important 
protocol deviations are identified, corrective actions are to be developed by the site and 
implemented promptly. Protocol deviations must be sent to the IRB/EC per their guidelines.  
For this study, all protocol deviations that meet the definition of important as defined in the MOPS 
relating to participant safety and confidentiality must be recorded on the study protocol deviation 
eCRF.  
11.2. 
Records to Be Kept 
Electronic case report form screens will be made available to sites for data entry. Participants must 
not be identified by name on any data submitted to the SMC. Participants will be identified by the 
patient identification number and study identification number provided upon randomization. 
11.3. 
Role of Data Management 
11.3.1. 
Instructions concerning entering study data on eCRFs will be provided by the data 
management team (DMT). Each clinical research site (CRS) is responsible for 
keying the data in a timely fashion. 
11.3.2. 
It is the responsibility of the DMT to ensure the quality of computerized data for 
this study. This role extends from protocol development to generation of the final 
study databases. 
11.4. 
Clinical Site Monitoring and Record Availability 
11.4.1. 
Site monitors, including representatives of the Sponsor, will visit the clinical 
research sites to review source and study data including the individual participant 
records,  consent records, eCRFs, supporting data, laboratory specimen records, 
and medical records (physicians’ progress notes, nurses’ notes, individuals’ 
hospital charts), to ensure protection of study participants, compliance with the 
protocol, and accuracy and completeness of records. The monitors also will inspect 
sites’ regulatory files to ensure that regulatory requirements are being followed 
and sites’ pharmacies to review product storage and management. 
11.4.2. 
The site investigator will make study documents (e.g., consent records, drug 
distribution forms, eCRFs) and pertinent hospital or clinic records readily 
available for inspection by the local IRB, the site monitors, the FDA, the OHRP, 


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the sponsor or designee, Western IRB (WIRB) other local, US, and international 
regulatory entities for confirmation of the study data.  
11.4.3. 
Given the epidemic spread of SARS-CoV-2 and the risk for visiting personnel, the 
study can be monitored remotely by clinical trial monitors. This will be decided 
based on the risk environment at the time of monitoring.  


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12. 
PARTICIPANTS 
12.1. 
Institutional Review Board (IRB) Review and Informed Consent 
This protocol and the informed consent document and any subsequent modifications will be 
reviewed and approved by the IRB or EC responsible for oversight of the study. Informed consent 
will be obtained from the participant either through a signed consent form or through appropriate 
remote consenting procedures. The consent form will describe the purpose of the study, the 
procedures to be followed, and the risks and benefits of participation. A copy of the consent form 
will be given to the participant and this fact will be documented in the participant’s record. 
12.2. 
Participant Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records that leave the site will be 
identified by coded number only to maintain participant confidentiality. All records will be kept 
locked. All computer entry and networking programs will be done with coded numbers only. 
Clinical information will not be released without written permission of the participant, except as 
necessary for monitoring by the IRB/EC, the FDA, OHRP, other local, US, and international 
regulatory entities as part of their duties.  
12.3. 
Study Discontinuation 
The study may be discontinued at any time by the Sponsor, FDA, IRB/EC, or OHRP as part of 
their duties to ensure that research participants are protected. 


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13. 
PUBLICATION OF RESEARCH FINDINGS 
Publication of the results of this trial will be governed by UNC policies as agreed with Ridgeback 
Biotherapeutics LP. Any presentation, abstract, or manuscript will be made available for 
collaboration and review by the Sponsor prior to submission.  


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14. 
BIOHAZARD CONTAINMENT 
As the transmission of SARS-CoV-2 and other droplet-borne pathogens can occur through contact 
with persons with active SARS-CoV-2 and infection-contaminated needles, blood, and blood 
products, appropriate blood and secretion precautions will be employed by all personnel in the 
clinical research setting and in drawing of blood, collection of respiratory samples, and shipping 
and handling of all specimens for this study, as currently recommended by the Centers for Disease 
Control and Prevention and the National Institutes of Health. 
All dangerous goods and materials, including diagnostic specimens and infectious substances, 
must be transported using packaging mandated by CFR 42 Part 72. Please refer to instructions 
detailed in the International Air Transport Association (IATA) Dangerous Goods Regulations.  
 
 


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15. 
REFERENCES 
 
1. 
Zou L, Ruan F, Huang M, et al. SARS-CoV-2 Viral Load in Upper Respiratory Specimens 
of Infected Patients. N Engl J Med. 2020;382(12):1177-1179. 
2. 
Chen J, Qi T, Liu L, et al. Clinical progression of patients with COVID-19 in Shanghai, 
China. J Infect. 2020;80(5):e1-e6. 
3. 
To KK, Tsang OT, Leung WS, et al. Temporal profiles of viral load in posterior 
oropharyngeal saliva samples and serum antibody responses during infection by SARS-
CoV-2: an observational cohort study. Lancet Infect Dis. 2020. 
4. 
Sheahan TP, Sims AC, Zhou S, et al. An orally bioavailable broad-spectrum antiviral 
inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses 
in mice. Sci Transl Med. 2020;12(541). 
5. 
Wolfel R, Corman VM, Guggemos W, et al. Virological assessment of hospitalized 
patients with COVID-2019. Nature. 2020. 
6. 
Organization TWH. Coronavirus (COVID-19). 2020; https://covid19.who.int. Accessed 
May 26, 2020. 
7. 
Team NCPERE. Vital surveillances: the epidemiological characteristics of an outbreak of 
2019 novel coronavirus diseases (COVID-19) – China. China CDC Weekly. 
2020;2(8):113-122. 
8. 
Guan WJ, Ni ZY, Hu Y, et al. Clinical Characteristics of Coronavirus Disease 2019 in 
China. N Engl J Med. 2020. 
9. 
Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel 
coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506. 
10. 
Wang D, Hu B, Hu C, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 
Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020. 
11. 
Wu Z, McGoogan JM. Characteristics of and Important Lessons From the Coronavirus 
Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72314 Cases From 
the Chinese Center for Disease Control and Prevention. JAMA. 2020. 
12. 
Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new 
coronavirus of probable bat origin. Nature. 2020. 
13. 
Li P, Fu JB, Li KF, et al. Transmission of COVID-19 in the terminal stage of incubation 
period: a familial cluster. Int J Infect Dis. 2020. 
14. 
Tong ZD, Tang A, Li KF, et al. Potential Presymptomatic Transmission of SARS-CoV-2, 
Zhejiang Province, China, 2020. Emerg Infect Dis. 2020;26(5):1052-1054. 
15. 
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(10229):1054-1062. 
16. 
Team C-I. Clinical and virologic characteristics of the first 12 patients with coronavirus 
disease 2019 (COVID-19) in the United States. Nat Med. 2020. 
17. 
Liu Y, Yan LM, Wan L, et al. Viral dynamics in mild and severe cases of COVID-19. 
Lancet Infect Dis. 2020. 
18. 
Organization TWH. Report of the WHO-China Joint Mission on Coronavirus Disease 2019 
(COVID-19). 2020; https://www.who.int/docs/default-source/coronaviruse/who-china-
joint-mission-on-covid-19-final-report.pdf. Accessed April 29, 2020. 


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19. 
Santarpia J, Rivera, DN, Herrera, VM, et al. Transmission Potential of SARS-CoV-2 in 
Viral Shedding Observed at the University of Nebraska Medical Center. medRxiv. 2020. 
20. 
Bi Q, Wu Y, Mei S, et al. Epidemiology and transmission of COVID-19 in 391 cases and 
1286 of their close contacts in Shenzhen, China: a retrospective cohort study. Lancet Infect 
Dis. 2020. 
21. 
Hernandez-Santiago BI, Beltran T, Stuyver L, Chu CK, Schinazi RF. Metabolism of the 
anti-hepatitis C virus nucleoside beta-D-N4-hydroxycytidine in different liver cells. 
Antimicrob Agents Chemother. 2004;48(12):4636-4642. 
22. 
Benson LS, Madden T, Tarleton J, Micks EA. Society of Family Planning interim clinical 
recommendations: contraceptive provision when healthcare access is restricted due to 
pandemic 
response. 
Society 
of 
Family 
Planning. 
28 
May 
2020. 
https://doi.org/10.46621/UYGR2287  
23. 
Spratt DI, Buchsbaum RJ. COVID-19 and Hypercoagulability: Potential Impact on 
Management with Oral Contraceptives, Estrogen Therapy and Pregnancy [published online 
ahead of print, 2020 Jul 29]. Endocrinology. 2020;bqaa121. doi:10.1210/endocr/bqaa121 
 
 


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16.
APPENDICES
16.1. 
Appendix 1: Health Organization Ordinal Scale for Clinical 
Improvement of COVID-19 Disease 
Source: World Health Organization web site: https://www.who.int/blueprint/priority-
diseases/key-action/COVID-
19_Treatment_Trial_Design_Master_Protocol_synopsis_Final_18022020.pdf 


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16.2. 
Appendix 2:  Contraceptive Guidance 
Definition of Women of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below): 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP: 
• Premenarchal 
• Premenopausal female with 1 of the following: 
o Documented hysterectomy 
o Documented bilateral salpingectomy 
o Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry. 
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
• Postmenopausal female 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
o A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT).  However, in the absence 
of 12 months of amenorrhea, confirmation with two FSH measurements in the 
postmenopausal range is required. 
Females on HRT and whose menopausal status is in doubt will be required to use one of 
the nonhormonal highly effective contraception methods if they wish to continue their 
HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrollment. 
 
 
 


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Contraception Requirements 
CONTRACEPTIVES ALLOWED DURING THE STUDY INCLUDEa: 
Highly Effective Methods That Have Low User Dependency  
Failure rate of <1% per year when used consistently and correctly. 
•
Progesterone-only subdermal contraceptive implantb
•
Intrauterine hormone-releasing system (IUS)c
•
Non-hormonal intrauterine device (IUD)
•
Bilateral tubal occlusion
•
Azoospermic partner (vasectomized or secondary to a medical cause)
This is a highly effective contraceptive method provided that the partner is the sole male sexual partner of the
WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of
contraception should be used. Spermatogenesis cycle is approximately 90 days.
Note: documentation of azoospermia for a male participant can come from the site personnel’s review of the
participant’s medical records, medical examination, or medical history interview.
Sexual Abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and lifestyle of the 
participant. 
Highly Effective Contraceptive Methods That Are User Dependentd (must be used in combination with a 
barrier method) 
Combined (estrogen- and progestogen-containing ) hormonal contraception  
− Oral 
− Intravaginal 
− Transdermal 
− Injectable 
Progestogen-only hormone contraceptionb 
− Oral 
− Injectable 
Barrier methods to be used with hormonal contraceptives above (male condoms are preferred method) 
• Male or female condom with or without spermicide
• Cervical cap, diaphragm, or sponge with spermicide
• A combination of male condom with either cervical cap, diaphragm, or sponge with spermicide (double
barrier methods) 
Footnotes: 
a)
Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive
methods for participants of clinical studies.
b)
If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited to those which
inhibit ovulation.
c)
IUS is a progestin-releasing IUD
d)
Failure rate of <1% per year when used consistently and correctly (and not in combination with barrier method). Typical
use failure rates are higher than perfect-use failure rates (i.e., when used consistently and correctly).
Note: The following are not acceptable methods of contraception alone or in combination: 
− Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides 
only, and lactational amenorrhea method. 
− Male and female condom should not be used together (due to risk of failure with friction).

SAP_001.pdf: 
Ridgeback Biotherapeutics, LP 
 
EIDD-2801-2003 
 
 
18FEB2021 
 
1 
 
 
  
 
STATISTICAL ANALYSIS PLAN 
PHASE IIA 
 
DATE and VERSION OF PLAN: 
 
18-FEB-2021, Version 2.0 
 
 
BASED ON: 
 
Protocol Version 5.0 
STUDY DRUG: 
EIDD-2801 
PROTOCOL NUMBER: 
EIDD-2801-2003 
STUDY TITLE: 
A Phase IIa, Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate the Safety, 
Tolerability, and Efficacy of EIDD-2801 to Eliminate SARS-CoV-2 Viral RNA Detection in 
Persons with COVID-19  
 
SPONSOR: 
Ridgeback Biotherapeutics, LP 
3480 Main Highway, Unit 402, Miami, FL 33133  
 
This study is being conducted in compliance with good clinical practice, 
including the archiving of essential documents. 


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SIGNATURE PAGE 
This document has been prepared and/or reviewed by: 
 
,    
Statistician, Pharstat Inc   
 
 
Date 
This document has been reviewed and approved  by: 
 
 
Chief Medical Officer, Ridgeback Biotherapeutics 
 
Date 
 
 


ics 
 
Da
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TABLE OF CONTENTS 
1. 
INTRODUCTION ........................................................................................................8 
2. 
STUDY OBJECTIVES AND ENDPOINTS ................................................................8 
2.1. 
Study Objectives ...........................................................................................................8 
2.1.1. 
Primary Objectives .......................................................................................................8 
2.1.2. 
Secondary Objectives ...................................................................................................8 
2.1.3. 
Exploratory Objectives .................................................................................................9 
2.2. 
Study Endpoints ............................................................................................................9 
2.2.1. 
Primary Endpoint ..........................................................................................................9 
2.2.2. 
Secondary Endpoint ......................................................................................................9 
2.2.3. 
Exploratory Endpoints ..................................................................................................9 
2.3. 
Statistical Hypotheses .................................................................................................10 
3. 
STUDY DESIGN .......................................................................................................10 
3.1. 
Definition of Study Drugs ..........................................................................................11 
3.2. 
Sample Size Considerations .......................................................................................11 
3.2.1. 
Sample Size Determination ........................................................................................11 
3.3. 
Randomization ............................................................................................................12 
3.4. 
Clinical Assessments ..................................................................................................12 
4. 
PLANNED ANALYSES ............................................................................................15 
4.1. 
Interim Analyses .........................................................................................................15 
4.2. 
Final Analysis .............................................................................................................15 
5. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING ...............................................................................................................16 
5.1. 
Data Management .......................................................................................................16 
5.2. 
Data Presentation Conventions ...................................................................................16 
5.3. 
Analysis Populations ..................................................................................................17 
5.3.1. 
Intent-to-Treat (ITT) ...................................................................................................17 
5.3.2. 
Modified Intent-to-Treat (mITT) ................................................................................17 
5.3.3. 
Safety Population ........................................................................................................17 
5.3.4. 
Per Protocol (PP) ........................................................................................................17 
5.3.5. 
Pharmacokinetic Population .......................................................................................17 
5.3.6. 
Subgroups ...................................................................................................................18 


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5.4. 
Baseline Definition .....................................................................................................18 
5.5. 
Derived and Transformed Data ..................................................................................18 
5.5.1. 
Study Day ...................................................................................................................18 
5.5.2. 
Change from Baseline .................................................................................................19 
5.5.3. 
Derived Endpoints ......................................................................................................19 
5.6. 
Missing Data and Outliers ..........................................................................................21 
6. 
TREATMENT COMPARISONS ...............................................................................23 
6.1. 
Data Display Treatment ..............................................................................................23 
7. 
STUDY POPULATION .............................................................................................24 
7.1. 
Subject Disposition .....................................................................................................24 
7.2. 
Protocol Deviations ....................................................................................................25 
7.3. 
Demographic and Baseline Characteristics ................................................................25 
7.4. 
Medical History ..........................................................................................................25 
7.5. 
Prior and Concomitant Medications ...........................................................................25 
8. 
SAFETY ANALYSES ...............................................................................................26 
8.1. 
Extent of Exposure .....................................................................................................26 
8.2. 
Adverse Events ...........................................................................................................26 
8.3. 
Pregnancies (as applicable) .........................................................................................27 
8.4. 
Clinical Laboratory Evaluations .................................................................................27 
8.5. 
Other Safety Measures ................................................................................................28 
8.5.1. 
Vital Signs ..................................................................................................................28 
8.5.2. 
Inflammatory Markers ................................................................................................28 
9. 
EFFICACY ANALYSES ...........................................................................................29 
9.1. 
Efficacy Analyses .......................................................................................................29 
9.2. 
RNA Sequencing ........................................................................................................30 
9.3. 
Participant Symptom Diary ........................................................................................30 
9.4. 
Ordinal Scale Clinical Improvement ..........................................................................31 
9.5. 
COVID Related Medical Visit ....................................................................................31 
9.6. 
Exploratory Analyses ..................................................................................................31 
10. 
CLINICAL PHARMACOLOGY DATA ANALYSES .............................................32 
10.1. 
Pharmacokinetic Analyses ..........................................................................................32 
10.2. 
Pharmacokinetic and Pharmacodynamic Analyses ....................................................32 
11. 
CHANGE FROM ANALYSIS PLANNED IN PROTOCOL ....................................33 


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11.1. 
REFERENCES ...........................................................................................................33 
11.2. 
DAIDS Adult Toxicity Table .....................................................................................33 
12. 
ATTACHMENTS .......................................................................................................34 
12.1. 
Table of Contents for Data Display Specifications ....................................................34 
 
 
 
 


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List of Abbreviations 
 
AE  
 
Adverse Event  
AIDS  
Acquired Immune Deficiency Syndrome 
ARDS  
Acute Respiratory Distress Syndrome 
ATC  
Anatomical Therapeutic Chemical 
BID 
 
Twice Daily 
BMI 
 
Body Mass Index 
CFR   
Code of Federal Regulations  
CI  
 
Confidence interval  
COVID-19 
Coronavirus Disease 2019 
CRS 
 
Cytokine Release Syndrome 
DAIDS 
Division of AIDS 
DMT  
Data Management Team 
DSS 
 
Drug Safety Services (Covance) 
EC 
 
Ethics Committee  
eCRF  
Electronic Case Report Form  
FDA  
Food and Drug Administration  
GCP 
 
Good Clinical Practice 
HAE  
Human airway epithelial cell culture 
IB  
 
Investigator Brochure  
ICU 
 
Intensive Care Unit 
ICF  
 
Informed Consent Form  
ID 
 
Identification 
  
 
IL 
 
Interleukin 
IND   
Investigational New Drug Application  
IRB  
 
Institutional Review Board  
IV  
 
Intravenous  
KM 
 
Kaplan-Meier 
m-ITT  
Modified Intention-To-Treat 
NIH   
National Institutes of Health  
NP 
 
Nasopharyngeal 
NPI 
 
Nonpharmacologic Intervention 
OHRP  
Office for Human Research Protections  
OP 
 
Oropharyngeal 


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PD 
 
Pharmacodynamic 
PHI  
 
Protected Health Information  
PI  
 
Principal Investigator  
PK 
 
Pharmacokinetic 
RT-PCR 
Reverse Transcription Polymerase Chain Reaction 
SAE   
Serious Adverse Event  
SAP   
Statistical Analysis Plan  
SARS-CoV 
Severe Acute Respiratory Syndrome coronavirus 
SARS-CoV-2  Severe Acute Respiratory Syndrome coronavirus 2  
SD 
 
Standard Deviation 
SMC  
Safety Monitoring Committee 
ULN  
Upper Limit of Normal 
UNC  
University of North Carolina 
WHO  
World Health Organization 
 


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1. 
INTRODUCTION 
This SAP describes the statistical methods to be used during the analysis and reporting for study 
EIDD-2801-2003. 
Study measurements and assessments, planned statistical methods, and derived variables are 
summarized in this plan.  Planned tables, figures, and listings are specified.  All decisions 
regarding final analyses, as defined in this SAP document, have been made prior to locking the 
database. 
This SAP should be read in conjunction with the study protocol and electronic Case Report Form 
(eCRF). Any further changes to the protocol or eCRF may necessitate updates to the SAP. This 
SAP supersedes the statistical considerations identified in the protocol; where considerations are 
substantially different, they will be so identified.  If additional analyses are required to 
supplement the planned analyses described in the SAP, they may be performed and will be 
identified in the Clinical Study Report (CSR). 
2. 
STUDY OBJECTIVES AND ENDPOINTS 
 
2.1. 
Study Objectives 
2.1.1. 
Primary Objectives 
 Primary Efficacy Objective: To determine if EIDD-2801 reduces the time to viral RNA 
negativity  
 Primary Safety Objective: To determine the safety and tolerability of EIDD-2801  
2.1.2. 
Secondary Objectives 
 To compare the incidence of grade 2 or higher AEs and drug-related AEs between 
treatment arms 
 To determine if EIDD-2801 reduces the time (days) to negativity of infectious virus 
isolation in NP swabs from SARS-CoV-2-infected adults 
 To determine if EIDD-2801 reduces the shedding of SARS-CoV-2 RNA in NP swabs 
compared to placebo as measured by median change in RNA at Treatment Days 3, 5, 7, 
14, and 28 as determined by quantitative RT-PCR 
 To determine if EIDD-2801 increases viral RNA mutation rate.  RNA mutation rate is 
measured by Next Generation sequencing 
 To determine if EIDD-2801 changes the severity and duration of self-reported symptoms 
of COVID-19 


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 To determine if EIDD-2801 treatment reduces the proportion of individuals that are 
hospitalized for COVID-19 related illness by Day 28 
 To characterize the pharmacokinetics (PK) of EIDD-2801 in patients with COVID-19 
following administration of study regimen 
 To determine the relationship between drug exposure and viral elimination dynamics 
including time to clearance 
2.1.3. 
Exploratory Objectives  
 To determine if EIDD-2801 will prevent the composite endpoint of hospitalization, 
oxygen desaturation, oxygen requirement, mechanical ventilation, or death by 28 days 
after study entry 
 To determine the comparability between site-collected NP and available OP swabs and 
available self-collected nasal mid-turbinate swabs for the quantification of SARS-CoV-2 
RNA or quantitative culture 
 To determine comparability between viral RNA detection and virus isolation from site-
collected NP swabs 
2.2. 
Study Endpoints 
2.2.1. 
Primary Endpoint 
 The viral RNA negativity determined by reverse-transcriptase polymerase chain reaction 
(RT-PCR) of NP swabs 
 Any adverse events (AEs) leading to early discontinuation of treatment; study drug-
related discontinuation of treatment; new Grade 3 or higher AEs (not already present at 
baseline); study drug-related new Grade 3 or higher AEs and serious AEs 
2.2.2. 
Secondary Endpoint 
 Incidence of Grade 2 or higher AEs and drug-related AEs 
 Infectious virus detection in NP swab samples cultured on Vero-cell cultures 
 Comparison of spike and RNA dependent RNA polymerase gene sequences using Next 
Generation sequencing 
 Patient reported symptoms of COVID-19 
 WHO 9-point ordinal scale 
 Concentrations of EIDD-2801 and EIDD-1931   
2.2.3. 
Exploratory Endpoints  
 RT-PCR of site collected NP swabs and available OP swabs 
 


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2.3. 
Statistical Hypotheses 
 
 EIDD-2801 treatment will decrease the time to clearance of SARS-CoV-2 virus in NP 
specimens from symptomatic SARS-CoV-2 infected adults compared to placebo For 
study Part 1, the distribution of days until SARS-CoV-2 viral RNA is not detectable (i.e., 
below the limit of quantification in NP swabs) can be compared between the 2 trial arms 
(drug vs. placebo) using an exact log-rank test. No hypothesis will be formally tested for 
study Parts 2-9.   
 EIDD-2801 will be safe and well tolerated in persons with symptomatic SARS-CoV-2 
infection 
 
The safety and tolerability endpoints will be presented descriptively. No hypotheses for safety 
and tolerability will be tested. 
3. 
STUDY DESIGN 
This is a Phase IIa, double-blind, placebo-controlled, randomized trial, designed to compare the 
safety, tolerability, and antiviral activity of EIDD-2801 versus placebo as measured by viral 
RNA detection in symptomatic adult outpatients with COVID-19.  The study is a multicenter 
trial. 
This study will enroll up to approximately 172 fully evaluable participants in multiple study 
parts. If participants in a dose group drop out or otherwise have missing or unevaluable primary 
or key secondary virology endpoint data, additional participants may be enrolled to ensure 
adequate data at each dose level. The total number of participants to be enrolled will not exceed 
204.  
In Part 1 of this study, approximately 44 eligible participants will be randomized 1:1 to receive 
EIDD-2801 200 mg BID (Arm A) or placebo (Arm B) orally BID for 5 days. Enrollment in 
Part 1 may be interrupted to initiate enrollment in a different cohort, and may resume at a later 
time point.  The study may continue to enroll the following optional study parts: 
 In Parts 2-4, approximately16 participants per part will be randomized 3:1 into Arms C 
and D (Part 2), Arms E and F (Part 3) and Arms G and H (Part 4) to receive treatment as 
follows: EIDD-2801 up to 800 mg or placebo orally BID for 5 days.  
 In Parts 5-9, approximately 16 participants per part will be randomized 3:1 into Arms I 
and J (Part 5), Arms K and L (Part 6), Arms M and N (Part 7), Arms O and P (Part 8), 
and Arms Q and R (Part 9) to receive treatment as follows: EIDD-2801 up to 800 mg or 
placebo orally BID for 5 days. 
The dose of EIDD-2801 evaluated in Part 1 will be 200 mg BID. The doses selected for 
subsequent study parts may be the same, higher or lower than the dose(s) studied in previous 
study parts, and will not exceed 800 mg BID. Doses will be chosen based on emerging virology 
and safety data from this and other ongoing studies. Selected doses will be communicated in an 
official memo/protocol clarification letter.  


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Participants who do not start study treatment will be replaced. The maximum number of 
participants enrolled will be 204. All study part sizes are approximate. Study parts may be 
combined for randomization purposes if the same dose is planned for more than one part.  
All participants will be followed for 5 days on treatment and an additional 23 days off treatment. 
At Study Entry (Day 1), all consented participants will have an in-person study visit at the 
clinical research center prior to IP administration. Either in-clinic visits or in-home visits will 
continue on days 3, 5, 7, 14, and 28. Information regarding participant demographics, COVID-19 
symptoms, medical and medication histories, and adverse events will be collected at screening. 
Thereafter, at each study visit, some or all of the following will be collected for each participant: 
vital signs, study daily diary entries, pregnancy test (where applicable), adverse event 
information, nasopharyngeal (NP) swab, hematology, chemistry, inflammatory markers, and 
pharmacokinetics (PK).  
In Part 1, randomization will be stratified by time (days) from symptom onset – “early” versus 
“late” presentation, where “early” and “late” presentations are defined by: 
 Early presentation:  enrollment (i.e., randomization date and time) 0 to  ≤60 hours from 
symptom onset 
 Late presentation: enrollment (i.e., randomization date and time) >60 to <168 hours from 
symptom onset 
Randomization will not be stratified in subsequent study parts.  
3.1. 
Definition of Study Drugs 
 
 To allow for variability in PK including intracellular half-life of 
the EIDD-1931- 5’-triphosphate and to account for uncertainty in scaling assumptions, doses of 
up to 800 mg are considered appropriate to explore a range of potentially efficacious doses. 
3.2. 
Sample Size Considerations 
3.2.1. 
Sample Size Determination 
This study is designed to evaluate the antiviral activity of EIDD-2801 by estimating the time 
(days) until elimination of viral RNA in NP swabs in people who receive EIDD-2801 compared 
to those who receive a blinded placebo. Kaplan-Meier (KM) estimation will be used with a 
corresponding exact log-rank test (for Part 1). The median time (days) until first non-detectable 
SARS-Cov-2 NP swabs will be estimated in each trial arm. Anticipating up to 10% missing data, 
enrolling n=44 participants total (approximately 22 per arm) in Part 1 will provide 88% power to 
detect a risk difference (active – placebo) of -35% for the primary endpoint using an alpha=0.10 
type I error rate and with viral RNA measured at Days 1, 3, 5, 7, 14, and 28. 
For Parts 2 to 9, no formal statistical hypotheses will be tested. In consideration of analysis of 
secondary virology endpoints in these dose range finding cohorts, separate power calculations 
were done for Parts 2 to 9. For Parts 2 to 9, sample size sensitivity was estimated based on the 
combined study parts to compare the change from baseline in viral RNA between participants 
treated with EIDD-2801 versus participants treated with placebo. A total 96 participants in the 


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active group and 32 participants in the placebo group will achieve 83% power to detect a 
between group difference of at least 0.6 SD in SARS-CoV-2 viral RNA change from baseline 
with a type I error rate of alpha=0.05 using a two-sided test. 
The proposed total sample size for the study is up to approximately 172 fully evaluable 
participants. If participants in a dose group drop out or otherwise have missing or unevaluable 
primary or key secondary virology endpoint data, additional participants may be enrolled to 
ensure adequate data at each dose level. The total number of participants to be enrolled will not 
exceed 204. 
3.3. 
Randomization 
In Part 1 of the study, eligible participants will be randomized using a 1:1 ratio to Arm A or B 
using permuted blocks. In all subsequent study parts, eligible participants will be randomized 
using a 3:1 ratio (EIDD-2801:placebo) to Arm C or D (Part 2), Arm E or F (Part 3), Arm G or H 
(Part 4), Arm I or J (Part 5), Arm K or L (Part 6), Arm M or N (Part 7), Arm O or P (Part 8), or 
Arm Q or R (Part 9).   
In Part 1, randomization will be stratified by “early” versus “late” time from symptom onset, 
where “early” time from symptom onset is defined by enrollment (i.e., randomization date and 
time) 0 to ≤ 60 hours from symptom onset and “late” is enrollment (i.e., randomization date and 
time) > 60 to ≤168 hours from symptom onset.  In subsequent study parts, randomization will not 
be stratified due to lack of availability of subjects in the “early” time from symptom onset. 
3.4. 
Clinical Assessments 
The timing of clinical assessments is presented in the 
Table 1 below. 


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Table 1: Schedule of Assessments 
SCHEDULE OF EVENTS 
Screening 
(in person 
or by 
phone) 
Study Entry / 
Enrollment 
Post-Entry Evaluations 
Premature Study 
Discontinuation 
Day 1 
Day 3 
Day 5 
Day 7 
Day 14 
Day 28 
(EOS) 
 
Visit Windows (days) 
Pre 
dose 
First 
Dose 
 
 
(±1 day) (±4 days) 
 
 
In-Clinic or In-Home Visit 
 
 
 
X 
X 1 
X 
 
X 
X 
In-Clinic Visit  
 
X 
 
 
 
 
X 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Documentation of Positive SARS-
CoV-2 Molecular Test2 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical history & COVID-19 
Symptom Screen 
X 
X 
 
 
 
 
 
X 
 
Vital signs 3 
 
X 
 
X 
X 
X 
X 
 
X 
Review inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
X 
 
Pregnancy Test in Women of 
Childbearing Potential 4 
 
X 
 
 
 
 
X 
 
X 
Study Kit and Study Diary 
Dispensed 5 
 
X 
 
 
 
 
 
 
 
EIDD-2801 or Placebo BID Daily 
Days 1-5 6 
 
 
X 
X 
X 
 
 
 
 
Review of Study Daily Diary7 
 
 
 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
 
X 
X 
X 
X 
X 
X 
Study Endpoint Determination 
 
 
 
X 
X 
X 
X 
X 
X 
Nasopharyngeal (NP) Swab 8 
 
X 
 
X 
X 
X 
X 
X 
X 
Oropharyngeal (OP) Swab  
 
X 
 
X 
X 
X 
X 
X 
X 
Self-Collected Nasal Mid-turbinate 
Swab 9 
 
X 
 
X 
X 
X 
X 
X 
X 
Safety labs 10 
X 
X 
 
X 
X 
X 
X 
X 
X 
Inflammatory Markers  
 
X 
 
X 
X 
X 
X 
X 
X 
Plasma for Immune Responses  
 
X 
 
X 
X 
X 
X 
X 
X 
Plasma for Immunoglobulin Assay 
 
X 
 
 
 
X 
X 
 
X 
Pharmacokinetics (Sparse) 11 
 
 
 
 
X 
 
 
 
 
Vital Status Follow-up  
 
 
 
 
 
 
 
 
X 
1. The Day 5 visit will be in-clinic for sites that are able to process PK samples, and may be in-home for other 
sites. 
2. Test to be performed within 96 hours of study entry. Rapid tests are acceptable for confirming infection. 


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3. Assessment includes measurements of temperature, blood pressure, respiratory rate, heart rate, and oxygen 
saturation. Height and weight should be recorded and may be obtained by participant’s self-report. 
4. High sensitivity pregnancy tests are required at Screening (urine or serum) within 24 hours of the first dose of 
study drug and on Day 28 (serum).  Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the absence of pregnancy at any time 
during the subject's participation in the study. 
5. Activities will include the collection of secondary contact information. 
6. First Dose will be administered in the morning of Day 1, if possible. Dosing is twice daily through Day 5 
(inclusive).  If the first dose on Day 1 is a late evening dose, the second dose may be taken on the morning of 
Day 2, in which case the final dose will be taken on the morning of Day 6.  In addition, if a participant misses 
up to 2 doses during Days 1 to 5, dosing may be extended into Day 6. 
7. Study treatment adherence will be assessed by review of the treatment adherence portion of the study diary and 
counting returned study drug and containers. 
8. The site at which virology testing will be performed (UNC at Chapel Hill) will collect 1 NP swab per timepoint 
and will divide the sample in preparation for analysis by infectivity versus PCR assay. All other study sites will 
collect 2 NP swabs (one per nostril) at each timepoint and 1 swab each will be prepared and shipped for analysis 
by infectivity versus PCR assay.   
9. Participants enrolled at the site at which virology testing will be performed (UNC at Chapel Hill) will have OP 
and nasal mid-turbinate swabs collected at the timepoints indicated. OP and nasal mid-turbinate swabs are not 
collected at all other study sites.  
10. Hematology and chemistry:  Results from hematology and chemistry will be evaluated before assessing a 
participant’s eligibility. Lab results obtained within 48 hours of enrollment (i.e., randomization date and time) 
are acceptable.  When screening and enrollment visits are combined, a single blood draw may be performed for 
both screening and baseline laboratory assessments. 
11. At all sites that are able to process PK samples, PK samples will be obtained immediately before the morning 
dose on Day 5 and at approximately 1 hour and 2 hours after the morning dose, where possible.  When possible, 
participants should fast overnight before their Day 5 visit (i.e. participants should arrive at the Day 5 visit 
having had no food or drink intake except for water in the previous 8 hours). 
 


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4. 
PLANNED ANALYSES 
4.1. 
Interim Analyses 
No formal interim analysis is planned.  
Interim virology data monitoring reports may be prepared after approximately the tenth 
participant in selected study parts has data available through study Day 7. Blinded data listings 
and pooled descriptive interim summaries of viral RNA and infectious virus may be reviewed to 
verify assumptions made for sizing this study, to determine whether to enroll subsequent dose 
parts and determine doses to be evaluated in subsequent parts. In addition, the sponsor may 
choose to review pooled, blinded virology data summaries periodically during enrollment.   
A sponsor-designated Data Review Group comprised of a limited number of sponsor personnel 
may also review unblinded virology data from ongoing cohorts if a sufficient number of subjects 
have been enrolled. Site personnel will remain blinded until the database is locked at the end of 
the study. These data may be shared with the IND sponsor. 
The following unblinded data analyses will be performed after completion of the selected parts. 
The database will be cleaned and locked for the unblinded analyses.  
 Planned unblinded analysis 1: after Parts 1-6 subjects have completed study 
  
4.2. 
Final Analysis 
 
Any data values requiring investigation or correction will be identified while programming the 
datasets and Tables, Figures, and Listings (TFLs). The final statistical analysis will be conducted 
when the last subject has completed the study and will be based on the locked database. 
 
 


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5. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING 
Tables and listings will be prepared in accordance with the current International Conference on 
Harmonization (ICH) Guidelines. Version 9.3 or higher of the SAS® system will be used to 
analyze the data as well as to generate tables, figures, and listings.   
All analyses will be performed separately for the following: 
 
1. Pooled Parts 1-9 
2. Part 1 Only  
3. Pooled Parts 2-9  
In the pooled analyses, subjects who received the same dose across study parts will be pooled 
together for safety and efficacy analyses. All subjects who received active EIDD-2801 across 
doses will be combined as an additional group in the analyses. Data listings will be sorted by 
dose level, study part, subject, and assessment time. 
General Summary Table and Individual Subject Data Listing Considerations: 
Summary tables and listings will be prepared according to ICH Guideline E3 and will include a 
‘footer’ providing explanatory notes that indicate: 
 
 Date of output generation. 
 SAS program name  
 Any other output specific details that require further elaboration  
 
If there are multiple assessments collected on the same scheduled time, the last assessment will 
be used.  Deviations from the analyses planned in the SAP will be identified in the final clinical 
study report. 
5.1. 
Data Management 
Data handling and transfer will take place as described in the Data Management Plan (DMP) for 
the study. 
 
SDTM datasets will be created based on the raw eCRF and laboratory data and adhere to CDISC 
SDTM Implementation Guide 3.2. Analysis datasets will be generated using (SAS®) version 9.3 
or later software and adhere to ADaM Implementation Guide 1.1 structure.  
5.2. 
Data Presentation Conventions 
 
Unless otherwise stated, continuous data will be summarized with the following descriptive 
statistics: number of non-missing observations (n), arithmetic mean, standard deviation (SD), 
median, minimum (min), maximum (max), and for PK parameters only, geometric mean, SD and 
geometric CV% for continuous variables. Categorical variables are summarized using counts and 
percentages. All reported p-values will be 2-sided. 


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The following conventions are applied to all data presentations and summaries. 
 For continuous variables, all mean and median values are formatted to one more decimal 
place than the measured value. Standard deviation values are formatted to two more 
decimal places than the measured value. Minimum and maximum values are presented 
with the same number of decimal places as the measured value. 
 For categorical variables, the number and percentage of responses are presented in the 
form XX (XX.X%) where the percentage is in the parentheses. 
5.3. 
Analysis Populations 
 
All populations will be defined after database lock when the relevant data are available. 
5.3.1. 
Intent-to-Treat (ITT) 
ITT (Randomized) population will include all subjects who are randomized. Subjects will be 
analyzed according to the treatment they were assigned. 
5.3.2. 
Modified Intent-to-Treat (mITT) 
mITT population will include all subjects who are randomized into the study and have at least 1 
post baseline viral RNA assessment. Subjects will be analyzed according to the treatment they 
actually received.      
5.3.3. 
Safety Population 
 
All subjects who are randomized and take at least 1 dose of study drug. Subjects will be analyzed 
according to the treatment they actually received.  All the safety analyses will be performed 
using the safety population. The patient diary and clinical outcome (Ordinal Scale Clinical 
Improvement, medial visit) data will also be analyzed using the safety population.   
5.3.4. 
Per Protocol (PP) 
Per protocol population will include subjects in the safety population who have no important 
protocol deviations leading to exclusion from the PP population and have completed the Day 28 
follow-up Visit. 
5.3.5. 
Pharmacokinetic Population 
 
All subjects in the Safety Population with at least one plasma PK concentrations of EIDD-
2801/EIDD-1931. 
 
 


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5.3.6. 
Subgroups 
 
If data permit, efficacy analyses will be performed by the following subgroups: 
 
 Number of risk factors for severe COVID-19: 0, 1-2 or >2 
 Age ≥65 or <65  
 Presence or absence of SARS-CoV-2 antibodies 
 Positive Infectivity at baseline (based on infectious virus isolation determined by 
isolation in Vero cell line culture)  
 
The risk factors for severe COVID-19 are: 
  
 Have a body mass index (BMI) ≥35 
 Have chronic kidney disease 
 Have diabetes 
 Have immunosuppressive disease 
 Are currently receiving immunosuppressive treatment 
 Are ≥65 years of age 
 Are ≥55 years of age AND have 
 cardiovascular disease, OR 
 hypertension, OR 
 chronic obstructive pulmonary disease/other chronic respiratory disease 
 
Additional COVID risk factors (i.e., cancer, pregnancy etc.), demographic and baseline 
characteristics may be explored as subgroups or as covariates for between treatment 
comparisons.  
5.4. 
Baseline Definition 
 
The baseline is defined as the last assessment prior to the first dose of study medication (i.e., 
measured at Day 1 pre-dose or at the screening visit). 
5.5. 
Derived and Transformed Data 
5.5.1. 
Study Day 
 
If the date of interest occurs on or after the first dose date then study day will be calculated as: 
 
 (date of interest – date of first dose) + 1.  
 
If the date of interest occurs prior to the first dose date then study day will be calculated as: 
 
 (date of interest – date of first dose).  
 
There is no study day 0 


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5.5.2. 
Change from Baseline 
 
Change from baseline is calculated as (post-baseline result – baseline result). 
 
Percent change from baseline is calculated as (change from baseline/baseline result * 100). 
 
If either the baseline or the post-baseline result is missing, the change from baseline and/or 
percentage change from baseline is set to missing as well.  
5.5.3. 
Derived Endpoints 
 SARS-CoV-2 RNA 
Efficacy Endpoint of SARS-CoV-2 RNA will be converted to log10 scale. Listings will include 
the values in log10 scale and in the original scale.  For SARS-CoV-2 RNA values reported as 
below the limit of detection/quantification (the lower limit of quantification is 1018 copies/mL), 
1017 copies/mL will be used in the analyses.   
SARS-COV-2 RNA below the limit of detection/quantification will be considered as 
undetectable (negative) in the analyses.  
 
 SARS-CoV-2 RNA Rate of Decline 
The individual rate of SARS-CoV-2 RNA decline will be derived as Average Area under the 
Curve minus Baseline (AAUCMB, i.e., the average daily viral load value minus baseline) for the 
five time intervals of: D1-D3, D1-D5, D1-D7, D1-D14 and D1-D28 using the following 
formulas: 






1
1
1
1
1
1
AUC
2
AAUC
t
t
t
t
x
x
t
t
n
n
n
i
i
i
i
i














, and 
AAUCMB=AAUC – Baseline (x at time i=1) 
 
where, xi is the data value at the ith time point and ti is the time value at the ith time point. 
 Time to non-detectable SARS-CoV-2 viral RNA in NP swabs based on PCR 
Two consecutive undetectable viral RNAs in NP swabs (or one negative with no further follow-
up) will be required to achieve the event. The date of the first undetectable result will be the 
event date. If the subject only has undetectable viral RNA at the last on study assessment, it will 
be counted as event at the time of the last assessment. Subjects not achieving the event and who 
complete the study follow-up will be censored at the last viral RNA assessment.  Subjects not 
achieving the event and dropped out before Day 28 will be censored at Day 28. 
Time to un-detectable = Date of Event (Censored) – date of first dose+1 
 Time to negativity of infectious virus isolation in NP swabs based on infectious virus 
isolation determined by isolation in Vero cell line culture  


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This endpoint will be derived similarly to time to undetectable viral RNAs in NP swabs based on 
PCR. Infectious virus will be measured at Days 1, 3, 5, and 7 and additional details will be 
provided in the CSR. 
 Time to COVID Symptom Resolution: 
Time to COVID Symptom Resolution will be derived based on subject overall assessment of 
COVID symptoms with resolution defined as 3 consecutive assessments in a resolved state. For 
subjects with mild, no symptoms or no diary data at the baseline, the time to resolution is defined 
as the first time where subject overall assessment is no symptoms for 3 consecutive assessments . 
For subjects with moderate or higher severity at the baseline, the time to resolution is defined as 
the first time where subject overall assessment is mild or no symptoms for 3 consecutive 
assessments. Subjects who completed study and have reached the resolved state on the last 2 
assessments will be considered as resolved on the day prior to the last assessment. Subjects who 
completed study and have reached the resolved state on the last assessment will be considered as 
resolved on the date of the last assessment. 
Subjects not achieving symptom resolution and completing the study will be censored at date of 
last COVID symptom diary. Subjects not achieving the event and dropped out before Day 28 
will be censored at Day 28. Subjects who do not achieve the event and do not complete the day 
28 diary due to hospitalization will be censored at day 28.  
Subject diary data collected within 28 days of first dose will be included in the derivation of the 
time to COVID symptom resolution endpoint.  
Time to resolution (days) = Date of resolution (Censored) – date of first dose+1 
 Time to patient reported general physical health of 3 or 4 (Very Good or Excellent) 
 
This endpoint will be derived similarly to the time to symptom resolution.  
 
 Time to patient reported returned to the (Pre-COVID) health  
 
This endpoint will be derived similarly to the time to symptom resolution. 
 
 Time to resolution of upper respiratory tract symptoms (based on the worst severity 
of the 5 symptoms measured: Cough, Shortness of breath, Sore throat, Nasal 
obstruction and Nasal discharge ) 
 
This endpoint will be derived similarly to the time to symptom resolution. 
 
 Time to resolution of common COVID symptoms (based on the worst severity of the 
13 symptoms measured: Cough, Shortness of breath, Feeling feverish, Muscle aches, 
Diarrhea, Vomiting, Nausea, Headache, Sore throat, Nasal obstruction, Nasal 
discharge, Fatigue and Chills)  
 
This endpoint will be derived similarly to the time to symptom resolution. 


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 Time to resolution of common COVID symptoms (based on the worst severity of the 
12 symptoms measured: Cough, Shortness of breath, Feeling feverish, Muscle aches, 
Diarrhea, Vomiting, Nausea, Headache, Sore throat, Nasal obstruction, Nasal 
discharge and Chills)  
 
This endpoint will be derived similarly to the time to symptom resolution. 
 
 Time to resolution of Cough  
 
This endpoint will be derived similarly to the time to symptom resolution. 
 
 
 COVID related medical visit 
 
A subject is considered to have a COVID related medical visit if the subject meets any of the 
following:  
1. Hospitalized based on the Hospitalization CRF or any outpatient medical visit 
(including telemedicine visits) 
2. Answered “Yes” to the Diary question ‘Sought urgent medical care at an emergency 
room or clinic’ 
3. Answered “Yes” to the Diary question “Been hospitalized for at least 24 consecutive 
hours” 
 
5.6. 
Missing Data and Outliers 
 
For subjects who prematurely discontinue the study, all available data will be included in the 
analyses. The planned safety and efficacy analyses will be based on the reported data.  
An investigation will be made concerning the sensitivity of the results if extreme outliers are 
detected within the data. 
 
Missing data will not be imputed.  However, for adverse events with missing onset dates, 
treatment emergent flags will be assigned based on the imputation below: 
 
Missing Adverse Event (AE) Onset Date 
 
When a missing or partial onset date has been recorded, the following algorithm will be 
performed, designed to conservatively assign AEs as treatment emergent when the AE end date 
is not before the date of first dose. 
 
 If the onset date is entirely missing, then the AE will be assigned as treatment emergent. 
 If the year of onset only is provided and the year is the same as the year of first dose of 
any study drug, then this event would be treatment-emergent. If the year of onset only is 


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provided and the year is not the same as the year of first dose, then the onset date will be 
imputed as the 1st of January of that year to determine if the event is treatment emergent. 
 If the month and year of onset are provided, and the month and year are equal to the 
month/year of first dose of any study drug, then this event would be treatment-emergent. 
In all other cases, the 1st day of the provided month/year of onset will imputed for the 
onset date to determine treatment emergent. Only if the provided month/year of onset is 
prior to the month/year of first dose would an event not be considered treatment-
emergent. 
AEs with end date prior to the date of first dose will not be considered treatment-emergent.    
AEs with missing severity will be excluded from the by severity summaries. TEAEs with 
missing relationship to study drug will be considered to be probably related to study drug in the 
summaries.  
 
Missing Data for SARS-COV-2 RNA Undetectable (Negative) Endpoint  
 
Subjects with missing SARS-COV-2 RNA at a visit(s) will be imputed based on the available 
non missing SAS-COV-2 RNA data described in the table below: 
 
Visit Before 
Visit After 
Imputation of Undetectable 
SAS-COV-2 RNA 
BLQ/BLD    
BLQ or BLD 
Negative   
>BLQ 
BLQ or BLD 
Positive  
BLQ/BLD or missing  
>BLQ 
Positive[1]  
Missing 
BLQ or BLD 
Missing 
any value 
Missing 
Missing  
BLD=below the limit of detection. BLQ=below the limit of quantification. 
[1] Subjects with missing baseline and reported the first post baseline value as >BLQ, the 
baseline will be imputed as >BLQ (Positive). 
 
Missing Data for SARS-COV-2 Infectious Virus   
 
Subjects with missing infectivity data will be imputed based rules in the table below: 
 
Visit Before 
Visit After 
Imputed Infectivity Result  
Negative    
Negative 
Negative 
Positive  
Positive  
Positive 
Negative or missing  
Positive 
Positive[1] 
Missing 
Negative 
Missing  
any value 
Missing 
Missing  
[1] Subjects with missing baseline and reported the first post baseline value of Positive, the 
baseline will be imputed as Positive. 


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6. 
TREATMENT COMPARISONS 
6.1. 
Data Display Treatment  
 
Data display treatment descriptors with actual treatment description will be defined as shown 
below: 
 
Study Part 
Treatment Description 
Treatment Display Code 
Part 1 
Part1:EIDD-2801 200 mg BID 
A  
 Part 1: Placebo 
B 
Parts 
2/3/4/5/6/7/8/9 
Parts 2-9:EIDD-2801 200, 400, or 800 
mg BID 
C/E/G/I/K/M/O/Q 
Parts 2-9: Placebo 
D/F/H/J/L/N/P/R 
Pooled 
Treatment 
EIDD-2801 200 mg BID 
1 
EIDD-2801 400 mg BID 
2 
EIDD-2801 800 mg BID 
3 
Placebo 
9 
 
 
 


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7. 
STUDY POPULATION 
7.1. 
Subject Disposition 
A summary table will be generated by study part and treatment to provide the following: 
 Number of subjects Randomized (ITT)   
 Number of subject randomized and not treated 
 Number and percentage (based on ITT) of subjects in the Safety population 
 Number and percentage (based on Safety) of subjects in the mITT population 
 Number and percentage (based on Safety) of subjects in the PK population 
 Number and percentage (based on Safety) of subjects in the PP population 
 Number and percentage of subjects in the safety population who completed the study 
 Number and percentage of subjects in the safety population who completed the 
Treatment 
 Number and percentage of subjects in the safety population who discontinued the 
study 
 Reason for discontinuation of study 
 
A subject listing noting treatment and study duration and reason for withdrawal from the study 
will be provided. Randomization details will be provided in the listing.  
A separate table will be provided by pooled treatment group to provide the following: 
 Number of subjects in the Safety population 
 Number and percentage of subjects in the mITT population 
 Number and percentage of subjects in the PK population 
 Number and percentage of subjects in the PP population 
 Number and percentage of subjects in the safety population who completed the study 
 Number and percentage of subjects in the safety population who completed the 
Treatment 
 Number and percentage of subjects in the safety population who discontinued the 
study 


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 Reason for discontinuation of study 
For subjects excluded from PP population, reasons for exclusion will be listed.  
7.2. 
Protocol Deviations 
 
Protocol deviations will be summarized and listed. All important protocol deviations, potentially 
leading to exclusion from the PP population, will be reviewed prior to database lock and 
unblinding. The reason for exclusion from PP will be documented and approved before 
unblinding.  
7.3. 
Demographic and Baseline Characteristics 
 
Demographic (age, sex, race, and ethnicity) and baseline characteristics (height, weight, and 
body mass index [BMI], vital signs, Smoking Status (current Smoker, ex-smoker or Non-
smoker), Days from Symptom Onset, D-dimer, CRP levels, WBC absolute neutrophils count and 
absolute lymphocyte count ) will be summarized and listed.   
 
The baseline viral RNA, baseline patient reported symptom will be summarized and listed.   
 
Demographic and baseline characteristics will be summarized for the ITT population by study 
part and treatment, and separately for the safety population for the pooled analyses.    
 
7.4. 
Medical History 
 
Medical history findings will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) Version 23.   Medical history will be summarized by the number and percentage of 
subjects within each SOC and PT. 
 
Ongoing medical conditions that are at increased risk for severe illness from COVID-19 will be 
reviewed and summarized separately. 
  
7.5. 
Prior and Concomitant Medications 
 
Medications used prior to the first dosing date of study drug will be recorded as prior 
medications.  Medications used on or after the first dosing date of study drug and during the 
study will be recorded as concomitant medications. 
 
Non-study medications will be coded to the medicinal product name using the World Health 
Organization Drug Dictionary (WHO-DD Version March 2017). 
 
Prior and concomitant medications will be summarized using Anatomical Therapeutic Chemical  
(ATC) Level 2 and Level 4 coded terms. 


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8. 
SAFETY ANALYSES 
 
The safety data including AEs, clinical laboratory data, and vital signs will be summarized using 
descriptive statistics and listed individually for each subject.   
8.1. 
Extent of Exposure 
 
Exposure duration in number of days will be summarized. The exposure duration is derived as 
(the date of last dose – the date of first dose+1).   
 
The number and percentage of subjects with number of doses received in the following 
categories will be summarized for the Safety population:  
 ≥1 and <5 doses 
 ≥5 and <9 doses 
 10 Doses  
 
Dosing records will be listed. A separate listing will be provided for subjects who did not 
complete the treatment (receiving all 10 doses) with reasons for each dose missed. 
8.2. 
Adverse Events 
Adverse events will be coded using MedDRA (Medical Dictionary for Regulatory Activities) 
Version 23. Any events reported after the initiation of study treatment and up to 14 days after the 
last dose of study treatment are defined as treatment-emergent AEs (TEAEs).   AEs started more 
than 14 days after the last dose of study treatment will be considered post treatment and will be 
summarized separately   
Adverse event summaries will summarize only TEAEs. Adverse events will be categorized by 
TEAE, serious TEAE (SAE), death, and discontinuation.  These categories will be further 
summarized by the causal relationship to study drug (Related and Possible related will be 
grouped together as Related;  AEs Reported as Unlikely and Not Related will be grouped 
together as Not Related).   
The Investigator will provide an assessment of the intensity of each AE.  Intensity will be 
assessed in terms of severity (mild, moderate, severe, potentially life-threatening or death).    
Subjects will be counted once and summarized under their highest severity within a SOC and PT. 
 
The following TEAE summary tables will be prepared: 
 
 Overall Summary of TEAEs (Any TEAE, TEAE Related to study drug, Grade 2 or higher 
TEAE, Grade 3 or higher TEAE, Drug related TEAEs, Drug related Grade 3 or higher 


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TEAE, TEAEs leading to study drug discontinuation, Drug related TEAEs leading to 
study drug discontinuation, Serious TEAE, TEAE leading to death)  
 Summary of TEAEs by SOC and PT 
 Summary of TEAEs by maximum severity SOC, and PT 
 Summary of Grade 2 or higher TEAEs by SOC and PT 
 Summary of Grade 3 or higher TEAEs by SOC and PT 
 Summary of Drug Related Grade 3 or higher TEAEs by SOC and PT 
 Summary of Drug Related TEAEs by SOC, and PT 
 Summary of TEAEs resulting in discontinuation from study drug by SOC and PT 
 Summary of Drug Related TEAEs resulting in discontinuation from study drug by SOC 
and PT 
 Summary of Serious TEAEs by SOC and PT 
 Summary of Drug Related Serious TEAEs by SOC and PT 
 Summary of Post Treatment AEs by SOC and PT 
8.3. 
Pregnancies (as applicable) 
If any female subjects become pregnant during the study, a listing will be provided. 
8.4. 
Clinical Laboratory Evaluations 
Individual data listings of laboratory results will be presented by study part, treatment, subject, 
and time point. Values outside of the laboratory’s reference range (i.e., those with high or low 
values) and lab toxicity grade will be included in the laboratory listings.    
Quantitative values and change from baseline in quantitative values will be summarized by 
planned nominal time and treatment for each quantitative lab.   For Laboratory data reported with  
“<” or “>” symbols, data will be presented in listings with their inequality symbols; however, for 
tabulation of summary statistics, the number associated with the inequality sign will be used for 
analysis.   
Laboratory abnormalities will be graded according to the DAIDS Table for Grading the Severity of 
Adult and Pediatric Adverse Events Corrected Version 2.1, if applicable. 
Any graded abnormality that occurs following the initiation of study drug and represents at least 
a 1-grade increase from the baseline assessment is defined as treatment-emergent. The number 
and percentage of subjects experiencing treatment-emergent graded laboratory abnormalities will 
be summarized. Laboratory abnormality shifts from baseline to worst post-baseline assessments 
will also be summarized for the treatment emergent abnormality. 


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A summary of treatment emergent Grade 3 and Grade 4 laboratory abnormalities by treatment 
will also be provided. 
Clinical Important LAB Findings 
 Platelets less than 50K 
 lipase >3xULN   
 Liver Function Test 
Liver Function tests (Alkaline Phosphatase, ALT, AST, Total or Direct Bilirubin and GGT) will 
be summarized separately.   Evaluation of drug-induced serious hepatotoxicity (eDISH) with 
log-log plots of peak post-baseline TB (x ULN) vs. peak post-baseline AST /ALT (x ULN) will 
be provided by treatment group. 
 
The number and (%) of subjects meeting the following criteria will be summarized by treatment 
group based on the liver function tests including the following: 
 
 ALT  ≥5xULN, ≥10xULN, and  ≥20xULN  
 AST  ≥5xULN, ≥10xULN, and  ≥20xULN  
 Total bilirubin≥2×ULN   
 ALT or AST >3xULN and Bilirubin >2xULN 
8.5. 
Other Safety Measures 
8.5.1. 
Vital Signs 
Vital sign assessments will be performed at the time points specified in Table 1. Vital sign 
results will be listed subject, and time point.  Vital signs will be summarized using descriptive 
statistics (n, mean, SD, median, min, and max) over time in terms of absolute values and changes 
from baseline at each scheduled time point for the safety analysis set. 
8.5.2. 
Inflammatory Markers 
Lab tests collected for inflammatory markers and immune responses will be summarized and 
listed. 
 
 


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9. 
EFFICACY ANALYSES 
9.1. 
Efficacy Analyses   
 
SARS-CoV-2 RNA 
 
The actual and change from baseline in SARS-CoV-2 RNA  (log 10) will be summarized by 
treatment and visit in tabular and graphic format using descriptive statistics for each specimen 
type.  Individual SARS-CoV-2 RNA over time will be plotted by treatment.   
 
Treatment comparisons between each active dose group and placebo group in SARS-CoV-2 
RNA change from baseline will be analyzed using a mixed model for repeated measures 
(MMRM) with restricted maximum likelihood estimation and an unstructured covariance matrix. 
This model corrects for dropout and accounts for the fact that measurements taken on the same 
subject over time tend to be correlated, by using all available information on subjects within the 
same covariate set to come up with an estimate of the treatment effect for a dropout free 
population. The statistical model will be fitted with terms for treatment group, visit, treatment by 
visit interaction, baseline SARS-CoV-2 RNA and baseline SARS-CoV-2 RNA by Visit 
interaction. The estimated treatment difference for “Active – Placebo” at each visit will be 
displayed in the summary of statistical analysis together with the 95% confidence interval and 
the associated p-value. Least Squares Means for each visit will also be presented with the 
standard error. Least Squares Means and estimated treatment differences for each visit and the 
associated 95% confidence interval will be displayed graphically.  
 
Sensitivity analyses will be conducted using an Analysis of Covariance (ANCOVA) model with 
terms for treatment group and baseline SARS-CoV-2 RNA by each study visit.  The estimated 
treatment difference for “Active – Placebo” at each visit will be displayed in the summary of 
statistical analysis together with the 95% confidence interval and the associated p-value. Least 
Squares Means for each visit will also be presented with the standard error. If parametric 
assumptions are violated, non-parametric tests (e.g., extended Mantel-Haenszel test) may be 
utilized to provide a p-value for sensitivity analysis. 
 
The number and percent of subjects with SARS-CoV-2 RNA of ≤LLOQ, or SARS-CoV-2 RNA 
reduction of ≥1, 2, or 3 log10 from baseline will be presented for each treatment group by visit.   
P-values for between-group comparison may be included as descriptive statistics using a 2 
sample binomial test. 
 
Time to response un-detectable Viral RNA will be summarized using Kaplan-Meier method. The 
median time to response and the cumulative probability of response by visit along with the 95% 
confidence intervals will be provided by treatment group.   
 
The baseline adjusted average area under curve (AAUCMB) through Day 3, Day 5, Day 7, Day 
14 and Day 28 will be derived and summarized by treatment group. Between groups 
comparisons will be performed using an ANCOVA model with terms for treatment group and 
baseline SARS-CoV-2 RNA.  The estimated treatment difference for “Active – Placebo” at each 
visit will be displayed in the summary of statistical analysis together with the 95% confidence 


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interval and the associated p-value. Least Squares Means for each visit will also be presented 
with the standard error.    
 
The number and percent of subjects with negative infectious virus isolation based on qPCR assay 
will be summarized for each treatment group by visit. P-values for between-group comparison 
may be included as descriptive statistics using a 2 sample binomial test. 
 
Time to negativity of infectious virus isolation will be summarized using Kaplan-Meier method. 
The median time to response and the cumulative probability of response by visit along with the 
95% confidence intervals will be provided by treatment group.   
 
9.2. 
RNA Sequencing 
 
Comparison of RNA dependent RNA polymerase gene sequences will be provided using Next 
Generation sequencing, amino acid mutations and nucleotide changes based on the detection of 
changes that occur at >=1% will be flagged by subject and visit.   
Treatment emergent mutations are defined as mutations that are not present at baseline. The 
number and percent of subjects with treatment emergent mutation at each amino acid position 
will be summarized by treatment group. The data will be presented separately based on the 
detection of changes occurring at  >=1%, >=3% or >=10%. The between treatment group 
comparisons will be performed using a 2 sample test based on the average number of treatment 
emergent mutations. 
 
Treatment emergent nucleotide changes are defined as nucleotide changes that are not present at 
baseline. The number and percent of subjects with treatment emergent nucleotide change at each 
amino acid position will be summarized by treatment group. The data will be presented 
separately based on the detection of changes occurring at  >=1%, >=3% or >=10%. The between 
treatment group comparisons will be performed using a 2 sample test based on the average 
number of treatment emergent nucleotide changes. 
 
The results of mutation analysis of SARS-CoV-2 nucleotide sequences compared to the 
reference SAS-CoV-2 Virus will be summarized by treatment and study visit. The results of 
mutation analysis of the post baseline vs. the baseline SARS-CoV-2 nucleotide sequences will be 
summarized by treatment.   The data will be presented separately based on the detection of 
changes occurring at  >=1%, >=3% or >=10%. 
9.3. 
Participant Symptom Diary 
 
Patient diary will be listed and individual symptom scores will be summarized by treatment and 
visit. The worst severity of all individual symptoms will be summarized by treatment and visit.  
 
The following time to response endpoints will be derived and summarized using KM method 
 
 Time to COVID Symptom Resolution (Overall) 
 Time to patient reported general physical health of 3 or 4 (Very Good or Excellent) 


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 Time to patient reported returned to the (Pre-COVID) health  
 Time to resolution of upper respiratory tract symptoms  
 Time to resolution of common symptoms  (based on the 13 or 12 symptoms) 
 Time to resolution of cough  
 
If the data warrants, the resolution or duration of individual symptoms may also be derived and 
summarized.  
 
9.4. 
Ordinal Scale Clinical Improvement 
 
Ordinal Scale Clinical Improvement data will be listed and summarized as a continuous score by 
treatment and visit. If the data permits, the time to hospitalization/death will be derived and 
summarized using KM method.  
 
9.5. 
COVID Related Medical Visit 
 
The number and percent of subjects with a COVID medical visit will be presented for each 
treatment group.  
 
The number and percent of subjects hospitalized during the study will also be summarized by 
treatment group. 
9.6. 
Exploratory Analyses   
 
 Composite endpoint of hospitalization, oxygen desaturation, oxygen requirement, 
mechanical ventilation, or death by 28 days after study entry. Hospitalization is defined 
as ≥24 hours of acute care. Oxygen desaturation is defined as oxygen saturation <93%, 
measured using pulse oximetry. Oxygen requirement will be measured using the World 
Health Organization (WHO) ordinal scale 
 
The number and percent of subjects meeting the endpoint criteria during the 28 days will be 
summarized by treatment.  
 
 Comparability between viral RNA non-negativity (i.e., above the limit of quantification) 
and virus isolation non-negativity from site collected NP swabs 
 
The viral RNA qualitative results (below or above the limit of quantification) determined by RT-
PCR and the qualitative results determined (Positive or Negative) by infectious virus detection 
cell cultures will be presented in a cross tabulation table.  Cohen’s kappa statistic will be 
estimated for the assessment of the between assay agreement. 
 
 


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10. 
CLINICAL PHARMACOLOGY DATA ANALYSES 
10.1. 
Pharmacokinetic Analyses 
Sparse blood sampling will be collected on Day 5, at prior to the morning dose, and where 
possible at approximately 1 and 2 hours after the morning dose. Plasma EIDD-2801/EIDD-1931 
concentrations will be determined by validated analytical procedures.  
Plasma concentration data will be summarized descriptively by planned time point.  
  
10.2. 
Pharmacokinetic and Pharmacodynamic Analyses 
  
The response-response relationship between Plasma EIDD-2801/EIDD-1931 trough 
concentration (pre-dose at day 5) and efficacy endpoint (i.e., change from baseline in SARS-
CoV-2 RNA at day 5) will be analyzed using a simple linear model. The paired concentration 
and efficacy endpoint(s) will be plotted with a fitted regression line superimposed. Additional 
statistical models will be explored if the data warrant.  


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11. 
CHANGE FROM ANALYSIS PLANNED IN PROTOCOL 
Due to lack of availability of subjects in the “early” time from symptom onset stratum, the 
between group comparison for the time to non-detectable SARS-CoV-2 viral RNA will be 
performed using an un-stratified log-rank test.   
Statistical comparisons of safety endpoints between treatment groups in Part 1 will not be 
performed. All safety data will be presented descriptively.  
11.1. 
REFERENCES 
11.2. 
DAIDS Adult Toxicity Table 
Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse 
Events, Version 2.1 July 2017. 
 
https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf 
 
 


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12. 
ATTACHMENTS 
12.1. 
Table of Contents for Data Display Specifications 
The TOC will be provided in a separate document.