Clinical trial NCT04392219
Conditions: Coronavirus
Keywords: Coronavirus EIDD-2801 ribonucleoside
Sponsor: Ridgeback Biotherapeutics, LP
Start date: 2020-04-10; Completion date: 2020-08-11
Enrollment: 130 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a First In Human study designed to assess the safety, tolerability and pharmacokinetics of EIDD-2801 in healthy human volunteers.

Detailed description:
This is a randomized, double-blind, placebo-controlled, First-in-Human study designed to evaluate the safety, tolerability, and pharmacokinetics of EIDD-2801 following oral administration to healthy volunteers.

Arms: arm 1: EIDD-2801: Part 1: Participants were randomized to receive 50 to 1600 mg EIDD-2801 powder-in bottle (fasted); Part 2: Participants were randomized to receive two single 200 mg doses (fed or fasted); Part 3: Participants were randomized to receive twice daily doses of EIDD-2801 in an open-label manner. arm 2: Placebo: Part 1: Participants were randomized to receive placebo (fasted); Part 3: Participants were randomized to receive placebo (fasted).
Interventions: intervention 1: EIDD-2801 intervention 2: Placebo
Intervention descriptions: intervention 1: Part 1:

Participants will be randomized to receive a single oral dose of EIDD-2801 or Placebo.

Part 2:

Two single oral doses of EIDD-2801 will be administered to participants, in an open-label manner.

Part 3:

Participants will be randomized to receive twice daily dosing either EIDD-2801 or Placebo. intervention 2: Part 1:

Participants will be randomized to receive a single oral dose of EIDD-2801 or Placebo.

Part 3:

Participants will be randomized to receive twice daily dosing either EIDD-2801 or Placebo.

Protocol documents:
Prot_000.pdf: 
Protocol Reference: EIDD-2801-1001-UK 
 CONFIDENTIAL  
 
 
 
 
 
 
 
Title of study: A Randomized, Double-blind, Placebo-controlled, First-in-human Study 
Designed to Evaluate the Safety, Tolerability, and Pharmacokinetics of EIDD-2801 
Following Oral Administration to Healthy Volunteers 
NCT Number: NCT04392219 
 
Document Type: Final Protocol  
 
         
Document Date: Version 1.1: 02 April 2020 
            
     Version 1.3: 17 June 2020 
            
     Version 2.1: 06 April 2020 
           
     Version 3.1: 13 April 2020 
            
     Version 4.1: 28 April 2020 
            
     Version 5.1: 11 June 2020 
 
 


Protocol Reference: EIDD-2801-1001-UK 
 CONFIDENTIAL  
 
 
 
 
 
 
 
Title of study: A Randomized, Double-blind, Placebo-controlled, First-in-human Study 
Designed to Evaluate the Safety, Tolerability, and Pharmacokinetics of EIDD-2801 
Following Oral Administration to Healthy Volunteers 
NCT Number: NCT04392219 
 
Document: Protocol, Version 1.1 
Date: 02 April 2020 
 


Clinical Study Protocol: EIDD-2801-1001-UK 
Version 1.1 (United Kingdom) 
Ridgeback Biotherapeutics 
Protocol Release Date: 02 April 2020  
Confidential 
Page 1 
A Randomized, Double-Blind, Placebo-Controlled, First-in-Human 
Study Designed to Evaluate the Safety, Tolerability, and 
Pharmacokinetics of EIDD-2801 Following Oral Administration to 
Healthy Volunteers 
(EIDD-2801-1001-UK) 
Protocol Version  1.1 (United Kingdom) 
Version Date 
 02 April 2020 
Sponsor Team: 
Ridgeback Biotherapeutics 
3162 Commodore Plaza, Suite 3E 
Miami, FL 33133-5815 
United States 
Medical Officer 
 
EudraCT Number 
2020-001407-17 
 
Confidential Information: The information contained in this document is the property of 
Ridgeback Biotherapeutics and may not be reproduced, published or disclosed to others without 
written authorization from Ridgeback Biotherapeutics. 


Clinical Study Protocol: EIDD-2801-1001-UK 
Version 1.1 (United Kingdom) 
Ridgeback Biotherapeutics 
Protocol Release Date: 02 April 2020  
Confidential 
Page 2 
STATEMENT OF COMPLIANCE 
The study will be carried out in accordance with Good Clinical Practice (GCP) as required by the 
following: 
 Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines. 
 Applicable International Conference on Harmonisation (ICH) GCP Guidelines. 
 United States Code of Federal Regulations (CFR) applicable to clinical studies 
(45 CFR Part 46; 21 CFR Part 50, 21 CFR Part 56, and 21 CFR Part 312). 
 Applicable laws and regulations. 


Clinical Study Protocol: EIDD-2801-1001-UK 
Ridgeback Biotherapeutics 
Version 1.1 (United Kingdom) 
Protocol Release Date: 02 April 2020 
SIGNATURE PAGE 
The signature below constitutes the approval of this protocol and the attachments and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable regulations and !CH guidelines. 
Principal Investigator: 
Signed: 
Date: 
Name 
Title 
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Confidential 
Page 3 


Clinical Study Protocol: EIDD-2801-1001-UK 
Version 1.1 (United Kingdom) 
Ridgeback Biotherapeutics 
Protocol Release Date: 02 April 2020  
Confidential 
Page 4 
TABLE OF CONTENTS 
STATEMENT OF COMPLIANCE ................................................................................................. 2 
SIGNATURE PAGE ...................................................................................................................... 3 
TABLE OF CONTENTS ............................................................................................................... 4 
LIST OF TABLES ......................................................................................................................... 8 
LIST OF FIGURES ....................................................................................................................... 9 
LIST OF APPENDICES .............................................................................................................. 10 
ABBREVIATIONS ...................................................................................................................... 11 
PROTOCOL SYNOPSIS ............................................................................................................ 14 
1.  INTRODUCTION ................................................................................................................... 23 
1.1. 
Background ............................................................................................................... 23 
1.2. 
Rationale for Development ........................................................................................ 23 
1.3. 
Nonclinical Overview ................................................................................................. 24 
1.3.1.  Mechanism of Action ................................................................................................. 24 
1.3.2.  In Vitro Pharmacology ............................................................................................... 25 
1.3.2.1. 
Antiviral Activity in Tissue Culture and in Human Airway Epithelium ............. 25 
1.3.2.2. 
Cytotoxicity of EIDD-1931 in Tissue Culture Utilizing Cells from Different 
Organs and Species ...................................................................................... 27 
1.3.2.3. 
Assessment of Mitochondrial Toxicity ............................................................ 27 
1.3.3.  In Vivo Pharmacology ............................................................................................... 27 
1.3.3.1. 
Coronavirus: SARS-CoV-1 and MERS-CoV .................................................. 27 
1.3.3.2. 
Influenza Virus ............................................................................................... 31 
1.3.3.3. 
Venezuelan Equine Encephalitis Virus .......................................................... 32 
 
 
1.4. 
Safety and Secondary Pharmacology ....................................................................... 32 
1.5. 
Nonclinical Pharmacokinetics and Metabolism ......................................................... 32 
1.5.1.  Overview ................................................................................................................... 32 
1.5.2.  Absorption ................................................................................................................. 32 
1.5.3.  Distribution ................................................................................................................ 33 
 
 
1.5.3.2. 
Tissue Distribution Studies ............................................................................ 33 
1.5.4.  Metabolism ................................................................................................................ 34 
1.5.4.1. 
Metabolic Stability of EIDD-1931 and EIDD-2801 ......................................... 34 
1.5.4.2. 
Uptake and Anabolism of EIDD-1931 in Tissue Culture and Primary Cells ... 35 
1.5.5.  Excretion ................................................................................................................... 36 
1.5.6.  Pharmacokinetic Drug Interactions ........................................................................... 36 
1.5.6.1. 
Cytochrome P450 (CYP) Inhibition ................................................................ 36 
1.5.6.2. 
CYP Induction ................................................................................................ 36 
 
 
 
 
 
 
 
 
 


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1.7. 
Potential Risks and Benefits ...................................................................................... 42 
1.7.1.  Potential Benefits ...................................................................................................... 42 
1.7.2.  Potential Risks ........................................................................................................... 42 
2.  OBJECTIVES ....................................................................................................................... 43 
2.1. 
Study Objectives ....................................................................................................... 43 
2.1.1.  Primary Objectives .................................................................................................... 43 
2.1.2.  Secondary Objective ................................................................................................. 43 
2.2. 
Study Outcome Measures ......................................................................................... 43 
2.2.1.  Primary Outcome Measures ...................................................................................... 43 
2.2.2.  Secondary Outcome Measures ................................................................................. 43 
3.  STUDY DESIGN ................................................................................................................... 44 
3.1. 
Overview ................................................................................................................... 44 
3.1.1.  Part 1  ....................................................................................................................... 44 
3.1.2.  Part 2  ....................................................................................................................... 44 
3.2. 
Rationale and Justification ........................................................................................ 45 
3.2.1.  Justification of Design ............................................................................................... 45 
3.2.2.  Justification of Starting Dose ..................................................................................... 45 
3.2.3.  Justification of Study Population ............................................................................... 47 
4.  STUDY POPULATION ......................................................................................................... 48 
4.1. 
Subject Inclusion Criteria ........................................................................................... 48 
4.2. 
Subject Exclusion Criteria ......................................................................................... 49 
5.  STUDY MEDICATION, RANDOMIZATION AND DOSE ADMINISTRATION ...................... 51 
5.1. 
Study Drug Description ............................................................................................. 51 
5.1.1.  Acquisition, Formulation, Packaging and Labeling .................................................... 51 
5.1.2.  Product Storage and Stability .................................................................................... 51 
5.2. 
Randomization .......................................................................................................... 51 
5.3. 
Dosage, Preparation and Administration of Study Drug ............................................ 52 
5.4. 
Drug Accountability ................................................................................................... 52 
5.5. 
Concomitant Medication/Treatments ......................................................................... 52 
6.  STUDY CONDUCT AND VISIT SCHEDULE ....................................................................... 54 
6.1. 
Study Conduct ........................................................................................................... 54 
6.1.1.  Study Windows and Rounding Principles .................................................................. 54 
6.1.2.  Restrictions ................................................................................................................ 54 
6.2. 
Screening .................................................................................................................. 55 
6.2.1.  Screening Visit .......................................................................................................... 55 
6.2.2.  Retesting Procedures ................................................................................................ 55 
6.2.3.  Study Visits ................................................................................................................ 56 
6.2.4.  Part 1  ....................................................................................................................... 56 
6.2.5.  Part 2  ....................................................................................................................... 56 


Clinical Study Protocol: EIDD-2801-1001-UK 
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6.3. 
Safety Follow-up and End-of-Study Visit ................................................................... 56 
6.4. 
Subject Withdrawal and Replacement ...................................................................... 56 
6.4.1.  Reasons for Withdrawal ............................................................................................ 56 
6.4.2.  Handling of Withdrawals ............................................................................................ 57 
6.4.3.  Documentation of Withdrawals .................................................................................. 58 
6.4.4.  Subject Replacement ................................................................................................ 58 
6.5. 
Unscheduled Visit(s) ................................................................................................. 58 
7.  STUDY PROCEDURES/EVALUATIONS ............................................................................. 59 
7.1. 
Demography and Medical History ............................................................................. 59 
7.2. 
Clinical Evaluations ................................................................................................... 59 
7.2.1.  Physical Examinations .............................................................................................. 59 
7.2.2.  Vital Sign Measurements and ECGs ......................................................................... 59 
7.2.3.  Adverse Events and Concomitant Medications ......................................................... 60 
7.3. 
Laboratory Evaluations .............................................................................................. 60 
7.3.1.  Routine Laboratory Panels ........................................................................................ 60 
7.3.2.  Pharmacokinetic Sampling ........................................................................................ 61 
7.3.3.  Peripheral Blood Mononuclear Cell Collection .......................................................... 62 
7.3.4.  Urine Collection ......................................................................................................... 62 
8.  SAFETY MONITORING, MANAGEMENT AND REPORTING ............................................ 63 
8.1. 
Definitions .................................................................................................................. 63 
8.1.1.  Adverse Events ......................................................................................................... 63 
8.1.2.  Serious Adverse Events ............................................................................................ 63 
8.2. 
Documenting Adverse Events ................................................................................... 64 
8.2.1.  Timeframe for Collection and Follow-up of AEs/SAEs .............................................. 64 
8.2.2.  Recording of Adverse Events/Serious Adverse Events ............................................ 65 
8.2.3.  Assessing Severity of Adverse Events ...................................................................... 65 
8.2.4.  Relationship to Study Drug ........................................................................................ 66 
8.2.5.  Classifying Adverse Event Outcome ......................................................................... 66 
8.3. 
Reporting Procedures ................................................................................................ 67 
8.3.1.  Serious Adverse Events ............................................................................................ 67 
8.3.2.  Pregnancy ................................................................................................................. 67 
8.4. 
Unmasking Treatment Assignment ........................................................................... 68 
9.  DOSE-ESCALATION AND HALTING RULES..................................................................... 69 
9.1. 
Guidelines for Dose-Escalation ................................................................................. 69 
9.2. 
Dose-Escalation Halting Rules .................................................................................. 69 
10. STATISTICAL CONSIDERATIONS ..................................................................................... 71 
10.1. 
General Considerations ............................................................................................. 71 
10.2. 
Sample Size Considerations ..................................................................................... 71 
10.3. 
Analysis Populations ................................................................................................. 71 
10.4. 
Analysis of Safety Data ............................................................................................. 71 
10.4.1. Extent of Exposure .................................................................................................... 71 
10.4.2. Adverse Events ......................................................................................................... 72 
10.4.3. Clinical Laboratory Results ........................................................................................ 72 
10.4.4. Other Parameters ...................................................................................................... 72 
10.5. 
Analysis of Pharmacokinetic Data ............................................................................. 72 


Clinical Study Protocol: EIDD-2801-1001-UK 
Version 1.1 (United Kingdom) 
Ridgeback Biotherapeutics 
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10.5.1. Statistical Analysis of Pharmacokinetic Data ............................................................ 73 
10.5.1.1.  Dose Proportionality ...................................................................................... 73 
10.5.1.2.  Food-Effect .................................................................................................... 74 
10.6. 
Peripheral Blood Mononuclear Cells ......................................................................... 74 
10.7. 
Interim Analyses ........................................................................................................ 74 
11. STUDY ADMINISTRATION .................................................................................................. 75 
11.1. 
Regulatory and Ethical Considerations ..................................................................... 75 
11.2. 
Ethical Standard ........................................................................................................ 75 
11.2.1. Ethics Committee Approval ....................................................................................... 75 
11.2.2. Informed Consent ...................................................................................................... 75 
11.3. 
Financing and Insurance ........................................................................................... 76 
11.4. 
Source Documentation and Access .......................................................................... 76 
11.5. 
Data Collection and Record Keeping ........................................................................ 76 
11.5.1. Data Collection .......................................................................................................... 76 
11.5.2. Study Records Retention .......................................................................................... 77 
11.5.3. Protocol Deviations ................................................................................................... 77 
11.6. 
Clinical Monitoring ..................................................................................................... 77 
11.7. 
Quality Control and Quality Assurance ..................................................................... 77 
11.8. 
Study Termination and Closure Procedures.............................................................. 78 
11.8.1. Study Termination ..................................................................................................... 78 
11.8.2. Termination Procedures ............................................................................................ 78 
11.9. 
Information Disclosure ............................................................................................... 78 
11.9.1. Confidentiality ............................................................................................................ 78 
11.9.2. Clinicaltrials.gov ........................................................................................................ 79 
11.9.3. Publication Policy ...................................................................................................... 79 
12. REFERENCES ...................................................................................................................... 80 
13. APPENDICES ....................................................................................................................... 81 


Clinical Study Protocol: EIDD-2801-1001-UK 
Version 1.1 (United Kingdom) 
Ridgeback Biotherapeutics 
Protocol Release Date: 02 April 2020  
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LIST OF TABLES 
Table 1: 
EIDD-1931 Antiviral Activity Against Influenza A and B Viruses in Tissue Culture and 
Primary Human Bronchial/Tracheal Epithelial Cells ................................................. 25 
Table 2: 
EIDD-1931 Antiviral Activity Against SARS and MERS Coronaviruses in Tissue 
Culture and Primary Human Bronchial/Tracheal Epithelial Cells ............................. 26 
Table 3: 
EIDD-1931 Antiviral Activity Against Togaviruses in Tissue Culture ........................ 26 
 
 
Table 5: 
Cytotoxicity (CC50) of EIDD-1931 in Mammalian Cell Lines .................................... 27 
Table 6: 
Metabolic Stability of EIDD-2801 in Plasma and Liver Microsomes ......................... 35 
Table 7: 
Metabolic Stability of EIDD-2801 in Simulated Gastric and Intestinal Fluids and in 
Buffered Saline with Fetal Bovine Serum ................................................................. 35 
Table 8: 
Metabolic Stability of EIDD-1931 in Plasma, Whole Blood and Liver and Intestinal 
Microsomes .............................................................................................................. 35 
 
 
 
Table 10:  Allowable Time Windows for Study Assessments/Visits .......................................... 54 
Table 11:  Laboratory Evaluations ............................................................................................. 61 
Table 12:  Adverse Event Outcomes ......................................................................................... 66 
Table 13:  Pharmacokinetic Parameters ................................................................................... 73 
 


Clinical Study Protocol: EIDD-2801-1001-UK 
Version 1.1 (United Kingdom) 
Ridgeback Biotherapeutics 
Protocol Release Date: 02 April 2020  
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LIST OF FIGURES 
Figure 1: 
Study Schema .......................................................................................................... 22 
Figure 2: 
Inhibition of SARS-CoV-2 by EIDD-1931 ................................................................. 26 
Figure 3: 
EIDD-2801 Prophylactic Treatment of SARS-CoV Infected Mice ............................ 28 
Figure 4: 
EIDD-2801 Treatment of SARS-CoV Infected Mice ................................................. 29 
Figure 5: 
EIDD-2801 Prophylactic Treatment of MERS-CoV Infected Mice ............................ 30 
Figure 6: 
EIDD-2801 Treatment of MERS-CoV Infected Mice ................................................ 31 
Figure 7: 
Tissue Distribution of EIDD-1931 and EIDD-2061 in Ferret Brain and Lung ............ 34 
 
 


Clinical Study Protocol: EIDD-2801-1001-UK 
Version 1.1 (United Kingdom) 
Ridgeback Biotherapeutics 
Protocol Release Date: 02 April 2020  
Confidential 
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LIST OF APPENDICES 
Appendix 1: 
Time and Events Schedule ............................................................................ 81 
Appendix 2: 
DMID Toxicity Grading Scale ......................................................................... 83 
Appendix 3: 
Contraception Guidance ................................................................................ 87 


Clinical Study Protocol: EIDD-2801-1001-UK 
Version 1.1 (United Kingdom) 
Ridgeback Biotherapeutics 
Protocol Release Date: 02 April 2020  
Confidential 
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ABBREVIATIONS 
AE 
adverse event 
AGP 
alpha1-acid glycoprotein 
ALT/SGPT 
alanine aminotransferase/serum glutamic pyruvic transaminase 
AST/SGOT 
aspartate aminotransferase/serum glutamic oxaloacetic transaminase 
AUC 
area under the curve 
BID 
twice-daily 
BMI 
body mass index 
CDC 
Centers for Disease Control and Prevention 
CEM 
a cell line of lymphoblastic cells derived from a child with leukemia 
CFR 
Code of Federal Regulations 
CHKV 
chikungunya virus 
CI 
confidence interval 
CoV 
coronavirus 
CRF 
case report form 
CTP 
cytosine triphosphate cytidine triphosphate 
CYP 
cytochrome P450 
DMSO 
dimethylsulfoxide 
DRF 
dose range finding 
DSS 
Drug Safety Services 
EBOV 
Ebola virus 
EC 
Ethics Committee 
EC50 
half maximal effective concentration 
ECGs 
electrocardiogram 
EEEV 
eastern equine encephalitis virus 
EIDD 
Emory Institute for Drug Development 
EOS 
end of study 
FDA 
Food and Drug Administration 
FE 
food-effect 
FIH 
first-in- human 
FSFV 
first-subject-first-visit 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
GGT 
gamma glutamyl transferase 
GI 
gastrointestinal 
GLP 
good laboratory practice 


Clinical Study Protocol: EIDD-2801-1001-UK 
Version 1.1 (United Kingdom) 
Ridgeback Biotherapeutics 
Protocol Release Date: 02 April 2020  
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HAE 
human airway epithelium 
HBV 
hepatitis b virus 
HCV 
hepatitis c virus 
HED 
human equivalent dose 
HIV 
human immunodeficiency virus 
HLGT 
high level group term 
HPMC 
hydroxypropyl methylcellulose 
HSA 
human serum albumin 
IAV 
influenza a virus 
IB 
Investigator’s Brochure 
IBV 
influenza b virus 
IC50 
half maximal inhibitory concentration 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IND 
Investigational New Drug 
LDH 
lactate dehydrogenase 
LSLV 
last-subject-last-visit 
MAD 
multiple ascending dose 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean cell volume 
MDCK 
Madin-Darby Canine Kidney Cells 
MERS 
Middle East Respiratory Syndrome 
MRSD 
maximum recommended starting dose 
MTD 
maximum tolerated dose 
NOAEL 
no-observed-adverse-effect-level 
NSAID 
nonsteroidal anti-inflammatory drug 
OTC 
over-the-counter 
PBMC 
peripheral blood mononuclear cells 
PBO 
placebo 
PI 
principal investigator 
 
 
PK 
pharmacokinetic 
RDW 
red cell distribution width 
RNA 
ribonucleic acid 
RSV 
respiratory syncytial virus 


Clinical Study Protocol: EIDD-2801-1001-UK 
Version 1.1 (United Kingdom) 
Ridgeback Biotherapeutics 
Protocol Release Date: 02 April 2020  
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SAD 
single ascending dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SARS 
Severe Acute Respiratory Syndrome 
SI 
selectivity index 
SMP 
safety management plan 
SOP 
standard operating procedure 
SUSAR 
suspected unexpected serious adverse event 
UTP 
uridine 5'-triphosphate 
VEEV 
Venezuelan equine encephalitis virus 
ZIKV 
Zika virus 


Clinical Study Protocol: EIDD-2801-1001-UK 
Version 1.1 (United Kingdom) 
Ridgeback Biotherapeutics 
Protocol Release Date: 02 April 2020  
Confidential 
Page 14 
PROTOCOL SYNOPSIS 
Sponsor: Ridgeback Biotherapeutics 
Title: A Randomized, Double-Blind, Placebo-Controlled, First-in-Human Study Designed to 
Evaluate the Safety, Tolerability, and Pharmacokinetics of EIDD-2801 Following Oral 
Administration to Healthy Volunteers (EIDD-2801-1001-UK) 
Short Title: EIDD-2801-1001-UK 
Development Phase: Phase 1 
Description of Study Drugs, Dose and Mode of Administration: EIDD-2801 and matching 
placebo (PBO) will be supplied
 
  
Part 1: A single oral dose of EIDD-2801 or PBO will be administered to subjects enrolled in 
Part 1 (P1; single ascending dose [SAD]) cohorts. The starting dose in the first SAD cohort will 
be 50 mg. The doses will be administered in an escalating manner. Dose levels will not increase 
by more than 3-fold for predicted nonpharmacologically active dose levels and by 2-fold for 
predicted pharmacologically active dose levels. 
 
Part 2: Subjects in Part 2 (P2)/food-effect (FE) will receive 2 single doses of EIDD-2801 with a 
14-day (minimum) washout period between doses. The dose for the P2/FE cohort is planned to 
be 100 mg but may be adjusted based on safety, tolerability, and/or pharmacokinetic (PK) data 
from P1. In any case, the dose assessed in the P2/FE cohort will have been given previously to 
subjects in a P1/SAD cohort successfully (i.e., no halting rules were met following dosing). 
Treatment Duration:  
Part 1: Subjects enrolled into P1/SAD cohorts will receive a single dose of study drug 
(EIDD-2801 or matching PBO).  
Part 2: Subjects enrolled into the P2/FE cohort will receive 2 single doses of EIDD-2801, with a 
washout period between doses. 
Subject Duration:  
Part 1: The maximum possible study duration for participants enrolled in P1/SAD cohorts will 
be approximately 43 days. 
Part 2: The maximum possible study duration for participants enrolled in the P2/FE cohort will 
be approximately 58 days. 
Objectives and Endpoints: 
Part 1: SAD Cohorts 
Primary: 
 
Objective: To determine the safety and tolerability of single ascending doses of EIDD-2801
o Endpoints:  
 
Results of safety evaluations including safety laboratory assessments, 
physical examination (PE), electrocardiograms (ECGs), vital signs, and 
adverse events (AEs). 
 


Clinical Study Protocol: EIDD-2801-1001-UK 
Version 1.1 (United Kingdom) 
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Secondary: 
 
Objective: To define PK of EIDD-2801 and EIDD-1931 in plasma and urine following 
single doses administered to healthy volunteers 
o Endpoints: 
 
Plasma PK parameters, including Cmax, tmax, t1/2, CL/F, λz, Vz/F, AUC0-inf 
and AUClast as appropriate 
 
Urinary excretion of EIDD-2801 and EIDD-1931 following single-dose 
administration 
Part 2: Single-Dose Food-Effect 
Primary: 
 
Objective: To assess the effect of food on the PK of EIDD-2801 and EIDD-1931 following 
a single oral dose 
o Endpoints: 
 
Plasma PK parameters, including Cmax, tmax, t1/2, CL/F, λz, Vz/F, AUC0-inf 
and AUClast as appropriate 
 
Urinary excretion of EIDD-2801 and EIDD-1931 following single-dose 
administration 
Secondary: 
 
Objective: To determine the safety and tolerability of single doses of EIDD-2801. 
o Endpoints: 
 
Results of safety evaluations, including safety laboratory assessments, PE, 
ECG, vital signs, and AEs 
Population:  
Part 1: P1/SAD cohorts will include 8 subjects each, 2 randomized to receive PBO and 
6 randomized to receive EIDD-2801. Initially, 4 SAD cohorts are planned for P1/SAD with the 
option to add an additional 3 cohorts based on study results. 
Part 2: Ten subjects will be enrolled into the P2/FE cohort; all subjects enrolled in the P2/FE 
cohort will receive EIDD-2801. One P2/FE cohort is planned for the study. If PK results 
obtained are equivocal, additional subjects may be enrolled into the P2/FE cohort at the 
previously tested dose or an additional P2/FE cohort may be added at a different dose. The site is 
strongly encouraged to ensure that women are represented in each cohort.  
Inclusion and exclusion criteria for study participation are as follows: 
Inclusion Criteria: subjects who meet all of the criteria at Screening will be eligible for study 
participation 
1. Male or female between the ages of 18 and 60, inclusive. 
2. Female subjects must be of non-childbearing potential. Non-childbearing potential is 
defined as women who: 
• 
are physiologically incapable of becoming pregnant including those who are 
surgically sterile, via hysterectomy, bilateral salpingectomy, and/or bilateral 
oophorectomy by reported medical history and/or medical records. Surgical 
sterilization to have occurred a minimum of 6 weeks, or at the Principal 
Investigator’s (PI’s; or designee) discretion, prior to Screening. 


Clinical Study Protocol: EIDD-2801-1001-UK 
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Ridgeback Biotherapeutics 
Protocol Release Date: 02 April 2020  
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• 
are post-menopausal (at least 45 years of age with amenorrhea for 12 months 
without an alternative medical reason with confirmatory follicle stimulating 
hormone (FSH) levels of ≥ 40 mIU/mL. The amenorrhea should not be induced 
by a medical condition such as anorexia nervosa, hypothyroid disease or 
polycystic ovarian disease, or by extreme exercise. It should not be due to 
concomitant medications that may have induced the amenorrhea such as oral 
contraceptives, hormones, gonadotropin-releasing hormones, anti-estrogens, or 
selective estrogen receptor modulators.) 
3. Male participants must agree to the use of effective contraception for study duration, 
i.e., from Check-in until 90 days following the last dose of study drug. 
4. Is in generally good health as determined by medical history, PEs (at Screening and/or 
Check-in), vital signs, and other screening procedures. 
5. Has a body mass index (BMI) of 18 to 30 kg/m2. 
6. Is willing and able to comply with all study procedures including providing informed 
consent. 
Exclusion Criteria: subjects who meet any of the following criteria at Screening (unless 
otherwise stated) will not be eligible for participation 
1. Females who are pregnant, planning to become pregnant, or breastfeeding. 
2. Has a clinically relevant acute or chronic medical condition or disease of the 
cardiovascular, gastrointestinal, hepatic, renal, endocrine, pulmonary, neurologic, or 
dermatologic systems as determined by the PI (or designee). 
3. Has any current or historical disease or disorder of the hematological system or 
significant liver disease or family history of bleeding/platelet disorders. 
4. Has a history of cancer (other than basal cell or squamous cell cancer of the skin), 
rheumatologic disease or blood dyscrasias. 
5. Has a history of gastrointestinal surgery or other condition that may interfere with 
absorption of study drug, in the option of the PI (or designee). 
6. Has a history of febrile illness within the 14 days prior to the first dose of study drug. 
7. Has a positive alcohol or drug screen at Screening or the Day -1 visit or has a history of 
alcohol or drug abuse within the past 5 years. 
8. Currently uses tobacco, nicotine or tobacco products, e-cigarettes or has stopped using 
tobacco products within the past 3 months and/or has a positive cotinine test at 
Screening or Check-in. 
9. Has any abnormal laboratory value of Grade 2 or higher, which is considered to be 
clinically significant by the PI (or designee). 
10. Has a total white cell count or absolute lymphocyte count outside the normal range, or 
hemoglobin or platelet levels below the lower limit of normal, at Screening of Day -1. 
11. Has values above the upper limit of normal for the following laboratory analytes: 
alanine aminotransferase (ALT/SGPT), alkaline phosphatase (serum), aspartate 
aminotransferase (AST/SGOT), at Screening or Day -1 
12. Positive test result for human immunodeficiency virus (HIV), hepatitis B virus (HBV), 
or hepatitis C virus (HCV). 
13. Has an autoimmune disease, is immunosuppressed or is in any way 


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immunocompromised. 
14. Has any of the following: 
• 
QTcF >450 ms confirmed by repeat measurement 
• 
QRS duration >110 ms confirmed by repeat measurement 
• 
PR interval >220 ms confirmed by repeat measurement 
• 
findings which would make QTc measurements difficult or QTc data 
uninterpretable 
• 
History of additional risk factors for torsades de pointes (e.g., heart failure, 
hypokalemia, family history of long QT syndrome). 
15. Except as noted, has used prescription drugs (other than hormone replacement therapy) 
within 14 days prior to the first dose of study drug unless, in the opinion of the PI (or 
designee), the drug will not interfere with study assessments. The following prescription 
drugs will be allowed: 
• 
Statins: Subjects who have been on a stable dose of statins for a minimum of 
6 months and who have normal creatine kinase at Screening. 
• 
Antihypertensives: Subjects who have been on a stable dose of 
antihypertensives for a minimum of 6 months and have controlled blood 
pressure and no active heart disease. 
16. Has received an experimental agent (vaccine, drug, biologic, device, blood product or 
medication) within 3 months prior to the first dose of study drug and agrees not to 
receive another experimental agent during the duration of this trial. 
17. Has donated blood within 30 days, plasma within 2 weeks, or platelets within 6 weeks 
prior to Screening or refuses to agree to not donate blood until 3 months after the End of 
Study (EOS) visit. 
18. Uses over-the-counter (OTC) medications or nutritional supplements (including, e.g., 
gingko biloba, aspirin at any dose, and nonsteroidal anti-inflammatory drugs [NSAIDs]) 
on a routine/scheduled basis, and/or is unwilling to abstain from such use for the 
duration of the study. 
19. Is unwilling to abstain from quinine containing products including quinine water, tonic 
water, bitter lemon, jello shots, any quinine preparations or Cinchona tree bark 
preparations (e.g., herbal medications containing Cinchona tree bark). 
20. Has any condition that would, in the opinion of the PI (or designee), put the subject at 
increased risk for participation in a clinical trial or confinement in a clinical research 
unit. 
Retesting for Inclusion/Exclusion Criteria: In the case where a parameter is outside of the 
acceptable limits for enrollment, measurement of the parameter can be repeated one time if both 
the following are met: 
 In the opinion of the PI (or designee), the parameter value does not represent a chronic 
condition that otherwise will preclude the volunteer from enrolling in the study; and 
 In the opinion of the PI (or designee), the abnormality is not likely to recur. 
General Investigational Plan: For all potential subjects, volunteers who express interest in the 
study will report to the clinic for informed consent. The study will be explained to the subject 


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and the Ethics Committee (EC)-approved Informed Consent Form (ICF) will be presented. The 
subject will be given the chance to review the document and ask any questions he/she may have. 
If, after reviewing the consent, the subject would like to participate in the study, then he/she will 
sign the ICF and begin screening for study entry; those satisfying all criteria will be enrolled into 
the study and admitted to the clinic on Day -1. Retesting will be allowed as described above. 
Part 1: For P1/SAD, the first cohort will be divided into 2 groups. The first group, a sentinel 
group, will include 2 subjects.  
On Day 1, one subject in the sentinel group will be administered PBO and one will be 
administered EIDD-2801. Analysis of the safety results for the sentinel group will be reviewed 
24 hours postdose. If no halting criteria have been met, the remainder of the subjects in Cohort 1 
(the second group) will be dosed. There will be no sentinel groups for the remaining cohorts. 
Following dosing on Day 1, subjects will remain in the clinic through completion of study 
assessments on Day 4, returning to the clinic on Day 9 for study assessments, and Day 15 for the 
EOS visit.  
Doses will be administered in an escalating manner following satisfactory review by the Sponsor 
and PI of the blinded safety and tolerability data (up to 72 hours post final dose). Dose-escalation 
will only occur if data from a minimum of 6 subjects have been reviewed from the previous 
lower dose group, such that data from a minimum of 4 subjects who have received EIDD-2801 
will be used to make the dose-escalation decision. Dose levels will not increase by more than 
3-fold for predicted nonpharmacologically active dose levels and by 2-fold for predicted 
pharmacologically active dose levels. The highest dose to be studied under this protocol will not 
exceed 200 mg. 
Part 2: For P2/FE, one cohort assessing the effect of food on EIDD-2801 and EIDD-1931 PK 
parameters will be enrolled; it is planned that the FE cohort will be at a dose of 100 mg 
EIDD-2801, although higher or lower doses may be selected based on safety and available PK 
data from P1.  
In addition to assessing the effect of food on dosing, peripheral blood mononuclear cells 
(PBMCs) will be collected from subjects following each dose; the PBMCs will be stored for 
analysis of EIDD-2061 levels at some point in the future.  
The 10 subjects enrolled in the FE cohort will all receive EIDD-2801; subjects will be 
randomized to treatment sequence; i.e., to receive drug in the fed then fasted state (Sequence 1) 
versus fasted then fed state (Sequence 2). Half of the subjects in the cohort will be randomized to 
Sequence 1 and the other half will be randomized to Sequence 2.  
Following dosing on Day 1, subjects will remain in the clinic through completion of study 
assessments on Day 4, returning to the clinic on Day 9 for study assessments, and Day 14 to 
begin the second dosing sequence on Day 15. Subjects will then be discharged from the clinic on 
Day 18, returning to the clinic on Day 23 for study assessments, and Day 30 for the EOS visit. 
There will be a 14-day (minimum) washout period between doses.Additional parts may be 
added to this study, including a SAD part in elderly healthy subjects, a multiple-ascending 
dose (MAD) part in healthy subjects, and a study of the safety, tolerability, and PK in 
Japanese subjects. These additional parts are not described in this protocol but may be 
added via a protocol amendment. It is planned that the MAD part will include 4 
dose-escalation cohorts (with the option to include an additional 3 cohorts), with subjects 
receiving BID doses for 7 days. It is planned that each MAD cohort will comprise 8 


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subjects, with 6 subjects receiving EIDD-2801 and 2 subjects randomized to PBO. 
Safety Monitoring and Potential Unblinding: Safety for this study will be continually 
monitored by the PI and Sponsor.  
Blinding: All study personnel will remain blinded to treatment assignment (i.e., EIDD-2801 or 
PBO) in P1, except for personnel at the bioanalytical laboratory, and the unblinded pharmacy 
staff and pharmacokineticist. If unblinding is required to manage subject safety or to support 
dose-escalation decisions, the decision to unblind lies solely with the PI. If possible and 
providing that it does not interfere with or delay any decision in the best interest of the subject, 
the PI will discuss the intended code-break with the Sponsor. 
Dose-Escalation Halting Rules: 
For Group 1 in P1/SAD, sentinel dosing will occur whereby 2 subjects (1 active and 1 PBO) will 
be dosed on 1 day and, providing no safety concerns arise, the remaining 6 subjects will be 
dosed after at least 24 hours. 
The study will be halted if one or more subjects experience a serious adverse event (SAE) that is 
considered to be related to EIDD-2801 or 2 or more subjects in the same group experience 
severe AEs that are considered to be related to EIDD-2801.  
Dose-escalation will stop if clinically relevant signs or symptoms of similar nature occur in 2 or 
more subjects in a group that, in the opinion of the PI, warrant stopping of dose-escalation. 
Data Monitoring, Safety Reporting and Unblinding: Data will be monitored throughout the 
course of the study by experienced clinical monitors according to the clinical monitoring plan. 
As data will be entered into an electronic case report form (CRF), data will be monitored to 
ensure accuracy as well as adherence to data entry instructions provided in the CRF guidelines. 
Procedures for reporting any SAE will be detailed in the protocol and forms and instructions 
provided to the site. 
Statistical Considerations: A complete description of all statistical analyses and methods will 
be presented in the Statistical Analysis Plan (SAP). The SAP will be reviewed and approved by 
the Sponsor and will be finalized prior to database lock. Plans for PK analyses will be included 
in the SAP. 
Determination of Sample Size: The sample sizes for the P1/SAD cohorts are typical for a 
Phase 1 first in human (FIH) study. The sample size for the P2/FE cohort is in accordance with 
FDA guidelines for sample size in food-effect studies. 


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Study Populations: 
Safety Population: All subjects who receive at least one dose of study drug. 
Pharmacokinetic Population:  All subjects receiving study drug who comply sufficiently with 
protocol requirements (i.e., no major protocol deviations) and for whom a sufficient number of 
analyzable PK samples have been obtained to permit the determination of the PK profile for 
EIDD-2801/EIDD-1931 and the statistical analysis of the results. 
Safety Analyses: Statistical methods for the safety analyses will be descriptive in nature. Safety 
data, including AEs, clinical laboratory data, vital signs, ECG parameters, and PEs. All 
appropriate AEs will be graded using the DMID toxicity scale (March 2014). Change from 
baseline will be included in summary tables for laboratory parameters. All laboratory data will 
be included in the data listings and all test values outside the normal range will be flagged. 
Pharmacokinetic Analyses: Plasma PK parameters for each dose level will be calculated from 
the concentrations of EIDD-2801 and EIDD-1931 measured in predose and postdose plasma 
samples. For each dose level, descriptive statistics will be presented. Figures will be created to 
display mean and individual subject EIDD-2801 and EIDD-1931 concentration versus time. 
Urine PK parameters will be calculated whenever possible for each subject based on the urine 
concentrations of EIDD-2801 and EIDD-1931. The following PK parameters will be calculated:


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Plasma PK Parameter 
Description 
AUClast 
The area under the plasma concentration-time curve, from time 0 to the last 
measurable non-zero concentration, as calculated by the linear up/log down 
trapezoidal method.
AUC0-inf 
The area under the plasma concentration-time curve from time 0 extrapolated 
to infinity. AUC0-inf is calculated as the sum of AUClast plus the ratio of the 
last measurable plasma concentration to the elimination rate constant (λz). 
Cmax 
Maximum observed concentration. 
tmax 
Time to reach Cmax. If the maximum value occurs at more than one time 
point, tmax is defined as the first time point with this value. 
λz 
Apparent terminal elimination rate constant; represents the fraction of 
medication eliminated per unit time. 
t½ 
Apparent terminal elimination half-life of medication, calculated as 0.693/λz.
Vz/F 
Apparent volume of distribution (EIDD-2801 only). 
CL/F 
Apparent oral drug clearance (EIDD-2801 only). 
Urine PK Parameter 
Description 
Ae 
Amount excreted in urine over the sampling interval. 
Fe 
Fraction of drug excreted in the urine over sampling interval. 
CLR 
Renal clearance, CLR = Ae/AUC where both Ae and AUC are determined 
over co-incident time ranges after dosing. 
Dose proportionality for PK parameters of EIDD-2801 and EIDD-1931 (AUC0-inf, AUC, and 
Cmax) will be assessed by the power model. The mean slope and the associated 90% confidence 
interval (CI) based on the power model will be reported. 
To assess the effect of food on the PK of EIDD-2801 and EIDD-1931, natural log transformed 
PK parameters from P2 (AUC0-inf, AUClast, and Cmax) will be analyzed using a mixed effects 
model with fixed effect terms for treatment (with or without food), period, and sequence and 
with subject as a random effect. Point estimates and their associated 90% CIs for the natural log 
transformed PK parameters for the difference between EIDD-2801 administered under fed 
relative to fasted conditions will be constructed. The point estimates and interval estimates will 
be back transformed to give estimates of the ratio and 90% CI for the geometric least squares 
mean ratio for fed/fasted to assess the effect of food. 
Interim Analyses: No formal interim analyses are planned for this study. Data from P1 cohorts 
may be locked, unblinded, and analyzed prior to conducting P2. 
 


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Figure 1: Study Schema 
 
  
 
 
SAD Dose 1 (50 mg QD )
SAD Dose 2 (TBD)
SAD Dose 3 (TBD)
SAD Dose 4 (TBD)
Review 
Safety Data
Review 
Safety Data
Review 
Safety Data
Sentinel Grp 1: 2 subjects
24 hr safety review
Grp 2: 6 subjects
Abbreviations:
SAD: single ascending dose
FE: food effect
Seq: treatment sequence number
 
 
PART 1: SAD Cohorts                                                                                                          
Following review of data from Part 1 cohort administered dose selected for Part 2
Sequence 1
Dose: Fed
Sequence 2
14 Day Washout
Dose: Fasted
Dose: Fasted
Dose: Fed
PART 2: Food Effect (FE) Cohort                                                                                              


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1. 
INTRODUCTION 
This study is a FIH study designed to assess the safety, tolerability and PK of EIDD-2801 in 
healthy human volunteers. EIDD-2801 is a ribonucleoside analog with broad-spectrum activity 
against many RNA viruses. It is currently being developed by Ridgeback Biotherapeutics as a 
treatment of infections caused by highly pathogenic coronaviruses (CoV), including COVID-19. 
In addition, EIDD-2801 is being developed in parallel as a treatment of uncomplicated influenza 
caused by all subtypes of circulating and emerging (drifted and shifted) influenza A virus (IAV) 
and influenza B virus (IBV), including seasonal, epidemic and pandemic strains.  
1.1. 
Background 
EIDD-2801 is the 5’-isopropyl ester prodrug of the broadly active, direct-acting antiviral 
ribonucleoside analog EIDD-1931. After oral delivery, the prodrug (EIDD-2801) is rapidly 
hydrolyzed by circulating esterases to produce high circulating (plasma) levels of EIDD-1931. In 
cell culture systems, EIDD-1931 has been shown to inhibit replication of multiple viral 
pathogens from multiple RNA virus families including pathogenic CoV (e.g., Middle East 
respiratory syndrome [MERS], severe acute respiratory syndrome [SARS]-CoV-1 and 
SARS-CoV-2), influenza viruses (seasonal, pandemic, and avian subtypes), respiratory syncytial 
virus (RSV), alphaviruses (e.g., Eastern equine encephalitis virus [EEEV], Venezuelan equine 
encephalitis virus [VEEV], and chikungunya virus [CHKV]), Filoviruses (e.g., Ebola virus 
[EBOV]), and Zika virus (ZIKV). In addition, EIDD-2801 is active against orthopoxviruses 
(tested against vaccinia virus) probably because orthopoxviruses encode their own unique RNA 
polymerase. 
 
 The primary mechanism of action of 
EIDD-2801 is inhibition of viral RNA replication by incorporation of the EIDD-1931 
monophosphate metabolite into the viral RNA genome resulting in induction of viral error 
catastrophe. 
1.2. 
Rationale for Development 
EIDD-2801 is being developed for the treatment of infections caused by RNA viruses, 
specifically for COVID-19 and other CoV infections, influenza, and VEEV. The FIH study is 
being conducted under an FDA Investigational New Drug (IND) for the treatment of 
uncomplicated influenza caused by all subtypes of circulating and emerging IAV and IBV, and 
under a Clinical Trial Application for infections with COVID-19. During conduct of the FIH 
study, the Sponsor intends to submit an IND for the treatment of COVID-19 patients in a MAD 
trial to help define a dose that may be efficacious in treating SARS-CoV-2 and MERS-CoV 
infections. 
EIDD-2801 has a unique dual mechanism of action against RNA viruses, including COVID-19 
and other CoV infections. The compound acts as a competitive, alternative substrate for the 
virally encoded RNA-dependent RNA-polymerase that upon incorporation into nascent chain 
RNA induces increased mutational frequency in the viral genome. Incorporation quickly results 
in the production of non-viable virus. Additionally, the active metabolite 
EIDD-1931-5’-triphosphate may act directly as a chain terminator and arrest replication by 


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exerting a next nucleoside effect. It is anticipated that the high barrier to resistance observed 
during in vitro passaging studies will translate to slow, if any, emergence of viral resistance. 
Resilience to viral escape is a distinguishing feature of EIDD-2801. 
Currently, there is no approved antiviral therapeutic for the treatment of SARS-CoV-2. An 
antiviral drug is urgently needed. 
 
 
 
 
 
 
1.3. 
Nonclinical Overview 
1.3.1. 
Mechanism of Action 
The mechanism of antiviral activity of EIDD-2801 is “lethal mutagenesis”; a concept that is 
predicated on increasing the viral mutation rate beyond a biologically-tolerable threshold, 
resulting in impairment of viral fitness and leading to viral extinction. 
The specifics of the mechanism are as follows. EIDD-2801 is rapidly taken up by cells and the 
5’-isopropylester cleaved to liberate EIDD-1931, which is in turn phosphorylated to EIDD-2061 
by host kinases (Hernandez-Santiago et al., 2004; Painter et al., 2019). The 5’-triphosphate, 
EIDD-2061, acts as a competitive alternative substrate for virally encoded RNA-directed RNA 
polymerases and EIDD-2061 is incorporated into nascent viral RNA. Owing to the ability of the 
N4-hydroxycytosine base of EIDD-1931 to tautomerize, EIDD-2061 can pair with either 
guanosine or adenosine, and consequently can substitute for either CTP or UTP, respectively 
(Flavell et al., 1974). This results in an accumulation of mutations that increases with each cycle 
of viral replication. The process whereby the mutation rate is increased by exposure to a drug is 
referred to as Viral Decay Acceleration (Mullins et al., 2011) and results in viral ablation. 
Significant work has gone into validating this mechanism of action for EIDD-2801/1931, and it 
has been shown for MERS-CoV, VEEV, and IAV that viruses grown in the presence of 
EIDD-1931 have significantly increased levels of transition mutations (Agostini et al., 2019; 
Toots et al., 2019; Urakova et al., 2018). Multi-log decreases in virus yields were observed after 
treatment with EIDD-1931. Additionally, it was demonstrated for VEEV that the infectivity of 
virions formed in the presence of EIDD-1931 decreases from ~20% to less than 0.2%, and that 
the infectious virions are significantly Impaired in their replication ability (Urakova et al., 2018). 
As a consequence of this mechanism of action, the generation of drug-resistant escape mutants is 
practically impossible. This same effect was demonstrated for CoV (Agostini et al., 2019) and 
influenza virus (Toots et al., 2019). Furthermore, given the unique mechanism of action, 
EIDD-2801 is expected to be active against viruses resistant to other antiviral agents which have 
a different mechanism of action. The only data generated to date regarding the activity of 
EIDD-1931 against viruses resistant to other nucleoside analogs found that EIDD-1931 was 


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active against CoV resistant to remdesivir in cell culture assays (T. Sheahan et al, preprint 
available at https://www.biorxiv.org/content/10.1101/2020.03.19.997890v1). 
As an alternative or additional mechanism of action, it has been theorized that incorporation of 
EIDD-2061 into viral genomic RNA can change the thermodynamics of RNA secondary 
structure and thus decrease the efficiency of the promoter regions involved in RNA genome 
replication (Stuyver et al., 2003). 
1.3.2. 
In Vitro Pharmacology 
1.3.2.1. 
Antiviral Activity in Tissue Culture and in Human Airway Epithelium 
The ribonucleoside analog EIDD-1931 is the parent of the prodrug EIDD-2801. EIDD-1931 
shows specific antiviral activity in different tissue culture cells and in the differentiated organoid 
model of human airway epithelium (HAE) with a selectivity index (SI) ranging from 21 to >100 
for all influenza viral isolates tested. It is active against IAV (pandemic and seasonal) and IBV 
strains, as well as against highly pathogenic H5N1 and H7N9 strains (Table 1). 
Table 1: 
EIDD-1931 Antiviral Activity Against Influenza A and B Viruses in Tissue 
Culture and Primary Human Bronchial/Tracheal Epithelial Cells 
Virus 
Strain 
Cell line 
EC50* 
(µM) 
CC50 
(µM) 
SI 
Reference 
IAV H1N1 
Ca/07/2009 
MDCK 
1.24 
68 
55 
NIAID Antiviral Testing Program 
IAV H1N1 
WSN/33 
MDCK 
1.1 
299.8 
275 
Yoon et al., 2018 
IAV H1N2 
WSN/33 
primary hBTEC 
5.4 
- 
- 
Yoon et al., 2018 
IAV H2N3 
Perth/16/2009 
MDCK 
0.88 
52 
59 
NIAID Antiviral Testing Program 
IAV H2N3 
Ohio/sw-10-132/2010 
MDCK 
3.2 
299.8 
94 
Yoon et al., 2018 
IAV H5N1 
Duck/MN/1525/81 
MDCK 
1.28 
27 
21 
NIAID Antiviral Testing Program 
IAV H5N1 
Vietnam/1203/2004 
MDCK 
0.14 
299.8 
2100 
Yoon et al., 2018 
IAV H7N9 
Anhui/1/2013 
MDCK 
0.13 
299.8 
2300 
Yoon et al., 2018 
IBV 
Florida/4/2006 
MDCK 
<0.4 
76 
>190 
NIAID Antiviral Testing Program 
IBV 
Brisbane/60/08 
MDCK 
0.006 
299.8 
50000 
Yoon et al., 2018 
IAV H1N1 
Ca/07/2009 
HAE-3D* 
0.08 
50 
625 
Toots et al., 2019 
IAV H1N1 
WSN/33 
HAE-3D* 
0.08 
50 
625 
Toots et al., 2019 
IBV 
Brisbane/60/08 
HAE-3D* 
0.06 
50 
833 
Toots et al., 2019 
* Human Airway Epithelium organoid model. 
EIDD-1931 also showed specific antiviral activity against human SARS-CoV-1, MERS-CoV 
(Table 2) and SARS-CoV-2 (Figure 2), against togaviruses VEEV, EEEV and Chikungunya 
virus (Table 3) 
 


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EIDD-1931 (NHC) antiviral activity (closed circles) and 
cytotoxicity (open squares) in Vero Cells infected with 
SARS- CoV-2. Vero cells were infected in duplicate with 
SARS-CoV- 2 clinical isolate virus at a multiplicity of infection 
(MOI) of 0.05 in the presence of a dose response of 
EIDD-2801 for 48 hours after which replication was measured 
through quantitation of cell viability by Cell-Titer-Glo assay. 
Cytotoxicity was measured in similarly treated but uninfected 
cultures. Reproduced from Sheahan et al 2020. 
Table 2: 
EIDD-1931 Antiviral Activity Against SARS and MERS Coronaviruses in Tissue 
Culture and Primary Human Bronchial/Tracheal Epithelial Cells 
Virus 
Strain 
Cell line 
EC50 
(µM) 
CC50 
(µM) 
SI 
Reference 
SARS-CoV-1 Urbani 
Vero76 
<0.4 
144 
>360 NIAID Antiviral Testing Program 
SARS-CoV-1 SARS-CoV-GFP(†) 
HAE-3D(*) 
<1 
>100 
>100 Tech. Report 25.038 
MERS-CoV 
GenBank Ac.No JX869059** DBT-9 
0.56 
>200 
>357 Agostini et al., 2019 
MERS-CoV 
Human ß-CoV C, Novel 2912 Vero E6 
<0.8 
20 
>25 
NIAID Antiviral Testing Program 
* Human Airway Epithelium organoid model; ** cDNA Derived clone 
Figure 2: Inhibition of SARS-CoV-2 by EIDD-1931 
 
Table 3: 
EIDD-1931 Antiviral Activity Against Togaviruses in Tissue Culture 
Virus 
Strain 
Cell line 
EC50 (µM) 
CC50 (µM) 
SI 
Reference 
VEEV 
TC-83 
Vero 
0.43 
>200 
>930 Urakova et al., 2018 
VEEV 
TC-83 
Vero76 
1.92 
32 
17 
NIAID Antiviral Testing Program
EEEV 
FL93-939 
Vero76 
1.08 
84 
78 
NIAID Antiviral Testing Program
CHKV 
S27 (VR-64) 
Vero76 
1.8 
96 
53 
NIAID Antiviral Testing Program


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1.3.2.2. 
Cytotoxicity of EIDD-1931 in Tissue Culture Utilizing Cells from 
Different Organs and Species 
EIDD-1931 was tested for cytotoxicity in human hepatic origin Huh7 and HepG2 cells, in human 
lymphoid CEM, human pancreatic BxPC-3, human prostate cancer PC-3, human muscle A204, 
human lung A549, human epithelial hEp-2, rat heart muscle H9c2, monkey kidney Vero, and 
canine kidney MDCK cell lines (Table 5). The compound exhibits low cytotoxicity in the 
majority of cells tested (half maximal effective concentration [EC50] values are in the range of 40 
to >100 µM) except in lymphoid origin CEM cells where the compound shows a 7.5 µM EC50 
value (Sticher et al., 2020; Urakova et al., 2018; Yoon et al., 2018). 
Table 5: 
Cytotoxicity (CC50) of EIDD-1931 in Mammalian Cell Lines 
Cell Line 
CEM 
HepG2 
PC-3 
A204 
A549 
BxPC-3 
Huh-7 
H9c-2 
Vero 
hEp-2 
MDCK 
CC50 
(µM) 
7.5 
42.3 
267.1 
84 
46 
48 
165.5 
81 
53 
272.4 
299.8 
Sources: Sticher et al., 2020, Yoon et al., 2018 
EIDD-2801 typically showed 2-4× lower activity and cytotoxicity than EIDD-1931 due to 
slightly slower uptake and anabolism in tissue culture. 
1.3.2.3. 
Assessment of Mitochondrial Toxicity 
Since EIDD-1931 is a nucleoside analog, additional investigations were performed to analyze 
whether observed cytotoxicity of EIDD-1931 is caused by mitochondrial toxicity. It was 
demonstrated that the prolonged treatment (14 days) with the compound does not result in 
selective killing of mitochondria or in mitochondrial dysfunction in CEM and HepG2 cells 
(Sticher et al., 2020). 
1.3.3. 
In Vivo Pharmacology 
The prodrug EIDD-2801 or its parent EIDD-1931 have been tested in animal models of RNA 
viral infection. An overview of results from the animal studies in indications to be pursued are 
described below. Additional detail is provided in the Investigator’s Brochure (IB). 
1.3.3.1. 
Coronavirus: SARS-CoV-1 and MERS-CoV 
In mouse models of SARS and MERS infection and disease, coronaviral disease was assessed by 
changes in body weight, measured daily, and lung hemorrhage, assessed in the large left lobe of 
the lung following sacrifice on Day 5 (SARS-CoV) or Day 6 (MERS-CoV). To assess 
production of infectious virions, virus was isolated from the lower left lobe of the lung following 
sacrifice on Day 5 (SARS-CoV) or Day 6 (MERS-CoV) and quantified using a plaque assay. 
The results demonstrated that, in mice infected with either SARS- or MERS-CoV, both 
prophylactic and therapeutic treatment with EIDD-2801 resulted in a reduction in virus 
replication, improvements in pulmonary function, and improvements in maintaining body weight 


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(i.e., reduced body weight loss). While EIDD-2801 doses of 50, 150 and 500 mg/kg BID were 
assessed in the CoV mouse experiments, 500 mg/kg BID yielded the most consistent therapeutic 
effect. 
A prophylactic, dose-escalation study was conducted in C57BL/6 mice infected with 
mouse-adapted SARS-CoV (SARS-MA15). Prophylactic oral treatment with EIDD-2801 was 
initiated 2 hours before intranasal infection and continued every 12 hours thereafter through the 
end of the study (Day 5; Figure 3). 
In mice treated BID with EIDD-2801, body weight loss observed with vehicle treatment was 
diminished in the 50 mg/kg treatment group, beginning on Day 3 post-infection. No body weight 
loss was seen in the 150 and 500 mg/kg treatment groups (Figure 3, Panel A). Lung hemorrhage 
was also significantly reduced on Day 5 post-infection, following treatment with 500 mg/kg 
EIDD-2801 (Figure 3, Panel B). When compared to vehicle control, a dose-dependent reduction 
in SARS-CoV lung titers at Day 5 was seen across all 3 treatment groups (Figure 3, Panel C) 
with significant differences among the vehicle, 150 mg/kg and 500 mg/kg groups. Thus, 
prophylactic treatment with EIDD-2801 resulted in a robust antiviral effect that was able to 
prevent SARS-CoV replication and disease. 
Figure 3: EIDD-2801 Prophylactic Treatment of SARS-CoV Infected Mice 
 
The antiviral activity of EIDD-2801 against SARS-CoV was compared when treatment was 
initiated at -2 hours (pre-infection) and 12, 24, or 48 hours post-infection. After initiation of 
treatment, all groups were dosed every 12 hours for the duration of the study (Figure 4). For 
SARS-challenged mice, initiating treatment at 12 hours post-infection significantly prevented 
body weight loss beginning on Day 2, a result similar to that seen when dosing prophylactically 


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(i.e., beginning at 2 hours pre-infection). Initiation of treatment with EIDD-2801 at 24 hours 
post-infection also significantly reduced body weight loss on Days 3 through5 post-infection. 
When EIDD-2801 treatment was initiated at 48 hours post-infection, body weight loss was only 
statistically different from vehicle on Day 4 post-infection (Figure 4, Panel A). Significant 
reductions in lung hemorrhage were seen when EIDD-2801 treatment was initiated before 
(-2 hours) and up to 24 hours after infection; a result that mirrored body weight loss data 
(Figure 4, Panel B). All mice treated with EIDD-2801 had significantly reduced viral loads in the 
lungs, even in the group where treatment was initiated 48-hour post-infection (Figure 4, 
Panel C). Pulmonary function, measured via whole body plethysmography (WPB), was assessed 
using the PenH metric which is a surrogate marker for bronchoconstriction or pulmonary 
obstruction. The administration of EIDD-2801 prior to infection (-2 hours) and at 12 hour 
post-infection completely abrogated the loss of pulmonary function observed in vehicle-treated 
animals (Figure 4, Panel D). Improved pulmonary function was also seen in the group where 
treatment was initiated 24 hours after virus challenge. 
Figure 4: EIDD-2801 Treatment of SARS-CoV Infected Mice 
 
EIDD-2801 was also tested to determine if it is active in vivo against MERS-CoV as described 
by Sheahan et. al (draft manuscript). The murine ortholog of the MERS-CoV receptor, dipeptidyl 
peptidase 4 (DPP4), does not support viral binding and entry. Thus, all in vivo studies described 
below were performed in genetically modified hDPP4 mice permissive for MERS infection. 
Prophylactic treatment starting at 2 hours before viral challenge with either 50, 150, or 


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500 mg/kg EIDD-2801 prevented body weight loss on Days 2 through 6 post-infection (Figure 5, 
Panel A), prevented lung hemorrhage measured on Day 6 (Figure 5, Panel B), and reduced virus 
lung titer on Day 6 to the limit of detection (Figure 5, Panel C). 
Figure 5: EIDD-2801 Prophylactic Treatment of MERS-CoV Infected Mice 
 
The effect of EIDD-2801 treatment on MERS-CoV infected mice is shown in Figure 6. When 
EIDD-2801 treatment was initiated 12 hours post-infection, there was no loss in body weight 
from Days 2 through 6 post-infection (Figure 6, Panel A) and no evidence of lung hemorrhage 
on Day 6 post-infection (Figure 6, Panel B). However, protection was not observed in groups 
where treatment was initiated either 24- or 48-hours post-infection. Conversely, virus lung titer 
on Day 6 post-infection was significantly reduced to the limit of detection in all treatment 
groups, regardless of the time treatment began (Figure 6, Panel C). To gauge the effect of the 
timing of EIDD-2801 treatment initiation on physiologic measures of lung disease, pulmonary 
function was assessed by whole body plethysmography. As expected, a loss of pulmonary 
function, as determined by measuring the PenH metric, was observed in vehicle-treated animals 
infected with MERS-CoV beginning on Day 2 post-infection (Figure 6, Panel D). Mirroring the 
body weight loss data, normal pulmonary function was observed in groups where treatment was 
initiated prior to or at 12 hours post-infection (Figure 6, Panel D). 


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Figure 6: EIDD-2801 Treatment of MERS-CoV Infected Mice 
 
1.3.3.2. 
Influenza Virus 
EIDD-2801 was tested in a ferret model of influenza virus infection and disease. Ferrets 
recapitulate hallmarks of human influenza infection, providing a clinically relevant animal model 
to investigate therapeutic intervention. Therapeutic oral dosing of influenza virus-infected ferrets 
reduced shed levels of pandemic and seasonal IAV by multiple orders of magnitude, and 
alleviated fever and inflammation while improving airway epithelium histopathology. 
Post-exposure prophylactic dosing was sterilizing (Toots et al., 2019). 
Ferrets infected with pandemic IAV and treated with EIDD-2801 at a dose of 7 mg/kg 
demonstrated significantly less viral shedding and inflammatory cellular infiltrates in nasal 
lavages, but mounted a normal humoral antiviral response (Toots et al., 2019). 
When examining the effect of delayed dosing, Toots et. al. (2019) demonstrated that treatment 
with 20 mg/kg of EIDD-2801 initiated 24 hours after challenge with IAV (H1N1) resulted in a 
rapid decrease in both shed virus and fever relative to control, with fever returning to baseline at 
24 hours. When oseltamivir (20 mg/kg) was dosed prophylactically as a positive control, a 
modest suppression of fever was observed; however, there was no reduction in shed virus titer. 


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1.3.3.3. 
Venezuelan Equine Encephalitis Virus 
Treatment with EIDD-1931 was evaluated in a mouse model of lethal VEEV infections. To be 
truly effective as a therapeutic agent for VEEV infection, a drug must penetrate the blood brain 
barrier and arrest virus replication in the brain. High plasma levels of EIDD-1931 are rapidly 
achieved in mice after oral dosing. Once in the plasma, EIDD-1931 is efficiently distributed into 
organs important in the pathology of VEEV infection, including the brain, where it is rapidly 
converted to its active 5’-triphosphate (EIDD-2061). EIDD-1931 showed a good safety profile in 
mice after 7 days of dosing with up to 1,000 mg/kg/day. In mouse model studies of VEEV 
infection, EIDD-1931 was 90-100% effective in protecting mice against lethal intranasal 
infection when therapeutic treatment was started as late as 24 hours post-infection, and partial 
protection was achieved when treatment was delayed for 48 hours post-infection (Painter et al., 
2019). 
 
 
 
 
 
1.4. 
Safety and Secondary Pharmacology 
The standard battery of safety pharmacology studies including studies assessing the 
cardiovascular, respiratory and central nervous systems have been conducted. The studies are 
discussed in the IB; results indicated that there were no adverse pharmacologic effects of 
EIDD-2801 on the cardiovascular, respiratory or central nervous systems. 
1.5. 
Nonclinical Pharmacokinetics and Metabolism 
1.5.1. 
Overview 
The uptake, metabolism and protein binding of EIDD-2801 and EIDD-1931 have been studied in 
plasma, microsomes, and non-hepatic cells from several species as outlined below. The PK and 
tissue distribution of EIDD-2801 and its metabolite EIDD-1931 have been studied extensively in 
rats, dogs and ferrets. Key results from these studies are presented below; additional detail can be 
found in the IB. 
1.5.2. 
Absorption 
EIDD-1931 is parent of the prodrug EIDD-2801. The appearance of EIDD-1931 is dependent on 
the absorption of EIDD-2801 and the rate of its conversion to EIDD-1931. 


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EIDD-2801 PK studies have been completed in dog, rat, mouse, ferret, and monkey. EIDD-2801 
was efficiently absorbed and rapidly converted to EIDD-1931 in each species. The tmax for 
EIDD-2801 (not observed in rodents) occurred at 0.5-1 hours, while the tmax for EIDD-1931 
occurred in 1-2 hours. 
1.5.3. 
Distribution 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.5.3.2. 
Tissue Distribution Studies 
EIDD-2801 is rapidly absorbed in the gut and converted to EIDD-1931 reaching Cmax in 
1-3 hours in mice, rats, ferrets, dogs and monkeys. EIDD-1931 is then widely distributed to 
tissues including lungs and brain, where it is rapidly taken up into cells and converted to 
EIDD-2061. Figure 7 shows the concentration of EIDD-1931 and EIDD-2061 in ferret brain and 
lung following single doses of 20 (Panels A and B) and 128 (Panels C and D) mg/kg. 


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Figure 7: Tissue Distribution of EIDD-1931 and EIDD-2061 in Ferret Brain and Lung 
 
1.5.4. 
Metabolism 
1.5.4.1. 
Metabolic Stability of EIDD-1931 and EIDD-2801 
EIDD-2801 was designed to be converted to EIDD-1931 by esterases in plasma or in cells. 
Stability has been assessed in plasma and liver microsomes from mouse, rat, dog, monkey and 
humans. The stability of EIDD-2801 in mouse, rat and monkey plasma is relatively short 
(≤0.4 hours) while the stability is longer in human and dog plasma (1-3 hours). EIDD-2801 
stability in mouse, rat, dog and monkey liver microsomes is very short, ranging from 0.02 to 
0.08 hours while the stability in human liver microsomes is 1.2 hours (Table 6). 


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Table 6: 
Metabolic Stability of EIDD-2801 in Plasma and Liver Microsomes 
Species 
Plasma stability 
LM stability 
t1/2 (h) 
t1/2 (h) 
Mouse 
0.017 
0.033 
Rat 
0.033 
0.017 
Dog 
3.2 
0.083 
Monkey 
0.40 
0.017 
Human 
1.05 
1.22 
EIDD-2801 is stable in simulated gastric and intestinal fluids (Table 7). 
Table 7: 
Metabolic Stability of EIDD-2801 in Simulated Gastric and Intestinal Fluids and 
in Buffered Saline with Fetal Bovine Serum 
Matrix 
t1/2 (hr) 
Simulated Gastric Fluid 
>24 
Simulated Intestinal Fluid 
>24 
Phosphate Buffered Saline plus 10% Fetal Bovine Serum* 
>24 
EIDD-1931 was found to be stable when incubated with all tested plasmas, whole blood, liver 
microsomes and liver S9 extracts and intestinal microsomes (Table 8). 
Table 8: 
Metabolic Stability of EIDD-1931 in Plasma, Whole Blood and Liver and 
Intestinal Microsomes 
Medium 
Plasma 
Whole Blood 
Liver Microsomes 
Liver S9 Stability 
Intestinal Microsomes 
Species 
t1/2 (h) 
t1/2 (h) 
t1/2 (h) 
t1/2 (h) 
t1/2 (h) 
Mouse 
 
>24 
>24 
 
>24 
Rat 
17 
 
>24 
>24 
 
Dog 
>24 
 
 
>24 
 
Monkey 
6.5 
>24 
>24 
>24 
>24 
Human 
10 
7 
>24 
20 
>24 
1.5.4.2. 
Uptake and Anabolism of EIDD-1931 in Tissue Culture and Primary 
Cells 
EIDD-1931 is efficiently taken up by tissue culture cells and converted to its pharmacologically 
active metabolite EIDD-2061 (EIDD-1931-5’-triphosphate). Intracellular EIDD-2061 
accumulates dose-dependently, with Cmax levels ~200-2000 pmol/106 cells (at 10-20 µM dose) in 
different cell lines. It reaches high levels relatively quickly, typically within 1-3 hours, though 
the tmax values vary widely between 1 and 24 hours depending on the cell line and dose 
concentration tested. Detailed data on the uptake and anabolism of EIDD-2801 is presented in 
the IB. 


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EIDD-2801 is also taken up by tissue culture cells and is converted to EIDD-1931 and then to 
EIDD-2061, but the process is slightly delayed compared to dosing with EIDD-1931. 
EIDD-1931 is also taken up and metabolized to EIDD-2061 by primary cells. EIDD-2061 is 
accumulated in all primary cells tested except in mouse primary hepatocytes where EIDD-1931 
is apparently extensively metabolized to cytidine and uridine which, in turn, quickly metabolize 
into CTP and UTP. The quick metabolism of EIDD-1931 consequently results in low levels of 
EIDD-2061 in mouse hepatocytes. The intracellular stability (t1/2) of EIDD-2061 is 4-5 hours in 
human astrocytes and hBTEC and is significantly shorter (0.2-1.1 hours) in primary hepatocytes. 
1.5.5. 
Excretion 
Currently, there is no data on excretion of EIDD-2801 or EIDD-1931. Excretion will be 
measured in urine during this study. 
1.5.6. 
Pharmacokinetic Drug Interactions 
1.5.6.1. 
Cytochrome P450 (CYP) Inhibition 
The purpose of this non-GLP in vitro study was to determine the time-dependent inhibitory 
potential of EIDD-2801 and EIDD-1931 on human cytochromes P450 (CYP) 1A2, 2B6, 2C8, 
2C9, 2C19, 2D6, and 3A4 (midazolam and testosterone substrates) enzyme activity, using pooled 
human liver microsomes in an half maximal inhibitory concentration (IC50) shift assay. 
Neither EIDD-2801 nor EIDD-1931 demonstrated inhibition greater than 31.4% for any of the 
CYP isozymes tested nor could the data for each assay condition be curve fit to determine 
time-dependent inhibition by these compounds. Full dose-response curves were not achieved at 
concentrations ranging from 0.00545 to 50.0 µM indicating EIDD-2801 and EIDD-1931 have no 
CYP inhibition potential at concentrations ranging from 0.00545 to 50.0 µM. Assay performance 
was acceptable based on the results for the positive control inhibitors. 
1.5.6.2. 
CYP Induction 
An assay was performed to determine the induction potential of EIDD-2801 on human CYP 
isoenzyme (1A2, 2B6, and 3A4) activity using 3 single-donor lots of inducible, cryopreserved 
human hepatocytes. Both enzyme activity and mRNA results demonstrated that EIDD-2801 did 
not show induction for any of the CYP isozymes. 
 
 
 
 
 
 
 


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1.7. 
Potential Risks and Benefits 
1.7.1. 
Potential Benefits 
As this is a FIH study in healthy volunteers, there is no direct benefit to subjects enrolled in the 
study. However, given the current pandemic situation and in vitro antiviral activity of 
EIDD-2801 against SARS-CoV-2, and the activity against several other viruses of public health 
concern, it is possible that participants may benefit from future availability of the drug. 
1.7.2. 
Potential Risks 
EIDD-2801 has never been administered to humans; therefore, the risks from EIDD-2801 to 
subjects participating in this trial are unknown. Although toxicology studies have been done, 
unexpected AEs may occur.
 
 
 
. Subjects will also be monitored for other end-organ 
effects through a range of safety assessments. 


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2. 
OBJECTIVES 
2.1. 
Study Objectives 
2.1.1. 
Primary Objectives 
The primary objective of Part 1 of the study is to determine the safety and tolerability of single 
ascending doses of EIDD-2801. 
The primary objective of Part 2 of the study is to assess the effect of food on the PK on 
EIDD-2801 and EIDD-1931 following a single oral dose. 
2.1.2. 
Secondary Objective 
The secondary objective of Part 1 of the study is to define the PK of EIDD-2801 and EIDD-1931 
in plasma and urine following singledoses administered to healthy volunteers. 
The secondary objective of Part 2 of the study is to determine the safety and tolerability of single 
doses of EIDD-2801. 
2.2. 
Study Outcome Measures 
2.2.1. 
Primary Outcome Measures 
The primary outcome measures for Part 1 of are results of safety evaluations including safety 
laboratory assessments, PEs, ECGs, vital signs, and AEs. 
The primary outcome measures for Part 2 of the study are plasma PK parameters including Cmax, 
tmax, t1/2, CL/F, λz, Vz/F, AUC0-inf and AUClast as appropriate. 
2.2.2. 
Secondary Outcome Measures 
The secondary outcome measures are as follows: 
 Single-dose plasma PK parameters, including Cmax, tmax, t1/2, CL/F, λz, Vz/F, 
AUC0-inf and AUClast as appropriate 
 Urinary excretion of EIDD-2801 and EIDD-1931 following single-dose 
administration. 
 Results of safety evaluations including safety laboratory assessments, PEs, ECGs, 
vital signs, and AEs (Part 2). 


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3. 
STUDY DESIGN 
3.1. 
Overview 
EIDD-2801-1001-UK is a Phase 1, randomized, double-blind, placebo-controlled, FIH, SAD 
study of the safety, tolerability and PK of EIDD-2801 and EIDD-1931 following oral 
administration of singledoses of EIDD-2801 to healthy volunteers. In addition, for a minimum of 
one cohort, the effect of food on the single-dose EIDD-2801 and EIDD-1931 PK parameters will 
be assessed in subjects taking open-label EIDD-2801. The overall objective of the study is to 
identify a starting dose for future safety and therapeutic intervention trials. 
The study is composed of 2 parts; Part 1 (P1) is the SAD study and Part 2 (P2) is the FE cohort 
study.  
3.1.1. 
Part 1 
A single oral dose of EIDD-2801 or PBO will be administered to subjects. Subjects will be 
randomized in a 3:1 ratio to receive either EIDD-2801 or PBO. 
Following dosing on Day 1, subjects will remain in the clinic through completion of study 
assessments on Day 4, returning to the clinic on Day 9 for study assessments, and Day 15 for the 
EOS visit. 
The first cohort will be divided into 2 groups. The first group, a sentinel group, will include 
2 subjects. On Day 1, one subject in the sentinel group will be administered PBO and one will be 
administered EIDD-2801. Analysis of the safety results for the sentinel group will be reviewed 
24 hours postdose. If no halting criteria (Section 9) have been met, the remainder of the subjects 
in Cohort 1 (the second group) will be dosed. There will be no sentinel groups for the remaining 
cohorts. 
After completion of each dosing cohort, safety and tolerability data will be reviewed to 
determine if any of the halting rules have been met. If not, then the subsequent cohort may be 
dosed. As PK data become available, these data may be used for dose-escalation decisions. 
The proposed dose-escalation scheme is shown in Figure 1, however, planned dose escalations 
will be determined based on ongoing review of the safety, tolerability, and available PK data. 
The starting dose in the first SAD cohort will be 50 mg. Dose levels will not increase by more 
than 3-fold for predicted nonpharmacologically active dose levels and by 2-fold for predicted 
pharmacologically active dose levels.
 
Four cohorts are initially planned for P1; however, up to an additional 3 cohorts may be enrolled. 
3.1.2. 
Part 2 
Two single oral doses of EIDD-2801 will be administered to subjects, in an open-label manner. 
The dose for the P2/FE cohort is planned to be 100 mg but may be adjusted based on safety, 


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tolerability, and/or PK data from P1. The dose assessed in the P2/FE cohort will have been given 
previously to subjects in a P1/SAD cohort successfully (i.e., no halting rules were met following 
dosing).  
Subjects will be randomized to treatment sequence; i.e., to receive drug in the fed then fasted 
state (Sequence 1) versus fasted then fed state (Sequence 2; Figure 1). Half of the subjects in the 
cohort will be randomized to Sequence 1 and the other half will be randomized to Sequence 2.  
Following dosing on Day 1, subjects will remain in the clinic through completion of study 
assessments on Day 4, returning to the clinic on Day 9 for study assessments, and Day 14 to 
begin the second dosing sequence on Day 15. Subjects will then be discharged from the clinic on 
Day 18, returning to the clinic on Day 23 for study assessments, and Day 30 for the EOS visit. 
There will be a 14-day (minimum) washout period between doses. 
One cohort of 10 subjects is planned for P2. However, if PK results obtained are equivocal, 
additional subjects may be enrolled into the P2/FE cohort at the previously tested dose or an 
additional P2/FE cohort may be added at a different dose. 
Additional parts may be added to this study, including a SAD part in elderly healthy 
subjects, a MAD part in healthy subjects, and a study of the safety, tolerability, and PK in 
Japanese subjects. These additional parts are not described in this protocol, but may be 
added via a protocol amendment. It is planned that the MAD part will include 
4 dose-escalation cohorts (with the option to include an additional 3 cohorts), with subjects 
receiving BID doses for 7 days. It is planned that each MAD cohort will comprise 
8 subjects, with 6 subjects receiving EIDD-2801 and 2 subjects randomized to PBO. 
3.2. 
Rationale and Justification 
3.2.1. 
Justification of Design 
The FIH study is a typical dose-escalation study designed to provide the maximum amount of 
data in the minimum number of subjects. The cohort size in P1 is planned to be 8 subjects 
(6 active:2 PBO). This number of subjects allows for a sufficient PK analysis, considered to be 
important because dose extrapolation from efficacious animal models to humans will be based 
on exposure. The duration of participation for each subject following dosing well exceeds 5 drug 
half-lives (up to 9.1 hours in dogs; 5 hours in ferrets) 
 
 The FE cohort is considered to be important to maximize exposure 
based on fed vs. fasted condition and obtaining this information early in Phase 1 will minimize 
study drug dose in all future studies. This design follows the FDA guidance document on 
assessing FE in clinical studies. 
3.2.2. 
Justification of Starting Dose 
 
 
 
 
 


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 The FDA guidance document 
(“Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult 
Healthy Volunteers”) provides guidance for when a safety factor smaller than 10 may be used to 
calculate the starting dose: 
 A smaller safety factor might also be used when toxicities produced by the 
therapeutic are easily monitored, reversible, predictable, and exhibit a 
moderate-to-shallow dose-response relationship with toxicities that are consistent 
across the tested species (both qualitatively and with respect to appropriately scaled 
dose and exposure). 
 A safety factor smaller than 10 could be justified when the NOAEL was determined 
based on toxicity studies of longer duration compared to the proposed clinical 
schedule in healthy volunteers. In this case, a greater margin of safety should be built 
into the NOAEL, as it was associated with a longer duration of exposure than that 
proposed in the clinical setting. This assumes that toxicities are cumulative, are not 
associated with acute peaks in therapeutic concentration (e.g., hypotension), and did 
not occur early in the repeat dose study. 
EIDD-2801 satisfies both of these criteria as follows: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Importantly, given the activity of EIDD-2801 versus SARS-CoV-2 (cause of COVID-19), the 
Sponsor thinks it is most prudent to start with a dose that is predicted to be a safe starting dose 
and is also as close as possible to a potential therapeutic dose that would allow the Sponsor to 


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move into COVID-19 patients as safely and expeditiously as possible. Based on modeling to 
animal data, a dose of 100 mg BID is projected to be an active dose in humans. 
3.2.3. 
Justification of Study Population 
Healthy volunteers are considered to be the appropriate population for conduct of the FIH study. 
Healthy volunteers without confounding medical conditions that may obscure the interpretation 
of AEs or affect absorption, distribution, metabolism and excretion of study drug will provide the 
most valuable data regarding the tolerability, safety, and plasma exposures observed and 
expected following single doses. EIDD-2801 is intended for eventual study in patients with 
potential CoV-2 infection as defined by the Centers for Disease Control and Prevention (CDC) in 
whom a range of AEs are expected based on the disease under study. Understanding the safety 
and PK profile in a normal population will better inform the use of EIDD-2801 in disease 
settings where complications are frequent, and AEs will need to be interpreted in context. While 
EIDD-2801 is being developed for the treatment of highly pathogenic CoV, there are plans 
underway to develop protocols for the treatment of influenza. Without safety data from healthy 
individuals, it will be more difficult to extrapolate the interpretation of AEs from one disease 
state to another. 


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4. 
STUDY POPULATION 
This study will enroll healthy volunteers; 8 subjects will be enrolled into each SAD cohort in P1 
and 10 subjects will be enrolled into the FE cohort in P2. 
The site is strongly encouraged to ensure that women are represented in each cohort. 
4.1. 
Subject Inclusion Criteria 
Subjects who meet all of the criteria at Screening will be eligible for study participation 
1. Male or female between the ages of 18 and 60, inclusive. 
2. Female subjects must be of non-childbearing potential. Non-childbearing potential is 
defined as women who: 
 are physiologically incapable of becoming pregnant including those who are 
surgically sterile, via hysterectomy, bilateral salpingectomy, and/or bilateral 
oophorectomy by reported medical history and/or medical records. Surgical 
sterilization to have occurred a minimum of 6 weeks, or at the PI’s (or 
designee’s) discretion, prior to Screening. 
 are post-menopausal (at least 45 years of age with amenorrhea for 12 months 
without an alternative medical reason with confirmatory FSH levels of ≥ 
40 mIU/mL. The amenorrhea should not be induced by a medical condition 
such as anorexia nervosa, hypothyroid disease or polycystic ovarian disease, 
or by extreme exercise. It should not be due to concomitant medications that 
may have induced the amenorrhea such as oral contraceptives, hormones, 
gonadotropin-releasing hormones, anti-estrogens, or selective estrogen 
receptor modulators). 
3. Male participants must agree to the use of effective contraception for study duration, 
i.e., from Check-in until 90 days after the EOS visit. 
4. Is in generally good health as determined by medical history, PEs (at Screening 
and/or Check-in), vital signs, and other screening procedures. 
5. Has a BMI of 18 to 30 kg/m2. 
6. Is willing and able to comply with all study procedures including providing informed 
consent. 


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4.2. 
Subject Exclusion Criteria 
Subjects who meet any of the following criteria at Screening (unless otherwise stated) will not be 
eligible for participation: 
1. Females who are pregnant, planning to become pregnant, or breastfeeding. 
2. Has a clinically relevant acute or chronic medical condition or disease of the 
cardiovascular, gastrointestinal, hepatic, renal, endocrine, pulmonary, neurologic, or 
dermatologic systems as determined by the PI (or designee). 
3. Has any current or historical disease or disorder of the hematological system or 
significant liver disease or family history of bleeding/platelet disorders. 
4. Has a history of cancer (other than basal cell or squamous cell cancer of the skin), 
rheumatologic disease or blood dyscrasias. 
5. Has a history of gastrointestinal surgery or other condition that may interfere with 
absorption of study drug, in the option of the PI (or designee). 
6. Has a history of febrile illness within the 14 days prior to the first dose of study drug. 
7. Has a positive alcohol or drug screen at Screening or the Day -1 visit or has a history 
of alcohol or drug abuse within the past 5 years. 
8. Currently uses tobacco, nicotine or tobacco products or e-cigarettes or stopped using 
tobacco products within the past 3 months and/or has a positive cotinine test at 
Screening or Check-in. 
9. Has any abnormal laboratory value of Grade 2 or higher, which is considered to be 
clinically significant by the PI (or designee). 
10. Has a total white cell count or absolute lymphocyte count outside the normal range, 
or hemoglobin or platelet levels below the lower limit of normal, at Screening or 
Day -1. 
11. Has values above the upper limit of normal for the following laboratory analytes: 
ALT/SGPT, alkaline phosphatase (serum), AST/SGOT, at Screening or Day -1.  
12. Positive test result for HIV, HBV, or HCV. 
13. Has an autoimmune disease, is immunosuppressed or is in any way 
immunocompromised. 
14. Has any of the following: 
 QTcF >450 ms confirmed by repeat measurement 


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 QRS duration >110 ms confirmed by repeat measurement 
 PR interval >220 ms confirmed by repeat measurements 
 findings which would make QTc measurements difficult or QTc data 
uninterpretable 
 history of additional risk factors for torsades de pointes (e.g., heart failure, 
hypokalemia, family history of long QT syndrome). 
15. Except as noted, has used prescription drugs (other than hormone replacement 
therapy) within 14 days prior to the first dose of study drug unless, in the opinion of 
the PI (or designee), the drug will not interfere with study assessments. The 
following prescription drugs will be allowed: 
 Statins: Subjects who have been on a stable dose of statins for a minimum of 
6 months and who have normal creatine kinase at Screening. 
 Antihypertensives: Subjects who have been on a stable dose of 
antihypertensives for a minimum of 6 months and have controlled blood 
pressure and no active heart disease. 
16. Has received an experimental agent (vaccine, drug, biologic, device, blood product 
or medication) within 3 months prior to the first dose of study drug and agrees not to 
receive another experimental agent during the duration of this trial. 
17. Has donated blood within 30 days, plasma within 2 weeks, or platelets within 6 
weeks prior to Screening or refuses to agree to not donate blood until 3 months after 
the EOS visit. 
18. Uses OTC medications or nutritional supplements (including, e.g., gingko biloba, 
aspirin at any dose, and NSAIDs) on a routine/scheduled basis and/or is unwilling to 
abstain from such use for the duration of the study. 
19. Is unwilling to abstain from quinine containing products including quinine water, 
tonic water, bitter lemon, jello shots, any quinine preparations or Cinchona tree bark 
preparations (e.g., herbal medications containing Cinchona tree bark). 
20. Has any condition that would, in the opinion of the PI (or designee), put the subject 
at increased risk for participation in a clinical trial or confinement in a clinical 
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5. 
STUDY MEDICATION, RANDOMIZATION AND DOSE 
ADMINISTRATION 
5.1. 
Study Drug Description 
EIDD-2801 and matching PBO will be supplied 
. 
 
 
 
 
 
 
 
 
 
. 
5.1.1. 
Acquisition, Formulation, Packaging and Labeling 
 
 
 
All study drug will be labeled according to the regulatory requirements for investigational 
product. 
5.1.2. 
Product Storage and Stability 
Study drug should be stored at controlled room temperature defined as 
 
. If excursions occur which 
are outside of this range, the pharmacy staff should contact Sponsor to determine the course of 
action. Additional stability data may be available which would allow continued use of the study 
drug, or study drug may need to be replaced. 
5.2. 
Randomization 
Unmasked study drug (EIDD-2801 and matching PBO) will be supplied to the study site 
pharmacy. The pharmacy staff will be unmasked with regards to treatment assignment. A 
randomization list will be provided to the pharmacy staff who will use that list to dispense 
masked study drug for administration to each study participant. In P1, 6 subjects will receive 


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EIDD-2801 while 2 subjects will be randomized to PBO. In P2, all 10 subjects in the FE cohort 
will receive EIDD-2801. The pharmacy staff will maintain the security of the randomization list 
ensuring that no study personnel outside of the pharmacy have access to identify treatment 
assignment. In the case that it becomes necessary to know a subject’s treatment assignment, 
unmasking procedures will be followed as discussed in Section 8.4. 
5.3. 
Dosage, Preparation and Administration of Study Drug 
Detailed instructions for extemporaneous compounding (as necessary), dispensing and 
administering study drug can be found in the pharmacy manual.  
 
 
 
 
 
 
 
 
 
 
 
5.4. 
Drug Accountability 
The site pharmacy must maintain records of receipt and disposition of all study drug supplied to 
the site by the Sponsor. The records must be maintained according to site standard operating 
procedures (SOPs) and should include at a minimum, receipt date, lot or batch number, amount 
and formulation received, 
, date, time and amount 
dispensed, subject identifier for each aliquot of study drug dispensed. In addition, the clinic staff 
must ensure that the time of dosing is identified for each subject. 
Monitors must verify drug accountability/dispensing records during the monitoring visit. 
Unused study drug must be disposed of according to the procedures described in the pharmacy 
manual. 
5.5. 
Concomitant Medication/Treatments 
 
 In this FIH study, limited types of concomitant 
medications are permitted. Adjustment of routine medications taken by subjects should be 
avoided during study participation except when subject safety could be affected by lack of 


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adjustment. There are no restrictions on treatment medications prescribed by the PI (or designee) 
to be used for AEs that occur during study participation. For additional restrictions, see 
Section 6.1.2. 


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6. 
STUDY CONDUCT AND VISIT SCHEDULE 
All study assessments will be conducted according to the Time and Events Schedule. 
6.1. 
Study Conduct 
6.1.1. 
Study Windows and Rounding Principles 
The time schedule described in the protocol for each scheduled activity should be followed as 
closely as possible. However, if it is not possible and if it is not otherwise specifically 
contraindicated per protocol, then the time windows detailed in Table 10 are allowed without 
incurring a protocol deviation. 
Table 10: Allowable Time Windows for Study Assessments/Visits 
Protocol Specified Time 
Allowable Window 
PK Samples and Associated Assessments 
Predose 
within 2 hours prior to dosing 
<2 hours 
± 5 minutes 
≥2 hours to 24 hours 
± 15 minutes (± 2 hours for urinalysis) 
>24 hours to 48 hours 
± 30 minutes 
>48 hours 
± 1 hour (PK) and ± 2 hours (safety)  
Study Visits - Parts 1 and 2 
Day −1 to Day 4 (Part 1) 
must occur on scheduled day 
Day −1 to Day 4 and Day 14 to Day 18 (Part 2) 
must occur on scheduled day 
Day 9 (Part 1) and Days 9 and 23 (Part 2) 
± 1 day 
End-of-Study (EOS) Visit 
± 2 days 
6.1.2. 
Restrictions 
Prior to arriving at the clinic for the Day -1 visit, subjects must abstain from consumption of 
alcoholic beverages for a minimum of 72 hours prior to Check-in. Subjects must continue to 
abstain from consumption of alcoholic beverages throughout clinic confinement. Subjects 
enrolled in P2/FE must continue to refrain from consuming alcoholic beverages from discharge 
on Day 4 through Check-in on Day 14, and then through the second clinic confinement to 
Day 18. After discharge on Day 4 (P1) or Day 18 (P2) subjects must minimize consumption of 
alcoholic beverages (i.e., limit of up to one serving per day) until the EOS procedures have been 
completed. 
All subjects must refrain from the following: 
 consuming quinine containing products from 72 hours prior to Check-in through to 
completion of the EOS procedures. 
 using nutraceuticals and nutritional/vitamin supplements (e.g., gingko biloba, 


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multivitamins) from 72 hours prior to Check-in through to completion of the EOS 
procedures. However, vitamin supplements required by a physician are exempt from 
this restriction. 
 taking OTC analgesics including aspirin (any dose) and NSAIDS from 72 hours 
before Check-in until completion of EOS study procedures unless prescribed by the 
PI (or designee). 
 use of tobacco, nicotine or tobacco products, or e-cigarettes from 3 months prior to 
Screening until the EOS visit. 
 strenuous exercise from 7 days before Check-in until the EOS visit. Subjects will 
otherwise maintain their normal level of physical activity during this time (i.e., will 
not begin a new exercise program nor participate in any unusually strenuous physical 
exertion). 
 Female subjects must not donate eggs/ovum from the time of Check-in until 
3 months after the EOS visit. 
All subjects in P1 should be dosed in the fasted state. Subjects should fast overnight for a 
minimum of 10 hours prior to dosing in the morning on Day 1. Following dosing, subjects may 
have water after 2 hours and food beginning 4 hours postdose. For subjects to be dosed in the fed 
state, subjects should have a high-fat breakfast as defined in the FDA guidance. Subjects must 
complete the meal within 30 minutes of starting the meal and should be dosed after 30 minutes 
of starting the meal. 
6.2. 
Screening 
6.2.1. 
Screening Visit 
Subjects who meet preliminary pre-screening criteria (as defined by the site) and are interested in 
participating in the study will arrive at the study site for administration of informed consent 
according to site SOPs. After the subject has signed and dated the ICF, screening procedures can 
begin. Assessments and procedures should be conducted as shown in the Time and Events 
Schedule Screening may be conducted as early as 28 days prior to dosing. 
6.2.2. 
Retesting Procedures 
In the case where a parameter is outside of the acceptable limits for enrollment, measurement of 
the parameter can be repeated one time if both the following are met: 
 In the opinion of the PI (or designee), the parameter value does not represent a 
chronic condition that otherwise will preclude the volunteer from enrolling in the 
study; and 
 In the opinion of the PI (or designee), the abnormality is not likely to recur. 


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6.2.3. 
Study Visits 
Subjects who satisfy entry criteria will return to the clinic for the Day -1 visit. Following review 
of I/E criteria, subjects who still qualify will be checked into the clinic and enrolled into the 
study. Following enrollment, clinical chemistry, hematology and urine samples will be collected 
to determine baseline values. Based on site standard practices, alternate subjects will also be 
enrolled into the study in case one of the selected subjects cannot be dosed. If all subjects can be 
dosed on the morning of Day 1, the alternates will be released and may be enrolled into 
subsequent cohorts. All assessments and procedures will be performed according to the Time and 
Events Schedule. 
6.2.4. 
Part 1 
Subjects will remain in the clinic through completion of study procedures on Day 4, returning to 
the clinic for procedures on Day 9. 
6.2.5. 
Part 2 
Subjects will remain in the clinic through completion of study procedures on Day 4, returning to 
the clinic on Day 9 for study assessments, and Day 14 to begin the second dosing sequence on 
Day 15. Subjects will then be discharged from the clinic on Day 18, returning to the clinic on 
Day 23 for study assessments. 
6.3. 
Safety Follow-up and End-of-Study Visit 
Subjects in P1 will return to the clinic for the EOS visit on Day 15. Subjects in the FE cohort 
(P2) will return for the EOS visit on Day 30. Subjects with drug-related AEs at the EOS visit will 
be followed as discussed in Section 8.2.1. 
6.4. 
Subject Withdrawal and Replacement 
As this is a small study with a limited number of subjects per cohort, it is critical that all subjects 
complete the study including postdose study assessments. Site personnel should emphasize this 
to study subjects at the time of informed consent so that subjects will understand this fact before 
agreeing to participate in the study. 
Subjects may voluntarily withdraw their consent for study participation at any time without 
penalty or loss of benefits to which they are otherwise entitled. An PI (or designee) may also 
withdraw a subject from receiving study drug or participation in the study for any reason. 
Subjects who withdraw or are withdrawn from the study should undergo withdrawal procedures 
as discussed below. These procedures would include follow-up safety evaluations. 
6.4.1. 
Reasons for Withdrawal 
If a subject withdraws or is withdrawn from the study, the primary consideration must be the 
health and welfare of the subject. The reasons for withdrawal might include but are not limited to 
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 Subject no longer meets eligibility criteria including subject withdraws consent from 
study participation (with or without a reason) 
 Subject becomes noncompliant 
 Medical disease or condition, or new clinical finding(s) for which continued 
participation, in the opinion of the PI (or designee) might compromise the safety of 
the subject, interfere with the subject's successful completion of this study, or 
interfere with the evaluation of responses 
 Subject Lost-to-Follow-up 
 Subject becomes pregnant, if applicable 
 Determined by a physician's discretion to require additional therapy not indicated in 
the protocol to ensure subject's health and well-being (or treatment failure, if 
applicable) 
The PI should be explicit regarding study follow-up (e.g. safety follow-up) that might be carried 
out. If the subject consents, every attempt will be made to follow all AEs through resolution, 
return to baseline, or until stabilized with sequelae for a maximum of 30 days following 
discontinuation. The procedures that collect safety data for the purposes of research must be 
inclusive in the original ICF or the PI may seek subsequent informed consent using an 
EC-approved ICF with the revised procedures. 
The PI will inform the subject that already collected data will be retained and analyzed even if 
the subject withdraws from this study. 
6.4.2. 
Handling of Withdrawals 
Subjects who withdraw from the study prior to receiving study drug (i.e., on Day -1 or before 
dosing on Day 1) will be discharged from the clinic and followed only if AEs are present which 
occurred due to participation in the study (e.g., AE resulting from a study procedure). In this 
case, the subject should be followed until the AE resolves or the PI determines that the AE has 
stabilized. 
Subjects who withdraw from the study after receiving study drug should have EOS assessments 
at the time of withdrawal or as quickly thereafter as possible. 
Subjects who do not return for follow-up procedures on Days 9/23 or 15/30 (P1 and P2) will be 
contacted by the site at least 3 times using the subject’s preferred method of communication (as 
determined at Check-in). If the site is unable to contact the person, then a certified letter will be 
sent. If the subject still cannot be reached or refuses to come back to the clinic after all attempts, 
the subject will be considered Lost-to-Follow-up and withdrawn from the study. 


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6.4.3. 
Documentation of Withdrawals 
If a subject withdraws or is withdrawn prior to completion of the study, the reason for this 
decision must be recorded in the CRF. If the subject is Lost-to-Follow-up, the site should 
document the attempts to contact the subject in the source documents. If the subject has an 
ongoing AE at the time of withdrawal, then the AE should be followed as detailed in 
Section 8.2.1. 
6.4.4. 
Subject Replacement 
If a subject withdraws from the study prior to receiving study drug, the subject will be replaced. 
In this case, designated alternate subjects, if available, will be first in line to replace the 
withdrawn subject. 
If a subject withdraws from the study after receiving study drug, then the decision to replace the 
subject will be made by the PI (or designee) in consultation with the Sponsor. Factors to consider 
will be the timing postdose of withdrawal and the number of safety and PK assessments 
completed prior to withdrawal. Subjects who are withdrawn because of an AE related to the 
study drug will not be replaced. 
6.5. 
Unscheduled Visit(s) 
If a subject experiences an AE after discharge from the clinic but prior to the EOS visit, the 
subject should be instructed to call the site. Based on the issue, the PI (or designee) may request 
that the subject return to the site for an unscheduled visit. In this case, procedures/assessments 
should be conducted as deemed appropriate for the situation by the PI (or designee). The visit 
should be recorded in the unscheduled visit page of the CRF. 


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7. 
STUDY PROCEDURES/EVALUATIONS 
7.1. 
Demography and Medical History 
Demographics including age, gender, race, ethnicity, and medical history will be recorded for 
each subject. All significant medical history should be recorded. In general, significant medical 
history should include all ongoing events and all events occurring within the last 6 months. 
Clinically relevant or clinically significant events occurring greater than 6 months ago should be 
recorded. All surgeries occurring in adulthood should be recorded. If surgeries occurred more 
than 2 years ago, then only the year needs to be recorded on the CRF. 
7.2. 
Clinical Evaluations 
7.2.1. 
Physical Examinations 
The PE will be performed by the PI or a designee that is licensed to perform a PE per local 
requirements. The initial PE performed at Screening and the final PE conducted at the EOS visit 
will include examination of all pertinent body systems as defined by the site standard PE body 
systems (general appearance, HEENT, lymphatic, cardiovascular, respiratory, gastrointestinal 
musculoskeletal, neurological, dermatological). 
Subsequent PEs will be performed as shown in the Time and Events Schedule and will be 
targeted to any new signs or symptoms, any change from the previous status or any body system 
deemed pertinent to that subject by the PI (or designee). Clinically significant abnormalities 
should be recorded in the CRF; those occurring prior to dosing will be included in medical 
history unless the abnormality was the direct result of study participation. 
7.2.2. 
Vital Sign Measurements and ECGs 
Vital signs include pulse rate, respiratory rate, blood pressure, and body temperature. Vital signs 
should be measured after the subject has been supine for a minimum of 5 minutes. Site standard 
ranges will be used for determining any out-of-range values. 
Height and weight should be measured, and BMI calculated at Screening as indicated in the 
Time and Events Schedule. 
Resting 12-lead ECGs should be recorded at the visits indicated in the Time and Events Schedule 
after the subject has been supine for a minimum of 5 minutes. The PI (or designee) will evaluate 
the ECG tracings to determine if there are out-of-range values; if out-or-range values are 
detected, the PI (or designee) will determine if they are clinically significant. Site standard 
ranges will be used to determine if any parameters are considered out-of-range. At the discretion 
of the PI (or designee), the ECG may be repeated if erroneous readings are suspected. 


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7.2.3. 
Adverse Events and Concomitant Medications 
Adverse Events: The PI is responsible for identifying and documenting events meeting the 
definition of an AE or SAE (Section 8.1). Once each day while the subject is in the clinic and 
once during each out-patient visit, the PI (or designee) should inquire about the occurrence of 
AEs. The following are examples of open-ended questions that may be used to obtain this 
information: “How are you feeling?”; "Have you had any medical problems recently?"; "Have 
you taken any new medicines since your last visit/assessment?" 
All AEs and SAEs must be documented in the source documents and recorded in the CRF. 
Concomitant Medications: All medications (prescription or over-the-counter), nutritional 
supplements, and nutraceuticals taken by the subject from 30 days prior to dosing through the 
EOS visit must be recorded in the CRF. Medication information should include indication, dose, 
frequency, and route of administration. Any medication taken for an AE/SAE should be 
documented as such. Refer to Section 5.5 for additional information. 
7.3. 
Laboratory Evaluations 
The laboratory will perform standard routine testing, and processing of all blood samples. For the 
entire study, the amount of blood collected from any one subject will not exceed 500 mL. 
7.3.1. 
Routine Laboratory Panels 
Blood and urine samples will be collected at the times indicated in the Time and Events 
Schedule. The analytes shown in the table below (Table 11) will be assessed. 
If a method to determine COVID-19 status becomes readily available, subjects may be tested at 
Screening and Check-in to confirm they are not positive for COVID-19 prior to dosing.  


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Table 11: Laboratory Evaluations 
CHEMISTRY PANEL 
Alanine Aminotransferase (ALT/SGPT) 
Albumin, Serum 
Albumin/Globulin (A/G) Ratio (calculation) 
Alkaline Phosphatase, Serum 
Amylase 
Aspartate Aminotransferase (AST/SGOT) 
Bilirubin, Total and Direct 
BUN 
BUN/Creatinine Ratio (calculation) 
Calcium, Serum 
Creatinine, Serum 
Creatinine Kinase (CK) 
Gamma Glutamyl Transferase (GGT) 
Lactate Dehydrogenase (LDH)  
Uric Acid 
Electrolyte Panel (Na+, K+, Cl-, Bicarb.) 
Phosphorus 
Globulin, Total  
Glucose, Serum 
Lipase 
Protein, Total, Serum 
 
HEMATOLOGY PANEL 
Hemoglobin 
Hematocrit 
White Blood Cell Count with differential (absolute and percentage) 
Red Blood Count 
Prothrombin Time (PT)/Partial Prothrombin Time (PTT) and International 
Normalized Ratio (INR) 
Mean cell hemoglobin (MCH), mean cell hemoglobin concentration (MCHC), 
mean cell volume (MCV), red cell distribution width (RDW; may be a 
Grade 1 abnormality) 
Platelets 
ADDITIONAL ASSESSMENTS 
Virology: Human Immunodeficiency Virus (HIV) serology, Hepatitis B Virus 
(HBV; Surface Antigen [HBsAg]), Hepatitis C Virus (HCV) 
Follicle-Stimulating Hormone (FSH; as applicable) 
PREGNANCY TEST 
Serum Pregnancy Test 
Urine Dipstick (optional blood follow-up) 
DRUG SCREENING 
Serum/urinalysis (per site SOP) 
Cotinine 
Urine Dipstick 
Alcohol Breathalyzer 
ROUTINE URINALYSIS 
Bilirubin 
Color and appearance 
Glucose 
Ketones  
Leukocytes 
Microscopic (including red blood cells [RBCs] and white blood cells [WBCs])
Nitrite 
Occult blood 
pH 
Protein 
Specific Gravity 
Urobilinogen 
7.3.2. 
Pharmacokinetic Sampling 
Samples for PK analysis will be collected as shown in the Time and Events Schedule. All 
samples will be analyzed to define the PK parameters for EIDD-2801 and the active metabolite, 
EIDD-1931. In order to preserve EIDD-2801, special handling procedures will be put in place. 
These procedures will be documented in the Laboratory Manual for the study. 
Depending on ongoing review of the PK data, timepoints may be modified or removed, and up to 
3 additional samples (in each period for the food-effect) may be added. 


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7.3.3. 
Peripheral Blood Mononuclear Cell Collection 
Peripheral blood mononuclear cells will be collected in P2. Blood will be collected into 
specialized tubes and processed according to procedures described in the Laboratory Manual. 
Depending on ongoing review of the data, timepoints may be modified or removed, and up to 
2 additional samples may be added. 
7.3.4. 
Urine Collection 
Urine will be collected over the time periods noted in the Time and Events Schedule. Samples 
will be collected for routine urinalysis and PK analysis according to site standard practices and 
as described in the Laboratory Manual. 


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8. 
SAFETY MONITORING, MANAGEMENT AND REPORTING 
8.1. 
Definitions 
8.1.1. 
Adverse Events 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product. 
Abnormal clinical laboratory findings (e.g. clinical chemistry, hematology) or other abnormal 
assessments that are judged by the PI (or designee) as clinically significant will be recorded as 
AEs or SAEs if they meet the definitions of an AE or an SAE as defined in this Section 8.1.2. 
Disease specific signs and symptoms which were ongoing prior to study entry will not be 
considered AEs unless they worsen (e.g. increase in frequency or severity) unexpectedly during 
the course of the trial. 
8.1.2. 
Serious Adverse Events 
An AE or suspected adverse reaction is considered “serious” if, in the view of either the PI (or 
designee) or Sponsor, it results in any of the following outcomes: 
 Death, 
 A life-threatening AE: An AE or suspected adverse reaction is considered 
“life-threatening” if, in the view of either the PI or Sponsor, its occurrence places the 
patient or subject at immediate risk of death. It does not include an AE or suspected 
adverse reaction that, had it occurred in a more severe form, might have caused 
death. 
 Inpatient hospitalization or prolongation of existing hospitalization, 
 A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions, or 
 A congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalizations may be considered serious when, based upon appropriate medical judgment they 
may jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 


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or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
Suspected adverse reaction means any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event. “Reasonable possibility” means there is evidence to 
suggest a causal relationship between the drug and the adverse event. Suspected adverse reaction 
implies a lesser degree of certainty about causality than adverse reaction, which means any 
adverse event caused by a drug. 
An AE or suspected adverse reaction is considered “unexpected” if 
 It is not listed in the IB or is not listed at the specificity or severity that has been 
observed; or, if an IB is not required or available, 
 Is not consistent with the risk information described in the general investigational 
plan or elsewhere in the current application as amended. For example, under this 
definition, hepatic necrosis would be unexpected (by virtue of greater severity) if the 
IB referred only to elevated hepatic enzymes or hepatitis. Similarly, cerebral 
thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater 
specificity) if the IB listed only cerebral vascular accidents. 
 “Unexpected” as used in this definition, also refers to AE or suspected adverse 
reactions that are mentioned in the IB as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the particular drug under investigation. 
As of the date of this protocol, there are no expected events listed in the current version of the 
IB; therefore, all AEs will be considered unexpected until such a time that the reference safety 
information in the IB is updated with any identified, expected events. 
8.2. 
Documenting Adverse Events 
8.2.1. 
Timeframe for Collection and Follow-up of AEs/SAEs 
All AEs/SAEs will be collected from the time of the first study drug administration until the 
subject has completed the EOS visit and been discontinued from the study. This includes 
subjects who discontinue early. Events considered related to study drug will be followed as 
noted: 
 AEs that are related to study drug and continue beyond the normal collection period 
(i.e., are ongoing at the time a subject exits the study) will be followed until 
resolution, return to baseline or until stabilized with sequelae for a maximum of 
30 days following discontinuation. After 30 days, the AE will be closed, and the 
outcome noted (see Table 12). 
 SAEs that are related to study drug and continue beyond the normal collection period 


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(i.e., are ongoing at the time a subject exits the study) will be followed until 
resolution, return to baseline or until stabilized with sequelae. 
 SAEs that are reported to the site within 30 days after the subject has been 
discontinued from the study (i.e., completed the EOS visit) will be recorded. Those 
that are considered related to study drug will be followed as noted in the bullet 
above. 
Note that all events which occurred prior to dosing with study drug should be recorded as 
medical history unless the event is directly related to study procedures. 
8.2.2. 
Recording of Adverse Events/Serious Adverse Events 
AEs/SAEs must be recorded in the CRF as indicated in the CRF completion instructions. 
Information to be collected includes event description, time of onset, clinician’s assessment of 
severity (Section 8.2.3), relationship to study drug (Section 8.2.4), outcome (Section 8.2.5), and 
time of resolution/stabilization of the event. All AEs occurring while on study must be 
documented appropriately regardless of relationship and will be followed to adequate resolution 
as described above (Section 8.2.1). All SAEs will be recorded as noted above; SAEs reported to 
the site within 30 days following the EOS visit will also be recorded. All SAEs must be entered 
onto the SAE form and reported as discussed below (Section 8.3.1). 
If an AE changes in severity, the highest severity will be recorded in the CRF. AEs characterized 
as intermittent require documentation of onset and duration of each episode. 
8.2.3. 
Assessing Severity of Adverse Events 
All AEs/SAEs will be assessed by the PI or those with the training and authority to make a 
medical judgment. AEs/SAEs will be graded according to the DMID Toxicity Grading Scale. 
For any AEs not specifically listed in the tables, the following guidelines should be used to grade 
severity: 
 Mild (Grade 1); asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
 Moderate (Grade 2); minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living. 
 Severe (Grade 3); medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care activities of daily living. 
 Life-threatening (Grade 4) Life-threatening consequences; urgent intervention 
indicated. 
 Death (Grade 5) Death related to AE. 


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Changes in the severity of an AE should be documented to allow an assessment of the duration 
of the event at each level of intensity to be performed. Adverse events characterized as 
intermittent require documentation of onset and duration of each episode. 
8.2.4. 
Relationship to Study Drug 
The PI’s (or designee’s) assessment of an AE's relationship to study drug is part of the 
documentation process, but it is not a factor in determining what is or is not reported in the study. 
If there is any doubt as to whether a clinical observation is an AE, the event should be reported. 
All AEs must have their relationship to study product assessed using the terms: related or not 
related. In a clinical trial, the study product must always be suspect. To help assess, the following 
guidelines are used. 
 Definite – The AE is clearly related to the study drug. 
 Probable – The AE is likely related to the study drug. 
 Possible – The AE may be related to the study drug. 
 Unlikely – The AE is doubtfully related to the study drug. 
 Unrelated – The AE is clearly NOT related to the study drug. 
8.2.5. 
Classifying Adverse Event Outcome 
All AEs/SAEs in the study must be assigned an outcome by site staff. The outcome will be 
included on the AE CRF. Possible outcomes are shown below: 
Table 12: Adverse Event Outcomes 
Outcome 
Description 
Recovered / Resolved 
AE resolved with no residual signs or symptoms; an event is considered resolved if it 
returns to baseline (pretreatment) values. 
Recovered / Resolved with sequelae 
AE stabilized but residual signs or symptoms remain; this includes stabilization of an 
event/condition with the expectation that it will remain chronic. 
Not Recovered / Not Resolved 
AE remains ongoing AND no or only minimal improvement has occurred. 
Ongoing 
AE has not yet resolved, but continues to improve/resolve and complete resolution is 
expected over time. 
Fatal 
Outcome of the AE is death. 
Unknown 
AE outcome is not known; usually because the subject has been Lost-to-Follow-up. 


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8.3. 
Reporting Procedures 
8.3.1. 
Serious Adverse Events 
The PI or clinical site personnel should notify Covance Drug Safety Services (DSS) 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 Notification 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. 
The responsibilities of Covance DSS include the following: 
 Prepare an AE reporting plan prior to the start of the study. Where this plan differs from 
the applicable site standard operating procedure on SAE reporting, the AE reporting plan 
will always take precedence. 
 Receive and review SAE report forms from the site and inform the Sponsor of the SAE 
within 1 working day of the initial notification to DSS. Drug Safety Services will delete 
any information from the SAE report forms that may identify the subject. 
 Write case narratives and enter the case into Covance’s safety database as defined in the 
AE reporting plan. 
 Produce appropriate reports of all Suspected Unexpected Serious Adverse Reactions and 
forward to the EC, Medicines and Healthcare Products Regulatory Agency, PI’s (or 
designee’s), and the Sponsor within the timeframes stipulated in the Clinical Trials 
Directive Guideline (ENTR/CT 3).  
The responsibility for reporting SAEs will be transferred to the Sponsor 28 days after the end of 
the study. 
8.3.2. 
Pregnancy 
Subjects in this study must be of non-childbearing potential. However, should a pregnancy occur 
any time from informed consent to the EOS visit, subjects must immediately report the event to 
the clinical site which in turn must immediately report the pregnancy to the Sponsor or their 
designee. The subject will be followed until the end of the pregnancy. A separate ICF will be 
used for consenting for follow-up pregnancy activities. Pregnancy will not be considered an AE 
unless deemed likely related to study drug. Pregnancy will not be considered an SAE unless there 
is an associated SAE. A spontaneous abortion (miscarriage) or abnormal outcome (including 
congenital anomalies) will be reported as an SAE. 


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8.4. 
Unmasking Treatment Assignment 
The following controls will be employed to maintain the double-blind status of the study: 
 Placebo will be identical in appearance to the EIDD-2801. 
 The PI and other members of staff involved with the study will remain blinded to the 
treatment randomization code in P1. 
 Interim bioanalytical data will be provided in a blinded manner. 
To maintain the blind, the PI will be provided with a sealed randomization code for each subject 
in P1, containing details of their treatment. These individual sealed envelopes will be kept in a 
limited access area that is accessible 24 hours a day. In order to manage subject safety or to 
support dose-escalation decisions (in the event of possibly treatment-related SAEs or severe 
AEs), the decision to unblind resides solely with the PI. Whenever possible and providing it does 
not interfere with or delay any decision in the best interest of the subject, the PI will discuss the 
intended code-break with the Sponsor. If it becomes necessary to break the code during the 
study, the date, time, and reason will be recorded in the subject’s source data and on the 
individual envelope and will be witnessed by a second person. 
The pharmacy and bioanalytical lab will have access to the treatment randomization and will be 
unblinded.  Pharmacokinetic personnel may be unblinded to perform interim PK analysis and to 
ensure that PK data are provided in a blinded manner for dose-escalation decisions.  


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9. 
DOSE-ESCALATION AND HALTING RULES 
9.1. 
Guidelines for Dose-Escalation 
Doses will be administered in an escalating manner following satisfactory review by the Sponsor 
and PI of the blinded safety and tolerability data up to 72 hours post final dose.
 
 
 As PK data 
become available, these data will be reviewed and may be used to assist in dose selection. 
Doses may be reduced and may be lower than the starting dose. There will be a minimum of 
4 days between dose escalations to allow sufficient time for an adequate safety review. 
Dose-escalation in P1 will only occur if data from a minimum of 6 subjects have been reviewed 
from the previous lower dose group, such that data from a minimum of 4 subjects who have 
received EIDD-2801 will be used to make the dose-escalation decision. 
The justification for this is as follows: 
 The study treatment is of a known pharmacological class for which the on-target effects 
in humans are well characterized. Based upon nonclinical data, no clinically important off 
target effects are expected within the proposed dose range. 
 A minimum of 4 subjects receiving the active drug is considered sufficient to characterize 
the safety profile of EIDD-2801. 
Between each dose-escalation, the PI will review all available data in a blinded manner to ensure 
it is safe to proceed with the planned dose-escalation. The results from all available safety 
assessments will be sent to the Sponsor prior to the start of each successive group/treatment 
period. Any clinically significant results will be discussed with the Sponsor before 
dose-escalation continues. Interim PK data may also be reviewed in terms of dose-escalation and 
to confirm that the study design remains appropriate. In the event of a disagreement between 
Sponsor and PI on the dose-escalation decision, the most conservative decision will be upheld. 
Dose levels will not increase by more than 3-fold for predicted nonpharmacologically active 
dose levels and by 2-fold for predicted pharmacologically active dose levels. 
 
 
 
9.2. 
Dose-Escalation Halting Rules 
For Group 1 in P1/SAD, sentinel dosing will occur whereby 2 subjects (1 active and 1 PBO) will 
be dosed on 1 day and, providing no safety concerns arise, the remaining 6 subjects will be dosed 
after at least 24 hours. 


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The study will be halted (i.e., no further dosing will occur) if one or more subjects experience an 
SAE that is considered to be related to EIDD-2801 or 2 or more subjects in the same group 
experience severe AEs that are considered to be related to EIDD-2801. If, following an internal 
safety review, the Sponsor deems it appropriate to restart the study, this can be done following 
approval of a substantial protocol amendment.  
Dose-escalation will stop if clinically relevant signs or symptoms of similar nature occur in 2 or 
more subjects in a group that, in the opinion of the PI, warrant stopping of dose-escalation. 


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10. 
STATISTICAL CONSIDERATIONS 
10.1. 
General Considerations 
All summaries will be provided by study part and treatment. Continuous variables will be 
summarized using descriptive statistics including number of observations (n), mean, standard 
deviation, minimum (min), median (med), and maximum (max). Categorical variables will be 
summarized using frequency counts and percentages. Note that PBO data from each dose level in 
Part 1 will be combined into one PBO group. 
No missing data imputation will be performed. 
Subject listings will be provided for all the data collected during the study period. 
Specific information about the statistical analysis will be provided in a SAP that will be reviewed 
and approved by the Sponsor and will be finalized before final database lock. If there is a 
discrepancy between the methods described in the protocol and final approved SAP, the SAP 
will take precedence. 
10.2. 
Sample Size Considerations 
No formal sample size calculation was conducted. The sample size of 8 per cohort 
(6 active: 2 PBO) for the SAD cohorts is considered adequate for a Phase 1 FIH study. The 
sample size of 10 subjects (all administered EIDD-2801) is in accordance with FDA guidelines 
for sample size in FE studies. 
10.3. 
Analysis Populations 
Safety Population: All subjects who receive at least one dose of study drug. 
Pharmacokinetic Population: All subjects receiving study drug who comply sufficiently with 
protocol requirements (i.e., no major protocol violations) and for whom a sufficient number of 
analyzable PK samples have been obtained to permit the determination of the PK profile for 
EIDD-2801/EIDD-1931 and the statistical analysis of the results. Subjects who experience an 
AE of vomiting before 2× the median tmax of the group may be excluded from the PK population. 
10.4. 
Analysis of Safety Data 
All safety analyses will be performed on the Safety Population as defined in Section 10.3. Safety 
will be assessed on the basis of AEs, clinical laboratory data, vital signs, ECG parameters, and 
PEs. 
10.4.1. 
Extent of Exposure 
Dosing data will be listed by study part. 


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10.4.2. 
Adverse Events 
Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
preferred term and system organ classification. Any events reported after the initiation of study 
treatment and through the EOS are defined as treatment-emergent. The occurrence of 
treatment-emergent AEs will be summarized using MedDRA preferred terms, system organ 
classifications, and severity. Separate summaries of treatment-emergent SAEs and AEs 
considered related to study treatment and AEs leading to study treatment discontinuation will be 
generated. All AEs will be listed for individual subjects showing both verbatim and preferred 
terms. 
10.4.3. 
Clinical Laboratory Results 
Laboratory abnormalities will be graded according to the DMID Toxicity Grading Scale. Any 
graded abnormality that occurs following the initiation of study treatment and represents at least 
a one-grade increase from the baseline assessment is defined as treatment-emergent. The number 
and percentage of subjects experiencing treatment-emergent graded toxicities will be 
summarized. Raw values and mean changes from baseline in clinical laboratory measures will be 
summarized. 
Listings of the clinical laboratory test results will be provided. Abnormal laboratory values will 
be flagged in the listings. 
10.4.4. 
Other Parameters 
Individual data for ECG parameters and vital sign measurements will be listed by subject and 
time point and summarized for each treatment. Individual data for PE will be listed by subject 
and time point. 
Concomitant medications will be coded using the World Health Organization-Drug Dictionary 
(WHO-DD) and summarized. 
10.5. 
Analysis of Pharmacokinetic Data 
Pharmacokinetic analysis as defined in the SAP will be conducted using the PK population 
defined in Section 10.3. In the event of discrepancies between analyses described in the SAP and 
this clinical study protocol, the SAP will supersede the protocol. 
 All samples will be analyzed and all concentrations listed. 
 Descriptive statistics will be performed for all time points available, with the 
exclusion of subjects who had any significant protocol deviation. 
 Pharmacokinetic parameters will be derived where possible for all subjects. Data 
from subjects with incomplete profiles (missed blood draws, lost samples, samples 
unable to be quantified) may be used if PK parameters can be estimated using the 
remaining data points. 


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 Descriptive statistics will be performed on all parameters available, and any missing 
parameters will be flagged. 
Plasma concentration data for EIDD-2801 and EIDD-1931 will be listed for individual subjects 
and summarized by study part and treatment. Individual and mean plasma concentration versus 
time plots for EIDD-2801 and EIDD-1931 will be provided. Urine concentration data for 
EIDD-2801 and EIDD-1931 will be listed. 
Plasma PK parameters of EIDD-2801 and EIDD-1931 for each subject will be estimated over the 
sampling interval using noncompartmental analysis and summarized by study part and treatment 
using descriptive statistics. Actual blood sampling times will be used for plasma PK analysis. 
Urine PK parameters of EIDD-2801 and EIDD-1931 will also be analyzed and summarized 
when possible. The PK parameters that will be estimated are listed in the table below.  
Table 13: Pharmacokinetic Parameters 
Plasma PK Parameter 
Description 
AUClast 
The area under the plasma concentration-time curve, from time 0 to the last measurable 
non-zero concentration, as calculated by the linear up/log down trapezoidal method. 
AUC0-inf 
The area under the plasma concentration-time curve from time 0 extrapolated to infinity. 
AUC0-inf is calculated as the sum of AUClast plus the ratio of the last measurable plasma 
concentration to the elimination rate constant (λz). 
Cmax 
Maximum observed concentration. 
tmax 
Time to reach Cmax. If the maximum value occurs at more than one time point, tmax is 
defined as the first time point with this value. 
λz 
Apparent terminal elimination rate constant; represents the fraction of medication 
eliminated per unit time. 
t½ 
Apparent terminal elimination half-life of medication, calculated as 0.693/λz. 
Vz/F 
Apparent volume of distribution (EIDD-2801 only). 
CL/F 
Apparent oral drug clearance (EIDD-2801 only). 
Urine PK Parameter 
Description 
Ae 
Amount excreted in urine over the sampling interval. 
Fe 
Fraction of drug excreted in the urine over sampling interval. 
CLR 
Renal clearance, CLR = Ae/AUC where both Ae and AUC are determined over co-incident 
time ranges after dosing. 
Additional PK parameters may be analyzed as appropriate. 
10.5.1. 
Statistical Analysis of Pharmacokinetic Data 
10.5.1.1. Dose Proportionality 
Dose proportionality for PK parameters of EIDD-2801 and EIDD-1931 (AUC0-inf, AUClast, and 
Cmax) will be assessed by the power model. The mean slope and the associated 90% CI based on 
the power model will be reported. 


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10.5.1.2. Food-Effect 
To assess the effect of food on the PK of EIDD-2801 and EIDD-1931, natural log transformed 
PK parameters from P2 (AUC0-inf, AUClast, and Cmax) will be analyzed using a mixed effects 
model with fixed-effect terms for treatment (with or without food), period, and sequence and 
with subject within sequence as a random effect. Point estimates and their associated 90% CIs 
for the natural log transformed PK parameters for the difference between EIDD-2801 
administered under fed relative to fasted conditions will be constructed. The point estimates and 
interval estimates will be back transformed to give estimates of the ratio and 90% CI for the 
geometric least squares mean ratio for fed/fasted to assess the effect of food. 
10.6. 
Peripheral Blood Mononuclear Cells 
PBMCs will be collected from subjects following each dose in Part 2.The PBMCs will be stored 
for analysis of EIDD-2061 levels at some point in the future and reported separately. 
10.7. 
Interim Analyses 
There are no formal interim analyses planned for this study. However, interim analyses may be 
implemented at the discretion of the Sponsor or health authority request. In addition, data from 
P1 cohorts may be locked, unblinded, and analyzed prior to conducting P2. 


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11. 
STUDY ADMINISTRATION 
11.1. 
Regulatory and Ethical Considerations 
11.2. 
Ethical Standard 
This study will be conducted in accordance with the protocol and with the following: 
 Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
International Ethical Guidelines. 
 Applicable ICH GCP Guidelines. 
 United States Code of Federal Regulations applicable to clinical studies (45 CFR Part 46; 
21 CFR Part 50, 21 CFR Part 56, and 21 CFR Part 312). 
 Applicable laws and regulations. 
11.2.1. 
Ethics Committee Approval 
The PI (or designee) must ensure that all required study-specific documents and/or information 
are submitted to the EC for review and approval as appropriate including but not limited to: 
 the protocol and any future protocol amendments 
 ICF and any other documents (electronic or paper) given to the subject 
 IB 
Any substantial protocol amendments, likely to affect the safety of the subjects or the conduct of 
the study, will require EC and regulatory authority (as locally required) approval before 
implementation of changes made to the study design, except for changes necessary to eliminate 
an immediate hazard to study subjects or any nonsubstantial changes, as defined by regulatory 
requirements. 
11.2.2. 
Informed Consent 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continuing throughout the individual’s study participation. Extensive discussion of 
risks and possible benefits of this therapy will be provided to the subjects and, if applicable, their 
families. Consent forms describing in detail the study interventions/products, study procedures, 
and risks are given to the subject and written documentation of informed consent is required 
prior to starting any screening procedures or intervention/administering study product. Consent 
forms will be EC-approved and the subject will be asked to read and review the document. 


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Upon reviewing the document, the PI (or designee) will explain the research study to the subject 
and answer any questions that may arise. The subjects will sign the ICF prior to any procedures 
being done specifically for the study. The subjects should have the opportunity to discuss the 
study with their surrogates or think about it prior to agreeing to participate. The subjects may 
withdraw consent at any time throughout the course of the trial. A copy of the ICF will be given 
to the subjects for their records. The rights and welfare of the subjects will be protected by 
emphasizing to them that the quality of their medical care will not be adversely affected if they 
decline to participate in this study. 
11.3. 
Financing and Insurance 
Financing and insurance will be addressed in a separate agreement. 
11.4. 
Source Documentation and Access 
The site will maintain appropriate medical and research records in compliance with ICH E6, 
Section 4.9 and regulatory and institutional requirements for the protection of confidentiality of 
subjects. The site will permit authorized representatives of the Sponsor, its designees, and 
appropriate regulatory agencies to examine (and when required by applicable law, to copy) 
clinical records for the purposes of quality assurance reviews, audits, and evaluation of the study 
safety and progress. These representatives will be permitted access to all source data and source 
documents, which include, but are not limited to, clinical and office charts, laboratory notes, 
memoranda, subjects’ memory aid or evaluation checklists, pharmacy dispensing records, 
recorded data from automated instruments, copies or transcriptions certified after verification as 
being accurate and complete, photographic negatives, microfilm or magnetic media, x-rays, and 
subject files and records kept at the pharmacy, at the laboratory, and medico-technical 
departments involved in the clinical trial. 
11.5. 
Data Collection and Record Keeping 
11.5.1. 
Data Collection 
Data collection and data entry are the responsibility of the clinical trial staff at the site. The PI is 
responsible for ensuring the accuracy, completeness, legibility, and timeliness of the data 
reported. All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data. 
A CRF must be completed for every subject who signs the ICF and has at least one 
protocol-specified assessment conducted. The CRF must be completed and processed according 
to the CRF guidelines and the SOPs of the site. All data should be entered into the CRF, where 
possible, within 3 days after each visit for any one subject. After the subject has completed the 
study, the PI must review and sign the signature page of the CRF indicating that he has reviewed 
the completed CRF and pertinent clinical data for that subject and that, to the best of his 
knowledge, all data recorded in the CRF accurately reflects the subject’s clinical performance in 
the study 


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11.5.2. 
Study Records Retention 
Study documents should be retained for a minimum of 5 years after the end of the study. These 
documents should be retained for a longer period; however, if required by local regulations. No 
records will be destroyed without the written consent of the Sponsor, if applicable. It is the 
responsibility of the Sponsor to inform the PI when these documents no longer need to be 
retained. 
11.5.3. 
Protocol Deviations 
A protocol deviation is any noncompliance with the protocol or study procedures detailed in the 
Laboratory or Pharmacy Manuals. The noncompliance may have been the result of action by the 
PI, site staff, or subject. All deviations should be handled in accordance with site SOPs. 
It is the responsibility of the site to use continuous vigilance to identify and report deviations 
within 5 working days of identification of the protocol deviation, or within 5 working days of the 
scheduled protocol-required activity. 
11.6. 
Clinical Monitoring 
Site monitoring is conducted to ensure that the human subjects’ protections, study and laboratory 
procedures, study intervention administration, and data collection processes are of high quality 
and meet Sponsor, ICH/GCP guidelines and applicable regulations, and that this trial is 
conducted in accordance with the protocol, protocol-specific MOP and applicable Sponsor SOPs. 
Experienced clinical monitors of the Sponsor or its designee will conduct site-monitoring visits 
as detailed in the clinical monitoring plan. 
Site visits will be made at standard intervals as defined by the Sponsor and may be made more 
frequently as directed by the Sponsor. Monitoring visits will include, but are not limited to, 
review of regulatory files, accountability records, CRFs, ICFs, medical and laboratory reports, 
and protocol and GCP compliance. Clinical monitors will have access to each participating site, 
study personnel, and all study documentation according to the site monitoring plan. Clinical 
monitors will meet with the site PI to discuss any problems and actions to be taken and will 
document site visit findings and discussions. As data are entered into a CRF, data will be 
monitored to ensure accuracy as well as adherence to data entry instructions provided in the CRF 
guidelines. 
11.7. 
Quality Control and Quality Assurance 
A quality management plan will be put in place for this study. The site is responsible for 
conducting routine quality assurance and quality control activities to internally monitor study 
progress and protocol compliance. The PI will provide direct access to all study-related sites, 
source data/data collection forms, and reports for the purpose of monitoring and auditing by the 
Sponsor, and inspection by local and regulatory authorities. The PI will ensure all study 
personnel are appropriately trained and applicable documentations are maintained on site. 


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11.8. 
Study Termination and Closure Procedures 
11.8.1. 
Study Termination 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided to the site. If the study is terminated or suspended, the PI (or 
designee) will inform study participants and the EC. The Sponsor will notify appropriate 
regulatory authorities. The Sponsor will provide the reason(s) for the termination or suspension. 
Study participants will be contacted, as applicable, and be informed of changes to study visit 
schedule. 
If suspended, the study may resume once issues that caused suspension of the study are resolved. 
11.8.2. 
Termination Procedures 
If the study is prematurely terminated, then the site must return all appropriate study data, 
resolve all data queries, complete final drug accountability, return any study drug remaining on 
site, and ship all biological samples (including PK and PBMCs) to the laboratory designated by 
the Sponsor. The PI (or designee) must notify the EC of study termination. 
11.9. 
Information Disclosure 
11.9.1. 
Confidentiality 
Subject confidentiality and privacy is strictly held in trust by the PI, site staff, and the Sponsor(s) 
and their agents. The study protocol, documentation, data, and all other information generated 
will be held in strict confidence. No information concerning the study or the data will be released 
to any unauthorized third party without prior written approval of the Sponsor. 
The study monitor or other authorized representatives of the Sponsor or regulatory agencies may 
inspect all documents and records required to be maintained by the PI, including but not limited 
to, medical records (office, clinic, or hospital) and pharmacy records for the participants in this 
study. The clinical study site will permit access to such records. 
The study participant’s contact information will be securely stored at the clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by the Sponsor, site, or regulatory requirements. 
Study participant research data will be transmitted to and stored securely by the Sponsor’s 
designated data center. This will not include the participant’s contact or identifying information. 
Individual participants and their research data will be identified by a unique study identification 
number. The study data entry and study management systems used by clinical sites will be 
secured and password protected. At the end of the study, all study databases will be de-identified 
and archived at a secure location. 


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11.9.2. 
Clinicaltrials.gov 
This clinical study will be registered on clinicaltrials.gov as required. 
11.9.3. 
Publication Policy 
All information generated from this study is the proprietary property of the Sponsor. It is the 
intent of the Sponsor to publish the results of the study in their entirety as deemed appropriate. 


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12. 
REFERENCES 
Agostini ML, Pruijssers AJ, Chappell JD, Gribble J, Lu X, Andres EL, et al. Small-Molecule 
Antiviral β-d-N4-Hydroxycytidine Inhibits a Proofreading-Intact Coronavirus with a High 
Genetic Barrier to Resistance. J Virol. 2019 Dec 15;93(24).  
Flavell RA, Sabo DL, Bandle EF, Weissmann C. Site-directed mutagenesis: generation of an 
extracistronic mutation in bacteriophage Q beta RNA. J Mol Biol. 1974 Oct 25;89(2):255–72.  
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 Dec;48(12):4636–42.  
Mullins JI, Heath L, Hughes JP, Li D, Essigmann JM, Harris KS, et al. Mutations based on viral 
decay acceleration in the HIV-1 genomes of a clinical population treated with the mutagenic 
nucleoside KP1461. Retrovirology. 2011 Oct 3;8(Suppl 2):P84.  
Painter GR, Bowen RA, Bluemling GR, DeBergh J, Edpuganti V, Gruddanti PR, et al. The 
prophylactic and therapeutic activity of a broadly active ribonucleoside analog in a murine model 
of intranasal venezuelan equine encephalitis virus infection. Antiviral Res. 2019;171:104597.  
Sticher ZM, Lu G, Mitchell DG, Marlow J, Moellering L, Bluemling GR, et al. Analysis of the 
Potential for N4-Hydroxycytidine To Inhibit Mitochondrial Replication and Function. 
Antimicrob Agents Chemother. 2020 27;64(2).  
Stuyver LJ, Whitaker T, McBrayer TR, Hernandez-Santiago BI, Lostia S, Tharnish PM, et al. 
Ribonucleoside analogue that blocks replication of bovine viral diarrhea and hepatitis C viruses 
in culture. Antimicrob Agents Chemother. 2003 Jan;47(1):244–54.  
Toots M, Yoon J-J, Cox RM, Hart M, Sticher ZM, Makhsous N, et al. Characterization of orally 
efficacious influenza drug with high resistance barrier in ferrets and human airway epithelia. Sci 
Transl Med. 2019 Oct 23;11(515):eaax5866.  
Urakova N, Kuznetsova V, Crossman DK, Sokratian A, Guthrie DB, Kolykhalov AA, et al. 
β-d-N4-Hydroxycytidine Is a Potent Anti-alphavirus Compound That Induces a High Level of 
Mutations in the Viral Genome. J Virol. 2018 01;92(3).  
Yoon J-J, Toots M, Lee S, Lee M-E, Ludeke B, Luczo JM, et al. Orally Efficacious 
Broad-Spectrum Ribonucleoside Analog Inhibitor of Influenza and Respiratory Syncytial 
Viruses. Antimicrob Agents Chemother. 2018;62(8). 


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13. 
APPENDICES 
Appendix 1: 
Time and Events Schedule 
Parts 1 and 2 
Visit
Screening 
(Days -28 to -2) Day -1
Day 1
Day 2
(24 hr)
Day 3
(48 hr)
Day 4 
(72 hr) Day 9 
Day 15 / EOS1 
(non-FE cohorts)
Food-Effect Cohort 
Day 14 Day 15 Day 16
(24 hr)
Day 17
(48 hr)
Day 18 
(72 hr) Day 23 
Day 30 / EOS 
ICF; Demography 
x 
 
 
 
 
 
 
 
I/E; Medical history 
x 
x 
 
 
 
 
 
 
Physical examination2 
x 
x 
 
x 
 
x 
x 
x 
Qualifying laboratory analyses3 
x 
x 
 
 
 
 
 
 
Drug screening and pregnancy test4 
x 
x 
 
 
 
 
x 
x 
Height, weight (BMI) 
x 
 
 
 
 
 
 
 
Clinic confinement5 
 
x 
x 
x 
x 
x 
 
 
Non-residential visit 
x 
 
 
 
 
 
x 
x 
Clinical chemistry and urinalysis6 
x 
x 
 
x 
 
x 
x 
x 
Hematology7 
x 
x 
 
x 
x 
x 
x 
x 
PBMC collection (FE cohort ONLY) 
 
 
x8 
x8 
 
 
 
 
ECG 
x 
 
x9 
 
 
x 
 
x 
Vital signs 
x 
x 
x10 
x 
x 
x 
x 
x 
Administer study drug 
 
 
x 
 
 
 
 
 
Plasma PK sample collection 
 
 
x11 
x12 
x12 
x12 
 
 
Urine PK sample collection 
 
 
x13 
x14 
x14 
 
 
 
Adverse events 
x15 
x15 
x15 
x 
x 
x 
x 
x 
Prior and/or Concomitant medications 
x 
x 
x 
x 
x 
x 
x 
x 
Abbreviations: BMI (body mass index); EOS (End of Study); FE (food-effect); ICF (Informed Consent Form); I/E 
(Inclusion/Exclusion Criteria); ECG (electrocardiogram); PBMC (peripheral blood mononuclear cell); PK (pharmacokinetic). 
1 On Day 15, conduct the EOS visit for all subjects except those in the FE cohort. 
2 A complete PE will be performed at Screening and/or Check-in, and EOS visits; on all other days, a limited PE will be 
conducted targeting any change from the previous status or any body system deemed pertinent to that subject by the PI (or 
designee).  
3 Laboratory analyses to qualify for study entry include: total white cell count or absolute lymphocyte count (values must be in 
the normal range), hemoglobin or platelet levels (values must not be below the lower limit of normal), and ALT/SGPT, alkaline 
phosphatase, AST/SGOT (values must not be above the upper limit of normal), plus virology (HIV/HCV/HBV) (all must be 
negative), and FSH (if required). 
4 Drug screening (urine drug screen, UDS), including a cotinine test, should be conducted at Screening, Day -1, Days 9 and 23, 
and at EOS. Pregnancy tests should be conducted in serum at Screening and in urine at all other times (i.e., Days -1, 9, and 23, 
and EOS). A positive urine pregnancy test will be confirmed with a serum pregnancy test. An alcohol breath test should be 
conducted at Screening and Day -1. 
5 Participants should be admitted to the clinic following review of final I/E criteria on Day -1 and discharged from the clinic 
following completion of study specific assessments on Day 4. Subjects in the FE cohort should be readmitted to the clinic on 
Study Day 14. 
6 Safety laboratory assessments include clinical chemistry and urinalysis. Baseline samples will be collected after clinic 
admission on Day -1.  
7 Hematology values include, but are not limited to, RBC, WBC with differential and platelets. PT/PTT and INR assessed only at 


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Screening. 
8 PBMCs will be collected 2- and 12-hr postdose on Day 1/15 and 24 hrs postdose (on Day 2/16). Depending on ongoing review 
of the data, timepoints may be modified or removed, and up to 2 additional samples may be collected. 
9 The baseline ECG should be conducted prior to dosing on Day 1/15. 
10 Vital signs include pulse rate, respiratory rate, blood pressure, and body temperature; on Day 1/15, VS should be taken 
predose, and at 2, 4, 8 and 12 hr postdose.  
11 PK samples should be collected predose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 9, 12, and 15 hr postdose on Day 1/15. Depending on 
ongoing review of the PK data, timepoints may be modified or removed, and up to 3 additional samples (in each period for the 
food-effect) may be added. 
12 PK samples should be collected at 24, 36, 48, and 72 hr postdose on Days 2/16, 3/17, 4/18 respectively. Depending on ongoing 
review of the PK data, timepoints may be modified or removed, and up to 3 additional samples (in each period for the 
food-effect) may be added. 
13 Urine samples for PK analysis should be collected predose (spot collection), and from 0 to 4, 4 to 8, 8 to 12, and 12 to 24 hr 
postdose. 
14 Urine samples for PK analysis should be collected from 24 to 36 and 36 to 48 hr postdose. 
15 Adverse events occurring prior to study drug administration should be recorded as medical history unless the event is directly 
related to a study specified procedure. 
 
 


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Appendix 2: 
DMID Toxicity Grading Scale 
Clinical Adverse Events 
 
 
 
VITAL SIGNS 
Mild (Grade 1) 
Moderate Grade 2) 
Severe (Grade 3) 
Fever (°C) Oral temperature; no recent hot or 
cold beverages or smoking. 
38.0 – 38.4 
38.5 – 38.9 
>39.0 
Tachycardia - beats per minute 
101 – 115 
116 – 130 
> 130 or ventricular 
dysrhythmias 
Bradycardia - beats per minute 
50 – 54 or 45-50 bpm if
baseline <60 bpm 
45 – 49 or 40-44 if 
baseline <60 bpm 
< 45 or <40 bpm if baseline 
<60 bpm 
Hypertension (systolic) - mm Hg [Assuming 
supine position, 10 min at rest conditions, not 
sleeping subjects, measurements on the same 
arm and several concordant results.] 
 
141-150 
 
151-160 
 
> 160 
Hypertension (diastolic) - mm Hg 
91-95 
96-100 
> 100 
Hypotension (systolic) - mm Hg 
85-89 
80-84 
< 80 
Tachypnea – breaths per minute 
23-25 
26-30 
>30 
CARDIOVASCULAR 
Grade 1 
Grade 2 
Grade 3 
Arrythmia 
 
asymptomatic, transient 
signs, no Rx required 
recurrent/persistent; 
symptomatic Rx required 
Hemorrhage, Blood Loss 
Estimated blood loss < 
100 mL 
Estimated blood loss > 
100 mL, no transfusion
required 
 
Transfusion required 
RESPIRATORY 
Grade 1 
Grade 2 
Grade 3 
Cough 
Transient-no treatment
Persistent cough; 
Interferes with daily activities
Bronchospasm, Acute 
transient; no treatment; 
71-80% FEV1 of peak 
flow 
requires treatment; 
normalizes with 
bronchodilator; FEV1 
60-70% (of peak flow)
no normalization with 
bronchodilator; FEV1 <60% of 
peak flow 
Dyspnea 
Does not interfere with 
usual and social 
activities 
Interferes with usual 
and social activities, no 
treatment 
Prevents daily and usual social 
activity or requires treatment 
GASTROINTESTINAL 
Grade 1 
Grade 2 
Grade 3 
Nausea 
No interference with 
activity 
Some interference with 
activity 
Prevents daily activities 
Vomiting 
No interference with 
activity or 1 - 2 
episodes/24 hours 
Some interference with
activity or > 2 
episodes/24 hours 
Prevents daily activity or 
requires IV hydration 
Diarrhea 
2 - 3 loose or watery 
stools or < 400 
gms/24 hours 
4 - 5 loose or watery 
stools or 400 - 800 
gms/24 hours 
6 or more loose or watery 
stools or > 800gms/24 hours or 
requires IV hydration 
Reactogenicity 
Local reactions 
Grade 1 
Grade 2 
Grade 3 
Pain 
Does not interfere with 
activity 
Repeated use of 
non-narcotic pain 
reliever > 24 hours or 
Any use of narcotic pain 
reliever or prevents daily 


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interferes with activity
activity 
Tenderness 
Discomfort only to touch
Discomfort with 
movement 
Significant discomfort at rest 
Erythema/Redness * 
2.5 - 5 cm 
5.1 - 10 cm 
> 10 cm 
Induration/Swelling ** 
2.5 - 5 cm and does not 
interfere with activity 
5.1 - 10 cm or interferes 
with activity 
> 10 cm or prevents daily 
activity 
SYSTEMIC 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Allergic Reaction 
pruritus without rash 
localized urticaria 
generalized urticaria; 
angioedema or anaphylaxis 
Headache 
No interference with 
activity 
Repeated use of 
non-narcotic pain 
reliever > 24 hours or 
some interference with 
activity 
Significant; any use of narcotic 
pain reliever or prevents daily 
activity 
Fatigue 
No interference with 
activity 
Some interference with 
activity 
Significant; prevents daily 
activity 
Myalgia 
No interference with 
activity 
Some interference with 
activity 
Significant; prevents daily 
activity 
All Other conditions 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Illness or clinical adverse event (as defined 
according to applicable regulations) 
No interference with 
activity 
Some interference with 
activity not requiring 
medical intervention 
Prevents daily activity and 
requires medical intervention
*In addition to grading the measured local reaction at the greatest single diameter, the measurement should be recorded as a 
continuous variable. 
**Induration/Swelling should be evaluated and graded using the functional scale as well as the actual 
measurement 
 
 


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Laboratory Adverse Events 
Blood, Serum, or Plasma * 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Sodium – Hyponatremia mEq/L 
132 – <LLN 
130 – 131 
<130 
Sodium – Hypernatremia mEq/L 
>ULN – 148 
149 – 150 
>150 
Potassium – Hyperkalemia mEq/L 
>ULN – 5.2 
5.3 – 5.4 
>5.4 
Potassium – Hypokalemia mEq/L 
<LLN-3.1 
<3.1 – 3.0 
<3.0 
Glucose – Hypoglycemia mg/dL 
65 – 67 
55 – 64 
<55 
Glucose – Hyperglycemia Fasting – mg/dL 
>ULN - 120 
121 – 130 
>130 
Glucose – Hyperglycemia Random – mg/dL 
140 – 159 
160 – 200 
>200 
Blood Urea Nitrogen mg/dL 
23-26 
27 – 31 
> 31 
Creatinine – mg/dL 
>ULN – 1.7 
1.8 – 2.0 
>2.0 
Calcium – hypocalcemia mg/dL 
8.0 – <LLN 
7.5 – 7.9 
<7.5 
Calcium – hypercalcemia mg/dL 
>ULN – 11.0 
11.1 – 11.5 
>11.5 
Magnesium – hypomagnesemia mg/dL 
1.3 – 1.5 
1.1 – 1.2 
<1.1 
Phosphorus – hypophosphatemia mg/dL 
2.3 – 2.5 
2.0 – 2.2 
<2.0 
CPK – mg/dL 
400-1000 
1001-1500 
>1500 
Albumin – Hypoalbuminemia g/dL 
2.8 – 3.0 
2.5 – 2.7 
< 2.5 
Total Protein – Hypoproteinemia g/dL 
5.2 – 5.4 
4.8 – 5.1 
< 4.8 
Alkaline phosphate – U/L 
132-240 
241– 360 
>360 
AST U/L 
44 – 105 
106-175 
>175 
ALT U/L 
44 – 105 
106-175 
>175 
Bilirubin (serum total) mg/dL 
1.3 - 2.0 
2.1 - 2.5 
> 2.5 
Bilirubin – when ALT >105 (Hy's law) 
1.3 -1.5 
1.6 – 2.0 
> 2.0 
Amylase- U/L 
200-270 
271-360 
>360 
Lipase- U/L 
176-270 
271-360 
>360 
Hemoglobin (Female) - g/dL 
11.0 – 11.5 
9.5 – 10.9 
< 9.5 
Hemoglobin (Male) - g/dL 
12.0 – 12.5 
10.0 – 11.9 
<10.0 
WBC Increase - cell/mm3 
11,001 – 15,000 
15,001 – 20,000 
> 20,000 
WBC Decrease - cell/mm3 
2,500 – 3,500 
1,500 – 2,499 
< 1500 
Lymphocytes Decrease - cell/mm3 
750 – 1,000 
500 – 749 
< 500 
Neutrophils Decrease - cell/mm3 
1,500 – 2,000 
1,000 – 1,499 
< 1000 
Eosinophils - cell/mm3 
500-750 
751-1500 
> 1500 
Platelets Decreased - cell/mm3 
120,000 – 130,000 
100,000 – 119,999 
<100,000 
PT – seconds (prothrombin time) 
> ULN-14.4 
14.5 – 15.7 
> 15.7 
PTT – seconds (partial thromboplastin time) 
>ULN-42.1 
42.2– 50.0 
> 50.0 
Fibrinogen increase - mg/dL 
>ULN – 500 
501 – 600 
> 600 
Fibrinogen decrease - mg/dL 
<LLN – 140 
125 – 139 
<125 
Urine * 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Protein 
1+ 
2+ 
>2+ 
Glucose 
1+ 
2+ 
>2+ 
Blood (microscopic) - red blood cells per high 
5-10 
11-50 
> 50 and/or gross 


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power field (rbc/hpf) 
blood 
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal parameters. 
* Institutional normal reference ranges should be provided to demonstrate that they are appropriate. 
 
 


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Appendix 3: 
Contraception Guidance 
Male subjects (even with a history of vasectomy) with partners of childbearing potential must 
use a male barrier method of contraception (i.e., male condom with spermicide) in addition to a 
second method of acceptable contraception from Check-in until 90 days after the EOS visit. 
Acceptable methods of contraception for female partners include: 
 hormonal injection 
 combined oral contraceptive pill or progestin/progestogen-only pill 
 combined hormonal patch 
 combined hormonal vaginal ring 
 surgical method (bilateral tubal ligation or Essure® [hysteroscopic bilateral tubal 
occlusion])  
 hormonal implant 
 hormonal or non-hormonal intrauterine device 
 OTC sponge with spermicide 
 cervical cap with spermicide 
 diaphragm with spermicide. 
An acceptable second method of contraception for male subjects is vasectomy that has been 
performed at least 90 days prior to the screening visit, with verbal confirmation of surgical 
success. 
For male subjects (even with a history of vasectomy), sexual intercourse with female partners 
who are pregnant or breastfeeding should be avoided unless condoms are used from the time of 
the first dose until 90 days after the EOS visit. Male subjects are required to refrain from 
donation of sperm from Check-in until 90 days after the EOS visit. 
Sexual Abstinence and Same-sex Relationships 
Subjects who practice true abstinence, because of the subject’s lifestyle choice (i.e., the subject 
should not become abstinent just for the purpose of study participation), are exempt from 
contraceptive requirements. Periodic abstinence (eg, calendar, ovulation, symptothermal, 
postovulation methods) and withdrawal are not acceptable methods of contraception. If a subject 
who is abstinent at the time of signing the ICF becomes sexually active they must agree to use 
contraception as described previously. 


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For subjects who are exclusively in same-sex relationships, contraceptive requirements do not 
apply. If a subject who is in a same-sex relationship at the time of signing the ICF becomes 
engaged in a heterosexual relationship, they must agree to use contraception as described 
previously. 


Protocol Reference: COVID-19 Generic Procedures 
 CONFIDENTIAL 
Title of study: COVID-19 Generic Procedures. 
NCT Number: NCT04392219 
Document: Protocol, Version 1.3 
Date: 17 June 2020 


Protocol 
COVID-19 Generic Procedures 
Information described herein is confidential and may be disclosed only with the express 
written permission of Covance CRU. 


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Protocol Reference: EIDD-2801-1001-UK 
 CONFIDENTIAL  
 
 
 
 
 
 
 
Title of study: A Randomized, Double-blind, Placebo-controlled, First-in-human Study 
Designed to Evaluate the Safety, Tolerability, and Pharmacokinetics of EIDD-2801 
Following Oral Administration to Healthy Volunteers 
NCT Number: NCT04392219 
 
Document: Protocol, Version 2.1 
Date: 06 April 2020 
 


Clinical Study Protocol: EIDD-2801-1001-UK 
Version 2.1 (United Kingdom) 
Ridgeback Biotherapeutics 
Protocol Release Date: 06 April 2020  
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Page 1 
A Randomized, Double-Blind, Placebo-Controlled, First-in-Human 
Study Designed to Evaluate the Safety, Tolerability, and 
Pharmacokinetics of EIDD-2801 Following Oral Administration to 
Healthy Volunteers 
 
(EIDD-2801-1001-UK) 
 
Protocol Version 2.1 (United Kingdom) 
Version Date 
06 April 2020 
Sponsor Team: 
Ridgeback Biotherapeutics 
3162 Commodore Plaza, Suite 3E 
Miami, FL 33133-5815 
United States 
Medical Officer 
 
EudraCT Number 
2020-001407-17 
 
Confidential Information: The information contained in this document is the property of 
Ridgeback Biotherapeutics and may not be reproduced, published or disclosed to others without 
written authorization from Ridgeback Biotherapeutics. 


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Ridgeback Biotherapeutics 
Protocol Release Date: 06 April 2020 
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Page 2 
SUMMARY OF CHANGES 
Changes from Version 1.1 (United Kingdom) to Version 2.1 (United Kingdom). 
The primary reason for this amendment was to include Part 3, a multiple ascending dose study of 
EIDD-2801 in healthy subjects. Additionally, the following updates were made: 

Results of an in vivo micronucleus assay were added.

The guidelines used to assess the severity of adverse events not presented in the DMID
Toxicity Grading Scale were updated, specifically those that were life-threatening or led
to death.

The timepoints for collection of peripheral blood mononuclear cells in Part 2 were
modified.

Minor clarifications were made and typographical errors were corrected.


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STATEMENT OF COMPLIANCE 
The study will be carried out in accordance with Good Clinical Practice (GCP) as required by the 
following: 
 Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines. 
 Applicable International Conference on Harmonisation (ICH) GCP Guidelines. 
 United States Code of Federal Regulations (CFR) applicable to clinical studies 
(45 CFR Part 46; 21 CFR Part 50, 21 CFR Part 56, and 21 CFR Part 312). 
 Applicable laws and regulations. 


Clinical Study Protocol: EIDD-2801 -1001-UK 
Ridgeback Biotherapeutics 
Version 2.1 (United Kingdom) 
Protocol Release Date: 06 April 2020 
SIGNATURE PAGE 
The signature below constitutes the approval of this protocol and the attachments and provides 
the necessary assurances that this study will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable regulations and ICH guidelines. 
Principal Investigator:
Signed: 
Date: 
Name 
Title 
Confidential 
Page4 


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Ridgeback Biotherapeutics 
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TABLE OF CONTENTS 
SUMMARY OF CHANGES .......................................................................................................... 2 
STATEMENT OF COMPLIANCE ................................................................................................. 3 
SIGNATURE PAGE ...................................................................................................................... 4 
TABLE OF CONTENTS ............................................................................................................... 5 
LIST OF TABLES ......................................................................................................................... 9 
LIST OF FIGURES ..................................................................................................................... 10 
LIST OF APPENDICES .............................................................................................................. 11 
ABBREVIATIONS ...................................................................................................................... 12 
PROTOCOL SYNOPSIS ............................................................................................................ 15 
1. INTRODUCTION ................................................................................................................... 25 
1.1. 
Background ............................................................................................................... 25 
1.2. 
Rationale for Development ........................................................................................ 25 
1.3. 
Nonclinical Overview ................................................................................................. 26 
1.3.1. Mechanism of Action ................................................................................................. 26 
1.3.2. In Vitro Pharmacology ............................................................................................... 27 
1.3.2.1. 
Antiviral Activity in Tissue Culture and in Human Airway Epithelium ............. 27 
1.3.2.2. 
Cytotoxicity of EIDD-1931 in Tissue Culture Utilizing Cells from Different 
Organs and Species ...................................................................................... 29 
1.3.2.3. 
Assessment of Mitochondrial Toxicity ............................................................ 29 
1.3.3. In Vivo Pharmacology ............................................................................................... 29 
1.3.3.1. 
Coronavirus: SARS-CoV and MERS-CoV ..................................................... 29 
1.3.3.2. 
Influenza Virus ............................................................................................... 33 
1.3.3.3. 
Venezuelan Equine Encephalitis Virus .......................................................... 34 
 
 
1.4. 
Safety and Secondary Pharmacology ....................................................................... 34 
1.5. 
Nonclinical Pharmacokinetics and Metabolism ......................................................... 34 
1.5.1. Overview ................................................................................................................... 34 
1.5.2. Absorption ................................................................................................................. 34 
1.5.3. Distribution ................................................................................................................ 35 
 
 
1.5.3.2. 
Tissue Distribution Studies ............................................................................ 35 
1.5.4. Metabolism ................................................................................................................ 36 
1.5.4.1. 
Metabolic Stability of EIDD-1931 and EIDD-2801 ......................................... 36 
1.5.4.2. 
Uptake and Anabolism of EIDD-1931 in Tissue Culture and Primary Cells ... 37 
1.5.5. Excretion ................................................................................................................... 38 
1.5.6. Pharmacokinetic Drug Interactions ........................................................................... 38 
1.5.6.1. 
Cytochrome P450 (CYP) Inhibition ................................................................ 38 
1.5.6.2. 
CYP Induction ................................................................................................ 38 
 
 
 
 
 
 


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1.7. 
Potential Risks and Benefits ...................................................................................... 44 
1.7.1. Potential Benefits ...................................................................................................... 44 
1.7.2. Potential Risks ........................................................................................................... 44 
2. OBJECTIVES ....................................................................................................................... 45 
2.1. 
Study Objectives ....................................................................................................... 45 
2.1.1. Primary Objectives .................................................................................................... 45 
2.1.2. Secondary Objectives ............................................................................................... 45 
2.1.3. Exploratory Objectives .............................................................................................. 45 
2.2. 
Study Outcome Measures ......................................................................................... 45 
2.2.1. Primary Outcome Measures ...................................................................................... 45 
2.2.2. Secondary Outcome Measures ................................................................................. 45 
3. STUDY DESIGN ................................................................................................................... 47 
3.1. 
Overview ................................................................................................................... 47 
3.1.1. Part 1 (Single Ascending Dose) ................................................................................ 47 
3.1.2. Part 2 (Food-Effect) ................................................................................................... 48 
3.1.3. Part 3 (Multiple Ascending Dose) .............................................................................. 48 
3.2. 
Rationale and Justification ........................................................................................ 49 
3.2.1. Justification of Design ............................................................................................... 49 
3.2.2. Justification of Starting Dose ..................................................................................... 49 
3.2.3. Justification of Study Population ............................................................................... 50 
4. STUDY POPULATION ......................................................................................................... 51 
4.1. 
Subject Inclusion Criteria ........................................................................................... 51 
4.2. 
Subject Exclusion Criteria ......................................................................................... 52 
5. STUDY MEDICATION, RANDOMIZATION AND DOSE ADMINISTRATION ...................... 54 
5.1. 
Study Drug Description ............................................................................................. 54 
5.1.1. Acquisition, Formulation, Packaging and Labeling .................................................... 54 
5.1.2. Product Storage and Stability .................................................................................... 54 
5.2. 
Randomization .......................................................................................................... 54 
5.3. 
Dosage, Preparation and Administration of Study Drug ............................................ 55 
5.4. 
Drug Accountability ................................................................................................... 55 
5.5. 
Concomitant Medication/Treatments ......................................................................... 55 
6. STUDY CONDUCT AND VISIT SCHEDULE ....................................................................... 57 
6.1. 
Study Conduct ........................................................................................................... 57 
6.1.1. Study Windows and Rounding Principles .................................................................. 57 
6.1.2. Restrictions ................................................................................................................ 57 
6.2. 
Screening .................................................................................................................. 58 


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6.2.1. Screening Visit .......................................................................................................... 58 
6.2.2. Retesting Procedures ................................................................................................ 59 
6.2.3. Study Visits ................................................................................................................ 59 
6.2.4. Part 1 (Single Ascending Dose) ................................................................................ 59 
6.2.5. Part 2 (Food-Effect) ................................................................................................... 59 
6.2.6. Part 3 (Multiple Ascending Dose) .............................................................................. 59 
6.3. 
Safety Follow-up and End-of-Study Visit ................................................................... 59 
6.4. 
Subject Withdrawal and Replacement ...................................................................... 60 
6.4.1. Reasons for Withdrawal ............................................................................................ 60 
6.4.2. Handling of Withdrawals ............................................................................................ 61 
6.4.3. Documentation of Withdrawals .................................................................................. 61 
6.4.4. Subject Replacement ................................................................................................ 61 
6.5. 
Unscheduled Visit(s) ................................................................................................. 61 
7. STUDY PROCEDURES/EVALUATIONS ............................................................................. 62 
7.1. 
Demography and Medical History ............................................................................. 62 
7.2. 
Clinical Evaluations ................................................................................................... 62 
7.2.1. Physical Examinations .............................................................................................. 62 
7.2.2. Vital Sign Measurements and ECGs ......................................................................... 62 
7.2.2.1. 
Continuous 12-lead ECG Monitoring (Part 3 Only) ........................................ 63 
7.2.3. Adverse Events and Concomitant Medications ......................................................... 63 
7.3. 
Laboratory Evaluations .............................................................................................. 63 
7.3.1. Routine Laboratory Panels ........................................................................................ 63 
7.3.2. Pharmacokinetic Sampling ........................................................................................ 65 
7.3.3. Peripheral Blood Mononuclear Cell Collection .......................................................... 66 
7.3.4. Urine Collection ......................................................................................................... 66 
8. SAFETY MONITORING, MANAGEMENT AND REPORTING ............................................ 67 
8.1. 
Definitions .................................................................................................................. 67 
8.1.1. Adverse Events ......................................................................................................... 67 
8.1.2. Serious Adverse Events ............................................................................................ 67 
8.2. 
Documenting Adverse Events ................................................................................... 68 
8.2.1. Timeframe for Collection and Follow-up of AEs/SAEs .............................................. 68 
8.2.2. Recording of Adverse Events/Serious Adverse Events ............................................ 69 
8.2.3. Assessing Severity of Adverse Events ...................................................................... 69 
8.2.4. Relationship to Study Drug ........................................................................................ 70 
8.2.5. Classifying Adverse Event Outcome ......................................................................... 70 
8.3. 
Reporting Procedures ................................................................................................ 71 
8.3.1. Serious Adverse Events ............................................................................................ 71 
8.3.2. Pregnancy ................................................................................................................. 71 
8.4. 
Unmasking Treatment Assignment ........................................................................... 72 
9. DOSE-ESCALATION AND HALTING RULES..................................................................... 73 
9.1. 
Guidelines for Dose-Escalation ................................................................................. 73 
9.2. 
Dose-Escalation Halting Rules .................................................................................. 74 
10. STATISTICAL CONSIDERATIONS ..................................................................................... 75 
10.1. 
General Considerations ............................................................................................. 75 


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10.2. 
Sample Size Considerations ..................................................................................... 75 
10.3. 
Analysis Populations ................................................................................................. 75 
10.4. 
Analysis of Safety Data ............................................................................................. 75 
10.4.1. Extent of Exposure .................................................................................................... 75 
10.4.2. Adverse Events ......................................................................................................... 76 
10.4.3. Clinical Laboratory Results ........................................................................................ 76 
10.4.4. Other Parameters ...................................................................................................... 76 
10.5. 
Analysis of Pharmacokinetic Data ............................................................................. 76 
10.5.1. Statistical Analysis of Pharmacokinetic Data ............................................................ 78 
10.5.1.1. Dose Proportionality ...................................................................................... 78 
10.5.1.2. Food-Effect .................................................................................................... 78 
10.6. 
Peripheral Blood Mononuclear Cells ......................................................................... 78 
10.7. 
Interim Analyses ........................................................................................................ 78 
11. STUDY ADMINISTRATION .................................................................................................. 79 
11.1. 
Regulatory and Ethical Considerations ..................................................................... 79 
11.2. 
Ethical Standard ........................................................................................................ 79 
11.2.1. Ethics Committee Approval ....................................................................................... 79 
11.2.2. Informed Consent ...................................................................................................... 79 
11.3. 
Financing and Insurance ........................................................................................... 80 
11.4. 
Source Documentation and Access .......................................................................... 80 
11.5. 
Data Collection and Record Keeping ........................................................................ 80 
11.5.1. Data Collection .......................................................................................................... 80 
11.5.2. Study Records Retention .......................................................................................... 81 
11.5.3. Protocol Deviations ................................................................................................... 81 
11.6. 
Clinical Monitoring ..................................................................................................... 81 
11.7. 
Quality Control and Quality Assurance ..................................................................... 81 
11.8. 
Study Termination and Closure Procedures.............................................................. 82 
11.8.1. Study Termination ..................................................................................................... 82 
11.8.2. Termination Procedures ............................................................................................ 82 
11.9. 
Information Disclosure ............................................................................................... 82 
11.9.1. Confidentiality ............................................................................................................ 82 
11.9.2. Clinicaltrials.gov ........................................................................................................ 83 
11.9.3. Publication Policy ...................................................................................................... 83 
12. REFERENCES ...................................................................................................................... 84 
13. APPENDICES ....................................................................................................................... 85 
 


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LIST OF TABLES 
Table 1: 
EIDD-1931 Antiviral Activity Against Influenza A and B Viruses in Tissue Culture and 
Primary Human Bronchial/Tracheal Epithelial Cells ................................................. 27 
Table 2: 
EIDD-1931 Antiviral Activity Against SARS and MERS Coronaviruses in Tissue 
Culture and Primary Human Bronchial/Tracheal Epithelial Cells ............................. 28 
Table 3: 
EIDD-1931 Antiviral Activity Against Togaviruses in Tissue Culture ........................ 28 
 
 
Table 5: 
Cytotoxicity (CC50) of EIDD-1931 in Mammalian Cell Lines .................................... 29 
Table 6: 
Metabolic Stability of EIDD-2801 in Plasma and Liver Microsomes ......................... 37 
Table 7: 
Metabolic Stability of EIDD-2801 in Simulated Gastric and Intestinal Fluids and in 
Buffered Saline with Fetal Bovine Serum ................................................................. 37 
Table 8: 
Metabolic Stability of EIDD-1931 in Plasma, Whole Blood and Liver and Intestinal 
Microsomes .............................................................................................................. 37 
 
 
 
Table 10: Allowable Time Windows for Study Assessments/Visits .......................................... 57 
Table 11: Laboratory Evaluations ............................................................................................. 65 
Table 12: Adverse Event Outcomes ......................................................................................... 70 
Table 13: Pharmacokinetic Parameters ................................................................................... 77 
 


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LIST OF FIGURES 
Figure 1: 
Study Schema .......................................................................................................... 24 
Figure 2: 
Inhibition of SARS-CoV-2 by EIDD-1931 ................................................................. 28 
Figure 3: 
EIDD-2801 Prophylactic Treatment of SARS-CoV Infected Mice ............................ 30 
Figure 4: 
EIDD-2801 Treatment of SARS-CoV Infected Mice ................................................. 31 
Figure 5: 
EIDD-2801 Prophylactic Treatment of MERS-CoV Infected Mice ............................ 32 
Figure 6: 
EIDD-2801 Treatment of MERS-CoV Infected Mice ................................................ 33 
Figure 7: 
Tissue Distribution of EIDD-1931 and EIDD-2061 in Ferret Brain and Lung ............ 36 
 
 


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LIST OF APPENDICES 
Appendix 1: 
Time and Events Schedule ............................................................................ 85 
Appendix 2: 
DMID Toxicity Grading Scale ......................................................................... 91 
Appendix 3: 
Contraception Guidance ................................................................................ 94 


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ABBREVIATIONS 
AE 
adverse event 
AGP 
alpha1-acid glycoprotein 
ALT/SGPT 
alanine aminotransferase/serum glutamic pyruvic transaminase 
AST/SGOT 
aspartate aminotransferase/serum glutamic oxaloacetic transaminase 
AUC 
area under the curve 
BID 
twice-daily 
BMI 
body mass index 
CDC 
Centers for Disease Control and Prevention 
CEM 
a cell line of lymphoblastic cells derived from a child with leukemia 
CFR 
Code of Federal Regulations 
CHKV 
Chikungunya virus 
CI 
confidence interval 
CoV 
coronavirus 
CRF 
case report form 
CTP 
cytosine triphosphate cytidine triphosphate 
CYP 
cytochrome P450 
DMID 
Division of Microbiology and Infectious Diseases 
DMSO 
dimethylsulfoxide 
DPP4 
dipeptidyl peptidase 4 
DRF 
dose range finding 
DSS 
Drug Safety Services 
EBOV 
Ebola virus 
EC 
Ethics Committee 
EC50 
Half-maximal effective concentration 
ECG 
electrocardiogram 
EEEV 
Eastern equine encephalitis virus 
EIDD 
Emory Institute for Drug Development 
EOS 
End of Study 
FDA 
Food and Drug Administration 
FE 
food-effect 
FIH 
first-in- human 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
GLP 
Good Laboratory Practice 


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HAE 
human airway epithelium 
HBV 
hepatitis b virus 
hBTEC 
human bronchial/tracheal epithelial cells 
HCV 
hepatitis c virus 
HED 
human equivalent dose 
HEENT 
head, eye, ear, nose and throat 
HIV 
human immunodeficiency virus 
HPMC 
hydroxypropyl methylcellulose 
IAV 
influenza a virus 
IB 
Investigator’s Brochure 
IBV 
influenza b virus 
IC50 
half maximal inhibitory concentration 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
MAD 
multiple ascending dose 
MDCK 
Madin-Darby Canine Kidney Cells 
MedDRA 
Medical Dictionary for Regulatory Activities 
MERS 
Middle East respiratory syndrome 
%MN-PCE 
percentage of micronuclei-polychromatic erythrocytes 
MRSD 
maximum recommended starting dose 
MTD 
maximum tolerated dose 
NOAEL 
no-observed-adverse-effect-level 
NSAID 
nonsteroidal anti-inflammatory drug 
OTC 
over-the-counter 
PBMC 
peripheral blood mononuclear cells 
PBO 
placebo 
PCE:TE 
polychromatic erythrocytes to total erythrocytes 
PE 
physical examination 
PI 
principal investigator 
 
 
PK 
pharmacokinetic 
QTc(F) 
QT interval corrected for heart rate (using Fridericia’s formula) 
RNA 
ribonucleic acid 
RSV 
respiratory syncytial virus 
SAD 
single ascending dose 
SAE 
serious adverse event 


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SAP 
statistical analysis plan 
SARS 
severe acute respiratory syndrome 
SI 
selectivity index 
SOP 
standard operating procedure 
UTP 
uridine 5'-triphosphate 
VEEV 
Venezuelan equine encephalitis virus 
ZIKV 
Zika virus 


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PROTOCOL SYNOPSIS 
Sponsor: Ridgeback Biotherapeutics 
Title: A Randomized, Double-Blind, Placebo-Controlled, First-in-Human Study Designed to 
Evaluate the Safety, Tolerability, and Pharmacokinetics of EIDD-2801 Following Oral 
Administration to Healthy Volunteers (EIDD-2801-1001-UK) 
Short Title: EIDD-2801-1001-UK 
Development Phase: Phase 1 
Description of Study Drugs, Dose and Mode of Administration: EIDD-2801 and matching 
placebo (PBO) will be supplied 
 
  
Part 1: A single oral dose of EIDD-2801 or PBO will be administered to subjects enrolled in 
Part 1 (P1; single ascending dose [SAD]) cohorts. The starting dose in the first SAD cohort will 
be 50 mg. The doses will be administered in an escalating manner. Dose levels will not increase 
by more than 3-fold for predicted nonpharmacologically active dose levels and by 2-fold for 
predicted pharmacologically active dose levels.
 
 
 
Part 2: Subjects in Part 2 (P2)/food-effect (FE) will receive 2 single doses of EIDD-2801 with a 
14-day (minimum) washout period between doses. The dose for the P2 cohort is planned to be 
100 mg but may be adjusted based on safety, tolerability, and/or pharmacokinetic (PK) data from 
P1. In any case, the dose assessed in P2 will have been given previously to subjects in a P1 
cohort successfully (i.e., no halting rules were met following dosing). 
Part 3: Multiple doses of EIDD-2801 or PBO will be administered to subjects enrolled in Part 3 
(P3; multiple ascending dose [MAD]) cohorts. Subjects will receive twice-daily (BID) doses for 
6 days, with a single dose administered on the morning of Day 7. The total daily dose will not 
exceed a dose shown to be safe and well-tolerated in P1. Doses in P3 may be administered in the 
fed state, following review of the PK data from P2. Additionally, depending on ongoing review 
of the safety, tolerability, and PK data, the dosing frequency and number of days of dosing may 
be changed; however, the dosing frequency will be no less than once-daily or no greater than 
three-times daily, and the number of days of dosing will be no fewer than 5 days and no greater 
than 10 days. 
Treatment Duration:  
Part 1: Subjects enrolled into P1/SAD cohorts will receive a single dose of study drug 
(EIDD-2801 or matching PBO).  
Part 2: Subjects enrolled into the P2/FE cohort will receive 2 single doses of EIDD-2801, with a 
washout period between doses. 
Part 3: Subjects in P3/MAD cohorts will receive study drug (EIDD-2801 or matching PBO) for 
6 days BID followed by a single dose of EIDD-2801 or PBO on Day 7. Depending on ongoing 
review of the safety, tolerability, and PK data, the number of days of dosing may be changed; 
however, will be no fewer than 5 days and no greater than 10 days. 


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Subject Duration:  
Part 1: The maximum possible study duration for participants enrolled in P1/SAD cohorts will 
be approximately 43 days. 
Part 2: The maximum possible study duration for participants enrolled in the P2/FE cohort will 
be approximately 58 days. 
Part 3: The maximum possible study duration for participants enrolled in P3/MAD will be 
approximately 49 days. 
Objectives and Endpoints: 
Part 1: SAD Cohorts 
Primary: 
 
Objective: To determine the safety and tolerability of single ascending doses of EIDD-2801. 
o Endpoints:  
 
Results of safety evaluations including safety laboratory assessments, 
physical examination (PE), electrocardiograms (ECGs), vital signs, and 
adverse events (AEs). 
Secondary: 
 
Objective: To define PK of EIDD-2801 and EIDD-1931 in plasma and urine following 
single doses administered to healthy volunteers. 
o Endpoints: 
 
Plasma PK parameters, including Cmax, tmax, t1/2, CL/F, λz, Vz/F, AUC0-inf 
and AUClast as appropriate 
 
Urinary excretion of EIDD-2801 and EIDD-1931 following single-dose 
administration. 
Part 2: Single-Dose Food-Effect 
Primary: 
 
Objective: To assess the effect of food on the PK of EIDD-2801 and EIDD-1931 following 
a single oral dose. 
o Endpoints: 
 
Plasma PK parameters, including Cmax, tmax, t1/2, CL/F, λz, Vz/F, AUC0-inf 
and AUClast as appropriate 
 
Urinary excretion of EIDD-2801 and EIDD-1931 following single-dose 
administration. 
Secondary: 
 
Objective: To determine the safety and tolerability of single doses of EIDD-2801. 
o Endpoints: 
 
Results of safety evaluations, including safety laboratory assessments, PEs, 
ECG, vital signs, and AEs. 
Part 3: MAD Cohorts 
Primary: 
 
Objective: To determine the safety and tolerability of multiple ascending doses of 
EIDD-2801. 


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o Endpoints: 
 
Results of safety evaluations, including safety laboratory assessments, PE, 
ECGs, vital signs, and AEs. 
Secondary: 
 
Objective: To define PK of EIDD-2801 and EIDD-1931 in plasma and urine following 
multiple doses administered to healthy volunteers. 
o Endpoints: 
 
Plasma PK parameters, including Ctrough, Cmax, tmax, t1/2, CL/F, λz, Vz/F, 
AUC0-inf (Day 1 dose only), AUCτ, RAAUCτ, and RACmax as appropriate 
 
Urinary excretion of EIDD-2801 and EIDD-1931 following multiple-dose 
administration. 
Exploratory: 
 
Objective: To collect data to assess the relationship between 
EIDD-2801/EIDD-1931 concentrations and QT interval corrected for heart 
rate (QTc). 
Population:  
Part 1: P1/SAD cohorts will include 8 subjects each, 2 randomized to receive PBO and 
6 randomized to receive EIDD-2801. Initially, 4 SAD cohorts are planned for P1 with the option 
to add an additional 3 cohorts based on study results. 
Part 2: Ten subjects will be enrolled into the P2/FE cohort; all subjects enrolled in the P2 cohort 
will receive EIDD-2801. One P2 cohort is planned for the study. If PK results obtained are 
equivocal, additional subjects may be enrolled into the P2 cohort at the previously tested dose or 
an additional P2 cohort may be added at a different dose.  
Part 3: P3/MAD cohorts will include 8 subjects, 2 randomized to receive PBO and 
6 randomized to receive EIDD-2801. Initially, 4 MAD cohorts are planned for P3 with the 
option to add an additional 3 cohorts based on study results. However, the number of cohorts 
may be reduced if the study objectives are met. Dose levels in P3 may be repeated for collection 
of peripheral blood mononuclear cells (PBMCs). 
The site is strongly encouraged to ensure that women are represented in each cohort. Inclusion 
and exclusion criteria for study participation are as follows: 
Inclusion Criteria: subjects who meet all of the criteria at Screening will be eligible for study 
participation 
1. Male or female between the ages of 18 and 60, inclusive. 
2. Female subjects must be of nonchildbearing potential. Nonchildbearing potential is 
defined as women who: 
• 
are physiologically incapable of becoming pregnant including those who are 
surgically sterile, via hysterectomy, bilateral salpingectomy, and/or bilateral 
oophorectomy by reported medical history and/or medical records. Surgical 
sterilization to have occurred a minimum of 6 weeks, or at the Principal 
Investigator’s (PI’s; or designee’s) discretion, prior to Screening. 
• 
are postmenopausal (at least 45 years of age with amenorrhea for 12 months 
without an alternative medical reason with confirmatory follicle stimulating 


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hormone (FSH) levels of ≥ 40 mIU/mL. The amenorrhea should not be induced 
by a medical condition such as anorexia nervosa, hypothyroid disease or 
polycystic ovarian disease, or by extreme exercise. It should not be due to 
concomitant medications that may have induced the amenorrhea such as oral 
contraceptives, hormones, gonadotropin-releasing hormones, anti-estrogens, or 
selective estrogen receptor modulators). 
3. Male participants must agree to the use of effective contraception for study duration, 
i.e., from Check-in until 90 days following the last dose of study drug. 
4. Is in generally good health as determined by medical history, PE (at Screening and/or 
Check-in), vital signs, and other screening procedures. 
5. Has a body mass index (BMI) of 18 to 30 kg/m2. 
6. Is willing and able to comply with all study procedures including providing informed 
consent. 
Exclusion Criteria: subjects who meet any of the following criteria at Screening (unless 
otherwise stated) will not be eligible for participation 
1. Females who are pregnant, planning to become pregnant, or breastfeeding. 
2. Has a clinically relevant acute or chronic medical condition or disease of the 
cardiovascular, gastrointestinal (GI), hepatic, renal, endocrine, pulmonary, neurologic, 
or dermatologic systems as determined by the PI (or designee). 
3. Has any current or historical disease or disorder of the hematological system or 
significant liver disease or family history of bleeding/platelet disorders. 
4. Has a history of cancer (other than basal cell or squamous cell cancer of the skin), 
rheumatologic disease or blood dyscrasias. 
5. Has a history of GI surgery or other condition that may interfere with absorption of 
study drug, in the option of the PI (or designee). 
6. Has a history of febrile illness within the 14 days prior to the first dose of study drug. 
7. Has a positive alcohol or drug screen at Screening or the Day -1 visit or has a history of 
alcohol or drug abuse within the past 5 years. 
8. Currently uses tobacco, nicotine or tobacco products, e-cigarettes or has stopped using 
tobacco products within the past 3 months and/or has a positive cotinine test at 
Screening or Check-in. 
9. Has any abnormal laboratory value of Grade 2 or higher, which is considered to be 
clinically significant by the PI (or designee). 
10. Has a total white cell count or absolute lymphocyte count outside the normal range, or 
hemoglobin or platelet levels below the lower limit of normal, at Screening of Day -1. 
11. Has values above the upper limit of normal for the following laboratory analytes: 
alanine aminotransferase (ALT/SGPT), alkaline phosphatase (serum), aspartate 
aminotransferase (AST/SGOT), at Screening or Day -1. 
12. Positive test result for human immunodeficiency virus (HIV), hepatitis B virus (HBV), 
or hepatitis C virus (HCV). 
13. Has an autoimmune disease, is immunosuppressed or is in any way 
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14. Has any of the following: 
• 
QT interval corrected for heart rate using Fridericia’s formula (QTcF) >450 ms 
confirmed by repeat measurement 
• 
QRS duration >110 ms confirmed by repeat measurement 
• 
PR interval >220 ms confirmed by repeat measurement 
• 
findings which would make QTc measurements difficult or QTc data 
uninterpretable 
• 
history of additional risk factors for torsades de pointes (e.g., heart failure, 
hypokalemia, family history of long QT syndrome). 
15. Except as noted, has used prescription drugs (other than hormone replacement therapy) 
within 14 days prior to the first dose of study drug unless, in the opinion of the PI (or 
designee), the drug will not interfere with study assessments. The following prescription 
drugs will be allowed: 
• 
Statins: Subjects who have been on a stable dose of statins for a minimum of 
6 months and who have normal creatine kinase at Screening. 
• 
Antihypertensives: Subjects who have been on a stable dose of 
antihypertensives for a minimum of 6 months and have controlled blood 
pressure and no active heart disease. 
16. Has received an experimental agent (vaccine, drug, biologic, device, blood product or 
medication) within 3 months prior to the first dose of study drug and agrees not to 
receive another experimental agent during the duration of this trial. 
17. Has donated blood within 30 days, plasma within 2 weeks, or platelets within 6 weeks 
prior to Screening or refuses to agree to not donate blood until 3 months after the End of 
Study (EOS) visit. 
18. Uses over-the-counter (OTC) medications or nutritional supplements (including, e.g., 
gingko biloba, aspirin at any dose, and nonsteroidal anti-inflammatory drugs [NSAIDs]) 
on a routine/scheduled basis, and/or is unwilling to abstain from such use for the 
duration of the study. 
19. Is unwilling to abstain from quinine containing products including quinine water, tonic 
water, bitter lemon, jello shots, any quinine preparations or Cinchona tree bark 
preparations (e.g., herbal medications containing Cinchona tree bark). 
20. Has any condition that would, in the opinion of the PI (or designee), put the subject at 
increased risk for participation in a clinical trial or confinement in a clinical research 
unit. 
Retesting for Inclusion/Exclusion Criteria: In the case where a parameter is outside of the 
acceptable limits for enrollment, measurement of the parameter can be repeated one time if both 
the following are met: 
 In the opinion of the PI (or designee), the parameter value does not represent a chronic 
condition that otherwise will preclude the volunteer from enrolling in the study; and 
 In the opinion of the PI (or designee), the abnormality is not likely to recur. 
General Investigational Plan: For all potential subjects, volunteers who express interest in the 
study will report to the clinic for informed consent. The study will be explained to the subject 


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and the Ethics Committee (EC)-approved informed consent form (ICF) will be presented. The 
subject will be given the chance to review the document and ask any questions he/she may have. 
If, after reviewing the consent, the subject would like to participate in the study, then he/she will 
sign the ICF and begin screening for study entry; those satisfying all criteria will be enrolled into 
the study and admitted to the clinic on Day -1. Retesting will be allowed as described above. 
Part 1: For P1/SAD, the first cohort will be divided into 2 groups. The first group, a sentinel 
group, will include 2 subjects.  
On Day 1, one subject in the sentinel group will be administered PBO and one will be 
administered EIDD-2801. Analysis of the safety results for the sentinel group will be reviewed 
24 hours postdose. If no halting criteria have been met, the remainder of the subjects in Cohort 1 
(the second group) will be dosed. There will be no sentinel groups for the remaining cohorts. 
Following dosing on Day 1, subjects will remain in the clinic through completion of study 
assessments on Day 4, returning to the clinic on Day 9 for study assessments, and Day 15 for the 
EOS visit.  
Doses will be administered in an escalating manner following satisfactory review by the Sponsor 
and PI of the blinded safety and tolerability data (up to 72 hours post final dose). Dose-escalation 
will only occur if data from a minimum of 6 subjects have been reviewed from the previous 
lower dose group, such that data from a minimum of 4 subjects who have received EIDD-2801 
will be used to make the dose-escalation decision. Dose levels will not increase by more than 
3-fold for predicted nonpharmacologically active dose levels and by 2-fold for predicted 
pharmacologically active dose levels. The highest dose to be studied under this protocol will not 
exceed 200 mg. 
Part 2: For P2/FE, one cohort assessing the effect of food on EIDD-2801 and EIDD-1931 PK 
parameters will be enrolled; it is planned that the P2 cohort will be at a dose of 100 mg 
EIDD-2801, although higher or lower doses may be selected based on safety and available PK 
data from P1.  
In addition to assessing the effect of food on dosing, PBMCs will be collected from subjects 
following each dose; the PBMCs will be stored for analysis of EIDD-2061 levels at some point 
in the future.  
The 10 subjects enrolled in the FE cohort will all receive EIDD-2801; subjects will be 
randomized to a treatment sequence (i.e., to receive drug in the fed then fasted state [Sequence 1] 
versus fasted then fed state [Sequence 2]). Half of the subjects in the cohort will be randomized 
to Sequence 1 and the other half will be randomized to Sequence 2.  
Following dosing on Day 1, subjects will remain in the clinic through completion of study 
assessments on Day 4, returning to the clinic on Day 9 for study assessments, and Day 14 to 
begin the second dosing sequence on Day 15. Subjects will then be discharged from the clinic on 
Day 18, returning to the clinic on Day 23 for study assessments, and Day 30 for the EOS visit. 
There will be a 14-day (minimum) washout period between doses. 
Part 3: For P3/MAD, subjects will receive BID doses on Day 1 through Day 6, inclusive, and 
will receive the final dose of study drug on the morning of Day 7. Subjects will remain 
domiciled at the site during the dosing period and until Day 10, returning to the clinic on Day 15 
for completion of study assessments, and Day 21 for the EOS visit. 
Doses in P3 may be administered in the fed state, following review of the PK data from P2. 
Additionally, depending on ongoing review of the safety, tolerability, and PK data, the dosing 


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frequency and number of days of dosing may be changed; however, the dosing frequency will be 
no less than once-daily or no greater than three-times daily, and the number of days of dosing 
will be no fewer than 5 days and no greater than 10 days.  
Part 3 may run in parallel with P1, providing that the total daily dose to be administered does not 
exceed a dose already shown to be safe and well-tolerated in P1. 
Peripheral blood mononuclear cells may be collected from subjects in P3, depending upon 
ongoing review of the data. The collection of these samples may be omitted from some cohorts, 
depending on ongoing review of the data. The PBMCs will be stored for analysis of EIDD-2061 
levels at some point in the future. In addition, continuous 12-lead ECG monitoring will be 
performed to collect data to assess the relationship between study drug concentrations and QTc 
interval. All data will be archived without extraction or analysis and will not be reported in the 
scope of this study.  
Additional parts may be added to this study, including a SAD part in elderly healthy 
subjects and a study of the safety, tolerability, and PK in Japanese subjects. These 
additional parts are not described in this protocol but may be added via a protocol 
amendment.  
Safety Monitoring and Potential Unblinding: Safety for this study will be continually 
monitored by the PI and Sponsor.  
Blinding: All study personnel will remain blinded to treatment assignment (i.e., EIDD-2801 or 
PBO) in P1 and P3, except for personnel at the bioanalytical laboratory, and the unblinded 
pharmacy staff and pharmacokineticist. If unblinding is required to manage subject safety or to 
support dose-escalation decisions, the decision to unblind lies solely with the PI. If possible and 
providing that it does not interfere with or delay any decision in the best interest of the subject, 
the PI will discuss the intended code-break with the Sponsor. 
Dose-Escalation Halting Rules: 
For Group 1 in P1/SAD, sentinel dosing will occur whereby 2 subjects (1 active and 1 PBO) will 
be dosed on 1 day and, providing no safety concerns arise, the remaining 6 subjects will be 
dosed after at least 24 hours. 
The study will be halted if one or more subjects experience a serious adverse event (SAE) that is 
considered to be related to EIDD-2801 or 2 or more subjects in the same group experience 
severe AEs that are considered to be related to EIDD-2801.  
Dose-escalation will stop if clinically relevant signs or symptoms of similar nature occur in 2 or 
more subjects in a group that, in the opinion of the PI, warrant stopping of dose-escalation. 
Data Monitoring, Safety Reporting and Unblinding: Data will be monitored throughout the 
course of the study by experienced clinical monitors according to the clinical monitoring plan. 
As data will be entered into an electronic case report form (CRF), data will be monitored to 
ensure accuracy as well as adherence to data entry instructions provided in the CRF guidelines. 
Procedures for reporting any SAE will be detailed in the protocol and forms and instructions 
provided to the site. 
Statistical Considerations: A complete description of all statistical analyses and methods will 
be presented in the statistical analysis plan (SAP). The SAP will be reviewed and approved by 
the Sponsor and will be finalized prior to database lock. Plans for PK analyses will be included 
in the SAP. 


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Determination of Sample Size: The sample sizes for the P1 and P3 cohorts are typical for a 
Phase 1 first in human (FIH) study. The sample size for the P2 cohort is in accordance with Food 
and Drug Administration (FDA) guidelines for sample size in FE studies. 
Study Populations: 
Safety Population: All subjects who receive at least one dose of study drug. 
Pharmacokinetic Population:  All subjects receiving study drug who comply sufficiently with 
protocol requirements (i.e., no major protocol deviations) and for whom a sufficient number of 
analyzable PK samples have been obtained to permit the determination of the PK profile for 
EIDD-2801/EIDD-1931 and the statistical analysis of the results. Subjects who experience an 
AE of vomiting before 2× the median tmax of the group may be excluded from the PK population. 
Safety Analyses: Statistical methods for the safety analyses will be descriptive in nature. Safety 
data, including AEs, clinical laboratory data, vital signs, ECG parameters, and PEs. All 
appropriate AEs will be graded using the Division of Microbiology and Infectious Diseases 
(DMID) toxicity scale (March 2014). Change from baseline will be included in summary tables 
for laboratory parameters. All laboratory data will be included in the data listings and all test 
values outside the normal range will be flagged. 
Pharmacokinetic Analyses: Plasma PK parameters for each dose level will be calculated from 
the concentrations of EIDD-2801 and EIDD-1931 measured in predose and postdose plasma 
samples. For each dose level, descriptive statistics will be presented. Figures will be created to 
display mean and individual subject EIDD-2801 and EIDD-1931 concentration versus time. 
Urine PK parameters will be calculated whenever possible for each subject based on the urine 
concentrations of EIDD-2801 and EIDD-1931. The following PK parameters will be calculated: 
Plasma PK Parameter 
Description 
AUClast 
The area under the plasma concentration-time curve, from time 0 to the last 
measurable non-zero concentration, as calculated by the linear up/log down 
trapezoidal method (P1 and P2 only). 
AUC0-inf 
The area under the plasma concentration-time curve from time 0 extrapolated 
to infinity. AUC0-inf is calculated as the sum of AUClast plus the ratio of the 
last measurable plasma concentration to the elimination rate constant (λz) 
(P1, P2, and Day 1 dose of P3). 
Cmax 
Maximum observed concentration. 
tmax 
Time to reach Cmax. If the maximum value occurs at more than one time 
point, tmax is defined as the first time point with this value. 
λz 
Apparent terminal elimination rate constant; represents the fraction of 
medication eliminated per unit time. 
t1/2 
Apparent terminal elimination half-life of medication, calculated as 0.693/λz. 
Vz/F 
Apparent volume of distribution (EIDD-2801 only). 
CL/F 
Apparent oral drug clearance (EIDD-2801 only). 
Ctrough 
Trough concentration (P3 only). 
AUCτ 
The area under the plasma concentration-time curve during a dosing interval 
(P3 only). 
RAAUCτ 
Observed accumulation ratio based on AUCτ (P3 only). 
RACmax 
Observed accumulation ratio based on Cmax (P3 only). 


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Urine PK Parameter 
Description 
Ae 
Amount excreted in urine over the sampling interval. 
Fe 
Fraction of drug excreted in the urine over sampling interval. 
CLR 
Renal clearance, CLR = Ae/AUC where both Ae and AUC are determined 
over co-incident time ranges after dosing. 
In P1, dose-proportionality for PK parameters of EIDD-2801 and EIDD-1931 (AUC0-inf, AUClast, 
and Cmax) will be assessed by the power model. The slope and the associated 90% confidence 
interval (CI) based on the power model will be reported. In P3 on Day 7, dose-proportionality for 
PK parameters of EIDD-2801 and EIDD-1931 (AUCτ and Cmax) will be assessed by the power 
model. The slope and associated 90% CI based on the power model will be reported. 
To assess the effect of food on the PK of EIDD-2801 and EIDD-1931, natural log-transformed 
PK parameters from P2 (AUC0-inf, AUClast, and Cmax) will be analyzed using a mixed-effects 
model with fixed effect terms for treatment (with or without food), period, and sequence and 
with subject within sequence as a random effect. Point estimates and their associated 90% CIs 
for the natural log-transformed PK parameters for the difference between EIDD-2801 
administered under fed relative to fasted conditions will be constructed. The point estimates and 
interval estimates will be back transformed to give estimates of the ratio and 90% CI for the 
geometric least squares mean ratio for fed/fasted to assess the effect of food. 
Interim Analyses: No formal interim analyses are planned for this study. Data from P1 cohorts 
may be locked, unblinded, and analyzed prior to conducting P2 and P3. 


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Figure 1: Study Schema 
 
 
 
SAD Dose 1 (50 mg QD )
SAD Dose 2 (TBD)
SAD Dose 3 (TBD)
SAD Dose 4 (TBD)
Review 
Safety Data
Review 
Safety Data
Review 
Safety Data
Sentinel Grp 1: 2 subjects
24 hr safety review
Grp 2: 6 subjects
Abbreviations:
SAD: single ascending dose
FE: food effect
Seq: treatment sequence number
 
PART 1: SAD Cohorts                                                                                                          
Following review of data from Part 1 cohort administered dose selected for Part 2
Sequence 1
Dose: Fed
Sequence 2
14 Day Washout
Dose: Fasted
Dose: Fasted
Dose: Fed
PART 2: Food Effect (FE) Cohort                                                                                              


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1. 
INTRODUCTION 
This study is a FIH study designed to assess the safety, tolerability and PK of EIDD-2801 in 
healthy human volunteers. EIDD-2801 is a ribonucleoside analog with broad-spectrum activity 
against many RNA viruses. It is currently being developed by Ridgeback Biotherapeutics as a 
treatment of infections caused by highly pathogenic coronaviruses (CoV), including COVID-19. 
In addition, EIDD-2801 is being developed in parallel as a treatment of uncomplicated influenza 
caused by all subtypes of circulating and emerging (drifted and shifted) influenza A virus (IAV) 
and influenza B virus (IBV), including seasonal, epidemic and pandemic strains.  
1.1. 
Background 
EIDD-2801 is the 5’-isopropyl ester prodrug of the broadly active, direct-acting antiviral 
ribonucleoside analog EIDD-1931. After oral delivery, the prodrug (EIDD-2801) is rapidly 
hydrolyzed by circulating esterases to produce high circulating (plasma) levels of EIDD-1931. In 
cell culture systems, EIDD-1931 has been shown to inhibit replication of multiple viral 
pathogens from multiple RNA virus families including pathogenic CoV (e.g., Middle East 
respiratory syndrome [MERS], severe acute respiratory syndrome [SARS]-CoV and 
SARS-CoV-2), influenza viruses (seasonal, pandemic, and avian subtypes), respiratory syncytial 
virus (RSV), alphaviruses (e.g., Eastern equine encephalitis virus [EEEV], Venezuelan equine 
encephalitis virus [VEEV], and Chikungunya virus [CHKV]), Filoviruses (e.g., Ebola virus 
[EBOV]), and Zika virus (ZIKV). In addition, EIDD-2801 is active against orthopoxviruses 
(tested against vaccinia virus) probably because orthopoxviruses encode their own unique RNA 
polymerase. 
 
 The primary mechanism of action of 
EIDD-2801 is inhibition of viral RNA replication by incorporation of the EIDD-1931 
monophosphate metabolite into the viral RNA genome resulting in induction of viral error 
catastrophe. 
1.2. 
Rationale for Development 
EIDD-2801 is being developed for the treatment of infections caused by RNA viruses, 
specifically for COVID-19 and other CoV infections, influenza, and VEEV. During conduct of 
the FIH study, the Sponsor intends to define a dose that may be active in treating SARS-CoV-2 
in patient studies. The multiple-dose data will also be informative with respect to the influenza 
development program. 
EIDD-2801 has a unique dual mechanism of action against RNA viruses, including COVID-19 
and other CoV infections. The compound acts as a competitive, alternative substrate for the 
virally encoded RNA-dependent RNA-polymerase that upon incorporation into nascent chain 
RNA induces increased mutational frequency in the viral genome. Incorporation quickly results 
in the production of non-viable virus. Additionally, the active metabolite, 
EIDD-1931-5’-triphosphate (EIDD-2061), may act directly as a chain terminator and arrest 
replication by exerting a next nucleoside effect. It is anticipated that the high barrier to resistance 
observed during in vitro passaging studies will translate to slow, if any, emergence of viral 
resistance. Resilience to viral escape is a distinguishing feature of EIDD-2801. 


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Currently, there is no approved antiviral therapeutic for the treatment of SARS-CoV-2. An 
antiviral drug is urgently needed. 
 
 
 
 
 
 
1.3. 
Nonclinical Overview 
1.3.1. 
Mechanism of Action 
The mechanism of antiviral activity of EIDD-2801 is “lethal mutagenesis”; a concept that is 
predicated on increasing the viral mutation rate beyond a biologically-tolerable threshold, 
resulting in impairment of viral fitness and leading to viral extinction. 
The specifics of the mechanism are as follows. EIDD-2801 is rapidly taken up by cells and the 
5’-isopropylester cleaved to liberate EIDD-1931, which is in turn phosphorylated to EIDD-2061 
by host kinases (Hernandez-Santiago et al., 2004; Painter et al., 2019). The 5’-triphosphate, 
EIDD-2061, acts as a competitive alternative substrate for virally encoded RNA-directed RNA 
polymerases and EIDD-2061 is incorporated into nascent viral RNA. Owing to the ability of the 
N4-hydroxycytosine base of EIDD-1931 to tautomerize, EIDD-2061 can pair with either 
guanosine or adenosine, and consequently can substitute for either CTP or UTP, respectively 
(Flavell et al., 1974). This results in an accumulation of mutations that increases with each cycle 
of viral replication. The process whereby the mutation rate is increased by exposure to a drug is 
referred to as Viral Decay Acceleration (Mullins et al., 2011) and results in viral ablation. 
Significant work has gone into validating this mechanism of action for EIDD-2801/1931, and it 
has been shown for MERS-CoV, VEEV, and IAV that viruses grown in the presence of 
EIDD-1931 have significantly increased levels of transition mutations (Agostini et al., 2019; 
Toots et al., 2019; Urakova et al., 2018). Multi-log decreases in virus yields were observed after 
treatment with EIDD-1931. Additionally, it was demonstrated for VEEV that the infectivity of 
virions formed in the presence of EIDD-1931 decreases from ~20% to <0.2%, and that the 
infectious virions are significantly Impaired in their replication ability (Urakova et al., 2018). As 
a consequence of this mechanism of action, the generation of drug-resistant escape mutants is 
practically impossible. This same effect was demonstrated for CoV (Agostini et al., 2019) and 
influenza virus (Toots et al., 2019). Furthermore, given the unique mechanism of action, 
EIDD-2801 is expected to be active against viruses resistant to other antiviral agents which have 
a different mechanism of action. The only data generated to date regarding the activity of 
EIDD-1931 against viruses resistant to other nucleoside analogs found that EIDD-1931 was 
active against CoV resistant to remdesivir in cell culture assays (T. Sheahan et al, preprint 
available at https://www.biorxiv.org/content/10.1101/2020.03.19.997890v1). 
As an alternative or additional mechanism of action, it has been theorized that incorporation of 
EIDD-2061 into viral genomic RNA can change the thermodynamics of RNA secondary 


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structure and thus decrease the efficiency of the promoter regions involved in RNA genome 
replication (Stuyver et al., 2003). 
1.3.2. 
In Vitro Pharmacology 
1.3.2.1. 
Antiviral Activity in Tissue Culture and in Human Airway Epithelium 
The ribonucleoside analog EIDD-1931 is the parent of the prodrug EIDD-2801. EIDD-1931 
shows specific antiviral activity in different tissue culture cells and in the differentiated organoid 
model of human airway epithelium (HAE) with a selectivity index (SI) ranging from 21 to >100 
for all influenza viral isolates tested. It is active against IAV (pandemic and seasonal) and IBV 
strains, as well as against highly pathogenic H5N1 and H7N9 strains (Table 1). 
Table 1: 
EIDD-1931 Antiviral Activity Against Influenza A and B Viruses in Tissue 
Culture and Primary Human Bronchial/Tracheal Epithelial Cells 
Virus 
Strain 
Cell line 
EC50* 
(µM) 
CC50 
(µM) 
SI 
Reference 
IAV H1N1 
Ca/07/2009 
MDCK 
1.24 
68 
55 
NIAID Antiviral Testing Program 
IAV H1N1 
WSN/33 
MDCK 
1.1 
299.8 
275 
Yoon et al., 2018 
IAV H1N2 
WSN/33 
primary hBTEC 
5.4 
- 
- 
Yoon et al., 2018 
IAV H2N3 
Perth/16/2009 
MDCK 
0.88 
52 
59 
NIAID Antiviral Testing Program 
IAV H2N3 
Ohio/sw-10-132/2010 
MDCK 
3.2 
299.8 
94 
Yoon et al., 2018 
IAV H5N1 
Duck/MN/1525/81 
MDCK 
1.28 
27 
21 
NIAID Antiviral Testing Program 
IAV H5N1 
Vietnam/1203/2004 
MDCK 
0.14 
299.8 
2100 
Yoon et al., 2018 
IAV H7N9 
Anhui/1/2013 
MDCK 
0.13 
299.8 
2300 
Yoon et al., 2018 
IBV 
Florida/4/2006 
MDCK 
<0.4 
76 
>190 
NIAID Antiviral Testing Program 
IBV 
Brisbane/60/08 
MDCK 
0.006 
299.8 
50000 
Yoon et al., 2018 
IAV H1N1 
Ca/07/2009 
HAE-3D* 
0.08 
50 
625 
Toots et al., 2019 
IAV H1N1 
WSN/33 
HAE-3D* 
0.08 
50 
625 
Toots et al., 2019 
IBV 
Brisbane/60/08 
HAE-3D* 
0.06 
50 
833 
Toots et al., 2019 
* Human Airway Epithelium organoid model. 
EIDD-1931 also showed specific antiviral activity against human SARS-CoV-1, MERS-CoV 
(Table 2) and SARS-CoV-2 (Figure 2), against togaviruses VEEV, EEEV and CHKV (Table 3) 
 


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EIDD-1931 (NHC) antiviral activity (closed circles) and 
cytotoxicity (open squares) in Vero Cells infected with SARS- 
CoV-2. Vero cells were infected in duplicate with SARS-CoV- 
2 clinical isolate virus at a multiplicity of infection (MOI) of 0.05 
in the presence of a dose response of EIDD-2801 for 48 hours 
after which replication was measured through quantitation of 
cell viability by Cell-Titer-Glo assay. Cytotoxicity was 
measured in similarly treated but uninfected cultures. 
Reproduced from Sheahan et al 2020. 
Table 2: 
EIDD-1931 Antiviral Activity Against SARS and MERS Coronaviruses in Tissue 
Culture and Primary Human Bronchial/Tracheal Epithelial Cells 
Virus 
Strain 
Cell line 
EC50 
(µM) 
CC50 
(µM) 
SI 
Reference 
SARS-CoV-1 Urbani 
Vero76 
<0.4 
144 
>360 NIAID Antiviral Testing Program 
SARS-CoV-1 SARS-CoV-GFP(†) 
HAE-3D(*) 
<1 
>100 
>100 Tech. Report 25.038 
MERS-CoV 
GenBank Ac.No JX869059** DBT-9 
0.56 
>200 
>357 Agostini et al., 2019 
MERS-CoV 
Human ß-CoV C, Novel 2912 Vero E6 
<0.8 
20 
>25 
NIAID Antiviral Testing Program 
* Human Airway Epithelium organoid model; ** cDNA Derived clone 
Figure 2: Inhibition of SARS-CoV-2 by EIDD-1931 
 
Table 3: 
EIDD-1931 Antiviral Activity Against Togaviruses in Tissue Culture 
Virus 
Strain 
Cell line 
EC50 (µM) 
CC50 (µM) 
SI 
Reference 
VEEV 
TC-83 
Vero 
0.43 
>200 
>930 Urakova et al., 2018 
VEEV 
TC-83 
Vero76 
1.92 
32 
17 
NIAID Antiviral Testing Program 
EEEV 
FL93-939 
Vero76 
1.08 
84 
78 
NIAID Antiviral Testing Program 
CHKV 
S27 (VR-64) 
Vero76 
1.8 
96 
53 
NIAID Antiviral Testing Program 


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1.3.2.2. 
Cytotoxicity of EIDD-1931 in Tissue Culture Utilizing Cells from 
Different Organs and Species 
EIDD-1931 was tested for cytotoxicity in human hepatic origin Huh7 and HepG2 cells, in human 
lymphoid CEM, human pancreatic BxPC-3, human prostate cancer PC-3, human muscle A204, 
human lung A549, human epithelial hEp-2, rat heart muscle H9c2, monkey kidney Vero, and 
canine kidney MDCK cell lines (Table 5). The compound exhibits low cytotoxicity in the 
majority of cells tested (half-maximal effective concentration [EC50] values are in the range of 40 
to >100 µM) except in lymphoid origin CEM cells where the compound shows a 7.5 µM EC50 
value (Sticher et al., 2020; Urakova et al., 2018; Yoon et al., 2018). 
Table 5: 
Cytotoxicity (CC50) of EIDD-1931 in Mammalian Cell Lines 
Cell Line 
CEM 
HepG2 
PC-3 
A204 
A549 
BxPC-3 
Huh-7 
H9c-2 
Vero 
hEp-2 
MDCK 
CC50 
(µM) 
7.5 
42.3 
267.1 
84 
46 
48 
165.5 
81 
53 
272.4 
299.8 
Sources: Sticher et al., 2020, Yoon et al., 2018 
EIDD-2801 typically showed 2-4× lower activity and cytotoxicity than EIDD-1931 due to 
slightly slower uptake and anabolism in tissue culture. 
1.3.2.3. 
Assessment of Mitochondrial Toxicity 
Since EIDD-1931 is a nucleoside analog, additional investigations were performed to analyze 
whether observed cytotoxicity of EIDD-1931 is caused by mitochondrial toxicity. It was 
demonstrated that the prolonged treatment (14 days) with the compound does not result in 
selective killing of mitochondria or in mitochondrial dysfunction in CEM and HepG2 cells 
(Sticher et al., 2020). 
1.3.3. 
In Vivo Pharmacology 
The prodrug EIDD-2801 or its parent EIDD-1931 have been tested in animal models of RNA 
viral infection. An overview of results from the animal studies in indications to be pursued are 
described below. Additional detail is provided in the Investigator’s Brochure (IB). 
1.3.3.1. 
Coronavirus: SARS-CoV and MERS-CoV 
In mouse models of SARS and MERS infection and disease, coronaviral disease was assessed by 
changes in body weight, measured daily, and lung hemorrhage, assessed in the large left lobe of 
the lung following sacrifice on Day 5 (SARS-CoV) or Day 6 (MERS-CoV). To assess 
production of infectious virions, virus was isolated from the lower left lobe of the lung following 
sacrifice on Day 5 (SARS-CoV) or Day 6 (MERS-CoV) and quantified using a plaque assay. 
The results demonstrated that, in mice infected with either SARS- or MERS-CoV, both 
prophylactic and therapeutic treatment with EIDD-2801 resulted in a reduction in virus 
replication, improvements in pulmonary function, and improvements in maintaining body weight 


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(i.e., reduced body weight loss). While EIDD-2801 doses of 50, 150 and 500 mg/kg BID were 
assessed in the CoV mouse experiments, 500 mg/kg BID yielded the most consistent therapeutic 
effect. 
A prophylactic, dose-escalation study was conducted in C57BL/6 mice infected with 
mouse-adapted SARS-CoV (SARS-MA15). Prophylactic oral treatment with EIDD-2801 was 
initiated 2 hours before intranasal infection and continued every 12 hours thereafter through the 
end of the study (Day 5; Figure 3). 
In mice treated BID with EIDD-2801, body weight loss observed with vehicle treatment was 
diminished in the 50 mg/kg treatment group, beginning on Day 3 post-infection. No body weight 
loss was seen in the 150 and 500 mg/kg treatment groups (Figure 3, Panel A). Lung hemorrhage 
was also significantly reduced on Day 5 post-infection, following treatment with 500 mg/kg 
EIDD-2801 (Figure 3, Panel B). When compared to vehicle control, a dose-dependent reduction 
in SARS-CoV lung titers at Day 5 was seen across all 3 treatment groups (Figure 3, Panel C) 
with significant differences among the vehicle, 150 mg/kg and 500 mg/kg groups. Thus, 
prophylactic treatment with EIDD-2801 resulted in a robust antiviral effect that was able to 
prevent SARS-CoV replication and disease. 
Figure 3: EIDD-2801 Prophylactic Treatment of SARS-CoV Infected Mice 
 
The antiviral activity of EIDD-2801 against SARS-CoV was compared when treatment was 
initiated at -2 hours (pre-infection) and 12, 24, or 48 hours post-infection. After initiation of 
treatment, all groups were dosed every 12 hours for the duration of the study (Figure 4). For 
SARS-challenged mice, initiating treatment at 12 hours post-infection significantly prevented 
body weight loss beginning on Day 2, a result similar to that seen when dosing prophylactically 


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(i.e., beginning at 2 hours pre-infection). Initiation of treatment with EIDD-2801 at 24 hours 
post-infection also significantly reduced body weight loss on Days 3 through5 post-infection. 
When EIDD-2801 treatment was initiated at 48 hours post-infection, body weight loss was only 
statistically different from vehicle on Day 4 post-infection (Figure 4, Panel A). Significant 
reductions in lung hemorrhage were seen when EIDD-2801 treatment was initiated before 
(-2 hours) and up to 24 hours after infection; a result that mirrored body weight loss data 
(Figure 4, Panel B). All mice treated with EIDD-2801 had significantly reduced viral loads in the 
lungs, even in the group where treatment was initiated 48-hour post-infection (Figure 4, 
Panel C). Pulmonary function, measured via whole body plethysmography, was assessed using 
the PenH metric which is a surrogate marker for bronchoconstriction or pulmonary obstruction. 
The administration of EIDD-2801 prior to infection (-2 hours) and at 12 hour post-infection 
completely abrogated the loss of pulmonary function observed in vehicle-treated animals 
(Figure 4, Panel D). Improved pulmonary function was also seen in the group where treatment 
was initiated 24 hours after virus challenge. 
Figure 4: EIDD-2801 Treatment of SARS-CoV Infected Mice 
 
EIDD-2801 was also tested to determine if it is active in vivo against MERS-CoV as described 
by Sheahan et. al (draft manuscript). The murine ortholog of the MERS-CoV receptor, dipeptidyl 
peptidase 4 (DPP4), does not support viral binding and entry. Thus, all in vivo studies described 
below were performed in genetically modified hDPP4 mice permissive for MERS infection. 
Prophylactic treatment starting at 2 hours before viral challenge with either 50, 150, or 


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500 mg/kg EIDD-2801 prevented body weight loss on Days 2 through 6 post-infection (Figure 5, 
Panel A), prevented lung hemorrhage measured on Day 6 (Figure 5, Panel B), and reduced virus 
lung titer on Day 6 to the limit of detection (Figure 5, Panel C). 
Figure 5: EIDD-2801 Prophylactic Treatment of MERS-CoV Infected Mice 
 
The effect of EIDD-2801 treatment on MERS-CoV infected mice is shown in Figure 6. When 
EIDD-2801 treatment was initiated 12 hours post-infection, there was no loss in body weight 
from Days 2 through 6 post-infection (Figure 6, Panel A) and no evidence of lung hemorrhage 
on Day 6 post-infection (Figure 6, Panel B). However, protection was not observed in groups 
where treatment was initiated either 24- or 48-hours post-infection. Conversely, virus lung titer 
on Day 6 post-infection was significantly reduced to the limit of detection in all treatment 
groups, regardless of the time treatment began (Figure 6, Panel C). To gauge the effect of the 
timing of EIDD-2801 treatment initiation on physiologic measures of lung disease, pulmonary 
function was assessed by whole body plethysmography. As expected, a loss of pulmonary 
function, as determined by measuring the PenH metric, was observed in vehicle-treated animals 
infected with MERS-CoV beginning on Day 2 post-infection (Figure 6, Panel D). Mirroring the 
body weight loss data, normal pulmonary function was observed in groups where treatment was 
initiated prior to or at 12 hours post-infection (Figure 6, Panel D). 


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Figure 6: EIDD-2801 Treatment of MERS-CoV Infected Mice 
 
1.3.3.2. 
Influenza Virus 
EIDD-2801 was tested in a ferret model of influenza virus infection and disease. Ferrets 
recapitulate hallmarks of human influenza infection, providing a clinically relevant animal model 
to investigate therapeutic intervention. Therapeutic oral dosing of influenza virus-infected ferrets 
reduced shed levels of pandemic and seasonal IAV by multiple orders of magnitude, and 
alleviated fever and inflammation while improving airway epithelium histopathology. 
Post-exposure prophylactic dosing was sterilizing (Toots et al., 2019). 
Ferrets infected with pandemic IAV and treated with EIDD-2801 at a dose of 7 mg/kg 
demonstrated significantly less viral shedding and inflammatory cellular infiltrates in nasal 
lavages, but mounted a normal humoral antiviral response (Toots et al., 2019). 
When examining the effect of delayed dosing, Toots et. al. (2019) demonstrated that treatment 
with 20 mg/kg of EIDD-2801 initiated 24 hours after challenge with IAV (H1N1) resulted in a 
rapid decrease in both shed virus and fever relative to control, with fever returning to baseline at 
24 hours. When oseltamivir (20 mg/kg) was dosed prophylactically as a positive control, a 
modest suppression of fever was observed; however, there was no reduction in shed virus titer. 


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1.3.3.3. 
Venezuelan Equine Encephalitis Virus 
Treatment with EIDD-1931 was evaluated in a mouse model of lethal VEEV infections. To be 
truly effective as a therapeutic agent for VEEV infection, a drug must penetrate the blood brain 
barrier and arrest virus replication in the brain. High plasma levels of EIDD-1931 are rapidly 
achieved in mice after oral dosing. Once in the plasma, EIDD-1931 is efficiently distributed into 
organs important in the pathology of VEEV infection, including the brain, where it is rapidly 
converted to its active 5’-triphosphate (EIDD-2061). EIDD-1931 showed a good safety profile in 
mice after 7 days of dosing with up to 1,000 mg/kg/day. In mouse model studies of VEEV 
infection, EIDD-1931 was 90-100% effective in protecting mice against lethal intranasal 
infection when therapeutic treatment was started as late as 24 hours post-infection, and partial 
protection was achieved when treatment was delayed for 48 hours post-infection (Painter et al., 
2019). 
 
 
 
 
 
 
 
 
 
1.4. 
Safety and Secondary Pharmacology 
The standard battery of safety pharmacology studies including studies assessing the 
cardiovascular, respiratory and central nervous systems have been conducted. The studies are 
discussed in the IB; results indicated that there were no adverse pharmacologic effects of 
EIDD-2801 on the cardiovascular, respiratory or central nervous systems. 
1.5. 
Nonclinical Pharmacokinetics and Metabolism 
1.5.1. 
Overview 
The uptake, metabolism and protein binding of EIDD-2801 and EIDD-1931 have been studied in 
plasma, microsomes, and non-hepatic cells from several species as outlined below. The PK and 
tissue distribution of prodrug EIDD-2801 and its active parent EIDD-1931 have been studied 
extensively in rats, dogs and ferrets. Key results from these studies are presented below; 
additional detail can be found in the IB. 
1.5.2. 
Absorption 
EIDD-1931 is parent of the prodrug EIDD-2801. The appearance of EIDD-1931 is dependent on 
the absorption of EIDD-2801 and the rate of its conversion to EIDD-1931. 


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EIDD-2801 PK studies have been completed in dog, rat, mouse, ferret, and monkey. EIDD-2801 
was efficiently absorbed and rapidly converted to EIDD-1931 in each species. The tmax for 
EIDD-2801 (not observed in rodents) occurred at 0.5-1 hours, while the tmax for EIDD-1931 
occurred at 1-2 hours. 
1.5.3. 
Distribution 
 
 
 
 
 
 
 
 
 
1.5.3.2. 
Tissue Distribution Studies 
EIDD-2801 is rapidly absorbed in the gut and converted to EIDD-1931 reaching Cmax in 
1-3 hours in mice, rats, ferrets, dogs and monkeys. EIDD-1931 is then widely distributed to 
tissues including lungs and brain, where it is rapidly taken up into cells and converted to 
EIDD-2061. Figure 7 shows the concentration of EIDD-1931 and EIDD-2061 in ferret brain and 
lung following single doses of 20 (Panels A and B) and 128 (Panels C and D) mg/kg. 


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Figure 7: Tissue Distribution of EIDD-1931 and EIDD-2061 in Ferret Brain and Lung 
 
1.5.4. 
Metabolism 
1.5.4.1. 
Metabolic Stability of EIDD-1931 and EIDD-2801 
EIDD-2801 was designed to be converted to EIDD-1931 by esterases in plasma or in cells. 
Stability has been assessed in plasma and liver microsomes from mouse, rat, dog, monkey and 
humans. The stability of EIDD-2801 in mouse, rat and monkey plasma is relatively short 
(≤0.4 hours) while the stability is longer in human and dog plasma (1-3 hours). EIDD-2801 
stability in mouse, rat, dog and monkey liver microsomes is very short, ranging from 0.02 to 
0.08 hours while the stability in human liver microsomes is 1.2 hours (Table 6). 


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Table 6: 
Metabolic Stability of EIDD-2801 in Plasma and Liver Microsomes 
Species 
Plasma stability 
LM stability 
t1/2 (h) 
t1/2 (h) 
Mouse 
0.017 
0.033 
Rat 
0.033 
0.017 
Dog 
3.2 
0.083 
Monkey 
0.40 
0.017 
Human 
1.05 
1.22 
EIDD-2801 is stable in simulated gastric and intestinal fluids (Table 7). 
Table 7: 
Metabolic Stability of EIDD-2801 in Simulated Gastric and Intestinal Fluids and 
in Buffered Saline with Fetal Bovine Serum 
Matrix 
t1/2 (hr) 
Simulated Gastric Fluid 
>24 
Simulated Intestinal Fluid 
>24 
Phosphate Buffered Saline plus 10% Fetal Bovine Serum* 
>24 
EIDD-1931 was found to be stable when incubated with all tested plasmas, whole blood, liver 
microsomes and liver S9 extracts and intestinal microsomes (Table 8). 
Table 8: 
Metabolic Stability of EIDD-1931 in Plasma, Whole Blood and Liver and 
Intestinal Microsomes 
Medium 
Plasma 
Whole Blood 
Liver Microsomes 
Liver S9 Stability 
Intestinal Microsomes 
Species 
t1/2 (h) 
t1/2 (h) 
t1/2 (h) 
t1/2 (h) 
t1/2 (h) 
Mouse 
 
>24 
>24 
 
>24 
Rat 
17 
 
>24 
>24 
 
Dog 
>24 
 
 
>24 
 
Monkey 
6.5 
>24 
>24 
>24 
>24 
Human 
10 
7 
>24 
20 
>24 
1.5.4.2. 
Uptake and Anabolism of EIDD-1931 in Tissue Culture and Primary 
Cells 
EIDD-1931 is efficiently taken up by tissue culture cells and converted to its pharmacologically 
active metabolite EIDD-2061 (EIDD-1931-5’-triphosphate). Intracellular EIDD-2061 
accumulates dose-dependently, with Cmax levels ~200-2000 pmol/106 cells (at 10-20 µM dose) in 
different cell lines. It reaches high levels relatively quickly, typically within 1-3 hours, though 
the tmax values vary widely between 1 and 24 hours depending on the cell line and dose 
concentration tested. Detailed data on the uptake and anabolism of EIDD-2801 is presented in 
the IB. 


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EIDD-2801 is also taken up by tissue culture cells and is converted to EIDD-1931 and then to 
EIDD-2061, but the process is slightly delayed compared to dosing with EIDD-1931. 
EIDD-1931 is also taken up and metabolized to EIDD-2061 by primary cells. EIDD-2061 is 
accumulated in all primary cells tested except in mouse primary hepatocytes where EIDD-1931 
is apparently extensively metabolized to cytidine and uridine which, in turn, quickly metabolize 
into CTP and UTP. The quick metabolism of EIDD-1931 consequently results in low levels of 
EIDD-2061 in mouse hepatocytes. The intracellular stability (t1/2) of EIDD-2061 is 4-5 hours in 
human astrocytes and hBTEC and is significantly shorter (0.2-1.1 hours) in primary hepatocytes. 
1.5.5. 
Excretion 
Currently, there is no data on excretion of EIDD-2801 or EIDD-1931. Excretion will be 
measured in urine during this study. 
1.5.6. 
Pharmacokinetic Drug Interactions 
1.5.6.1. 
Cytochrome P450 (CYP) Inhibition 
The purpose of this non-GLP in vitro study was to determine the time-dependent inhibitory 
potential of EIDD-2801 and EIDD-1931 on human cytochromes P450 (CYP) 1A2, 2B6, 2C8, 
2C9, 2C19, 2D6, and 3A4 (midazolam and testosterone substrates) enzyme activity, using pooled 
human liver microsomes in an half-maximal inhibitory concentration (IC50) shift assay. 
Neither EIDD-2801 nor EIDD-1931 demonstrated inhibition greater than 31.4% for any of the 
CYP isozymes tested nor could the data for each assay condition be curve fit to determine 
time-dependent inhibition by these compounds. Full dose-response curves were not achieved at 
concentrations ranging from 0.00545 to 50.0 µM indicating EIDD-2801 and EIDD-1931 have no 
CYP inhibition potential at concentrations ranging from 0.00545 to 50.0 µM. Assay performance 
was acceptable based on the results for the positive control inhibitors. 
1.5.6.2. 
CYP Induction 
An assay was performed to determine the induction potential of EIDD-2801 on human CYP 
isoenzyme (1A2, 2B6, and 3A4) activity using 3 single-donor lots of inducible, cryopreserved 
human hepatocytes. Both enzyme activity and mRNA results demonstrated that EIDD-2801 did 
not show induction for any of the CYP isozymes. 
 
 
 
 
 
 
 


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1.7. 
Potential Risks and Benefits 
1.7.1. 
Potential Benefits 
As this is a FIH study in healthy volunteers, there is no direct benefit to subjects enrolled in the 
study. However, given the current pandemic situation and in vitro antiviral activity of 
EIDD-2801 against SARS-CoV-2, and the activity against several other viruses of public health 
concern, it is possible that participants may benefit from future availability of the drug. 
1.7.2. 
Potential Risks 
EIDD-2801 has never been administered to humans; therefore, the risks from EIDD-2801 to 
subjects participating in this trial are unknown. Although toxicology studies have been done, 
unexpected AEs may occur.
 
 
 
 Subjects will also be monitored for other end-organ 
effects through a range of safety assessments. 


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2. 
OBJECTIVES 
2.1. 
Study Objectives 
2.1.1. 
Primary Objectives 
The primary objective of Part 1 of the study is to determine the safety and tolerability of single 
ascending doses of EIDD-2801. 
The primary objective of Part 2 of the study is to assess the effect of food on the PK on 
EIDD-2801 and EIDD-1931 following a single oral dose. 
The primary objective of Part 3 of the study is to determine the safety and tolerability of multiple 
ascending doses of EIDD-2801. 
2.1.2. 
Secondary Objectives 
The secondary objectives of Part 1 and Part 3 of the study is to define the PK of EIDD-2801 and 
EIDD-1931 in plasma and urine following single and multiple doses administered to healthy 
volunteers. 
The secondary objective of Part 2 of the study is to determine the safety and tolerability of single 
doses of EIDD-2801. 
2.1.3. 
Exploratory Objectives 
The exploratory objective of Part 3 is to collect data to assess the relationship between 
EIDD-2801/EIDD-1931 concentrations and QTc 
2.2. 
Study Outcome Measures 
2.2.1. 
Primary Outcome Measures 
The primary outcome measures for Parts 1 and 3 of are results of safety evaluations including 
safety laboratory assessments, PEs, ECGs, vital signs, and AEs. 
The primary outcome measures for Part 2 of the study are plasma PK parameters including Cmax, 
tmax, t1/2, CL/F, λz, Vz/F, AUC0-inf and AUClast as appropriate. 
2.2.2. 
Secondary Outcome Measures 
The secondary outcome measures are as follows: 
 Single-dose plasma PK parameters, including Cmax, tmax, t1/2, CL/F, λz, Vz/F, 
AUC0-inf and AUClast as appropriate (Part 1) 
 Multiple-dose plasma PK parameters, including Ctrough, Cmax, tmax, t1/2, CL/F, λz, 


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Vz/F, AUCτ, AUC0-inf (Day 1 dose only), RAAUCτ and RACmax, as appropriate (Part 3) 
 Urinary excretion of EIDD-2801 and EIDD-1931 following single- and 
multiple-dose administration (Parts 1 and 3). 
 Results of safety evaluations including safety laboratory assessments, PEs, ECGs, 
vital signs, and AEs (Part 2). 


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3. 
STUDY DESIGN 
3.1. 
Overview 
EIDD-2801-1001-UK is a Phase 1, randomized, double-blind, placebo-controlled, FIH, SAD, 
and MAD study of the safety, tolerability and PK of EIDD-2801 and EIDD-1931 following oral 
administration of single and multiple doses of EIDD-2801 to healthy volunteers. In addition, for 
a minimum of one cohort, the effect of food on the single-dose EIDD-2801 and EIDD-1931 PK 
parameters will be assessed in subjects taking open-label EIDD-2801. The overall objective of 
the study is to identify a starting dose for future safety and therapeutic intervention trials. 
The study is composed of 3 parts; P1 is the SAD study, P2 is the FE cohort study, and P3 is the 
MAD study.  
3.1.1. 
Part 1 (Single Ascending Dose) 
A single oral dose of EIDD-2801 or PBO will be administered to subjects. Subjects will be 
randomized in a 3:1 ratio to receive either EIDD-2801 or PBO. 
Following dosing on Day 1, subjects will remain in the clinic through completion of study 
assessments on Day 4, returning to the clinic on Day 9 for study assessments, and Day 15 for the 
EOS visit. 
The first cohort will be divided into 2 groups. The first group, a sentinel group, will include 
2 subjects. On Day 1, one subject in the sentinel group will be administered PBO and one will be 
administered EIDD-2801. Analysis of the safety results for the sentinel group will be reviewed 
24 hours postdose. If no halting criteria (Section 9) have been met, the remainder of the subjects 
in Cohort 1 (the second group) will be dosed. There will be no sentinel groups for the remaining 
cohorts. 
After completion of each dosing cohort, safety and tolerability data will be reviewed to 
determine if any of the halting rules have been met. If not, then the subsequent cohort may be 
dosed. As PK data become available, these data may be used for dose-escalation decisions. 
The proposed dose-escalation scheme is shown in Figure 1, however, planned dose escalations 
will be determined based on ongoing review of the safety, tolerability, and available PK data. 
The starting dose in the first SAD cohort will be 50 mg. Dose levels will not increase by more 
than 3-fold for predicted nonpharmacologically active dose levels and by 2-fold for predicted 
pharmacologically active dose levels.
 
 
 
Four cohorts are initially planned for P1; however, up to an additional 3 cohorts may be enrolled. 


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3.1.2. 
Part 2 (Food-Effect) 
Two single oral doses of EIDD-2801 will be administered to subjects, in an open-label manner. 
The dose for the P2/FE cohort is planned to be 100 mg but may be adjusted based on safety, 
tolerability, and/or PK data from P1. The dose assessed in the P2 cohort will have been given 
previously to subjects in a P1 cohort successfully (i.e., no halting rules were met following 
dosing).  
Subjects will be randomized to a treatment sequence; i.e., to receive drug in the fed then fasted 
state (Sequence 1) versus fasted then fed state (Sequence 2; Figure 1). Half of the subjects in the 
cohort will be randomized to Sequence 1 and the other half will be randomized to Sequence 2.  
Following dosing on Day 1, subjects will remain in the clinic through completion of study 
assessments on Day 4, returning to the clinic on Day 9 for study assessments, and Day 14 to 
begin the second dosing sequence on Day 15. Subjects will then be discharged from the clinic on 
Day 18, returning to the clinic on Day 23 for study assessments, and Day 30 for the EOS visit. 
There will be a 14-day (minimum) washout period between doses. 
One cohort of 10 subjects is planned for P2. However, if PK results obtained are equivocal, 
additional subjects may be enrolled into the P2/FE cohort at the previously tested dose or an 
additional P2/FE cohort may be added at a different dose. 
3.1.3. 
Part 3 (Multiple Ascending Dose) 
Subjects in P3 will be randomized in a 3:1 ratio to receive either EIDD-2801 or PBO. 
Twice-daily dosing will be administered to subjects on Day 1 through Day 6, inclusive, and a 
final dose will be administered on the morning of Day 7. Depending on ongoing review of the 
safety, tolerability, and PK data, the dosing frequency and number of days of dosing may be 
changed; however, the dosing frequency will be no less than once-daily or no greater than 
three-times daily, and the number of days of dosing will be no fewer than 5 days and no greater 
than 10 days.  
This protocol has been written assuming 7 days of dosing; however, should the number of days 
of dosing be modified, the timepoints for study assessments may similarly be changed; 
representative examples of Time and Events Schedules are presented for 5 and 7 days of dosing. 
The total daily dose will not exceed a dose shown to be safe and well-tolerated in P1. Doses in 
P3 may be administered in the fed state, following review of the PK data obtained from P2. 
Part 3 may run in parallel with P1, providing that the total daily dose to be administered does not 
exceed a dose already shown to be safe and well-tolerated in P1. 
Subjects will remain domiciled at the site during the dosing period and until Day 10, returning to 
the clinic on Day 15 for completion of study assessments, and Day 21 for the EOS visit. 
Four cohorts are initially planned for P3; however, up to an additional 3 cohorts may be enrolled, 
or the number of cohorts may be reduced if the study objectives are met. Dose levels in P3 may 
be repeated for collection of PBMCs. 


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Additional parts may be added to this study, including a SAD part in elderly healthy 
subjects and a study of the safety, tolerability, and PK in Japanese subjects. These 
additional parts are not described in this protocol, but may be added via a protocol 
amendment. 
3.2. 
Rationale and Justification 
3.2.1. 
Justification of Design 
The FIH study is a typical dose-escalation study designed to provide the maximum amount of 
data in the minimum number of subjects. The cohort size in P1 and P3 is planned to be 8 subjects 
(6 active:2 PBO). This number of subjects allows for a sufficient PK analysis, considered to be 
important because dose extrapolation from efficacious animal models to humans will be based 
on exposure. The duration of participation for each subject following dosing well exceeds 5 drug 
half-lives (up to 9.1 hours in dogs; 5 hours in ferrets) 
 
. The FE cohort is considered to be important to maximize exposure 
based on fed vs. fasted condition and obtaining this information early in Phase 1 will minimize 
study drug dose in all future studies. This design follows the FDA guidance document on 
assessing FE in clinical studies. 
3.2.2. 
Justification of Starting Dose 
 
.
 
 
 The FDA guidance document 
(“Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult 
Healthy Volunteers”) provides guidance for when a safety factor smaller than 10 may be used to 
calculate the starting dose: 
 A smaller safety factor might also be used when toxicities produced by the 
therapeutic are easily monitored, reversible, predictable, and exhibit a 
moderate-to-shallow dose-response relationship with toxicities that are consistent 
across the tested species (both qualitatively and with respect to appropriately scaled 
dose and exposure). 
 A safety factor smaller than 10 could be justified when the NOAEL was determined 
based on toxicity studies of longer duration compared to the proposed clinical 
schedule in healthy volunteers. In this case, a greater margin of safety should be built 
into the NOAEL, as it was associated with a longer duration of exposure than that 
proposed in the clinical setting. This assumes that toxicities are cumulative, are not 
associated with acute peaks in therapeutic concentration (e.g., hypotension), and did 
not occur early in the repeat dose study. 


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EIDD-2801 satisfies both of these criteria as follows: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Importantly, given the activity of EIDD-2801 versus SARS-CoV-2 (cause of COVID-19), the 
Sponsor thinks it is most prudent to start with a dose that is predicted to be a safe starting dose 
and is also as close as possible to a potential therapeutic dose that would allow the Sponsor to 
move into COVID-19 patients as safely and expeditiously as possible. Based on modeling to 
animal data, a dose of 100 mg BID is projected to be an active dose in humans. 
3.2.3. 
Justification of Study Population 
Healthy volunteers are considered to be the appropriate population for conduct of the FIH study. 
Healthy volunteers without confounding medical conditions that may obscure the interpretation 
of AEs or affect absorption, distribution, metabolism and excretion of study drug will provide the 
most valuable data regarding the tolerability, safety, and plasma exposures observed and 
expected following single doses and multiple doses up to 10 days. EIDD-2801 is intended for 
eventual study in patients with potential CoV-2 infection as defined by the Centers for Disease 
Control and Prevention (CDC) in whom a range of AEs are expected based on the disease under 
study. Understanding the safety and PK profile in a normal population will better inform the use 
of EIDD-2801 in disease settings where complications are frequent, and AEs will need to be 
interpreted in context. While EIDD-2801 is being developed for the treatment of highly 
pathogenic CoV, there are plans underway to develop protocols for the treatment of influenza. 
Without safety data from healthy individuals, it will be more difficult to extrapolate the 
interpretation of AEs from one disease state to another. 


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4. 
STUDY POPULATION 
This study will enroll healthy volunteers; 8 subjects will be enrolled into each SAD and MAD 
cohort in P1 and P3, and 10 subjects will be enrolled into the FE cohort in P2. 
The site is strongly encouraged to ensure that women are represented in each cohort. 
4.1. 
Subject Inclusion Criteria 
Subjects who meet all of the criteria at Screening will be eligible for study participation 
1. Male or female between the ages of 18 and 60, inclusive. 
2. Female subjects must be of nonchildbearing potential. Nonchildbearing potential is 
defined as women who: 
 are physiologically incapable of becoming pregnant including those who are 
surgically sterile, via hysterectomy, bilateral salpingectomy, and/or bilateral 
oophorectomy by reported medical history and/or medical records. Surgical 
sterilization to have occurred a minimum of 6 weeks, or at the PI’s (or 
designee’s) discretion, prior to Screening. 
 are post-menopausal (at least 45 years of age with amenorrhea for 12 months 
without an alternative medical reason with confirmatory FSH levels of 
≥40 mIU/mL. The amenorrhea should not be induced by a medical condition 
such as anorexia nervosa, hypothyroid disease or polycystic ovarian disease, 
or by extreme exercise. It should not be due to concomitant medications that 
may have induced the amenorrhea such as oral contraceptives, hormones, 
gonadotropin-releasing hormones, anti-estrogens, or selective estrogen 
receptor modulators). 
3. Male participants must agree to the use of effective contraception for study duration, 
i.e., from Check-in until 90 days after the EOS visit. 
4. Is in generally good health as determined by medical history, PEs (at Screening 
and/or Check-in), vital signs, and other screening procedures. 
5. Has a BMI of 18 to 30 kg/m2. 
6. Is willing and able to comply with all study procedures including providing informed 
consent. 


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4.2. 
Subject Exclusion Criteria 
Subjects who meet any of the following criteria at Screening (unless otherwise stated) will not be 
eligible for participation: 
1. Females who are pregnant, planning to become pregnant, or breastfeeding. 
2. Has a clinically relevant acute or chronic medical condition or disease of the 
cardiovascular, GI, hepatic, renal, endocrine, pulmonary, neurologic, or dermatologic 
systems as determined by the PI (or designee). 
3. Has any current or historical disease or disorder of the hematological system or 
significant liver disease or family history of bleeding/platelet disorders. 
4. Has a history of cancer (other than basal cell or squamous cell cancer of the skin), 
rheumatologic disease or blood dyscrasias. 
5. Has a history of GI surgery or other condition that may interfere with absorption of 
study drug, in the option of the PI (or designee). 
6. Has a history of febrile illness within the 14 days prior to the first dose of study drug. 
7. Has a positive alcohol or drug screen at Screening or the Day -1 visit or has a history 
of alcohol or drug abuse within the past 5 years. 
8. Currently uses tobacco, nicotine or tobacco products or e-cigarettes or stopped using 
tobacco products within the past 3 months and/or has a positive cotinine test at 
Screening or Check-in. 
9. Has any abnormal laboratory value of Grade 2 or higher, which is considered to be 
clinically significant by the PI (or designee). 
10. Has a total white cell count or absolute lymphocyte count outside the normal range, 
or hemoglobin or platelet levels below the lower limit of normal, at Screening or 
Day -1. 
11. Has values above the upper limit of normal for the following laboratory analytes: 
ALT/SGPT, alkaline phosphatase (serum), AST/SGOT, at Screening or Day -1.  
12. Positive test result for HIV, HBV, or HCV. 
13. Has an autoimmune disease, is immunosuppressed or is in any way 
immunocompromised. 
14. Has any of the following: 
 QTcF >450 ms confirmed by repeat measurement 


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 QRS duration >110 ms confirmed by repeat measurement 
 PR interval >220 ms confirmed by repeat measurements 
 findings which would make QTc measurements difficult or QTc data 
uninterpretable 
 history of additional risk factors for torsades de pointes (e.g., heart failure, 
hypokalemia, family history of long QT syndrome). 
15. Except as noted, has used prescription drugs (other than hormone replacement 
therapy) within 14 days prior to the first dose of study drug unless, in the opinion of 
the PI (or designee), the drug will not interfere with study assessments. The 
following prescription drugs will be allowed: 
 Statins: Subjects who have been on a stable dose of statins for a minimum of 
6 months and who have normal creatine kinase at Screening. 
 Antihypertensives: Subjects who have been on a stable dose of 
antihypertensives for a minimum of 6 months and have controlled blood 
pressure and no active heart disease. 
16. Has received an experimental agent (vaccine, drug, biologic, device, blood product 
or medication) within 3 months prior to the first dose of study drug and agrees not to 
receive another experimental agent during the duration of this trial. 
17. Has donated blood within 30 days, plasma within 2 weeks, or platelets within 6 
weeks prior to Screening or refuses to agree to not donate blood until 3 months after 
the EOS visit. 
18. Uses OTC medications or nutritional supplements (including, e.g., gingko biloba, 
aspirin at any dose, and NSAIDs) on a routine/scheduled basis and/or is unwilling to 
abstain from such use for the duration of the study. 
19. Is unwilling to abstain from quinine containing products including quinine water, 
tonic water, bitter lemon, jello shots, any quinine preparations or Cinchona tree bark 
preparations (e.g., herbal medications containing Cinchona tree bark). 
20. Has any condition that would, in the opinion of the PI (or designee), put the subject 
at increased risk for participation in a clinical trial or confinement in a clinical 
research unit. 


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5. 
STUDY MEDICATION, RANDOMIZATION AND DOSE 
ADMINISTRATION 
5.1. 
Study Drug Description 
EIDD-2801 and matching PBO will be supplied 
 
. 
 
 
 
 
 
 
 
5.1.1. 
Acquisition, Formulation, Packaging and Labeling 
 
 
 
 
All study drug will be labeled according to the regulatory requirements for investigational 
product. 
5.1.2. 
Product Storage and Stability 
Study drug should be stored at controlled room temperature defined as 
 
. If excursions occur which 
are outside of this range, the pharmacy staff should contact Sponsor to determine the course of 
action. Additional stability data may be available which would allow continued use of the study 
drug, or study drug may need to be replaced. 
5.2. 
Randomization 
Unmasked study drug (EIDD-2801 and matching PBO) will be supplied to the study site 
pharmacy. The pharmacy staff will be unmasked with regards to treatment assignment. A 
randomization list will be provided to the pharmacy staff who will use that list to dispense 
masked study drug for administration to each study participant. In P1 and P3, 6 subjects will 


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receive EIDD-2801 while 2 subjects will be randomized to PBO. In P2, all 10 subjects in the FE 
cohort will receive EIDD-2801. The pharmacy staff will maintain the security of the 
randomization list ensuring that no study personnel outside of the pharmacy have access to 
identify treatment assignment. In the case that it becomes necessary to know a subject’s 
treatment assignment, unmasking procedures will be followed as discussed in Section 8.4. 
5.3. 
Dosage, Preparation and Administration of Study Drug 
Detailed instructions for extemporaneous compounding (as necessary), dispensing and 
administering study drug can be found in the pharmacy manual. 
 
 
 
 
 
 
 
 
 
 
 
5.4. 
Drug Accountability 
The site pharmacy must maintain records of receipt and disposition of all study drug supplied to 
the site by the Sponsor. The records must be maintained according to site standard operating 
procedures (SOPs) and should include at a minimum, receipt date, lot or batch number, amount 
and formulation received, 
 date, time and amount 
dispensed, subject identifier for each aliquot of study drug dispensed. In addition, the clinic staff 
must ensure that the time of dosing is identified for each subject. 
Monitors must verify drug accountability/dispensing records during the monitoring visit. 
Unused study drug must be disposed of according to the procedures described in the pharmacy 
manual. 
5.5. 
Concomitant Medication/Treatments 
 
 In this FIH study, limited types of concomitant 
medications are permitted. Adjustment of routine medications taken by subjects should be 
avoided during study participation except when subject safety could be affected by lack of 


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adjustment. There are no restrictions on treatment medications prescribed by the PI (or designee) 
to be used for AEs that occur during study participation. For additional restrictions, see 
Section 6.1.2. 


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6. 
STUDY CONDUCT AND VISIT SCHEDULE 
All study assessments will be conducted according to the Time and Events Schedule. 
6.1. 
Study Conduct 
6.1.1. 
Study Windows and Rounding Principles 
The time schedule described in the protocol for each scheduled activity should be followed as 
closely as possible. However, if it is not possible and if it is not otherwise specifically 
contraindicated per protocol, then the time windows detailed in Table 10 are allowed without 
incurring a protocol deviation. 
Table 10: Allowable Time Windows for Study Assessments/Visits 
Protocol Specified Time 
Allowable Window 
PK Samples and Associated Assessments 
Predose 
within 2 hours prior to dosing 
<2 hours 
± 5 minutes 
≥2 hours to 24 hours 
± 15 minutes (± 2 hours for urinalysis) 
>24 hours to 48 hours 
± 30 minutes 
>48 hours 
± 1 hour (PK) and ± 2 hours (safety)  
Study Visits - Parts 1 and 2 
Day −1 to Day 4 (Part 1) 
must occur on scheduled day 
Day −1 to Day 4 and Day 14 to Day 18 (Part 2) 
must occur on scheduled day 
Day 9 (Part 1) and Days 9 and 23 (Part 2) 
± 1 day 
End-of-Study (EOS) Visit 
± 2 days 
Study Visits - Part 3 
Day −1 to Day 10 
must occur on scheduled day 
Day 15 
± 1 day 
Day 21/EOS Visit 
± 2 days 
6.1.2. 
Restrictions 
Prior to arriving at the clinic for the Day -1 visit, subjects must abstain from consumption of 
alcoholic beverages for a minimum of 72 hours prior to Check-in. Subjects must continue to 
abstain from consumption of alcoholic beverages throughout clinic confinement. Subjects 
enrolled in P2 must continue to refrain from consuming alcoholic beverages from discharge on 
Day 4 through Check-in on Day 14, and then through the second clinic confinement to Day 18. 
After discharge on Day 4 (P1), Day 18 (P2), or Day 10 (P3), subjects must minimize 
consumption of alcoholic beverages (i.e., limit of up to one serving per day) until the EOS 
procedures have been completed. 


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All subjects must refrain from the following: 
 consuming quinine containing products from 72 hours prior to Check-in through to 
completion of the EOS procedures. 
 using nutraceuticals and nutritional/vitamin supplements (e.g., gingko biloba, 
multivitamins) from 72 hours prior to Check-in through to completion of the EOS 
procedures. However, vitamin supplements required by a physician are exempt from 
this restriction. 
 taking OTC analgesics including aspirin (any dose) and NSAIDS from 72 hours 
before Check-in until completion of EOS study procedures unless prescribed by the 
PI (or designee). 
 use of tobacco, nicotine or tobacco products, or e-cigarettes from 3 months prior to 
Screening until the EOS visit. 
 strenuous exercise from 7 days before Check-in until the EOS visit. Subjects will 
otherwise maintain their normal level of physical activity during this time (i.e., will 
not begin a new exercise program nor participate in any unusually strenuous physical 
exertion). 
 Female subjects must not donate eggs/ovum from the time of Check-in until 
3 months after the EOS visit. 
All subjects in P1 should be dosed in the fasted state. Subjects should fast overnight for a 
minimum of 10 hours prior to dosing in the morning on Day 1. Following dosing, subjects may 
have water after 2 hours and food beginning 4 hours postdose. For subjects to be dosed in the fed 
state, subjects should have a high-fat breakfast as defined in the FDA guidance. Subjects must 
complete the meal within 30 minutes of starting the meal and should be dosed after 30 minutes 
of starting the meal. Doses in P3 may be administered in the fed state, following review of the 
PK data from P2. 
6.2. 
Screening 
6.2.1. 
Screening Visit 
Subjects who meet preliminary pre-screening criteria (as defined by the site) and are interested in 
participating in the study will arrive at the study site for administration of informed consent 
according to site standard operating procedures (SOPs). After the subject has signed and dated 
the ICF, screening procedures can begin. Assessments and procedures should be conducted as 
shown in the Time and Events Schedule Screening may be conducted as early as 28 days prior to 
dosing. 


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6.2.2. 
Retesting Procedures 
In the case where a parameter is outside of the acceptable limits for enrollment, measurement of 
the parameter can be repeated one time if both the following are met: 
 In the opinion of the PI (or designee), the parameter value does not represent a 
chronic condition that otherwise will preclude the volunteer from enrolling in the 
study; and 
 In the opinion of the PI (or designee), the abnormality is not likely to recur. 
6.2.3. 
Study Visits 
Subjects who satisfy entry criteria will return to the clinic for the Day -1 visit. Following review 
of I/E criteria, subjects who still qualify will be checked into the clinic and enrolled into the 
study. Following enrollment, clinical chemistry, hematology and urine samples will be collected 
to determine baseline values. Based on site standard practices, alternate subjects will also be 
enrolled into the study in case one of the selected subjects cannot be dosed. If all subjects can be 
dosed on the morning of Day 1, the alternates will be released and may be enrolled into 
subsequent cohorts. All assessments and procedures will be performed according to the 
Time and Events Schedule. 
6.2.4. 
Part 1 (Single Ascending Dose) 
Subjects will remain in the clinic through completion of study procedures on Day 4, returning to 
the clinic for procedures on Day 9. 
6.2.5. 
Part 2 (Food-Effect) 
Subjects will remain in the clinic through completion of study procedures on Day 4, returning to 
the clinic on Day 9 for study assessments, and Day 14 to begin the second dosing sequence on 
Day 15. Subjects will then be discharged from the clinic on Day 18, returning to the clinic on 
Day 23 for study assessments. 
6.2.6. 
Part 3 (Multiple Ascending Dose) 
Subjects will remain in the clinic through dosing and completion of study procedures on Day 10, 
returning to the clinic on Day 15 for study assessments. Depending on ongoing review of the 
safety, tolerability, and PK data, the number of days of dosing may be changed; however, the 
number of days of dosing will be no fewer than 5 days and no greater than 10 days. 
6.3. 
Safety Follow-up and End-of-Study Visit 
Subjects in P1 will return to the clinic for the EOS visit on Day 15. Subjects in the FE cohort 
(P2) will return for the EOS visit on Day 30. Subjects in P3 will return for the EOS visit on 
Day 21. Subjects with drug-related AEs at the EOS visit will be followed as discussed in 
Section 8.2.1. 


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6.4. 
Subject Withdrawal and Replacement 
As this is a small study with a limited number of subjects per cohort, it is critical that all subjects 
complete the study including postdose study assessments. Site personnel should emphasize this 
to study subjects at the time of informed consent so that subjects will understand this fact before 
agreeing to participate in the study. 
Subjects may voluntarily withdraw their consent for study participation at any time without 
penalty or loss of benefits to which they are otherwise entitled. An PI (or designee) may also 
withdraw a subject from receiving study drug or participation in the study for any reason. 
Subjects who withdraw or are withdrawn from the study should undergo withdrawal procedures 
as discussed below. These procedures would include follow-up safety evaluations. 
6.4.1. 
Reasons for Withdrawal 
If a subject withdraws or is withdrawn from the study, the primary consideration must be the 
health and welfare of the subject. The reasons for withdrawal might include but are not limited to 
the following: 
 Subject no longer meets eligibility criteria including subject withdraws consent from 
study participation (with or without a reason) 
 Subject becomes noncompliant 
 Medical disease or condition, or new clinical finding(s) for which continued 
participation, in the opinion of the PI (or designee) might compromise the safety of 
the subject, interfere with the subject's successful completion of this study, or 
interfere with the evaluation of responses 
 Subject Lost-to-Follow-up 
 Subject becomes pregnant, if applicable 
 Determined by a physician's discretion to require additional therapy not indicated in 
the protocol to ensure subject's health and well-being (or treatment failure, if 
applicable) 
The PI should be explicit regarding study follow-up (e.g. safety follow-up) that might be carried 
out. If the subject consents, every attempt will be made to follow all AEs through resolution, 
return to baseline, or until stabilized with sequelae for a maximum of 30 days following 
discontinuation. The procedures that collect safety data for the purposes of research must be 
inclusive in the original ICF or the PI may seek subsequent informed consent using an 
EC-approved ICF with the revised procedures. 
The PI will inform the subject that already collected data will be retained and analyzed even if 
the subject withdraws from this study. 


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6.4.2. 
Handling of Withdrawals 
Subjects who withdraw from the study prior to receiving study drug (i.e., on Day -1 or before 
dosing on Day 1) will be discharged from the clinic and followed only if AEs are present which 
occurred due to participation in the study (e.g., AE resulting from a study procedure). In this 
case, the subject should be followed until the AE resolves or the PI determines that the AE has 
stabilized. 
Subjects who withdraw from the study after receiving study drug should have EOS assessments 
at the time of withdrawal or as quickly thereafter as possible. 
Subjects who do not return for follow-up procedures on Days 9/23 or 15/30 (P1 and P2), or 
Days 15 or 21 (P3) will be contacted by the site at least 3 times using the subject’s preferred 
method of communication (as determined at Check-in). If the site is unable to contact the person, 
then a certified letter will be sent. If the subject still cannot be reached or refuses to come back to 
the clinic after all attempts, the subject will be considered Lost-to-Follow-up and withdrawn 
from the study. 
6.4.3. 
Documentation of Withdrawals 
If a subject withdraws or is withdrawn prior to completion of the study, the reason for this 
decision must be recorded in the CRF. If the subject is Lost-to-Follow-up, the site should 
document the attempts to contact the subject in the source documents. If the subject has an 
ongoing AE at the time of withdrawal, then the AE should be followed as detailed in 
Section 8.2.1. 
6.4.4. 
Subject Replacement 
If a subject withdraws from the study prior to receiving study drug, the subject will be replaced. 
In this case, designated alternate subjects, if available, will be first in line to replace the 
withdrawn subject. 
If a subject withdraws from the study after receiving study drug, then the decision to replace the 
subject will be made by the PI (or designee) in consultation with the Sponsor. Factors to consider 
will be the timing postdose of withdrawal and the number of safety and PK assessments 
completed prior to withdrawal. Subjects who are withdrawn because of an AE related to the 
study drug will not be replaced. 
6.5. 
Unscheduled Visit(s) 
If a subject experiences an AE after discharge from the clinic but prior to the EOS visit, the 
subject should be instructed to call the site. Based on the issue, the PI (or designee) may request 
that the subject return to the site for an unscheduled visit. In this case, procedures/assessments 
should be conducted as deemed appropriate for the situation by the PI (or designee). The visit 
should be recorded in the unscheduled visit page of the CRF. 


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7. 
STUDY PROCEDURES/EVALUATIONS 
7.1. 
Demography and Medical History 
Demographics including age, gender, race, ethnicity, and medical history will be recorded for 
each subject. All significant medical history should be recorded. In general, significant medical 
history should include all ongoing events and all events occurring within the last 6 months. 
Clinically relevant or clinically significant events occurring greater than 6 months ago should be 
recorded. All surgeries occurring in adulthood should be recorded. If surgeries occurred more 
than 2 years ago, then only the year needs to be recorded on the CRF. 
7.2. 
Clinical Evaluations 
7.2.1. 
Physical Examinations 
The PE will be performed by the PI or a designee that is licensed to perform a PE per local 
requirements. The initial PE performed at Screening and the final PE conducted at the EOS visit 
will include examination of all pertinent body systems as defined by the site standard PE body 
systems (general appearance, HEENT, lymphatic, cardiovascular, respiratory, GI, 
musculoskeletal, neurological, dermatological). 
Subsequent PEs will be performed as shown in the Time and Events Schedule and will be 
targeted to any new signs or symptoms, any change from the previous status or any body system 
deemed pertinent to that subject by the PI (or designee). Clinically significant abnormalities 
should be recorded in the CRF; those occurring prior to dosing will be included in medical 
history unless the abnormality was the direct result of study participation. 
7.2.2. 
Vital Sign Measurements and ECGs 
Vital signs include pulse rate, respiratory rate, blood pressure, and body temperature. Vital signs 
should be measured after the subject has been supine for a minimum of 5 minutes. Site standard 
ranges will be used for determining any out-of-range values. 
Height and weight should be measured, and BMI calculated at Screening as indicated in the 
Time and Events Schedule. 
Resting 12-lead ECGs should be recorded at the visits indicated in the Time and Events Schedule 
after the subject has been supine for a minimum of 5 minutes. The PI (or designee) will evaluate 
the ECG tracings to determine if there are out-of-range values; if out-or-range values are 
detected, the PI (or designee) will determine if they are clinically significant. Site standard 
ranges will be used to determine if any parameters are considered out-of-range. At the discretion 
of the PI (or designee), the ECG may be repeated if erroneous readings are suspected. 


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7.2.2.1. 
Continuous 12-lead ECG Monitoring (Part 3 Only) 
Continuous 12-lead ECG monitoring using a digital recorder will take place at the times 
indicated in the Time and Events Schedule, in P3 only. 
All continuous 12-lead ECG data collected will be archived without extraction or analysis and 
will not be reported in the scope of this study.  
Subjects will be supine for at least 10 minutes before the extraction timepoint and for 5 minutes 
from the start of each extraction timepoint (each extraction will last for 5 minutes). 
Environmental distractions (e.g., television, radio, conversation) should be avoided during the 
pre-ECG resting period and during ECG recording. 
When coinciding, PK sampling should always be performed after the ECG extraction time 
window. If a separate ECG machine is being used for safety assessments, that machine should be 
in place prior to the extraction window to permit safety ECGs to be recorded irrespective of the 
extraction window. If the machine is not in place prior to the extraction window, safety ECGs 
must be recorded after the extraction window. If an integral system is used, safety ECGs may be 
recorded irrespective of the extraction window.  
7.2.3. 
Adverse Events and Concomitant Medications 
Adverse Events: The PI is responsible for identifying and documenting events meeting the 
definition of an AE or SAE (Section 8.1). Once each day while the subject is in the clinic and 
once during each out-patient visit, the PI (or designee) should inquire about the occurrence of 
AEs. The following are examples of open-ended questions that may be used to obtain this 
information: “How are you feeling?”; "Have you had any medical problems recently?"; "Have 
you taken any new medicines since your last visit/assessment?" 
All AEs and SAEs must be documented in the source documents and recorded in the CRF. 
Concomitant Medications: All medications (prescription or over-the-counter), nutritional 
supplements, and nutraceuticals taken by the subject from 30 days prior to dosing through the 
EOS visit must be recorded in the CRF. Medication information should include indication, dose, 
frequency, and route of administration. Any medication taken for an AE/SAE should be 
documented as such. Refer to Section 5.5 for additional information. 
7.3. 
Laboratory Evaluations 
The laboratory will perform standard routine testing, and processing of all blood samples. For the 
entire study, the amount of blood collected from any one subject will not exceed 500 mL. 
7.3.1. 
Routine Laboratory Panels 
Blood and urine samples will be collected at the times indicated in the 
Time and Events Schedule. The analytes shown in the table below (Table 11) will be assessed. 


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If a method to determine COVID-19 status becomes readily available, subjects may be tested at 
Screening and Check-in to confirm they are not positive for COVID-19 prior to dosing.  


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Table 11: Laboratory Evaluations 
CHEMISTRY PANEL 
Alanine Aminotransferase (ALT/SGPT) 
Albumin, Serum 
Albumin/Globulin (A/G) Ratio (calculation) 
Alkaline Phosphatase, Serum 
Amylase 
Aspartate Aminotransferase (AST/SGOT) 
Bilirubin, Total and Direct 
BUN 
BUN/Creatinine Ratio (calculation) 
Calcium, Serum 
Creatinine, Serum 
Creatinine Kinase (CK) 
Gamma Glutamyl Transferase (GGT) 
Lactate Dehydrogenase (LDH)  
Uric Acid 
Electrolyte Panel (Na+, K+, Cl-, Bicarb.) 
Phosphorus 
Globulin, Total  
Glucose, Serum 
Lipase 
Protein, Total, Serum 
HEMATOLOGY PANEL 
Hemoglobin 
Hematocrit 
White Blood Cell Count with differential (absolute and percentage) 
Red Blood Count 
Prothrombin Time (PT)/Partial Prothrombin Time (PTT) and International 
Normalized Ratio (INR) 
Mean cell hemoglobin (MCH), mean cell hemoglobin concentration (MCHC), 
mean cell volume (MCV), red cell distribution width (RDW; may be a 
Grade 1 abnormality) 
Platelets 
ADDITIONAL ASSESSMENTS 
Virology: Human Immunodeficiency Virus (HIV) serology, Hepatitis B Virus 
(HBV; Surface Antigen [HBsAg]), Hepatitis C Virus (HCV) 
Follicle-Stimulating Hormone (FSH; as applicable) 
PREGNANCY TEST 
Serum Pregnancy Test 
Urine Dipstick (optional blood follow-up) 
DRUG SCREENING 
Serum/urinalysis (per site SOP) 
Cotinine 
Urine Dipstick 
Alcohol Breathalyzer 
ROUTINE URINALYSIS 
Bilirubin 
Color and appearance 
Glucose 
Ketones  
Leukocytes 
Microscopic (including red blood cells [RBCs] and white blood cells [WBCs]) 
Nitrite 
Occult blood 
pH 
Protein 
Specific Gravity 
Urobilinogen 
7.3.2. 
Pharmacokinetic Sampling 
Samples for PK analysis will be collected as shown in the Time and Events Schedule. All 
samples will be analyzed to define the PK parameters for prodrug EIDD-2801 and the active 
parent, EIDD-1931. In order to preserve EIDD-2801, special handling procedures will be put in 
place. These procedures will be documented in the laboratory manual for the study. 
Depending on ongoing review of the PK data, timepoints may be modified or removed, and up to 
3 additional samples (in each period for the food-effect) may be added. 


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7.3.3. 
Peripheral Blood Mononuclear Cell Collection 
Peripheral blood mononuclear cells will be collected in P2 and P3. Blood will be collected into 
specialized tubes and processed according to procedures described in the laboratory manual. 
Depending on ongoing review of the data, timepoints may be modified or removed, and up to 
2 additional samples may be added. 
7.3.4. 
Urine Collection 
Urine will be collected over the time periods noted in the Time and Events Schedule. Samples 
will be collected for routine urinalysis and PK analysis according to site standard practices and 
as described in the laboratory manual. 


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8. 
SAFETY MONITORING, MANAGEMENT AND REPORTING 
8.1. 
Definitions 
8.1.1. 
Adverse Events 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product. 
Abnormal clinical laboratory findings (e.g. clinical chemistry, hematology) or other abnormal 
assessments that are judged by the PI (or designee) as clinically significant will be recorded as 
AEs or SAEs if they meet the definitions of an AE or an SAE as defined in this Section 8.1.2. 
Disease specific signs and symptoms which were ongoing prior to study entry will not be 
considered AEs unless they worsen (e.g. increase in frequency or severity) unexpectedly during 
the course of the trial. 
8.1.2. 
Serious Adverse Events 
An AE or suspected adverse reaction is considered “serious” if, in the view of either the PI (or 
designee) or Sponsor, it results in any of the following outcomes: 
 Death, 
 A life-threatening AE: An AE or suspected adverse reaction is considered 
“life-threatening” if, in the view of either the PI or Sponsor, its occurrence places the 
patient or subject at immediate risk of death. It does not include an AE or suspected 
adverse reaction that, had it occurred in a more severe form, might have caused 
death. 
 Inpatient hospitalization or prolongation of existing hospitalization, 
 A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions, or 
 A congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalizations may be considered serious when, based upon appropriate medical judgment they 
may jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 


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or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
Suspected adverse reaction means any AE for which there is a reasonable possibility that the 
drug caused the AE. “Reasonable possibility” means there is evidence to suggest a causal 
relationship between the drug and the adverse event. Suspected adverse reaction implies a lesser 
degree of certainty about causality than adverse reaction, which means any adverse event caused 
by a drug. 
An AE or suspected adverse reaction is considered “unexpected” if 
 It is not listed in the IB or is not listed at the specificity or severity that has been 
observed; or, if an IB is not required or available, 
 Is not consistent with the risk information described in the general investigational 
plan or elsewhere in the current application as amended. For example, under this 
definition, hepatic necrosis would be unexpected (by virtue of greater severity) if the 
IB referred only to elevated hepatic enzymes or hepatitis. Similarly, cerebral 
thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater 
specificity) if the IB listed only cerebral vascular accidents. 
 “Unexpected” as used in this definition, also refers to AE or suspected adverse 
reactions that are mentioned in the IB as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the particular drug under investigation. 
As of the date of this protocol, there are no expected events listed in the current version of the 
IB; therefore, all AEs will be considered unexpected until such a time that the reference safety 
information in the IB is updated with any identified, expected events. 
8.2. 
Documenting Adverse Events 
8.2.1. 
Timeframe for Collection and Follow-up of AEs/SAEs 
All AEs/SAEs will be collected from the time of the first study drug administration until the 
subject has completed the EOS visit and been discontinued from the study. This includes 
subjects who discontinue early. Events considered related to study drug will be followed as 
noted: 
 AEs that are related to study drug and continue beyond the normal collection period 
(i.e., are ongoing at the time a subject exits the study) will be followed until 
resolution, return to baseline or until stabilized with sequelae for a maximum of 
30 days following discontinuation. After 30 days, the AE will be closed, and the 
outcome noted (see Table 12). 
 SAEs that are related to study drug and continue beyond the normal collection period 


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(i.e., are ongoing at the time a subject exits the study) will be followed until 
resolution, return to baseline or until stabilized with sequelae. 
 Serious AEs that are reported to the site within 30 days after the subject has been 
discontinued from the study (i.e., completed the EOS visit) will be recorded. Those 
that are considered related to study drug will be followed as noted in the bullet 
above. 
Note that all events which occurred prior to dosing with study drug should be recorded as 
medical history unless the event is directly related to study procedures. 
8.2.2. 
Recording of Adverse Events/Serious Adverse Events 
AEs/SAEs must be recorded in the CRF as indicated in the CRF completion instructions. 
Information to be collected includes event description, time of onset, clinician’s assessment of 
severity (Section 8.2.3), relationship to study drug (Section 8.2.4), outcome (Section 8.2.5), and 
time of resolution/stabilization of the event. All AEs occurring while on study must be 
documented appropriately regardless of relationship and will be followed to adequate resolution 
as described above (Section 8.2.1). All SAEs will be recorded as noted above; SAEs reported to 
the site within 30 days following the EOS visit will also be recorded. All SAEs must be entered 
onto the SAE form and reported as discussed below (Section 8.3.1). 
If an AE changes in severity, the highest severity will be recorded in the CRF. AEs characterized 
as intermittent require documentation of onset and duration of each episode. 
8.2.3. 
Assessing Severity of Adverse Events 
All AEs/SAEs will be assessed by the PI or those with the training and authority to make a 
medical judgment. AEs/SAEs will be graded according to the DMID Toxicity Grading Scale. 
For any AEs not specifically listed in the tables, the following guidelines should be used to grade 
severity: 
 Mild (Grade 1); asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
 Moderate (Grade 2); minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living. 
 Severe (Grade 3); medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care activities of daily living. 
o Life-threatening; life-threatening consequences; urgent intervention 
indicated. 
o Death; death related to AE. 


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Changes in the severity of an AE should be documented to allow an assessment of the duration 
of the event at each level of intensity to be performed. Adverse events characterized as 
intermittent require documentation of onset and duration of each episode. 
8.2.4. 
Relationship to Study Drug 
The PI’s (or designee’s) assessment of an AE’s relationship to study drug is part of the 
documentation process, but it is not a factor in determining what is or is not reported in the study. 
If there is any doubt as to whether a clinical observation is an AE, the event should be reported. 
All AEs must have their relationship to study product assessed using the terms: related or not 
related. In a clinical trial, the study product must always be suspect. To help assess, the following 
guidelines are used. 
 Definite – The AE is clearly related to the study drug. 
 Probable – The AE is likely related to the study drug. 
 Possible – The AE may be related to the study drug. 
 Unlikely – The AE is doubtfully related to the study drug. 
 Unrelated – The AE is clearly NOT related to the study drug. 
8.2.5. 
Classifying Adverse Event Outcome 
All AEs/SAEs in the study must be assigned an outcome by site staff. The outcome will be 
included on the AE CRF. Possible outcomes are shown below: 
Table 12: Adverse Event Outcomes 
Outcome 
Description 
Recovered / Resolved 
AE resolved with no residual signs or symptoms; an event is considered resolved if it 
returns to baseline (pretreatment) values. 
Recovered / Resolved with sequelae 
AE stabilized but residual signs or symptoms remain; this includes stabilization of an 
event/condition with the expectation that it will remain chronic. 
Not Recovered / Not Resolved 
AE remains ongoing AND no or only minimal improvement has occurred. 
Ongoing 
AE has not yet resolved, but continues to improve/resolve and complete resolution is 
expected over time. 
Fatal 
Outcome of the AE is death. 
Unknown 
AE outcome is not known; usually because the subject has been Lost-to-Follow-up. 


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8.3. 
Reporting Procedures 
8.3.1. 
Serious Adverse Events 
The PI or clinical site personnel should notify Covance Drug Safety Services (DSS) 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 Notification 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. 
The responsibilities of Covance DSS include the following: 
 Prepare an AE reporting plan prior to the start of the study. Where this plan differs from 
the applicable site standard operating procedure on SAE reporting, the AE reporting plan 
will always take precedence. 
 Receive and review SAE report forms from the site and inform the Sponsor of the SAE 
within 1 working day of the initial notification to DSS. Drug Safety Services will delete 
any information from the SAE report forms that may identify the subject. 
 Write case narratives and enter the case into Covance’s safety database as defined in the 
AE reporting plan. 
 Produce appropriate reports of all Suspected Unexpected Serious Adverse Reactions and 
forward to the EC, Medicines and Healthcare Products Regulatory Agency, PI’s (or 
designee’s), and the Sponsor within the timeframes stipulated in the Clinical Trials 
Directive Guideline (ENTR/CT 3).  
The responsibility for reporting SAEs will be transferred to the Sponsor 28 days after the end of 
the study. 
8.3.2. 
Pregnancy 
Subjects in this study must be of non-childbearing potential. However, should a pregnancy occur 
any time from informed consent to the EOS visit, subjects must immediately report the event to 
the clinical site which in turn must immediately report the pregnancy to the Sponsor or their 
designee. The subject will be followed until the end of the pregnancy. A separate ICF will be 
used for consenting for follow-up pregnancy activities. Pregnancy will not be considered an AE 
unless deemed likely related to study drug. Pregnancy will not be considered an SAE unless there 
is an associated SAE. A spontaneous abortion (miscarriage) or abnormal outcome (including 
congenital anomalies) will be reported as an SAE. 


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8.4. 
Unmasking Treatment Assignment 
The following controls will be employed to maintain the double-blind status of the study: 
 Placebo will be identical in appearance to the EIDD-2801. 
 The PI and other members of staff involved with the study will remain blinded to the 
treatment randomization code in P1 and P3. 
 Interim bioanalytical data will be provided in a blinded manner. 
To maintain the blind, the PI will be provided with a sealed randomization code for each subject 
in P1 and P3, containing details of their treatment. These individual sealed envelopes will be 
kept in a limited access area that is accessible 24 hours a day. In order to manage subject safety 
or to support dose-escalation decisions (in the event of possibly treatment-related SAEs or severe 
AEs), the decision to unblind resides solely with the PI. Whenever possible and providing it does 
not interfere with or delay any decision in the best interest of the subject, the PI will discuss the 
intended code-break with the Sponsor. If it becomes necessary to break the code during the 
study, the date, time, and reason will be recorded in the subject’s source data and on the 
individual envelope and will be witnessed by a second person. 
The pharmacy and bioanalytical lab will have access to the treatment randomization and will be 
unblinded. Pharmacokinetic personnel may be unblinded to perform interim PK analysis and to 
ensure that PK data are provided in a blinded manner for dose-escalation decisions.  


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9. 
DOSE-ESCALATION AND HALTING RULES 
9.1. 
Guidelines for Dose-Escalation 
Doses will be administered in an escalating manner following satisfactory review by the Sponsor 
and PI of the blinded safety and tolerability data up to 72 hours post final dose. 
 
 
 
 
 
As PK data become available, these data will be reviewed and 
may be used to assist in dose selection. 
Doses may be reduced and may be lower than the starting dose. There will be a minimum of 
4 days between dose escalations to allow sufficient time for an adequate safety review. 
Dose-escalation in P1 and P3 will only occur if data from a minimum of 6 subjects have been 
reviewed from the previous lower dose group, such that data from a minimum of 4 subjects who 
have received EIDD-2801 will be used to make the dose-escalation decision. 
The justification for this is as follows: 
 The study treatment is of a known pharmacological class for which the on-target effects 
in humans are well characterized. Based upon nonclinical data, no clinically important off 
target effects are expected within the proposed dose range. 
 A minimum of 4 subjects receiving the active drug is considered sufficient to characterize 
the safety profile of EIDD-2801. 
Between each dose-escalation, the PI will review all available data in a blinded manner to ensure 
it is safe to proceed with the planned dose-escalation. The results from all available safety 
assessments will be sent to the Sponsor prior to the start of each successive group/treatment 
period. Any clinically significant results will be discussed with the Sponsor before 
dose-escalation continues. Interim PK data may also be reviewed in terms of dose-escalation and 
to confirm that the study design remains appropriate. In the event of a disagreement between 
Sponsor and PI on the dose-escalation decision, the most conservative decision will be upheld. 
Dose levels will not increase by more than 3-fold for predicted nonpharmacologically active 
dose levels and by 2-fold for predicted pharmacologically active dose levels. 
 
 
 
Dose levels in P3 may be repeated for collection of PBMCs. 


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9.2. 
Dose-Escalation Halting Rules 
For Group 1 in P1, sentinel dosing will occur whereby 2 subjects (1 active and 1 PBO) will be 
dosed on 1 day and, providing no safety concerns arise, the remaining 6 subjects will be dosed 
after at least 24 hours. 
The study will be halted (i.e., no further dosing will occur) if one or more subjects experience an 
SAE that is considered to be related to EIDD-2801 or 2 or more subjects in the same group 
experience severe AEs that are considered to be related to EIDD-2801. If, following an internal 
safety review, the Sponsor deems it appropriate to restart the study, this can be done following 
approval of a substantial protocol amendment.  
Dose-escalation will stop if clinically relevant signs or symptoms of similar nature occur in 2 or 
more subjects in a group that, in the opinion of the PI, warrant stopping of dose-escalation. 


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10. 
STATISTICAL CONSIDERATIONS 
10.1. 
General Considerations 
All summaries will be provided by study part and treatment. Continuous variables will be 
summarized using descriptive statistics including number of observations (n), mean, standard 
deviation, minimum (min), median (med), and maximum (max). Categorical variables will be 
summarized using frequency counts and percentages. Note that PBO data from each dose level in 
Parts 1 and 3 will be combined into one PBO group. 
No missing data imputation will be performed. 
Subject listings will be provided for all the data collected during the study period. 
Specific information about the statistical analysis will be provided in a SAP that will be reviewed 
and approved by the Sponsor and will be finalized before final database lock. If there is a 
discrepancy between the methods described in the protocol and final approved SAP, the SAP 
will take precedence. 
10.2. 
Sample Size Considerations 
No formal sample size calculation was conducted. The sample size of 8 per cohort 
(6 active: 2 PBO) for the SAD and MAD cohorts is considered adequate for a Phase 1 FIH study. 
The sample size of 10 subjects (all administered EIDD-2801) is in accordance with FDA 
guidelines for sample size in FE studies. 
10.3. 
Analysis Populations 
Safety Population: All subjects who receive at least one dose of study drug. 
Pharmacokinetic Population: All subjects receiving study drug who comply sufficiently with 
protocol requirements (i.e., no major protocol violations) and for whom a sufficient number of 
analyzable PK samples have been obtained to permit the determination of the PK profile for 
EIDD-2801/EIDD-1931 and the statistical analysis of the results. Subjects who experience an 
AE of vomiting before 2× the median tmax of the group may be excluded from the PK population. 
10.4. 
Analysis of Safety Data 
All safety analyses will be performed on the Safety Population as defined in Section 10.3. Safety 
will be assessed on the basis of AEs, clinical laboratory data, vital signs, ECG parameters, and 
PEs. 
10.4.1. 
Extent of Exposure 
Dosing data will be listed by study part. 


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10.4.2. 
Adverse Events 
Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
preferred term and system organ classification. Any events reported after the initiation of study 
treatment and through the EOS are defined as treatment-emergent. The occurrence of 
treatment-emergent AEs will be summarized using MedDRA preferred terms, system organ 
classifications, and severity. Separate summaries of treatment-emergent SAEs and AEs 
considered related to study treatment and AEs leading to study treatment discontinuation will be 
generated. All AEs will be listed for individual subjects showing both verbatim and preferred 
terms. 
10.4.3. 
Clinical Laboratory Results 
Laboratory abnormalities will be graded according to the DMID Toxicity Grading Scale. Any 
graded abnormality that occurs following the initiation of study treatment and represents at least 
a one-grade increase from the baseline assessment is defined as treatment-emergent. The number 
and percentage of subjects experiencing treatment-emergent graded toxicities will be 
summarized. Raw values and mean changes from baseline in clinical laboratory measures will be 
summarized. 
Listings of the clinical laboratory test results will be provided. Abnormal laboratory values will 
be flagged in the listings. 
10.4.4. 
Other Parameters 
Individual data for ECG parameters and vital sign measurements will be listed by subject and 
time point and summarized for each treatment. Individual data for PE will be listed by subject 
and time point. 
Concomitant medications will be coded using the World Health Organization-Drug Dictionary 
(WHO-DD) and summarized. 
10.5. 
Analysis of Pharmacokinetic Data 
Pharmacokinetic analysis as defined in the SAP will be conducted using the PK population 
defined in Section 10.3. In the event of discrepancies between analyses described in the SAP and 
this clinical study protocol, the SAP will supersede the protocol. 
 All samples will be analyzed and all concentrations listed. 
 Descriptive statistics will be performed for all time points available, with the 
exclusion of subjects who had any significant protocol deviation. 
 Pharmacokinetic parameters will be derived where possible for all subjects. Data 
from subjects with incomplete profiles (missed blood draws, lost samples, samples 
unable to be quantified) may be used if PK parameters can be estimated using the 
remaining data points. 


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 Descriptive statistics will be performed on all parameters available, and any missing 
parameters will be flagged. 
Plasma concentration data for EIDD-2801 and EIDD-1931 will be listed for individual subjects 
and summarized by study part and treatment. Individual and mean plasma concentration versus 
time plots for EIDD-2801 and EIDD-1931 will be provided. Urine concentration data for 
EIDD-2801 and EIDD-1931 will be listed. 
Plasma PK parameters of EIDD-2801 and EIDD-1931 for each subject will be estimated over the 
sampling interval using noncompartmental analysis and summarized by study part and treatment 
using descriptive statistics. Actual blood sampling times will be used for plasma PK analysis. 
Urine PK parameters of EIDD-2801 and EIDD-1931 will also be analyzed and summarized 
when possible. The PK parameters that will be estimated are listed in the table below.  
Table 13: Pharmacokinetic Parameters 
Plasma PK Parameter 
Description 
AUClast 
The area under the plasma concentration-time curve, from time 0 to the last measurable 
non-zero concentration, as calculated by the linear up/log down trapezoidal method (P1 and 
P2 only). 
AUC0-inf 
The area under the plasma concentration-time curve from time 0 extrapolated to infinity. 
AUC0-inf is calculated as the sum of AUClast plus the ratio of the last measurable plasma 
concentration to the elimination rate constant (λz) (P1, P2, and Day 1 dose of P3). 
Cmax 
Maximum observed concentration. 
tmax 
Time to reach Cmax. If the maximum value occurs at more than one time point, tmax is 
defined as the first time point with this value. 
λz 
Apparent terminal elimination rate constant; represents the fraction of medication 
eliminated per unit time. 
t½ 
Apparent terminal elimination half-life of medication, calculated as 0.693/λz. 
Vz/F 
Apparent volume of distribution (EIDD-2801 only). 
CL/F 
Apparent oral drug clearance (EIDD-2801 only). 
Ctrough 
Trough concentration (P3 only). 
AUCτ 
The area under the plasma concentration-time curve during a dosing interval (P3 only). 
RAAUCτ 
Observed accumulation ratio based on AUCτ (P3 only). 
RACmax 
Observed accumulation ratio based on Cmax (P3 only). 
Urine PK Parameter 
Description 
Ae 
Amount excreted in urine over the sampling interval. 
Fe 
Fraction of drug excreted in the urine over sampling interval. 
CLR 
Renal clearance, CLR = Ae/AUC where both Ae and AUC are determined over co-incident 
time ranges after dosing. 
Additional PK parameters may be analyzed as appropriate. 


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10.5.1. 
Statistical Analysis of Pharmacokinetic Data 
10.5.1.1. Dose Proportionality 
In P1, dose-proportionality for PK parameters of EIDD-2801 and EIDD-1931 (AUC0-inf, AUClast, 
and Cmax) will be assessed by the power model. The slope and the associated 90% CI based on 
the power model will be reported. 
In Part 3 on Day 7 dose-proportionality for PK parameters of EIDD-2801 and EIDD-1931 
(AUCτ, and Cmax) will be assessed by the power model. The slope and the associated 90% CI 
based on the power model will be reported. 
10.5.1.2. Food-Effect 
To assess the effect of food on the PK of EIDD-2801 and EIDD-1931, natural log transformed 
PK parameters from P2 (AUC0-inf, AUClast, and Cmax) will be analyzed using a mixed-effects 
model with fixed-effect terms for treatment (with or without food), period, and sequence and 
with subject within sequence as a random effect. Point estimates and their associated 90% CIs 
for the natural log-transformed PK parameters for the difference between EIDD-2801 
administered under fed relative to fasted conditions will be constructed. The point estimates and 
interval estimates will be back transformed to give estimates of the ratio and 90% CI for the 
geometric least squares mean ratio for fed/fasted to assess the effect of food. 
10.6. 
Peripheral Blood Mononuclear Cells 
Peripheral blood mononuclear cellss will be collected from subjects following each dose in Part 
2. Depending upon ongoing review of the data, PBMCs may be collected from subjects in P3; 
the collection of these samples may be omitted from some cohorts in P3. 
The PBMCs will be stored for analysis of EIDD-2061 levels at some point in the future and 
reported separately. 
10.7. 
Interim Analyses 
There are no formal interim analyses planned for this study. However, interim analyses may be 
implemented at the discretion of the Sponsor or health authority request. In addition, data from 
P1 cohorts may be locked, unblinded, and analyzed prior to conducting P2 and P3. 


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11. 
STUDY ADMINISTRATION 
11.1. 
Regulatory and Ethical Considerations 
11.2. 
Ethical Standard 
This study will be conducted in accordance with the protocol and with the following: 
 Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
International Ethical Guidelines. 
 Applicable ICH GCP Guidelines. 
 United States CRFs applicable to clinical studies (45 CFR Part 46; 21 CFR Part 50, 21 
CFR Part 56, and 21 CFR Part 312). 
 Applicable laws and regulations. 
11.2.1. 
Ethics Committee Approval 
The PI (or designee) must ensure that all required study-specific documents and/or information 
are submitted to the EC for review and approval as appropriate including but not limited to: 
 the protocol and any future protocol amendments 
 ICF and any other documents (electronic or paper) given to the subject 
 IB 
Any substantial protocol amendments, likely to affect the safety of the subjects or the conduct of 
the study, will require EC and regulatory authority (as locally required) approval before 
implementation of changes made to the study design, except for changes necessary to eliminate 
an immediate hazard to study subjects or any nonsubstantial changes, as defined by regulatory 
requirements. 
11.2.2. 
Informed Consent 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continuing throughout the individual’s study participation. Extensive discussion of 
risks and possible benefits of this therapy will be provided to the subjects and, if applicable, their 
families. Consent forms describing in detail the study interventions/products, study procedures, 
and risks are given to the subject and written documentation of informed consent is required 
prior to starting any screening procedures or intervention/administering study product. Consent 
forms will be EC-approved and the subject will be asked to read and review the document. 


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Upon reviewing the document, the PI (or designee) will explain the research study to the subject 
and answer any questions that may arise. The subjects will sign the ICF prior to any procedures 
being done specifically for the study. The subjects should have the opportunity to discuss the 
study with their surrogates or think about it prior to agreeing to participate. The subjects may 
withdraw consent at any time throughout the course of the trial. A copy of the ICF will be given 
to the subjects for their records. The rights and welfare of the subjects will be protected by 
emphasizing to them that the quality of their medical care will not be adversely affected if they 
decline to participate in this study. 
11.3. 
Financing and Insurance 
Financing and insurance will be addressed in a separate agreement. 
11.4. 
Source Documentation and Access 
The site will maintain appropriate medical and research records in compliance with ICH E6, 
Section 4.9 and regulatory and institutional requirements for the protection of confidentiality of 
subjects. The site will permit authorized representatives of the Sponsor, its designees, and 
appropriate regulatory agencies to examine (and when required by applicable law, to copy) 
clinical records for the purposes of quality assurance reviews, audits, and evaluation of the study 
safety and progress. These representatives will be permitted access to all source data and source 
documents, which include, but are not limited to, clinical and office charts, laboratory notes, 
memoranda, subjects’ memory aid or evaluation checklists, pharmacy dispensing records, 
recorded data from automated instruments, copies or transcriptions certified after verification as 
being accurate and complete, photographic negatives, microfilm or magnetic media, x-rays, and 
subject files and records kept at the pharmacy, at the laboratory, and medico-technical 
departments involved in the clinical trial. 
11.5. 
Data Collection and Record Keeping 
11.5.1. 
Data Collection 
Data collection and data entry are the responsibility of the clinical trial staff at the site. The PI is 
responsible for ensuring the accuracy, completeness, legibility, and timeliness of the data 
reported. All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data. 
A CRF must be completed for every subject who signs the ICF and has at least one 
protocol-specified assessment conducted. The CRF must be completed and processed according 
to the CRF guidelines and the SOPs of the site. All data should be entered into the CRF, where 
possible, within 3 days after each visit for any one subject. After the subject has completed the 
study, the PI must review and sign the signature page of the CRF indicating that he has reviewed 
the completed CRF and pertinent clinical data for that subject and that, to the best of his 
knowledge, all data recorded in the CRF accurately reflects the subject’s clinical performance in 
the study 


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11.5.2. 
Study Records Retention 
Study documents should be retained for a minimum of 5 years after the end of the study. These 
documents should be retained for a longer period; however, if required by local regulations. No 
records will be destroyed without the written consent of the Sponsor, if applicable. It is the 
responsibility of the Sponsor to inform the PI when these documents no longer need to be 
retained. 
11.5.3. 
Protocol Deviations 
A protocol deviation is any noncompliance with the protocol or study procedures detailed in the 
laboratory or pharmacy manuals. The noncompliance may have been the result of action by the 
PI, site staff, or subject. All deviations should be handled in accordance with site SOPs. 
It is the responsibility of the site to use continuous vigilance to identify and report deviations 
within 5 working days of identification of the protocol deviation, or within 5 working days of the 
scheduled protocol-required activity. 
11.6. 
Clinical Monitoring 
Site monitoring is conducted to ensure that the human subjects’ protections, study and laboratory 
procedures, study intervention administration, and data collection processes are of high quality 
and meet Sponsor, ICH/GCP guidelines and applicable regulations, and that this trial is 
conducted in accordance with the protocol, protocol-specific MOP and applicable Sponsor SOPs. 
Experienced clinical monitors of the Sponsor or its designee will conduct site-monitoring visits 
as detailed in the clinical monitoring plan. 
Site visits will be made at standard intervals as defined by the Sponsor and may be made more 
frequently as directed by the Sponsor. Monitoring visits will include, but are not limited to, 
review of regulatory files, accountability records, CRFs, ICFs, medical and laboratory reports, 
and protocol and GCP compliance. Clinical monitors will have access to each participating site, 
study personnel, and all study documentation according to the site monitoring plan. Clinical 
monitors will meet with the site PI to discuss any problems and actions to be taken and will 
document site visit findings and discussions. As data are entered into a CRF, data will be 
monitored to ensure accuracy as well as adherence to data entry instructions provided in the CRF 
guidelines. 
11.7. 
Quality Control and Quality Assurance 
A quality management plan will be put in place for this study. The site is responsible for 
conducting routine quality assurance and quality control activities to internally monitor study 
progress and protocol compliance. The PI will provide direct access to all study-related sites, 
source data/data collection forms, and reports for the purpose of monitoring and auditing by the 
Sponsor, and inspection by local and regulatory authorities. The PI will ensure all study 
personnel are appropriately trained and applicable documentations are maintained on site. 


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11.8. 
Study Termination and Closure Procedures 
11.8.1. 
Study Termination 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided to the site. If the study is terminated or suspended, the PI (or 
designee) will inform study participants and the EC. The Sponsor will notify appropriate 
regulatory authorities. The Sponsor will provide the reason(s) for the termination or suspension. 
Study participants will be contacted, as applicable, and be informed of changes to study visit 
schedule. 
If suspended, the study may resume once issues that caused suspension of the study are resolved. 
11.8.2. 
Termination Procedures 
If the study is prematurely terminated, then the site must return all appropriate study data, 
resolve all data queries, complete final drug accountability, return any study drug remaining on 
site, and ship all biological samples (including PK and PBMCs) to the laboratory designated by 
the Sponsor. The PI (or designee) must notify the EC of study termination. 
11.9. 
Information Disclosure 
11.9.1. 
Confidentiality 
Subject confidentiality and privacy is strictly held in trust by the PI, site staff, and the Sponsor(s) 
and their agents. The study protocol, documentation, data, and all other information generated 
will be held in strict confidence. No information concerning the study or the data will be released 
to any unauthorized third party without prior written approval of the Sponsor. 
The study monitor or other authorized representatives of the Sponsor or regulatory agencies may 
inspect all documents and records required to be maintained by the PI, including but not limited 
to, medical records (office, clinic, or hospital) and pharmacy records for the participants in this 
study. The clinical study site will permit access to such records. 
The study participant’s contact information will be securely stored at the clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by the Sponsor, site, or regulatory requirements. 
Study participant research data will be transmitted to and stored securely by the Sponsor’s 
designated data center. This will not include the participant’s contact or identifying information. 
Individual participants and their research data will be identified by a unique study identification 
number. The study data entry and study management systems used by clinical sites will be 
secured and password-protected. At the end of the study, all study databases will be de-identified 
and archived at a secure location. 


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11.9.2. 
Clinicaltrials.gov 
This clinical study will be registered on clinicaltrials.gov as required. 
11.9.3. 
Publication Policy 
All information generated from this study is the proprietary property of the Sponsor. It is the 
intent of the Sponsor to publish the results of the study in their entirety as deemed appropriate. 


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12. 
REFERENCES 
Agostini ML, Pruijssers AJ, Chappell JD, Gribble J, Lu X, Andres EL, et al. Small-Molecule 
Antiviral β-d-N4-Hydroxycytidine Inhibits a Proofreading-Intact Coronavirus with a High 
Genetic Barrier to Resistance. J Virol. 2019 Dec 15;93(24).  
Flavell RA, Sabo DL, Bandle EF, Weissmann C. Site-directed mutagenesis: generation of an 
extracistronic mutation in bacteriophage Q beta RNA. J Mol Biol. 1974 Oct 25;89(2):255–72.  
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 Dec;48(12):4636–42.  
Mullins JI, Heath L, Hughes JP, Li D, Essigmann JM, Harris KS, et al. Mutations based on viral 
decay acceleration in the HIV-1 genomes of a clinical population treated with the mutagenic 
nucleoside KP1461. Retrovirology. 2011 Oct 3;8(Suppl 2):P84.  
Painter GR, Bowen RA, Bluemling GR, DeBergh J, Edpuganti V, Gruddanti PR, et al. The 
prophylactic and therapeutic activity of a broadly active ribonucleoside analog in a murine model 
of intranasal venezuelan equine encephalitis virus infection. Antiviral Res. 2019;171:104597.  
Sticher ZM, Lu G, Mitchell DG, Marlow J, Moellering L, Bluemling GR, et al. Analysis of the 
Potential for N4-Hydroxycytidine To Inhibit Mitochondrial Replication and Function. 
Antimicrob Agents Chemother. 2020 27;64(2).  
Stuyver LJ, Whitaker T, McBrayer TR, Hernandez-Santiago BI, Lostia S, Tharnish PM, et al. 
Ribonucleoside analogue that blocks replication of bovine viral diarrhea and hepatitis C viruses 
in culture. Antimicrob Agents Chemother. 2003 Jan;47(1):244–54.  
Toots M, Yoon J-J, Cox RM, Hart M, Sticher ZM, Makhsous N, et al. Characterization of orally 
efficacious influenza drug with high resistance barrier in ferrets and human airway epithelia. Sci 
Transl Med. 2019 Oct 23;11(515):eaax5866.  
Urakova N, Kuznetsova V, Crossman DK, Sokratian A, Guthrie DB, Kolykhalov AA, et al. 
β-d-N4-Hydroxycytidine Is a Potent Anti-alphavirus Compound That Induces a High Level of 
Mutations in the Viral Genome. J Virol. 2018 01;92(3).  
Yoon J-J, Toots M, Lee S, Lee M-E, Ludeke B, Luczo JM, et al. Orally Efficacious 
Broad-Spectrum Ribonucleoside Analog Inhibitor of Influenza and Respiratory Syncytial 
Viruses. Antimicrob Agents Chemother. 2018;62(8). 


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13. 
APPENDICES 
Appendix 1: 
Time and Events Schedule 
Parts 1 and 2 
Visit 
Screening 
(Days -28 to -2) Day -1 Day 1 Day 2 
(24 hr) 
Day 3 
(48 hr) 
Day 4 
(72 hr) Day 9 
Day 15 / EOS1 
(non-FE cohorts) 
Food-Effect Cohort 
Day 14 Day 15 Day 16 
(24 hr) 
Day 17 
(48 hr) 
Day 18 
(72 hr) Day 23 
Day 30 / EOS 
ICF; Demography 
x 
 
 
 
 
 
 
 
I/E; Medical history 
x 
x 
 
 
 
 
 
 
Physical examination2 
x 
x 
 
x 
 
x 
x 
x 
Qualifying laboratory analyses3 
x 
x 
 
 
 
 
 
 
Drug screening and pregnancy test4 
x 
x 
 
 
 
 
x 
x 
Height, weight (BMI) 
x 
 
 
 
 
 
 
 
Clinic confinement5 
 
x 
x 
x 
x 
x 
 
 
Non-residential visit 
x 
 
 
 
 
 
x 
x 
Clinical chemistry and urinalysis6 
x 
x 
 
x 
 
x 
x 
x 
Hematology7 
x 
x 
 
x 
x 
x 
x 
x 
PBMC collection (FE cohort ONLY) 
 
 
x8 
x8 
 
 
 
 
ECG 
x 
 
x9 
 
 
x 
 
x 
Vital signs 
x 
x 
x10 
x 
x 
x 
x 
x 
Administer study drug 
 
 
x 
 
 
 
 
 
Plasma PK sample collection 
 
 
x11 
x12 
x12 
x12 
 
 
Urine PK sample collection 
 
 
x13 
x14 
x14 
 
 
 
Adverse events 
x15 
x15 
x15 
x 
x 
x 
x 
x 
Prior and/or Concomitant medications 
x 
x 
x 
x 
x 
x 
x 
x 
Abbreviations: BMI (body mass index); EOS (End of Study); FE (food-effect); ICF (Informed Consent Form); I/E 
(Inclusion/Exclusion Criteria); ECG (electrocardiogram); PBMC (peripheral blood mononuclear cell); PK (pharmacokinetic). 
1 On Day 15, conduct the EOS visit for all subjects except those in the FE cohort. 
2 A complete PE will be performed at Screening and/or Check-in, and EOS visits; on all other days, a limited PE will be 
conducted targeting any change from the previous status or any body system deemed pertinent to that subject by the PI (or 
designee).  
3 Laboratory analyses to qualify for study entry include: total white cell count or absolute lymphocyte count (values must be in 
the normal range), hemoglobin or platelet levels (values must not be below the lower limit of normal), and ALT/SGPT, alkaline 
phosphatase, AST/SGOT (values must not be above the upper limit of normal), plus virology (HIV/HCV/HBV) (all must be 
negative), and FSH (if required). 
4 Drug screening (urine drug screen, UDS), including a cotinine test, should be conducted at Screening, Day -1, Days 9 and 23, 
and at EOS. Pregnancy tests should be conducted in serum at Screening and in urine at all other times (i.e., Days -1, 9, and 23, 
and EOS). A positive urine pregnancy test will be confirmed with a serum pregnancy test. An alcohol breath test should be 
conducted at Screening and Day -1. 
5 Participants should be admitted to the clinic following review of final I/E criteria on Day -1 and discharged from the clinic 
following completion of study specific assessments on Day 4. Subjects in the FE cohort should be readmitted to the clinic on 
Study Day 14. 
6 Safety laboratory assessments include clinical chemistry and urinalysis. Baseline samples will be collected after clinic 
admission on Day -1.  
7 Hematology values include, but are not limited to, RBC, WBC with differential and platelets. PT/PTT and INR assessed only at 


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Screening. 
8 PBMCs will be collected 2 hr postdose on Day 1/15, and predose and 8 hrs postdose (on Day 16). Depending on ongoing 
review of the data, timepoints may be modified or removed, and up to 2 additional samples may be collected. 
9 The baseline ECG should be conducted prior to dosing on Day 1/15. 
10 Vital signs include pulse rate, respiratory rate, blood pressure, and body temperature; on Day 1/15, VS should be taken 
predose, and at 2, 4, 8 and 12 hr postdose.  
11 PK samples should be collected predose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 9, 12, and 15 hr postdose on Day 1/15. Depending on 
ongoing review of the PK data, timepoints may be modified or removed, and up to 3 additional samples (in each period for the 
food-effect) may be added. 
12 PK samples should be collected at 24, 36, 48, and 72 hr postdose on Days 2/16, 3/17, 4/18 respectively. Depending on ongoing 
review of the PK data, timepoints may be modified or removed, and up to 3 additional samples (in each period for the 
food-effect) may be added. 
13 Urine samples for PK analysis should be collected predose (spot collection), and from 0 to 4, 4 to 8, 8 to 12, and 12 to 24 hr 
postdose. 
14 Urine samples for PK analysis should be collected from 24 to 36 and 36 to 48 hr postdose. 
15 Adverse events occurring prior to study drug administration should be recorded as medical history unless the event is directly 
related to a study specified procedure. 
 
 


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Part 3 (7 Days of Dosing) 
Visit
Screening 
(Days -28 to -2) Day -1 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8 
Day 9 
Day 10 
Day 15 Day 21 / 
EOS 
ICF; Demography 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
I/E; Medical history 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination1 
x 
x 
 
x 
 
 
 
 
 
x 
 
 
x 
x 
Qualifying laboratory 
analyses2 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Drug screening and pregnancy 
test3 
x 
x 
 
 
 
 
 
 
 
 
 
 
x 
x 
Height, weight (BMI) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinic confinement4 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Non-residential visit 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
Clinical chemistry and 
urinalysis5 
x 
x 
 
 
x 
 
 
x 
 
 
 
x 
 
x 
Hematology6 
x 
x 
 
 
x 
 
 
x 
 
 
 
x 
x 
x 
PBMC collection7 
 
 
x 
 
 
 
x 
 
 
 
 
 
 
 
ECG8 
x 
 
x 
 
 
 
 
 
x 
 
 
x 
 
x 
Continuous 12-lead ECG 
 
 
x9 
 
 
 
 
 
x10 
x10 
 
 
 
x 
Vital signs11 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Administer study drug12 
 
 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
Plasma PK sample collection13 
 
 
x 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
Urine PK sample collection14 
 
 
x 
 
 
 
 
 
x 
x 
x 
x 
 
 
Adverse events 
x15 
x15 
x15 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Prior and/or Concomitant 
medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Abbreviations: BID (twice daily); BMI (body mass index); EOS (End of Study); ICF (Informed Consent Form); I/E (Inclusion/Exclusion Criteria); ECG (electrocardiogram); PK 
(pharmacokinetic). 
1 A complete PE will be performed at Screening and/or Check-in, and EOS visits; on all other days, a limited PE will be conducted targeting any change from the previous status or 
any body system deemed pertinent to that subject by the PI (or designee). 
2 Laboratory analyses to qualify for study entry include: total white cell count or absolute lymphocyte count (values must be in the normal range), hemoglobin or platelet levels 
(values must not be below the lower limit of normal), and ALT/SGPT, alkaline phosphatase, AST/SGOT (values must not be above the upper limit of normal), plus virology 


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Version 2.1 (United Kingdom) 
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Protocol Release Date: 06 April 2020  
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Page 88 
(HIV/HCV/HBV) (all must be negative), and FSH (if required). 
3 Drug screening (urine drug screen, UDS), including cotinine, should be conducted at Screening, Day -1, Day 15, and at EOS. Pregnancy tests should be conducted in serum at 
Screening and in urine at all other times (i.e., Days -1 and 15, and EOS). A positive urine pregnancy test will be confirmed with a serum pregnancy test. An alcohol breath test 
should be conducted at Screening and Day -1. 
4 Participants should be admitted to the clinic following review of final I/E criteria on Day -1 and discharged from the clinic following completion of study specific assessments on 
Day 10. 
5 Safety laboratory assessments include clinical chemistry and urinalysis. Baseline samples will be collected after clinic admission on Day -1. On Days 3 and 6, the assessment will 
be pre-am dose. On Day 10, the assessment will be 72 hrs post-am dose on Day 7. 
6 Hematology values include, but are not limited to, RBC, WBC with differential and platelets. PT/PTT and INR assessed only at Screening. 
7 PBMCs will be collected 2 hrs postdose, relative to the first daily dose on Day 1, and pre-am dose and 2 and 8 hrs postdose relative to the first daily dose on Day 5. Depending on 
ongoing review of the data, timepoints may be modified or removed, and up to 2 additional samples may be collected. Additionally, PMBC collection may be omitted from some 
cohorts. 
8 The baseline ECG should be conducted prior to first dosing on Day 1. On Day 1, ECG should be taken predose and 2 hours post-am dose. On Day 7, ECG should be taken 
predose, 2 hrs, and 72 hrs (Day 10) postdose. 
9 On Day 1, monitor for 12-lead ECG recording will be worn from 2 hrs predose to 12 hrs postdose. Extraction timepoints will be 60, 45, and 30 minutes predose and at 0.5, 1, 1.5, 
2, 2.5, 3, 4, 6, 9, and 12 hrs postdose. 
10 On Day 7, monitor for 12-lead ECG recording will be worn from dosing (0 hr) to 25 hrs (Day 8) postdose. Extraction timepoints will be at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 9, 12, and 
24 hrs postdose. 
11 Vital signs include pulse rate, respiratory rate, blood pressure, and body temperature. On Day 1, VS should be taken pre-am dose, and at 2, 4, and 8 hrs post-am dose. On Day 2 
through 6, VS should be taken pre-am dose. On Day 7, VS should be taken predose, and 2, 4, 8, 24 (Day 8), 48 (Day 9), and 72 (Day 10) hrs postdose.  
12 Study drug should be administered BID, 12 hrs apart on Days 1 through 6. On Day 7, study drug should be administered once in the morning only (0 hr).  Depending on ongoing 
review of the safety, tolerability, and PK data, the dosing frequency and the number of days of dosing may be changed; however, the dosing frequency will be no less than 
once-daily or no greater than three-times daily, and the number of days of dosing will be no fewer than 5 days and no greater than 10 days. 
13 On Day 1, PK samples should be collected pre-am dose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 9, and 12 hrs post-am dose. On Days 4 through 6, PK samples should be collected 
pre-am dose. On Day 7, PK samples should be collected predose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 9, 12, 15, 24 (Day 8), 48 (Day 9), 72 (Day 10), and 192 (Day 15) hrs postdose. 
Depending on ongoing review of the PK data, timepoints may be modified or removed, and up to 3 additional samples may be added. 
14 On Day 1, urine samples for PK analysis should be collected predose (spot collection), and from 0 to 4, 4 to 8, and 8 to 12 hrs postdose. On Day 7, urine samples for PK analysis 
should be collected predose (spot collection), and from 0 to 4, 4 to 8, 8 to 12, 12 to 24 (Day 8), 24 to 48 (Day 9), and 48 to 72 hrs (Day 10).  Sampling timepoints may be modified, 
removed, or additional timepoints added depending upon ongoing review of the data. The 12-hour urine collection should occur prior to the second daily dose administration. 
15 Adverse events occurring prior to study drug administration should be recorded as medical history unless the event is directly related to a study specified procedure. 
 


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Part 3 (5 Days of Dosing) 
Visit 
Screening 
(Days -28 to 
-2) 
Day -1 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 Day 13 Day 19 
/EOS 
ICF; Demography 
x 
 
 
 
 
 
 
 
 
 
 
 
I/E; Medical history 
x 
x 
 
 
 
 
 
 
 
 
 
 
Physical examination1 
x 
x 
 
x 
 
 
 
x 
 
 
x 
x 
Qualifying laboratory 
analyses2 
x 
x 
 
 
 
 
 
 
 
 
 
 
Drug screening and 
pregnancy test3 
x 
x 
 
 
 
 
 
 
 
 
x 
x 
Height, weight (BMI) 
x 
 
 
 
 
 
 
 
 
 
 
 
Clinic confinement4 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Non-residential visit 
x 
 
 
 
 
 
 
 
 
 
x 
x 
Clinical chemistry and 
urinalysis5 
x 
x 
 
 
x 
 
x 
 
 
x 
 
x 
Hematology6 
x 
x 
 
 
x 
 
x 
 
 
x 
x 
x 
PBMC collection7 
 
 
x 
 
 
 
x 
 
 
 
 
 
ECG8 
x 
 
x 
 
 
 
x 
 
 
x 
 
x 
Continuous 12-lead ECG 
 
 
x9 
 
 
 
x10 
x10 
 
 
 
x 
Vital signs11 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Administer study drug12 
 
 
x 
x 
x 
x 
x 
 
 
 
 
 
Plasma PK sample 
collection13 
 
 
x 
 
 
x 
x 
x 
x 
x 
x 
 
Urine PK sample 
collection14 
 
 
x 
 
 
 
x 
x 
x 
x 
 
 
Adverse events 
x15 
x15 
x15 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Prior and/or 
Concomitant 
medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Abbreviations: BID (twice daily); BMI (body mass index); EOS (End of Study); ICF (Informed Consent Form); I/E 
(Inclusion/Exclusion Criteria); ECG (electrocardiogram); PK (pharmacokinetic). 
1 A complete PE will be performed at Screening and/or Check-in, and EOS visits; on all other days, a limited PE will be 
conducted targeting any change from the previous status or any body system deemed pertinent to that subject by the PI (or 
designee). 
2 Laboratory analyses to qualify for study entry include: total white cell count or absolute lymphocyte count (values must be in 
the normal range), hemoglobin or platelet levels (values must not be below the lower limit of normal), and ALT/SGPT, alkaline 
phosphatase, AST/SGOT (values must not be above the upper limit of normal), plus virology (HIV/HCV/HBV) (all must be 
negative), and FSH (if required). 
3 Drug screening (urine drug screen, UDS), including cotinine, should be conducted at Screening, Day -1, Day 13, and at EOS. 
Pregnancy tests should be conducted in serum at Screening and in urine at all other times (i.e., Days -1 and 13, and EOS). A 
positive urine pregnancy test will be confirmed with a serum pregnancy test. An alcohol breath test should be conducted at 
Screening and Day -1. 
4 Participants should be admitted to the clinic following review of final I/E criteria on Day -1 and discharged from the clinic 
following completion of study specific assessments on Day 8. 
5 Safety laboratory assessments include clinical chemistry and urinalysis. Baseline samples will be collected after clinic 
admission on Day -1. On Days 3 and 5, the assessment will be pre-am dose. On Day 8, the assessment will be 72 hrs post-am 
dose on Day 5. 
6 Hematology values include, but are not limited to, RBC, WBC with differential and platelets. PT/PTT and INR assessed only at 


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Protocol Release Date: 06 April 2020  
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Screening. 
7 PBMCs will be collected 2 hrs postdose, relative to the first daily dose on Day 1, and pre-am dose and 2 and 8 hrs postdose 
relative to the first daily dose on Day 5. Depending on ongoing review of the data, timepoints may be modified or removed, and 
up to 2 additional samples may be collected. Additionally, PMBC collection may be omitted from some cohorts. 
8 The baseline ECG should be conducted prior to first dosing on Day 1. On Day 1, ECG should be taken predose and 2 hours 
post-am dose. On Day 5, ECG should be taken predose, 2 hrs, and 72 hrs (Day 8) postdose. 
9 On Day 1, monitor for 12-lead ECG recording will be worn from 2 hrs predose to 12 hrs postdose. Extraction timepoints will be 
60, 45, and 30 minutes predose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 9, and 12 hrs postdose. 
10 On Day 5, monitor for 12-lead ECG recording will be worn from dosing (0 hr) to 25 hrs (Day 6) postdose. Extraction 
timepoints will be at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 9, 12, and 24 hrs postdose. 
11 Vital signs include pulse rate, respiratory rate, blood pressure, and body temperature. On Day 1, VS should be taken pre-am 
dose, and at 2, 4, and 8 hrs post-am dose. On Day 2 through 4, VS should be taken pre-am dose. On Day 5, VS should be taken 
predose, and 2, 4, 8, 24 (Day 6), 48 (Day 7), and 72 (Day 8) hrs postdose.  
12 Study drug should be administered BID, 12 hrs apart on Days 1 through 4. On Day 5, study drug should be administered once 
in the morning only (0 hr).  Depending on ongoing review of the safety, tolerability, and PK data, the dosing frequency and the 
number of days of dosing may be changed; however, the dosing frequency will be no less than once-daily or no greater than 
three-times daily, and the number of days of dosing will be no fewer than 5 days and no greater than 10 days. 
13 On Day 1, PK samples should be collected pre-am dose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 9, and 12 hrs post-am dose. On Days 2 
through 4, PK samples should be collected pre-am dose. On Day 5, PK samples should be collected predose and at 0.5, 1, 1.5, 2, 
2.5, 3, 4, 6, 9, 12, 15, 24 (Day 6), 48 (Day 7), 72 (Day 8), and 192 (Day 13) hrs postdose. Depending on ongoing review of the 
PK data, timepoints may be modified or removed, and up to 3 additional samples may be added. 
14 On Day 1, urine samples for PK analysis should be collected predose (spot collection), and from 0 to 4, 4 to 8, and 8 to 12 hrs 
postdose. On Day 5, urine samples for PK analysis should be collected predose (spot collection), and from 0 to 4, 4 to 8, 8 to 12, 
12 to 24 (Day 6), 24 to 48 (Day 7), and 48 to 72 hrs (Day 8).  Sampling timepoints may be modified, removed, or additional 
timepoints added depending upon ongoing review of the data. The 12-hour urine collection should occur prior to the second daily 
dose administration. 
15 Adverse events occurring prior to study drug administration should be recorded as medical history unless the event is directly 
related to a study specified procedure. 
 


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Version 2.1 (United Kingdom) 
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Protocol Release Date: 06 April 2020  
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Appendix 2: 
DMID Toxicity Grading Scale 
Clinical Adverse Events 
VITAL SIGNS 
Mild (Grade 1) 
Moderate Grade 2) 
Severe (Grade 3) 
Fever (°C) Oral temperature; no recent hot or 
cold beverages or smoking. 
38.0 – 38.4 
38.5 – 38.9 
>39.0 
Tachycardia - beats per minute 
101 – 115 
116 – 130 
> 130 or ventricular 
dysrhythmias 
Bradycardia - beats per minute 
50 - 54 or 45 - 50 bpm if 
baseline <60 bpm 
45 - 49 or 40 - 44 if 
baseline <60 bpm 
< 45 or <40 bpm if baseline 
<60 bpm 
Hypertension (systolic) - mm Hg [Assuming 
supine position, 10 min at rest conditions, not 
sleeping subjects, measurements on the same 
arm and several concordant results.] 
 
141 - 150 
 
151 - 160 
 
> 160 
Hypertension (diastolic) - mm Hg 
91 - 95 
96 - 100 
> 100 
Hypotension (systolic) - mm Hg 
85 - 89 
80 - 84 
< 80 
Tachypnea – breaths per minute 
23 - 25 
26 - 30 
>30 
CARDIOVASCULAR 
Grade 1 
Grade 2 
Grade 3 
Arrythmia 
 
asymptomatic, transient 
signs, no Rx required 
recurrent/persistent; 
symptomatic Rx required 
Hemorrhage, Blood Loss 
Estimated blood loss 
< 100 mL 
Estimated blood loss 
> 100 mL, no 
transfusion 
required 
Transfusion required 
RESPIRATORY 
Grade 1 
Grade 2 
Grade 3 
Cough 
Transient-no treatment 
Persistent cough; 
Interferes with daily activities 
Bronchospasm, Acute 
transient; no treatment; 
71-  80% FEV1 of peak 
flow 
requires treatment; 
normalizes with 
bronchodilator; FEV1 
60 - 70% (of peak flow) 
no normalization with 
bronchodilator; FEV1 <60% of 
peak flow 
Dyspnea 
Does not interfere with 
usual and social 
activities 
Interferes with usual 
and social activities, no 
treatment 
Prevents daily and usual social 
activity or requires treatment 
GASTROINTESTINAL 
Grade 1 
Grade 2 
Grade 3 
Nausea 
No interference with 
activity 
Some interference with 
activity 
Prevents daily activities 
Vomiting 
No interference with 
activity or 1 - 2 
episodes/24 hours 
Some interference with 
activity or > 2 
episodes/24 hours 
Prevents daily activity or 
requires IV hydration 
Diarrhea 
2 - 3 loose or watery 
stools or < 400 
gms/24 hours 
4 - 5 loose or watery 
stools or 400 - 800 
gms/24 hours 
6 or more loose or watery 
stools or > 800gms/24 hours or 
requires IV hydration 


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Reactogenicity 
Local reactions 
Grade 1 
Grade 2 
Grade 3 
Pain 
Does not interfere with 
activity 
Repeated use of 
non-narcotic pain 
reliever > 24 hours or 
interferes with activity 
Any use of narcotic pain 
reliever or prevents daily 
activity 
Tenderness 
Discomfort only to touch 
Discomfort with 
movement 
Significant discomfort at rest 
Erythema/Redness * 
2.5 - 5 cm 
5.1 - 10 cm 
> 10 cm 
Induration/Swelling ** 
2.5 - 5 cm and does not 
interfere with activity 
5.1 - 10 cm or interferes 
with activity 
> 10 cm or prevents daily 
activity 
SYSTEMIC 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Allergic Reaction 
pruritus without rash 
localized urticaria 
generalized urticaria; 
angioedema or anaphylaxis 
Headache 
No interference with 
activity 
Repeated use of 
non-narcotic pain 
reliever > 24 hours or 
some interference with 
activity 
Significant; any use of narcotic 
pain reliever or prevents daily 
activity 
Fatigue 
No interference with 
activity 
Some interference with 
activity 
Significant; prevents daily 
activity 
Myalgia 
No interference with 
activity 
Some interference with 
activity 
Significant; prevents daily 
activity 
All Other conditions 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Illness or clinical adverse event (as defined 
according to applicable regulations) 
No interference with 
activity 
Some interference with 
activity not requiring 
medical intervention 
Prevents daily activity and 
requires medical intervention 
*In addition to grading the measured local reaction at the greatest single diameter, the measurement should be recorded as a 
continuous variable. 
**Induration/Swelling should be evaluated and graded using the functional scale as well as the actual 
measurement 
 
 


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Laboratory Adverse Events 
Blood, Serum, or Plasma * 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Sodium – Hyponatremia mEq/L 
132 – <LLN 
130 – 131 
<130 
Sodium – Hypernatremia mEq/L 
>ULN – 148 
149 – 150 
>150 
Potassium – Hyperkalemia mEq/L 
>ULN – 5.2 
5.3 – 5.4 
>5.4 
Potassium – Hypokalemia mEq/L 
<LLN-3.1 
<3.1 – 3.0 
<3.0 
Glucose – Hypoglycemia mg/dL 
65 – 67 
55 – 64 
<55 
Glucose – Hyperglycemia Fasting – mg/dL 
>ULN - 120 
121 – 130 
>130 
Glucose – Hyperglycemia Random – mg/dL 
140 – 159 
160 – 200 
>200 
Blood Urea Nitrogen mg/dL 
23-26 
27 – 31 
> 31 
Creatinine – mg/dL 
>ULN – 1.7 
1.8 – 2.0 
>2.0 
Calcium – hypocalcemia mg/dL 
8.0 – <LLN 
7.5 – 7.9 
<7.5 
Calcium – hypercalcemia mg/dL 
>ULN – 11.0 
11.1 – 11.5 
>11.5 
Magnesium – hypomagnesemia mg/dL 
1.3 – 1.5 
1.1 – 1.2 
<1.1 
Phosphorus – hypophosphatemia mg/dL 
2.3 – 2.5 
2.0 – 2.2 
<2.0 
CPK – mg/dL 
400-1000 
1001-1500 
>1500 
Albumin – Hypoalbuminemia g/dL 
2.8 – 3.0 
2.5 – 2.7 
< 2.5 
Total Protein – Hypoproteinemia g/dL 
5.2 – 5.4 
4.8 – 5.1 
< 4.8 
Alkaline phosphate – U/L 
132-240 
241– 360 
>360 
AST U/L 
44 – 105 
106-175 
>175 
ALT U/L 
44 – 105 
106-175 
>175 
Bilirubin (serum total) mg/dL 
1.3 - 2.0 
2.1 - 2.5 
> 2.5 
Bilirubin – when ALT >105 (Hy's law) 
1.3 -1.5 
1.6 – 2.0 
> 2.0 
Amylase- U/L 
200-270 
271-360 
>360 
Lipase- U/L 
176-270 
271-360 
>360 
Hemoglobin (Female) - g/dL 
11.0 – 11.5 
9.5 – 10.9 
< 9.5 
Hemoglobin (Male) - g/dL 
12.0 – 12.5 
10.0 – 11.9 
<10.0 
WBC Increase - cell/mm3 
11,001 – 15,000 
15,001 – 20,000 
> 20,000 
WBC Decrease - cell/mm3 
2,500 – 3,500 
1,500 – 2,499 
< 1500 
Lymphocytes Decrease - cell/mm3 
750 – 1,000 
500 – 749 
< 500 
Neutrophils Decrease - cell/mm3 
1,500 – 2,000 
1,000 – 1,499 
< 1000 
Eosinophils - cell/mm3 
500-750 
751-1500 
> 1500 
Platelets Decreased - cell/mm3 
120,000 – 130,000 
100,000 – 119,999 
<100,000 
PT – seconds (prothrombin time) 
> ULN-14.4 
14.5 – 15.7 
> 15.7 
PTT – seconds (partial thromboplastin time) 
>ULN-42.1 
42.2– 50.0 
> 50.0 
Fibrinogen increase - mg/dL 
>ULN – 500 
501 – 600 
> 600 
Fibrinogen decrease - mg/dL 
<LLN – 140 
125 – 139 
<125 
Urine * 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Protein 
1+ 
2+ 
>2+ 
Glucose 
1+ 
2+ 
>2+ 
Blood (microscopic) - red blood cells per high 
power field (rbc/hpf) 
5-10 
11-50 
> 50 and/or gross 
blood 
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal parameters. 
* Institutional normal reference ranges should be provided to demonstrate that they are appropriate. 
 


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Appendix 3: 
Contraception Guidance 
Male subjects (even with a history of vasectomy) with partners of childbearing potential must 
use a male barrier method of contraception (i.e., male condom with spermicide) in addition to a 
second method of acceptable contraception from Check-in until 90 days after the EOS visit. 
Acceptable methods of contraception for female partners include: 
 hormonal injection 
 combined oral contraceptive pill or progestin/progestogen-only pill 
 combined hormonal patch 
 combined hormonal vaginal ring 
 surgical method (bilateral tubal ligation or Essure® [hysteroscopic bilateral tubal 
occlusion])  
 hormonal implant 
 hormonal or non-hormonal intrauterine device 
 OTC sponge with spermicide 
 cervical cap with spermicide 
 diaphragm with spermicide. 
An acceptable second method of contraception for male subjects is vasectomy that has been 
performed at least 90 days prior to the screening visit, with verbal confirmation of surgical 
success. 
For male subjects (even with a history of vasectomy), sexual intercourse with female partners 
who are pregnant or breastfeeding should be avoided unless condoms are used from the time of 
the first dose until 90 days after the EOS visit. Male subjects are required to refrain from 
donation of sperm from Check-in until 90 days after the EOS visit. 
Sexual Abstinence and Same-sex Relationships 
Subjects who practice true abstinence, because of the subject’s lifestyle choice (i.e., the subject 
should not become abstinent just for the purpose of study participation), are exempt from 
contraceptive requirements. Periodic abstinence (eg, calendar, ovulation, symptothermal, 
postovulation methods) and withdrawal are not acceptable methods of contraception. If a subject 
who is abstinent at the time of signing the ICF becomes sexually active they must agree to use 
contraception as described previously. 


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For subjects who are exclusively in same-sex relationships, contraceptive requirements do not 
apply. If a subject who is in a same-sex relationship at the time of signing the ICF becomes 
engaged in a heterosexual relationship, they must agree to use contraception as described 
previously. 


Protocol Reference: EIDD-2801-1001-UK 
 CONFIDENTIAL  
 
 
 
 
 
 
 
Title of study: A Randomized, Double-blind, Placebo-controlled, First-in-human Study 
Designed to Evaluate the Safety, Tolerability, and Pharmacokinetics of EIDD-2801 
Following Oral Administration to Healthy Volunteers 
NCT Number: NCT04392219 
 
Document: Protocol, Version 3.1 
Date: 13 April 2020 
 


Clinical Study Protocol: EIDD-2801-1001-UK 
Version 3.1 (United Kingdom) 
Ridgeback Biotherapeutics 
Protocol Release Date: 13 April 2020 
Confidential 
Page 1 
A Randomized, Double-Blind, Placebo-Controlled, First-in-Human 
Study Designed to Evaluate the Safety, Tolerability, and 
Pharmacokinetics of EIDD-2801 Following Oral Administration to 
Healthy Volunteers 
(EIDD-2801-1001-UK) 
Protocol Version 3.1 (United Kingdom) 
Version Date 
13 April 2020 
Sponsor Team: 
Ridgeback Biotherapeutics 
3162 Commodore Plaza, Suite 3E 
Miami, FL 33133-5815 
United States 
Medical Officer 
 
EudraCT Number 
2020-001407-17 
Confidential Information: The information contained in this document is the property of 
Ridgeback Biotherapeutics and may not be reproduced, published or disclosed to others without 
written authorization from Ridgeback Biotherapeutics. 


Clinical Study Protocol: EIDD-2801-1001-UK 
Version 3.1 (United Kingdom) 
Ridgeback Biotherapeutics 
Protocol Release Date: 13 April 2020  
Confidential 
Page 2 
SUMMARY OF CHANGES 
Changes from Version 1.1 (United Kingdom) to Version 2.1 (United Kingdom). 
The primary reason for this amendment was to include Part 3, a multiple ascending dose study of 
EIDD-2801 in healthy subjects. Additionally, the following updates were made: 
 Results of an in vivo micronucleus assay were added. 
 The guidelines used to assess the severity of adverse events not presented in the DMID 
Toxicity Grading Scale were updated, specifically those that were life-threatening or led 
to death. 
 The timepoints for collection of peripheral blood mononuclear cells in Part 2 were 
modified. 
 Minor clarifications were made and typographical errors were corrected. 
Changes from Version 2.1 (United Kingdom) to Version 3.1 (United Kingdom). 
 Clarified that this study will be conducted at 1 site in the United Kingdom and up to 
3 sites in the United States, and that integrated data across all sites will be used for 
dose-escalation decisions. 
 The number of cohorts initially planned for Part 1 (single ascending dose) has been 
reduced from 4 to 3. 
 The number of days of dosing in Part 3 (multiple ascending dose) was decreased from 
7 days to 5.5 days. However, the number of days of dosing may be further reduced 
depending on ongoing review of the safety, tolerability, and pharmacokinetic data. 
 Added a rationale for the appropriateness of a 4-day interval between dose escalations. 
 Added a dose-escalation stopping criteria for reductions in platelets and lymphocytes. 
 Clarified that assessments of human immunodeficiency virus, hepatitis B virus, and 
hepatitis C virus will only be conducted at Screening. 
 Minor clarification and typographical corrections. 


Clinical Study Protocol: EIDD-2801-1001-UK 
Version 3.1 (United Kingdom) 
Ridgeback Biotherapeutics 
Protocol Release Date: 13 April 2020  
Confidential 
Page 3 
STATEMENT OF COMPLIANCE 
The study will be carried out in accordance with Good Clinical Practice (GCP) as required by the 
following: 
 Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines. 
 Applicable International Conference on Harmonisation (ICH) GCP Guidelines. 
 United States Code of Federal Regulations (CFR) applicable to clinical studies 
(45 CFR Part 46; 21 CFR Part 50, 21 CFR Part 56, and 21 CFR Part 312). 
 Applicable laws and regulations. 


Clinical Study Protocol: EIDD-2801-1001-UK 
Ridgeback Biotherapeutics 
Version 3.1 (United Kingdom) 
Protocol Release Date: 13 April 2020 
SIGNATURE PAGE 
The signature below constitutes the approval of this protocol and the attachments and provides 
the necessary assurances that this study will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable regulations and ICH guidelines. 
:::;•! 
Executive Medical Director 
Covance Clinical Research Unit Limited 
Confidential 
Date: 
Page 4 


Clinical Study Protocol: EIDD-2801-1001-UK 
Version 3.1 (United Kingdom) 
Ridgeback Biotherapeutics 
Protocol Release Date: 13 April 2020  
Confidential 
Page 5 
TABLE OF CONTENTS 
SUMMARY OF CHANGES .......................................................................................................... 2 
STATEMENT OF COMPLIANCE ................................................................................................. 3 
SIGNATURE PAGE ...................................................................................................................... 4 
TABLE OF CONTENTS ............................................................................................................... 5 
LIST OF TABLES ......................................................................................................................... 9 
LIST OF FIGURES ..................................................................................................................... 10 
LIST OF APPENDICES .............................................................................................................. 11 
ABBREVIATIONS ...................................................................................................................... 12 
PROTOCOL SYNOPSIS ............................................................................................................ 15 
1. INTRODUCTION ................................................................................................................... 25 
1.1. 
Background ............................................................................................................... 25 
1.2. 
Rationale for Development ........................................................................................ 25 
1.3. 
Nonclinical Overview ................................................................................................. 26 
1.3.1. Mechanism of Action ................................................................................................. 26 
1.3.2. In Vitro Pharmacology ............................................................................................... 27 
1.3.2.1. 
Antiviral Activity in Tissue Culture and in Human Airway Epithelium ............. 27 
1.3.2.2. 
Cytotoxicity of EIDD-1931 in Tissue Culture Utilizing Cells from Different 
Organs and Species ...................................................................................... 29 
1.3.2.3. 
Assessment of Mitochondrial Toxicity ............................................................ 29 
1.3.3. In Vivo Pharmacology ............................................................................................... 29 
1.3.3.1. 
Coronavirus: SARS-CoV and MERS-CoV ..................................................... 29 
1.3.3.2. 
Influenza Virus ............................................................................................... 33 
1.3.3.3. 
Venezuelan Equine Encephalitis Virus .......................................................... 34 
 
 
1.4. 
Safety and Secondary Pharmacology ....................................................................... 34 
1.5. 
Nonclinical Pharmacokinetics and Metabolism ......................................................... 34 
1.5.1. Overview ................................................................................................................... 34 
1.5.2. Absorption ................................................................................................................. 34 
1.5.3. Distribution ................................................................................................................ 35 
 
 
1.5.3.2. 
Tissue Distribution Studies ............................................................................ 35 
1.5.4. Metabolism ................................................................................................................ 36 
1.5.4.1. 
Metabolic Stability of EIDD-1931 and EIDD-2801 ......................................... 36 
1.5.4.2. 
Uptake and Anabolism of EIDD-1931 in Tissue Culture and Primary Cells ... 37 
1.5.5. Excretion ................................................................................................................... 38 
1.5.6. Pharmacokinetic Drug Interactions ........................................................................... 38 
1.5.6.1. 
Cytochrome P450 (CYP) Inhibition ................................................................ 38 
1.5.6.2. 
CYP Induction ................................................................................................ 38 
 
 
 
 
 
 


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1.7. 
Potential Risks and Benefits ...................................................................................... 44 
1.7.1. Potential Benefits ...................................................................................................... 44 
1.7.2. Potential Risks ........................................................................................................... 44 
2. OBJECTIVES ....................................................................................................................... 45 
2.1. 
Study Objectives ....................................................................................................... 45 
2.1.1. Primary Objectives .................................................................................................... 45 
2.1.2. Secondary Objectives ............................................................................................... 45 
2.1.3. Exploratory Objectives .............................................................................................. 45 
2.2. 
Study Outcome Measures ......................................................................................... 45 
2.2.1. Primary Outcome Measures ...................................................................................... 45 
2.2.2. Secondary Outcome Measures ................................................................................. 45 
3. STUDY DESIGN ................................................................................................................... 47 
3.1. 
Overview ................................................................................................................... 47 
3.1.1. Part 1 (Single Ascending Dose) ................................................................................ 47 
3.1.2. Part 2 (Food-Effect) ................................................................................................... 48 
3.1.3. Part 3 (Multiple Ascending Dose) .............................................................................. 48 
3.2. 
Rationale and Justification ........................................................................................ 49 
3.2.1. Justification of Design ............................................................................................... 49 
3.2.2. Justification of Starting Dose ..................................................................................... 49 
3.2.3. Justification of Study Population ............................................................................... 50 
4. STUDY POPULATION ......................................................................................................... 51 
4.1. 
Subject Inclusion Criteria ........................................................................................... 51 
4.2. 
Subject Exclusion Criteria ......................................................................................... 52 
5. STUDY MEDICATION, RANDOMIZATION AND DOSE ADMINISTRATION ...................... 54 
5.1. 
Study Drug Description ............................................................................................. 54 
5.1.1. Acquisition, Formulation, Packaging and Labeling .................................................... 54 
5.1.2. Product Storage and Stability .................................................................................... 54 
5.2. 
Randomization .......................................................................................................... 54 
5.3. 
Dosage, Preparation and Administration of Study Drug ............................................ 55 
5.4. 
Drug Accountability ................................................................................................... 55 
5.5. 
Concomitant Medication/Treatments ......................................................................... 55 
6. STUDY CONDUCT AND VISIT SCHEDULE ....................................................................... 57 
6.1. 
Study Conduct ........................................................................................................... 57 
6.1.1. Study Windows and Rounding Principles .................................................................. 57 
6.1.2. Restrictions ................................................................................................................ 57 
6.2. 
Screening .................................................................................................................. 58 


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6.2.1. Screening Visit .......................................................................................................... 58 
6.2.2. Retesting Procedures ................................................................................................ 59 
6.2.3. Study Visits ................................................................................................................ 59 
6.2.4. Part 1 (Single Ascending Dose) ................................................................................ 59 
6.2.5. Part 2 (Food-Effect) ................................................................................................... 59 
6.2.6. Part 3 (Multiple Ascending Dose) .............................................................................. 59 
6.3. 
Safety Follow-up and End-of-Study Visit ................................................................... 59 
6.4. 
Subject Withdrawal and Replacement ...................................................................... 60 
6.4.1. Reasons for Withdrawal ............................................................................................ 60 
6.4.2. Handling of Withdrawals ............................................................................................ 61 
6.4.3. Documentation of Withdrawals .................................................................................. 61 
6.4.4. Subject Replacement ................................................................................................ 61 
6.5. 
Unscheduled Visit(s) ................................................................................................. 61 
7. STUDY PROCEDURES/EVALUATIONS ............................................................................. 63 
7.1. 
Demography and Medical History ............................................................................. 63 
7.2. 
Clinical Evaluations ................................................................................................... 63 
7.2.1. Physical Examinations .............................................................................................. 63 
7.2.2. Vital Sign Measurements and ECGs ......................................................................... 63 
7.2.2.1. 
Continuous 12-lead ECG Monitoring (Part 3 Only) ........................................ 64 
7.2.3. Adverse Events and Concomitant Medications ......................................................... 64 
7.3. 
Laboratory Evaluations .............................................................................................. 64 
7.3.1. Routine Laboratory Panels ........................................................................................ 64 
7.3.2. Pharmacokinetic Sampling ........................................................................................ 66 
7.3.3. Peripheral Blood Mononuclear Cell Collection .......................................................... 67 
7.3.4. Urine Collection ......................................................................................................... 67 
8. SAFETY MONITORING, MANAGEMENT AND REPORTING ............................................ 68 
8.1. 
Definitions .................................................................................................................. 68 
8.1.1. Adverse Events ......................................................................................................... 68 
8.1.2. Serious Adverse Events ............................................................................................ 68 
8.2. 
Documenting Adverse Events ................................................................................... 69 
8.2.1. Timeframe for Collection and Follow-up of AEs/SAEs .............................................. 69 
8.2.2. Recording of Adverse Events/Serious Adverse Events ............................................ 70 
8.2.3. Assessing Severity of Adverse Events ...................................................................... 70 
8.2.4. Relationship to Study Drug ........................................................................................ 71 
8.2.5. Classifying Adverse Event Outcome ......................................................................... 71 
8.3. 
Reporting Procedures ................................................................................................ 72 
8.3.1. Serious Adverse Events ............................................................................................ 72 
8.3.2. Pregnancy ................................................................................................................. 72 
8.4. 
Unmasking Treatment Assignment ........................................................................... 73 
9. DOSE-ESCALATION AND HALTING RULES..................................................................... 74 
9.1. 
Guidelines for Dose-Escalation ................................................................................. 74 
9.2. 
Dose-Escalation Halting Rules .................................................................................. 75 
10. STATISTICAL CONSIDERATIONS ..................................................................................... 76 
10.1. 
General Considerations ............................................................................................. 76 


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Ridgeback Biotherapeutics 
Protocol Release Date: 13 April 2020  
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10.2. 
Sample Size Considerations ..................................................................................... 76 
10.3. 
Analysis Populations ................................................................................................. 76 
10.4. 
Analysis of Safety Data ............................................................................................. 76 
10.4.1. Extent of Exposure .................................................................................................... 76 
10.4.2. Adverse Events ......................................................................................................... 77 
10.4.3. Clinical Laboratory Results ........................................................................................ 77 
10.4.4. Other Parameters ...................................................................................................... 77 
10.5. 
Analysis of Pharmacokinetic Data ............................................................................. 77 
10.5.1. Statistical Analysis of Pharmacokinetic Data ............................................................ 79 
10.5.1.1. Dose Proportionality ...................................................................................... 79 
10.5.1.2. Food-Effect .................................................................................................... 79 
10.6. 
Peripheral Blood Mononuclear Cells ......................................................................... 79 
10.7. 
Interim Analyses ........................................................................................................ 79 
11. STUDY ADMINISTRATION .................................................................................................. 80 
11.1. 
Regulatory and Ethical Considerations ..................................................................... 80 
11.2. 
Ethical Standard ........................................................................................................ 80 
11.2.1. Ethics Committee Approval ....................................................................................... 80 
11.2.2. Informed Consent ...................................................................................................... 80 
11.3. 
Financing and Insurance ........................................................................................... 81 
11.4. 
Source Documentation and Access .......................................................................... 81 
11.5. 
Data Collection and Record Keeping ........................................................................ 81 
11.5.1. Data Collection .......................................................................................................... 81 
11.5.2. Study Records Retention .......................................................................................... 82 
11.5.3. Protocol Deviations ................................................................................................... 82 
11.6. 
Clinical Monitoring ..................................................................................................... 82 
11.7. 
Quality Control and Quality Assurance ..................................................................... 82 
11.8. 
Study Termination and Closure Procedures.............................................................. 83 
11.8.1. Study Termination ..................................................................................................... 83 
11.8.2. Termination Procedures ............................................................................................ 83 
11.9. 
Information Disclosure ............................................................................................... 83 
11.9.1. Confidentiality ............................................................................................................ 83 
11.9.2. Clinicaltrials.gov ........................................................................................................ 84 
11.9.3. Publication Policy ...................................................................................................... 84 
12. REFERENCES ...................................................................................................................... 85 
13. APPENDICES ....................................................................................................................... 86 
 


Clinical Study Protocol: EIDD-2801-1001-UK 
Version 3.1 (United Kingdom) 
Ridgeback Biotherapeutics 
Protocol Release Date: 13 April 2020  
Confidential 
Page 9 
LIST OF TABLES 
Table 1: 
EIDD-1931 Antiviral Activity Against Influenza A and B Viruses in Tissue Culture and 
Primary Human Bronchial/Tracheal Epithelial Cells ................................................. 27 
Table 2: 
EIDD-1931 Antiviral Activity Against SARS and MERS Coronaviruses in Tissue 
Culture and Primary Human Bronchial/Tracheal Epithelial Cells ............................. 28 
Table 3: 
EIDD-1931 Antiviral Activity Against Togaviruses in Tissue Culture ........................ 28 
 
 
Table 5: 
Cytotoxicity (CC50) of EIDD-1931 in Mammalian Cell Lines .................................... 29 
Table 6: 
Metabolic Stability of EIDD-2801 in Plasma and Liver Microsomes ......................... 37 
Table 7: 
Metabolic Stability of EIDD-2801 in Simulated Gastric and Intestinal Fluids and in 
Buffered Saline with Fetal Bovine Serum ................................................................. 37 
Table 8: 
Metabolic Stability of EIDD-1931 in Plasma, Whole Blood and Liver and Intestinal 
Microsomes .............................................................................................................. 37 
 
 
 
Table 10: Allowable Time Windows for Study Assessments/Visits .......................................... 57 
Table 11: Laboratory Evaluations ............................................................................................. 66 
Table 12: Adverse Event Outcomes ......................................................................................... 71 
Table 13: Pharmacokinetic Parameters ................................................................................... 78 
 


Clinical Study Protocol: EIDD-2801-1001-UK 
Version 3.1 (United Kingdom) 
Ridgeback Biotherapeutics 
Protocol Release Date: 13 April 2020  
Confidential 
Page 10 
LIST OF FIGURES 
Figure 1: 
Study Schema .......................................................................................................... 24 
Figure 2: 
Inhibition of SARS-CoV-2 by EIDD-1931 ................................................................. 28 
Figure 3: 
EIDD-2801 Prophylactic Treatment of SARS-CoV Infected Mice ............................ 30 
Figure 4: 
EIDD-2801 Treatment of SARS-CoV Infected Mice ................................................. 31 
Figure 5: 
EIDD-2801 Prophylactic Treatment of MERS-CoV Infected Mice ............................ 32 
Figure 6: 
EIDD-2801 Treatment of MERS-CoV Infected Mice ................................................ 33 
Figure 7: 
Tissue Distribution of EIDD-1931 and EIDD-2061 in Ferret Brain and Lung ............ 36 
 
 


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LIST OF APPENDICES 
Appendix 1: 
Time and Events Schedule ............................................................................ 86 
Appendix 2: 
DMID Toxicity Grading Scale ......................................................................... 90 
Appendix 3: 
Contraception Guidance ................................................................................ 93 


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ABBREVIATIONS 
AE 
adverse event 
AGP 
alpha1-acid glycoprotein 
ALT/SGPT 
alanine aminotransferase/serum glutamic pyruvic transaminase 
AST/SGOT 
aspartate aminotransferase/serum glutamic oxaloacetic transaminase 
AUC 
area under the curve 
BID 
twice-daily 
BMI 
body mass index 
CDC 
Centers for Disease Control and Prevention 
CEM 
a cell line of lymphoblastic cells derived from a child with leukemia 
CFR 
Code of Federal Regulations 
CHKV 
Chikungunya virus 
CI 
confidence interval 
CoV 
coronavirus 
CRF 
case report form 
CTP 
cytosine triphosphate cytidine triphosphate 
CYP 
cytochrome P450 
DMID 
Division of Microbiology and Infectious Diseases 
DMSO 
dimethylsulfoxide 
DPP4 
dipeptidyl peptidase 4 
DRF 
dose range finding 
DSS 
Drug Safety Services 
EBOV 
Ebola virus 
EC 
Ethics Committee 
EC50 
Half-maximal effective concentration 
ECG 
electrocardiogram 
EEEV 
Eastern equine encephalitis virus 
EIDD 
Emory Institute for Drug Development 
EOS 
End of Study 
FDA 
Food and Drug Administration 
FE 
food-effect 
FIH 
first-in- human 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
GLP 
Good Laboratory Practice 


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HAE 
human airway epithelium 
HBV 
hepatitis b virus 
hBTEC 
human bronchial/tracheal epithelial cells 
HCV 
hepatitis c virus 
HED 
human equivalent dose 
HEENT 
head, eye, ear, nose and throat 
HIV 
human immunodeficiency virus 
HPMC 
hydroxypropyl methylcellulose 
IAV 
influenza a virus 
IB 
Investigator’s Brochure 
IBV 
influenza b virus 
IC50 
half maximal inhibitory concentration 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
MAD 
multiple ascending dose 
MDCK 
Madin-Darby Canine Kidney Cells 
MedDRA 
Medical Dictionary for Regulatory Activities 
MERS 
Middle East respiratory syndrome 
%MN-PCE 
percentage of micronuclei-polychromatic erythrocytes 
MRSD 
maximum recommended starting dose 
MTD 
maximum tolerated dose 
NOAEL 
no-observed-adverse-effect-level 
NSAID 
nonsteroidal anti-inflammatory drug 
OTC 
over-the-counter 
PBMC 
peripheral blood mononuclear cells 
PBO 
placebo 
PCE:TE 
polychromatic erythrocytes to total erythrocytes 
PE 
physical examination 
PI 
principal investigator 
 
 
PK 
pharmacokinetic 
QTc(F) 
QT interval corrected for heart rate (using Fridericia’s formula) 
RNA 
ribonucleic acid 
RSV 
respiratory syncytial virus 
SAD 
single ascending dose 
SAE 
serious adverse event 


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SAP 
statistical analysis plan 
SARS 
severe acute respiratory syndrome 
SI 
selectivity index 
SOP 
standard operating procedure 
UTP 
uridine 5'-triphosphate 
VEEV 
Venezuelan equine encephalitis virus 
ZIKV 
Zika virus 


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PROTOCOL SYNOPSIS 
Sponsor: Ridgeback Biotherapeutics 
Title: A Randomized, Double-Blind, Placebo-Controlled, First-in-Human Study Designed to 
Evaluate the Safety, Tolerability, and Pharmacokinetics of EIDD-2801 Following Oral 
Administration to Healthy Volunteers (EIDD-2801-1001-UK) 
Short Title: EIDD-2801-1001-UK 
Development Phase: Phase 1 
Study Sites: This study will be conducted at 1 site in the United Kingdom and up to 3 sites in 
the United States. 
Description of Study Drugs, Dose and Mode of Administration: EIDD-2801 and matching 
placebo (PBO) will be supplied 
 
  
Part 1: A single oral dose of EIDD-2801 or PBO will be administered to subjects enrolled in 
Part 1 (P1; single ascending dose [SAD]) cohorts. The starting dose in the first SAD cohort will 
be 50 mg. The doses will be administered in an escalating manner. Dose levels will not increase 
by more than 3-fold for predicted nonpharmacologically active dose levels and by 2-fold for 
predicted pharmacologically active dose levels.
 
 
 
Part 2: Subjects in Part 2 (P2)/food-effect (FE) will receive 2 single doses of EIDD-2801 with a 
14-day (minimum) washout period between doses. The dose for the P2 cohort is planned to be 
100 mg but may be adjusted based on safety, tolerability, and/or pharmacokinetic (PK) data from 
P1. In any case, the dose assessed in P2 will have been given previously to subjects in a P1 
cohort successfully (i.e., no halting rules were met following dosing). 
Part 3: Multiple doses of EIDD-2801 or PBO will be administered to subjects enrolled in Part 3 
(P3; multiple ascending dose [MAD]) cohorts. Subjects will receive twice-daily (BID) doses for 
5 days, with a single dose administered on the morning of Day 6 for collection of steady-state 
PK samples during waking hours. The total daily dose will not exceed a dose shown to be safe 
and well-tolerated in P1. Doses in P3 may be administered in the fed state, following review of 
the PK data from P2. Additionally, depending on ongoing review of the safety, tolerability, and 
PK data, the number of days of dosing may be reduced and the dosing frequency may be 
changed; the dosing frequency will be no less than once-daily or no greater than three-times 
daily. 
Treatment Duration:  
Part 1: Subjects enrolled into P1/SAD cohorts will receive a single dose of study drug 
(EIDD-2801 or matching PBO).  
Part 2: Subjects enrolled into the P2/FE cohort will receive 2 single doses of EIDD-2801, with a 
washout period between doses. 
Part 3: Subjects in P3/MAD cohorts will receive study drug (EIDD-2801 or matching PBO) for 
5 days BID followed by a single dose of EIDD-2801 or PBO on Day 6. Depending on ongoing 
review of the safety, tolerability, and PK data, the number of days of dosing may be reduced. 


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Subject Duration:  
Part 1: The maximum possible study duration for participants enrolled in P1/SAD cohorts will 
be approximately 43 days. 
Part 2: The maximum possible study duration for participants enrolled in the P2/FE cohort will 
be approximately 58 days. 
Part 3: The maximum possible study duration for participants enrolled in P3/MAD will be 
approximately 48 days. 
Objectives and Endpoints: 
Part 1: SAD Cohorts 
Primary: 
 
Objective: To determine the safety and tolerability of single ascending doses of EIDD-2801. 
o Endpoints:  
 
Results of safety evaluations including safety laboratory assessments, 
physical examination (PE), electrocardiograms (ECGs), vital signs, and 
adverse events (AEs). 
Secondary: 
 
Objective: To define PK of EIDD-2801 and EIDD-1931 in plasma and urine following 
single doses administered to healthy volunteers. 
o Endpoints: 
 
Plasma PK parameters, including Cmax, tmax, t1/2, CL/F, λz, Vz/F, AUC0-inf 
and AUClast as appropriate 
 
Urinary excretion of EIDD-2801 and EIDD-1931 following single-dose 
administration. 
Part 2: Single-Dose Food-Effect 
Primary: 
 
Objective: To assess the effect of food on the PK of EIDD-2801 and EIDD-1931 following 
a single oral dose. 
o Endpoints: 
 
Plasma PK parameters, including Cmax, tmax, t1/2, CL/F, λz, Vz/F, AUC0-inf 
and AUClast as appropriate 
 
Urinary excretion of EIDD-2801 and EIDD-1931 following single-dose 
administration. 
Secondary: 
 
Objective: To determine the safety and tolerability of single doses of EIDD-2801. 
o Endpoints: 
 
Results of safety evaluations, including safety laboratory assessments, PEs, 
ECG, vital signs, and AEs. 
Part 3: MAD Cohorts 
Primary: 
 
Objective: To determine the safety and tolerability of multiple ascending doses of 
EIDD-2801. 


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o Endpoints: 
 
Results of safety evaluations, including safety laboratory assessments, PE, 
ECGs, vital signs, and AEs. 
Secondary: 
 
Objective: To define PK of EIDD-2801 and EIDD-1931 in plasma and urine following 
multiple doses administered to healthy volunteers. 
o Endpoints: 
 
Plasma PK parameters, including Ctrough, Cmax, tmax, t1/2, CL/F, λz, Vz/F, 
AUC0-inf (Day 1 dose only), AUCτ, RAAUCτ, and RACmax as appropriate 
 
Urinary excretion of EIDD-2801 and EIDD-1931 following multiple-dose 
administration. 
Exploratory: 
 
Objective: To collect data to assess the relationship between 
EIDD-2801/EIDD-1931 concentrations and QT interval corrected for heart 
rate (QTc). 
Population:  
Part 1: P1/SAD cohorts will include 8 subjects each, 2 randomized to receive PBO and 
6 randomized to receive EIDD-2801. Initially, 3 SAD cohorts are planned for P1 with the option 
to add an additional 3 cohorts based on study results. 
Part 2: Ten subjects will be enrolled into the P2/FE cohort; all subjects enrolled in the P2 cohort 
will receive EIDD-2801. One P2 cohort is planned for the study. If PK results obtained are 
equivocal, additional subjects may be enrolled into the P2 cohort at the previously tested dose or 
an additional P2 cohort may be added at a different dose.  
Part 3: P3/MAD cohorts will include 8 subjects, 2 randomized to receive PBO and 
6 randomized to receive EIDD-2801. Initially, 3 MAD cohorts are planned for P3 with the 
option to add an additional 3 cohorts based on study results. However, the number of cohorts 
may be reduced if the study objectives are met. Dose levels in P3 may be repeated for collection 
of peripheral blood mononuclear cells (PBMCs), providing that the dose level did not meet the 
dose-escalation halting criteria. 
The site is strongly encouraged to ensure that women are represented in each cohort. Inclusion 
and exclusion criteria for study participation are as follows: 
Inclusion Criteria: subjects who meet all of the criteria at Screening will be eligible for study 
participation 
1. Male or female between the ages of 18 and 60, inclusive. 
2. Female subjects must be of nonchildbearing potential. Nonchildbearing potential is 
defined as women who: 
• 
are physiologically incapable of becoming pregnant including those who are 
surgically sterile, via hysterectomy, bilateral salpingectomy, and/or bilateral 
oophorectomy by reported medical history and/or medical records. Surgical 
sterilization to have occurred a minimum of 6 weeks, or at the Principal 
Investigator’s (PI’s; or designee’s) discretion, prior to Screening. 
• 
are postmenopausal (at least 45 years of age with amenorrhea for 12 months 


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without an alternative medical reason with confirmatory follicle stimulating 
hormone (FSH) levels of ≥ 40 mIU/mL. The amenorrhea should not be induced 
by a medical condition such as anorexia nervosa, hypothyroid disease or 
polycystic ovarian disease, or by extreme exercise. It should not be due to 
concomitant medications that may have induced the amenorrhea such as oral 
contraceptives, hormones, gonadotropin-releasing hormones, anti-estrogens, or 
selective estrogen receptor modulators). 
3. Male participants must agree to the use of effective contraception for study duration, 
i.e., from Check-in until 90 days following the last dose of study drug. 
4. Is in generally good health as determined by medical history, PE (at Screening and/or 
Check-in), vital signs, and other screening procedures. 
5. Has a body mass index (BMI) of 18 to 30 kg/m2. 
6. Is willing and able to comply with all study procedures including providing informed 
consent. 
Exclusion Criteria: subjects who meet any of the following criteria at Screening (unless 
otherwise stated) will not be eligible for participation 
1. Females who are pregnant, planning to become pregnant, or breastfeeding. 
2. Has a clinically relevant acute or chronic medical condition or disease of the 
cardiovascular, gastrointestinal (GI), hepatic, renal, endocrine, pulmonary, neurologic, 
or dermatologic systems as determined by the PI (or designee). 
3. Has any current or historical disease or disorder of the hematological system or 
significant liver disease or family history of bleeding/platelet disorders. 
4. Has a history of cancer (other than basal cell or squamous cell cancer of the skin), 
rheumatologic disease or blood dyscrasias. 
5. Has a history of GI surgery or other condition that may interfere with absorption of 
study drug, in the option of the PI (or designee). 
6. Has a history of febrile illness within the 14 days prior to the first dose of study drug. 
7. Has a positive alcohol or drug screen at Screening or the Day -1 visit or has a history of 
alcohol or drug abuse within the past 5 years. 
8. Currently uses tobacco, nicotine or tobacco products, e-cigarettes or has stopped using 
tobacco products within the past 3 months and/or has a positive cotinine test at 
Screening or Check-in. 
9. Has any abnormal laboratory value of Grade 2 or higher, which is considered to be 
clinically significant by the PI (or designee). 
10. Has a total white cell count or absolute lymphocyte count outside the normal range, or 
hemoglobin or platelet levels below the lower limit of normal, at Screening of Day -1. 
11. Has values above the upper limit of normal for the following laboratory analytes: 
alanine aminotransferase (ALT/SGPT), alkaline phosphatase (serum), aspartate 
aminotransferase (AST/SGOT), at Screening or Day -1. 
12. Positive test result for human immunodeficiency virus (HIV), hepatitis B virus (HBV), 
or hepatitis C virus (HCV). 
13. Has an autoimmune disease, is immunosuppressed or is in any way 


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immunocompromised. 
14. Has any of the following: 
• 
QT interval corrected for heart rate using Fridericia’s formula (QTcF) >450 ms 
confirmed by repeat measurement 
• 
QRS duration >110 ms confirmed by repeat measurement 
• 
PR interval >220 ms confirmed by repeat measurement 
• 
findings which would make QTc measurements difficult or QTc data 
uninterpretable 
• 
history of additional risk factors for torsades de pointes (e.g., heart failure, 
hypokalemia, family history of long QT syndrome). 
15. Except as noted, has used prescription drugs (other than hormone replacement therapy) 
within 14 days prior to the first dose of study drug unless, in the opinion of the PI (or 
designee), the drug will not interfere with study assessments. The following prescription 
drugs will be allowed: 
• 
Statins: Subjects who have been on a stable dose of statins for a minimum of 
6 months and who have normal creatine kinase at Screening. 
• 
Antihypertensives: Subjects who have been on a stable dose of 
antihypertensives for a minimum of 6 months and have controlled blood 
pressure and no active heart disease. 
16. Has received an experimental agent (vaccine, drug, biologic, device, blood product or 
medication) within 3 months prior to the first dose of study drug and agrees not to 
receive another experimental agent during the duration of this trial. 
17. Has donated blood within 30 days, plasma within 2 weeks, or platelets within 6 weeks 
prior to Screening or refuses to agree to not donate blood until 3 months after the End of 
Study (EOS) visit. 
18. Uses over-the-counter (OTC) medications or nutritional supplements (including, e.g., 
gingko biloba, aspirin at any dose, and nonsteroidal anti-inflammatory drugs [NSAIDs]) 
on a routine/scheduled basis, and/or is unwilling to abstain from such use for the 
duration of the study. 
19. Is unwilling to abstain from quinine containing products including quinine water, tonic 
water, bitter lemon, jello shots, any quinine preparations or Cinchona tree bark 
preparations (e.g., herbal medications containing Cinchona tree bark). 
20. Has any condition that would, in the opinion of the PI (or designee), put the subject at 
increased risk for participation in a clinical trial or confinement in a clinical research 
unit. 
Retesting for Inclusion/Exclusion Criteria: In the case where a parameter is outside of the 
acceptable limits for enrollment, measurement of the parameter can be repeated one time if both 
the following are met: 
 In the opinion of the PI (or designee), the parameter value does not represent a chronic 
condition that otherwise will preclude the volunteer from enrolling in the study; and 
 In the opinion of the PI (or designee), the abnormality is not likely to recur. 


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General Investigational Plan: For all potential subjects, volunteers who express interest in the 
study will report to the clinic for informed consent. The study will be explained to the subject 
and the Ethics Committee (EC)-approved informed consent form (ICF) will be presented. The 
subject will be given the chance to review the document and ask any questions he/she may have. 
If, after reviewing the consent, the subject would like to participate in the study, then he/she will 
sign the ICF and begin screening for study entry; those satisfying all criteria will be enrolled into 
the study and admitted to the clinic on Day -1. Retesting will be allowed as described above. 
Part 1: For P1/SAD, the first cohort will be divided into 2 groups. The first group, a sentinel 
group, will include 2 subjects.  
On Day 1, one subject in the sentinel group will be administered PBO and one will be 
administered EIDD-2801. Analysis of the safety results for the sentinel group will be reviewed 
24 hours postdose. If no halting criteria have been met, the remainder of the subjects in Cohort 1 
(the second group) will be dosed. There will be no sentinel groups for the remaining cohorts. 
Following dosing on Day 1, subjects will remain in the clinic through completion of study 
assessments on Day 4, returning to the clinic on Day 9 for study assessments, and Day 15 for the 
EOS visit.  
Doses will be administered in an escalating manner following satisfactory review by the Sponsor 
and PI of the blinded safety and tolerability data (up to 72 hours post final dose). Integrated data 
from all applicable sites will be used to make dose-escalation decisions. Dose-escalation will 
only occur if data from a minimum of 6 subjects (across all sites) have been reviewed from the 
previous lower dose group, such that data from a minimum of 4 subjects (across all sites) who 
have received EIDD-2801 will be used to make the dose-escalation decision. Dose levels will 
not increase by more than 3-fold for predicted nonpharmacologically active dose levels and by 
2-fold for predicted pharmacologically active dose levels. The highest dose to be studied under 
this protocol will not exceed 200 mg. 
Part 2: For P2/FE, one cohort assessing the effect of food on EIDD-2801 and EIDD-1931 PK 
parameters will be enrolled; it is planned that the P2 cohort will be at a dose of 100 mg 
EIDD-2801, although higher or lower doses may be selected based on safety and available PK 
data from P1.  
In addition to assessing the effect of food on dosing, PBMCs will be collected from subjects 
following each dose; the PBMCs will be stored for analysis of EIDD-2061 levels at some point 
in the future.  
The 10 subjects enrolled in the FE cohort will all receive EIDD-2801; subjects will be 
randomized to a treatment sequence (i.e., to receive drug in the fed then fasted state [Sequence 1] 
versus fasted then fed state [Sequence 2]). Half of the subjects in the cohort will be randomized 
to Sequence 1 and the other half will be randomized to Sequence 2.  
Following dosing on Day 1, subjects will remain in the clinic through completion of study 
assessments on Day 4, returning to the clinic on Day 9 for study assessments, and Day 14 to 
begin the second dosing sequence on Day 15. Subjects will then be discharged from the clinic on 
Day 18, returning to the clinic on Day 23 for study assessments, and Day 30 for the EOS visit. 
There will be a 14-day (minimum) washout period between doses. 
Part 3: For P3/MAD, subjects will receive BID doses on Day 1 through Day 5, inclusive, and 
will receive the final dose of study drug on the morning of Day 6 for collection of steady-state 
PK samples during waking hours. Subjects will remain domiciled at the site during the dosing 


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period and until Day 9, returning to the clinic on Day 14 for completion of study assessments, 
and Day 20 for the EOS visit. 
Doses in P3 may be administered in the fed state, following review of the PK data from P2. 
Additionally, depending on ongoing review of the safety, tolerability, and PK data, the number 
of days of dosing may be reduced and the dosing frequency changed; the dosing frequency will 
be no less than once-daily or no greater than three-times daily. If the number of days of dosing 
are reduced, the timepoints for subsequent assessments and the period for which subjects are 
domiciled at the clinic will similarly be changed (subjects will be domiciled for 3 days post final 
dose). 
Part 3 may run in parallel with P1, providing that the total daily dose to be administered does not 
exceed a dose already shown to be safe and well-tolerated in P1. 
Peripheral blood mononuclear cells may be collected from subjects in P3, depending upon 
ongoing review of the data. The collection of these samples may be omitted from some cohorts, 
depending on ongoing review of the data. The PBMCs will be stored for analysis of EIDD-2061 
levels at some point in the future. In addition, continuous 12-lead ECG monitoring will be 
performed to collect data to assess the relationship between study drug concentrations and QTc 
interval. All data will be archived without extraction or analysis and will not be reported in the 
scope of this study.  
Additional parts may be added to this study, including a SAD part in elderly healthy 
subjects and a study of the safety, tolerability, and PK in Japanese subjects. These 
additional parts are not described in this protocol but may be added via a protocol 
amendment.  
Safety Monitoring and Potential Unblinding: Safety for this study will be continually 
monitored by the PI and Sponsor.  
Blinding: All study personnel will remain blinded to treatment assignment (i.e., EIDD-2801 or 
PBO) in P1 and P3, except for personnel at the bioanalytical laboratory, and the unblinded 
pharmacy staff and pharmacokineticist. If unblinding is required to manage subject safety or to 
support dose-escalation decisions, the decision to unblind lies solely with the PI. If possible and 
providing that it does not interfere with or delay any decision in the best interest of the subject, 
the PI will discuss the intended code-break with the Sponsor. 
Dose-Escalation Halting Rules: 
For Group 1 in P1/SAD, sentinel dosing will occur whereby 2 subjects (1 active and 1 PBO) will 
be dosed on 1 day and, providing no safety concerns arise, the remaining 6 subjects will be 
dosed after at least 24 hours. 
The study will be halted if one or more subjects experience a serious adverse event (SAE) that is 
considered to be related to EIDD-2801 or 2 or more subjects in the same group experience 
severe AEs that are considered to be related to EIDD-2801.  
Additionally, if 2 or more subjects experience a reduction of platelets greater than 50% over 
baseline levels or a reduction in lymphocytes (absolute count) to Grade 3/severe levels without 
an alternate cause, the PI and Sponsor will review the data. If, after review of unblinded data, it 
is determined that these events are probably related to study drug, no further dose escalations 
will occur. 
Dose-escalation will stop if clinically relevant signs or symptoms of similar nature occur in 2 or 


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more subjects in a group that, in the opinion of the PI, warrant stopping of dose-escalation. 
Data Monitoring, Safety Reporting and Unblinding: Data will be monitored throughout the 
course of the study by experienced clinical monitors according to the clinical monitoring plan. 
As data will be entered into an electronic case report form (CRF), data will be monitored to 
ensure accuracy as well as adherence to data entry instructions provided in the CRF guidelines. 
Procedures for reporting any SAE will be detailed in the protocol and forms and instructions 
provided to the site. 
Statistical Considerations: A complete description of all statistical analyses and methods will 
be presented in the statistical analysis plan (SAP). The SAP will be reviewed and approved by 
the Sponsor and will be finalized prior to database lock. Plans for PK analyses will be included 
in the SAP. 
Determination of Sample Size: The sample sizes for the P1 and P3 cohorts are typical for a 
Phase 1 first in human (FIH) study. The sample size for the P2 cohort is in accordance with Food 
and Drug Administration (FDA) guidelines for sample size in FE studies. 
Study Populations: 
Safety Population: All subjects who receive at least one dose of study drug. 
Pharmacokinetic Population:  All subjects receiving study drug who comply sufficiently with 
protocol requirements (i.e., no major protocol deviations) and for whom a sufficient number of 
analyzable PK samples have been obtained to permit the determination of the PK profile for 
EIDD-2801/EIDD-1931 and the statistical analysis of the results. Subjects who experience an 
AE of vomiting before 2× the median tmax of the group may be excluded from the PK population. 
Safety Analyses: Statistical methods for the safety analyses will be descriptive in nature. Safety 
data, including AEs, clinical laboratory data, vital signs, ECG parameters, and PEs. All 
appropriate AEs will be graded using the Division of Microbiology and Infectious Diseases 
(DMID) toxicity scale (March 2014). Change from baseline will be included in summary tables 
for laboratory parameters. All laboratory data will be included in the data listings and all test 
values outside the normal range will be flagged. 
Pharmacokinetic Analyses: Plasma PK parameters for each dose level will be calculated from 
the concentrations of EIDD-2801 and EIDD-1931 measured in predose and postdose plasma 
samples. For each dose level, descriptive statistics will be presented. Figures will be created to 
display mean and individual subject EIDD-2801 and EIDD-1931 concentration versus time. 
Urine PK parameters will be calculated whenever possible for each subject based on the urine 
concentrations of EIDD-2801 and EIDD-1931. The following PK parameters will be calculated: 
Plasma PK Parameter 
Description 
AUClast 
The area under the plasma concentration-time curve, from time 0 to the last 
measurable non-zero concentration, as calculated by the linear up/log down 
trapezoidal method (P1 and P2 only). 
AUC0-inf 
The area under the plasma concentration-time curve from time 0 extrapolated 
to infinity. AUC0-inf is calculated as the sum of AUClast plus the ratio of the 
last measurable plasma concentration to the elimination rate constant (λz) 
(P1, P2, and Day 1 dose of P3). 
Cmax 
Maximum observed concentration. 
tmax 
Time to reach Cmax. If the maximum value occurs at more than one time 
point, tmax is defined as the first time point with this value. 


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λz 
Apparent terminal elimination rate constant; represents the fraction of 
medication eliminated per unit time. 
t1/2 
Apparent terminal elimination half-life of medication, calculated as 0.693/λz. 
Vz/F 
Apparent volume of distribution (EIDD-2801 only). 
CL/F 
Apparent oral drug clearance (EIDD-2801 only). 
Ctrough 
Trough concentration (P3 only). 
AUCτ 
The area under the plasma concentration-time curve during a dosing interval 
(P3 only). 
RAAUCτ 
Observed accumulation ratio based on AUCτ (P3 only). 
RACmax 
Observed accumulation ratio based on Cmax (P3 only). 
Urine PK Parameter 
Description 
Ae 
Amount excreted in urine over the sampling interval. 
Fe 
Fraction of drug excreted in the urine over sampling interval. 
CLR 
Renal clearance, CLR = Ae/AUC where both Ae and AUC are determined 
over co-incident time ranges after dosing. 
In P1, dose-proportionality for PK parameters of EIDD-2801 and EIDD-1931 (AUC0-inf, AUClast, 
and Cmax) will be assessed by the power model. The slope and the associated 90% confidence 
interval (CI) based on the power model will be reported. In P3 on Day 6, dose-proportionality for 
PK parameters of EIDD-2801 and EIDD-1931 (AUCτ and Cmax) will be assessed by the power 
model. The slope and associated 90% CI based on the power model will be reported. 
To assess the effect of food on the PK of EIDD-2801 and EIDD-1931, natural log-transformed 
PK parameters from P2 (AUC0-inf, AUClast, and Cmax) will be analyzed using a mixed-effects 
model with fixed effect terms for treatment (with or without food), period, and sequence and 
with subject within sequence as a random effect. Point estimates and their associated 90% CIs 
for the natural log-transformed PK parameters for the difference between EIDD-2801 
administered under fed relative to fasted conditions will be constructed. The point estimates and 
interval estimates will be back transformed to give estimates of the ratio and 90% CI for the 
geometric least squares mean ratio for fed/fasted to assess the effect of food. 
Interim Analyses: No formal interim analyses are planned for this study. Data from P1 cohorts 
may be locked, unblinded, and analyzed prior to conducting P2 and P3. 


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Figure 1: Study Schema 
 
SAD Dose 1 (50 mg QD )
SAD Dose 2 (TBD)
SAD Dose 3 (TBD)
Review 
Safety Data
Review 
Safety Data
Sentinel Grp 1: 2 subjects
24 hr safety review
Grp 2: 6 subjects
PART 1: SAD Cohorts                                                                                                          
Following review of data from Part 1 cohort administered dose selected for Part 2
Sequence 1
Dose: Fed
Sequence 2
14 Day Washout
Dose: Fasted
Dose: Fasted
Dose: Fed
PART 2: Food Effect (FE) Cohort                                                                                              
MAD Dose 1 (TBD**)
MAD Dose 2 (TBD**)
MAD Dose 3 (TBD**)
Review 
Safety Data
Review 
Safety Data
PART 3: MAD Cohorts                                                                                                                      
Abbreviations:
FE: food effect 
SAD: single ascending dose
MAD: multiple ascending dose
**The total daily dose in Part 3 will not exceed a dose shown to be safe and well-tolerated in Part 1


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1. 
INTRODUCTION 
This study is being conducted at sites across the United Kingdom and the United States. 
Country-specific protocol amendments have been prepared; with the exception of regional 
regulatory requirements, the study is consistent across countries and data will be reported in a 
single clinical study report. 
This study is a FIH study designed to assess the safety, tolerability and PK of EIDD-2801 in 
healthy human volunteers. EIDD-2801 is a ribonucleoside analog with broad-spectrum activity 
against many RNA viruses. It is currently being developed by Ridgeback Biotherapeutics as a 
treatment of infections caused by highly pathogenic coronaviruses (CoV), including COVID-19. 
In addition, EIDD-2801 is being developed in parallel as a treatment of uncomplicated influenza 
caused by all subtypes of circulating and emerging (drifted and shifted) influenza A virus (IAV) 
and influenza B virus (IBV), including seasonal, epidemic and pandemic strains.  
1.1. 
Background 
EIDD-2801 is the 5’-isopropyl ester prodrug of the broadly active, direct-acting antiviral 
ribonucleoside analog EIDD-1931. After oral delivery, the prodrug (EIDD-2801) is rapidly 
hydrolyzed by circulating esterases to produce high circulating (plasma) levels of EIDD-1931. In 
cell culture systems, EIDD-1931 has been shown to inhibit replication of multiple viral 
pathogens from multiple RNA virus families including pathogenic CoV (e.g., Middle East 
respiratory syndrome [MERS], severe acute respiratory syndrome [SARS]-CoV and 
SARS-CoV-2), influenza viruses (seasonal, pandemic, and avian subtypes), respiratory syncytial 
virus (RSV), alphaviruses (e.g., Eastern equine encephalitis virus [EEEV], Venezuelan equine 
encephalitis virus [VEEV], and Chikungunya virus [CHKV]), Filoviruses (e.g., Ebola virus 
[EBOV]), and Zika virus (ZIKV). In addition, EIDD-2801 is active against orthopoxviruses 
(tested against vaccinia virus) probably because orthopoxviruses encode their own unique RNA 
polymerase. 
 
 The primary mechanism of action of 
EIDD-2801 is inhibition of viral RNA replication by incorporation of the EIDD-1931 
monophosphate metabolite into the viral RNA genome resulting in induction of viral error 
catastrophe. 
1.2. 
Rationale for Development 
EIDD-2801 is being developed for the treatment of infections caused by RNA viruses, 
specifically for COVID-19 and other CoV infections, influenza, and VEEV. During conduct of 
the FIH study, the Sponsor intends to define a dose that may be active in treating COVID-19 in 
patient studies.  
EIDD-2801 has a unique dual mechanism of action against RNA viruses, including 
SARS-CoV-2 and other CoV infections. The compound acts as a competitive, alternative 
substrate for the virally encoded RNA-dependent RNA-polymerase that upon incorporation into 
nascent chain RNA induces increased mutational frequency in the viral genome. Incorporation 
quickly results in the production of non-viable virus. Additionally, the active metabolite, 


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EIDD-1931-5’-triphosphate (EIDD-2061), may act directly as a chain terminator and arrest 
replication by exerting a next nucleoside effect. It is anticipated that the high barrier to resistance 
observed during in vitro passaging studies will translate to slow, if any, emergence of viral 
resistance. Resilience to viral escape is a distinguishing feature of EIDD-2801. 
Currently, there is no approved antiviral therapeutic for the treatment of COVID-19. An antiviral 
drug is urgently needed. 
 
 
 
 
 
 
1.3. 
Nonclinical Overview 
1.3.1. 
Mechanism of Action 
The mechanism of antiviral activity of EIDD-2801 is “lethal mutagenesis”; a concept that is 
predicated on increasing the viral mutation rate beyond a biologically-tolerable threshold, 
resulting in impairment of viral fitness and leading to viral extinction. 
The specifics of the mechanism are as follows. EIDD-2801 is rapidly taken up by cells and the 
5’-isopropylester cleaved to liberate EIDD-1931, which is in turn phosphorylated to EIDD-2061 
by host kinases (Hernandez-Santiago et al., 2004; Painter et al., 2019). The 5’-triphosphate, 
EIDD-2061, acts as a competitive alternative substrate for virally encoded RNA-directed RNA 
polymerases and EIDD-2061 is incorporated into nascent viral RNA. Owing to the ability of the 
N4-hydroxycytosine base of EIDD-1931 to tautomerize, EIDD-2061 can pair with either 
guanosine or adenosine, and consequently can substitute for either CTP or UTP, respectively 
(Flavell et al., 1974). This results in an accumulation of mutations that increases with each cycle 
of viral replication. The process whereby the mutation rate is increased by exposure to a drug is 
referred to as Viral Decay Acceleration (Mullins et al., 2011) and results in viral ablation. 
Significant work has gone into validating this mechanism of action for EIDD-2801/1931, and it 
has been shown for MERS-CoV, VEEV, and IAV that viruses grown in the presence of 
EIDD-1931 have significantly increased levels of transition mutations (Agostini et al., 2019; 
Toots et al., 2019; Urakova et al., 2018). Multi-log decreases in virus yields were observed after 
treatment with EIDD-1931. Additionally, it was demonstrated for VEEV that the infectivity of 
virions formed in the presence of EIDD-1931 decreases from ~20% to <0.2%, and that the 
infectious virions are significantly Impaired in their replication ability (Urakova et al., 2018). As 
a consequence of this mechanism of action, the generation of drug-resistant escape mutants is 
practically impossible. This same effect was demonstrated for CoV (Agostini et al., 2019) and 
influenza virus (Toots et al., 2019). Furthermore, given the unique mechanism of action, 
EIDD-2801 is expected to be active against viruses resistant to other antiviral agents which have 
a different mechanism of action. The only data generated to date regarding the activity of 
EIDD-1931 against viruses resistant to other nucleoside analogs found that EIDD-1931 was 


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active against CoV resistant to remdesivir in cell culture assays (T. Sheahan et al, preprint 
available at https://www.biorxiv.org/content/10.1101/2020.03.19.997890v1). 
As an alternative or additional mechanism of action, it has been theorized that incorporation of 
EIDD-2061 into viral genomic RNA can change the thermodynamics of RNA secondary 
structure and thus decrease the efficiency of the promoter regions involved in RNA genome 
replication (Stuyver et al., 2003). 
1.3.2. 
In Vitro Pharmacology 
1.3.2.1. 
Antiviral Activity in Tissue Culture and in Human Airway Epithelium 
The ribonucleoside analog EIDD-1931 is the parent of the prodrug EIDD-2801. EIDD-1931 
shows specific antiviral activity in different tissue culture cells and in the differentiated organoid 
model of human airway epithelium (HAE) with a selectivity index (SI) ranging from 21 to >100 
for all influenza viral isolates tested. It is active against IAV (pandemic and seasonal) and IBV 
strains, as well as against highly pathogenic H5N1 and H7N9 strains (Table 1). 
Table 1: 
EIDD-1931 Antiviral Activity Against Influenza A and B Viruses in Tissue 
Culture and Primary Human Bronchial/Tracheal Epithelial Cells 
Virus 
Strain 
Cell line 
EC50* 
(µM) 
CC50 
(µM) 
SI 
Reference 
IAV H1N1 
Ca/07/2009 
MDCK 
1.24 
68 
55 
NIAID Antiviral Testing Program 
IAV H1N1 
WSN/33 
MDCK 
1.1 
299.8 
275 
Yoon et al., 2018 
IAV H1N2 
WSN/33 
primary hBTEC 
5.4 
- 
- 
Yoon et al., 2018 
IAV H2N3 
Perth/16/2009 
MDCK 
0.88 
52 
59 
NIAID Antiviral Testing Program 
IAV H2N3 
Ohio/sw-10-132/2010 
MDCK 
3.2 
299.8 
94 
Yoon et al., 2018 
IAV H5N1 
Duck/MN/1525/81 
MDCK 
1.28 
27 
21 
NIAID Antiviral Testing Program 
IAV H5N1 
Vietnam/1203/2004 
MDCK 
0.14 
299.8 
2100 
Yoon et al., 2018 
IAV H7N9 
Anhui/1/2013 
MDCK 
0.13 
299.8 
2300 
Yoon et al., 2018 
IBV 
Florida/4/2006 
MDCK 
<0.4 
76 
>190 
NIAID Antiviral Testing Program 
IBV 
Brisbane/60/08 
MDCK 
0.006 
299.8 
50000 
Yoon et al., 2018 
IAV H1N1 
Ca/07/2009 
HAE-3D* 
0.08 
50 
625 
Toots et al., 2019 
IAV H1N1 
WSN/33 
HAE-3D* 
0.08 
50 
625 
Toots et al., 2019 
IBV 
Brisbane/60/08 
HAE-3D* 
0.06 
50 
833 
Toots et al., 2019 
* Human Airway Epithelium organoid model. 
EIDD-1931 also showed specific antiviral activity against human SARS-CoV, MERS-CoV 
(Table 2) and SARS-CoV-2 (Figure 2), against togaviruses VEEV, EEEV and CHKV (Table 3) 
 


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EIDD-1931 (NHC) antiviral activity (closed circles) and 
cytotoxicity (open squares) in Vero Cells infected with SARS- 
CoV-2. Vero cells were infected in duplicate with SARS-CoV- 
2 clinical isolate virus at a multiplicity of infection (MOI) of 0.05 
in the presence of a dose response of EIDD-2801 for 48 hours 
after which replication was measured through quantitation of 
cell viability by Cell-Titer-Glo assay. Cytotoxicity was 
measured in similarly treated but uninfected cultures. 
Reproduced from Sheahan et al 2020. 
Table 2: 
EIDD-1931 Antiviral Activity Against SARS and MERS Coronaviruses in Tissue 
Culture and Primary Human Bronchial/Tracheal Epithelial Cells 
Virus 
Strain 
Cell line 
EC50 
(µM) 
CC50 
(µM) 
SI 
Reference 
SARS-CoV-1 Urbani 
Vero76 
<0.4 
144 
>360 NIAID Antiviral Testing Program 
SARS-CoV-1 SARS-CoV-GFP(†) 
HAE-3D(*) 
<1 
>100 
>100 Tech. Report 25.038 
MERS-CoV 
GenBank Ac.No JX869059** DBT-9 
0.56 
>200 
>357 Agostini et al., 2019 
MERS-CoV 
Human ß-CoV C, Novel 2912 Vero E6 
<0.8 
20 
>25 
NIAID Antiviral Testing Program 
* Human Airway Epithelium organoid model; ** cDNA Derived clone 
Figure 2: Inhibition of SARS-CoV-2 by EIDD-1931 
 
Table 3: 
EIDD-1931 Antiviral Activity Against Togaviruses in Tissue Culture 
Virus 
Strain 
Cell line 
EC50 (µM) 
CC50 (µM) 
SI 
Reference 
VEEV 
TC-83 
Vero 
0.43 
>200 
>930 Urakova et al., 2018 
VEEV 
TC-83 
Vero76 
1.92 
32 
17 
NIAID Antiviral Testing Program 
EEEV 
FL93-939 
Vero76 
1.08 
84 
78 
NIAID Antiviral Testing Program 
CHKV 
S27 (VR-64) 
Vero76 
1.8 
96 
53 
NIAID Antiviral Testing Program 


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1.3.2.2. 
Cytotoxicity of EIDD-1931 in Tissue Culture Utilizing Cells from 
Different Organs and Species 
EIDD-1931 was tested for cytotoxicity in human hepatic origin Huh7 and HepG2 cells, in human 
lymphoid CEM, human pancreatic BxPC-3, human prostate cancer PC-3, human muscle A204, 
human lung A549, human epithelial hEp-2, rat heart muscle H9c2, monkey kidney Vero, and 
canine kidney MDCK cell lines (Table 5). The compound exhibits low cytotoxicity in the 
majority of cells tested (half-maximal effective concentration [EC50] values are in the range of 40 
to >100 µM) except in lymphoid origin CEM cells where the compound shows a 7.5 µM EC50 
value (Sticher et al., 2020; Urakova et al., 2018; Yoon et al., 2018). 
Table 5: 
Cytotoxicity (CC50) of EIDD-1931 in Mammalian Cell Lines 
Cell Line 
CEM 
HepG2 
PC-3 
A204 
A549 
BxPC-3 
Huh-7 
H9c-2 
Vero 
hEp-2 
MDCK 
CC50 
(µM) 
7.5 
42.3 
267.1 
84 
46 
48 
165.5 
81 
53 
272.4 
299.8 
Sources: Sticher et al., 2020, Yoon et al., 2018 
EIDD-2801 typically showed 2-4× lower activity and cytotoxicity than EIDD-1931 due to 
slightly slower uptake and anabolism in tissue culture. 
1.3.2.3. 
Assessment of Mitochondrial Toxicity 
Since EIDD-1931 is a nucleoside analog, additional investigations were performed to analyze 
whether observed cytotoxicity of EIDD-1931 is caused by mitochondrial toxicity. It was 
demonstrated that the prolonged treatment (14 days) with the compound does not result in 
selective killing of mitochondria or in mitochondrial dysfunction in CEM and HepG2 cells 
(Sticher et al., 2020). 
1.3.3. 
In Vivo Pharmacology 
The prodrug EIDD-2801 or its parent EIDD-1931 have been tested in animal models of RNA 
viral infection. An overview of results from the animal studies in indications to be pursued are 
described below. Additional detail is provided in the Investigator’s Brochure (IB). 
1.3.3.1. 
Coronavirus: SARS-CoV and MERS-CoV 
In mouse models of SARS and MERS infection and disease, coronaviral disease was assessed by 
changes in body weight, measured daily, and lung hemorrhage, assessed in the large left lobe of 
the lung following sacrifice on Day 5 (SARS-CoV) or Day 6 (MERS-CoV). To assess 
production of infectious virions, virus was isolated from the lower left lobe of the lung following 
sacrifice on Day 5 (SARS-CoV) or Day 6 (MERS-CoV) and quantified using a plaque assay. 
The results demonstrated that, in mice infected with either SARS- or MERS-CoV, both 
prophylactic and therapeutic treatment with EIDD-2801 resulted in a reduction in virus 
replication, improvements in pulmonary function, and improvements in maintaining body weight 


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(i.e., reduced body weight loss). While EIDD-2801 doses of 50, 150 and 500 mg/kg BID were 
assessed in the CoV mouse experiments, 500 mg/kg BID yielded the most consistent therapeutic 
effect. 
A prophylactic, dose-escalation study was conducted in C57BL/6 mice infected with 
mouse-adapted SARS-CoV (SARS-MA15). Prophylactic oral treatment with EIDD-2801 was 
initiated 2 hours before intranasal infection and continued every 12 hours thereafter through the 
end of the study (Day 5; Figure 3). 
In mice treated BID with EIDD-2801, body weight loss observed with vehicle treatment was 
diminished in the 50 mg/kg treatment group, beginning on Day 3 post-infection. No body weight 
loss was seen in the 150 and 500 mg/kg treatment groups (Figure 3, Panel A). Lung hemorrhage 
was also significantly reduced on Day 5 post-infection, following treatment with 500 mg/kg 
EIDD-2801 (Figure 3, Panel B). When compared to vehicle control, a dose-dependent reduction 
in SARS-CoV lung titers at Day 5 was seen across all 3 treatment groups (Figure 3, Panel C) 
with significant differences among the vehicle, 150 mg/kg and 500 mg/kg groups. Thus, 
prophylactic treatment with EIDD-2801 resulted in a robust antiviral effect that was able to 
prevent SARS-CoV replication and disease. 
Figure 3: EIDD-2801 Prophylactic Treatment of SARS-CoV Infected Mice 
 
The antiviral activity of EIDD-2801 against SARS-CoV was compared when treatment was 
initiated at -2 hours (pre-infection) and 12, 24, or 48 hours post-infection. After initiation of 
treatment, all groups were dosed every 12 hours for the duration of the study (Figure 4). For 
SARS-challenged mice, initiating treatment at 12 hours post-infection significantly prevented 
body weight loss beginning on Day 2, a result similar to that seen when dosing prophylactically 


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(i.e., beginning at 2 hours pre-infection). Initiation of treatment with EIDD-2801 at 24 hours 
post-infection also significantly reduced body weight loss on Days 3 through5 post-infection. 
When EIDD-2801 treatment was initiated at 48 hours post-infection, body weight loss was only 
statistically different from vehicle on Day 4 post-infection (Figure 4, Panel A). Significant 
reductions in lung hemorrhage were seen when EIDD-2801 treatment was initiated before 
(-2 hours) and up to 24 hours after infection; a result that mirrored body weight loss data 
(Figure 4, Panel B). All mice treated with EIDD-2801 had significantly reduced viral loads in the 
lungs, even in the group where treatment was initiated 48-hour post-infection (Figure 4, 
Panel C). Pulmonary function, measured via whole body plethysmography, was assessed using 
the PenH metric which is a surrogate marker for bronchoconstriction or pulmonary obstruction. 
The administration of EIDD-2801 prior to infection (-2 hours) and at 12 hour post-infection 
completely abrogated the loss of pulmonary function observed in vehicle-treated animals 
(Figure 4, Panel D). Improved pulmonary function was also seen in the group where treatment 
was initiated 24 hours after virus challenge. 
Figure 4: EIDD-2801 Treatment of SARS-CoV Infected Mice 
 
EIDD-2801 was also tested to determine if it is active in vivo against MERS-CoV as described 
by Sheahan et. al (draft manuscript). The murine ortholog of the MERS-CoV receptor, dipeptidyl 
peptidase 4 (DPP4), does not support viral binding and entry. Thus, all in vivo studies described 
below were performed in genetically modified hDPP4 mice permissive for MERS infection. 
Prophylactic treatment starting at 2 hours before viral challenge with either 50, 150, or 


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500 mg/kg EIDD-2801 prevented body weight loss on Days 2 through 6 post-infection (Figure 5, 
Panel A), prevented lung hemorrhage measured on Day 6 (Figure 5, Panel B), and reduced virus 
lung titer on Day 6 to the limit of detection (Figure 5, Panel C). 
Figure 5: EIDD-2801 Prophylactic Treatment of MERS-CoV Infected Mice 
 
The effect of EIDD-2801 treatment on MERS-CoV infected mice is shown in Figure 6. When 
EIDD-2801 treatment was initiated 12 hours post-infection, there was no loss in body weight 
from Days 2 through 6 post-infection (Figure 6, Panel A) and no evidence of lung hemorrhage 
on Day 6 post-infection (Figure 6, Panel B). However, protection was not observed in groups 
where treatment was initiated either 24- or 48-hours post-infection. Conversely, virus lung titer 
on Day 6 post-infection was significantly reduced to the limit of detection in all treatment 
groups, regardless of the time treatment began (Figure 6, Panel C). To gauge the effect of the 
timing of EIDD-2801 treatment initiation on physiologic measures of lung disease, pulmonary 
function was assessed by whole body plethysmography. As expected, a loss of pulmonary 
function, as determined by measuring the PenH metric, was observed in vehicle-treated animals 
infected with MERS-CoV beginning on Day 2 post-infection (Figure 6, Panel D). Mirroring the 
body weight loss data, normal pulmonary function was observed in groups where treatment was 
initiated prior to or at 12 hours post-infection (Figure 6, Panel D). 


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Figure 6: EIDD-2801 Treatment of MERS-CoV Infected Mice 
 
1.3.3.2. 
Influenza Virus 
EIDD-2801 was tested in a ferret model of influenza virus infection and disease. Ferrets 
recapitulate hallmarks of human influenza infection, providing a clinically relevant animal model 
to investigate therapeutic intervention. Therapeutic oral dosing of influenza virus-infected ferrets 
reduced shed levels of pandemic and seasonal IAV by multiple orders of magnitude, and 
alleviated fever and inflammation while improving airway epithelium histopathology. 
Post-exposure prophylactic dosing was sterilizing (Toots et al., 2019). 
Ferrets infected with pandemic IAV and treated with EIDD-2801 at a dose of 7 mg/kg 
demonstrated significantly less viral shedding and inflammatory cellular infiltrates in nasal 
lavages, but mounted a normal humoral antiviral response (Toots et al., 2019). 
When examining the effect of delayed dosing, Toots et. al. (2019) demonstrated that treatment 
with 20 mg/kg of EIDD-2801 initiated 24 hours after challenge with IAV (H1N1) resulted in a 
rapid decrease in both shed virus and fever relative to control, with fever returning to baseline at 
24 hours. When oseltamivir (20 mg/kg) was dosed prophylactically as a positive control, a 
modest suppression of fever was observed; however, there was no reduction in shed virus titer. 


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1.3.3.3. 
Venezuelan Equine Encephalitis Virus 
Treatment with EIDD-1931 was evaluated in a mouse model of lethal VEEV infections. To be 
truly effective as a therapeutic agent for VEEV infection, a drug must penetrate the blood brain 
barrier and arrest virus replication in the brain. High plasma levels of EIDD-1931 are rapidly 
achieved in mice after oral dosing. Once in the plasma, EIDD-1931 is efficiently distributed into 
organs important in the pathology of VEEV infection, including the brain, where it is rapidly 
converted to its active 5’-triphosphate (EIDD-2061). EIDD-1931 showed a good safety profile in 
mice after 7 days of dosing with up to 1,000 mg/kg/day. In mouse model studies of VEEV 
infection, EIDD-1931 was 90-100% effective in protecting mice against lethal intranasal 
infection when therapeutic treatment was started as late as 24 hours post-infection, and partial 
protection was achieved when treatment was delayed for 48 hours post-infection (Painter et al., 
2019). 
 
 
 
 
 
 
 
 
 
1.4. 
Safety and Secondary Pharmacology 
The standard battery of safety pharmacology studies including studies assessing the 
cardiovascular, respiratory and central nervous systems have been conducted. The studies are 
discussed in the IB; results indicated that there were no adverse pharmacologic effects of 
EIDD-2801 on the cardiovascular, respiratory or central nervous systems. 
1.5. 
Nonclinical Pharmacokinetics and Metabolism 
1.5.1. 
Overview 
The uptake, metabolism and protein binding of EIDD-2801 and EIDD-1931 have been studied in 
plasma, microsomes, and non-hepatic cells from several species as outlined below. The PK and 
tissue distribution of prodrug EIDD-2801 and its active parent EIDD-1931 have been studied 
extensively in rats, dogs and ferrets. Key results from these studies are presented below; 
additional detail can be found in the IB. 
1.5.2. 
Absorption 
EIDD-1931 is parent of the prodrug EIDD-2801. The appearance of EIDD-1931 is dependent on 
the absorption of EIDD-2801 and the rate of its conversion to EIDD-1931. 


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EIDD-2801 PK studies have been completed in dog, rat, mouse, ferret, and monkey. EIDD-2801 
was efficiently absorbed and rapidly converted to EIDD-1931 in each species. The tmax for 
EIDD-2801 (not observed in rodents) occurred at 0.5-1 hours, while the tmax for EIDD-1931 
occurred at 1-2 hours. 
1.5.3. 
Distribution 
 
 
 
 
 
 
 
 
 
1.5.3.2. 
Tissue Distribution Studies 
EIDD-2801 is rapidly absorbed in the gut and converted to EIDD-1931 reaching Cmax in 
1-3 hours in mice, rats, ferrets, dogs and monkeys. EIDD-1931 is then widely distributed to 
tissues including lungs and brain, where it is rapidly taken up into cells and converted to 
EIDD-2061. Figure 7 shows the concentration of EIDD-1931 and EIDD-2061 in ferret brain and 
lung following single doses of 20 (Panels A and B) and 128 (Panels C and D) mg/kg. 


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Figure 7: Tissue Distribution of EIDD-1931 and EIDD-2061 in Ferret Brain and Lung 
 
1.5.4. 
Metabolism 
1.5.4.1. 
Metabolic Stability of EIDD-1931 and EIDD-2801 
EIDD-2801 was designed to be converted to EIDD-1931 by esterases in plasma or in cells. 
Stability has been assessed in plasma and liver microsomes from mouse, rat, dog, monkey and 
humans. The stability of EIDD-2801 in mouse, rat and monkey plasma is relatively short 
(≤0.4 hours) while the stability is longer in human and dog plasma (1-3 hours). EIDD-2801 
stability in mouse, rat, dog and monkey liver microsomes is very short, ranging from 0.02 to 
0.08 hours while the stability in human liver microsomes is 1.2 hours (Table 6). 


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Table 6: 
Metabolic Stability of EIDD-2801 in Plasma and Liver Microsomes 
Species 
Plasma stability 
LM stability 
t1/2 (h) 
t1/2 (h) 
Mouse 
0.017 
0.033 
Rat 
0.033 
0.017 
Dog 
3.2 
0.083 
Monkey 
0.40 
0.017 
Human 
1.05 
1.22 
EIDD-2801 is stable in simulated gastric and intestinal fluids (Table 7). 
Table 7: 
Metabolic Stability of EIDD-2801 in Simulated Gastric and Intestinal Fluids and 
in Buffered Saline with Fetal Bovine Serum 
Matrix 
t1/2 (hr) 
Simulated Gastric Fluid 
>24 
Simulated Intestinal Fluid 
>24 
Phosphate Buffered Saline plus 10% Fetal Bovine Serum* 
>24 
EIDD-1931 was found to be stable when incubated with all tested plasmas, whole blood, liver 
microsomes and liver S9 extracts and intestinal microsomes (Table 8). 
Table 8: 
Metabolic Stability of EIDD-1931 in Plasma, Whole Blood and Liver and 
Intestinal Microsomes 
Medium 
Plasma 
Whole Blood 
Liver Microsomes 
Liver S9 Stability 
Intestinal Microsomes 
Species 
t1/2 (h) 
t1/2 (h) 
t1/2 (h) 
t1/2 (h) 
t1/2 (h) 
Mouse 
 
>24 
>24 
 
>24 
Rat 
17 
 
>24 
>24 
 
Dog 
>24 
 
 
>24 
 
Monkey 
6.5 
>24 
>24 
>24 
>24 
Human 
10 
7 
>24 
20 
>24 
1.5.4.2. 
Uptake and Anabolism of EIDD-1931 in Tissue Culture and Primary 
Cells 
EIDD-1931 is efficiently taken up by tissue culture cells and converted to its pharmacologically 
active metabolite EIDD-2061 (EIDD-1931-5’-triphosphate). Intracellular EIDD-2061 
accumulates dose-dependently, with Cmax levels ~200-2000 pmol/106 cells (at 10-20 µM dose) in 
different cell lines. It reaches high levels relatively quickly, typically within 1-3 hours, though 
the tmax values vary widely between 1 and 24 hours depending on the cell line and dose 
concentration tested. Detailed data on the uptake and anabolism of EIDD-2801 is presented in 
the IB. 


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EIDD-2801 is also taken up by tissue culture cells and is converted to EIDD-1931 and then to 
EIDD-2061, but the process is slightly delayed compared to dosing with EIDD-1931. 
EIDD-1931 is also taken up and metabolized to EIDD-2061 by primary cells. EIDD-2061 is 
accumulated in all primary cells tested except in mouse primary hepatocytes where EIDD-1931 
is apparently extensively metabolized to cytidine and uridine which, in turn, quickly metabolize 
into CTP and UTP. The quick metabolism of EIDD-1931 consequently results in low levels of 
EIDD-2061 in mouse hepatocytes. The intracellular stability (t1/2) of EIDD-2061 is 4-5 hours in 
human astrocytes and hBTEC and is significantly shorter (0.2-1.1 hours) in primary hepatocytes. 
1.5.5. 
Excretion 
Currently, there is no data on excretion of EIDD-2801 or EIDD-1931. Excretion will be 
measured in urine during this study. 
1.5.6. 
Pharmacokinetic Drug Interactions 
1.5.6.1. 
Cytochrome P450 (CYP) Inhibition 
The purpose of this non-GLP in vitro study was to determine the time-dependent inhibitory 
potential of EIDD-2801 and EIDD-1931 on human cytochromes P450 (CYP) 1A2, 2B6, 2C8, 
2C9, 2C19, 2D6, and 3A4 (midazolam and testosterone substrates) enzyme activity, using pooled 
human liver microsomes in an half-maximal inhibitory concentration (IC50) shift assay. 
Neither EIDD-2801 nor EIDD-1931 demonstrated inhibition greater than 31.4% for any of the 
CYP isozymes tested nor could the data for each assay condition be curve fit to determine 
time-dependent inhibition by these compounds. Full dose-response curves were not achieved at 
concentrations ranging from 0.00545 to 50.0 µM indicating EIDD-2801 and EIDD-1931 have no 
CYP inhibition potential at concentrations ranging from 0.00545 to 50.0 µM. Assay performance 
was acceptable based on the results for the positive control inhibitors. 
1.5.6.2. 
CYP Induction 
An assay was performed to determine the induction potential of EIDD-2801 on human CYP 
isoenzyme (1A2, 2B6, and 3A4) activity using 3 single-donor lots of inducible, cryopreserved 
human hepatocytes. Both enzyme activity and mRNA results demonstrated that EIDD-2801 did 
not show induction for any of the CYP isozymes. 
 
 
 
 
 
 
 


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1.7. 
Potential Risks and Benefits 
1.7.1. 
Potential Benefits 
As this is a FIH study in healthy volunteers, there is no direct benefit to subjects enrolled in the 
study. However, given the current pandemic situation and in vitro antiviral activity of 
EIDD-2801 against SARS-CoV-2, and the activity against several other viruses of public health 
concern, it is possible that participants may benefit from future availability of the drug. 
1.7.2. 
Potential Risks 
EIDD-2801 has never been administered to humans; therefore, the risks from EIDD-2801 to 
subjects participating in this trial are unknown. Although toxicology studies have been done, 
unexpected AEs may occur.
 
 
 
. Subjects will also be monitored for other end-organ 
effects through a range of safety assessments. 


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2. 
OBJECTIVES 
2.1. 
Study Objectives 
2.1.1. 
Primary Objectives 
The primary objective of Part 1 of the study is to determine the safety and tolerability of single 
ascending doses of EIDD-2801. 
The primary objective of Part 2 of the study is to assess the effect of food on the PK on 
EIDD-2801 and EIDD-1931 following a single oral dose. 
The primary objective of Part 3 of the study is to determine the safety and tolerability of multiple 
ascending doses of EIDD-2801. 
2.1.2. 
Secondary Objectives 
The secondary objectives of Part 1 and Part 3 of the study is to define the PK of EIDD-2801 and 
EIDD-1931 in plasma and urine following single and multiple doses administered to healthy 
volunteers. 
The secondary objective of Part 2 of the study is to determine the safety and tolerability of single 
doses of EIDD-2801. 
2.1.3. 
Exploratory Objectives 
The exploratory objective of Part 3 is to collect data to assess the relationship between 
EIDD-2801/EIDD-1931 concentrations and QTc 
2.2. 
Study Outcome Measures 
2.2.1. 
Primary Outcome Measures 
The primary outcome measures for Parts 1 and 3 of are results of safety evaluations including 
safety laboratory assessments, PEs, ECGs, vital signs, and AEs. 
The primary outcome measures for Part 2 of the study are plasma PK parameters including Cmax, 
tmax, t1/2, CL/F, λz, Vz/F, AUC0-inf and AUClast as appropriate. 
2.2.2. 
Secondary Outcome Measures 
The secondary outcome measures are as follows: 
 Single-dose plasma PK parameters, including Cmax, tmax, t1/2, CL/F, λz, Vz/F, 
AUC0-inf and AUClast as appropriate (Part 1) 
 Multiple-dose plasma PK parameters, including Ctrough, Cmax, tmax, t1/2, CL/F, λz, 


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Vz/F, AUCτ, AUC0-inf (Day 1 dose only), RAAUCτ and RACmax, as appropriate (Part 3) 
 Urinary excretion of EIDD-2801 and EIDD-1931 following single- and 
multiple-dose administration (Parts 1 and 3). 
 Results of safety evaluations including safety laboratory assessments, PEs, ECGs, 
vital signs, and AEs (Part 2). 


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3. 
STUDY DESIGN 
3.1. 
Overview 
EIDD-2801-1001-UK is a Phase 1, randomized, double-blind, placebo-controlled, FIH, SAD, 
and MAD study of the safety, tolerability and PK of EIDD-2801 and EIDD-1931 following oral 
administration of single and multiple doses of EIDD-2801 to healthy volunteers. In addition, for 
a minimum of one cohort, the effect of food on the single-dose EIDD-2801 and EIDD-1931 PK 
parameters will be assessed in subjects taking open-label EIDD-2801. The overall objective of 
the study is to identify a starting dose for future safety and therapeutic intervention trials. 
The study is composed of 3 parts; P1 is the SAD study, P2 is the FE cohort study, and P3 is the 
MAD study.  
This study will be conducted at 1 site in the United Kingdom and up to 3 sites in the United 
States. 
3.1.1. 
Part 1 (Single Ascending Dose) 
A single oral dose of EIDD-2801 or PBO will be administered to subjects. Subjects will be 
randomized in a 3:1 ratio to receive either EIDD-2801 or PBO. 
Following dosing on Day 1, subjects will remain in the clinic through completion of study 
assessments on Day 4, returning to the clinic on Day 9 for study assessments, and Day 15 for the 
EOS visit. 
The first cohort will be divided into 2 groups. The first group, a sentinel group, will include 
2 subjects. On Day 1, one subject in the sentinel group will be administered PBO and one will be 
administered EIDD-2801. Analysis of the safety results for the sentinel group will be reviewed 
24 hours postdose. If no halting criteria (Section 9) have been met, the remainder of the subjects 
in Cohort 1 (the second group) will be dosed. There will be no sentinel groups for the remaining 
cohorts. 
After completion of each dosing cohort, safety and tolerability data will be reviewed to 
determine if any of the halting rules have been met. If not, then the subsequent cohort may be 
dosed following review of the 72-hour safety data. As PK data become available, these data may 
be used for dose-escalation decisions. 
The proposed dose-escalation scheme is shown in Figure 1, however, planned dose escalations 
will be determined based on ongoing review of the safety, tolerability, and available PK data. 
The starting dose in the first SAD cohort will be 50 mg. Dose levels will not increase by more 
than 3-fold for predicted nonpharmacologically active dose levels and by 2-fold for predicted 
pharmacologically active dose levels.
 
 
 


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Three cohorts are initially planned for P1; however, up to an additional 3 cohorts may be 
enrolled. 
3.1.2. 
Part 2 (Food-Effect) 
Two single oral doses of EIDD-2801 will be administered to subjects, in an open-label manner. 
The dose for the P2/FE cohort is planned to be 100 mg but may be adjusted based on safety, 
tolerability, and/or PK data from P1. The dose assessed in the P2 cohort will have been given 
previously to subjects in a P1 cohort successfully (i.e., no halting rules were met following 
dosing).  
Subjects will be randomized to a treatment sequence; i.e., to receive drug in the fed then fasted 
state (Sequence 1) versus fasted then fed state (Sequence 2; Figure 1). Half of the subjects in the 
cohort will be randomized to Sequence 1 and the other half will be randomized to Sequence 2.  
Following dosing on Day 1, subjects will remain in the clinic through completion of study 
assessments on Day 4, returning to the clinic on Day 9 for study assessments, and Day 14 to 
begin the second dosing sequence on Day 15. Subjects will then be discharged from the clinic on 
Day 18, returning to the clinic on Day 23 for study assessments, and Day 30 for the EOS visit. 
There will be a 14-day (minimum) washout period between doses. 
One cohort of 10 subjects is planned for P2. However, if PK results obtained are equivocal, 
additional subjects may be enrolled into the P2/FE cohort at the previously tested dose or an 
additional P2/FE cohort may be added at a different dose. 
3.1.3. 
Part 3 (Multiple Ascending Dose) 
Subjects in P3 will be randomized in a 3:1 ratio to receive either EIDD-2801 or PBO. 
Twice-daily dosing will be administered to subjects on Day 1 through Day 5, inclusive, and a 
final dose will be administered on the morning of Day 6 for collection of steady-state PK 
samples during waking hours. Depending on ongoing review of the safety, tolerability, and PK 
data, the number of days of dosing may be reduced and the dosing frequency may be changed; 
the dosing frequency will be no less than once-daily or no greater than three-times daily.  
The proposed dose-escalation scheme is shown in Figure 1. The total daily dose will not exceed 
a dose shown to be safe and well-tolerated in P1. Doses in P3 may be administered in the fed 
state, following review of the PK data obtained from P2. Part 3 may run in parallel with P1, 
providing that the total daily dose to be administered does not exceed a dose already shown to be 
safe and well-tolerated in P1. 
Subjects will remain domiciled at the site during the dosing period and until Day 9, returning to 
the clinic on Day 14 for completion of study assessments, and Day 20 for the EOS visit. If the 
number of days of dosing are reduced, the timepoints for subsequent assessments and the period 
for which subjects are domiciled at the clinic will similarly be changed (subjects will be 
domiciled for 3 days post final dose). 


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Three cohorts are initially planned for P3; however, up to an additional 3 cohorts may be 
enrolled, or the number of cohorts may be reduced if the study objectives are met. Dose levels in 
P3 may be repeated for collection of PBMCs, providing that the dose level did not meet the 
dose-escalation halting criteria. 
Additional parts may be added to this study, including a SAD part in elderly healthy 
subjects and a study of the safety, tolerability, and PK in Japanese subjects. These 
additional parts are not described in this protocol, but may be added via a protocol 
amendment. 
3.2. 
Rationale and Justification 
3.2.1. 
Justification of Design 
The FIH study is a typical dose-escalation study designed to provide the maximum amount of 
data in the minimum number of subjects. The cohort size in P1 and P3 is planned to be 8 subjects 
(6 active:2 PBO). This number of subjects allows for a sufficient PK analysis, considered to be 
important because dose extrapolation from efficacious animal models to humans will be based 
on exposure. The duration of participation for each subject following dosing well exceeds 5 drug 
half-lives (up to 9.1 hours in dogs; 5 hours in ferrets) 
 
 The FE cohort is considered to be important to maximize exposure 
based on fed vs. fasted condition and obtaining this information early in Phase 1 will minimize 
study drug dose in all future studies. This design follows the FDA guidance document on 
assessing FE in clinical studies. 
3.2.2. 
Justification of Starting Dose 
 
 
 
 
The FDA guidance document 
(“Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult 
Healthy Volunteers”) provides guidance for when a safety factor smaller than 10 may be used to 
calculate the starting dose: 
 A smaller safety factor might also be used when toxicities produced by the 
therapeutic are easily monitored, reversible, predictable, and exhibit a 
moderate-to-shallow dose-response relationship with toxicities that are consistent 
across the tested species (both qualitatively and with respect to appropriately scaled 
dose and exposure). 
 A safety factor smaller than 10 could be justified when the NOAEL was determined 
based on toxicity studies of longer duration compared to the proposed clinical 
schedule in healthy volunteers. In this case, a greater margin of safety should be built 


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into the NOAEL, as it was associated with a longer duration of exposure than that 
proposed in the clinical setting. This assumes that toxicities are cumulative, are not 
associated with acute peaks in therapeutic concentration (e.g., hypotension), and did 
not occur early in the repeat dose study. 
EIDD-2801 satisfies both of these criteria as follows: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Importantly, given the activity of EIDD-2801 versus SARS-CoV-2 (cause of COVID-19), the 
Sponsor thinks it is most prudent to start with a dose that is predicted to be a safe starting dose 
and is also as close as possible to a potential therapeutic dose that would allow the Sponsor to 
move into COVID-19 patients as safely and expeditiously as possible. Based on modeling to 
animal data, a dose of 100 mg BID is projected to be an active dose in humans. 
3.2.3. 
Justification of Study Population 
Healthy volunteers are considered to be the appropriate population for conduct of the FIH study. 
Healthy volunteers without confounding medical conditions that may obscure the interpretation 
of AEs or affect absorption, distribution, metabolism and excretion of study drug will provide the 
most valuable data regarding the tolerability, safety, and plasma exposures observed and 
expected following single doses and multiple doses up to 10 days. EIDD-2801 is intended for 
eventual study in patients with potential CoV-2 infection as defined by the Centers for Disease 
Control and Prevention (CDC) in whom a range of AEs are expected based on the disease under 
study. Understanding the safety and PK profile in a normal population will better inform the use 
of EIDD-2801 in disease settings where complications are frequent, and AEs will need to be 
interpreted in context.  


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4. 
STUDY POPULATION 
This study will enroll healthy volunteers; 8 subjects will be enrolled into each SAD and MAD 
cohort in P1 and P3, and 10 subjects will be enrolled into the FE cohort in P2. 
The site is strongly encouraged to ensure that women are represented in each cohort. 
4.1. 
Subject Inclusion Criteria 
Subjects who meet all of the criteria at Screening will be eligible for study participation 
1. Male or female between the ages of 18 and 60, inclusive. 
2. Female subjects must be of nonchildbearing potential. Nonchildbearing potential is 
defined as women who: 
 are physiologically incapable of becoming pregnant including those who are 
surgically sterile, via hysterectomy, bilateral salpingectomy, and/or bilateral 
oophorectomy by reported medical history and/or medical records. Surgical 
sterilization to have occurred a minimum of 6 weeks, or at the PI’s (or 
designee’s) discretion, prior to Screening. 
 are post-menopausal (at least 45 years of age with amenorrhea for 12 months 
without an alternative medical reason with confirmatory FSH levels of 
≥40 mIU/mL. The amenorrhea should not be induced by a medical condition 
such as anorexia nervosa, hypothyroid disease or polycystic ovarian disease, 
or by extreme exercise. It should not be due to concomitant medications that 
may have induced the amenorrhea such as oral contraceptives, hormones, 
gonadotropin-releasing hormones, anti-estrogens, or selective estrogen 
receptor modulators). 
3. Male participants must agree to the use of effective contraception for study duration, 
i.e., from Check-in until 90 days after the EOS visit. 
4. Is in generally good health as determined by medical history, PEs (at Screening 
and/or Check-in), vital signs, and other screening procedures. 
5. Has a BMI of 18 to 30 kg/m2. 
6. Is willing and able to comply with all study procedures including providing informed 
consent. 


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4.2. 
Subject Exclusion Criteria 
Subjects who meet any of the following criteria at Screening (unless otherwise stated) will not be 
eligible for participation: 
1. Females who are pregnant, planning to become pregnant, or breastfeeding. 
2. Has a clinically relevant acute or chronic medical condition or disease of the 
cardiovascular, GI, hepatic, renal, endocrine, pulmonary, neurologic, or dermatologic 
systems as determined by the PI (or designee). 
3. Has any current or historical disease or disorder of the hematological system or 
significant liver disease or family history of bleeding/platelet disorders. 
4. Has a history of cancer (other than basal cell or squamous cell cancer of the skin), 
rheumatologic disease or blood dyscrasias. 
5. Has a history of GI surgery or other condition that may interfere with absorption of 
study drug, in the option of the PI (or designee). 
6. Has a history of febrile illness within the 14 days prior to the first dose of study drug. 
7. Has a positive alcohol or drug screen at Screening or the Day -1 visit or has a history 
of alcohol or drug abuse within the past 5 years. 
8. Currently uses tobacco, nicotine or tobacco products or e-cigarettes or stopped using 
tobacco products within the past 3 months and/or has a positive cotinine test at 
Screening or Check-in. 
9. Has any abnormal laboratory value of Grade 2 or higher, which is considered to be 
clinically significant by the PI (or designee). 
10. Has a total white cell count or absolute lymphocyte count outside the normal range, 
or hemoglobin or platelet levels below the lower limit of normal, at Screening or 
Day -1. 
11. Has values above the upper limit of normal for the following laboratory analytes: 
ALT/SGPT, alkaline phosphatase (serum), AST/SGOT, at Screening or Day -1.  
12. Positive test result for HIV, HBV, or HCV. 
13. Has an autoimmune disease, is immunosuppressed or is in any way 
immunocompromised. 
14. Has any of the following: 
 QTcF >450 ms confirmed by repeat measurement 


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 QRS duration >110 ms confirmed by repeat measurement 
 PR interval >220 ms confirmed by repeat measurements 
 findings which would make QTc measurements difficult or QTc data 
uninterpretable 
 history of additional risk factors for torsades de pointes (e.g., heart failure, 
hypokalemia, family history of long QT syndrome). 
15. Except as noted, has used prescription drugs (other than hormone replacement 
therapy) within 14 days prior to the first dose of study drug unless, in the opinion of 
the PI (or designee), the drug will not interfere with study assessments. The 
following prescription drugs will be allowed: 
 Statins: Subjects who have been on a stable dose of statins for a minimum of 
6 months and who have normal creatine kinase at Screening. 
 Antihypertensives: Subjects who have been on a stable dose of 
antihypertensives for a minimum of 6 months and have controlled blood 
pressure and no active heart disease. 
16. Has received an experimental agent (vaccine, drug, biologic, device, blood product 
or medication) within 3 months prior to the first dose of study drug and agrees not to 
receive another experimental agent during the duration of this trial. 
17. Has donated blood within 30 days, plasma within 2 weeks, or platelets within 6 
weeks prior to Screening or refuses to agree to not donate blood until 3 months after 
the EOS visit. 
18. Uses OTC medications or nutritional supplements (including, e.g., gingko biloba, 
aspirin at any dose, and NSAIDs) on a routine/scheduled basis and/or is unwilling to 
abstain from such use for the duration of the study. 
19. Is unwilling to abstain from quinine containing products including quinine water, 
tonic water, bitter lemon, jello shots, any quinine preparations or Cinchona tree bark 
preparations (e.g., herbal medications containing Cinchona tree bark). 
20. Has any condition that would, in the opinion of the PI (or designee), put the subject 
at increased risk for participation in a clinical trial or confinement in a clinical 
research unit. 


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5. 
STUDY MEDICATION, RANDOMIZATION AND DOSE 
ADMINISTRATION 
5.1. 
Study Drug Description 
EIDD-2801 and matching PBO will be supplied 
 
 
 
 
 
 
 
 
 
 
 
 
5.1.1. 
Acquisition, Formulation, Packaging and Labeling 
 
 
 
 
All study drug will be labeled according to the regulatory requirements for investigational 
product. 
5.1.2. 
Product Storage and Stability 
Study drug should be stored at controlled room temperature defined as 
 
s. If excursions occur which 
are outside of this range, the pharmacy staff should contact Sponsor to determine the course of 
action. Additional stability data may be available which would allow continued use of the study 
drug, or study drug may need to be replaced. 
5.2. 
Randomization 
Unmasked study drug (EIDD-2801 and matching PBO) will be supplied to the study site 
pharmacy. The pharmacy staff will be unmasked with regards to treatment assignment. A 
randomization list will be provided to the pharmacy staff who will use that list to dispense 
masked study drug for administration to each study participant. In P1 and P3, 6 subjects will 


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receive EIDD-2801 while 2 subjects will be randomized to PBO. In P2, all 10 subjects in the FE 
cohort will receive EIDD-2801. The pharmacy staff will maintain the security of the 
randomization list ensuring that no study personnel outside of the pharmacy have access to 
identify treatment assignment. In the case that it becomes necessary to know a subject’s 
treatment assignment, unmasking procedures will be followed as discussed in Section 8.4. 
5.3. 
Dosage, Preparation and Administration of Study Drug 
Detailed instructions for extemporaneous compounding (as necessary), dispensing and 
administering study drug can be found in the pharmacy manual. 
 
 
 
 
 
 
 
 
 
 
 
5.4. 
Drug Accountability 
The site pharmacy must maintain records of receipt and disposition of all study drug supplied to 
the site by the Sponsor. The records must be maintained according to site standard operating 
procedures (SOPs) and should include at a minimum, receipt date, lot or batch number, amount 
and formulation received, 
, date, time and amount 
dispensed, subject identifier for each aliquot of study drug dispensed. In addition, the clinic staff 
must ensure that the time of dosing is identified for each subject. 
Monitors must verify drug accountability/dispensing records during the monitoring visit. 
Unused study drug must be disposed of according to the procedures described in the pharmacy 
manual. 
5.5. 
Concomitant Medication/Treatments 
 
 In this FIH study, limited types of concomitant 
medications are permitted. Adjustment of routine medications taken by subjects should be 
avoided during study participation except when subject safety could be affected by lack of 


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adjustment. There are no restrictions on treatment medications prescribed by the PI (or designee) 
to be used for AEs that occur during study participation. For additional restrictions, see 
Section 6.1.2. 


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6. 
STUDY CONDUCT AND VISIT SCHEDULE 
All study assessments will be conducted according to the Time and Events Schedule. 
6.1. 
Study Conduct 
6.1.1. 
Study Windows and Rounding Principles 
The time schedule described in the protocol for each scheduled activity should be followed as 
closely as possible. However, if it is not possible and if it is not otherwise specifically 
contraindicated per protocol, then the time windows detailed in Table 10 are allowed without 
incurring a protocol deviation. 
Table 10: Allowable Time Windows for Study Assessments/Visits 
Protocol Specified Time 
Allowable Window 
PK Samples and Associated Assessments 
Predose 
within 2 hours prior to dosing 
<2 hours 
± 5 minutes 
≥2 hours to 24 hours 
± 15 minutes (± 2 hours for urinalysis) 
>24 hours to 48 hours 
± 30 minutes 
>48 hours 
± 1 hour (PK) and ± 2 hours (safety)  
Study Visits - Parts 1 and 2 
Day −1 to Day 4 (Part 1) 
must occur on scheduled day 
Day −1 to Day 4 and Day 14 to Day 18 (Part 2) 
must occur on scheduled day 
Day 9 (Part 1) and Days 9 and 23 (Part 2) 
± 1 day 
End-of-Study (EOS) Visit 
± 2 days 
Study Visits - Part 3 
Day −1 to Day 9 
must occur on scheduled day 
Day 14 
± 1 day 
Day 20/EOS Visit 
± 2 days 
6.1.2. 
Restrictions 
Prior to arriving at the clinic for the Day -1 visit, subjects must abstain from consumption of 
alcoholic beverages for a minimum of 72 hours prior to Check-in. Subjects must continue to 
abstain from consumption of alcoholic beverages throughout clinic confinement. Subjects 
enrolled in P2 must continue to refrain from consuming alcoholic beverages from discharge on 
Day 4 through Check-in on Day 14, and then through the second clinic confinement to Day 18. 
After discharge on Day 4 (P1), Day 18 (P2), or Day 9 (P3), subjects must minimize consumption 
of alcoholic beverages (i.e., limit of up to one serving per day) until the EOS procedures have 
been completed. 


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All subjects must refrain from the following: 
 consuming quinine containing products from 72 hours prior to Check-in through to 
completion of the EOS procedures. 
 using nutraceuticals and nutritional/vitamin supplements (e.g., gingko biloba, 
multivitamins) from 72 hours prior to Check-in through to completion of the EOS 
procedures. However, vitamin supplements required by a physician are exempt from 
this restriction. 
 taking OTC analgesics including aspirin (any dose) and NSAIDS from 72 hours 
before Check-in until completion of EOS study procedures unless prescribed by the 
PI (or designee). 
 use of tobacco, nicotine or tobacco products, or e-cigarettes from 3 months prior to 
Screening until the EOS visit. 
 strenuous exercise from 7 days before Check-in until the EOS visit. Subjects will 
otherwise maintain their normal level of physical activity during this time (i.e., will 
not begin a new exercise program nor participate in any unusually strenuous physical 
exertion). 
 Female subjects must not donate eggs/ovum from the time of Check-in until 
3 months after the EOS visit. 
All subjects in P1 should be dosed in the fasted state. Subjects should fast overnight for a 
minimum of 10 hours prior to dosing in the morning on Day 1. Following dosing, subjects may 
have water after 2 hours and food beginning 4 hours postdose. For subjects to be dosed in the fed 
state, subjects should have a high-fat breakfast as defined in the FDA guidance. Subjects must 
complete the meal within 30 minutes of starting the meal and should be dosed after 30 minutes 
of starting the meal. Doses in P3 may be administered in the fed state, following review of the 
PK data from P2. 
6.2. 
Screening 
6.2.1. 
Screening Visit 
Subjects who meet preliminary pre-screening criteria (as defined by the site) and are interested in 
participating in the study will arrive at the study site for administration of informed consent 
according to site standard operating procedures (SOPs). After the subject has signed and dated 
the ICF, screening procedures can begin. Assessments and procedures should be conducted as 
shown in the Time and Events Schedule Screening may be conducted as early as 28 days prior to 
dosing. 


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6.2.2. 
Retesting Procedures 
In the case where a parameter is outside of the acceptable limits for enrollment, measurement of 
the parameter can be repeated one time if both the following are met: 
 In the opinion of the PI (or designee), the parameter value does not represent a 
chronic condition that otherwise will preclude the volunteer from enrolling in the 
study; and 
 In the opinion of the PI (or designee), the abnormality is not likely to recur. 
6.2.3. 
Study Visits 
Subjects who satisfy entry criteria will return to the clinic for the Day -1 visit. Following review 
of I/E criteria, subjects who still qualify will be checked into the clinic and enrolled into the 
study. Following enrollment, clinical chemistry, hematology and urine samples will be collected 
to determine baseline values. Based on site standard practices, alternate subjects will also be 
enrolled into the study in case one of the selected subjects cannot be dosed. If all subjects can be 
dosed on the morning of Day 1, the alternates will be released and may be enrolled into 
subsequent cohorts. All assessments and procedures will be performed according to the 
Time and Events Schedule. 
6.2.4. 
Part 1 (Single Ascending Dose) 
Subjects will remain in the clinic through completion of study procedures on Day 4, returning to 
the clinic for procedures on Day 9. 
6.2.5. 
Part 2 (Food-Effect) 
Subjects will remain in the clinic through completion of study procedures on Day 4, returning to 
the clinic on Day 9 for study assessments, and Day 14 to begin the second dosing sequence on 
Day 15. Subjects will then be discharged from the clinic on Day 18, returning to the clinic on 
Day 23 for study assessments. 
6.2.6. 
Part 3 (Multiple Ascending Dose) 
Subjects will remain in the clinic through dosing and completion of study procedures on Day 9, 
returning to the clinic on Day 14 for study assessments. Depending on ongoing review of the 
safety, tolerability, and PK data, the number of days of dosing may be reduced. If the number of 
days of dosing are reduced, the timepoints for subsequent assessments and the period for which 
subjects are domiciled at the clinic will similarly be changed (subjects will be domiciled for 
3 days post final dose). 
6.3. 
Safety Follow-up and End-of-Study Visit 
Subjects in P1 will return to the clinic for the EOS visit on Day 15. Subjects in the FE cohort 
(P2) will return for the EOS visit on Day 30. Subjects in P3 will return for the EOS visit on 


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Day 20. Subjects with drug-related AEs at the EOS visit will be followed as discussed in 
Section 8.2.1. 
6.4. 
Subject Withdrawal and Replacement 
As this is a small study with a limited number of subjects per cohort, it is critical that all subjects 
complete the study including postdose study assessments. Site personnel should emphasize this 
to study subjects at the time of informed consent so that subjects will understand this fact before 
agreeing to participate in the study. 
Subjects may voluntarily withdraw their consent for study participation at any time without 
penalty or loss of benefits to which they are otherwise entitled. An PI (or designee) may also 
withdraw a subject from receiving study drug or participation in the study for any reason. 
Subjects who withdraw or are withdrawn from the study should undergo withdrawal procedures 
as discussed below. These procedures would include follow-up safety evaluations. 
6.4.1. 
Reasons for Withdrawal 
If a subject withdraws or is withdrawn from the study, the primary consideration must be the 
health and welfare of the subject. The reasons for withdrawal might include but are not limited to 
the following: 
 Subject no longer meets eligibility criteria including subject withdraws consent from 
study participation (with or without a reason) 
 Subject becomes noncompliant 
 Medical disease or condition, or new clinical finding(s) for which continued 
participation, in the opinion of the PI (or designee) might compromise the safety of 
the subject, interfere with the subject's successful completion of this study, or 
interfere with the evaluation of responses 
 Subject Lost-to-Follow-up 
 Subject becomes pregnant, if applicable 
 Determined by a physician's discretion to require additional therapy not indicated in 
the protocol to ensure subject's health and well-being (or treatment failure, if 
applicable) 
The PI should be explicit regarding study follow-up (e.g. safety follow-up) that might be carried 
out. If the subject consents, every attempt will be made to follow all AEs through resolution, 
return to baseline, or until stabilized with sequelae for a maximum of 30 days following 
discontinuation. The procedures that collect safety data for the purposes of research must be 
inclusive in the original ICF or the PI may seek subsequent informed consent using an 
EC-approved ICF with the revised procedures. 


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The PI will inform the subject that already collected data will be retained and analyzed even if 
the subject withdraws from this study. 
6.4.2. 
Handling of Withdrawals 
Subjects who withdraw from the study prior to receiving study drug (i.e., on Day -1 or before 
dosing on Day 1) will be discharged from the clinic and followed only if AEs are present which 
occurred due to participation in the study (e.g., AE resulting from a study procedure). In this 
case, the subject should be followed until the AE resolves or the PI determines that the AE has 
stabilized. 
Subjects who withdraw from the study after receiving study drug should have EOS assessments 
at the time of withdrawal or as quickly thereafter as possible. 
Subjects who do not return for follow-up procedures on Days 9/23 or 15/30 (P1 and P2), or 
Days 14 or 20 (P3) will be contacted by the site at least 3 times using the subject’s preferred 
method of communication (as determined at Check-in). If the site is unable to contact the person, 
then a certified letter will be sent. If the subject still cannot be reached or refuses to come back to 
the clinic after all attempts, the subject will be considered Lost-to-Follow-up and withdrawn 
from the study. 
6.4.3. 
Documentation of Withdrawals 
If a subject withdraws or is withdrawn prior to completion of the study, the reason for this 
decision must be recorded in the CRF. If the subject is Lost-to-Follow-up, the site should 
document the attempts to contact the subject in the source documents. If the subject has an 
ongoing AE at the time of withdrawal, then the AE should be followed as detailed in 
Section 8.2.1. 
6.4.4. 
Subject Replacement 
If a subject withdraws from the study prior to receiving study drug, the subject will be replaced. 
In this case, designated alternate subjects, if available, will be first in line to replace the 
withdrawn subject. 
If a subject withdraws from the study after receiving study drug, then the decision to replace the 
subject will be made by the PI (or designee) in consultation with the Sponsor. Factors to consider 
will be the timing postdose of withdrawal and the number of safety and PK assessments 
completed prior to withdrawal. Subjects who are withdrawn because of an AE related to the 
study drug will not be replaced. 
6.5. 
Unscheduled Visit(s) 
If a subject experiences an AE after discharge from the clinic but prior to the EOS visit, the 
subject should be instructed to call the site. Based on the issue, the PI (or designee) may request 
that the subject return to the site for an unscheduled visit. In this case, procedures/assessments 


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should be conducted as deemed appropriate for the situation by the PI (or designee). The visit 
should be recorded in the unscheduled visit page of the CRF. 


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7. 
STUDY PROCEDURES/EVALUATIONS 
7.1. 
Demography and Medical History 
Demographics including age, gender, race, ethnicity, and medical history will be recorded for 
each subject. All significant medical history should be recorded. In general, significant medical 
history should include all ongoing events and all events occurring within the last 6 months. 
Clinically relevant or clinically significant events occurring greater than 6 months ago should be 
recorded. All surgeries occurring in adulthood should be recorded. If surgeries occurred more 
than 2 years ago, then only the year needs to be recorded on the CRF. 
7.2. 
Clinical Evaluations 
7.2.1. 
Physical Examinations 
The PE will be performed by the PI or a designee that is licensed to perform a PE per local 
requirements. The initial PE performed at Screening and the final PE conducted at the EOS visit 
will include examination of all pertinent body systems as defined by the site standard PE body 
systems (general appearance, HEENT, lymphatic, cardiovascular, respiratory, GI, 
musculoskeletal, neurological, dermatological). 
Subsequent PEs will be performed as shown in the Time and Events Schedule and will be 
targeted to any new signs or symptoms, any change from the previous status or any body system 
deemed pertinent to that subject by the PI (or designee). Clinically significant abnormalities 
should be recorded in the CRF; those occurring prior to dosing will be included in medical 
history unless the abnormality was the direct result of study participation. 
7.2.2. 
Vital Sign Measurements and ECGs 
Vital signs include pulse rate, respiratory rate, blood pressure, and body temperature. Vital signs 
should be measured after the subject has been supine for a minimum of 5 minutes. Site standard 
ranges will be used for determining any out-of-range values. 
Height and weight should be measured, and BMI calculated at Screening as indicated in the 
Time and Events Schedule. 
Resting 12-lead ECGs should be recorded at the visits indicated in the Time and Events Schedule 
after the subject has been supine for a minimum of 5 minutes. The PI (or designee) will evaluate 
the ECG tracings to determine if there are out-of-range values; if out-or-range values are 
detected, the PI (or designee) will determine if they are clinically significant. Site standard 
ranges will be used to determine if any parameters are considered out-of-range. At the discretion 
of the PI (or designee), the ECG may be repeated if erroneous readings are suspected. 


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7.2.2.1. 
Continuous 12-lead ECG Monitoring (Part 3 Only) 
Continuous 12-lead ECG monitoring using a digital recorder will take place at the times 
indicated in the Time and Events Schedule, in P3 only. 
All continuous 12-lead ECG data collected will be archived without extraction or analysis and 
will not be reported in the scope of this study.  
Subjects will be supine for at least 10 minutes before the extraction timepoint and for 5 minutes 
from the start of each extraction timepoint (each extraction will last for 5 minutes). 
Environmental distractions (e.g., television, radio, conversation) should be avoided during the 
pre-ECG resting period and during ECG recording. 
When coinciding, PK sampling should always be performed after the ECG extraction time 
window. If a separate ECG machine is being used for safety assessments, that machine should be 
in place prior to the extraction window to permit safety ECGs to be recorded irrespective of the 
extraction window. If the machine is not in place prior to the extraction window, safety ECGs 
must be recorded after the extraction window. If an integral system is used, safety ECGs may be 
recorded irrespective of the extraction window.  
7.2.3. 
Adverse Events and Concomitant Medications 
Adverse Events: The PI is responsible for identifying and documenting events meeting the 
definition of an AE or SAE (Section 8.1). Once each day while the subject is in the clinic and 
once during each out-patient visit, the PI (or designee) should inquire about the occurrence of 
AEs. The following are examples of open-ended questions that may be used to obtain this 
information: “How are you feeling?”; "Have you had any medical problems recently?"; "Have 
you taken any new medicines since your last visit/assessment?" 
All AEs and SAEs must be documented in the source documents and recorded in the CRF. 
Concomitant Medications: All medications (prescription or over-the-counter), nutritional 
supplements, and nutraceuticals taken by the subject from 30 days prior to dosing through the 
EOS visit must be recorded in the CRF. Medication information should include indication, dose, 
frequency, and route of administration. Any medication taken for an AE/SAE should be 
documented as such. Refer to Section 5.5 for additional information. 
7.3. 
Laboratory Evaluations 
The laboratory will perform standard routine testing, and processing of all blood samples. For the 
entire study, the amount of blood collected from any one subject will not exceed 500 mL. 
7.3.1. 
Routine Laboratory Panels 
Blood and urine samples will be collected at the times indicated in the 
Time and Events Schedule. The analytes shown in the table below (Table 11) will be assessed. 


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If a method to determine COVID-19 status becomes readily available, subjects may be tested at 
Screening and Check-in to confirm they are not positive for COVID-19 prior to dosing.  


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Table 11: Laboratory Evaluations 
CHEMISTRY PANEL 
Alanine Aminotransferase (ALT/SGPT) 
Albumin, Serum 
Albumin/Globulin (A/G) Ratio (calculation) 
Alkaline Phosphatase, Serum 
Amylase 
Aspartate Aminotransferase (AST/SGOT) 
Bilirubin, Total and Direct 
BUN 
BUN/Creatinine Ratio (calculation) 
Calcium, Serum 
Creatinine, Serum 
Creatinine Kinase (CK) 
Gamma Glutamyl Transferase (GGT) 
Lactate Dehydrogenase (LDH)  
Uric Acid 
Electrolyte Panel (Na+, K+, Cl-, Bicarb.) 
Phosphorus 
Globulin, Total  
Glucose, Serum 
Lipase 
Protein, Total, Serum 
HEMATOLOGY PANEL 
Hemoglobin 
Hematocrit 
White Blood Cell Count with differential (absolute and percentage) 
Red Blood Count 
Prothrombin Time (PT)/Partial Prothrombin Time (PTT) and International 
Normalized Ratio (INR) 
Mean cell hemoglobin (MCH), mean cell hemoglobin concentration (MCHC), 
mean cell volume (MCV), red cell distribution width (RDW; may be a 
Grade 1 abnormality) 
Platelets 
ADDITIONAL ASSESSMENTS 
Virology: Human Immunodeficiency Virus (HIV) serology, Hepatitis B Virus 
(HBV; Surface Antigen [HBsAg]), Hepatitis C Virus (HCV) 
Follicle-Stimulating Hormone (FSH; as applicable) 
PREGNANCY TEST 
Serum Pregnancy Test 
Urine Dipstick (optional blood follow-up) 
DRUG SCREENING 
Serum/urinalysis (per site SOP) 
Cotinine 
Urine Dipstick 
Alcohol Breathalyzer 
ROUTINE URINALYSIS 
Bilirubin 
Color and appearance 
Glucose 
Ketones  
Leukocytes 
Microscopic (including red blood cells [RBCs] and white blood cells [WBCs]) 
Nitrite 
Occult blood 
pH 
Protein 
Specific Gravity 
Urobilinogen 
7.3.2. 
Pharmacokinetic Sampling 
Samples for PK analysis will be collected as shown in the Time and Events Schedule. All 
samples will be analyzed to define the PK parameters for prodrug EIDD-2801 and the active 
parent, EIDD-1931. In order to preserve EIDD-2801, special handling procedures will be put in 
place. These procedures will be documented in the laboratory manual for the study. 
Depending on ongoing review of the PK data, timepoints may be modified or removed, and up to 
3 additional samples (in each period for the food-effect) may be added. 


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7.3.3. 
Peripheral Blood Mononuclear Cell Collection 
Peripheral blood mononuclear cells will be collected in P2 and P3. Blood will be collected into 
specialized tubes and processed according to procedures described in the laboratory manual. 
Depending on ongoing review of the data, timepoints may be modified or removed, and up to 
2 additional samples may be added. 
7.3.4. 
Urine Collection 
Urine will be collected over the time periods noted in the Time and Events Schedule. Samples 
will be collected for routine urinalysis and PK analysis according to site standard practices and 
as described in the laboratory manual. 


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8. 
SAFETY MONITORING, MANAGEMENT AND REPORTING 
8.1. 
Definitions 
8.1.1. 
Adverse Events 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product. 
Abnormal clinical laboratory findings (e.g. clinical chemistry, hematology) or other abnormal 
assessments that are judged by the PI (or designee) as clinically significant will be recorded as 
AEs or SAEs if they meet the definitions of an AE or an SAE as defined in this Section 8.1.2. 
Disease specific signs and symptoms which were ongoing prior to study entry will not be 
considered AEs unless they worsen (e.g. increase in frequency or severity) unexpectedly during 
the course of the trial. 
8.1.2. 
Serious Adverse Events 
An AE or suspected adverse reaction is considered “serious” if, in the view of either the PI (or 
designee) or Sponsor, it results in any of the following outcomes: 
 Death, 
 A life-threatening AE: An AE or suspected adverse reaction is considered 
“life-threatening” if, in the view of either the PI or Sponsor, its occurrence places the 
patient or subject at immediate risk of death. It does not include an AE or suspected 
adverse reaction that, had it occurred in a more severe form, might have caused 
death. 
 Inpatient hospitalization or prolongation of existing hospitalization, 
 A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions, or 
 A congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalizations may be considered serious when, based upon appropriate medical judgment they 
may jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 


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or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
Suspected adverse reaction means any AE for which there is a reasonable possibility that the 
drug caused the AE. “Reasonable possibility” means there is evidence to suggest a causal 
relationship between the drug and the adverse event. Suspected adverse reaction implies a lesser 
degree of certainty about causality than adverse reaction, which means any adverse event caused 
by a drug. 
An AE or suspected adverse reaction is considered “unexpected” if 
 It is not listed in the IB or is not listed at the specificity or severity that has been 
observed; or, if an IB is not required or available, 
 Is not consistent with the risk information described in the general investigational 
plan or elsewhere in the current application as amended. For example, under this 
definition, hepatic necrosis would be unexpected (by virtue of greater severity) if the 
IB referred only to elevated hepatic enzymes or hepatitis. Similarly, cerebral 
thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater 
specificity) if the IB listed only cerebral vascular accidents. 
 “Unexpected” as used in this definition, also refers to AE or suspected adverse 
reactions that are mentioned in the IB as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the particular drug under investigation. 
As of the date of this protocol, there are no expected events listed in the current version of the 
IB; therefore, all AEs will be considered unexpected until such a time that the reference safety 
information in the IB is updated with any identified, expected events. 
8.2. 
Documenting Adverse Events 
8.2.1. 
Timeframe for Collection and Follow-up of AEs/SAEs 
All AEs/SAEs will be collected from the time of the first study drug administration until the 
subject has completed the EOS visit and been discontinued from the study. This includes 
subjects who discontinue early. Events considered related to study drug will be followed as 
noted: 
 AEs that are related to study drug and continue beyond the normal collection period 
(i.e., are ongoing at the time a subject exits the study) will be followed until 
resolution, return to baseline or until stabilized with sequelae for a maximum of 
30 days following discontinuation. After 30 days, the AE will be closed, and the 
outcome noted (see Table 12). 
 SAEs that are related to study drug and continue beyond the normal collection period 


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(i.e., are ongoing at the time a subject exits the study) will be followed until 
resolution, return to baseline or until stabilized with sequelae. 
 Serious AEs that are reported to the site within 30 days after the subject has been 
discontinued from the study (i.e., completed the EOS visit) will be recorded. Those 
that are considered related to study drug will be followed as noted in the bullet 
above. 
Note that all events which occurred prior to dosing with study drug should be recorded as 
medical history unless the event is directly related to study procedures. 
8.2.2. 
Recording of Adverse Events/Serious Adverse Events 
AEs/SAEs must be recorded in the CRF as indicated in the CRF completion instructions. 
Information to be collected includes event description, time of onset, clinician’s assessment of 
severity (Section 8.2.3), relationship to study drug (Section 8.2.4), outcome (Section 8.2.5), and 
time of resolution/stabilization of the event. All AEs occurring while on study must be 
documented appropriately regardless of relationship and will be followed to adequate resolution 
as described above (Section 8.2.1). All SAEs will be recorded as noted above; SAEs reported to 
the site within 30 days following the EOS visit will also be recorded. All SAEs must be entered 
onto the SAE form and reported as discussed below (Section 8.3.1). 
If an AE changes in severity, the highest severity will be recorded in the CRF. AEs characterized 
as intermittent require documentation of onset and duration of each episode. 
8.2.3. 
Assessing Severity of Adverse Events 
All AEs/SAEs will be assessed by the PI or those with the training and authority to make a 
medical judgment. AEs/SAEs will be graded according to the DMID Toxicity Grading Scale. 
For any AEs not specifically listed in the tables, the following guidelines should be used to grade 
severity: 
 Mild (Grade 1); asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
 Moderate (Grade 2); minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living. 
 Severe (Grade 3); medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care activities of daily living. 
o Life-threatening; life-threatening consequences; urgent intervention 
indicated. 
o Death; death related to AE. 


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Changes in the severity of an AE should be documented to allow an assessment of the duration 
of the event at each level of intensity to be performed. Adverse events characterized as 
intermittent require documentation of onset and duration of each episode. 
8.2.4. 
Relationship to Study Drug 
The PI’s (or designee’s) assessment of an AE’s relationship to study drug is part of the 
documentation process, but it is not a factor in determining what is or is not reported in the study. 
If there is any doubt as to whether a clinical observation is an AE, the event should be reported. 
All AEs must have their relationship to study product assessed using the terms: related or not 
related. In a clinical trial, the study product must always be suspect. To help assess, the following 
guidelines are used. 
 Definite – The AE is clearly related to the study drug. 
 Probable – The AE is likely related to the study drug. 
 Possible – The AE may be related to the study drug. 
 Unlikely – The AE is doubtfully related to the study drug. 
 Unrelated – The AE is clearly NOT related to the study drug. 
8.2.5. 
Classifying Adverse Event Outcome 
All AEs/SAEs in the study must be assigned an outcome by site staff. The outcome will be 
included on the AE CRF. Possible outcomes are shown below: 
Table 12: Adverse Event Outcomes 
Outcome 
Description 
Recovered / Resolved 
AE resolved with no residual signs or symptoms; an event is considered resolved if it 
returns to baseline (pretreatment) values. 
Recovered / Resolved with sequelae 
AE stabilized but residual signs or symptoms remain; this includes stabilization of an 
event/condition with the expectation that it will remain chronic. 
Not Recovered / Not Resolved 
AE remains ongoing AND no or only minimal improvement has occurred. 
Ongoing 
AE has not yet resolved, but continues to improve/resolve and complete resolution is 
expected over time. 
Fatal 
Outcome of the AE is death. 
Unknown 
AE outcome is not known; usually because the subject has been Lost-to-Follow-up. 


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8.3. 
Reporting Procedures 
8.3.1. 
Serious Adverse Events 
The PI or clinical site personnel should notify Covance Drug Safety Services (DSS) 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 Notification 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. 
The responsibilities of Covance DSS include the following: 
 Prepare an AE reporting plan prior to the start of the study. Where this plan differs from 
the applicable site standard operating procedure on SAE reporting, the AE reporting plan 
will always take precedence. 
 Receive and review SAE report forms from the site and inform the Sponsor of the SAE 
within 1 working day of the initial notification to DSS. Drug Safety Services will delete 
any information from the SAE report forms that may identify the subject. 
 Write case narratives and enter the case into Covance’s safety database as defined in the 
AE reporting plan. 
 Produce appropriate reports of all Suspected Unexpected Serious Adverse Reactions and 
forward to the EC, Medicines and Healthcare Products Regulatory Agency, PI’s (or 
designee’s), and the Sponsor within the timeframes stipulated in the Clinical Trials 
Directive Guideline (ENTR/CT 3).  
The responsibility for reporting SAEs will be transferred to the Sponsor 28 days after the end of 
the study. 
8.3.2. 
Pregnancy 
Subjects in this study must be of non-childbearing potential. However, should a pregnancy occur 
any time from informed consent to the EOS visit, subjects must immediately report the event to 
the clinical site which in turn must immediately report the pregnancy to the Sponsor or their 
designee. The subject will be followed until the end of the pregnancy. A separate ICF will be 
used for consenting for follow-up pregnancy activities. Pregnancy will not be considered an AE 
unless deemed likely related to study drug. Pregnancy will not be considered an SAE unless there 
is an associated SAE. A spontaneous abortion (miscarriage) or abnormal outcome (including 
congenital anomalies) will be reported as an SAE. 


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8.4. 
Unmasking Treatment Assignment 
The following controls will be employed to maintain the double-blind status of the study: 
 Placebo will be identical in appearance to the EIDD-2801. 
 The PI and other members of staff involved with the study will remain blinded to the 
treatment randomization code in P1 and P3. 
 Interim bioanalytical data will be provided in a blinded manner. 
To maintain the blind, the PI will be provided with a sealed randomization code for each subject 
in P1 and P3, containing details of their treatment. These individual sealed envelopes will be 
kept in a limited access area that is accessible 24 hours a day. In order to manage subject safety 
or to support dose-escalation decisions (in the event of possibly treatment-related SAEs or severe 
AEs), the decision to unblind resides solely with the PI. Whenever possible and providing it does 
not interfere with or delay any decision in the best interest of the subject, the PI will discuss the 
intended code-break with the Sponsor. If it becomes necessary to break the code during the 
study, the date, time, and reason will be recorded in the subject’s source data and on the 
individual envelope and will be witnessed by a second person. 
The pharmacy and bioanalytical lab will have access to the treatment randomization and will be 
unblinded. Pharmacokinetic personnel may be unblinded to perform interim PK analysis and to 
ensure that PK data are provided in a blinded manner for dose-escalation decisions.  


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9. 
DOSE-ESCALATION AND HALTING RULES 
9.1. 
Guidelines for Dose-Escalation 
Doses will be administered in an escalating manner following satisfactory review by the Sponsor 
and PI of the blinded safety and tolerability data up to 72 hours post final dose. 
 
 
 
 
 
As PK data become available, these data will be reviewed and 
may be used to assist in dose selection. 
Doses may be reduced and may be lower than the starting dose. There will be a minimum of 
4 days between dose escalations to allow sufficient time for an adequate safety review. 
 
 
 
Integrated data from all applicable sites will be used to make dose-escalation decisions. 
Dose-escalation in P1 and P3 will only occur if data from a minimum of 6 subjects (across all 
sites) have been reviewed from the previous lower dose group, such that data from a minimum of 
4 subjects (across all sites) who have received EIDD-2801 will be used to make the 
dose-escalation decision. 
The justification for this is as follows: 
 The study treatment is of a known pharmacological class for which the on-target effects 
in humans are well characterized. Based upon nonclinical data, no clinically important off 
target effects are expected within the proposed dose range. 
 A minimum of 4 subjects receiving the active drug is considered sufficient to characterize 
the safety profile of EIDD-2801. 
Between each dose-escalation, the PI will review all available data in a blinded manner to ensure 
it is safe to proceed with the planned dose-escalation. The results from all available safety 
assessments will be sent to the Sponsor prior to the start of each successive group/treatment 
period. Any clinically significant results will be discussed with the Sponsor before 
dose-escalation continues. Interim PK data may also be reviewed in terms of dose-escalation and 
to confirm that the study design remains appropriate. In the event of a disagreement between 
Sponsor and PI on the dose-escalation decision, the most conservative decision will be upheld. 
Dose levels will not increase by more than 3-fold for predicted nonpharmacologically active 
dose levels and by 2-fold for predicted pharmacologically active dose levels. 
 


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Dose levels in P3 may be repeated for collection of PBMCs, providing that the dose level did not 
meet the dose-escalation halting criteria. 
9.2. 
Dose-Escalation Halting Rules 
For Group 1 in P1, sentinel dosing will occur whereby 2 subjects (1 active and 1 PBO) will be 
dosed on 1 day and, providing no safety concerns arise, the remaining 6 subjects will be dosed 
after at least 24 hours. 
The study will be halted (i.e., no further dosing will occur) if one or more subjects experience an 
SAE that is considered to be related to EIDD-2801 or 2 or more subjects in the same group 
experience severe AEs that are considered to be related to EIDD-2801. If, following an internal 
safety review, the Sponsor deems it appropriate to restart the study, this can be done following 
approval of a substantial protocol amendment.  
Additionally, if 2 or more subjects experience a reduction of platelets greater than 50% over 
baseline levels or a reduction in lymphocytes (absolute count) to Grade 3/severe levels without 
an alternate cause, the PI and Sponsor will review the data. If, after review of unblinded data, it 
is determined that these events are probably related to study drug, no further dose escalations 
will occur. In this case, additional cohorts may be enrolled at a lower dose. 
Dose-escalation will stop if clinically relevant signs or symptoms of similar nature occur in 2 or 
more subjects in a group that, in the opinion of the PI, warrant stopping of dose-escalation. 


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10. 
STATISTICAL CONSIDERATIONS 
10.1. 
General Considerations 
All summaries will be provided by study part and treatment. Continuous variables will be 
summarized using descriptive statistics including number of observations (n), mean, standard 
deviation, minimum (min), median (med), and maximum (max). Categorical variables will be 
summarized using frequency counts and percentages. Note that PBO data from each dose level in 
Parts 1 and 3 will be combined into one PBO group. 
No missing data imputation will be performed. 
Subject listings will be provided for all the data collected during the study period. 
Specific information about the statistical analysis will be provided in a SAP that will be reviewed 
and approved by the Sponsor and will be finalized before final database lock. If there is a 
discrepancy between the methods described in the protocol and final approved SAP, the SAP 
will take precedence. 
10.2. 
Sample Size Considerations 
No formal sample size calculation was conducted. The sample size of 8 per cohort 
(6 active: 2 PBO) for the SAD and MAD cohorts is considered adequate for a Phase 1 FIH study. 
The sample size of 10 subjects (all administered EIDD-2801) is in accordance with FDA 
guidelines for sample size in FE studies. 
10.3. 
Analysis Populations 
Safety Population: All subjects who receive at least one dose of study drug. 
Pharmacokinetic Population: All subjects receiving study drug who comply sufficiently with 
protocol requirements (i.e., no major protocol violations) and for whom a sufficient number of 
analyzable PK samples have been obtained to permit the determination of the PK profile for 
EIDD-2801/EIDD-1931 and the statistical analysis of the results. Subjects who experience an 
AE of vomiting before 2× the median tmax of the group may be excluded from the PK population. 
10.4. 
Analysis of Safety Data 
All safety analyses will be performed on the Safety Population as defined in Section 10.3. Safety 
will be assessed on the basis of AEs, clinical laboratory data, vital signs, ECG parameters, and 
PEs. 
10.4.1. 
Extent of Exposure 
Dosing data will be listed by study part. 


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10.4.2. 
Adverse Events 
Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
preferred term and system organ classification. Any events reported after the initiation of study 
treatment and through the EOS are defined as treatment-emergent. The occurrence of 
treatment-emergent AEs will be summarized using MedDRA preferred terms, system organ 
classifications, and severity. Separate summaries of treatment-emergent SAEs and AEs 
considered related to study treatment and AEs leading to study treatment discontinuation will be 
generated. All AEs will be listed for individual subjects showing both verbatim and preferred 
terms. 
10.4.3. 
Clinical Laboratory Results 
Laboratory abnormalities will be graded according to the DMID Toxicity Grading Scale. Any 
graded abnormality that occurs following the initiation of study treatment and represents at least 
a one-grade increase from the baseline assessment is defined as treatment-emergent. The number 
and percentage of subjects experiencing treatment-emergent graded toxicities will be 
summarized. Raw values and mean changes from baseline in clinical laboratory measures will be 
summarized. 
Listings of the clinical laboratory test results will be provided. Abnormal laboratory values will 
be flagged in the listings. 
10.4.4. 
Other Parameters 
Individual data for ECG parameters and vital sign measurements will be listed by subject and 
time point and summarized for each treatment. Individual data for PE will be listed by subject 
and time point. 
Concomitant medications will be coded using the World Health Organization-Drug Dictionary 
(WHO-DD) and summarized. 
10.5. 
Analysis of Pharmacokinetic Data 
Pharmacokinetic analysis as defined in the SAP will be conducted using the PK population 
defined in Section 10.3. In the event of discrepancies between analyses described in the SAP and 
this clinical study protocol, the SAP will supersede the protocol. 
 All samples will be analyzed and all concentrations listed. 
 Descriptive statistics will be performed for all time points available, with the 
exclusion of subjects who had any significant protocol deviation. 
 Pharmacokinetic parameters will be derived where possible for all subjects. Data 
from subjects with incomplete profiles (missed blood draws, lost samples, samples 
unable to be quantified) may be used if PK parameters can be estimated using the 
remaining data points. 


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 Descriptive statistics will be performed on all parameters available, and any missing 
parameters will be flagged. 
Plasma concentration data for EIDD-2801 and EIDD-1931 will be listed for individual subjects 
and summarized by study part and treatment. Individual and mean plasma concentration versus 
time plots for EIDD-2801 and EIDD-1931 will be provided. Urine concentration data for 
EIDD-2801 and EIDD-1931 will be listed. 
Plasma PK parameters of EIDD-2801 and EIDD-1931 for each subject will be estimated over the 
sampling interval using noncompartmental analysis and summarized by study part and treatment 
using descriptive statistics. Actual blood sampling times will be used for plasma PK analysis. 
Urine PK parameters of EIDD-2801 and EIDD-1931 will also be analyzed and summarized 
when possible. The PK parameters that will be estimated are listed in the table below.  
Table 13: Pharmacokinetic Parameters 
Plasma PK Parameter 
Description 
AUClast 
The area under the plasma concentration-time curve, from time 0 to the last measurable 
non-zero concentration, as calculated by the linear up/log down trapezoidal method (P1 and 
P2 only). 
AUC0-inf 
The area under the plasma concentration-time curve from time 0 extrapolated to infinity. 
AUC0-inf is calculated as the sum of AUClast plus the ratio of the last measurable plasma 
concentration to the elimination rate constant (λz) (P1, P2, and Day 1 dose of P3). 
Cmax 
Maximum observed concentration. 
tmax 
Time to reach Cmax. If the maximum value occurs at more than one time point, tmax is 
defined as the first time point with this value. 
λz 
Apparent terminal elimination rate constant; represents the fraction of medication 
eliminated per unit time. 
t½ 
Apparent terminal elimination half-life of medication, calculated as 0.693/λz. 
Vz/F 
Apparent volume of distribution (EIDD-2801 only). 
CL/F 
Apparent oral drug clearance (EIDD-2801 only). 
Ctrough 
Trough concentration (P3 only). 
AUCτ 
The area under the plasma concentration-time curve during a dosing interval (P3 only). 
RAAUCτ 
Observed accumulation ratio based on AUCτ (P3 only). 
RACmax 
Observed accumulation ratio based on Cmax (P3 only). 
Urine PK Parameter 
Description 
Ae 
Amount excreted in urine over the sampling interval. 
Fe 
Fraction of drug excreted in the urine over sampling interval. 
CLR 
Renal clearance, CLR = Ae/AUC where both Ae and AUC are determined over co-incident 
time ranges after dosing. 
Additional PK parameters may be analyzed as appropriate. 


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10.5.1. 
Statistical Analysis of Pharmacokinetic Data 
10.5.1.1. Dose Proportionality 
In P1, dose-proportionality for PK parameters of EIDD-2801 and EIDD-1931 (AUC0-inf, AUClast, 
and Cmax) will be assessed by the power model. The slope and the associated 90% CI based on 
the power model will be reported. 
In Part 3 on Day 6 dose-proportionality for PK parameters of EIDD-2801 and EIDD-1931 
(AUCτ, and Cmax) will be assessed by the power model. The slope and the associated 90% CI 
based on the power model will be reported. 
10.5.1.2. Food-Effect 
To assess the effect of food on the PK of EIDD-2801 and EIDD-1931, natural log transformed 
PK parameters from P2 (AUC0-inf, AUClast, and Cmax) will be analyzed using a mixed-effects 
model with fixed-effect terms for treatment (with or without food), period, and sequence and 
with subject within sequence as a random effect. Point estimates and their associated 90% CIs 
for the natural log-transformed PK parameters for the difference between EIDD-2801 
administered under fed relative to fasted conditions will be constructed. The point estimates and 
interval estimates will be back transformed to give estimates of the ratio and 90% CI for the 
geometric least squares mean ratio for fed/fasted to assess the effect of food. 
10.6. 
Peripheral Blood Mononuclear Cells 
Peripheral blood mononuclear cellss will be collected from subjects following each dose in P2. 
Depending upon ongoing review of the data, PBMCs may be collected from subjects in P3; the 
collection of these samples may be omitted from some cohorts in P3. 
The PBMCs will be stored for analysis of EIDD-2061 levels at some point in the future and 
reported separately. 
10.7. 
Interim Analyses 
There are no formal interim analyses planned for this study. However, interim analyses may be 
implemented at the discretion of the Sponsor or health authority request. In addition, data from 
P1 cohorts may be locked, unblinded, and analyzed prior to conducting P2 and P3. 


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11. 
STUDY ADMINISTRATION 
11.1. 
Regulatory and Ethical Considerations 
11.2. 
Ethical Standard 
This study will be conducted in accordance with the protocol and with the following: 
 Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
International Ethical Guidelines. 
 Applicable ICH GCP Guidelines. 
 United States CRFs applicable to clinical studies (45 CFR Part 46; 21 CFR Part 50, 21 
CFR Part 56, and 21 CFR Part 312). 
 Applicable laws and regulations. 
11.2.1. 
Ethics Committee Approval 
The PI (or designee) must ensure that all required study-specific documents and/or information 
are submitted to the EC for review and approval as appropriate including but not limited to: 
 the protocol and any future protocol amendments 
 ICF and any other documents (electronic or paper) given to the subject 
 IB 
Any substantial protocol amendments, likely to affect the safety of the subjects or the conduct of 
the study, will require EC and regulatory authority (as locally required) approval before 
implementation of changes made to the study design, except for changes necessary to eliminate 
an immediate hazard to study subjects or any nonsubstantial changes, as defined by regulatory 
requirements. 
11.2.2. 
Informed Consent 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continuing throughout the individual’s study participation. Extensive discussion of 
risks and possible benefits of this therapy will be provided to the subjects and, if applicable, their 
families. Consent forms describing in detail the study interventions/products, study procedures, 
and risks are given to the subject and written documentation of informed consent is required 
prior to starting any screening procedures or intervention/administering study product. Consent 
forms will be EC-approved and the subject will be asked to read and review the document. 


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Upon reviewing the document, the PI (or designee) will explain the research study to the subject 
and answer any questions that may arise. The subjects will sign the ICF prior to any procedures 
being done specifically for the study. The subjects should have the opportunity to discuss the 
study with their surrogates or think about it prior to agreeing to participate. The subjects may 
withdraw consent at any time throughout the course of the trial. A copy of the ICF will be given 
to the subjects for their records. The rights and welfare of the subjects will be protected by 
emphasizing to them that the quality of their medical care will not be adversely affected if they 
decline to participate in this study. 
11.3. 
Financing and Insurance 
Financing and insurance will be addressed in a separate agreement. 
11.4. 
Source Documentation and Access 
The site will maintain appropriate medical and research records in compliance with ICH E6, 
Section 4.9 and regulatory and institutional requirements for the protection of confidentiality of 
subjects. The site will permit authorized representatives of the Sponsor, its designees, and 
appropriate regulatory agencies to examine (and when required by applicable law, to copy) 
clinical records for the purposes of quality assurance reviews, audits, and evaluation of the study 
safety and progress. These representatives will be permitted access to all source data and source 
documents, which include, but are not limited to, clinical and office charts, laboratory notes, 
memoranda, subjects’ memory aid or evaluation checklists, pharmacy dispensing records, 
recorded data from automated instruments, copies or transcriptions certified after verification as 
being accurate and complete, photographic negatives, microfilm or magnetic media, x-rays, and 
subject files and records kept at the pharmacy, at the laboratory, and medico-technical 
departments involved in the clinical trial. 
11.5. 
Data Collection and Record Keeping 
11.5.1. 
Data Collection 
Data collection and data entry are the responsibility of the clinical trial staff at the site. The PI is 
responsible for ensuring the accuracy, completeness, legibility, and timeliness of the data 
reported. All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data. 
A CRF must be completed for every subject who signs the ICF and has at least one 
protocol-specified assessment conducted. The CRF must be completed and processed according 
to the CRF guidelines and the SOPs of the site. All data should be entered into the CRF, where 
possible, within 3 days after each visit for any one subject. After the subject has completed the 
study, the PI must review and sign the signature page of the CRF indicating that he has reviewed 
the completed CRF and pertinent clinical data for that subject and that, to the best of his 
knowledge, all data recorded in the CRF accurately reflects the subject’s clinical performance in 
the study 


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11.5.2. 
Study Records Retention 
Study documents should be retained for a minimum of 5 years after the end of the study. These 
documents should be retained for a longer period; however, if required by local regulations. No 
records will be destroyed without the written consent of the Sponsor, if applicable. It is the 
responsibility of the Sponsor to inform the PI when these documents no longer need to be 
retained. 
11.5.3. 
Protocol Deviations 
A protocol deviation is any noncompliance with the protocol or study procedures detailed in the 
laboratory or pharmacy manuals. The noncompliance may have been the result of action by the 
PI, site staff, or subject. All deviations should be handled in accordance with site SOPs. 
It is the responsibility of the site to use continuous vigilance to identify and report deviations 
within 5 working days of identification of the protocol deviation, or within 5 working days of the 
scheduled protocol-required activity. 
11.6. 
Clinical Monitoring 
Site monitoring is conducted to ensure that the human subjects’ protections, study and laboratory 
procedures, study intervention administration, and data collection processes are of high quality 
and meet Sponsor, ICH/GCP guidelines and applicable regulations, and that this trial is 
conducted in accordance with the protocol, protocol-specific MOP and applicable Sponsor SOPs. 
Experienced clinical monitors of the Sponsor or its designee will conduct site-monitoring visits 
as detailed in the clinical monitoring plan. 
Site visits will be made at standard intervals as defined by the Sponsor and may be made more 
frequently as directed by the Sponsor. Monitoring visits will include, but are not limited to, 
review of regulatory files, accountability records, CRFs, ICFs, medical and laboratory reports, 
and protocol and GCP compliance. Clinical monitors will have access to each participating site, 
study personnel, and all study documentation according to the site monitoring plan. Clinical 
monitors will meet with the site PI to discuss any problems and actions to be taken and will 
document site visit findings and discussions. As data are entered into a CRF, data will be 
monitored to ensure accuracy as well as adherence to data entry instructions provided in the CRF 
guidelines. 
11.7. 
Quality Control and Quality Assurance 
A quality management plan will be put in place for this study. The site is responsible for 
conducting routine quality assurance and quality control activities to internally monitor study 
progress and protocol compliance. The PI will provide direct access to all study-related sites, 
source data/data collection forms, and reports for the purpose of monitoring and auditing by the 
Sponsor, and inspection by local and regulatory authorities. The PI will ensure all study 
personnel are appropriately trained and applicable documentations are maintained on site. 


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11.8. 
Study Termination and Closure Procedures 
11.8.1. 
Study Termination 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided to the site. If the study is terminated or suspended, the PI (or 
designee) will inform study participants and the EC. The Sponsor will notify appropriate 
regulatory authorities. The Sponsor will provide the reason(s) for the termination or suspension. 
Study participants will be contacted, as applicable, and be informed of changes to study visit 
schedule. 
If suspended, the study may resume once issues that caused suspension of the study are resolved. 
11.8.2. 
Termination Procedures 
If the study is prematurely terminated, then the site must return all appropriate study data, 
resolve all data queries, complete final drug accountability, return any study drug remaining on 
site, and ship all biological samples (including PK and PBMCs) to the laboratory designated by 
the Sponsor. The PI (or designee) must notify the EC of study termination. 
11.9. 
Information Disclosure 
11.9.1. 
Confidentiality 
Subject confidentiality and privacy is strictly held in trust by the PI, site staff, and the Sponsor(s) 
and their agents. The study protocol, documentation, data, and all other information generated 
will be held in strict confidence. No information concerning the study or the data will be released 
to any unauthorized third party without prior written approval of the Sponsor. 
The study monitor or other authorized representatives of the Sponsor or regulatory agencies may 
inspect all documents and records required to be maintained by the PI, including but not limited 
to, medical records (office, clinic, or hospital) and pharmacy records for the participants in this 
study. The clinical study site will permit access to such records. 
The study participant’s contact information will be securely stored at the clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by the Sponsor, site, or regulatory requirements. 
Study participant research data will be transmitted to and stored securely by the Sponsor’s 
designated data center. This will not include the participant’s contact or identifying information. 
Individual participants and their research data will be identified by a unique study identification 
number. The study data entry and study management systems used by clinical sites will be 
secured and password-protected. At the end of the study, all study databases will be de-identified 
and archived at a secure location. 


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11.9.2. 
Clinicaltrials.gov 
This clinical study will be registered on clinicaltrials.gov as required. 
11.9.3. 
Publication Policy 
All information generated from this study is the proprietary property of the Sponsor. It is the 
intent of the Sponsor to publish the results of the study in their entirety as deemed appropriate. 


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12. 
REFERENCES 
Agostini ML, Pruijssers AJ, Chappell JD, Gribble J, Lu X, Andres EL, et al. Small-Molecule 
Antiviral β-d-N4-Hydroxycytidine Inhibits a Proofreading-Intact Coronavirus with a High 
Genetic Barrier to Resistance. J Virol. 2019 Dec 15;93(24).  
Flavell RA, Sabo DL, Bandle EF, Weissmann C. Site-directed mutagenesis: generation of an 
extracistronic mutation in bacteriophage Q beta RNA. J Mol Biol. 1974 Oct 25;89(2):255–72.  
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 Dec;48(12):4636–42.  
Mullins JI, Heath L, Hughes JP, Li D, Essigmann JM, Harris KS, et al. Mutations based on viral 
decay acceleration in the HIV-1 genomes of a clinical population treated with the mutagenic 
nucleoside KP1461. Retrovirology. 2011 Oct 3;8(Suppl 2):P84.  
Painter GR, Bowen RA, Bluemling GR, DeBergh J, Edpuganti V, Gruddanti PR, et al. The 
prophylactic and therapeutic activity of a broadly active ribonucleoside analog in a murine model 
of intranasal venezuelan equine encephalitis virus infection. Antiviral Res. 2019;171:104597.  
Sticher ZM, Lu G, Mitchell DG, Marlow J, Moellering L, Bluemling GR, et al. Analysis of the 
Potential for N4-Hydroxycytidine To Inhibit Mitochondrial Replication and Function. 
Antimicrob Agents Chemother. 2020 27;64(2).  
Stuyver LJ, Whitaker T, McBrayer TR, Hernandez-Santiago BI, Lostia S, Tharnish PM, et al. 
Ribonucleoside analogue that blocks replication of bovine viral diarrhea and hepatitis C viruses 
in culture. Antimicrob Agents Chemother. 2003 Jan;47(1):244–54.  
Toots M, Yoon J-J, Cox RM, Hart M, Sticher ZM, Makhsous N, et al. Characterization of orally 
efficacious influenza drug with high resistance barrier in ferrets and human airway epithelia. Sci 
Transl Med. 2019 Oct 23;11(515):eaax5866.  
Urakova N, Kuznetsova V, Crossman DK, Sokratian A, Guthrie DB, Kolykhalov AA, et al. 
β-d-N4-Hydroxycytidine Is a Potent Anti-alphavirus Compound That Induces a High Level of 
Mutations in the Viral Genome. J Virol. 2018 01;92(3).  
Yoon J-J, Toots M, Lee S, Lee M-E, Ludeke B, Luczo JM, et al. Orally Efficacious 
Broad-Spectrum Ribonucleoside Analog Inhibitor of Influenza and Respiratory Syncytial 
Viruses. Antimicrob Agents Chemother. 2018;62(8). 


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13. 
APPENDICES 
Appendix 1: 
Time and Events Schedule 
Parts 1 and 2 
Visit 
Screening 
(Days -28 to -2) Day -1 Day 1 Day 2 
(24 hr) 
Day 3 
(48 hr) 
Day 4 
(72 hr) Day 9 
Day 15 / EOS1 
(non-FE cohorts) 
Food-Effect Cohort 
Day 14 Day 15 Day 16 
(24 hr) 
Day 17 
(48 hr) 
Day 18 
(72 hr) Day 23 
Day 30 / EOS 
ICF; Demography 
x 
 
 
 
 
 
 
 
I/E; Medical history 
x 
x 
 
 
 
 
 
 
Physical examination2 
x 
x 
 
x 
 
x 
x 
x 
Qualifying laboratory analyses3 
x 
x 
 
 
 
 
 
 
Drug screening and pregnancy test4 
x 
x 
 
 
 
 
x 
x 
Height, weight (BMI) 
x 
 
 
 
 
 
 
 
Clinic confinement5 
 
x 
x 
x 
x 
x 
 
 
Non-residential visit 
x 
 
 
 
 
 
x 
x 
Clinical chemistry and urinalysis6 
x 
x 
 
x 
 
x 
x 
x 
Hematology7 
x 
x 
 
x 
x 
x 
x 
x 
PBMC collection (FE cohort ONLY) 
 
 
x8 
x8 
 
 
 
 
ECG 
x 
 
x9 
 
 
x 
 
x 
Vital signs 
x 
x 
x10 
x 
x 
x 
x 
x 
Administer study drug 
 
 
x 
 
 
 
 
 
Plasma PK sample collection 
 
 
x11 
x12 
x12 
x12 
 
 
Urine PK sample collection 
 
 
x13 
x14 
x14 
 
 
 
Adverse events 
x15 
x15 
x15 
x 
x 
x 
x 
x 
Prior and/or Concomitant medications 
x 
x 
x 
x 
x 
x 
x 
x 
Abbreviations: BMI (body mass index); EOS (End of Study); FE (food-effect); ICF (Informed Consent Form); I/E 
(Inclusion/Exclusion Criteria); ECG (electrocardiogram); PBMC (peripheral blood mononuclear cell); PK (pharmacokinetic). 
1 On Day 15, conduct the EOS visit for all subjects except those in the FE cohort. 
2 A complete PE will be performed at Screening and/or Check-in, and EOS visits; on all other days, a limited PE will be 
conducted targeting any change from the previous status or any body system deemed pertinent to that subject by the PI (or 
designee).  
3 Laboratory analyses to qualify for study entry include: total white cell count or absolute lymphocyte count (values must be in 
the normal range), hemoglobin or platelet levels (values must not be below the lower limit of normal), and ALT/SGPT, alkaline 
phosphatase, AST/SGOT (values must not be above the upper limit of normal), plus virology (HIV/HCV/HBV; tested at 
Screening only; all must be negative), and FSH (if required). 
4 Drug screening (urine drug screen, UDS), including a cotinine test, should be conducted at Screening, Day -1, Days 9 and 23, 
and at EOS. Pregnancy tests should be conducted in serum at Screening and in urine at all other times (i.e., Days -1, 9, and 23, 
and EOS). A positive urine pregnancy test will be confirmed with a serum pregnancy test. An alcohol breath test should be 
conducted at Screening and Day -1. 
5 Participants should be admitted to the clinic following review of final I/E criteria on Day -1 and discharged from the clinic 
following completion of study specific assessments on Day 4. Subjects in the FE cohort should be readmitted to the clinic on 
Study Day 14. 
6 Safety laboratory assessments include clinical chemistry and urinalysis. Baseline samples will be collected after clinic 
admission on Day -1.  
7 Hematology values include, but are not limited to, RBC, WBC with differential and platelets. PT/PTT and INR assessed only at 


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Screening. 
8 PBMCs will be collected 2 hr postdose on Day 1/15, and predose and 8 hrs postdose (on Day 16). Depending on ongoing 
review of the data, timepoints may be modified or removed, and up to 2 additional samples may be collected. 
9 The baseline ECG should be conducted prior to dosing on Day 1/15. 
10 Vital signs include pulse rate, respiratory rate, blood pressure, and body temperature; on Day 1/15, VS should be taken 
predose, and at 2, 4, 8 and 12 hr postdose.  
11 PK samples should be collected predose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 9, 12, and 15 hr postdose on Day 1/15. Depending on 
ongoing review of the PK data, timepoints may be modified or removed, and up to 3 additional samples (in each period for the 
food-effect) may be added. 
12 PK samples should be collected at 24, 36, 48, and 72 hr postdose on Days 2/16, 3/17, 4/18 respectively. Depending on ongoing 
review of the PK data, timepoints may be modified or removed, and up to 3 additional samples (in each period for the 
food-effect) may be added. 
13 Urine samples for PK analysis should be collected predose (spot collection), and from 0 to 4, 4 to 8, 8 to 12, and 12 to 24 hr 
postdose. 
14 Urine samples for PK analysis should be collected from 24 to 36 and 36 to 48 hr postdose. 
15 Adverse events occurring prior to study drug administration should be recorded as medical history unless the event is directly 
related to a study specified procedure. 
 
 


Clinical Study Protocol: EIDD-2801-1001-UK 
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Part 3 
Visit
Screening 
(Days -28 to 
-2) 
Day -1 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 Day 9 Day 14 
Day 
20 
/EOS 
ICF; Demography 
x 
 
 
 
 
 
 
 
 
 
 
 
 
I/E; Medical history 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
Physical examination1 
x 
x 
 
x 
 
 
 
 
x 
 
 
x 
x 
Qualifying laboratory 
analyses2 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
Drug screening and 
pregnancy test3 
x 
x 
 
 
 
 
 
 
 
 
 
x 
x 
Height, weight (BMI) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Clinic confinement4 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Non-residential visit 
x 
 
 
 
 
 
 
 
 
 
 
x 
x 
Clinical chemistry and 
urinalysis5 
x 
x 
 
 
x 
 
 
x 
 
 
x 
 
x 
Hematology6 
x 
x 
 
 
x 
 
 
x 
 
 
x 
x 
x 
PBMC collection7 
 
 
x 
 
 
 
 
x 
 
 
 
 
 
ECG8 
x 
 
x 
 
 
 
 
x 
 
 
x 
 
x 
Continuous 12-lead 
ECG 
 
 
x9 
 
 
 
 
x10 
 
x10 
 
 
x 
Vital signs11 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Administer study 
drug12 
 
 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
Plasma PK sample 
collection13 
 
 
x 
 
 
x 
 
x 
x 
x 
x 
x 
 
Urine PK sample 
collection14 
 
 
x 
 
 
 
 
x 
x 
x 
x 
 
 
Adverse events 
x15 
x15 
x15 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Prior and/or 
Concomitant 
medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Abbreviations: BID (twice daily); BMI (body mass index); EOS (End of Study); ICF (Informed Consent Form); I/E 
(Inclusion/Exclusion Criteria); ECG (electrocardiogram); PK (pharmacokinetic). 
1 A complete PE will be performed at Screening and/or Check-in, and EOS visits; on all other days, a limited PE will be 
conducted targeting any change from the previous status or any body system deemed pertinent to that subject by the PI (or 
designee). 
2 Laboratory analyses to qualify for study entry include: total white cell count or absolute lymphocyte count (values must be in 
the normal range), hemoglobin or platelet levels (values must not be below the lower limit of normal), and ALT/SGPT, alkaline 
phosphatase, AST/SGOT (values must not be above the upper limit of normal), plus virology (HIV/HCV/HBV; tested at 
Screening only; all must be negative), and FSH (if required). 
3 Drug screening (urine drug screen, UDS), including cotinine, should be conducted at Screening, Day -1, Day 14, and at EOS. 
Pregnancy tests should be conducted in serum at all timepoints. An alcohol breath test should be conducted at Screening and 
Day -1. 
4 Participants should be admitted to the clinic following review of final I/E criteria on Day -1 and discharged from the clinic 
following completion of study specific assessments on Day 9. 
5 Safety laboratory assessments include clinical chemistry and urinalysis. Baseline samples will be collected after clinic 
admission on Day -1. On Days 3 and 6, the assessment will be pre-am dose. On Day 9, the assessment will be 72 hrs post-am 
dose on Day 6. 


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6 Hematology values include, but are not limited to, RBC, WBC with differential and platelets. PT/PTT and INR assessed only at 
Screening. 
7 PBMCs will be collected 2 hrs postdose, relative to the first daily dose on Day 1, and pre-am dose and 2 and 8 hrs postdose 
relative to the first daily dose on Day 6. Depending on ongoing review of the data, timepoints may be modified or removed, and 
up to 2 additional samples may be collected. Additionally, PMBC collection may be omitted from some cohorts. 
8 The baseline ECG should be conducted prior to first dosing on Day 1. On Day 1, ECG should be taken predose and 2 hours 
post-am dose. On Day 6, ECG should be taken predose, 2 hrs, and 72 hrs (Day 9) postdose. 
9 On Day 1, monitor for 12-lead ECG recording will be worn from 2 hrs predose to 12 hrs postdose. Extraction timepoints will be 
60, 45, and 30 minutes predose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 9, and 12 hrs postdose. 
10 On Day 6, monitor for 12-lead ECG recording will be worn from dosing (0 hr) to 25 hrs (Day 6) postdose. Extraction 
timepoints will be at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 9, 12, and 24 hrs postdose. 
11 Vital signs include pulse rate, respiratory rate, blood pressure, and body temperature. On Day 1, VS should be taken pre-am 
dose, and at 2, 4, and 8 hrs post-am dose. On Day 2 through 5, VS should be taken pre-am dose. On Day 6, VS should be taken 
predose, and 2, 4, 8, 24 (Day 7), 48 (Day 8), and 72 (Day 9) hrs postdose.  
12 Study drug should be administered BID, 12 hrs apart on Days 1 through 5. On Day 6, study drug should be administered once 
in the morning only (0 hr).  Depending on ongoing review of the safety, tolerability, and PK data, the number of days of dosing 
may be reduced and the dosing frequency changed; the dosing frequency will be no less than once-daily or no greater than 
three-times daily. If the number of days of dosing are reduced, the timepoints for subsequent assessments and the period for 
which subjects are domiciled at the clinic will similarly be changed (subjects will be domiciled for 3 days post final dose). 
13 On Day 1, PK samples should be collected pre-am dose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 9, and 12 hrs post-am dose. On Day 4, 
the PK sample should be collected pre-am dose. On Day 6, PK samples should be collected predose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 
6, 9, 12, 15, 24 (Day 7), 48 (Day 8), 72 (Day 9), and 192 (Day 14) hrs postdose. Depending on ongoing review of the PK data, 
timepoints may be modified or removed, and up to 3 additional samples may be added. 
14 On Day 1, urine samples for PK analysis should be collected predose (spot collection), and from 0 to 4, 4 to 8, and 8 to 12 hrs 
postdose. On Day 6, urine samples for PK analysis should be collected predose (spot collection), and from 0 to 4, 4 to 8, 8 to 12, 
12 to 24 (Day 7), 24 to 48 (Day 8), and 48 to 72 hrs (Day 9).  Sampling timepoints may be modified, removed, or additional 
timepoints added depending upon ongoing review of the data. The 12-hour urine collection should occur prior to the second daily 
dose administration. 
15 Adverse events occurring prior to study drug administration should be recorded as medical history unless the event is directly 
related to a study specified procedure. 
 


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Version 3.1 (United Kingdom) 
Ridgeback Biotherapeutics 
Protocol Release Date: 13 April 2020  
Confidential 
Page 90 
Appendix 2: 
DMID Toxicity Grading Scale 
Clinical Adverse Events 
VITAL SIGNS 
Mild (Grade 1) 
Moderate Grade 2) 
Severe (Grade 3) 
Fever (°C) Oral temperature; no recent hot or 
cold beverages or smoking. 
38.0 – 38.4 
38.5 – 38.9 
>39.0 
Tachycardia - beats per minute 
101 – 115 
116 – 130 
> 130 or ventricular 
dysrhythmias 
Bradycardia - beats per minute 
50 - 54 or 45 - 50 bpm if 
baseline <60 bpm 
45 - 49 or 40 - 44 if 
baseline <60 bpm 
< 45 or <40 bpm if baseline 
<60 bpm 
Hypertension (systolic) - mm Hg [Assuming 
supine position, 10 min at rest conditions, not 
sleeping subjects, measurements on the same 
arm and several concordant results.] 
 
141 - 150 
 
151 - 160 
 
> 160 
Hypertension (diastolic) - mm Hg 
91 - 95 
96 - 100 
> 100 
Hypotension (systolic) - mm Hg 
85 - 89 
80 - 84 
< 80 
Tachypnea – breaths per minute 
23 - 25 
26 - 30 
>30 
CARDIOVASCULAR 
Grade 1 
Grade 2 
Grade 3 
Arrythmia 
 
asymptomatic, transient 
signs, no Rx required 
recurrent/persistent; 
symptomatic Rx required 
Hemorrhage, Blood Loss 
Estimated blood loss 
< 100 mL 
Estimated blood loss 
> 100 mL, no 
transfusion 
required 
Transfusion required 
RESPIRATORY 
Grade 1 
Grade 2 
Grade 3 
Cough 
Transient-no treatment 
Persistent cough; 
Interferes with daily activities 
Bronchospasm, Acute 
transient; no treatment; 
71-  80% FEV1 of peak 
flow 
requires treatment; 
normalizes with 
bronchodilator; FEV1 
60 - 70% (of peak flow) 
no normalization with 
bronchodilator; FEV1 <60% of 
peak flow 
Dyspnea 
Does not interfere with 
usual and social 
activities 
Interferes with usual 
and social activities, no 
treatment 
Prevents daily and usual social 
activity or requires treatment 
GASTROINTESTINAL 
Grade 1 
Grade 2 
Grade 3 
Nausea 
No interference with 
activity 
Some interference with 
activity 
Prevents daily activities 
Vomiting 
No interference with 
activity or 1 - 2 
episodes/24 hours 
Some interference with 
activity or > 2 
episodes/24 hours 
Prevents daily activity or 
requires IV hydration 
Diarrhea 
2 - 3 loose or watery 
stools or < 400 
gms/24 hours 
4 - 5 loose or watery 
stools or 400 - 800 
gms/24 hours 
6 or more loose or watery 
stools or > 800gms/24 hours or 
requires IV hydration 


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Reactogenicity 
Local reactions 
Grade 1 
Grade 2 
Grade 3 
Pain 
Does not interfere with 
activity 
Repeated use of 
non-narcotic pain 
reliever > 24 hours or 
interferes with activity 
Any use of narcotic pain 
reliever or prevents daily 
activity 
Tenderness 
Discomfort only to touch 
Discomfort with 
movement 
Significant discomfort at rest 
Erythema/Redness * 
2.5 - 5 cm 
5.1 - 10 cm 
> 10 cm 
Induration/Swelling ** 
2.5 - 5 cm and does not 
interfere with activity 
5.1 - 10 cm or interferes 
with activity 
> 10 cm or prevents daily 
activity 
SYSTEMIC 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Allergic Reaction 
pruritus without rash 
localized urticaria 
generalized urticaria; 
angioedema or anaphylaxis 
Headache 
No interference with 
activity 
Repeated use of 
non-narcotic pain 
reliever > 24 hours or 
some interference with 
activity 
Significant; any use of narcotic 
pain reliever or prevents daily 
activity 
Fatigue 
No interference with 
activity 
Some interference with 
activity 
Significant; prevents daily 
activity 
Myalgia 
No interference with 
activity 
Some interference with 
activity 
Significant; prevents daily 
activity 
All Other conditions 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Illness or clinical adverse event (as defined 
according to applicable regulations) 
No interference with 
activity 
Some interference with 
activity not requiring 
medical intervention 
Prevents daily activity and 
requires medical intervention 
*In addition to grading the measured local reaction at the greatest single diameter, the measurement should be recorded as a 
continuous variable. 
**Induration/Swelling should be evaluated and graded using the functional scale as well as the actual 
measurement 
 
 


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Protocol Release Date: 13 April 2020  
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Laboratory Adverse Events 
Blood, Serum, or Plasma * 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Sodium – Hyponatremia mEq/L 
132 – <LLN 
130 – 131 
<130 
Sodium – Hypernatremia mEq/L 
>ULN – 148 
149 – 150 
>150 
Potassium – Hyperkalemia mEq/L 
>ULN – 5.2 
5.3 – 5.4 
>5.4 
Potassium – Hypokalemia mEq/L 
<LLN-3.1 
<3.1 – 3.0 
<3.0 
Glucose – Hypoglycemia mg/dL 
65 – 67 
55 – 64 
<55 
Glucose – Hyperglycemia Fasting – mg/dL 
>ULN - 120 
121 – 130 
>130 
Glucose – Hyperglycemia Random – mg/dL 
140 – 159 
160 – 200 
>200 
Blood Urea Nitrogen mg/dL 
23-26 
27 – 31 
> 31 
Creatinine – mg/dL 
>ULN – 1.7 
1.8 – 2.0 
>2.0 
Calcium – hypocalcemia mg/dL 
8.0 – <LLN 
7.5 – 7.9 
<7.5 
Calcium – hypercalcemia mg/dL 
>ULN – 11.0 
11.1 – 11.5 
>11.5 
Magnesium – hypomagnesemia mg/dL 
1.3 – 1.5 
1.1 – 1.2 
<1.1 
Phosphorus – hypophosphatemia mg/dL 
2.3 – 2.5 
2.0 – 2.2 
<2.0 
CPK – mg/dL 
400-1000 
1001-1500 
>1500 
Albumin – Hypoalbuminemia g/dL 
2.8 – 3.0 
2.5 – 2.7 
< 2.5 
Total Protein – Hypoproteinemia g/dL 
5.2 – 5.4 
4.8 – 5.1 
< 4.8 
Alkaline phosphate – U/L 
132-240 
241– 360 
>360 
AST U/L 
44 – 105 
106-175 
>175 
ALT U/L 
44 – 105 
106-175 
>175 
Bilirubin (serum total) mg/dL 
1.3 - 2.0 
2.1 - 2.5 
> 2.5 
Bilirubin – when ALT >105 (Hy's law) 
1.3 -1.5 
1.6 – 2.0 
> 2.0 
Amylase- U/L 
200-270 
271-360 
>360 
Lipase- U/L 
176-270 
271-360 
>360 
Hemoglobin (Female) - g/dL 
11.0 – 11.5 
9.5 – 10.9 
< 9.5 
Hemoglobin (Male) - g/dL 
12.0 – 12.5 
10.0 – 11.9 
<10.0 
WBC Increase - cell/mm3 
11,001 – 15,000 
15,001 – 20,000 
> 20,000 
WBC Decrease - cell/mm3 
2,500 – 3,500 
1,500 – 2,499 
< 1500 
Lymphocytes Decrease - cell/mm3 
750 – 1,000 
500 – 749 
< 500 
Neutrophils Decrease - cell/mm3 
1,500 – 2,000 
1,000 – 1,499 
< 1000 
Eosinophils - cell/mm3 
500-750 
751-1500 
> 1500 
Platelets Decreased - cell/mm3 
120,000 – 130,000 
100,000 – 119,999 
<100,000 
PT – seconds (prothrombin time) 
> ULN-14.4 
14.5 – 15.7 
> 15.7 
PTT – seconds (partial thromboplastin time) 
>ULN-42.1 
42.2– 50.0 
> 50.0 
Fibrinogen increase - mg/dL 
>ULN – 500 
501 – 600 
> 600 
Fibrinogen decrease - mg/dL 
<LLN – 140 
125 – 139 
<125 
Urine * 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Protein 
1+ 
2+ 
>2+ 
Glucose 
1+ 
2+ 
>2+ 
Blood (microscopic) - red blood cells per high 
power field (rbc/hpf) 
5-10 
11-50 
> 50 and/or gross 
blood 
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal parameters. 
* Institutional normal reference ranges should be provided to demonstrate that they are appropriate. 
 


Clinical Study Protocol: EIDD-2801-1001-UK 
Version 3.1 (United Kingdom) 
Ridgeback Biotherapeutics 
Protocol Release Date: 13 April 2020  
Confidential 
Page 93 
Appendix 3: 
Contraception Guidance 
Male subjects (regardless of fertility status) with partners of childbearing potential must use a 
male barrier method of contraception (i.e., male condom with spermicide) in addition to a second 
method of acceptable contraception from Check-in until 90 days after the EOS visit. Acceptable 
methods of contraception for female partners include: 
 hormonal injection 
 combined oral contraceptive pill or progestin/progestogen-only pill 
 combined hormonal patch 
 combined hormonal vaginal ring 
 surgical method (bilateral tubal ligation or Essure® [hysteroscopic bilateral tubal 
occlusion])  
 hormonal implant 
 hormonal or non-hormonal intrauterine device 
 OTC sponge with spermicide 
 cervical cap with spermicide 
 diaphragm with spermicide. 
An acceptable second method of contraception for male subjects is vasectomy that has been 
performed at least 90 days prior to the screening visit, with verbal confirmation of surgical 
success. 
For male subjects (even with a history of vasectomy), sexual intercourse with female partners 
who are pregnant or breastfeeding should be avoided unless condoms are used from the time of 
the first dose until 90 days after the EOS visit. Male subjects are required to refrain from 
donation of sperm from Check-in until 90 days after the EOS visit. 
Sexual Abstinence and Same-sex Relationships 
Subjects who practice true abstinence, because of the subject’s lifestyle choice (i.e., the subject 
should not become abstinent just for the purpose of study participation), are exempt from 
contraceptive requirements. Periodic abstinence (eg, calendar, ovulation, symptothermal, 
postovulation methods) and withdrawal are not acceptable methods of contraception. If a subject 
who is abstinent at the time of signing the ICF becomes sexually active they must agree to use 
contraception as described previously. 


Clinical Study Protocol: EIDD-2801-1001-UK 
Version 3.1 (United Kingdom) 
Ridgeback Biotherapeutics 
Protocol Release Date: 13 April 2020  
Confidential 
Page 94 
For subjects who are exclusively in same-sex relationships, contraceptive requirements do not 
apply. If a subject who is in a same-sex relationship at the time of signing the ICF becomes 
engaged in a heterosexual relationship, they must agree to use contraception as described 
previously. 


Protocol Reference: EIDD-2801-1001-UK 
 CONFIDENTIAL  
 
 
 
 
 
 
 
Title of study: A Randomized, Double-blind, Placebo-controlled, First-in-human Study 
Designed to Evaluate the Safety, Tolerability, and Pharmacokinetics of EIDD-2801 
Following Oral Administration to Healthy Volunteers 
NCT Number: NCT04392219 
 
Document: Protocol, Version 4.1 
Date: 28 April 2020 
 


Clinical Study Protocol: EIDD-2801-1001-UK 
Version 4.1 (United Kingdom) 
Ridgeback Biotherapeutics 
Protocol Release Date: 28 April 2020  
Confidential 
Page 1 
A Randomized, Double-Blind, Placebo-Controlled, First-in-Human 
Study Designed to Evaluate the Safety, Tolerability, and 
Pharmacokinetics of EIDD-2801 Following Oral Administration to 
Healthy Volunteers 
 
(EIDD-2801-1001-UK) 
 
Protocol Version 4.1 (United Kingdom) 
Version Date 
28 April 2020 
Sponsor Team: 
Ridgeback Biotherapeutics 
3162 Commodore Plaza, Suite 3E 
Miami, FL 33133-5815 
United States 
Medical Officer 
 
EudraCT Number 
2020-001407-17 
 
Confidential Information: The information contained in this document is the property of 
Ridgeback Biotherapeutics and may not be reproduced, published or disclosed to others without 
written authorization from Ridgeback Biotherapeutics. 


Clinical Study Protocol: EIDD-2801-1001-UK 
Version 4.1 (United Kingdom) 
Ridgeback Biotherapeutics 
Protocol Release Date: 28 April 2020  
Confidential 
Page 2 
SUMMARY OF CHANGES 
Changes from Version 1.1 (United Kingdom) to Version 2.1 (United Kingdom). 
The primary reason for this amendment was to include Part 3, a multiple ascending dose study of 
EIDD-2801 in healthy subjects. Additionally, the following updates were made: 
 Results of an in vivo micronucleus assay were added. 
 The guidelines used to assess the severity of adverse events not presented in the DMID 
Toxicity Grading Scale were updated, specifically those that were life-threatening or led 
to death. 
 The timepoints for collection of peripheral blood mononuclear cells in Part 2 were 
modified. 
 Minor clarifications were made and typographical errors were corrected. 
Changes from Version 2.1 (United Kingdom) to Version 3.1 (United Kingdom). 
 Clarified that this study will be conducted at 1 site in the United Kingdom and up to 
3 sites in the United States, and that integrated data across all sites will be used for 
dose-escalation decisions. 
 The number of cohorts initially planned for Part 1 (single ascending dose) has been 
reduced from 4 to 3. 
 The number of days of dosing in Part 3 (multiple ascending dose) was decreased from 
7 days to 5.5 days. However, the number of days of dosing may be further reduced 
depending on ongoing review of the safety, tolerability, and pharmacokinetic data. 
 Added a rationale for the appropriateness of a 4-day interval between dose escalations. 
 Added a dose-escalation stopping criteria for reductions in platelets and lymphocytes. 
 Clarified that assessments of human immunodeficiency virus, hepatitis B virus, and 
hepatitis C virus will only be conducted at Screening. 
 Minor clarification and typographical corrections. 
Changes from Version 3.1 (United Kingdom) to Version 4.1 (United Kingdom). 
 The total daily dose to be administered in this protocol will not exceed 800 mg. A 
rationale for the increase in the maximum dose to be studied is provided in Section 9.2. 
 The number of additional cohorts in Parts 1 and 3 has been increased to 4. 


Clinical Study Protocol: EIDD-2801-1001-UK 
Version 4.1 (United Kingdom) 
Ridgeback Biotherapeutics 
Protocol Release Date: 28 April 2020  
Confidential 
Page 3 
 Pregnancy tests in Part 3 will be conducted in serum at Screening and in urine at all other 
timepoints. A positive urine pregnancy test will be confirmed with a serum pregnancy 
test. 
 Clarified that pregnancy, urine drug of abuse, cotinine, and alcohol breath tests will 
additionally be performed at Check-in to second treatment period in Part 2. 
 An additional pharmacokinetic blood sampling timepoint was added in Part 1, and two 
additional pharmacokinetic blood sampling timepoints were added to each of Parts 2 
and 3. 
 Timepoints for continuous 12-lead monitoring in Part 3 were updated. 
 Timepoints for collection of peripheral blood mononuclear cells in Part 2 were updated. 
 The storage conditions for the study drug were updated. 
 Minor clarification and typographical corrections. 


Clinical Study Protocol: EIDD-2801-1001-UK 
Version 4.1 (United Kingdom) 
Ridgeback Biotherapeutics 
Protocol Release Date: 28 April 2020  
Confidential 
Page 4 
STATEMENT OF COMPLIANCE 
The study will be carried out in accordance with Good Clinical Practice (GCP) as required by the 
following: 
 Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines. 
 Applicable International Conference on Harmonisation (ICH) GCP Guidelines. 
 United States Code of Federal Regulations (CFR) applicable to clinical studies 
(45 CFR Part 46; 21 CFR Part 50, 21 CFR Part 56, and 21 CFR Part 312). 
 Applicable laws and regulations. 


Clinical Study Protocol: EIDD-2801-1001-UK 
Ridgeback Biotherapeutics 
Version 4.1 (United Kingdom) 
Protocol Release Date: 28 April 2020 
SIGNATURE PAGE 
The signature below constitutes the approval of this protocol and the attachments and provides 
the necessary assurances that this study will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable regulations and ICH guidelines. 
Principal Investigator: 
Signed: 
 
 
Date: 
Executive Medical Director 
Covance Clinical Research Unit Limited 
Confidential 
Page 5 


Clinical Study Protocol: EIDD-2801-1001-UK 
Version 4.1 (United Kingdom) 
Ridgeback Biotherapeutics 
Protocol Release Date: 28 April 2020  
Confidential 
Page 6 
TABLE OF CONTENTS 
SUMMARY OF CHANGES .......................................................................................................... 2 
STATEMENT OF COMPLIANCE ................................................................................................. 4 
SIGNATURE PAGE ...................................................................................................................... 5 
TABLE OF CONTENTS ............................................................................................................... 6 
LIST OF TABLES ....................................................................................................................... 10 
LIST OF FIGURES ..................................................................................................................... 11 
LIST OF APPENDICES .............................................................................................................. 12 
ABBREVIATIONS ...................................................................................................................... 13 
PROTOCOL SYNOPSIS ............................................................................................................ 16 
1. INTRODUCTION ................................................................................................................... 26 
1.1. 
Background ............................................................................................................... 26 
1.2. 
Rationale for Development ........................................................................................ 26 
1.3. 
Nonclinical Overview ................................................................................................. 27 
1.3.1. Mechanism of Action ................................................................................................. 27 
1.3.2. In Vitro Pharmacology ............................................................................................... 28 
1.3.2.1. 
Antiviral Activity in Tissue Culture and in Human Airway Epithelium ............. 28 
1.3.2.2. 
Cytotoxicity of EIDD-1931 in Tissue Culture Utilizing Cells from Different 
Organs and Species ...................................................................................... 30 
1.3.2.3. 
Assessment of Mitochondrial Toxicity ............................................................ 30 
1.3.3. In Vivo Pharmacology ............................................................................................... 30 
1.3.3.1. 
Coronavirus: SARS-CoV and MERS-CoV ..................................................... 30 
1.3.3.2. 
Influenza Virus ............................................................................................... 34 
1.3.3.3. 
Venezuelan Equine Encephalitis Virus .......................................................... 35 
 
 
1.4. 
Safety and Secondary Pharmacology ....................................................................... 35 
1.5. 
Nonclinical Pharmacokinetics and Metabolism ......................................................... 35 
1.5.1. Overview ................................................................................................................... 35 
1.5.2. Absorption ................................................................................................................. 35 
1.5.3. Distribution ................................................................................................................ 36 
 
 
1.5.3.2. 
Tissue Distribution Studies ............................................................................ 36 
1.5.4. Metabolism ................................................................................................................ 37 
1.5.4.1. 
Metabolic Stability of EIDD-1931 and EIDD-2801 ......................................... 37 
1.5.4.2. 
Uptake and Anabolism of EIDD-1931 in Tissue Culture and Primary Cells ... 38 
1.5.5. Excretion ................................................................................................................... 39 
1.5.6. Pharmacokinetic Drug Interactions ........................................................................... 39 
1.5.6.1. 
Cytochrome P450 (CYP) Inhibition ................................................................ 39 
1.5.6.2. 
CYP Induction ................................................................................................ 39 
 
 
 
 
 
 


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1.7. 
Potential Risks and Benefits ...................................................................................... 45 
1.7.1. Potential Benefits ...................................................................................................... 45 
1.7.2. Potential Risks ........................................................................................................... 45 
2. OBJECTIVES ....................................................................................................................... 46 
2.1. 
Study Objectives ....................................................................................................... 46 
2.1.1. Primary Objectives .................................................................................................... 46 
2.1.2. Secondary Objectives ............................................................................................... 46 
2.1.3. Exploratory Objectives .............................................................................................. 46 
2.2. 
Study Outcome Measures ......................................................................................... 46 
2.2.1. Primary Outcome Measures ...................................................................................... 46 
2.2.2. Secondary Outcome Measures ................................................................................. 46 
3. STUDY DESIGN ................................................................................................................... 48 
3.1. 
Overview ................................................................................................................... 48 
3.1.1. Part 1 (Single Ascending Dose) ................................................................................ 48 
3.1.2. Part 2 (Food-Effect) ................................................................................................... 49 
3.1.3. Part 3 (Multiple Ascending Dose) .............................................................................. 49 
3.2. 
Rationale and Justification ........................................................................................ 50 
3.2.1. Justification of Design ............................................................................................... 50 
3.2.2. Justification of Starting Dose ..................................................................................... 50 
3.2.3. Justification of Study Population ............................................................................... 51 
4. STUDY POPULATION ......................................................................................................... 52 
4.1. 
Subject Inclusion Criteria ........................................................................................... 52 
4.2. 
Subject Exclusion Criteria ......................................................................................... 53 
5. STUDY MEDICATION, RANDOMIZATION AND DOSE ADMINISTRATION ...................... 55 
5.1. 
Study Drug Description ............................................................................................. 55 
5.1.1. Acquisition, Formulation, Packaging and Labeling .................................................... 55 
5.1.2. Product Storage and Stability .................................................................................... 55 
5.2. 
Randomization .......................................................................................................... 55 
5.3. 
Dosage, Preparation and Administration of Study Drug ............................................ 56 
5.4. 
Drug Accountability ................................................................................................... 56 
5.5. 
Concomitant Medication/Treatments ......................................................................... 56 
6. STUDY CONDUCT AND VISIT SCHEDULE ....................................................................... 58 
6.1. 
Study Conduct ........................................................................................................... 58 
6.1.1. Study Windows and Rounding Principles .................................................................. 58 
6.1.2. Restrictions ................................................................................................................ 58 
6.2. 
Screening .................................................................................................................. 59 


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6.2.1. Screening Visit .......................................................................................................... 59 
6.2.2. Retesting Procedures ................................................................................................ 60 
6.2.3. Study Visits ................................................................................................................ 60 
6.2.4. Part 1 (Single Ascending Dose) ................................................................................ 60 
6.2.5. Part 2 (Food-Effect) ................................................................................................... 60 
6.2.6. Part 3 (Multiple Ascending Dose) .............................................................................. 60 
6.3. 
Safety Follow-up and End-of-Study Visit ................................................................... 60 
6.4. 
Subject Withdrawal and Replacement ...................................................................... 61 
6.4.1. Reasons for Withdrawal ............................................................................................ 61 
6.4.2. Handling of Withdrawals ............................................................................................ 62 
6.4.3. Documentation of Withdrawals .................................................................................. 62 
6.4.4. Subject Replacement ................................................................................................ 62 
6.5. 
Unscheduled Visit(s) ................................................................................................. 62 
7. STUDY PROCEDURES/EVALUATIONS ............................................................................. 64 
7.1. 
Demography and Medical History ............................................................................. 64 
7.2. 
Clinical Evaluations ................................................................................................... 64 
7.2.1. Physical Examinations .............................................................................................. 64 
7.2.2. Vital Sign Measurements and ECGs ......................................................................... 64 
7.2.2.1. 
Continuous 12-lead ECG Monitoring (Part 3 Only) ........................................ 65 
7.2.3. Adverse Events and Concomitant Medications ......................................................... 65 
7.3. 
Laboratory Evaluations .............................................................................................. 65 
7.3.1. Routine Laboratory Panels ........................................................................................ 65 
7.3.2. Pharmacokinetic Sampling ........................................................................................ 67 
7.3.3. Peripheral Blood Mononuclear Cell Collection .......................................................... 68 
7.3.4. Urine Collection ......................................................................................................... 68 
8. SAFETY MONITORING, MANAGEMENT AND REPORTING ............................................ 69 
8.1. 
Definitions .................................................................................................................. 69 
8.1.1. Adverse Events ......................................................................................................... 69 
8.1.2. Serious Adverse Events ............................................................................................ 69 
8.2. 
Documenting Adverse Events ................................................................................... 70 
8.2.1. Timeframe for Collection and Follow-up of AEs/SAEs .............................................. 70 
8.2.2. Recording of Adverse Events/Serious Adverse Events ............................................ 71 
8.2.3. Assessing Severity of Adverse Events ...................................................................... 71 
8.2.4. Relationship to Study Drug ........................................................................................ 72 
8.2.5. Classifying Adverse Event Outcome ......................................................................... 72 
8.3. 
Reporting Procedures ................................................................................................ 73 
8.3.1. Serious Adverse Events ............................................................................................ 73 
8.3.2. Pregnancy ................................................................................................................. 73 
8.4. 
Unmasking Treatment Assignment ........................................................................... 74 
9. DOSE-ESCALATION AND HALTING RULES..................................................................... 75 
9.1. 
Guidelines for Dose-Escalation ................................................................................. 75 
9.2. 
Rationale for Highest Dose ....................................................................................... 76 
9.2.1. Clinical Safety ............................................................................................................ 76 
9.2.2. Pharmacokinetics ...................................................................................................... 77 


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9.2.3. Rationale to Exceed the Maximum Single Dose Limit of 200 mg .............................. 77 
9.3. 
Dose-Escalation Halting Rules .................................................................................. 78 
10. STATISTICAL CONSIDERATIONS ..................................................................................... 79 
10.1. 
General Considerations ............................................................................................. 79 
10.2. 
Sample Size Considerations ..................................................................................... 79 
10.3. 
Analysis Populations ................................................................................................. 79 
10.4. 
Analysis of Safety Data ............................................................................................. 79 
10.4.1. Extent of Exposure .................................................................................................... 79 
10.4.2. Adverse Events ......................................................................................................... 80 
10.4.3. Clinical Laboratory Results ........................................................................................ 80 
10.4.4. Other Parameters ...................................................................................................... 80 
10.5. 
Analysis of Pharmacokinetic Data ............................................................................. 80 
10.5.1. Statistical Analysis of Pharmacokinetic Data ............................................................ 82 
10.5.1.1. Dose Proportionality ...................................................................................... 82 
10.5.1.2. Food-Effect .................................................................................................... 82 
10.6. 
Peripheral Blood Mononuclear Cells ......................................................................... 82 
10.7. 
Interim Analyses ........................................................................................................ 82 
11. STUDY ADMINISTRATION .................................................................................................. 83 
11.1. 
Regulatory and Ethical Considerations ..................................................................... 83 
11.2. 
Ethical Standard ........................................................................................................ 83 
11.2.1. Ethics Committee Approval ....................................................................................... 83 
11.2.2. Informed Consent ...................................................................................................... 83 
11.3. 
Financing and Insurance ........................................................................................... 84 
11.4. 
Source Documentation and Access .......................................................................... 84 
11.5. 
Data Collection and Record Keeping ........................................................................ 84 
11.5.1. Data Collection .......................................................................................................... 84 
11.5.2. Study Records Retention .......................................................................................... 85 
11.5.3. Protocol Deviations ................................................................................................... 85 
11.6. 
Clinical Monitoring ..................................................................................................... 85 
11.7. 
Quality Control and Quality Assurance ..................................................................... 85 
11.8. 
Study Termination and Closure Procedures.............................................................. 86 
11.8.1. Study Termination ..................................................................................................... 86 
11.8.2. Termination Procedures ............................................................................................ 86 
11.9. 
Information Disclosure ............................................................................................... 86 
11.9.1. Confidentiality ............................................................................................................ 86 
11.9.2. Clinicaltrials.gov ........................................................................................................ 87 
11.9.3. Publication Policy ...................................................................................................... 87 
12. REFERENCES ...................................................................................................................... 88 
13. APPENDICES ....................................................................................................................... 89 
 


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LIST OF TABLES 
Table 1: 
EIDD-1931 Antiviral Activity Against Influenza A and B Viruses in Tissue Culture and 
Primary Human Bronchial/Tracheal Epithelial Cells ................................................. 28 
Table 2: 
EIDD-1931 Antiviral Activity Against SARS and MERS Coronaviruses in Tissue 
Culture and Primary Human Bronchial/Tracheal Epithelial Cells ............................. 29 
Table 3: 
EIDD-1931 Antiviral Activity Against Togaviruses in Tissue Culture ........................ 29 
 
 
Table 5: 
Cytotoxicity (CC50) of EIDD-1931 in Mammalian Cell Lines .................................... 30 
Table 6: 
Metabolic Stability of EIDD-2801 in Plasma and Liver Microsomes ......................... 38 
Table 7: 
Metabolic Stability of EIDD-2801 in Simulated Gastric and Intestinal Fluids and in 
Buffered Saline with Fetal Bovine Serum ................................................................. 38 
Table 8: 
Metabolic Stability of EIDD-1931 in Plasma, Whole Blood and Liver and Intestinal 
Microsomes .............................................................................................................. 38 
 
 
 
Table 10: Allowable Time Windows for Study Assessments/Visits .......................................... 58 
Table 11: Laboratory Evaluations ............................................................................................. 67 
Table 12: Adverse Event Outcomes ......................................................................................... 72 
Table 13: Pharmacokinetic Parameters ................................................................................... 81 
 


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LIST OF FIGURES 
Figure 1: 
Study Schema .......................................................................................................... 25 
Figure 2: 
Inhibition of SARS-CoV-2 by EIDD-1931 ................................................................. 29 
Figure 3: 
EIDD-2801 Prophylactic Treatment of SARS-CoV Infected Mice ............................ 31 
Figure 4: 
EIDD-2801 Treatment of SARS-CoV Infected Mice ................................................. 32 
Figure 5: 
EIDD-2801 Prophylactic Treatment of MERS-CoV Infected Mice ............................ 33 
Figure 6: 
EIDD-2801 Treatment of MERS-CoV Infected Mice ................................................ 34 
Figure 7: 
Tissue Distribution of EIDD-1931 and EIDD-2061 in Ferret Brain and Lung ............ 37 
 
 


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LIST OF APPENDICES 
Appendix 1: 
Time and Events Schedule ............................................................................ 89 
Appendix 2: 
DMID Toxicity Grading Scale ......................................................................... 93 
Appendix 3: 
Contraception Guidance ................................................................................ 96 


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ABBREVIATIONS 
AE 
adverse event 
AGP 
alpha1-acid glycoprotein 
ALT/SGPT 
alanine aminotransferase/serum glutamic pyruvic transaminase 
AST/SGOT 
aspartate aminotransferase/serum glutamic oxaloacetic transaminase 
AUC 
area under the curve 
BID 
twice-daily 
BMI 
body mass index 
CDC 
Centers for Disease Control and Prevention 
CEM 
a cell line of lymphoblastic cells derived from a child with leukemia 
CFR 
Code of Federal Regulations 
CHKV 
Chikungunya virus 
CI 
confidence interval 
CoV 
coronavirus 
CRF 
case report form 
CTP 
cytosine triphosphate cytidine triphosphate 
CYP 
cytochrome P450 
DMID 
Division of Microbiology and Infectious Diseases 
DMSO 
dimethylsulfoxide 
DPP4 
dipeptidyl peptidase 4 
DRF 
dose range finding 
DSS 
Drug Safety Services 
EBOV 
Ebola virus 
EC 
Ethics Committee 
EC50 
Half-maximal effective concentration 
ECG 
electrocardiogram 
EEEV 
Eastern equine encephalitis virus 
EIDD 
Emory Institute for Drug Development 
EOS 
End of Study 
FDA 
Food and Drug Administration 
FE 
food-effect 
FIH 
first-in- human 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
GLP 
Good Laboratory Practice 


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HAE 
human airway epithelium 
HBV 
hepatitis b virus 
hBTEC 
human bronchial/tracheal epithelial cells 
HCV 
hepatitis c virus 
HED 
human equivalent dose 
HEENT 
head, eye, ear, nose and throat 
HIV 
human immunodeficiency virus 
HPMC 
hydroxypropyl methylcellulose 
IAV 
influenza a virus 
IB 
Investigator’s Brochure 
IBV 
influenza b virus 
IC50 
half maximal inhibitory concentration 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
MAD 
multiple ascending dose 
MDCK 
Madin-Darby Canine Kidney Cells 
MedDRA 
Medical Dictionary for Regulatory Activities 
MERS 
Middle East respiratory syndrome 
%MN-PCE 
percentage of micronuclei-polychromatic erythrocytes 
MRSD 
maximum recommended starting dose 
MTD 
maximum tolerated dose 
NOAEL 
no-observed-adverse-effect-level 
NSAID 
nonsteroidal anti-inflammatory drug 
OTC 
over-the-counter 
PBMC 
peripheral blood mononuclear cells 
PBO 
placebo 
PCE:TE 
polychromatic erythrocytes to total erythrocytes 
PE 
physical examination 
PI 
principal investigator 
 
 
PK 
pharmacokinetic 
QTc(F) 
QT interval corrected for heart rate (using Fridericia’s formula) 
RNA 
ribonucleic acid 
RSV 
respiratory syncytial virus 
SAD 
single ascending dose 
SAE 
serious adverse event 


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SAP 
statistical analysis plan 
SARS 
severe acute respiratory syndrome 
SI 
selectivity index 
SOP 
standard operating procedure 
UTP 
uridine 5'-triphosphate 
VEEV 
Venezuelan equine encephalitis virus 
ZIKV 
Zika virus 


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PROTOCOL SYNOPSIS 
Sponsor: Ridgeback Biotherapeutics 
Title: A Randomized, Double-Blind, Placebo-Controlled, First-in-Human Study Designed to 
Evaluate the Safety, Tolerability, and Pharmacokinetics of EIDD-2801 Following Oral 
Administration to Healthy Volunteers (EIDD-2801-1001-UK) 
Short Title: EIDD-2801-1001-UK 
Development Phase: Phase 1 
Study Sites: This study will be conducted at 1 site in the United Kingdom and up to 3 sites in 
the United States. 
Description of Study Drugs, Dose and Mode of Administration: EIDD-2801 and matching 
placebo (PBO) will be supplied 
 
  
Part 1: A single oral dose of EIDD-2801 or PBO will be administered to subjects enrolled in 
Part 1 (P1; single ascending dose [SAD]) cohorts. The starting dose in the first SAD cohort will 
be 50 mg. The doses will be administered in an escalating manner. Dose levels will not increase 
by more than 3-fold for predicted nonpharmacologically active dose levels and by 2-fold for 
predicted pharmacologically active dose levels.
 
 
 
Part 2: Subjects in Part 2 (P2)/food-effect (FE) will receive 2 single doses of EIDD-2801 with a 
14-day (minimum) washout period between doses. The dose for the P2 cohort is planned to be 
100 mg but may be adjusted based on safety, tolerability, and/or pharmacokinetic (PK) data from 
P1. In any case, the dose assessed in P2 will have been given previously to subjects in a P1 
cohort successfully (i.e., no halting rules were met following dosing). 
Part 3: Multiple doses of EIDD-2801 or PBO will be administered to subjects enrolled in Part 3 
(P3; multiple ascending dose [MAD]) cohorts. Subjects will receive twice-daily (BID) doses for 
5 days, with a single dose administered on the morning of Day 6 for collection of steady-state 
PK samples during waking hours. The total daily dose will not exceed a dose shown to be safe 
and well-tolerated in P1. Doses in P3 may be administered in the fed state, following review of 
the PK data from P2. Additionally, depending on ongoing review of the safety, tolerability, and 
PK data, the number of days of dosing may be reduced and the dosing frequency may be 
changed; the dosing frequency will be no less than once-daily or no greater than three-times 
daily. 
Treatment Duration:  
Part 1: Subjects enrolled into P1/SAD cohorts will receive a single dose of study drug 
(EIDD-2801 or matching PBO).  
Part 2: Subjects enrolled into the P2/FE cohort will receive 2 single doses of EIDD-2801, with a 
washout period between doses. 
Part 3: Subjects in P3/MAD cohorts will receive study drug (EIDD-2801 or matching PBO) for 
5 days BID followed by a single dose of EIDD-2801 or PBO on Day 6. Depending on ongoing 
review of the safety, tolerability, and PK data, the number of days of dosing may be reduced. 


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Subject Duration:  
Part 1: The maximum possible study duration for participants enrolled in P1/SAD cohorts will 
be approximately 43 days. 
Part 2: The maximum possible study duration for participants enrolled in the P2/FE cohort will 
be approximately 58 days. 
Part 3: The maximum possible study duration for participants enrolled in P3/MAD will be 
approximately 48 days. 
Objectives and Endpoints: 
Part 1: SAD Cohorts 
Primary: 
 
Objective: To determine the safety and tolerability of single ascending doses of EIDD-2801. 
o Endpoints:  
 
Results of safety evaluations including safety laboratory assessments, 
physical examination (PE), electrocardiograms (ECGs), vital signs, and 
adverse events (AEs). 
Secondary: 
 
Objective: To define PK of EIDD-2801 and EIDD-1931 in plasma and urine following 
single doses administered to healthy volunteers. 
o Endpoints: 
 
Plasma PK parameters, including Cmax, tmax, t1/2, CL/F, λz, Vz/F, AUC0-inf 
and AUClast as appropriate 
 
Urinary excretion of EIDD-2801 and EIDD-1931 following single-dose 
administration. 
Part 2: Single-Dose Food-Effect 
Primary: 
 
Objective: To assess the effect of food on the PK of EIDD-2801 and EIDD-1931 following 
a single oral dose. 
o Endpoints: 
 
Plasma PK parameters, including Cmax, tmax, t1/2, CL/F, λz, Vz/F, AUC0-inf 
and AUClast as appropriate 
 
Urinary excretion of EIDD-2801 and EIDD-1931 following single-dose 
administration. 
Secondary: 
 
Objective: To determine the safety and tolerability of single doses of EIDD-2801. 
o Endpoints: 
 
Results of safety evaluations, including safety laboratory assessments, PEs, 
ECG, vital signs, and AEs. 
Part 3: MAD Cohorts 
Primary: 
 
Objective: To determine the safety and tolerability of multiple ascending doses of 
EIDD-2801. 


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o Endpoints: 
 
Results of safety evaluations, including safety laboratory assessments, PE, 
ECGs, vital signs, and AEs. 
Secondary: 
 
Objective: To define PK of EIDD-2801 and EIDD-1931 in plasma and urine following 
multiple doses administered to healthy volunteers. 
o Endpoints: 
 
Plasma PK parameters, including Ctrough, Cmax, tmax, t1/2, CL/F, λz, Vz/F, 
AUC0-inf (Day 1 dose only), AUCτ, RAAUCτ, and RACmax as appropriate 
 
Urinary excretion of EIDD-2801 and EIDD-1931 following multiple-dose 
administration. 
Exploratory: 
 
Objective: To collect data to assess the relationship between 
EIDD-2801/EIDD-1931 concentrations and QT interval corrected for heart 
rate (QTc). 
Population:  
Part 1: P1/SAD cohorts will include 8 subjects each, 2 randomized to receive PBO and 
6 randomized to receive EIDD-2801. Initially, 3 SAD cohorts are planned for P1 with the option 
to add an additional 4 cohorts based on study results. 
Part 2: Ten subjects will be enrolled into the P2/FE cohort; all subjects enrolled in the P2 cohort 
will receive EIDD-2801. One P2 cohort is planned for the study. If PK results obtained are 
equivocal, additional subjects may be enrolled into the P2 cohort at the previously tested dose or 
an additional P2 cohort may be added at a different dose.  
Part 3: P3/MAD cohorts will include 8 subjects, 2 randomized to receive PBO and 
6 randomized to receive EIDD-2801. Initially, 3 MAD cohorts are planned for P3 with the 
option to add an additional 4 cohorts based on study results. However, the number of cohorts 
may be reduced if the study objectives are met. Dose levels in P3 may be repeated for collection 
of peripheral blood mononuclear cells (PBMCs), providing that the dose level did not meet the 
dose-escalation halting criteria. 
The site is strongly encouraged to ensure that women are represented in each cohort. Inclusion 
and exclusion criteria for study participation are as follows: 
Inclusion Criteria: subjects who meet all of the criteria at Screening will be eligible for study 
participation 
1. Male or female between the ages of 18 and 60, inclusive. 
2. Female subjects must be of nonchildbearing potential. Nonchildbearing potential is 
defined as women who: 
• 
are physiologically incapable of becoming pregnant including those who are 
surgically sterile, via hysterectomy, bilateral salpingectomy, and/or bilateral 
oophorectomy by reported medical history and/or medical records. Surgical 
sterilization to have occurred a minimum of 6 weeks, or at the Principal 
Investigator’s (PI’s; or designee’s) discretion, prior to Screening. 
• 
are postmenopausal (at least 45 years of age with amenorrhea for 12 months 


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without an alternative medical reason with confirmatory follicle stimulating 
hormone (FSH) levels of ≥ 40 mIU/mL. The amenorrhea should not be induced 
by a medical condition such as anorexia nervosa, hypothyroid disease or 
polycystic ovarian disease, or by extreme exercise. It should not be due to 
concomitant medications that may have induced the amenorrhea such as oral 
contraceptives, hormones, gonadotropin-releasing hormones, anti-estrogens, or 
selective estrogen receptor modulators). 
3. Male participants must agree to the use of effective contraception for study duration,
i.e., from Check-in until 90 days following the last dose of study drug.
4. Is in generally good health as determined by medical history, PE (at Screening and/or
Check-in), vital signs, and other screening procedures.
5. Has a body mass index (BMI) of 18 to 30 kg/m2.
6. Is willing and able to comply with all study procedures including providing informed
consent.
Exclusion Criteria: subjects who meet any of the following criteria at Screening (unless 
otherwise stated) will not be eligible for participation 
1. Females who are pregnant, planning to become pregnant, or breastfeeding.
2. Has a clinically relevant acute or chronic medical condition or disease of the
cardiovascular, gastrointestinal (GI), hepatic, renal, endocrine, pulmonary, neurologic,
or dermatologic systems as determined by the PI (or designee).
3. Has any current or historical disease or disorder of the hematological system or
significant liver disease or family history of bleeding/platelet disorders.
4. Has a history of cancer (other than basal cell or squamous cell cancer of the skin),
rheumatologic disease or blood dyscrasias.
5. Has a history of GI surgery or other condition that may interfere with absorption of
study drug, in the option of the PI (or designee).
6. Has a history of febrile illness within the 14 days prior to the first dose of study drug.
7. Has a positive alcohol or drug screen at Screening or the Day -1 visit or has a history of
alcohol or drug abuse within the past 5 years.
8. Currently uses tobacco, nicotine or tobacco products, e-cigarettes or has stopped using
tobacco products within the past 3 months and/or has a positive cotinine test at
Screening or Check-in.
9. Has any abnormal laboratory value of Grade 2 or higher, which is considered to be
clinically significant by the PI (or designee).
10. Has a total white cell count or absolute lymphocyte count outside the normal range, or
hemoglobin or platelet levels below the lower limit of normal, at Screening of Day -1.
11. Has values above the upper limit of normal for the following laboratory analytes:
alanine aminotransferase (ALT/SGPT), alkaline phosphatase (serum), aspartate
aminotransferase (AST/SGOT), at Screening or Day -1.
12. Positive test result for human immunodeficiency virus (HIV), hepatitis B virus (HBV),
or hepatitis C virus (HCV).
13. Has an autoimmune disease, is immunosuppressed or is in any way


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immunocompromised. 
14. Has any of the following: 
• 
QT interval corrected for heart rate using Fridericia’s formula (QTcF) >450 ms 
confirmed by repeat measurement 
• 
QRS duration >110 ms confirmed by repeat measurement 
• 
PR interval >220 ms confirmed by repeat measurement 
• 
findings which would make QTc measurements difficult or QTc data 
uninterpretable 
• 
history of additional risk factors for torsades de pointes (e.g., heart failure, 
hypokalemia, family history of long QT syndrome). 
15. Except as noted, has used prescription drugs (other than hormone replacement therapy) 
within 14 days prior to the first dose of study drug unless, in the opinion of the PI (or 
designee), the drug will not interfere with study assessments. The following prescription 
drugs will be allowed: 
• 
Statins: Subjects who have been on a stable dose of statins for a minimum of 
6 months and who have normal creatine kinase at Screening. 
• 
Antihypertensives: Subjects who have been on a stable dose of 
antihypertensives for a minimum of 6 months and have controlled blood 
pressure and no active heart disease. 
16. Has received an experimental agent (vaccine, drug, biologic, device, blood product or 
medication) within 3 months prior to the first dose of study drug and agrees not to 
receive another experimental agent during the duration of this trial. 
17. Has donated blood within 30 days, plasma within 2 weeks, or platelets within 6 weeks 
prior to Screening or refuses to agree to not donate blood until 3 months after the End of 
Study (EOS) visit. 
18. Uses over-the-counter (OTC) medications or nutritional supplements (including, e.g., 
gingko biloba, aspirin at any dose, and nonsteroidal anti-inflammatory drugs [NSAIDs]) 
on a routine/scheduled basis, and/or is unwilling to abstain from such use for the 
duration of the study. 
19. Is unwilling to abstain from quinine containing products including quinine water, tonic 
water, bitter lemon, jello shots, any quinine preparations or Cinchona tree bark 
preparations (e.g., herbal medications containing Cinchona tree bark). 
20. Has any condition that would, in the opinion of the PI (or designee), put the subject at 
increased risk for participation in a clinical trial or confinement in a clinical research 
unit. 
Retesting for Inclusion/Exclusion Criteria: In the case where a parameter is outside of the 
acceptable limits for enrollment, measurement of the parameter can be repeated one time if both 
the following are met: 
 In the opinion of the PI (or designee), the parameter value does not represent a chronic 
condition that otherwise will preclude the volunteer from enrolling in the study; and 
 In the opinion of the PI (or designee), the abnormality is not likely to recur. 


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General Investigational Plan: For all potential subjects, volunteers who express interest in the 
study will report to the clinic for informed consent. The study will be explained to the subject 
and the Ethics Committee (EC)-approved informed consent form (ICF) will be presented. The 
subject will be given the chance to review the document and ask any questions he/she may have. 
If, after reviewing the consent, the subject would like to participate in the study, then he/she will 
sign the ICF and begin screening for study entry; those satisfying all criteria will be enrolled into 
the study and admitted to the clinic on Day -1. Retesting will be allowed as described above. 
Part 1: For P1/SAD, the first cohort will be divided into 2 groups. The first group, a sentinel 
group, will include 2 subjects.  
On Day 1, one subject in the sentinel group will be administered PBO and one will be 
administered EIDD-2801. Analysis of the safety results for the sentinel group will be reviewed 
24 hours postdose. If no halting criteria have been met, the remainder of the subjects in Cohort 1 
(the second group) will be dosed. There will be no sentinel groups for the remaining cohorts. 
Following dosing on Day 1, subjects will remain in the clinic through completion of study 
assessments on Day 4, returning to the clinic on Day 9 for study assessments, and Day 15 for the 
EOS visit.  
Doses will be administered in an escalating manner following satisfactory review by the Sponsor 
and PI of the blinded safety and tolerability data (up to 72 hours post final dose). Integrated data 
from all applicable sites will be used to make dose-escalation decisions. Dose-escalation will 
only occur if data from a minimum of 6 subjects (across all sites) have been reviewed from the 
previous lower dose group, such that data from a minimum of 4 subjects (across all sites) who 
have received EIDD-2801 will be used to make the dose-escalation decision. Dose levels will 
not increase by more than 3-fold for predicted nonpharmacologically active dose levels and by 
2-fold for predicted pharmacologically active dose levels. The highest total daily dose to be 
studied under this protocol will not exceed 800 mg. 
Part 2: For P2/FE, one cohort assessing the effect of food on EIDD-2801 and EIDD-1931 PK 
parameters will be enrolled; it is planned that the P2 cohort will be at a dose of 100 mg 
EIDD-2801, although higher or lower doses may be selected based on safety and available PK 
data from P1.  
In addition to assessing the effect of food on dosing, PBMCs will be collected from subjects 
following each dose; the PBMCs will be stored for analysis of EIDD-2061 levels at some point 
in the future.  
The 10 subjects enrolled in the FE cohort will all receive EIDD-2801; subjects will be 
randomized to a treatment sequence (i.e., to receive drug in the fed then fasted state [Sequence 1] 
versus fasted then fed state [Sequence 2]). Half of the subjects in the cohort will be randomized 
to Sequence 1 and the other half will be randomized to Sequence 2.  
Following dosing on Day 1, subjects will remain in the clinic through completion of study 
assessments on Day 4, returning to the clinic on Day 9 for study assessments, and Day 14 to 
begin the second dosing sequence on Day 15. Subjects will then be discharged from the clinic on 
Day 18, returning to the clinic on Day 23 for study assessments, and Day 30 for the EOS visit. 
There will be a 14-day (minimum) washout period between doses. 
Part 3: For P3/MAD, subjects will receive BID doses on Day 1 through Day 5, inclusive, and 
will receive the final dose of study drug on the morning of Day 6 for collection of steady-state 
PK samples during waking hours. Subjects will remain domiciled at the site during the dosing 


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period and until Day 9, returning to the clinic on Day 14 for completion of study assessments, 
and Day 20 for the EOS visit. 
Doses in P3 may be administered in the fed state, following review of the PK data from P2. 
Additionally, depending on ongoing review of the safety, tolerability, and PK data, the number 
of days of dosing may be reduced and the dosing frequency changed; the dosing frequency will 
be no less than once-daily or no greater than three-times daily. If the number of days of dosing 
are reduced, the timepoints for subsequent assessments and the period for which subjects are 
domiciled at the clinic will similarly be changed (subjects will be domiciled for 3 days post final 
dose). 
Part 3 may run in parallel with P1, providing that the total daily dose to be administered does not 
exceed a dose already shown to be safe and well-tolerated in P1. 
Peripheral blood mononuclear cells may be collected from subjects in P3, depending upon 
ongoing review of the data. The collection of these samples may be omitted from some cohorts, 
depending on ongoing review of the data. The PBMCs will be stored for analysis of EIDD-2061 
levels at some point in the future. In addition, continuous 12-lead ECG monitoring will be 
performed to collect data to assess the relationship between study drug concentrations and QTc 
interval. All data will be archived without extraction or analysis and will not be reported in the 
scope of this study.  
Additional parts may be added to this study, including a SAD part in elderly healthy 
subjects and a study of the safety, tolerability, and PK in Japanese subjects. These 
additional parts are not described in this protocol but may be added via a protocol 
amendment.  
Safety Monitoring and Potential Unblinding: Safety for this study will be continually 
monitored by the PI and Sponsor.  
Blinding: All study personnel will remain blinded to treatment assignment (i.e., EIDD-2801 or 
PBO) in P1 and P3, except for personnel at the bioanalytical laboratory, and the unblinded 
pharmacy staff and pharmacokineticist. If unblinding is required to manage subject safety or to 
support dose-escalation decisions, the decision to unblind lies solely with the PI. If possible and 
providing that it does not interfere with or delay any decision in the best interest of the subject, 
the PI will discuss the intended code-break with the Sponsor. 
Dose-Escalation Halting Rules: 
For Group 1 in P1/SAD, sentinel dosing will occur whereby 2 subjects (1 active and 1 PBO) will 
be dosed on 1 day and, providing no safety concerns arise, the remaining 6 subjects will be 
dosed after at least 24 hours. 
The study will be halted if one or more subjects experience a serious adverse event (SAE) that is 
considered to be related to EIDD-2801 or 2 or more subjects in the same group experience 
severe AEs that are considered to be related to EIDD-2801.  
Additionally, if 2 or more subjects experience a reduction of platelets greater than 50% over 
baseline levels or a reduction in lymphocytes (absolute count) to Grade 3/severe levels without 
an alternate cause, the PI and Sponsor will review the data. If, after review of unblinded data, it 
is determined that these events are probably related to study drug, no further dose escalations 
will occur. 
Dose-escalation will stop if clinically relevant signs or symptoms of similar nature occur in 2 or 


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more subjects in a group that, in the opinion of the PI, warrant stopping of dose-escalation. 
Data Monitoring, Safety Reporting and Unblinding: Data will be monitored throughout the 
course of the study by experienced clinical monitors according to the clinical monitoring plan. 
As data will be entered into an electronic case report form (CRF), data will be monitored to 
ensure accuracy as well as adherence to data entry instructions provided in the CRF guidelines. 
Procedures for reporting any SAE will be detailed in the protocol and forms and instructions 
provided to the site. 
Statistical Considerations: A complete description of all statistical analyses and methods will 
be presented in the statistical analysis plan (SAP). The SAP will be reviewed and approved by 
the Sponsor and will be finalized prior to database lock. Plans for PK analyses will be included 
in the SAP. 
Determination of Sample Size: The sample sizes for the P1 and P3 cohorts are typical for a 
Phase 1 first in human (FIH) study. The sample size for the P2 cohort is in accordance with Food 
and Drug Administration (FDA) guidelines for sample size in FE studies. 
Study Populations: 
Safety Population: All subjects who receive at least one dose of study drug. 
Pharmacokinetic Population:  All subjects receiving study drug who comply sufficiently with 
protocol requirements (i.e., no major protocol deviations) and for whom a sufficient number of 
analyzable PK samples have been obtained to permit the determination of the PK profile for 
EIDD-2801/EIDD-1931 and the statistical analysis of the results. Subjects who experience an 
AE of vomiting before 2× the median tmax of the group may be excluded from the PK population. 
Safety Analyses: Statistical methods for the safety analyses will be descriptive in nature. Safety 
data, including AEs, clinical laboratory data, vital signs, ECG parameters, and PEs. All 
appropriate AEs will be graded using the Division of Microbiology and Infectious Diseases 
(DMID) toxicity scale (March 2014). Change from baseline will be included in summary tables 
for laboratory parameters. All laboratory data will be included in the data listings and all test 
values outside the normal range will be flagged. 
Pharmacokinetic Analyses: Plasma PK parameters for each dose level will be calculated from 
the concentrations of EIDD-2801 and EIDD-1931 measured in predose and postdose plasma 
samples. For each dose level, descriptive statistics will be presented. Figures will be created to 
display mean and individual subject EIDD-2801 and EIDD-1931 concentration versus time. 
Urine PK parameters will be calculated whenever possible for each subject based on the urine 
concentrations of EIDD-2801 and EIDD-1931. The following PK parameters will be calculated: 
Plasma PK Parameter 
Description 
AUClast 
The area under the plasma concentration-time curve, from time 0 to the last 
measurable non-zero concentration, as calculated by the linear up/log down 
trapezoidal method (P1 and P2 only). 
AUC0-inf 
The area under the plasma concentration-time curve from time 0 extrapolated 
to infinity. AUC0-inf is calculated as the sum of AUClast plus the ratio of the 
last measurable plasma concentration to the elimination rate constant (λz) 
(P1, P2, and Day 1 dose of P3). 
Cmax 
Maximum observed concentration. 
tmax 
Time to reach Cmax. If the maximum value occurs at more than one time 
point, tmax is defined as the first time point with this value. 


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λz 
Apparent terminal elimination rate constant; represents the fraction of 
medication eliminated per unit time. 
t1/2 
Apparent terminal elimination half-life of medication, calculated as 0.693/λz. 
Vz/F 
Apparent volume of distribution (EIDD-2801 only). 
CL/F 
Apparent oral drug clearance (EIDD-2801 only). 
Ctrough 
Trough concentration (P3 only). 
AUCτ 
The area under the plasma concentration-time curve during a dosing interval 
(P3 only). 
RAAUCτ 
Observed accumulation ratio based on AUCτ (P3 only). 
RACmax 
Observed accumulation ratio based on Cmax (P3 only). 
Urine PK Parameter 
Description 
Ae 
Amount excreted in urine over the sampling interval. 
Fe 
Fraction of drug excreted in the urine over sampling interval. 
CLR 
Renal clearance, CLR = Ae/AUC where both Ae and AUC are determined 
over co-incident time ranges after dosing. 
In P1, dose-proportionality for PK parameters of EIDD-2801 and EIDD-1931 (AUC0-inf, AUClast, 
and Cmax) will be assessed by the power model. The slope and the associated 90% confidence 
interval (CI) based on the power model will be reported. In P3 on Day 6, dose-proportionality for 
PK parameters of EIDD-2801 and EIDD-1931 (AUCτ and Cmax) will be assessed by the power 
model. The slope and associated 90% CI based on the power model will be reported. 
To assess the effect of food on the PK of EIDD-2801 and EIDD-1931, natural log-transformed 
PK parameters from P2 (AUC0-inf, AUClast, and Cmax) will be analyzed using a mixed-effects 
model with fixed effect terms for treatment (with or without food), period, and sequence and 
with subject within sequence as a random effect. Point estimates and their associated 90% CIs 
for the natural log-transformed PK parameters for the difference between EIDD-2801 
administered under fed relative to fasted conditions will be constructed. The point estimates and 
interval estimates will be back transformed to give estimates of the ratio and 90% CI for the 
geometric least squares mean ratio for fed/fasted to assess the effect of food. 
Interim Analyses: No formal interim analyses are planned for this study. Data from P1 cohorts 
may be locked, unblinded, and analyzed prior to conducting P2 and P3. 


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Figure 1: Study Schema 
 
SAD Dose 1 (50 mg QD )
SAD Dose 2 (TBD)
SAD Dose 3 (TBD)
Review 
Safety Data
Review 
Safety Data
Sentinel Grp 1: 2 subjects
24 hr safety review
Grp 2: 6 subjects
PART 1: SAD Cohorts                                                                                                          
Following review of data from Part 1 cohort administered dose selected for Part 2
Sequence 1
Dose: Fed
Sequence 2
Minimum 14-Day Washout
Dose: Fasted
Dose: Fasted
Dose: Fed
PART 2: Food Effect (FE) Cohort                                                                                              
MAD Dose 1 (TBD***)
MAD Dose 2 (TBD***)
MAD Dose 3 (TBD***)
Review 
Safety Data
Review 
Safety Data
PART 3: MAD Cohorts**                                                                                                                    
Abbreviations:
FE: food effect 
SAD: single ascending dose
MAD: multiple ascending dose
** Part 3 may run in parallel with Part 1, providing that the total daily dose to be administered does not exceed 
a dose already shown to be safe and well tolerated in Part 1
***The total daily dose in Part 3 will not exceed a dose shown to be safe and well-tolerated in Part 1


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1. 
INTRODUCTION 
This study is being conducted at sites across the United Kingdom and the United States. 
Country-specific protocol amendments have been prepared; with the exception of regional 
regulatory requirements, the study is consistent across countries and data will be reported in a 
single clinical study report. 
This study is a FIH study designed to assess the safety, tolerability and PK of EIDD-2801 in 
healthy human volunteers. EIDD-2801 is a ribonucleoside analog with broad-spectrum activity 
against many RNA viruses. It is currently being developed by Ridgeback Biotherapeutics as a 
treatment of infections caused by highly pathogenic coronaviruses (CoV), including COVID-19. 
In addition, EIDD-2801 is being developed in parallel as a treatment of uncomplicated influenza 
caused by all subtypes of circulating and emerging (drifted and shifted) influenza A virus (IAV) 
and influenza B virus (IBV), including seasonal, epidemic and pandemic strains.  
1.1. 
Background 
EIDD-2801 is the 5’-isopropyl ester prodrug of the broadly active, direct-acting antiviral 
ribonucleoside analog EIDD-1931. After oral delivery, the prodrug (EIDD-2801) is rapidly 
hydrolyzed by circulating esterases to produce high circulating (plasma) levels of EIDD-1931. In 
cell culture systems, EIDD-1931 has been shown to inhibit replication of multiple viral 
pathogens from multiple RNA virus families including pathogenic CoV (e.g., Middle East 
respiratory syndrome [MERS], severe acute respiratory syndrome [SARS]-CoV and 
SARS-CoV-2), influenza viruses (seasonal, pandemic, and avian subtypes), respiratory syncytial 
virus (RSV), alphaviruses (e.g., Eastern equine encephalitis virus [EEEV], Venezuelan equine 
encephalitis virus [VEEV], and Chikungunya virus [CHKV]), Filoviruses (e.g., Ebola virus 
[EBOV]), and Zika virus (ZIKV). In addition, EIDD-2801 is active against orthopoxviruses 
(tested against vaccinia virus) probably because orthopoxviruses encode their own unique RNA 
polymerase. 
 
 The primary mechanism of action of 
EIDD-2801 is inhibition of viral RNA replication by incorporation of the EIDD-1931 
monophosphate metabolite into the viral RNA genome resulting in induction of viral error 
catastrophe. 
1.2. 
Rationale for Development 
EIDD-2801 is being developed for the treatment of infections caused by RNA viruses, 
specifically for COVID-19 and other CoV infections, influenza, and VEEV. During conduct of 
the FIH study, the Sponsor intends to define a dose that may be active in treating COVID-19 in 
patient studies.  
EIDD-2801 has a unique dual mechanism of action against RNA viruses, including 
SARS-CoV-2 and other CoV infections. The compound acts as a competitive, alternative 
substrate for the virally encoded RNA-dependent RNA-polymerase that upon incorporation into 
nascent chain RNA induces increased mutational frequency in the viral genome. Incorporation 
quickly results in the production of non-viable virus. Additionally, the active metabolite, 


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EIDD-1931-5’-triphosphate (EIDD-2061), may act directly as a chain terminator and arrest 
replication by exerting a next nucleoside effect. It is anticipated that the high barrier to resistance 
observed during in vitro passaging studies will translate to slow, if any, emergence of viral 
resistance. Resilience to viral escape is a distinguishing feature of EIDD-2801. 
Currently, there is no approved antiviral therapeutic for the treatment of COVID-19. An antiviral 
drug is urgently needed. 
 
 
 
 
 
 
1.3. 
Nonclinical Overview 
1.3.1. 
Mechanism of Action 
The mechanism of antiviral activity of EIDD-2801 is “lethal mutagenesis”; a concept that is 
predicated on increasing the viral mutation rate beyond a biologically-tolerable threshold, 
resulting in impairment of viral fitness and leading to viral extinction. 
The specifics of the mechanism are as follows. EIDD-2801 is rapidly taken up by cells and the 
5’-isopropylester cleaved to liberate EIDD-1931, which is in turn phosphorylated to EIDD-2061 
by host kinases (Hernandez-Santiago et al., 2004; Painter et al., 2019). The 5’-triphosphate, 
EIDD-2061, acts as a competitive alternative substrate for virally encoded RNA-directed RNA 
polymerases and EIDD-2061 is incorporated into nascent viral RNA. Owing to the ability of the 
N4-hydroxycytosine base of EIDD-1931 to tautomerize, EIDD-2061 can pair with either 
guanosine or adenosine, and consequently can substitute for either CTP or UTP, respectively 
(Flavell et al., 1974). This results in an accumulation of mutations that increases with each cycle 
of viral replication. The process whereby the mutation rate is increased by exposure to a drug is 
referred to as Viral Decay Acceleration (Mullins et al., 2011) and results in viral ablation. 
Significant work has gone into validating this mechanism of action for EIDD-2801/1931, and it 
has been shown for MERS-CoV, VEEV, and IAV that viruses grown in the presence of 
EIDD-1931 have significantly increased levels of transition mutations (Agostini et al., 2019; 
Toots et al., 2019; Urakova et al., 2018). Multi-log decreases in virus yields were observed after 
treatment with EIDD-1931. Additionally, it was demonstrated for VEEV that the infectivity of 
virions formed in the presence of EIDD-1931 decreases from ~20% to <0.2%, and that the 
infectious virions are significantly Impaired in their replication ability (Urakova et al., 2018). As 
a consequence of this mechanism of action, the generation of drug-resistant escape mutants is 
practically impossible. This same effect was demonstrated for CoV (Agostini et al., 2019) and 
influenza virus (Toots et al., 2019). Furthermore, given the unique mechanism of action, 
EIDD-2801 is expected to be active against viruses resistant to other antiviral agents which have 
a different mechanism of action. The only data generated to date regarding the activity of 
EIDD-1931 against viruses resistant to other nucleoside analogs found that EIDD-1931 was 


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active against CoV resistant to remdesivir in cell culture assays (T. Sheahan et al, preprint 
available at https://www.biorxiv.org/content/10.1101/2020.03.19.997890v1). 
As an alternative or additional mechanism of action, it has been theorized that incorporation of 
EIDD-2061 into viral genomic RNA can change the thermodynamics of RNA secondary 
structure and thus decrease the efficiency of the promoter regions involved in RNA genome 
replication (Stuyver et al., 2003). 
1.3.2. 
In Vitro Pharmacology 
1.3.2.1. 
Antiviral Activity in Tissue Culture and in Human Airway Epithelium 
The ribonucleoside analog EIDD-1931 is the parent of the prodrug EIDD-2801. EIDD-1931 
shows specific antiviral activity in different tissue culture cells and in the differentiated organoid 
model of human airway epithelium (HAE) with a selectivity index (SI) ranging from 21 to >100 
for all influenza viral isolates tested. It is active against IAV (pandemic and seasonal) and IBV 
strains, as well as against highly pathogenic H5N1 and H7N9 strains (Table 1). 
Table 1: 
EIDD-1931 Antiviral Activity Against Influenza A and B Viruses in Tissue 
Culture and Primary Human Bronchial/Tracheal Epithelial Cells 
Virus 
Strain 
Cell line 
EC50* 
(µM) 
CC50 
(µM) 
SI 
Reference 
IAV H1N1 
Ca/07/2009 
MDCK 
1.24 
68 
55 
NIAID Antiviral Testing Program 
IAV H1N1 
WSN/33 
MDCK 
1.1 
299.8 
275 
Yoon et al., 2018 
IAV H1N2 
WSN/33 
primary hBTEC 
5.4 
- 
- 
Yoon et al., 2018 
IAV H2N3 
Perth/16/2009 
MDCK 
0.88 
52 
59 
NIAID Antiviral Testing Program 
IAV H2N3 
Ohio/sw-10-132/2010 
MDCK 
3.2 
299.8 
94 
Yoon et al., 2018 
IAV H5N1 
Duck/MN/1525/81 
MDCK 
1.28 
27 
21 
NIAID Antiviral Testing Program 
IAV H5N1 
Vietnam/1203/2004 
MDCK 
0.14 
299.8 
2100 
Yoon et al., 2018 
IAV H7N9 
Anhui/1/2013 
MDCK 
0.13 
299.8 
2300 
Yoon et al., 2018 
IBV 
Florida/4/2006 
MDCK 
<0.4 
76 
>190 
NIAID Antiviral Testing Program 
IBV 
Brisbane/60/08 
MDCK 
0.006 
299.8 
50000 
Yoon et al., 2018 
IAV H1N1 
Ca/07/2009 
HAE-3D* 
0.08 
50 
625 
Toots et al., 2019 
IAV H1N1 
WSN/33 
HAE-3D* 
0.08 
50 
625 
Toots et al., 2019 
IBV 
Brisbane/60/08 
HAE-3D* 
0.06 
50 
833 
Toots et al., 2019 
* Human Airway Epithelium organoid model. 
EIDD-1931 also showed specific antiviral activity against human SARS-CoV, MERS-CoV 
(Table 2) and SARS-CoV-2 (Figure 2), against togaviruses VEEV, EEEV and CHKV (Table 3) 
 


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EIDD-1931 (NHC) antiviral activity (closed circles) and 
cytotoxicity (open squares) in Vero Cells infected with SARS- 
CoV-2. Vero cells were infected in duplicate with SARS-CoV- 
2 clinical isolate virus at a multiplicity of infection (MOI) of 0.05 
in the presence of a dose response of EIDD-2801 for 48 hours 
after which replication was measured through quantitation of 
cell viability by Cell-Titer-Glo assay. Cytotoxicity was 
measured in similarly treated but uninfected cultures. 
Reproduced from Sheahan et al 2020. 
Table 2: 
EIDD-1931 Antiviral Activity Against SARS and MERS Coronaviruses in Tissue 
Culture and Primary Human Bronchial/Tracheal Epithelial Cells 
Virus 
Strain 
Cell line 
EC50 
(µM) 
CC50 
(µM) 
SI 
Reference 
SARS-CoV-1 Urbani 
Vero76 
<0.4 
144 
>360 NIAID Antiviral Testing Program 
SARS-CoV-1 SARS-CoV-GFP(†) 
HAE-3D(*) 
<1 
>100 
>100 Tech. Report 25.038 
MERS-CoV 
GenBank Ac.No JX869059** DBT-9 
0.56 
>200 
>357 Agostini et al., 2019 
MERS-CoV 
Human ß-CoV C, Novel 2912 Vero E6 
<0.8 
20 
>25 
NIAID Antiviral Testing Program 
* Human Airway Epithelium organoid model; ** cDNA Derived clone 
Figure 2: Inhibition of SARS-CoV-2 by EIDD-1931 
 
Table 3: 
EIDD-1931 Antiviral Activity Against Togaviruses in Tissue Culture 
Virus 
Strain 
Cell line 
EC50 (µM) 
CC50 (µM) 
SI 
Reference 
VEEV 
TC-83 
Vero 
0.43 
>200 
>930 Urakova et al., 2018 
VEEV 
TC-83 
Vero76 
1.92 
32 
17 
NIAID Antiviral Testing Program 
EEEV 
FL93-939 
Vero76 
1.08 
84 
78 
NIAID Antiviral Testing Program 
CHKV 
S27 (VR-64) 
Vero76 
1.8 
96 
53 
NIAID Antiviral Testing Program 


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1.3.2.2. 
Cytotoxicity of EIDD-1931 in Tissue Culture Utilizing Cells from 
Different Organs and Species 
EIDD-1931 was tested for cytotoxicity in human hepatic origin Huh7 and HepG2 cells, in human 
lymphoid CEM, human pancreatic BxPC-3, human prostate cancer PC-3, human muscle A204, 
human lung A549, human epithelial hEp-2, rat heart muscle H9c2, monkey kidney Vero, and 
canine kidney MDCK cell lines (Table 5). The compound exhibits low cytotoxicity in the 
majority of cells tested (half-maximal effective concentration [EC50] values are in the range of 40 
to >100 µM) except in lymphoid origin CEM cells where the compound shows a 7.5 µM EC50 
value (Sticher et al., 2020; Urakova et al., 2018; Yoon et al., 2018). 
Table 5: 
Cytotoxicity (CC50) of EIDD-1931 in Mammalian Cell Lines 
Cell Line 
CEM 
HepG2 
PC-3 
A204 
A549 
BxPC-3 
Huh-7 
H9c-2 
Vero 
hEp-2 
MDCK 
CC50 
(µM) 
7.5 
42.3 
267.1 
84 
46 
48 
165.5 
81 
53 
272.4 
299.8 
Sources: Sticher et al., 2020, Yoon et al., 2018 
EIDD-2801 typically showed 2-4× lower activity and cytotoxicity than EIDD-1931 due to 
slightly slower uptake and anabolism in tissue culture. 
1.3.2.3. 
Assessment of Mitochondrial Toxicity 
Since EIDD-1931 is a nucleoside analog, additional investigations were performed to analyze 
whether observed cytotoxicity of EIDD-1931 is caused by mitochondrial toxicity. It was 
demonstrated that the prolonged treatment (14 days) with the compound does not result in 
selective killing of mitochondria or in mitochondrial dysfunction in CEM and HepG2 cells 
(Sticher et al., 2020). 
1.3.3. 
In Vivo Pharmacology 
The prodrug EIDD-2801 or its parent EIDD-1931 have been tested in animal models of RNA 
viral infection. An overview of results from the animal studies in indications to be pursued are 
described below. Additional detail is provided in the Investigator’s Brochure (IB). 
1.3.3.1. 
Coronavirus: SARS-CoV and MERS-CoV 
In mouse models of SARS and MERS infection and disease, coronaviral disease was assessed by 
changes in body weight, measured daily, and lung hemorrhage, assessed in the large left lobe of 
the lung following sacrifice on Day 5 (SARS-CoV) or Day 6 (MERS-CoV). To assess 
production of infectious virions, virus was isolated from the lower left lobe of the lung following 
sacrifice on Day 5 (SARS-CoV) or Day 6 (MERS-CoV) and quantified using a plaque assay. 
The results demonstrated that, in mice infected with either SARS- or MERS-CoV, both 
prophylactic and therapeutic treatment with EIDD-2801 resulted in a reduction in virus 
replication, improvements in pulmonary function, and improvements in maintaining body weight 


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(i.e., reduced body weight loss). While EIDD-2801 doses of 50, 150 and 500 mg/kg BID were 
assessed in the CoV mouse experiments, 500 mg/kg BID yielded the most consistent therapeutic 
effect. 
A prophylactic, dose-escalation study was conducted in C57BL/6 mice infected with 
mouse-adapted SARS-CoV (SARS-MA15). Prophylactic oral treatment with EIDD-2801 was 
initiated 2 hours before intranasal infection and continued every 12 hours thereafter through the 
end of the study (Day 5; Figure 3). 
In mice treated BID with EIDD-2801, body weight loss observed with vehicle treatment was 
diminished in the 50 mg/kg treatment group, beginning on Day 3 post-infection. No body weight 
loss was seen in the 150 and 500 mg/kg treatment groups (Figure 3, Panel A). Lung hemorrhage 
was also significantly reduced on Day 5 post-infection, following treatment with 500 mg/kg 
EIDD-2801 (Figure 3, Panel B). When compared to vehicle control, a dose-dependent reduction 
in SARS-CoV lung titers at Day 5 was seen across all 3 treatment groups (Figure 3, Panel C) 
with significant differences among the vehicle, 150 mg/kg and 500 mg/kg groups. Thus, 
prophylactic treatment with EIDD-2801 resulted in a robust antiviral effect that was able to 
prevent SARS-CoV replication and disease. 
Figure 3: EIDD-2801 Prophylactic Treatment of SARS-CoV Infected Mice 
 
The antiviral activity of EIDD-2801 against SARS-CoV was compared when treatment was 
initiated at -2 hours (pre-infection) and 12, 24, or 48 hours post-infection. After initiation of 
treatment, all groups were dosed every 12 hours for the duration of the study (Figure 4). For 
SARS-challenged mice, initiating treatment at 12 hours post-infection significantly prevented 
body weight loss beginning on Day 2, a result similar to that seen when dosing prophylactically 


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(i.e., beginning at 2 hours pre-infection). Initiation of treatment with EIDD-2801 at 24 hours 
post-infection also significantly reduced body weight loss on Days 3 through5 post-infection. 
When EIDD-2801 treatment was initiated at 48 hours post-infection, body weight loss was only 
statistically different from vehicle on Day 4 post-infection (Figure 4, Panel A). Significant 
reductions in lung hemorrhage were seen when EIDD-2801 treatment was initiated before 
(-2 hours) and up to 24 hours after infection; a result that mirrored body weight loss data 
(Figure 4, Panel B). All mice treated with EIDD-2801 had significantly reduced viral loads in the 
lungs, even in the group where treatment was initiated 48-hour post-infection (Figure 4, 
Panel C). Pulmonary function, measured via whole body plethysmography, was assessed using 
the PenH metric which is a surrogate marker for bronchoconstriction or pulmonary obstruction. 
The administration of EIDD-2801 prior to infection (-2 hours) and at 12 hour post-infection 
completely abrogated the loss of pulmonary function observed in vehicle-treated animals 
(Figure 4, Panel D). Improved pulmonary function was also seen in the group where treatment 
was initiated 24 hours after virus challenge. 
Figure 4: EIDD-2801 Treatment of SARS-CoV Infected Mice 
 
EIDD-2801 was also tested to determine if it is active in vivo against MERS-CoV as described 
by Sheahan et. al (draft manuscript). The murine ortholog of the MERS-CoV receptor, dipeptidyl 
peptidase 4 (DPP4), does not support viral binding and entry. Thus, all in vivo studies described 
below were performed in genetically modified hDPP4 mice permissive for MERS infection. 
Prophylactic treatment starting at 2 hours before viral challenge with either 50, 150, or 


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500 mg/kg EIDD-2801 prevented body weight loss on Days 2 through 6 post-infection (Figure 5, 
Panel A), prevented lung hemorrhage measured on Day 6 (Figure 5, Panel B), and reduced virus 
lung titer on Day 6 to the limit of detection (Figure 5, Panel C). 
Figure 5: EIDD-2801 Prophylactic Treatment of MERS-CoV Infected Mice 
 
The effect of EIDD-2801 treatment on MERS-CoV infected mice is shown in Figure 6. When 
EIDD-2801 treatment was initiated 12 hours post-infection, there was no loss in body weight 
from Days 2 through 6 post-infection (Figure 6, Panel A) and no evidence of lung hemorrhage 
on Day 6 post-infection (Figure 6, Panel B). However, protection was not observed in groups 
where treatment was initiated either 24- or 48-hours post-infection. Conversely, virus lung titer 
on Day 6 post-infection was significantly reduced to the limit of detection in all treatment 
groups, regardless of the time treatment began (Figure 6, Panel C). To gauge the effect of the 
timing of EIDD-2801 treatment initiation on physiologic measures of lung disease, pulmonary 
function was assessed by whole body plethysmography. As expected, a loss of pulmonary 
function, as determined by measuring the PenH metric, was observed in vehicle-treated animals 
infected with MERS-CoV beginning on Day 2 post-infection (Figure 6, Panel D). Mirroring the 
body weight loss data, normal pulmonary function was observed in groups where treatment was 
initiated prior to or at 12 hours post-infection (Figure 6, Panel D). 


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Figure 6: EIDD-2801 Treatment of MERS-CoV Infected Mice 
 
1.3.3.2. 
Influenza Virus 
EIDD-2801 was tested in a ferret model of influenza virus infection and disease. Ferrets 
recapitulate hallmarks of human influenza infection, providing a clinically relevant animal model 
to investigate therapeutic intervention. Therapeutic oral dosing of influenza virus-infected ferrets 
reduced shed levels of pandemic and seasonal IAV by multiple orders of magnitude, and 
alleviated fever and inflammation while improving airway epithelium histopathology. 
Post-exposure prophylactic dosing was sterilizing (Toots et al., 2019). 
Ferrets infected with pandemic IAV and treated with EIDD-2801 at a dose of 7 mg/kg 
demonstrated significantly less viral shedding and inflammatory cellular infiltrates in nasal 
lavages, but mounted a normal humoral antiviral response (Toots et al., 2019). 
When examining the effect of delayed dosing, Toots et. al. (2019) demonstrated that treatment 
with 20 mg/kg of EIDD-2801 initiated 24 hours after challenge with IAV (H1N1) resulted in a 
rapid decrease in both shed virus and fever relative to control, with fever returning to baseline at 
24 hours. When oseltamivir (20 mg/kg) was dosed prophylactically as a positive control, a 
modest suppression of fever was observed; however, there was no reduction in shed virus titer. 


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1.3.3.3. 
Venezuelan Equine Encephalitis Virus 
Treatment with EIDD-1931 was evaluated in a mouse model of lethal VEEV infections. To be 
truly effective as a therapeutic agent for VEEV infection, a drug must penetrate the blood brain 
barrier and arrest virus replication in the brain. High plasma levels of EIDD-1931 are rapidly 
achieved in mice after oral dosing. Once in the plasma, EIDD-1931 is efficiently distributed into 
organs important in the pathology of VEEV infection, including the brain, where it is rapidly 
converted to its active 5’-triphosphate (EIDD-2061). EIDD-1931 showed a good safety profile in 
mice after 7 days of dosing with up to 1,000 mg/kg/day. In mouse model studies of VEEV 
infection, EIDD-1931 was 90-100% effective in protecting mice against lethal intranasal 
infection when therapeutic treatment was started as late as 24 hours post-infection, and partial 
protection was achieved when treatment was delayed for 48 hours post-infection (Painter et al., 
2019). 
 
 
 
 
 
 
 
 
 
1.4. 
Safety and Secondary Pharmacology 
The standard battery of safety pharmacology studies including studies assessing the 
cardiovascular, respiratory and central nervous systems have been conducted. The studies are 
discussed in the IB; results indicated that there were no adverse pharmacologic effects of 
EIDD-2801 on the cardiovascular, respiratory or central nervous systems. 
1.5. 
Nonclinical Pharmacokinetics and Metabolism 
1.5.1. 
Overview 
The uptake, metabolism and protein binding of EIDD-2801 and EIDD-1931 have been studied in 
plasma, microsomes, and non-hepatic cells from several species as outlined below. The PK and 
tissue distribution of prodrug EIDD-2801 and its active parent EIDD-1931 have been studied 
extensively in rats, dogs and ferrets. Key results from these studies are presented below; 
additional detail can be found in the IB. 
1.5.2. 
Absorption 
EIDD-1931 is parent of the prodrug EIDD-2801. The appearance of EIDD-1931 is dependent on 
the absorption of EIDD-2801 and the rate of its conversion to EIDD-1931. 


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EIDD-2801 PK studies have been completed in dog, rat, mouse, ferret, and monkey. EIDD-2801 
was efficiently absorbed and rapidly converted to EIDD-1931 in each species. The tmax for 
EIDD-2801 (not observed in rodents) occurred at 0.5-1 hours, while the tmax for EIDD-1931 
occurred at 1-2 hours. 
1.5.3. 
Distribution 
 
 
 
 
 
 
 
 
 
1.5.3.2. 
Tissue Distribution Studies 
EIDD-2801 is rapidly absorbed in the gut and converted to EIDD-1931 reaching Cmax in 
1-3 hours in mice, rats, ferrets, dogs and monkeys. EIDD-1931 is then widely distributed to 
tissues including lungs and brain, where it is rapidly taken up into cells and converted to 
EIDD-2061. Figure 7 shows the concentration of EIDD-1931 and EIDD-2061 in ferret brain and 
lung following single doses of 20 (Panels A and B) and 128 (Panels C and D) mg/kg. 


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Figure 7: Tissue Distribution of EIDD-1931 and EIDD-2061 in Ferret Brain and Lung 
 
1.5.4. 
Metabolism 
1.5.4.1. 
Metabolic Stability of EIDD-1931 and EIDD-2801 
EIDD-2801 was designed to be converted to EIDD-1931 by esterases in plasma or in cells. 
Stability has been assessed in plasma and liver microsomes from mouse, rat, dog, monkey and 
humans. The stability of EIDD-2801 in mouse, rat and monkey plasma is relatively short 
(≤0.4 hours) while the stability is longer in human and dog plasma (1-3 hours). EIDD-2801 
stability in mouse, rat, dog and monkey liver microsomes is very short, ranging from 0.02 to 
0.08 hours while the stability in human liver microsomes is 1.2 hours (Table 6). 


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Table 6: 
Metabolic Stability of EIDD-2801 in Plasma and Liver Microsomes 
Species 
Plasma stability 
LM stability 
t1/2 (h) 
t1/2 (h) 
Mouse 
0.017 
0.033 
Rat 
0.033 
0.017 
Dog 
3.2 
0.083 
Monkey 
0.40 
0.017 
Human 
1.05 
1.22 
EIDD-2801 is stable in simulated gastric and intestinal fluids (Table 7). 
Table 7: 
Metabolic Stability of EIDD-2801 in Simulated Gastric and Intestinal Fluids and 
in Buffered Saline with Fetal Bovine Serum 
Matrix 
t1/2 (hr) 
Simulated Gastric Fluid 
>24 
Simulated Intestinal Fluid 
>24 
Phosphate Buffered Saline plus 10% Fetal Bovine Serum* 
>24 
EIDD-1931 was found to be stable when incubated with all tested plasmas, whole blood, liver 
microsomes and liver S9 extracts and intestinal microsomes (Table 8). 
Table 8: 
Metabolic Stability of EIDD-1931 in Plasma, Whole Blood and Liver and 
Intestinal Microsomes 
Medium 
Plasma 
Whole Blood 
Liver Microsomes 
Liver S9 Stability 
Intestinal Microsomes 
Species 
t1/2 (h) 
t1/2 (h) 
t1/2 (h) 
t1/2 (h) 
t1/2 (h) 
Mouse 
 
>24 
>24 
 
>24 
Rat 
17 
 
>24 
>24 
 
Dog 
>24 
 
 
>24 
 
Monkey 
6.5 
>24 
>24 
>24 
>24 
Human 
10 
7 
>24 
20 
>24 
1.5.4.2. 
Uptake and Anabolism of EIDD-1931 in Tissue Culture and Primary 
Cells 
EIDD-1931 is efficiently taken up by tissue culture cells and converted to its pharmacologically 
active metabolite EIDD-2061 (EIDD-1931-5’-triphosphate). Intracellular EIDD-2061 
accumulates dose-dependently, with Cmax levels ~200-2000 pmol/106 cells (at 10-20 µM dose) in 
different cell lines. It reaches high levels relatively quickly, typically within 1-3 hours, though 
the tmax values vary widely between 1 and 24 hours depending on the cell line and dose 
concentration tested. Detailed data on the uptake and anabolism of EIDD-2801 is presented in 
the IB. 


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EIDD-2801 is also taken up by tissue culture cells and is converted to EIDD-1931 and then to 
EIDD-2061, but the process is slightly delayed compared to dosing with EIDD-1931. 
EIDD-1931 is also taken up and metabolized to EIDD-2061 by primary cells. EIDD-2061 is 
accumulated in all primary cells tested except in mouse primary hepatocytes where EIDD-1931 
is apparently extensively metabolized to cytidine and uridine which, in turn, quickly metabolize 
into CTP and UTP. The quick metabolism of EIDD-1931 consequently results in low levels of 
EIDD-2061 in mouse hepatocytes. The intracellular stability (t1/2) of EIDD-2061 is 4-5 hours in 
human astrocytes and hBTEC and is significantly shorter (0.2-1.1 hours) in primary hepatocytes. 
1.5.5. 
Excretion 
Currently, there is no data on excretion of EIDD-2801 or EIDD-1931. Excretion will be 
measured in urine during this study. 
1.5.6. 
Pharmacokinetic Drug Interactions 
1.5.6.1. 
Cytochrome P450 (CYP) Inhibition 
The purpose of this non-GLP in vitro study was to determine the time-dependent inhibitory 
potential of EIDD-2801 and EIDD-1931 on human cytochromes P450 (CYP) 1A2, 2B6, 2C8, 
2C9, 2C19, 2D6, and 3A4 (midazolam and testosterone substrates) enzyme activity, using pooled 
human liver microsomes in an half-maximal inhibitory concentration (IC50) shift assay. 
Neither EIDD-2801 nor EIDD-1931 demonstrated inhibition greater than 31.4% for any of the 
CYP isozymes tested nor could the data for each assay condition be curve fit to determine 
time-dependent inhibition by these compounds. Full dose-response curves were not achieved at 
concentrations ranging from 0.00545 to 50.0 µM indicating EIDD-2801 and EIDD-1931 have no 
CYP inhibition potential at concentrations ranging from 0.00545 to 50.0 µM. Assay performance 
was acceptable based on the results for the positive control inhibitors. 
1.5.6.2. 
CYP Induction 
An assay was performed to determine the induction potential of EIDD-2801 on human CYP 
isoenzyme (1A2, 2B6, and 3A4) activity using 3 single-donor lots of inducible, cryopreserved 
human hepatocytes. Both enzyme activity and mRNA results demonstrated that EIDD-2801 did 
not show induction for any of the CYP isozymes. 
 
 
 
 
 
 
 


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1.7. 
Potential Risks and Benefits 
1.7.1. 
Potential Benefits 
As this is a FIH study in healthy volunteers, there is no direct benefit to subjects enrolled in the 
study. However, given the current pandemic situation and in vitro antiviral activity of 
EIDD-2801 against SARS-CoV-2, and the activity against several other viruses of public health 
concern, it is possible that participants may benefit from future availability of the drug. 
1.7.2. 
Potential Risks 
EIDD-2801 has never been administered to humans; therefore, the risks from EIDD-2801 to 
subjects participating in this trial are unknown. Although toxicology studies have been done, 
unexpected AEs may occur.
 
 
 
. Subjects will also be monitored for other end-organ 
effects through a range of safety assessments. 


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2. 
OBJECTIVES 
2.1. 
Study Objectives 
2.1.1. 
Primary Objectives 
The primary objective of Part 1 of the study is to determine the safety and tolerability of single 
ascending doses of EIDD-2801. 
The primary objective of Part 2 of the study is to assess the effect of food on the PK on 
EIDD-2801 and EIDD-1931 following a single oral dose. 
The primary objective of Part 3 of the study is to determine the safety and tolerability of multiple 
ascending doses of EIDD-2801. 
2.1.2. 
Secondary Objectives 
The secondary objectives of Part 1 and Part 3 of the study is to define the PK of EIDD-2801 and 
EIDD-1931 in plasma and urine following single and multiple doses administered to healthy 
volunteers. 
The secondary objective of Part 2 of the study is to determine the safety and tolerability of single 
doses of EIDD-2801. 
2.1.3. 
Exploratory Objectives 
The exploratory objective of Part 3 is to collect data to assess the relationship between 
EIDD-2801/EIDD-1931 concentrations and QTc. 
2.2. 
Study Outcome Measures 
2.2.1. 
Primary Outcome Measures 
The primary outcome measures for Parts 1 and 3 of are results of safety evaluations including 
safety laboratory assessments, PEs, ECGs, vital signs, and AEs. 
The primary outcome measures for Part 2 of the study are plasma PK parameters including Cmax, 
tmax, t1/2, CL/F, λz, Vz/F, AUC0-inf and AUClast as appropriate. 
2.2.2. 
Secondary Outcome Measures 
The secondary outcome measures are as follows: 
 Single-dose plasma PK parameters, including Cmax, tmax, t1/2, CL/F, λz, Vz/F, 
AUC0-inf and AUClast as appropriate (Part 1) 
 Multiple-dose plasma PK parameters, including Ctrough, Cmax, tmax, t1/2, CL/F, λz, 


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Vz/F, AUCτ, AUC0-inf (Day 1 dose only), RAAUCτ and RACmax, as appropriate (Part 3) 
 Urinary excretion of EIDD-2801 and EIDD-1931 following single- and 
multiple-dose administration (Parts 1 and 3). 
 Results of safety evaluations including safety laboratory assessments, PEs, ECGs, 
vital signs, and AEs (Part 2). 


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3. 
STUDY DESIGN 
3.1. 
Overview 
EIDD-2801-1001-UK is a Phase 1, randomized, double-blind, placebo-controlled, FIH, SAD, 
and MAD study of the safety, tolerability and PK of EIDD-2801 and EIDD-1931 following oral 
administration of single and multiple doses of EIDD-2801 to healthy volunteers. In addition, for 
a minimum of one cohort, the effect of food on the single-dose EIDD-2801 and EIDD-1931 PK 
parameters will be assessed in subjects taking open-label EIDD-2801. The overall objective of 
the study is to identify a starting dose for future safety and therapeutic intervention trials. 
The study is composed of 3 parts; P1 is the SAD study, P2 is the FE cohort study, and P3 is the 
MAD study.  
This study will be conducted at 1 site in the United Kingdom and up to 3 sites in the United 
States. 
3.1.1. 
Part 1 (Single Ascending Dose) 
A single oral dose of EIDD-2801 or PBO will be administered to subjects. Subjects will be 
randomized in a 3:1 ratio to receive either EIDD-2801 or PBO. 
Following dosing on Day 1, subjects will remain in the clinic through completion of study 
assessments on Day 4, returning to the clinic on Day 9 for study assessments, and Day 15 for the 
EOS visit. 
The first cohort will be divided into 2 groups. The first group, a sentinel group, will include 
2 subjects. On Day 1, one subject in the sentinel group will be administered PBO and one will be 
administered EIDD-2801. Analysis of the safety results for the sentinel group will be reviewed 
24 hours postdose. If no halting criteria (Section 9) have been met, the remainder of the subjects 
in Cohort 1 (the second group) will be dosed. There will be no sentinel groups for the remaining 
cohorts. 
After completion of each dosing cohort, safety and tolerability data will be reviewed to 
determine if any of the halting rules have been met. If not, then the subsequent cohort may be 
dosed following review of the 72-hour safety data. As PK data become available, these data may 
be used for dose-escalation decisions. 
The proposed dose-escalation scheme is shown in Figure 1, however, planned dose escalations 
will be determined based on ongoing review of the safety, tolerability, and available PK data. 
The starting dose in the first SAD cohort will be 50 mg. Dose levels will not increase by more 
than 3-fold for predicted nonpharmacologically active dose levels and by 2-fold for predicted 
pharmacologically active dose levels. The highest total daily dose to be studied under this 
protocol will not exceed 800 mg (Section 9.2). 


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Three cohorts are initially planned for P1; however, up to an additional 4 cohorts may be 
enrolled. 
3.1.2. 
Part 2 (Food-Effect) 
Two single oral doses of EIDD-2801 will be administered to subjects, in an open-label manner. 
The dose for the P2/FE cohort is planned to be 100 mg but may be adjusted based on safety, 
tolerability, and/or PK data from P1. The dose assessed in the P2 cohort will have been given 
previously to subjects in a P1 cohort successfully (i.e., no halting rules were met following 
dosing).  
Subjects will be randomized to a treatment sequence; i.e., to receive drug in the fed then fasted 
state (Sequence 1) versus fasted then fed state (Sequence 2; Figure 1). Half of the subjects in the 
cohort will be randomized to Sequence 1 and the other half will be randomized to Sequence 2.  
Following dosing on Day 1, subjects will remain in the clinic through completion of study 
assessments on Day 4, returning to the clinic on Day 9 for study assessments, and Day 14 to 
begin the second dosing sequence on Day 15. Subjects will then be discharged from the clinic on 
Day 18, returning to the clinic on Day 23 for study assessments, and Day 30 for the EOS visit. 
There will be a 14-day (minimum) washout period between doses. 
One cohort of 10 subjects is planned for P2. However, if PK results obtained are equivocal, 
additional subjects may be enrolled into the P2/FE cohort at the previously tested dose or an 
additional P2/FE cohort may be added at a different dose. 
3.1.3. 
Part 3 (Multiple Ascending Dose) 
Subjects in P3 will be randomized in a 3:1 ratio to receive either EIDD-2801 or PBO. 
Twice-daily dosing will be administered to subjects on Day 1 through Day 5, inclusive, and a 
final dose will be administered on the morning of Day 6 for collection of steady-state PK 
samples during waking hours. Depending on ongoing review of the safety, tolerability, and PK 
data, the number of days of dosing may be reduced and the dosing frequency may be changed; 
the dosing frequency will be no less than once-daily or no greater than three-times daily.  
The proposed dose-escalation scheme is shown in Figure 1. The total daily dose will not exceed 
a dose shown to be safe and well-tolerated in P1. Doses in P3 may be administered in the fed 
state, following review of the PK data obtained from P2. Part 3 may run in parallel with P1, 
providing that the total daily dose to be administered does not exceed a dose already shown to be 
safe and well-tolerated in P1. 
Subjects will remain domiciled at the site during the dosing period and until Day 9, returning to 
the clinic on Day 14 for completion of study assessments, and Day 20 for the EOS visit. If the 
number of days of dosing are reduced, the timepoints for subsequent assessments and the period 
for which subjects are domiciled at the clinic will similarly be changed (subjects will be 
domiciled for 3 days post final dose). 


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Three cohorts are initially planned for P3; however, up to an additional 4 cohorts may be 
enrolled, or the number of cohorts may be reduced if the study objectives are met. Dose levels in 
P3 may be repeated for collection of PBMCs, providing that the dose level did not meet the 
dose-escalation halting criteria. 
Additional parts may be added to this study, including a SAD part in elderly healthy 
subjects and a study of the safety, tolerability, and PK in Japanese subjects. These 
additional parts are not described in this protocol, but may be added via a protocol 
amendment. 
3.2. 
Rationale and Justification 
3.2.1. 
Justification of Design 
The FIH study is a typical dose-escalation study designed to provide the maximum amount of 
data in the minimum number of subjects. The cohort size in P1 and P3 is planned to be 8 subjects 
(6 active:2 PBO). This number of subjects allows for a sufficient PK analysis, considered to be 
important because dose extrapolation from efficacious animal models to humans will be based 
on exposure. The duration of participation for each subject following dosing well exceeds 5 drug 
half-lives (up to 9.1 hours in dogs; 5 hours in ferrets) 
 
 The FE cohort is considered to be important to maximize exposure 
based on fed vs. fasted condition and obtaining this information early in Phase 1 will minimize 
study drug dose in all future studies. This design follows the FDA guidance document on 
assessing FE in clinical studies. 
3.2.2. 
Justification of Starting Dose 
 
 
 
 
The FDA guidance document 
(“Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult 
Healthy Volunteers”) provides guidance for when a safety factor smaller than 10 may be used to 
calculate the starting dose: 
 A smaller safety factor might also be used when toxicities produced by the 
therapeutic are easily monitored, reversible, predictable, and exhibit a 
moderate-to-shallow dose-response relationship with toxicities that are consistent 
across the tested species (both qualitatively and with respect to appropriately scaled 
dose and exposure). 
 A safety factor smaller than 10 could be justified when the NOAEL was determined 
based on toxicity studies of longer duration compared to the proposed clinical 
schedule in healthy volunteers. In this case, a greater margin of safety should be built 


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into the NOAEL, as it was associated with a longer duration of exposure than that 
proposed in the clinical setting. This assumes that toxicities are cumulative, are not 
associated with acute peaks in therapeutic concentration (e.g., hypotension), and did 
not occur early in the repeat dose study. 
EIDD-2801 satisfies both of these criteria as follows: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Importantly, given the activity of EIDD-2801 versus SARS-CoV-2 (cause of COVID-19), the 
Sponsor thinks it is most prudent to start with a dose that is predicted to be a safe starting dose 
and is also as close as possible to a potential therapeutic dose that would allow the Sponsor to 
move into COVID-19 patients as safely and expeditiously as possible. Based on modeling to 
animal data, a dose of 100 mg BID is projected to be an active dose in humans. 
3.2.3. 
Justification of Study Population 
Healthy volunteers are considered to be the appropriate population for conduct of the FIH study. 
Healthy volunteers without confounding medical conditions that may obscure the interpretation 
of AEs or affect absorption, distribution, metabolism and excretion of study drug will provide the 
most valuable data regarding the tolerability, safety, and plasma exposures observed and 
expected following single doses and multiple doses up to 10 days. EIDD-2801 is intended for 
eventual study in patients with potential CoV-2 infection as defined by the Centers for Disease 
Control and Prevention (CDC) in whom a range of AEs are expected based on the disease under 
study. Understanding the safety and PK profile in a normal population will better inform the use 
of EIDD-2801 in disease settings where complications are frequent, and AEs will need to be 
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4. 
STUDY POPULATION 
This study will enroll healthy volunteers; 8 subjects will be enrolled into each SAD and MAD 
cohort in P1 and P3, and 10 subjects will be enrolled into the FE cohort in P2. 
The site is strongly encouraged to ensure that women are represented in each cohort. 
4.1. 
Subject Inclusion Criteria 
Subjects who meet all of the criteria at Screening will be eligible for study participation 
1. Male or female between the ages of 18 and 60, inclusive. 
2. Female subjects must be of nonchildbearing potential. Nonchildbearing potential is 
defined as women who: 
 are physiologically incapable of becoming pregnant including those who are 
surgically sterile, via hysterectomy, bilateral salpingectomy, and/or bilateral 
oophorectomy by reported medical history and/or medical records. Surgical 
sterilization to have occurred a minimum of 6 weeks, or at the PI’s (or 
designee’s) discretion, prior to Screening. 
 are post-menopausal (at least 45 years of age with amenorrhea for 12 months 
without an alternative medical reason with confirmatory FSH levels of 
≥40 mIU/mL. The amenorrhea should not be induced by a medical condition 
such as anorexia nervosa, hypothyroid disease or polycystic ovarian disease, 
or by extreme exercise. It should not be due to concomitant medications that 
may have induced the amenorrhea such as oral contraceptives, hormones, 
gonadotropin-releasing hormones, anti-estrogens, or selective estrogen 
receptor modulators). 
3. Male participants must agree to the use of effective contraception for study duration, 
i.e., from Check-in until 90 days after the EOS visit. 
4. Is in generally good health as determined by medical history, PEs (at Screening 
and/or Check-in), vital signs, and other screening procedures. 
5. Has a BMI of 18 to 30 kg/m2. 
6. Is willing and able to comply with all study procedures including providing informed 
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4.2. 
Subject Exclusion Criteria 
Subjects who meet any of the following criteria at Screening (unless otherwise stated) will not be 
eligible for participation: 
1. Females who are pregnant, planning to become pregnant, or breastfeeding. 
2. Has a clinically relevant acute or chronic medical condition or disease of the 
cardiovascular, GI, hepatic, renal, endocrine, pulmonary, neurologic, or dermatologic 
systems as determined by the PI (or designee). 
3. Has any current or historical disease or disorder of the hematological system or 
significant liver disease or family history of bleeding/platelet disorders. 
4. Has a history of cancer (other than basal cell or squamous cell cancer of the skin), 
rheumatologic disease or blood dyscrasias. 
5. Has a history of GI surgery or other condition that may interfere with absorption of 
study drug, in the option of the PI (or designee). 
6. Has a history of febrile illness within the 14 days prior to the first dose of study drug. 
7. Has a positive alcohol or drug screen at Screening or the Day -1 visit or has a history 
of alcohol or drug abuse within the past 5 years. 
8. Currently uses tobacco, nicotine or tobacco products or e-cigarettes or stopped using 
tobacco products within the past 3 months and/or has a positive cotinine test at 
Screening or Check-in. 
9. Has any abnormal laboratory value of Grade 2 or higher, which is considered to be 
clinically significant by the PI (or designee). 
10. Has a total white cell count or absolute lymphocyte count outside the normal range, 
or hemoglobin or platelet levels below the lower limit of normal, at Screening or 
Day -1. 
11. Has values above the upper limit of normal for the following laboratory analytes: 
ALT/SGPT, alkaline phosphatase (serum), AST/SGOT, at Screening or Day -1.  
12. Positive test result for HIV, HBV, or HCV. 
13. Has an autoimmune disease, is immunosuppressed or is in any way 
immunocompromised. 
14. Has any of the following: 
 QTcF >450 ms confirmed by repeat measurement 


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 QRS duration >110 ms confirmed by repeat measurement 
 PR interval >220 ms confirmed by repeat measurements 
 findings which would make QTc measurements difficult or QTc data 
uninterpretable 
 history of additional risk factors for torsades de pointes (e.g., heart failure, 
hypokalemia, family history of long QT syndrome). 
15. Except as noted, has used prescription drugs (other than hormone replacement 
therapy) within 14 days prior to the first dose of study drug unless, in the opinion of 
the PI (or designee), the drug will not interfere with study assessments. The 
following prescription drugs will be allowed: 
 Statins: Subjects who have been on a stable dose of statins for a minimum of 
6 months and who have normal creatine kinase at Screening. 
 Antihypertensives: Subjects who have been on a stable dose of 
antihypertensives for a minimum of 6 months and have controlled blood 
pressure and no active heart disease. 
16. Has received an experimental agent (vaccine, drug, biologic, device, blood product 
or medication) within 3 months prior to the first dose of study drug and agrees not to 
receive another experimental agent during the duration of this trial. 
17. Has donated blood within 30 days, plasma within 2 weeks, or platelets within 6 
weeks prior to Screening or refuses to agree to not donate blood until 3 months after 
the EOS visit. 
18. Uses OTC medications or nutritional supplements (including, e.g., gingko biloba, 
aspirin at any dose, and NSAIDs) on a routine/scheduled basis and/or is unwilling to 
abstain from such use for the duration of the study. 
19. Is unwilling to abstain from quinine containing products including quinine water, 
tonic water, bitter lemon, jello shots, any quinine preparations or Cinchona tree bark 
preparations (e.g., herbal medications containing Cinchona tree bark). 
20. Has any condition that would, in the opinion of the PI (or designee), put the subject 
at increased risk for participation in a clinical trial or confinement in a clinical 
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5. 
STUDY MEDICATION, RANDOMIZATION AND DOSE 
ADMINISTRATION 
5.1. 
Study Drug Description 
EIDD-2801 and matching PBO will be supplied 
 
 
 
 
 
 
 
 
 
 
 
 
5.1.1. 
Acquisition, Formulation, Packaging and Labeling 
 
 
 
 
All study drug will be labeled according to the regulatory requirements for investigational 
product. 
5.1.2. 
Product Storage and Stability 
Study drug should be stored at controlled room temperature defined as 
 
. If excursions occur which 
are outside of this range, the pharmacy staff should contact Sponsor to determine the course of 
action. Additional stability data may be available which would allow continued use of the study 
drug, or study drug may need to be replaced. 
5.2. 
Randomization 
Unmasked study drug (EIDD-2801 and matching PBO) will be supplied to the study site 
pharmacy. The pharmacy staff will be unmasked with regards to treatment assignment. A 
randomization list will be provided to the pharmacy staff who will use that list to dispense 
masked study drug for administration to each study participant. In P1 and P3, 6 subjects will 


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receive EIDD-2801 while 2 subjects will be randomized to PBO. In P2, all 10 subjects in the FE 
cohort will receive EIDD-2801. The pharmacy staff will maintain the security of the 
randomization list ensuring that no study personnel outside of the pharmacy have access to 
identify treatment assignment. In the case that it becomes necessary to know a subject’s 
treatment assignment, unmasking procedures will be followed as discussed in Section 8.4. 
5.3. 
Dosage, Preparation and Administration of Study Drug 
Detailed instructions for extemporaneous compounding (as necessary), dispensing and 
administering study drug can be found in the pharmacy manual. 
 
 
 
 
 
 
 
 
 
 
 
 
5.4. 
Drug Accountability 
The site pharmacy must maintain records of receipt and disposition of all study drug supplied to 
the site by the Sponsor. The records must be maintained according to site standard operating 
procedures (SOPs) and should include at a minimum, receipt date, lot or batch number, amount 
and formulation received, 
, date, time and amount 
dispensed, subject identifier for each aliquot of study drug dispensed. In addition, the clinic staff 
must ensure that the time of dosing is identified for each subject. 
Monitors must verify drug accountability/dispensing records during the monitoring visit. 
Unused study drug must be disposed of according to the procedures described in the pharmacy 
manual. 
5.5. 
Concomitant Medication/Treatments 
 
 In this FIH study, limited types of concomitant 
medications are permitted. Adjustment of routine medications taken by subjects should be 
avoided during study participation except when subject safety could be affected by lack of 


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adjustment. There are no restrictions on treatment medications prescribed by the PI (or designee) 
to be used for AEs that occur during study participation. For additional restrictions, see 
Section 6.1.2. 


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6. 
STUDY CONDUCT AND VISIT SCHEDULE 
All study assessments will be conducted according to the Time and Events Schedule. 
6.1. 
Study Conduct 
6.1.1. 
Study Windows and Rounding Principles 
The time schedule described in the protocol for each scheduled activity should be followed as 
closely as possible. However, if it is not possible and if it is not otherwise specifically 
contraindicated per protocol, then the time windows detailed in Table 10 are allowed without 
incurring a protocol deviation. 
Table 10: Allowable Time Windows for Study Assessments/Visits 
Protocol Specified Time 
Allowable Window 
PK Samples and Associated Assessments 
Predose 
within 2 hours prior to dosing 
<2 hours 
± 5 minutes 
≥2 hours to 24 hours 
± 15 minutes (± 2 hours for urinalysis) 
>24 hours to 48 hours 
± 30 minutes 
>48 hours 
± 1 hour (PK) and ± 2 hours (safety)  
Study Visits - Parts 1 and 2 
Day −1 to Day 4 (Part 1) 
must occur on scheduled day 
Day −1 to Day 4 and Day 14 to Day 18 (Part 2) 
must occur on scheduled day 
Day 9 (Part 1) and Days 9 and 23 (Part 2) 
± 1 day 
End-of-Study (EOS) Visit 
± 2 days 
Study Visits - Part 3 
Day −1 to Day 9 
must occur on scheduled day 
Day 14 
± 1 day 
Day 20/EOS Visit 
± 2 days 
6.1.2. 
Restrictions 
Prior to arriving at the clinic for the Day -1 visit, subjects must abstain from consumption of 
alcoholic beverages for a minimum of 72 hours prior to Check-in. Subjects must continue to 
abstain from consumption of alcoholic beverages throughout clinic confinement. Subjects 
enrolled in P2 must continue to refrain from consuming alcoholic beverages from discharge on 
Day 4 through Check-in on Day 14, and then through the second clinic confinement to Day 18. 
After discharge on Day 4 (P1), Day 18 (P2), or Day 9 (P3), subjects must minimize consumption 
of alcoholic beverages (i.e., limit of up to one serving per day) until the EOS procedures have 
been completed. 


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All subjects must refrain from the following: 
 consuming quinine containing products from 72 hours prior to Check-in through to 
completion of the EOS procedures. 
 using nutraceuticals and nutritional/vitamin supplements (e.g., gingko biloba, 
multivitamins) from 72 hours prior to Check-in through to completion of the EOS 
procedures. However, vitamin supplements required by a physician are exempt from 
this restriction. 
 taking OTC analgesics including aspirin (any dose) and NSAIDS from 72 hours 
before Check-in until completion of EOS study procedures unless prescribed by the 
PI (or designee). 
 use of tobacco, nicotine or tobacco products, or e-cigarettes from 3 months prior to 
Screening until the EOS visit. 
 strenuous exercise from 7 days before Check-in until the EOS visit. Subjects will 
otherwise maintain their normal level of physical activity during this time (i.e., will 
not begin a new exercise program nor participate in any unusually strenuous physical 
exertion). 
 Female subjects must not donate eggs/ovum from the time of Check-in until 
3 months after the EOS visit. 
All subjects in P1 should be dosed in the fasted state. Subjects should fast overnight for a 
minimum of 10 hours prior to dosing in the morning on Day 1. Following dosing, subjects may 
have water after 2 hours and food beginning 4 hours postdose. For subjects to be dosed in the fed 
state, subjects should have a high-fat breakfast as defined in the FDA guidance. Subjects must 
complete the meal within 30 minutes of starting the meal and should be dosed after 30 minutes 
of starting the meal. Doses in P3 may be administered in the fed state, following review of the 
PK data from P2. 
6.2. 
Screening 
6.2.1. 
Screening Visit 
Subjects who meet preliminary pre-screening criteria (as defined by the site) and are interested in 
participating in the study will arrive at the study site for administration of informed consent 
according to site standard operating procedures (SOPs). After the subject has signed and dated 
the ICF, screening procedures can begin. Assessments and procedures should be conducted as 
shown in the Time and Events Schedule Screening may be conducted as early as 28 days prior to 
dosing. 


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6.2.2. 
Retesting Procedures 
In the case where a parameter is outside of the acceptable limits for enrollment, measurement of 
the parameter can be repeated one time if both the following are met: 
 In the opinion of the PI (or designee), the parameter value does not represent a 
chronic condition that otherwise will preclude the volunteer from enrolling in the 
study; and 
 In the opinion of the PI (or designee), the abnormality is not likely to recur. 
6.2.3. 
Study Visits 
Subjects who satisfy entry criteria will return to the clinic for the Day -1 visit. Following review 
of I/E criteria, subjects who still qualify will be checked into the clinic and enrolled into the 
study. Following enrollment, clinical chemistry, hematology and urine samples will be collected 
to determine baseline values. Based on site standard practices, alternate subjects will also be 
enrolled into the study in case one of the selected subjects cannot be dosed. If all subjects can be 
dosed on the morning of Day 1, the alternates will be released and may be enrolled into 
subsequent cohorts. All assessments and procedures will be performed according to the 
Time and Events Schedule. 
6.2.4. 
Part 1 (Single Ascending Dose) 
Subjects will remain in the clinic through completion of study procedures on Day 4, returning to 
the clinic for procedures on Day 9. 
6.2.5. 
Part 2 (Food-Effect) 
Subjects will remain in the clinic through completion of study procedures on Day 4, returning to 
the clinic on Day 9 for study assessments, and Day 14 to begin the second dosing sequence on 
Day 15. Subjects will then be discharged from the clinic on Day 18, returning to the clinic on 
Day 23 for study assessments. 
6.2.6. 
Part 3 (Multiple Ascending Dose) 
Subjects will remain in the clinic through dosing and completion of study procedures on Day 9, 
returning to the clinic on Day 14 for study assessments. Depending on ongoing review of the 
safety, tolerability, and PK data, the number of days of dosing may be reduced. If the number of 
days of dosing are reduced, the timepoints for subsequent assessments and the period for which 
subjects are domiciled at the clinic will similarly be changed (subjects will be domiciled for 
3 days post final dose). 
6.3. 
Safety Follow-up and End-of-Study Visit 
Subjects in P1 will return to the clinic for the EOS visit on Day 15. Subjects in the FE cohort 
(P2) will return for the EOS visit on Day 30. Subjects in P3 will return for the EOS visit on 


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Day 20. Subjects with drug-related AEs at the EOS visit will be followed as discussed in 
Section 8.2.1. 
6.4. 
Subject Withdrawal and Replacement 
As this is a small study with a limited number of subjects per cohort, it is critical that all subjects 
complete the study including postdose study assessments. Site personnel should emphasize this 
to study subjects at the time of informed consent so that subjects will understand this fact before 
agreeing to participate in the study. 
Subjects may voluntarily withdraw their consent for study participation at any time without 
penalty or loss of benefits to which they are otherwise entitled. An PI (or designee) may also 
withdraw a subject from receiving study drug or participation in the study for any reason. 
Subjects who withdraw or are withdrawn from the study should undergo withdrawal procedures 
as discussed below. These procedures would include follow-up safety evaluations. 
6.4.1. 
Reasons for Withdrawal 
If a subject withdraws or is withdrawn from the study, the primary consideration must be the 
health and welfare of the subject. The reasons for withdrawal might include but are not limited to 
the following: 
 Subject no longer meets eligibility criteria including subject withdraws consent from 
study participation (with or without a reason) 
 Subject becomes noncompliant 
 Medical disease or condition, or new clinical finding(s) for which continued 
participation, in the opinion of the PI (or designee) might compromise the safety of 
the subject, interfere with the subject's successful completion of this study, or 
interfere with the evaluation of responses 
 Subject Lost-to-Follow-up 
 Subject becomes pregnant, if applicable 
 Determined by a physician's discretion to require additional therapy not indicated in 
the protocol to ensure subject's health and well-being (or treatment failure, if 
applicable) 
The PI should be explicit regarding study follow-up (e.g. safety follow-up) that might be carried 
out. If the subject consents, every attempt will be made to follow all AEs through resolution, 
return to baseline, or until stabilized with sequelae for a maximum of 30 days following 
discontinuation. The procedures that collect safety data for the purposes of research must be 
inclusive in the original ICF or the PI may seek subsequent informed consent using an 
EC-approved ICF with the revised procedures. 


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The PI will inform the subject that already collected data will be retained and analyzed even if 
the subject withdraws from this study. 
6.4.2. 
Handling of Withdrawals 
Subjects who withdraw from the study prior to receiving study drug (i.e., on Day -1 or before 
dosing on Day 1) will be discharged from the clinic and followed only if AEs are present which 
occurred due to participation in the study (e.g., AE resulting from a study procedure). In this 
case, the subject should be followed until the AE resolves or the PI determines that the AE has 
stabilized. 
Subjects who withdraw from the study after receiving study drug should have EOS assessments 
at the time of withdrawal or as quickly thereafter as possible. 
Subjects who do not return for follow-up procedures on Days 9/23 or 15/30 (P1 and P2), or 
Days 14 or 20 (P3) will be contacted by the site at least 3 times using the subject’s preferred 
method of communication (as determined at Check-in). If the site is unable to contact the person, 
then a certified letter will be sent. If the subject still cannot be reached or refuses to come back to 
the clinic after all attempts, the subject will be considered Lost-to-Follow-up and withdrawn 
from the study. 
6.4.3. 
Documentation of Withdrawals 
If a subject withdraws or is withdrawn prior to completion of the study, the reason for this 
decision must be recorded in the CRF. If the subject is Lost-to-Follow-up, the site should 
document the attempts to contact the subject in the source documents. If the subject has an 
ongoing AE at the time of withdrawal, then the AE should be followed as detailed in 
Section 8.2.1. 
6.4.4. 
Subject Replacement 
If a subject withdraws from the study prior to receiving study drug, the subject will be replaced. 
In this case, designated alternate subjects, if available, will be first in line to replace the 
withdrawn subject. 
If a subject withdraws from the study after receiving study drug, then the decision to replace the 
subject will be made by the PI (or designee) in consultation with the Sponsor. Factors to consider 
will be the timing postdose of withdrawal and the number of safety and PK assessments 
completed prior to withdrawal. Subjects who are withdrawn because of an AE related to the 
study drug will not be replaced. 
6.5. 
Unscheduled Visit(s) 
If a subject experiences an AE after discharge from the clinic but prior to the EOS visit, the 
subject should be instructed to call the site. Based on the issue, the PI (or designee) may request 
that the subject return to the site for an unscheduled visit. In this case, procedures/assessments 


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should be conducted as deemed appropriate for the situation by the PI (or designee). The visit 
should be recorded in the unscheduled visit page of the CRF. 


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7. 
STUDY PROCEDURES/EVALUATIONS 
7.1. 
Demography and Medical History 
Demographics including age, gender, race, ethnicity, and medical history will be recorded for 
each subject. All significant medical history should be recorded. In general, significant medical 
history should include all ongoing events and all events occurring within the last 6 months. 
Clinically relevant or clinically significant events occurring greater than 6 months ago should be 
recorded. All surgeries occurring in adulthood should be recorded. If surgeries occurred more 
than 2 years ago, then only the year needs to be recorded on the CRF. 
7.2. 
Clinical Evaluations 
7.2.1. 
Physical Examinations 
The PE will be performed by the PI or a designee that is licensed to perform a PE per local 
requirements. The initial PE performed at Screening and the final PE conducted at the EOS visit 
will include examination of all pertinent body systems as defined by the site standard PE body 
systems (general appearance, HEENT, lymphatic, cardiovascular, respiratory, GI, 
musculoskeletal, neurological, dermatological). 
Subsequent PEs will be performed as shown in the Time and Events Schedule and will be 
targeted to any new signs or symptoms, any change from the previous status or any body system 
deemed pertinent to that subject by the PI (or designee). Clinically significant abnormalities 
should be recorded in the CRF; those occurring prior to dosing will be included in medical 
history unless the abnormality was the direct result of study participation. 
7.2.2. 
Vital Sign Measurements and ECGs 
Vital signs include pulse rate, respiratory rate, blood pressure, and body temperature. Vital signs 
should be measured after the subject has been supine for a minimum of 5 minutes. Site standard 
ranges will be used for determining any out-of-range values. 
Height and weight should be measured, and BMI calculated at Screening as indicated in the 
Time and Events Schedule. 
Resting 12-lead ECGs should be recorded at the visits indicated in the Time and Events Schedule 
after the subject has been supine for a minimum of 5 minutes. The PI (or designee) will evaluate 
the ECG tracings to determine if there are out-of-range values; if out-or-range values are 
detected, the PI (or designee) will determine if they are clinically significant. Site standard 
ranges will be used to determine if any parameters are considered out-of-range. At the discretion 
of the PI (or designee), the ECG may be repeated if erroneous readings are suspected. 


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7.2.2.1. 
Continuous 12-lead ECG Monitoring (Part 3 Only) 
Continuous 12-lead ECG monitoring using a digital recorder will take place at the 
times indicated in the Time and Events Schedule, in P3 only. 
All continuous 12-lead ECG data collected will be archived without extraction or analysis and 
will not be reported in the scope of this study.  
Subjects will be supine for at least 10 minutes before the extraction timepoint and for 5 minutes 
from the start of each extraction timepoint (each extraction will last for 5 minutes). 
Environmental distractions (e.g., television, radio, conversation) should be avoided during the 
pre-ECG resting period and during ECG recording. 
When coinciding, PK sampling should always be performed after the ECG extraction time 
window. If a separate ECG machine is being used for safety assessments, that machine should be 
in place prior to the extraction window to permit safety ECGs to be recorded irrespective of the 
extraction window. If the machine is not in place prior to the extraction window, safety ECGs 
must be recorded after the extraction window. If an integral system is used, safety ECGs may be 
recorded irrespective of the extraction window.  
7.2.3. 
Adverse Events and Concomitant Medications 
Adverse Events: The PI is responsible for identifying and documenting events meeting the 
definition of an AE or SAE (Section 8.1). Once each day while the subject is in the clinic and 
once during each out-patient visit, the PI (or designee) should inquire about the occurrence of 
AEs. The following are examples of open-ended questions that may be used to obtain this 
information: “How are you feeling?”; "Have you had any medical problems recently?"; "Have 
you taken any new medicines since your last visit/assessment?" 
All AEs and SAEs must be documented in the source documents and recorded in the CRF. 
Concomitant Medications: All medications (prescription or over-the-counter), nutritional 
supplements, and nutraceuticals taken by the subject from 30 days prior to dosing through the 
EOS visit must be recorded in the CRF. Medication information should include indication, dose, 
frequency, and route of administration. Any medication taken for an AE/SAE should be 
documented as such. Refer to Section 5.5 for additional information. 
7.3. 
Laboratory Evaluations 
The laboratory will perform standard routine testing, and processing of all blood samples. For the 
entire study, the amount of blood collected from any one subject will not exceed 500 mL. 
7.3.1. 
Routine Laboratory Panels 
Blood and urine samples will be collected at the times indicated in the 
Time and Events Schedule. The analytes shown in the table below (Table 11) will be assessed. 


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If a method to determine COVID-19 status becomes readily available, subjects may be tested at 
Screening and Check-in to confirm they are not positive for COVID-19 prior to dosing.  


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Table 11: Laboratory Evaluations 
CHEMISTRY PANEL 
Alanine Aminotransferase (ALT/SGPT) 
Albumin, Serum 
Albumin/Globulin (A/G) Ratio (calculation) 
Alkaline Phosphatase, Serum 
Amylase 
Aspartate Aminotransferase (AST/SGOT) 
Bilirubin, Total and Direct 
BUN 
BUN/Creatinine Ratio (calculation) 
Calcium, Serum 
Creatinine, Serum 
Creatinine Kinase (CK) 
Gamma Glutamyl Transferase (GGT) 
Lactate Dehydrogenase (LDH)  
Uric Acid 
Electrolyte Panel (Na+, K+, Cl-, Bicarb.) 
Phosphorus 
Globulin, Total  
Glucose, Serum 
Lipase 
Protein, Total, Serum 
HEMATOLOGY PANEL 
Hemoglobin 
Hematocrit 
White Blood Cell Count with differential (absolute and percentage) 
Red Blood Count 
Prothrombin Time (PT)/Partial Prothrombin Time (PTT) and International 
Normalized Ratio (INR) 
Mean cell hemoglobin (MCH), mean cell hemoglobin concentration (MCHC), 
mean cell volume (MCV), red cell distribution width (RDW; may be a 
Grade 1 abnormality) 
Platelets 
ADDITIONAL ASSESSMENTS 
Virology: Human Immunodeficiency Virus (HIV) serology, Hepatitis B Virus 
(HBV; Surface Antigen [HBsAg]), Hepatitis C Virus (HCV) 
Follicle-Stimulating Hormone (FSH; as applicable) 
PREGNANCY TEST 
Serum Pregnancy Test 
Urine Dipstick (optional blood follow-up) 
DRUG SCREENING 
Serum/urinalysis (per site SOP) 
Cotinine 
Urine Dipstick 
Alcohol Breathalyzer 
ROUTINE URINALYSIS 
Bilirubin 
Color and appearance 
Glucose 
Ketones  
Leukocytes 
Microscopic (including red blood cells [RBCs] and white blood cells [WBCs]) 
Nitrite 
Occult blood 
pH 
Protein 
Specific Gravity 
Urobilinogen 
7.3.2. 
Pharmacokinetic Sampling 
Samples for PK analysis will be collected as shown in the Time and Events Schedule. All 
samples will be analyzed to define the PK parameters for prodrug EIDD-2801 and the active 
parent, EIDD-1931. In order to preserve EIDD-2801, special handling procedures will be put in 
place. These procedures will be documented in the laboratory manual for the study. 
Depending on ongoing review of the PK data, timepoints may be modified or removed, and up to 
3 additional samples (in each period for the food-effect) may be added. 


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7.3.3. 
Peripheral Blood Mononuclear Cell Collection 
Peripheral blood mononuclear cells will be collected in P2 and P3. Blood will be collected into 
specialized tubes and processed according to procedures described in the laboratory manual. 
Depending on ongoing review of the data, timepoints may be modified or removed, and up to 
2 additional samples may be added. 
7.3.4. 
Urine Collection 
Urine will be collected over the time periods noted in the Time and Events Schedule. Samples 
will be collected for routine urinalysis and PK analysis according to site standard practices and 
as described in the laboratory manual. 


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8. 
SAFETY MONITORING, MANAGEMENT AND REPORTING 
8.1. 
Definitions 
8.1.1. 
Adverse Events 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product. 
Abnormal clinical laboratory findings (e.g. clinical chemistry, hematology) or other abnormal 
assessments that are judged by the PI (or designee) as clinically significant will be recorded as 
AEs or SAEs if they meet the definitions of an AE or an SAE as defined in this Section 8.1.2. 
Disease specific signs and symptoms which were ongoing prior to study entry will not be 
considered AEs unless they worsen (e.g. increase in frequency or severity) unexpectedly during 
the course of the trial. 
8.1.2. 
Serious Adverse Events 
An AE or suspected adverse reaction is considered “serious” if, in the view of either the PI (or 
designee) or Sponsor, it results in any of the following outcomes: 
 Death, 
 A life-threatening AE: An AE or suspected adverse reaction is considered 
“life-threatening” if, in the view of either the PI or Sponsor, its occurrence places the 
patient or subject at immediate risk of death. It does not include an AE or suspected 
adverse reaction that, had it occurred in a more severe form, might have caused 
death. 
 Inpatient hospitalization or prolongation of existing hospitalization, 
 A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions, or 
 A congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalizations may be considered serious when, based upon appropriate medical judgment they 
may jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 


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or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
Suspected adverse reaction means any AE for which there is a reasonable possibility that the 
drug caused the AE. “Reasonable possibility” means there is evidence to suggest a causal 
relationship between the drug and the adverse event. Suspected adverse reaction implies a lesser 
degree of certainty about causality than adverse reaction, which means any adverse event caused 
by a drug. 
An AE or suspected adverse reaction is considered “unexpected” if 
 It is not listed in the IB or is not listed at the specificity or severity that has been 
observed; or, if an IB is not required or available, 
 Is not consistent with the risk information described in the general investigational 
plan or elsewhere in the current application as amended. For example, under this 
definition, hepatic necrosis would be unexpected (by virtue of greater severity) if the 
IB referred only to elevated hepatic enzymes or hepatitis. Similarly, cerebral 
thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater 
specificity) if the IB listed only cerebral vascular accidents. 
 “Unexpected” as used in this definition, also refers to AE or suspected adverse 
reactions that are mentioned in the IB as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the particular drug under investigation. 
As of the date of this protocol, there are no expected events listed in the current version of the 
IB; therefore, all AEs will be considered unexpected until such a time that the reference safety 
information in the IB is updated with any identified, expected events. 
8.2. 
Documenting Adverse Events 
8.2.1. 
Timeframe for Collection and Follow-up of AEs/SAEs 
All AEs/SAEs will be collected from the time of the first study drug administration until the 
subject has completed the EOS visit and been discontinued from the study. This includes 
subjects who discontinue early. Events considered related to study drug will be followed as 
noted: 
 AEs that are related to study drug and continue beyond the normal collection period 
(i.e., are ongoing at the time a subject exits the study) will be followed until 
resolution, return to baseline or until stabilized with sequelae for a maximum of 
30 days following discontinuation. After 30 days, the AE will be closed, and the 
outcome noted (see Table 12). 
 SAEs that are related to study drug and continue beyond the normal collection period 


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(i.e., are ongoing at the time a subject exits the study) will be followed until 
resolution, return to baseline or until stabilized with sequelae. 
 Serious AEs that are reported to the site within 30 days after the subject has been 
discontinued from the study (i.e., completed the EOS visit) will be recorded. Those 
that are considered related to study drug will be followed as noted in the bullet 
above. 
Note that all events which occurred prior to dosing with study drug should be recorded as 
medical history unless the event is directly related to study procedures. 
8.2.2. 
Recording of Adverse Events/Serious Adverse Events 
AEs/SAEs must be recorded in the CRF as indicated in the CRF completion instructions. 
Information to be collected includes event description, time of onset, clinician’s assessment of 
severity (Section 8.2.3), relationship to study drug (Section 8.2.4), outcome (Section 8.2.5), and 
time of resolution/stabilization of the event. All AEs occurring while on study must be 
documented appropriately regardless of relationship and will be followed to adequate resolution 
as described above (Section 8.2.1). All SAEs will be recorded as noted above; SAEs reported to 
the site within 30 days following the EOS visit will also be recorded. All SAEs must be entered 
onto the SAE form and reported as discussed below (Section 8.3.1). 
If an AE changes in severity, the highest severity will be recorded in the CRF. AEs characterized 
as intermittent require documentation of onset and duration of each episode. 
8.2.3. 
Assessing Severity of Adverse Events 
All AEs/SAEs will be assessed by the PI or those with the training and authority to make a 
medical judgment. AEs/SAEs will be graded according to the DMID Toxicity Grading Scale. 
For any AEs not specifically listed in the tables, the following guidelines should be used to grade 
severity: 
 Mild (Grade 1); asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
 Moderate (Grade 2); minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living. 
 Severe (Grade 3); medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care activities of daily living. 
o Life-threatening; life-threatening consequences; urgent intervention 
indicated. 
o Death; death related to AE. 


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Changes in the severity of an AE should be documented to allow an assessment of the duration 
of the event at each level of intensity to be performed. Adverse events characterized as 
intermittent require documentation of onset and duration of each episode. 
8.2.4. 
Relationship to Study Drug 
The PI’s (or designee’s) assessment of an AE’s relationship to study drug is part of the 
documentation process, but it is not a factor in determining what is or is not reported in the study. 
If there is any doubt as to whether a clinical observation is an AE, the event should be reported. 
All AEs must have their relationship to study product assessed using the terms: related or not 
related. In a clinical trial, the study product must always be suspect. To help assess, the following 
guidelines are used. 
 Definite – The AE is clearly related to the study drug. 
 Probable – The AE is likely related to the study drug. 
 Possible – The AE may be related to the study drug. 
 Unlikely – The AE is doubtfully related to the study drug. 
 Unrelated – The AE is clearly NOT related to the study drug. 
8.2.5. 
Classifying Adverse Event Outcome 
All AEs/SAEs in the study must be assigned an outcome by site staff. The outcome will be 
included on the AE CRF. Possible outcomes are shown below: 
Table 12: Adverse Event Outcomes 
Outcome 
Description 
Recovered / Resolved 
AE resolved with no residual signs or symptoms; an event is considered resolved if it 
returns to baseline (pretreatment) values. 
Recovered / Resolved with sequelae 
AE stabilized but residual signs or symptoms remain; this includes stabilization of an 
event/condition with the expectation that it will remain chronic. 
Not Recovered / Not Resolved 
AE remains ongoing AND no or only minimal improvement has occurred. 
Ongoing 
AE has not yet resolved, but continues to improve/resolve and complete resolution is 
expected over time. 
Fatal 
Outcome of the AE is death. 
Unknown 
AE outcome is not known; usually because the subject has been Lost-to-Follow-up. 


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8.3. 
Reporting Procedures 
8.3.1. 
Serious Adverse Events 
The PI or clinical site personnel should notify Covance Drug Safety Services (DSS) 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 Notification 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. 
The responsibilities of Covance DSS include the following: 
 Prepare an AE reporting plan prior to the start of the study. Where this plan differs from 
the applicable site standard operating procedure on SAE reporting, the AE reporting plan 
will always take precedence. 
 Receive and review SAE report forms from the site and inform the Sponsor of the SAE 
within 1 working day of the initial notification to DSS. Drug Safety Services will delete 
any information from the SAE report forms that may identify the subject. 
 Write case narratives and enter the case into Covance’s safety database as defined in the 
AE reporting plan. 
 Produce appropriate reports of all Suspected Unexpected Serious Adverse Reactions and 
forward to the EC, Medicines and Healthcare Products Regulatory Agency, PI’s (or 
designee’s), and the Sponsor within the timeframes stipulated in the Clinical Trials 
Directive Guideline (ENTR/CT 3).  
The responsibility for reporting SAEs will be transferred to the Sponsor 28 days after the end of 
the study. 
8.3.2. 
Pregnancy 
Subjects in this study must be of non-childbearing potential. However, should a pregnancy occur 
any time from informed consent to the EOS visit, subjects must immediately report the event to 
the clinical site which in turn must immediately report the pregnancy to the Sponsor or their 
designee. The subject will be followed until the end of the pregnancy. A separate ICF will be 
used for consenting for follow-up pregnancy activities. Pregnancy will not be considered an AE 
unless deemed likely related to study drug. Pregnancy will not be considered an SAE unless there 
is an associated SAE. A spontaneous abortion (miscarriage) or abnormal outcome (including 
congenital anomalies) will be reported as an SAE. 


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8.4. 
Unmasking Treatment Assignment 
The following controls will be employed to maintain the double-blind status of the study: 
 Placebo will be identical in appearance to the EIDD-2801. 
 The PI and other members of staff involved with the study will remain blinded to the 
treatment randomization code in P1 and P3. 
 Interim bioanalytical data will be provided in a blinded manner. 
To maintain the blind, the PI will be provided with a sealed randomization code for each subject 
in P1 and P3, containing details of their treatment. These individual sealed envelopes will be 
kept in a limited access area that is accessible 24 hours a day. In order to manage subject safety 
or to support dose-escalation decisions (in the event of possibly treatment-related SAEs or severe 
AEs), the decision to unblind resides solely with the PI. Whenever possible and providing it does 
not interfere with or delay any decision in the best interest of the subject, the PI will discuss the 
intended code-break with the Sponsor. If it becomes necessary to break the code during the 
study, the date, time, and reason will be recorded in the subject’s source data and on the 
individual envelope and will be witnessed by a second person. 
The pharmacy and bioanalytical lab will have access to the treatment randomization and will be 
unblinded. Pharmacokinetic personnel may be unblinded to perform interim PK analysis and to 
ensure that PK data are provided in a blinded manner for dose-escalation decisions.  


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9. 
DOSE-ESCALATION AND HALTING RULES 
9.1. 
Guidelines for Dose-Escalation 
Doses will be administered in an escalating manner following satisfactory review by the Sponsor 
and PI of the blinded safety and tolerability data up to 72 hours post final dose. 
 
 
 
 
As PK data become available, these data will be reviewed and 
may be used to assist in dose selection. 
Doses may be reduced and may be lower than the starting dose. There will be a minimum of 
4 days between dose escalations to allow sufficient time for an adequate safety review. 
 
 
 
Integrated data from all applicable sites will be used to make dose-escalation decisions. 
Dose-escalation in P1 and P3 will only occur if data from a minimum of 6 subjects (across all 
sites) have been reviewed from the previous lower dose group, such that data from a minimum of 
4 subjects (across all sites) who have received EIDD-2801 will be used to make the 
dose-escalation decision. 
The justification for this is as follows: 
 The study treatment is of a known pharmacological class for which the on-target effects 
in humans are well characterized. Based upon nonclinical data, no clinically important off 
target effects are expected within the proposed dose range. 
 A minimum of 4 subjects receiving the active drug is considered sufficient to characterize 
the safety profile of EIDD-2801. 
Between each dose-escalation, the PI will review all available data in a blinded manner to ensure 
it is safe to proceed with the planned dose-escalation. The results from all available safety 
assessments will be sent to the Sponsor prior to the start of each successive group/treatment 
period. Any clinically significant results will be discussed with the Sponsor before 
dose-escalation continues. Interim PK data may also be reviewed in terms of dose-escalation and 
to confirm that the study design remains appropriate. In the event of a disagreement between 
Sponsor and PI on the dose-escalation decision, the most conservative decision will be upheld. 
Dose levels will not increase by more than 3-fold for predicted nonpharmacologically active 
dose levels and by 2-fold for predicted pharmacologically active dose levels. The highest total 
daily dose to be studied under this protocol will not exceed 800 mg (Section 9.2). 


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Dose levels in P3 may be repeated for collection of PBMCs, providing that the dose level did not 
meet the dose-escalation halting criteria. 
9.2. 
Rationale for Highest Dose 
9.2.1. 
Clinical Safety 
At the time of this amendment, 24 healthy subjects were administered a single dose of 50, 100, 
or 200 mg EIDD-2801 or placebo in P1. There were 6 males and 2 females at each dose level, 
and the age range was 22 to 60 years. No clinically significant abnormalities or changes from 
baseline were reported for vital signs, ECGs, or PEs.  
Thirteen treatment-emergent AEs were reported across the 3 dose levels; 11 of these were mild 
and 2 were moderate in severity. One AE was considered to be probably related, 6 were possibly 
related, and 6 were unlikely related to EIDD-2801.  
The most frequently reported AEs were headache (4 reports), aching legs, and nausea (2 reports 
each).  
 Two of the reports of headache (1 at 100mg and 1 at 200mg) were considered possibly 
related to EIDD-2801 because they started within 2 hours of dosing; 1 was mild in 
severity (200 mg) and did not require treatment, and 1 was moderate in severity 
(100 mg), which resolved after a single dose of 1 g acetaminophen. Both headaches 
resolved within 24 hours.  
 The two AEs of aching legs were considered unlikely related to EIDD-2801.  
 At 100 mg, 1 subject reported nausea that was considered possibly related to EIDD-2801 
because it started approximately 4 hours after dosing; this event was moderate in severity 
and resolved approximately 40 minutes after onset following a single episode of 
vomiting. At 200 mg, 1 subject reported nausea that was considered unlikely related to 
EIDD-2801 because it started > 36 hours after dosing.  
 Other AEs of interest included 1 report of each of loose stools and abdominal pain; both 
were mild in severity and reported by the same subject at the 200 mg dose level. The 
loose stools were considered probably related to EIDD-2801; they started approximately 
13.5 hours after dosing and resolved 3 days after dosing. The abdominal pain started 
approximately 24 hours after dosing and resolved after 4.5 hours.  
Laboratory safety data have been reviewed through Day 9 at the 50 and 100 mg dose levels and 
through Day 4 at the 200 mg dose level. There were no clinically significant abnormalities or 
changes from baseline. Specifically, there were no reductions in platelets or absolute lymphocyte 
counts.  
 


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9.2.2. 
Pharmacokinetics 
Pharmacokinetic data have been reviewed post dosing for the 50, 100, and 200 mg dose levels. 
No concentrations of EIDD-2801 (the ester prodrug) were quantifiable in any of the samples at 
either dose level, thus PK parameters were not calculable for EIDD-2801. EIDD-1931 (the active 
drug) appeared rapidly in plasma, with a median tmax of 1 hour at all dose levels. EIDD-1931 
concentrations increased in a dose-proportional manner between 50 and 200 mg. EIDD-1931 
concentrations declined in a monophasic manner and remained quantifiable until 6 hours 
postdose for the 50 and 100 mg doses, and until between 6 and 9 hours for the 200 mg dose. The 
geometric mean terminal elimination half-life was approximately 1.0 hour at all dose levels. At 
400 mg, geometric mean systemic exposure is predicted to achieve an approximate area under 
the concentration versus time curve from time zero to 24 hours postdose (AUC0-24) of 
3593 ng•h/mL and Cmax of 1889 ng/mL 
 
 
9.2.3. 
Rationale to Exceed the Maximum Single Dose Limit of 200 mg 
 
  
Based on the clinical data collected to date, it is considered acceptable to exceed 200 mg because 
EIDD-2801 has been well tolerated and the PK behaved in a predictable manner.  
 
 
 
 
 
 
 
 
 
 
 
  
Ongoing modelling suggests that the therapeutic dose level required to treat highly pathogenic 
CoV may be 200 mg BID. In order to escalate to this dose level in P3, a dose level of 400 mg 
must be shown to be safe and well tolerated in P1. Additionally, in order to allow for unpredicted 
differences in PK at higher dose levels compared with that seen at the dose levels already 
evaluated, dose levels of 600 and 800 mg are planned for P1; this will allow escalation to a 
maximum of 400 mg BID in P3 if required to achieve therapeutic exposures.  
 
  


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9.3. 
Dose-Escalation Halting Rules 
For Group 1 in P1, sentinel dosing will occur whereby 2 subjects (1 active and 1 PBO) will be 
dosed on 1 day and, providing no safety concerns arise, the remaining 6 subjects will be dosed 
after at least 24 hours. 
The study will be halted (i.e., no further dosing will occur) if one or more subjects experience an 
SAE that is considered to be related to EIDD-2801 or 2 or more subjects in the same group 
experience severe AEs that are considered to be related to EIDD-2801. If, following an internal 
safety review, the Sponsor deems it appropriate to restart the study, this can be done following 
approval of a substantial protocol amendment.  
Additionally, if 2 or more subjects experience a reduction of platelets greater than 50% over 
baseline levels or a reduction in lymphocytes (absolute count) to Grade 3/severe levels without 
an alternate cause, the PI and Sponsor will review the data. If, after review of unblinded data, it 
is determined that these events are probably related to study drug, no further dose escalations 
will occur. In this case, additional cohorts may be enrolled at a lower dose. 
Dose-escalation will stop if clinically relevant signs or symptoms of similar nature occur in 2 or 
more subjects in a group that, in the opinion of the PI, warrant stopping of dose-escalation. 


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10. 
STATISTICAL CONSIDERATIONS 
10.1. 
General Considerations 
All summaries will be provided by study part and treatment. Continuous variables will be 
summarized using descriptive statistics including number of observations (n), mean, standard 
deviation, minimum (min), median (med), and maximum (max). Categorical variables will be 
summarized using frequency counts and percentages. Note that PBO data from each dose level in 
Parts 1 and 3 will be combined into one PBO group. 
No missing data imputation will be performed. 
Subject listings will be provided for all the data collected during the study period. 
Specific information about the statistical analysis will be provided in a SAP that will be reviewed 
and approved by the Sponsor and will be finalized before final database lock. If there is a 
discrepancy between the methods described in the protocol and final approved SAP, the SAP 
will take precedence. 
10.2. 
Sample Size Considerations 
No formal sample size calculation was conducted. The sample size of 8 per cohort 
(6 active: 2 PBO) for the SAD and MAD cohorts is considered adequate for a Phase 1 FIH study. 
The sample size of 10 subjects (all administered EIDD-2801) is in accordance with FDA 
guidelines for sample size in FE studies. 
10.3. 
Analysis Populations 
Safety Population: All subjects who receive at least one dose of study drug. 
Pharmacokinetic Population: All subjects receiving study drug who comply sufficiently with 
protocol requirements (i.e., no major protocol violations) and for whom a sufficient number of 
analyzable PK samples have been obtained to permit the determination of the PK profile for 
EIDD-2801/EIDD-1931 and the statistical analysis of the results. Subjects who experience an 
AE of vomiting before 2× the median tmax of the group may be excluded from the PK population. 
10.4. 
Analysis of Safety Data 
All safety analyses will be performed on the Safety Population as defined in Section 10.3. Safety 
will be assessed on the basis of AEs, clinical laboratory data, vital signs, ECG parameters, and 
PEs. 
10.4.1. 
Extent of Exposure 
Dosing data will be listed by study part. 


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10.4.2. 
Adverse Events 
Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
preferred term and system organ classification. Any events reported after the initiation of study 
treatment and through the EOS are defined as treatment-emergent. The occurrence of 
treatment-emergent AEs will be summarized using MedDRA preferred terms, system organ 
classifications, and severity. Separate summaries of treatment-emergent SAEs and AEs 
considered related to study treatment and AEs leading to study treatment discontinuation will be 
generated. All AEs will be listed for individual subjects showing both verbatim and preferred 
terms. 
10.4.3. 
Clinical Laboratory Results 
Laboratory abnormalities will be graded according to the DMID Toxicity Grading Scale. Any 
graded abnormality that occurs following the initiation of study treatment and represents at least 
a one-grade increase from the baseline assessment is defined as treatment-emergent. The number 
and percentage of subjects experiencing treatment-emergent graded toxicities will be 
summarized. Raw values and mean changes from baseline in clinical laboratory measures will be 
summarized. 
Listings of the clinical laboratory test results will be provided. Abnormal laboratory values will 
be flagged in the listings. 
10.4.4. 
Other Parameters 
Individual data for ECG parameters and vital sign measurements will be listed by subject and 
time point and summarized for each treatment. Individual data for PE will be listed by subject 
and time point. 
Concomitant medications will be coded using the World Health Organization-Drug Dictionary 
(WHO-DD) and summarized. 
10.5. 
Analysis of Pharmacokinetic Data 
Pharmacokinetic analysis as defined in the SAP will be conducted using the PK population 
defined in Section 10.3. In the event of discrepancies between analyses described in the SAP and 
this clinical study protocol, the SAP will supersede the protocol. 
 All samples will be analyzed and all concentrations listed. 
 Descriptive statistics will be performed for all time points available, with the 
exclusion of subjects who had any significant protocol deviation. 
 Pharmacokinetic parameters will be derived where possible for all subjects. Data 
from subjects with incomplete profiles (missed blood draws, lost samples, samples 
unable to be quantified) may be used if PK parameters can be estimated using the 
remaining data points. 


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 Descriptive statistics will be performed on all parameters available, and any missing 
parameters will be flagged. 
Plasma concentration data for EIDD-2801 and EIDD-1931 will be listed for individual subjects 
and summarized by study part and treatment. Individual and mean plasma concentration versus 
time plots for EIDD-2801 and EIDD-1931 will be provided. Urine concentration data for 
EIDD-2801 and EIDD-1931 will be listed. 
Plasma PK parameters of EIDD-2801 and EIDD-1931 for each subject will be estimated over the 
sampling interval using noncompartmental analysis and summarized by study part and treatment 
using descriptive statistics. Actual blood sampling times will be used for plasma PK analysis. 
Urine PK parameters of EIDD-2801 and EIDD-1931 will also be analyzed and summarized 
when possible. The PK parameters that will be estimated are listed in the table below.  
Table 13: Pharmacokinetic Parameters 
Plasma PK Parameter 
Description 
AUClast 
The area under the plasma concentration-time curve, from time 0 to the last measurable 
non-zero concentration, as calculated by the linear up/log down trapezoidal method (P1 and 
P2 only). 
AUC0-inf 
The area under the plasma concentration-time curve from time 0 extrapolated to infinity. 
AUC0-inf is calculated as the sum of AUClast plus the ratio of the last measurable plasma 
concentration to the elimination rate constant (λz) (P1, P2, and Day 1 dose of P3). 
Cmax 
Maximum observed concentration. 
tmax 
Time to reach Cmax. If the maximum value occurs at more than one time point, tmax is 
defined as the first time point with this value. 
λz 
Apparent terminal elimination rate constant; represents the fraction of medication 
eliminated per unit time. 
t½ 
Apparent terminal elimination half-life of medication, calculated as 0.693/λz. 
Vz/F 
Apparent volume of distribution (EIDD-2801 only). 
CL/F 
Apparent oral drug clearance (EIDD-2801 only). 
Ctrough 
Trough concentration (P3 only). 
AUCτ 
The area under the plasma concentration-time curve during a dosing interval (P3 only). 
RAAUCτ 
Observed accumulation ratio based on AUCτ (P3 only). 
RACmax 
Observed accumulation ratio based on Cmax (P3 only). 
Urine PK Parameter 
Description 
Ae 
Amount excreted in urine over the sampling interval. 
Fe 
Fraction of drug excreted in the urine over sampling interval. 
CLR 
Renal clearance, CLR = Ae/AUC where both Ae and AUC are determined over co-incident 
time ranges after dosing. 
Additional PK parameters may be analyzed as appropriate. 


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10.5.1. 
Statistical Analysis of Pharmacokinetic Data 
10.5.1.1. Dose Proportionality 
In P1, dose-proportionality for PK parameters of EIDD-2801 and EIDD-1931 (AUC0-inf, AUClast, 
and Cmax) will be assessed by the power model. The slope and the associated 90% CI based on 
the power model will be reported. 
In Part 3 on Day 6 dose-proportionality for PK parameters of EIDD-2801 and EIDD-1931 
(AUCτ, and Cmax) will be assessed by the power model. The slope and the associated 90% CI 
based on the power model will be reported. 
10.5.1.2. Food-Effect 
To assess the effect of food on the PK of EIDD-2801 and EIDD-1931, natural log transformed 
PK parameters from P2 (AUC0-inf, AUClast, and Cmax) will be analyzed using a mixed-effects 
model with fixed-effect terms for treatment (with or without food), period, and sequence and 
with subject within sequence as a random effect. Point estimates and their associated 90% CIs 
for the natural log-transformed PK parameters for the difference between EIDD-2801 
administered under fed relative to fasted conditions will be constructed. The point estimates and 
interval estimates will be back transformed to give estimates of the ratio and 90% CI for the 
geometric least squares mean ratio for fed/fasted to assess the effect of food. 
10.6. 
Peripheral Blood Mononuclear Cells 
Peripheral blood mononuclear cells will be collected from subjects following each dose in P2. 
Depending upon ongoing review of the data, PBMCs may be collected from subjects in P3; the 
collection of these samples may be omitted from some cohorts in P3. 
The PBMCs will be stored for analysis of EIDD-2061 levels at some point in the future and 
reported separately. 
10.7. 
Interim Analyses 
There are no formal interim analyses planned for this study. However, interim analyses may be 
implemented at the discretion of the Sponsor or health authority request. In addition, data from 
P1 cohorts may be locked, unblinded, and analyzed prior to conducting P2 and P3. 


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11. 
STUDY ADMINISTRATION 
11.1. 
Regulatory and Ethical Considerations 
11.2. 
Ethical Standard 
This study will be conducted in accordance with the protocol and with the following: 
 Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
International Ethical Guidelines. 
 Applicable ICH GCP Guidelines. 
 United States CRFs applicable to clinical studies (45 CFR Part 46; 21 CFR Part 50, 21 
CFR Part 56, and 21 CFR Part 312). 
 Applicable laws and regulations. 
11.2.1. 
Ethics Committee Approval 
The PI (or designee) must ensure that all required study-specific documents and/or information 
are submitted to the EC for review and approval as appropriate including but not limited to: 
 the protocol and any future protocol amendments 
 ICF and any other documents (electronic or paper) given to the subject 
 IB 
Any substantial protocol amendments, likely to affect the safety of the subjects or the conduct of 
the study, will require EC and regulatory authority (as locally required) approval before 
implementation of changes made to the study design, except for changes necessary to eliminate 
an immediate hazard to study subjects or any nonsubstantial changes, as defined by regulatory 
requirements. 
11.2.2. 
Informed Consent 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continuing throughout the individual’s study participation. Extensive discussion of 
risks and possible benefits of this therapy will be provided to the subjects and, if applicable, their 
families. Consent forms describing in detail the study interventions/products, study procedures, 
and risks are given to the subject and written documentation of informed consent is required 
prior to starting any screening procedures or intervention/administering study product. Consent 
forms will be EC-approved and the subject will be asked to read and review the document. 


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Upon reviewing the document, the PI (or designee) will explain the research study to the subject 
and answer any questions that may arise. The subjects will sign the ICF prior to any procedures 
being done specifically for the study. The subjects should have the opportunity to discuss the 
study with their surrogates or think about it prior to agreeing to participate. The subjects may 
withdraw consent at any time throughout the course of the trial. A copy of the ICF will be given 
to the subjects for their records. The rights and welfare of the subjects will be protected by 
emphasizing to them that the quality of their medical care will not be adversely affected if they 
decline to participate in this study. 
11.3. 
Financing and Insurance 
Financing and insurance will be addressed in a separate agreement. 
11.4. 
Source Documentation and Access 
The site will maintain appropriate medical and research records in compliance with ICH E6, 
Section 4.9 and regulatory and institutional requirements for the protection of confidentiality of 
subjects. The site will permit authorized representatives of the Sponsor, its designees, and 
appropriate regulatory agencies to examine (and when required by applicable law, to copy) 
clinical records for the purposes of quality assurance reviews, audits, and evaluation of the study 
safety and progress. These representatives will be permitted access to all source data and source 
documents, which include, but are not limited to, clinical and office charts, laboratory notes, 
memoranda, subjects’ memory aid or evaluation checklists, pharmacy dispensing records, 
recorded data from automated instruments, copies or transcriptions certified after verification as 
being accurate and complete, photographic negatives, microfilm or magnetic media, x-rays, and 
subject files and records kept at the pharmacy, at the laboratory, and medico-technical 
departments involved in the clinical trial. 
11.5. 
Data Collection and Record Keeping 
11.5.1. 
Data Collection 
Data collection and data entry are the responsibility of the clinical trial staff at the site. The PI is 
responsible for ensuring the accuracy, completeness, legibility, and timeliness of the data 
reported. All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data. 
A CRF must be completed for every subject who signs the ICF and has at least one 
protocol-specified assessment conducted. The CRF must be completed and processed according 
to the CRF guidelines and the SOPs of the site. All data should be entered into the CRF, where 
possible, within 3 days after each visit for any one subject. After the subject has completed the 
study, the PI must review and sign the signature page of the CRF indicating that he has reviewed 
the completed CRF and pertinent clinical data for that subject and that, to the best of his 
knowledge, all data recorded in the CRF accurately reflects the subject’s clinical performance in 
the study 


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11.5.2. 
Study Records Retention 
Study documents should be retained for a minimum of 5 years after the end of the study. These 
documents should be retained for a longer period; however, if required by local regulations. No 
records will be destroyed without the written consent of the Sponsor, if applicable. It is the 
responsibility of the Sponsor to inform the PI when these documents no longer need to be 
retained. 
11.5.3. 
Protocol Deviations 
A protocol deviation is any noncompliance with the protocol or study procedures detailed in the 
laboratory or pharmacy manuals. The noncompliance may have been the result of action by the 
PI, site staff, or subject. All deviations should be handled in accordance with site SOPs. 
It is the responsibility of the site to use continuous vigilance to identify and report deviations 
within 5 working days of identification of the protocol deviation, or within 5 working days of the 
scheduled protocol-required activity. 
11.6. 
Clinical Monitoring 
Site monitoring is conducted to ensure that the human subjects’ protections, study and laboratory 
procedures, study intervention administration, and data collection processes are of high quality 
and meet Sponsor, ICH/GCP guidelines and applicable regulations, and that this trial is 
conducted in accordance with the protocol, protocol-specific MOP and applicable Sponsor SOPs. 
Experienced clinical monitors of the Sponsor or its designee will conduct site-monitoring visits 
as detailed in the clinical monitoring plan. 
Site visits will be made at standard intervals as defined by the Sponsor and may be made more 
frequently as directed by the Sponsor. Monitoring visits will include, but are not limited to, 
review of regulatory files, accountability records, CRFs, ICFs, medical and laboratory reports, 
and protocol and GCP compliance. Clinical monitors will have access to each participating site, 
study personnel, and all study documentation according to the site monitoring plan. Clinical 
monitors will meet with the site PI to discuss any problems and actions to be taken and will 
document site visit findings and discussions. As data are entered into a CRF, data will be 
monitored to ensure accuracy as well as adherence to data entry instructions provided in the CRF 
guidelines. 
11.7. 
Quality Control and Quality Assurance 
A quality management plan will be put in place for this study. The site is responsible for 
conducting routine quality assurance and quality control activities to internally monitor study 
progress and protocol compliance. The PI will provide direct access to all study-related sites, 
source data/data collection forms, and reports for the purpose of monitoring and auditing by the 
Sponsor, and inspection by local and regulatory authorities. The PI will ensure all study 
personnel are appropriately trained and applicable documentations are maintained on site. 


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11.8. 
Study Termination and Closure Procedures 
11.8.1. 
Study Termination 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided to the site. If the study is terminated or suspended, the PI (or 
designee) will inform study participants and the EC. The Sponsor will notify appropriate 
regulatory authorities. The Sponsor will provide the reason(s) for the termination or suspension. 
Study participants will be contacted, as applicable, and be informed of changes to study visit 
schedule. 
If suspended, the study may resume once issues that caused suspension of the study are resolved. 
11.8.2. 
Termination Procedures 
If the study is prematurely terminated, then the site must return all appropriate study data, 
resolve all data queries, complete final drug accountability, return any study drug remaining on 
site, and ship all biological samples (including PK and PBMCs) to the laboratory designated by 
the Sponsor. The PI (or designee) must notify the EC of study termination. 
11.9. 
Information Disclosure 
11.9.1. 
Confidentiality 
Subject confidentiality and privacy is strictly held in trust by the PI, site staff, and the Sponsor(s) 
and their agents. The study protocol, documentation, data, and all other information generated 
will be held in strict confidence. No information concerning the study or the data will be released 
to any unauthorized third party without prior written approval of the Sponsor. 
The study monitor or other authorized representatives of the Sponsor or regulatory agencies may 
inspect all documents and records required to be maintained by the PI, including but not limited 
to, medical records (office, clinic, or hospital) and pharmacy records for the participants in this 
study. The clinical study site will permit access to such records. 
The study participant’s contact information will be securely stored at the clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by the Sponsor, site, or regulatory requirements. 
Study participant research data will be transmitted to and stored securely by the Sponsor’s 
designated data center. This will not include the participant’s contact or identifying information. 
Individual participants and their research data will be identified by a unique study identification 
number. The study data entry and study management systems used by clinical sites will be 
secured and password-protected. At the end of the study, all study databases will be de-identified 
and archived at a secure location. 


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11.9.2. 
Clinicaltrials.gov 
This clinical study will be registered on clinicaltrials.gov as required. 
11.9.3. 
Publication Policy 
All information generated from this study is the proprietary property of the Sponsor. It is the 
intent of the Sponsor to publish the results of the study in their entirety as deemed appropriate. 


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12. 
REFERENCES 
Agostini ML, Pruijssers AJ, Chappell JD, Gribble J, Lu X, Andres EL, et al. Small-Molecule 
Antiviral β-d-N4-Hydroxycytidine Inhibits a Proofreading-Intact Coronavirus with a High 
Genetic Barrier to Resistance. J Virol. 2019 Dec 15;93(24).  
Flavell RA, Sabo DL, Bandle EF, Weissmann C. Site-directed mutagenesis: generation of an 
extracistronic mutation in bacteriophage Q beta RNA. J Mol Biol. 1974 Oct 25;89(2):255–72.  
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 Dec;48(12):4636–42.  
Mullins JI, Heath L, Hughes JP, Li D, Essigmann JM, Harris KS, et al. Mutations based on viral 
decay acceleration in the HIV-1 genomes of a clinical population treated with the mutagenic 
nucleoside KP1461. Retrovirology. 2011 Oct 3;8(Suppl 2):P84.  
Painter GR, Bowen RA, Bluemling GR, DeBergh J, Edpuganti V, Gruddanti PR, et al. The 
prophylactic and therapeutic activity of a broadly active ribonucleoside analog in a murine model 
of intranasal venezuelan equine encephalitis virus infection. Antiviral Res. 2019;171:104597.  
Sticher ZM, Lu G, Mitchell DG, Marlow J, Moellering L, Bluemling GR, et al. Analysis of the 
Potential for N4-Hydroxycytidine To Inhibit Mitochondrial Replication and Function. 
Antimicrob Agents Chemother. 2020 27;64(2).  
Stuyver LJ, Whitaker T, McBrayer TR, Hernandez-Santiago BI, Lostia S, Tharnish PM, et al. 
Ribonucleoside analogue that blocks replication of bovine viral diarrhea and hepatitis C viruses 
in culture. Antimicrob Agents Chemother. 2003 Jan;47(1):244–54.  
Toots M, Yoon J-J, Cox RM, Hart M, Sticher ZM, Makhsous N, et al. Characterization of orally 
efficacious influenza drug with high resistance barrier in ferrets and human airway epithelia. Sci 
Transl Med. 2019 Oct 23;11(515):eaax5866.  
Urakova N, Kuznetsova V, Crossman DK, Sokratian A, Guthrie DB, Kolykhalov AA, et al. 
β-d-N4-Hydroxycytidine Is a Potent Anti-alphavirus Compound That Induces a High Level of 
Mutations in the Viral Genome. J Virol. 2018 01;92(3).  
Yoon J-J, Toots M, Lee S, Lee M-E, Ludeke B, Luczo JM, et al. Orally Efficacious 
Broad-Spectrum Ribonucleoside Analog Inhibitor of Influenza and Respiratory Syncytial 
Viruses. Antimicrob Agents Chemother. 2018;62(8). 


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13. 
APPENDICES 
Appendix 1: 
Time and Events Schedule 
Parts 1 and 2 
Visit 
Screening 
(Days -28 to -2) Day -1 Day 1 Day 2 
(24 hr) 
Day 3 
(48 hr) 
Day 4 
(72 hr) Day 9 
Day 15 / EOS1 
(non-FE cohorts) 
Food-Effect Cohort 
Day 14 Day 15 Day 16 
(24 hr) 
Day 17 
(48 hr) 
Day 18 
(72 hr) Day 23 
Day 30 / EOS 
ICF; Demography 
x 
 
 
 
 
 
 
 
I/E; Medical history 
x 
x 
 
 
 
 
 
 
Physical examination2 
x 
x 
 
x 
 
x 
x 
x 
Qualifying laboratory analyses3 
x 
x 
 
 
 
 
 
 
Drug screening and pregnancy test4 
x 
x 
 
 
 
 
x 
x 
Height, weight (BMI) 
x 
 
 
 
 
 
 
 
Clinic confinement5 
 
x 
x 
x 
x 
x 
 
 
Non-residential visit 
x 
 
 
 
 
 
x 
x 
Clinical chemistry and urinalysis6 
x 
x 
 
x 
 
x 
x 
x 
Hematology7 
x 
x 
 
x 
x 
x 
x 
x 
PBMC collection (FE cohort ONLY) 
 
 
x8 
x8 
 
 
 
 
ECG 
x 
 
x9 
 
 
x 
 
x 
Vital signs 
x 
x 
x10 
x 
x 
x 
x 
x 
Administer study drug 
 
 
x 
 
 
 
 
 
Plasma PK sample collection 
 
 
x11 
x12 
x12 
x12 
 
 
Urine PK sample collection 
 
 
x13 
x14 
x14 
 
 
 
Adverse events 
x15 
x15 
x15 
x 
x 
x 
x 
x 
Prior and/or Concomitant medications 
x 
x 
x 
x 
x 
x 
x 
x 
Abbreviations: BMI (body mass index); EOS (End of Study); FE (food-effect); ICF (Informed Consent Form); I/E 
(Inclusion/Exclusion Criteria); ECG (electrocardiogram); PBMC (peripheral blood mononuclear cell); PK (pharmacokinetic). 
1 On Day 15, conduct the EOS visit for all subjects except those in the FE cohort. 
2 A complete PE will be performed at Screening and/or Check-in, and EOS visits; on all other days, a limited PE will be 
conducted targeting any change from the previous status or any body system deemed pertinent to that subject by the PI (or 
designee).  
3 Laboratory analyses to qualify for study entry include: total white cell count or absolute lymphocyte count (values must be in 
the normal range), hemoglobin or platelet levels (values must not be below the lower limit of normal), and ALT/SGPT, alkaline 
phosphatase, AST/SGOT (values must not be above the upper limit of normal), plus virology (HIV/HCV/HBV; tested at 
Screening only; all must be negative), and FSH (if required). 
4 Drug screening (urine drug screen, UDS), including a cotinine test, should be conducted at Screening, Day -1, Days 9, 14, and 
23, and at EOS. Pregnancy tests should be conducted in serum at Screening and in urine at all other times (i.e., Days -1, 9, 14, 
and 23, and at EOS). A positive urine pregnancy test will be confirmed with a serum pregnancy test. An alcohol breath test 
should be conducted at Screening and Days -1 and 14. 
5 Participants should be admitted to the clinic following review of final I/E criteria on Day -1 and discharged from the clinic 
following completion of study specific assessments on Day 4. Subjects in the FE cohort should be readmitted to the clinic on 
Study Day 14. 
6 Safety laboratory assessments include clinical chemistry and urinalysis. Baseline samples will be collected after clinic 
admission on Day -1.  
7 Hematology values include, but are not limited to, RBC, WBC with differential and platelets. PT/PTT and INR assessed only at 


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Screening. 
8 PBMCs will be collected predose, and 2, and 8 hrs postdose on Days 1 and15. Depending on ongoing review of the data, 
timepoints may be modified or removed, and up to 2 additional samples may be collected. 
9 The baseline ECG should be conducted prior to dosing on Day 1/15. 
10 Vital signs include pulse rate, respiratory rate, blood pressure, and body temperature; on Day 1/15, VS should be taken 
predose, and at 2, 4, 8 and 12 hr postdose.  
11 PK samples should be collected predose and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 9, 12, and 15 hr postdose on Day 1/15. 
Depending on ongoing review of the PK data, timepoints may be modified or removed, and up to 3 additional samples (in each 
period for the food-effect) may be added. 
12 PK samples should be collected at 24, 36, 48, and 72 hr postdose on Days 2/16, 3/17, 4/18 respectively. Depending on ongoing 
review of the PK data, timepoints may be modified or removed, and up to 3 additional samples (in each period for the 
food-effect) may be added. 
13 Urine samples for PK analysis should be collected predose (spot collection), and from 0 to 4, 4 to 8, 8 to 12, and 12 to 24 hr 
postdose. 
14 Urine samples for PK analysis should be collected from 24 to 36 and 36 to 48 hr postdose. 
15 Adverse events occurring prior to study drug administration should be recorded as medical history unless the event is directly 
related to a study specified procedure. 
 
 


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Part 3 
Visit
Screening 
(Days -28 to 
-2) 
Day -1 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 Day 9 Day 14 
Day 
20 
/EOS 
ICF; Demography 
x 
 
 
 
 
 
 
 
 
 
 
 
 
I/E; Medical history 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
Physical examination1 
x 
x 
 
x 
 
 
 
 
x 
 
 
x 
x 
Qualifying laboratory 
analyses2 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
Drug screening and 
pregnancy test3 
x 
x 
 
 
 
 
 
 
 
 
 
x 
x 
Height, weight (BMI) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Clinic confinement4 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Non-residential visit 
x 
 
 
 
 
 
 
 
 
 
 
x 
x 
Clinical chemistry and 
urinalysis5 
x 
x 
 
 
x 
 
 
x 
 
 
x 
 
x 
Hematology6 
x 
x 
 
 
x 
 
 
x 
 
 
x 
x 
x 
PBMC collection7 
 
 
x 
 
 
 
 
x 
 
 
 
 
 
ECG8 
x 
 
x 
 
 
 
 
x 
 
 
x 
 
x 
Continuous 12-lead 
ECG 
 
 
x9 
 
 
 
 
x10 
x10 
 
 
 
 
Vital signs11 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Administer study 
drug12 
 
 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
Plasma PK sample 
collection13 
 
 
x 
 
 
x 
 
x 
x 
x 
x 
x 
 
Urine PK sample 
collection14 
 
 
x 
 
 
 
 
x 
x 
x 
x 
 
 
Adverse events 
x15 
x15 
x15 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Prior and/or 
Concomitant 
medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Abbreviations: BID (twice daily); BMI (body mass index); EOS (End of Study); ICF (Informed Consent Form); I/E 
(Inclusion/Exclusion Criteria); ECG (electrocardiogram); PK (pharmacokinetic). 
1 A complete PE will be performed at Screening and/or Check-in, and EOS visits; on all other days, a limited PE will be 
conducted targeting any change from the previous status or any body system deemed pertinent to that subject by the PI (or 
designee). 
2 Laboratory analyses to qualify for study entry include: total white cell count or absolute lymphocyte count (values must be in 
the normal range), hemoglobin or platelet levels (values must not be below the lower limit of normal), and ALT/SGPT, alkaline 
phosphatase, AST/SGOT (values must not be above the upper limit of normal), plus virology (HIV/HCV/HBV; tested at 
Screening only; all must be negative), and FSH (if required). 
3 Drug screening (urine drug screen, UDS), including cotinine, should be conducted at Screening, Day -1, Day 14, and at EOS. 
Pregnancy tests should be conducted in serum at Screening and in urine at all other timepoints. A positive urine pregnancy test 
will be confirmed with a serum pregnancy test. An alcohol breath test should be conducted at Screening and Day -1. 
4 Participants should be admitted to the clinic following review of final I/E criteria on Day -1 and discharged from the clinic 
following completion of study specific assessments on Day 9. 
5 Safety laboratory assessments include clinical chemistry and urinalysis. Baseline samples will be collected after clinic 
admission on Day -1. On Days 3 and 6, the assessment will be pre-am dose. On Day 9, the assessment will be 72 hrs post-am 
dose on Day 6. 


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6 Hematology values include, but are not limited to, RBC, WBC with differential and platelets. PT/PTT and INR assessed only at 
Screening. 
7 PBMCs will be collected 2 hrs postdose, relative to the first daily dose on Day 1, and pre-am dose and 2 and 8 hrs postdose 
relative to the first daily dose on Day 6. Depending on ongoing review of the data, timepoints may be modified or removed, and 
up to 2 additional samples may be collected. Additionally, PMBC collection may be omitted from some cohorts. 
8 The baseline ECG should be conducted prior to first dosing on Day 1. On Day 1, ECG should be taken predose and 2 hours 
post-am dose. On Day 6, ECG should be taken predose, 2 hrs, and 72 hrs (Day 9) postdose. 
9 On Day 1, monitor for 12-lead ECG recording will be worn from 2 hrs prior to the first of the daily doses to 12 hrs following 
the first of the daily doses. Extraction timepoints will be 60, 45, and 30 minutes prior to the first of the daily doses and at 0.25, 
0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 9, and 12 hrs following the first of the daily doses. 
10 On Day 6, monitor for 12-lead ECG recording will be worn from 2 hours prior to dosing (0 hr) to 25 hrs (Day 7) postdose. 
Extraction timepoints will be at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 9, 12, and 24 hrs postdose. 
11 Vital signs include pulse rate, respiratory rate, blood pressure, and body temperature. On Day 1, VS should be taken pre-am 
dose, and at 2, 4, and 8 hrs post-am dose. On Day 2 through 5, VS should be taken pre-am dose. On Day 6, VS should be taken 
predose, and 2, 4, 8, 24 (Day 7), 48 (Day 8), and 72 (Day 9) hrs postdose.  
12 Study drug should be administered BID, 12 hrs apart on Days 1 through 5. On Day 6, study drug should be administered once 
in the morning only (0 hr).  Depending on ongoing review of the safety, tolerability, and PK data, the number of days of dosing 
may be reduced and the dosing frequency changed; the dosing frequency will be no less than once-daily or no greater than 
three-times daily. If the number of days of dosing are reduced, the timepoints for subsequent assessments and the period for 
which subjects are domiciled at the clinic will similarly be changed (subjects will be domiciled for 3 days post final dose). 
13 On Day 1, PK samples should be collected pre-am dose and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 9, and 12 hrs post-am dose. On 
Day 4, the PK sample should be collected pre-am dose. On Day 6, PK samples should be collected predose and at 0.25, 0.5, 1, 
1.5, 2, 2.5, 3, 4, 6, 9, 12, 15, 24 (Day 7), 48 (Day 8), 72 (Day 9), and 192 (Day 14) hrs postdose. Depending on ongoing review of 
the PK data, timepoints may be modified or removed, and up to 3 additional samples may be added. 
14 On Day 1, urine samples for PK analysis should be collected predose (spot collection), and from 0 to 4, 4 to 8, and 8 to 12 hrs 
postdose. On Day 6, urine samples for PK analysis should be collected predose (spot collection), and from 0 to 4, 4 to 8, 8 to 12, 
12 to 24 (Day 7), 24 to 48 (Day 8), and 48 to 72 hrs (Day 9).  Sampling timepoints may be modified, removed, or additional 
timepoints added depending upon ongoing review of the data. The 12-hour urine collection should occur prior to the second daily 
dose administration. 
15 Adverse events occurring prior to study drug administration should be recorded as medical history unless the event is directly 
related to a study specified procedure. 
 


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Appendix 2: 
DMID Toxicity Grading Scale 
Clinical Adverse Events 
VITAL SIGNS 
Mild (Grade 1) 
Moderate Grade 2) 
Severe (Grade 3) 
Fever (°C) Oral temperature; no recent hot or 
cold beverages or smoking. 
38.0 – 38.4 
38.5 – 38.9 
>39.0 
Tachycardia - beats per minute 
101 – 115 
116 – 130 
> 130 or ventricular 
dysrhythmias 
Bradycardia - beats per minute 
50 - 54 or 45 - 50 bpm if 
baseline <60 bpm 
45 - 49 or 40 - 44 if 
baseline <60 bpm 
< 45 or <40 bpm if baseline 
<60 bpm 
Hypertension (systolic) - mm Hg [Assuming 
supine position, 10 min at rest conditions, not 
sleeping subjects, measurements on the same 
arm and several concordant results.] 
 
141 - 150 
 
151 - 160 
 
> 160 
Hypertension (diastolic) - mm Hg 
91 - 95 
96 - 100 
> 100 
Hypotension (systolic) - mm Hg 
85 - 89 
80 - 84 
< 80 
Tachypnea – breaths per minute 
23 - 25 
26 - 30 
>30 
CARDIOVASCULAR 
Grade 1 
Grade 2 
Grade 3 
Arrythmia 
 
asymptomatic, transient 
signs, no Rx required 
recurrent/persistent; 
symptomatic Rx required 
Hemorrhage, Blood Loss 
Estimated blood loss 
< 100 mL 
Estimated blood loss 
> 100 mL, no 
transfusion 
required 
Transfusion required 
RESPIRATORY 
Grade 1 
Grade 2 
Grade 3 
Cough 
Transient-no treatment 
Persistent cough; 
Interferes with daily activities 
Bronchospasm, Acute 
transient; no treatment; 
71-  80% FEV1 of peak 
flow 
requires treatment; 
normalizes with 
bronchodilator; FEV1 
60 - 70% (of peak flow) 
no normalization with 
bronchodilator; FEV1 <60% of 
peak flow 
Dyspnea 
Does not interfere with 
usual and social 
activities 
Interferes with usual 
and social activities, no 
treatment 
Prevents daily and usual social 
activity or requires treatment 
GASTROINTESTINAL 
Grade 1 
Grade 2 
Grade 3 
Nausea 
No interference with 
activity 
Some interference with 
activity 
Prevents daily activities 
Vomiting 
No interference with 
activity or 1 - 2 
episodes/24 hours 
Some interference with 
activity or > 2 
episodes/24 hours 
Prevents daily activity or 
requires IV hydration 
Diarrhea 
2 - 3 loose or watery 
stools or < 400 
gms/24 hours 
4 - 5 loose or watery 
stools or 400 - 800 
gms/24 hours 
6 or more loose or watery 
stools or > 800gms/24 hours or 
requires IV hydration 


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Reactogenicity 
Local reactions 
Grade 1 
Grade 2 
Grade 3 
Pain 
Does not interfere with 
activity 
Repeated use of 
non-narcotic pain 
reliever > 24 hours or 
interferes with activity 
Any use of narcotic pain 
reliever or prevents daily 
activity 
Tenderness 
Discomfort only to touch 
Discomfort with 
movement 
Significant discomfort at rest 
Erythema/Redness * 
2.5 - 5 cm 
5.1 - 10 cm 
> 10 cm 
Induration/Swelling ** 
2.5 - 5 cm and does not 
interfere with activity 
5.1 - 10 cm or interferes 
with activity 
> 10 cm or prevents daily 
activity 
SYSTEMIC 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Allergic Reaction 
pruritus without rash 
localized urticaria 
generalized urticaria; 
angioedema or anaphylaxis 
Headache 
No interference with 
activity 
Repeated use of 
non-narcotic pain 
reliever > 24 hours or 
some interference with 
activity 
Significant; any use of narcotic 
pain reliever or prevents daily 
activity 
Fatigue 
No interference with 
activity 
Some interference with 
activity 
Significant; prevents daily 
activity 
Myalgia 
No interference with 
activity 
Some interference with 
activity 
Significant; prevents daily 
activity 
All Other conditions 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Illness or clinical adverse event (as defined 
according to applicable regulations) 
No interference with 
activity 
Some interference with 
activity not requiring 
medical intervention 
Prevents daily activity and 
requires medical intervention 
*In addition to grading the measured local reaction at the greatest single diameter, the measurement should be recorded as a 
continuous variable. 
**Induration/Swelling should be evaluated and graded using the functional scale as well as the actual 
measurement 
 
 


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Laboratory Adverse Events 
Blood, Serum, or Plasma * 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Sodium – Hyponatremia mEq/L 
132 – <LLN 
130 – 131 
<130 
Sodium – Hypernatremia mEq/L 
>ULN – 148 
149 – 150 
>150 
Potassium – Hyperkalemia mEq/L 
>ULN – 5.2 
5.3 – 5.4 
>5.4 
Potassium – Hypokalemia mEq/L 
<LLN-3.1 
<3.1 – 3.0 
<3.0 
Glucose – Hypoglycemia mg/dL 
65 – 67 
55 – 64 
<55 
Glucose – Hyperglycemia Fasting – mg/dL 
>ULN - 120 
121 – 130 
>130 
Glucose – Hyperglycemia Random – mg/dL 
140 – 159 
160 – 200 
>200 
Blood Urea Nitrogen mg/dL 
23-26 
27 – 31 
> 31 
Creatinine – mg/dL 
>ULN – 1.7 
1.8 – 2.0 
>2.0 
Calcium – hypocalcemia mg/dL 
8.0 – <LLN 
7.5 – 7.9 
<7.5 
Calcium – hypercalcemia mg/dL 
>ULN – 11.0 
11.1 – 11.5 
>11.5 
Magnesium – hypomagnesemia mg/dL 
1.3 – 1.5 
1.1 – 1.2 
<1.1 
Phosphorus – hypophosphatemia mg/dL 
2.3 – 2.5 
2.0 – 2.2 
<2.0 
CPK – mg/dL 
400-1000 
1001-1500 
>1500 
Albumin – Hypoalbuminemia g/dL 
2.8 – 3.0 
2.5 – 2.7 
< 2.5 
Total Protein – Hypoproteinemia g/dL 
5.2 – 5.4 
4.8 – 5.1 
< 4.8 
Alkaline phosphate – U/L 
132-240 
241– 360 
>360 
AST U/L 
44 – 105 
106-175 
>175 
ALT U/L 
44 – 105 
106-175 
>175 
Bilirubin (serum total) mg/dL 
1.3 - 2.0 
2.1 - 2.5 
> 2.5 
Bilirubin – when ALT >105 (Hy's law) 
1.3 -1.5 
1.6 – 2.0 
> 2.0 
Amylase- U/L 
200-270 
271-360 
>360 
Lipase- U/L 
176-270 
271-360 
>360 
Hemoglobin (Female) - g/dL 
11.0 – 11.5 
9.5 – 10.9 
< 9.5 
Hemoglobin (Male) - g/dL 
12.0 – 12.5 
10.0 – 11.9 
<10.0 
WBC Increase - cell/mm3 
11,001 – 15,000 
15,001 – 20,000 
> 20,000 
WBC Decrease - cell/mm3 
2,500 – 3,500 
1,500 – 2,499 
< 1500 
Lymphocytes Decrease - cell/mm3 
750 – 1,000 
500 – 749 
< 500 
Neutrophils Decrease - cell/mm3 
1,500 – 2,000 
1,000 – 1,499 
< 1000 
Eosinophils - cell/mm3 
500-750 
751-1500 
> 1500 
Platelets Decreased - cell/mm3 
120,000 – 130,000 
100,000 – 119,999 
<100,000 
PT – seconds (prothrombin time) 
> ULN-14.4 
14.5 – 15.7 
> 15.7 
PTT – seconds (partial thromboplastin time) 
>ULN-42.1 
42.2– 50.0 
> 50.0 
Fibrinogen increase - mg/dL 
>ULN – 500 
501 – 600 
> 600 
Fibrinogen decrease - mg/dL 
<LLN – 140 
125 – 139 
<125 
Urine * 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Protein 
1+ 
2+ 
>2+ 
Glucose 
1+ 
2+ 
>2+ 
Blood (microscopic) - red blood cells per high 
power field (rbc/hpf) 
5-10 
11-50 
> 50 and/or gross 
blood 
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal parameters. 
* Institutional normal reference ranges should be provided to demonstrate that they are appropriate. 
 


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Ridgeback Biotherapeutics 
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Page 96 
Appendix 3: 
Contraception Guidance 
Male subjects (regardless of fertility status) with partners of childbearing potential must use a 
male barrier method of contraception (i.e., male condom with spermicide) in addition to a second 
method of acceptable contraception from Check-in until 90 days after the EOS visit. Acceptable 
methods of contraception for female partners include: 
 hormonal injection 
 combined oral contraceptive pill or progestin/progestogen-only pill 
 combined hormonal patch 
 combined hormonal vaginal ring 
 surgical method (bilateral tubal ligation or Essure® [hysteroscopic bilateral tubal 
occlusion])  
 hormonal implant 
 hormonal or non-hormonal intrauterine device 
 OTC sponge with spermicide 
 cervical cap with spermicide 
 diaphragm with spermicide. 
An acceptable second method of contraception for male subjects is vasectomy that has been 
performed at least 90 days prior to the screening visit, with verbal confirmation of surgical 
success. 
For male subjects (even with a history of vasectomy), sexual intercourse with female partners 
who are pregnant or breastfeeding should be avoided unless condoms are used from the time of 
the first dose until 90 days after the EOS visit. Male subjects are required to refrain from 
donation of sperm from Check-in until 90 days after the EOS visit. 
Sexual Abstinence and Same-sex Relationships 
Subjects who practice true abstinence, because of the subject’s lifestyle choice (i.e., the subject 
should not become abstinent just for the purpose of study participation), are exempt from 
contraceptive requirements. Periodic abstinence (eg, calendar, ovulation, symptothermal, 
postovulation methods) and withdrawal are not acceptable methods of contraception. If a subject 
who is abstinent at the time of signing the ICF becomes sexually active they must agree to use 
contraception as described previously. 


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Ridgeback Biotherapeutics 
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For subjects who are exclusively in same-sex relationships, contraceptive requirements do not 
apply. If a subject who is in a same-sex relationship at the time of signing the ICF becomes 
engaged in a heterosexual relationship, they must agree to use contraception as described 
previously. 


Protocol Reference: EIDD-2801-1001-UK 
 CONFIDENTIAL  
 
 
 
 
 
 
 
Title of study: A Randomized, Double-blind, Placebo-controlled, First-in-human Study 
Designed to Evaluate the Safety, Tolerability, and Pharmacokinetics of EIDD-2801 
Following Oral Administration to Healthy Volunteers 
NCT Number: NCT04392219 
 
Document: Protocol, Version 5.1 
Date: 11 June 2020 
 


Clinical Study Protocol: EIDD-2801-1001-UK 
Version 5.1 (United Kingdom) 
Ridgeback Biotherapeutics 
Protocol Release Date: 11 June 2020  
Confidential 
Page 1 
A Randomized, Double-Blind, Placebo-Controlled, First-in-Human 
Study Designed to Evaluate the Safety, Tolerability, and 
Pharmacokinetics of EIDD-2801 Following Oral Administration to 
Healthy Volunteers 
 
(EIDD-2801-1001-UK) 
 
Protocol Version 5.1 (United Kingdom) 
Version Date 
11 June 2020 
Sponsor Team: 
Ridgeback Biotherapeutics 
3162 Commodore Plaza, Suite 3E 
Miami, FL 33133-5815 
United States 
Medical Officer 
 
EudraCT Number 
2020-001407-17 
 
Confidential Information: The information contained in this document is the property of 
Ridgeback Biotherapeutics and may not be reproduced, published or disclosed to others without 
written authorization from Ridgeback Biotherapeutics. 


Clinical Study Protocol: EIDD-2801-1001-UK 
Version 5.1 (United Kingdom) 
Ridgeback Biotherapeutics 
Protocol Release Date: 11 June 2020  
Confidential 
Page 2 
SUMMARY OF CHANGES 
Changes from Version 1.1 (United Kingdom) to Version 2.1 (United Kingdom). 
The primary reason for this amendment was to include Part 3, a multiple ascending dose study of 
EIDD-2801 in healthy subjects. Additionally, the following updates were made: 
 Results of an in vivo micronucleus assay were added. 
 The guidelines used to assess the severity of adverse events not presented in the DMID 
Toxicity Grading Scale were updated, specifically those that were life-threatening or led 
to death. 
 The timepoints for collection of peripheral blood mononuclear cells in Part 2 were 
modified. 
 Minor clarifications were made and typographical errors were corrected. 
Changes from Version 2.1 (United Kingdom) to Version 3.1 (United Kingdom). 
 Clarified that this study will be conducted at 1 site in the United Kingdom and up to 
3 sites in the United States, and that integrated data across all sites will be used for 
dose-escalation decisions. 
 The number of cohorts initially planned for Part 1 (single ascending dose) has been 
reduced from 4 to 3. 
 The number of days of dosing in Part 3 (multiple ascending dose) was decreased from 
7 days to 5.5 days. However, the number of days of dosing may be further reduced 
depending on ongoing review of the safety, tolerability, and pharmacokinetic data. 
 Added a rationale for the appropriateness of a 4-day interval between dose escalations. 
 Added a dose-escalation stopping criteria for reductions in platelets and lymphocytes. 
 Clarified that assessments of human immunodeficiency virus, hepatitis B virus, and 
hepatitis C virus will only be conducted at Screening. 
 Minor clarification and typographical corrections. 
Changes from Version 3.1 (United Kingdom) to Version 4.1 (United Kingdom). 
 The total daily dose to be administered in this protocol will not exceed 800 mg. A 
rationale for the increase in the maximum dose to be studied is provided in Section 9.2. 
 The number of additional cohorts in Parts 1 and 3 has been increased to 4. 


Clinical Study Protocol: EIDD-2801-1001-UK 
Version 5.1 (United Kingdom) 
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Protocol Release Date: 11 June 2020  
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 Pregnancy tests in Part 3 will be conducted in serum at Screening and in urine at all other 
timepoints. A positive urine pregnancy test will be confirmed with a serum pregnancy 
test. 
 Clarified that pregnancy, urine drug of abuse, cotinine, and alcohol breath tests will 
additionally be performed at Check-in to second treatment period in Part 2. 
 An additional pharmacokinetic blood sampling timepoint was added in Part 1, and two 
additional pharmacokinetic blood sampling timepoints were added to each of Parts 2 
and 3. 
 Timepoints for continuous 12-lead monitoring in Part 3 were updated. 
 Timepoints for collection of peripheral blood mononuclear cells in Part 2 were updated. 
 The storage conditions for the study drug were updated. 
 Minor clarification and typographical corrections. 
Changes from Version 4.1 (United Kingdom) to Version 5.1 (United Kingdom). 
 The total daily dose to be administered in this protocol will not exceed 1600 mg. A 
rationale for the increase in the maximum dose to be studied is provided in Section 9.2. 
 The number of additional cohorts in Part 1 was increased to 7. 
 The number of additional cohorts in Part 3 was increased to 6. 
 Continuous 12-lead electrocardiogram monitoring was added in Part 1. 


Clinical Study Protocol: EIDD-2801-1001-UK 
Version 5.1 (United Kingdom) 
Ridgeback Biotherapeutics 
Protocol Release Date: 11 June 2020  
Confidential 
Page 4 
STATEMENT OF COMPLIANCE 
The study will be carried out in accordance with Good Clinical Practice (GCP) as required by the 
following: 
 Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines. 
 Applicable International Conference on Harmonisation (ICH) GCP Guidelines. 
 United States Code of Federal Regulations (CFR) applicable to clinical studies 
(45 CFR Part 46; 21 CFR Part 50, 21 CFR Part 56, and 21 CFR Part 312). 
 Applicable laws and regulations. 


Clinical Study Protocol: EIDD-2801 -1 001 -UK 
Ridgeback Biotherapeutics 
Version 5.1 (United Kingdom) 
Protocol Release Date: 11 June 2020 
SIGNATURE PAGE 
The signature below constitutes the approval of this protocol and the attachments and provides 
the necessary assurances that this study will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable regulations and ICH guidelines. 
Principal Investigator: 
Signed: 
Date: 
 
Executive Medical Director 
Covance Clinical Research Unit Limited 
Confidential 
Page 5 


Clinical Study Protocol: EIDD-2801-1001-UK 
Version 5.1 (United Kingdom) 
Ridgeback Biotherapeutics 
Protocol Release Date: 11 June 2020  
Confidential 
Page 6 
TABLE OF CONTENTS 
SUMMARY OF CHANGES .......................................................................................................... 2 
STATEMENT OF COMPLIANCE ................................................................................................. 4 
SIGNATURE PAGE ...................................................................................................................... 5 
TABLE OF CONTENTS ............................................................................................................... 6 
LIST OF TABLES ....................................................................................................................... 10 
LIST OF FIGURES ..................................................................................................................... 11 
LIST OF APPENDICES .............................................................................................................. 12 
ABBREVIATIONS ...................................................................................................................... 13 
PROTOCOL SYNOPSIS ............................................................................................................ 16 
1. INTRODUCTION ................................................................................................................... 26 
1.1. 
Background ............................................................................................................... 26 
1.2. 
Rationale for Development ........................................................................................ 26 
1.3. 
Nonclinical Overview ................................................................................................. 27 
1.3.1. Mechanism of Action ................................................................................................. 27 
1.3.2. In Vitro Pharmacology ............................................................................................... 28 
1.3.2.1. 
Antiviral Activity in Tissue Culture and in Human Airway Epithelium ............. 28 
1.3.2.2. 
Cytotoxicity of EIDD-1931 in Tissue Culture Utilizing Cells from Different 
Organs and Species ...................................................................................... 30 
1.3.2.3. 
Assessment of Mitochondrial Toxicity ............................................................ 30 
1.3.3. In Vivo Pharmacology ............................................................................................... 30 
1.3.3.1. 
Coronavirus: SARS-CoV and MERS-CoV ..................................................... 30 
1.3.3.2. 
Influenza Virus ............................................................................................... 34 
1.3.3.3. 
Venezuelan Equine Encephalitis Virus .......................................................... 35 
 
 
1.4. 
Safety and Secondary Pharmacology ....................................................................... 35 
1.5. 
Nonclinical Pharmacokinetics and Metabolism ......................................................... 35 
1.5.1. Overview ................................................................................................................... 35 
1.5.2. Absorption ................................................................................................................. 35 
1.5.3. Distribution ................................................................................................................ 36 
 
 
1.5.3.2. 
Tissue Distribution Studies ............................................................................ 36 
1.5.4. Metabolism ................................................................................................................ 37 
1.5.4.1. 
Metabolic Stability of EIDD-1931 and EIDD-2801 ......................................... 37 
1.5.4.2. 
Uptake and Anabolism of EIDD-1931 in Tissue Culture and Primary Cells ... 38 
1.5.5. Excretion ................................................................................................................... 39 
1.5.6. Pharmacokinetic Drug Interactions ........................................................................... 39 
1.5.6.1. 
Cytochrome P450 (CYP) Inhibition ................................................................ 39 
1.5.6.2. 
CYP Induction ................................................................................................ 39 
 
 
 
 
 
 


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1.7. 
Potential Risks and Benefits ...................................................................................... 45 
1.7.1. Potential Benefits ...................................................................................................... 45 
1.7.2. Potential Risks ........................................................................................................... 45 
2. OBJECTIVES ....................................................................................................................... 46 
2.1. 
Study Objectives ....................................................................................................... 46 
2.1.1. Primary Objectives .................................................................................................... 46 
2.1.2. Secondary Objectives ............................................................................................... 46 
2.1.3. Exploratory Objectives .............................................................................................. 46 
2.2. 
Study Outcome Measures ......................................................................................... 46 
2.2.1. Primary Outcome Measures ...................................................................................... 46 
2.2.2. Secondary Outcome Measures ................................................................................. 46 
3. STUDY DESIGN ................................................................................................................... 48 
3.1. 
Overview ................................................................................................................... 48 
3.1.1. Part 1 (Single Ascending Dose) ................................................................................ 48 
3.1.2. Part 2 (Food-Effect) ................................................................................................... 49 
3.1.3. Part 3 (Multiple Ascending Dose) .............................................................................. 49 
3.2. 
Rationale and Justification ........................................................................................ 50 
3.2.1. Justification of Design ............................................................................................... 50 
3.2.2. Justification of Starting Dose ..................................................................................... 50 
3.2.3. Justification of Study Population ............................................................................... 51 
4. STUDY POPULATION ......................................................................................................... 52 
4.1. 
Subject Inclusion Criteria ........................................................................................... 52 
4.2. 
Subject Exclusion Criteria ......................................................................................... 53 
5. STUDY MEDICATION, RANDOMIZATION AND DOSE ADMINISTRATION ...................... 55 
5.1. 
Study Drug Description ............................................................................................. 55 
5.1.1. Acquisition, Formulation, Packaging and Labeling .................................................... 55 
5.1.2. Product Storage and Stability .................................................................................... 55 
5.2. 
Randomization .......................................................................................................... 55 
5.3. 
Dosage, Preparation and Administration of Study Drug ............................................ 56 
5.4. 
Drug Accountability ................................................................................................... 56 
5.5. 
Concomitant Medication/Treatments ......................................................................... 56 
6. STUDY CONDUCT AND VISIT SCHEDULE ....................................................................... 58 
6.1. 
Study Conduct ........................................................................................................... 58 
6.1.1. Study Windows and Rounding Principles .................................................................. 58 
6.1.2. Restrictions ................................................................................................................ 58 
6.2. 
Screening .................................................................................................................. 59 


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6.2.1. Screening Visit .......................................................................................................... 59 
6.2.2. Retesting Procedures ................................................................................................ 60 
6.2.3. Study Visits ................................................................................................................ 60 
6.2.4. Part 1 (Single Ascending Dose) ................................................................................ 60 
6.2.5. Part 2 (Food-Effect) ................................................................................................... 60 
6.2.6. Part 3 (Multiple Ascending Dose) .............................................................................. 60 
6.3. 
Safety Follow-up and End-of-Study Visit ................................................................... 60 
6.4. 
Subject Withdrawal and Replacement ...................................................................... 61 
6.4.1. Reasons for Withdrawal ............................................................................................ 61 
6.4.2. Handling of Withdrawals ............................................................................................ 62 
6.4.3. Documentation of Withdrawals .................................................................................. 62 
6.4.4. Subject Replacement ................................................................................................ 62 
6.5. 
Unscheduled Visit(s) ................................................................................................. 62 
7. STUDY PROCEDURES/EVALUATIONS ............................................................................. 64 
7.1. 
Demography and Medical History ............................................................................. 64 
7.2. 
Clinical Evaluations ................................................................................................... 64 
7.2.1. Physical Examinations .............................................................................................. 64 
7.2.2. Vital Sign Measurements and ECGs ......................................................................... 64 
7.2.2.1. 
Continuous 12-lead ECG Monitoring (Parts 1 and 3 Only) ............................ 65 
7.2.3. Adverse Events and Concomitant Medications ......................................................... 65 
7.3. 
Laboratory Evaluations .............................................................................................. 65 
7.3.1. Routine Laboratory Panels ........................................................................................ 65 
7.3.2. Pharmacokinetic Sampling ........................................................................................ 67 
7.3.3. Peripheral Blood Mononuclear Cell Collection .......................................................... 68 
7.3.4. Urine Collection ......................................................................................................... 68 
8. SAFETY MONITORING, MANAGEMENT AND REPORTING ............................................ 69 
8.1. 
Definitions .................................................................................................................. 69 
8.1.1. Adverse Events ......................................................................................................... 69 
8.1.2. Serious Adverse Events ............................................................................................ 69 
8.2. 
Documenting Adverse Events ................................................................................... 70 
8.2.1. Timeframe for Collection and Follow-up of AEs/SAEs .............................................. 70 
8.2.2. Recording of Adverse Events/Serious Adverse Events ............................................ 71 
8.2.3. Assessing Severity of Adverse Events ...................................................................... 71 
8.2.4. Relationship to Study Drug ........................................................................................ 72 
8.2.5. Classifying Adverse Event Outcome ......................................................................... 72 
8.3. 
Reporting Procedures ................................................................................................ 73 
8.3.1. Serious Adverse Events ............................................................................................ 73 
8.3.2. Pregnancy ................................................................................................................. 73 
8.4. 
Unmasking Treatment Assignment ........................................................................... 74 
9. DOSE-ESCALATION AND HALTING RULES..................................................................... 75 
9.1. 
Guidelines for Dose-Escalation ................................................................................. 75 
9.2. 
Rationale for Highest Dose ....................................................................................... 76 
9.2.1. Clinical Safety ............................................................................................................ 76 
9.2.1.1. 
Single Ascending Doses ................................................................................ 76 


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9.2.1.2. 
Multiple Ascending Doses ............................................................................. 77 
9.2.2. Pharmacokinetics ...................................................................................................... 78 
9.2.2.1. 
Single Ascending Doses ................................................................................ 78 
9.2.2.2. 
Multiple Ascending Doses ............................................................................. 78 
9.2.3. Rationale to Exceed the Maximum Single Dose Limit of 800 mg .............................. 79 
9.3. 
Dose-Escalation Halting Rules .................................................................................. 80 
10. STATISTICAL CONSIDERATIONS ..................................................................................... 81 
10.1. 
General Considerations ............................................................................................. 81 
10.2. 
Sample Size Considerations ..................................................................................... 81 
10.3. 
Analysis Populations ................................................................................................. 81 
10.4. 
Analysis of Safety Data ............................................................................................. 81 
10.4.1. Extent of Exposure .................................................................................................... 81 
10.4.2. Adverse Events ......................................................................................................... 82 
10.4.3. Clinical Laboratory Results ........................................................................................ 82 
10.4.4. Other Parameters ...................................................................................................... 82 
10.5. 
Analysis of Pharmacokinetic Data ............................................................................. 82 
10.5.1. Statistical Analysis of Pharmacokinetic Data ............................................................ 84 
10.5.1.1. Dose Proportionality ...................................................................................... 84 
10.5.1.2. Food-Effect .................................................................................................... 84 
10.6. 
Peripheral Blood Mononuclear Cells ......................................................................... 84 
10.7. 
Interim Analyses ........................................................................................................ 84 
11. STUDY ADMINISTRATION .................................................................................................. 85 
11.1. 
Regulatory and Ethical Considerations ..................................................................... 85 
11.2. 
Ethical Standard ........................................................................................................ 85 
11.2.1. Ethics Committee Approval ....................................................................................... 85 
11.2.2. Informed Consent ...................................................................................................... 85 
11.3. 
Financing and Insurance ........................................................................................... 86 
11.4. 
Source Documentation and Access .......................................................................... 86 
11.5. 
Data Collection and Record Keeping ........................................................................ 86 
11.5.1. Data Collection .......................................................................................................... 86 
11.5.2. Study Records Retention .......................................................................................... 87 
11.5.3. Protocol Deviations ................................................................................................... 87 
11.6. 
Clinical Monitoring ..................................................................................................... 87 
11.7. 
Quality Control and Quality Assurance ..................................................................... 87 
11.8. 
Study Termination and Closure Procedures.............................................................. 88 
11.8.1. Study Termination ..................................................................................................... 88 
11.8.2. Termination Procedures ............................................................................................ 88 
11.9. 
Information Disclosure ............................................................................................... 88 
11.9.1. Confidentiality ............................................................................................................ 88 
11.9.2. Clinicaltrials.gov ........................................................................................................ 89 
11.9.3. Publication Policy ...................................................................................................... 89 
12. REFERENCES ...................................................................................................................... 90 
13. APPENDICES ....................................................................................................................... 91 
 


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LIST OF TABLES 
Table 1: 
EIDD-1931 Antiviral Activity Against Influenza A and B Viruses in Tissue Culture and 
Primary Human Bronchial/Tracheal Epithelial Cells ................................................. 28 
Table 2: 
EIDD-1931 Antiviral Activity Against SARS and MERS Coronaviruses in Tissue 
Culture and Primary Human Bronchial/Tracheal Epithelial Cells ............................. 29 
Table 3: 
EIDD-1931 Antiviral Activity Against Togaviruses in Tissue Culture ........................ 29 
 
 
Table 5: 
Cytotoxicity (CC50) of EIDD-1931 in Mammalian Cell Lines .................................... 30 
Table 6: 
Metabolic Stability of EIDD-2801 in Plasma and Liver Microsomes ......................... 38 
Table 7: 
Metabolic Stability of EIDD-2801 in Simulated Gastric and Intestinal Fluids and in 
Buffered Saline with Fetal Bovine Serum ................................................................. 38 
Table 8: 
Metabolic Stability of EIDD-1931 in Plasma, Whole Blood and Liver and Intestinal 
Microsomes .............................................................................................................. 38 
 
 
 
Table 10: Allowable Time Windows for Study Assessments/Visits .......................................... 58 
Table 11: Laboratory Evaluations ............................................................................................. 67 
Table 12: Adverse Event Outcomes ......................................................................................... 72 
Table 13: Pharmacokinetic Parameters ................................................................................... 83 
 


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LIST OF FIGURES 
Figure 1: 
Study Schema .......................................................................................................... 25 
Figure 2: 
Inhibition of SARS-CoV-2 by EIDD-1931 ................................................................. 29 
Figure 3: 
EIDD-2801 Prophylactic Treatment of SARS-CoV Infected Mice ............................ 31 
Figure 4: 
EIDD-2801 Treatment of SARS-CoV Infected Mice ................................................. 32 
Figure 5: 
EIDD-2801 Prophylactic Treatment of MERS-CoV Infected Mice ............................ 33 
Figure 6: 
EIDD-2801 Treatment of MERS-CoV Infected Mice ................................................ 34 
Figure 7: 
Tissue Distribution of EIDD-1931 and EIDD-2061 in Ferret Brain and Lung ............ 37 
 
 


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LIST OF APPENDICES 
Appendix 1: 
Time and Events Schedule ............................................................................ 91 
Appendix 2: 
DMID Toxicity Grading Scale ......................................................................... 95 
Appendix 3: 
Contraception Guidance ................................................................................ 98 


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ABBREVIATIONS 
AE 
adverse event 
AGP 
alpha1-acid glycoprotein 
ALT/SGPT 
alanine aminotransferase/serum glutamic pyruvic transaminase 
AST/SGOT 
aspartate aminotransferase/serum glutamic oxaloacetic transaminase 
AUC 
area under the curve 
BID 
twice-daily 
BMI 
body mass index 
CDC 
Centers for Disease Control and Prevention 
CEM 
a cell line of lymphoblastic cells derived from a child with leukemia 
CFR 
Code of Federal Regulations 
CHKV 
Chikungunya virus 
CI 
confidence interval 
CoV 
coronavirus 
CRF 
case report form 
CTP 
cytosine triphosphate cytidine triphosphate 
CYP 
cytochrome P450 
DMID 
Division of Microbiology and Infectious Diseases 
DMSO 
dimethylsulfoxide 
DPP4 
dipeptidyl peptidase 4 
DRF 
dose range finding 
DSS 
Drug Safety Services 
EBOV 
Ebola virus 
EC 
Ethics Committee 
EC50 
Half-maximal effective concentration 
ECG 
electrocardiogram 
EEEV 
Eastern equine encephalitis virus 
EIDD 
Emory Institute for Drug Development 
EOS 
End of Study 
FDA 
Food and Drug Administration 
FE 
food-effect 
FIH 
first-in- human 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
GLP 
Good Laboratory Practice 


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HAE 
human airway epithelium 
HBV 
hepatitis b virus 
hBTEC 
human bronchial/tracheal epithelial cells 
HCV 
hepatitis c virus 
HED 
human equivalent dose 
HEENT 
head, eye, ear, nose and throat 
HIV 
human immunodeficiency virus 
HPMC 
hydroxypropyl methylcellulose 
IAV 
influenza a virus 
IB 
Investigator’s Brochure 
IBV 
influenza b virus 
IC50 
half maximal inhibitory concentration 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
MAD 
multiple ascending dose 
MDCK 
Madin-Darby Canine Kidney Cells 
MedDRA 
Medical Dictionary for Regulatory Activities 
MERS 
Middle East respiratory syndrome 
%MN-PCE 
percentage of micronuclei-polychromatic erythrocytes 
MRSD 
maximum recommended starting dose 
MTD 
maximum tolerated dose 
NOAEL 
no-observed-adverse-effect-level 
NSAID 
nonsteroidal anti-inflammatory drug 
OTC 
over-the-counter 
PBMC 
peripheral blood mononuclear cells 
PBO 
placebo 
PCE:TE 
polychromatic erythrocytes to total erythrocytes 
PE 
physical examination 
PI 
principal investigator 
 
 
PK 
pharmacokinetic 
QTc(F) 
QT interval corrected for heart rate (using Fridericia’s formula) 
RNA 
ribonucleic acid 
RSV 
respiratory syncytial virus 
SAD 
single ascending dose 
SAE 
serious adverse event 


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SAP 
statistical analysis plan 
SARS 
severe acute respiratory syndrome 
SI 
selectivity index 
SOP 
standard operating procedure 
UTP 
uridine 5'-triphosphate 
VEEV 
Venezuelan equine encephalitis virus 
ZIKV 
Zika virus 


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PROTOCOL SYNOPSIS 
Sponsor: Ridgeback Biotherapeutics 
Title: A Randomized, Double-Blind, Placebo-Controlled, First-in-Human Study Designed to 
Evaluate the Safety, Tolerability, and Pharmacokinetics of EIDD-2801 Following Oral 
Administration to Healthy Volunteers (EIDD-2801-1001-UK) 
Short Title: EIDD-2801-1001-UK 
Development Phase: Phase 1 
Study Sites: This study will be conducted at 1 site in the United Kingdom and up to 3 sites in 
the United States. 
Description of Study Drugs, Dose and Mode of Administration: EIDD-2801 and matching 
placebo (PBO) will be supplied 
 
  
Part 1: A single oral dose of EIDD-2801 or PBO will be administered to subjects enrolled in 
Part 1 (P1; single ascending dose [SAD]) cohorts. The starting dose in the first SAD cohort will 
be 50 mg. The doses will be administered in an escalating manner. Dose levels will not increase 
by more than 3-fold for predicted nonpharmacologically active dose levels and by 2-fold for 
predicted pharmacologically active dose levels.
 
 
 
Part 2: Subjects in Part 2 (P2)/food-effect (FE) will receive 2 single doses of EIDD-2801 with a 
14-day (minimum) washout period between doses. The dose for the P2 cohort is planned to be 
100 mg but may be adjusted based on safety, tolerability, and/or pharmacokinetic (PK) data from 
P1. In any case, the dose assessed in P2 will have been given previously to subjects in a P1 
cohort successfully (i.e., no halting rules were met following dosing). 
Part 3: Multiple doses of EIDD-2801 or PBO will be administered to subjects enrolled in Part 3 
(P3; multiple ascending dose [MAD]) cohorts. Subjects will receive twice-daily (BID) doses for 
5 days, with a single dose administered on the morning of Day 6 for collection of steady-state 
PK samples during waking hours. The total daily dose will not exceed a dose shown to be safe 
and well-tolerated in P1. Doses in P3 may be administered in the fed state, following review of 
the PK data from P2. Additionally, depending on ongoing review of the safety, tolerability, and 
PK data, the number of days of dosing may be reduced and the dosing frequency may be 
changed; the dosing frequency will be no less than once-daily or no greater than three-times 
daily. 
Treatment Duration:  
Part 1: Subjects enrolled into P1/SAD cohorts will receive a single dose of study drug 
(EIDD-2801 or matching PBO).  
Part 2: Subjects enrolled into the P2/FE cohort will receive 2 single doses of EIDD-2801, with a 
washout period between doses. 
Part 3: Subjects in P3/MAD cohorts will receive study drug (EIDD-2801 or matching PBO) for 
5 days BID followed by a single dose of EIDD-2801 or PBO on Day 6. Depending on ongoing 
review of the safety, tolerability, and PK data, the number of days of dosing may be reduced. 


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Subject Duration:  
Part 1: The maximum possible study duration for participants enrolled in P1/SAD cohorts will 
be approximately 43 days. 
Part 2: The maximum possible study duration for participants enrolled in the P2/FE cohort will 
be approximately 58 days. 
Part 3: The maximum possible study duration for participants enrolled in P3/MAD will be 
approximately 48 days. 
Objectives and Endpoints: 
Part 1: SAD Cohorts 
Primary: 
 
Objective: To determine the safety and tolerability of single ascending doses of EIDD-2801. 
o Endpoints:  
 
Results of safety evaluations including safety laboratory assessments, 
physical examination (PE), electrocardiograms (ECGs), vital signs, and 
adverse events (AEs). 
Secondary: 
 
Objective: To define PK of EIDD-2801 and EIDD-1931 in plasma and urine following 
single doses administered to healthy volunteers. 
o Endpoints: 
 
Plasma PK parameters, including Cmax, tmax, t1/2, CL/F, λz, Vz/F, AUC0-inf 
and AUClast as appropriate 
 
Urinary excretion of EIDD-2801 and EIDD-1931 following single-dose 
administration. 
Exploratory: 
 
Objective: To collect data to assess the relationship between EIDD-2801/EIDD-1931 
concentrations and QT interval corrected for heart rate (QTc). 
Part 2: Single-Dose Food-Effect 
Primary: 
 
Objective: To assess the effect of food on the PK of EIDD-2801 and EIDD-1931 following 
a single oral dose. 
o Endpoints: 
 
Plasma PK parameters, including Cmax, tmax, t1/2, CL/F, λz, Vz/F, AUC0-inf 
and AUClast as appropriate 
 
Urinary excretion of EIDD-2801 and EIDD-1931 following single-dose 
administration. 
Secondary: 
 
Objective: To determine the safety and tolerability of single doses of EIDD-2801. 
o Endpoints: 
 
Results of safety evaluations, including safety laboratory assessments, PEs, 
ECG, vital signs, and AEs. 
 


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Part 3: MAD Cohorts 
Primary: 
 
Objective: To determine the safety and tolerability of multiple ascending doses of 
EIDD-2801. 
o Endpoints: 
 
Results of safety evaluations, including safety laboratory assessments, PE, 
ECGs, vital signs, and AEs. 
Secondary: 
 
Objective: To define PK of EIDD-2801 and EIDD-1931 in plasma and urine following 
multiple doses administered to healthy volunteers. 
o Endpoints: 
 
Plasma PK parameters, including Ctrough, Cmax, tmax, t1/2, CL/F, λz, Vz/F, 
AUC0-inf (Day 1 dose only), AUCτ, RAAUCτ, and RACmax as appropriate 
 
Urinary excretion of EIDD-2801 and EIDD-1931 following multiple-dose 
administration. 
Exploratory: 
 
Objective: To collect data to assess the relationship between EIDD-2801/EIDD-1931 
concentrations and QTc. 
Population:  
Part 1: P1/SAD cohorts will include 8 subjects each, 2 randomized to receive PBO and 
6 randomized to receive EIDD-2801. Initially, 3 SAD cohorts are planned for P1 with the option 
to add an additional 7 cohorts based on study results. 
Part 2: Ten subjects will be enrolled into the P2/FE cohort; all subjects enrolled in the P2 cohort 
will receive EIDD-2801. One P2 cohort is planned for the study. If PK results obtained are 
equivocal, additional subjects may be enrolled into the P2 cohort at the previously tested dose or 
an additional P2 cohort may be added at a different dose.  
Part 3: P3/MAD cohorts will include 8 subjects, 2 randomized to receive PBO and 
6 randomized to receive EIDD-2801. Initially, 3 MAD cohorts are planned for P3 with the 
option to add an additional 6 cohorts based on study results. However, the number of cohorts 
may be reduced if the study objectives are met. Dose levels in P3 may be repeated for collection 
of peripheral blood mononuclear cells (PBMCs), providing that the dose level did not meet the 
dose-escalation halting criteria. 
The site is strongly encouraged to ensure that women are represented in each cohort. Inclusion 
and exclusion criteria for study participation are as follows: 
Inclusion Criteria: subjects who meet all of the criteria at Screening will be eligible for study 
participation 
1. Male or female between the ages of 18 and 60, inclusive. 
2. Female subjects must be of nonchildbearing potential. Nonchildbearing potential is 
defined as women who: 
• 
are physiologically incapable of becoming pregnant including those who are 
surgically sterile, via hysterectomy, bilateral salpingectomy, and/or bilateral 
oophorectomy by reported medical history and/or medical records. Surgical 


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sterilization to have occurred a minimum of 6 weeks, or at the Principal 
Investigator’s (PI’s; or designee’s) discretion, prior to Screening. 
• 
are postmenopausal (at least 45 years of age with amenorrhea for 12 months 
without an alternative medical reason with confirmatory follicle stimulating 
hormone (FSH) levels of ≥ 40 mIU/mL. The amenorrhea should not be induced 
by a medical condition such as anorexia nervosa, hypothyroid disease or 
polycystic ovarian disease, or by extreme exercise. It should not be due to 
concomitant medications that may have induced the amenorrhea such as oral 
contraceptives, hormones, gonadotropin-releasing hormones, anti-estrogens, or 
selective estrogen receptor modulators). 
3. Male participants must agree to the use of effective contraception for study duration, 
i.e., from Check-in until 90 days following the last dose of study drug. 
4. Is in generally good health as determined by medical history, PE (at Screening and/or 
Check-in), vital signs, and other screening procedures. 
5. Has a body mass index (BMI) of 18 to 30 kg/m2. 
6. Is willing and able to comply with all study procedures including providing informed 
consent. 
Exclusion Criteria: subjects who meet any of the following criteria at Screening (unless 
otherwise stated) will not be eligible for participation 
1. Females who are pregnant, planning to become pregnant, or breastfeeding. 
2. Has a clinically relevant acute or chronic medical condition or disease of the 
cardiovascular, gastrointestinal (GI), hepatic, renal, endocrine, pulmonary, neurologic, 
or dermatologic systems as determined by the PI (or designee). 
3. Has any current or historical disease or disorder of the hematological system or 
significant liver disease or family history of bleeding/platelet disorders. 
4. Has a history of cancer (other than basal cell or squamous cell cancer of the skin), 
rheumatologic disease or blood dyscrasias. 
5. Has a history of GI surgery or other condition that may interfere with absorption of 
study drug, in the option of the PI (or designee). 
6. Has a history of febrile illness within the 14 days prior to the first dose of study drug. 
7. Has a positive alcohol or drug screen at Screening or the Day -1 visit or has a history of 
alcohol or drug abuse within the past 5 years. 
8. Currently uses tobacco, nicotine or tobacco products, e-cigarettes or has stopped using 
tobacco products within the past 3 months and/or has a positive cotinine test at 
Screening or Check-in. 
9. Has any abnormal laboratory value of Grade 2 or higher, which is considered to be 
clinically significant by the PI (or designee). 
10. Has a total white cell count or absolute lymphocyte count outside the normal range, or 
hemoglobin or platelet levels below the lower limit of normal, at Screening of Day -1. 
11. Has values above the upper limit of normal for the following laboratory analytes: 
alanine aminotransferase (ALT/SGPT), alkaline phosphatase (serum), aspartate 
aminotransferase (AST/SGOT), at Screening or Day -1. 
12. Positive test result for human immunodeficiency virus (HIV), hepatitis B virus (HBV), 


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or hepatitis C virus (HCV). 
13. Has an autoimmune disease, is immunosuppressed or is in any way 
immunocompromised. 
14. Has any of the following: 
• 
QT interval corrected for heart rate using Fridericia’s formula (QTcF) >450 ms 
confirmed by repeat measurement 
• 
QRS duration >110 ms confirmed by repeat measurement 
• 
PR interval >220 ms confirmed by repeat measurement 
• 
findings which would make QTc measurements difficult or QTc data 
uninterpretable 
• 
history of additional risk factors for torsades de pointes (e.g., heart failure, 
hypokalemia, family history of long QT syndrome). 
15. Except as noted, has used prescription drugs (other than hormone replacement therapy) 
within 14 days prior to the first dose of study drug unless, in the opinion of the PI (or 
designee), the drug will not interfere with study assessments. The following prescription 
drugs will be allowed: 
• 
Statins: Subjects who have been on a stable dose of statins for a minimum of 
6 months and who have normal creatine kinase at Screening. 
• 
Antihypertensives: Subjects who have been on a stable dose of 
antihypertensives for a minimum of 6 months and have controlled blood 
pressure and no active heart disease. 
16. Has received an experimental agent (vaccine, drug, biologic, device, blood product or 
medication) within 3 months prior to the first dose of study drug and agrees not to 
receive another experimental agent during the duration of this trial. 
17. Has donated blood within 30 days, plasma within 2 weeks, or platelets within 6 weeks 
prior to Screening or refuses to agree to not donate blood until 3 months after the End of 
Study (EOS) visit. 
18. Uses over-the-counter (OTC) medications or nutritional supplements (including, e.g., 
gingko biloba, aspirin at any dose, and nonsteroidal anti-inflammatory drugs [NSAIDs]) 
on a routine/scheduled basis, and/or is unwilling to abstain from such use for the 
duration of the study. 
19. Is unwilling to abstain from quinine containing products including quinine water, tonic 
water, bitter lemon, jello shots, any quinine preparations or Cinchona tree bark 
preparations (e.g., herbal medications containing Cinchona tree bark). 
20. Has any condition that would, in the opinion of the PI (or designee), put the subject at 
increased risk for participation in a clinical trial or confinement in a clinical research 
unit. 
Retesting for Inclusion/Exclusion Criteria: In the case where a parameter is outside of the 
acceptable limits for enrollment, measurement of the parameter can be repeated one time if both 
the following are met: 
 In the opinion of the PI (or designee), the parameter value does not represent a chronic 
condition that otherwise will preclude the volunteer from enrolling in the study; and 


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 In the opinion of the PI (or designee), the abnormality is not likely to recur. 
General Investigational Plan: For all potential subjects, volunteers who express interest in the 
study will report to the clinic for informed consent. The study will be explained to the subject 
and the Ethics Committee (EC)-approved informed consent form (ICF) will be presented. The 
subject will be given the chance to review the document and ask any questions he/she may have. 
If, after reviewing the consent, the subject would like to participate in the study, then he/she will 
sign the ICF and begin screening for study entry; those satisfying all criteria will be enrolled into 
the study and admitted to the clinic on Day -1. Retesting will be allowed as described above. 
Part 1: For P1/SAD, the first cohort will be divided into 2 groups. The first group, a sentinel 
group, will include 2 subjects.  
On Day 1, one subject in the sentinel group will be administered PBO and one will be 
administered EIDD-2801. Analysis of the safety results for the sentinel group will be reviewed 
24 hours postdose. If no halting criteria have been met, the remainder of the subjects in Cohort 1 
(the second group) will be dosed. There will be no sentinel groups for the remaining cohorts. 
Following dosing on Day 1, subjects will remain in the clinic through completion of study 
assessments on Day 4, returning to the clinic on Day 9 for study assessments, and Day 15 for the 
EOS visit.  
Doses will be administered in an escalating manner following satisfactory review by the Sponsor 
and PI of the blinded safety and tolerability data (up to 72 hours post final dose). Integrated data 
from all applicable sites will be used to make dose-escalation decisions. Dose-escalation will 
only occur if data from a minimum of 6 subjects (across all sites) have been reviewed from the 
previous lower dose group, such that data from a minimum of 4 subjects (across all sites) who 
have received EIDD-2801 will be used to make the dose-escalation decision. Dose levels will 
not increase by more than 3-fold for predicted nonpharmacologically active dose levels and by 
2-fold for predicted pharmacologically active dose levels. The highest total daily dose to be 
studied under this protocol will not exceed 1600 mg. 
Continuous 12-lead ECG monitoring will be performed to collect data to assess the relationship 
between study drug concentrations and QTc interval. All data will be archived without extraction 
or analysis and will not be reported in the scope of this study. 
Part 2: For P2/FE, one cohort assessing the effect of food on EIDD-2801 and EIDD-1931 PK 
parameters will be enrolled; it is planned that the P2 cohort will be at a dose of 100 mg 
EIDD-2801, although higher or lower doses may be selected based on safety and available PK 
data from P1.  
In addition to assessing the effect of food on dosing, PBMCs will be collected from subjects 
following each dose; the PBMCs will be stored for analysis of EIDD-2061 levels at some point 
in the future.  
The 10 subjects enrolled in the FE cohort will all receive EIDD-2801; subjects will be 
randomized to a treatment sequence (i.e., to receive drug in the fed then fasted state [Sequence 1] 
versus fasted then fed state [Sequence 2]). Half of the subjects in the cohort will be randomized 
to Sequence 1 and the other half will be randomized to Sequence 2.  
Following dosing on Day 1, subjects will remain in the clinic through completion of study 
assessments on Day 4, returning to the clinic on Day 9 for study assessments, and Day 14 to 
begin the second dosing sequence on Day 15. Subjects will then be discharged from the clinic on 
Day 18, returning to the clinic on Day 23 for study assessments, and Day 30 for the EOS visit. 


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There will be a 14-day (minimum) washout period between doses. 
Part 3: For P3/MAD, subjects will receive BID doses on Day 1 through Day 5, inclusive, and 
will receive the final dose of study drug on the morning of Day 6 for collection of steady-state 
PK samples during waking hours. Subjects will remain domiciled at the site during the dosing 
period and until Day 9, returning to the clinic on Day 14 for completion of study assessments, 
and Day 20 for the EOS visit. 
Doses in P3 may be administered in the fed state, following review of the PK data from P2. 
Additionally, depending on ongoing review of the safety, tolerability, and PK data, the number 
of days of dosing may be reduced and the dosing frequency changed; the dosing frequency will 
be no less than once-daily or no greater than three-times daily. If the number of days of dosing 
are reduced, the timepoints for subsequent assessments and the period for which subjects are 
domiciled at the clinic will similarly be changed (subjects will be domiciled for 3 days post final 
dose). 
Part 3 may run in parallel with P1, providing that the total daily dose to be administered does not 
exceed a dose already shown to be safe and well-tolerated in P1. 
Peripheral blood mononuclear cells may be collected from subjects in P3, depending upon 
ongoing review of the data. The collection of these samples may be omitted from some cohorts, 
depending on ongoing review of the data. The PBMCs will be stored for analysis of EIDD-2061 
levels at some point in the future. In addition, continuous 12-lead ECG monitoring will be 
performed to collect data to assess the relationship between study drug concentrations and QTc 
interval. All data will be archived without extraction or analysis and will not be reported in the 
scope of this study.  
Additional parts may be added to this study, including a SAD part in elderly healthy 
subjects and a study of the safety, tolerability, and PK in Japanese subjects. These 
additional parts are not described in this protocol but may be added via a protocol 
amendment.  
Safety Monitoring and Potential Unblinding: Safety for this study will be continually 
monitored by the PI and Sponsor.  
Blinding: All study personnel will remain blinded to treatment assignment (i.e., EIDD-2801 or 
PBO) in P1 and P3, except for personnel at the bioanalytical laboratory, and the unblinded 
pharmacy staff and pharmacokineticist. If unblinding is required to manage subject safety or to 
support dose-escalation decisions, the decision to unblind lies solely with the PI. If possible and 
providing that it does not interfere with or delay any decision in the best interest of the subject, 
the PI will discuss the intended code-break with the Sponsor. 
Dose-Escalation Halting Rules: 
For Group 1 in P1/SAD, sentinel dosing will occur whereby 2 subjects (1 active and 1 PBO) will 
be dosed on 1 day and, providing no safety concerns arise, the remaining 6 subjects will be 
dosed after at least 24 hours. 
The study will be halted if one or more subjects experience a serious adverse event (SAE) that is 
considered to be related to EIDD-2801 or 2 or more subjects in the same group experience 
severe AEs that are considered to be related to EIDD-2801.  
Additionally, if 2 or more subjects experience a reduction of platelets greater than 50% over 
baseline levels or a reduction in lymphocytes (absolute count) to Grade 3/severe levels without 


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an alternate cause, the PI and Sponsor will review the data. If, after review of unblinded data, it 
is determined that these events are probably related to study drug, no further dose escalations 
will occur. 
Dose-escalation will stop if clinically relevant signs or symptoms of similar nature occur in 2 or 
more subjects in a group that, in the opinion of the PI, warrant stopping of dose-escalation. 
Data Monitoring, Safety Reporting and Unblinding: Data will be monitored throughout the 
course of the study by experienced clinical monitors according to the clinical monitoring plan. 
As data will be entered into an electronic case report form (CRF), data will be monitored to 
ensure accuracy as well as adherence to data entry instructions provided in the CRF guidelines. 
Procedures for reporting any SAE will be detailed in the protocol and forms and instructions 
provided to the site. 
Statistical Considerations: A complete description of all statistical analyses and methods will 
be presented in the statistical analysis plan (SAP). The SAP will be reviewed and approved by 
the Sponsor and will be finalized prior to database lock. Plans for PK analyses will be included 
in the SAP. 
Determination of Sample Size: The sample sizes for the P1 and P3 cohorts are typical for a 
Phase 1 first in human (FIH) study. The sample size for the P2 cohort is in accordance with Food 
and Drug Administration (FDA) guidelines for sample size in FE studies. 
Study Populations: 
Safety Population: All subjects who receive at least one dose of study drug. 
Pharmacokinetic Population:  All subjects receiving study drug who comply sufficiently with 
protocol requirements (i.e., no major protocol deviations) and for whom a sufficient number of 
analyzable PK samples have been obtained to permit the determination of the PK profile for 
EIDD-2801/EIDD-1931 and the statistical analysis of the results. Subjects who experience an 
AE of vomiting before 2× the median tmax of the group may be excluded from the PK population. 
Safety Analyses: Statistical methods for the safety analyses will be descriptive in nature. Safety 
data, including AEs, clinical laboratory data, vital signs, ECG parameters, and PEs. All 
appropriate AEs will be graded using the Division of Microbiology and Infectious Diseases 
(DMID) toxicity scale (March 2014). Change from baseline will be included in summary tables 
for laboratory parameters. All laboratory data will be included in the data listings and all test 
values outside the normal range will be flagged. 
Pharmacokinetic Analyses: Plasma PK parameters for each dose level will be calculated from 
the concentrations of EIDD-2801 and EIDD-1931 measured in predose and postdose plasma 
samples. For each dose level, descriptive statistics will be presented. Figures will be created to 
display mean and individual subject EIDD-2801 and EIDD-1931 concentration versus time. 
Urine PK parameters will be calculated whenever possible for each subject based on the urine 
concentrations of EIDD-2801 and EIDD-1931. The following PK parameters will be calculated: 
Plasma PK Parameter 
Description 
AUClast 
The area under the plasma concentration-time curve, from time 0 to the last 
measurable non-zero concentration, as calculated by the linear up/log down 
trapezoidal method (P1 and P2 only). 


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AUC0-inf 
The area under the plasma concentration-time curve from time 0 extrapolated 
to infinity. AUC0-inf is calculated as the sum of AUClast plus the ratio of the 
last measurable plasma concentration to the elimination rate constant (λz) 
(P1, P2, and Day 1 dose of P3). 
Cmax 
Maximum observed concentration. 
tmax 
Time to reach Cmax. If the maximum value occurs at more than one time 
point, tmax is defined as the first time point with this value. 
λz 
Apparent terminal elimination rate constant; represents the fraction of 
medication eliminated per unit time. 
t1/2 
Apparent terminal elimination half-life of medication, calculated as 0.693/λz. 
Vz/F 
Apparent volume of distribution (EIDD-2801 only). 
CL/F 
Apparent oral drug clearance (EIDD-2801 only). 
Ctrough 
Trough concentration (P3 only). 
AUCτ 
The area under the plasma concentration-time curve during a dosing interval 
(P3 only). 
RAAUCτ 
Observed accumulation ratio based on AUCτ (P3 only). 
RACmax 
Observed accumulation ratio based on Cmax (P3 only). 
Urine PK Parameter 
Description 
Ae 
Amount excreted in urine over the sampling interval. 
Fe 
Fraction of drug excreted in the urine over sampling interval. 
CLR 
Renal clearance, CLR = Ae/AUC where both Ae and AUC are determined 
over co-incident time ranges after dosing. 
In P1, dose-proportionality for PK parameters of EIDD-2801 and EIDD-1931 (AUC0-inf, AUClast, 
and Cmax) will be assessed by the power model. The slope and the associated 90% confidence 
interval (CI) based on the power model will be reported. In P3 on Day 6, dose-proportionality for 
PK parameters of EIDD-2801 and EIDD-1931 (AUCτ and Cmax) will be assessed by the power 
model. The slope and associated 90% CI based on the power model will be reported. 
To assess the effect of food on the PK of EIDD-2801 and EIDD-1931, natural log-transformed 
PK parameters from P2 (AUC0-inf, AUClast, and Cmax) will be analyzed using a mixed-effects 
model with fixed effect terms for treatment (with or without food), period, and sequence and 
with subject within sequence as a random effect. Point estimates and their associated 90% CIs 
for the natural log-transformed PK parameters for the difference between EIDD-2801 
administered under fed relative to fasted conditions will be constructed. The point estimates and 
interval estimates will be back transformed to give estimates of the ratio and 90% CI for the 
geometric least squares mean ratio for fed/fasted to assess the effect of food. 
Interim Analyses: No formal interim analyses are planned for this study. Data from P1 cohorts 
may be locked, unblinded, and analyzed prior to conducting P2 and P3. 


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Figure 1: Study Schema 
 
SAD Dose 1 (50 mg QD )
SAD Dose 2 (TBD)
SAD Dose 3 (TBD)
Review 
Safety Data
Review 
Safety Data
Sentinel Grp 1: 2 subjects
24 hr safety review
Grp 2: 6 subjects
PART 1: SAD Cohorts                                                                                                          
Following review of data from Part 1 cohort administered dose selected for Part 2
Sequence 1
Dose: Fed
Sequence 2
Minimum 14-Day Washout
Dose: Fasted
Dose: Fasted
Dose: Fed
PART 2: Food Effect (FE) Cohort                                                                                              
MAD Dose 1 (TBD***)
MAD Dose 2 (TBD***)
MAD Dose 3 (TBD***)
Review 
Safety Data
Review 
Safety Data
PART 3: MAD Cohorts**                                                                                                                    
Abbreviations:
FE: food effect 
SAD: single ascending dose
MAD: multiple ascending dose
** Part 3 may run in parallel with Part 1, providing that the total daily dose to be administered does not exceed 
a dose already shown to be safe and well tolerated in Part 1
***The total daily dose in Part 3 will not exceed a dose shown to be safe and well-tolerated in Part 1


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1. 
INTRODUCTION 
This study is being conducted at sites across the United Kingdom and the United States. 
Country-specific protocol amendments have been prepared; with the exception of regional 
regulatory requirements, the study is consistent across countries and data will be reported in a 
single clinical study report. 
This study is a FIH study designed to assess the safety, tolerability and PK of EIDD-2801 in 
healthy human volunteers. EIDD-2801 is a ribonucleoside analog with broad-spectrum activity 
against many RNA viruses. It is currently being developed by Ridgeback Biotherapeutics as a 
treatment of infections caused by highly pathogenic coronaviruses (CoV), including COVID-19. 
In addition, EIDD-2801 is being developed in parallel as a treatment of uncomplicated influenza 
caused by all subtypes of circulating and emerging (drifted and shifted) influenza A virus (IAV) 
and influenza B virus (IBV), including seasonal, epidemic and pandemic strains.  
1.1. 
Background 
EIDD-2801 is the 5’-isopropyl ester prodrug of the broadly active, direct-acting antiviral 
ribonucleoside analog EIDD-1931. After oral delivery, the prodrug (EIDD-2801) is rapidly 
hydrolyzed by circulating esterases to produce high circulating (plasma) levels of EIDD-1931. In 
cell culture systems, EIDD-1931 has been shown to inhibit replication of multiple viral 
pathogens from multiple RNA virus families including pathogenic CoV (e.g., Middle East 
respiratory syndrome [MERS], severe acute respiratory syndrome [SARS]-CoV and 
SARS-CoV-2), influenza viruses (seasonal, pandemic, and avian subtypes), respiratory syncytial 
virus (RSV), alphaviruses (e.g., Eastern equine encephalitis virus [EEEV], Venezuelan equine 
encephalitis virus [VEEV], and Chikungunya virus [CHKV]), Filoviruses (e.g., Ebola virus 
[EBOV]), and Zika virus (ZIKV). In addition, EIDD-2801 is active against orthopoxviruses 
(tested against vaccinia virus) probably because orthopoxviruses encode their own unique RNA 
polymerase. 
 
 The primary mechanism of action of 
EIDD-2801 is inhibition of viral RNA replication by incorporation of the EIDD-1931 
monophosphate metabolite into the viral RNA genome resulting in induction of viral error 
catastrophe. 
1.2. 
Rationale for Development 
EIDD-2801 is being developed for the treatment of infections caused by RNA viruses, 
specifically for COVID-19 and other CoV infections, influenza, and VEEV. During conduct of 
the FIH study, the Sponsor intends to define a dose that may be active in treating COVID-19 in 
patient studies.  
EIDD-2801 has a unique dual mechanism of action against RNA viruses, including 
SARS-CoV-2 and other CoV infections. The compound acts as a competitive, alternative 
substrate for the virally encoded RNA-dependent RNA-polymerase that upon incorporation into 
nascent chain RNA induces increased mutational frequency in the viral genome. Incorporation 
quickly results in the production of non-viable virus. Additionally, the active metabolite, 


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EIDD-1931-5’-triphosphate (EIDD-2061), may act directly as a chain terminator and arrest 
replication by exerting a next nucleoside effect. It is anticipated that the high barrier to resistance 
observed during in vitro passaging studies will translate to slow, if any, emergence of viral 
resistance. Resilience to viral escape is a distinguishing feature of EIDD-2801. 
Currently, there is no approved antiviral therapeutic for the treatment of COVID-19. An antiviral 
drug is urgently needed. 
 
 
 
 
 
 
1.3. 
Nonclinical Overview 
1.3.1. 
Mechanism of Action 
The mechanism of antiviral activity of EIDD-2801 is “lethal mutagenesis”; a concept that is 
predicated on increasing the viral mutation rate beyond a biologically-tolerable threshold, 
resulting in impairment of viral fitness and leading to viral extinction. 
The specifics of the mechanism are as follows. EIDD-2801 is rapidly taken up by cells and the 
5’-isopropylester cleaved to liberate EIDD-1931, which is in turn phosphorylated to EIDD-2061 
by host kinases (Hernandez-Santiago et al., 2004; Painter et al., 2019). The 5’-triphosphate, 
EIDD-2061, acts as a competitive alternative substrate for virally encoded RNA-directed RNA 
polymerases and EIDD-2061 is incorporated into nascent viral RNA. Owing to the ability of the 
N4-hydroxycytosine base of EIDD-1931 to tautomerize, EIDD-2061 can pair with either 
guanosine or adenosine, and consequently can substitute for either CTP or UTP, respectively 
(Flavell et al., 1974). This results in an accumulation of mutations that increases with each cycle 
of viral replication. The process whereby the mutation rate is increased by exposure to a drug is 
referred to as Viral Decay Acceleration (Mullins et al., 2011) and results in viral ablation. 
Significant work has gone into validating this mechanism of action for EIDD-2801/1931, and it 
has been shown for MERS-CoV, VEEV, and IAV that viruses grown in the presence of 
EIDD-1931 have significantly increased levels of transition mutations (Agostini et al., 2019; 
Toots et al., 2019; Urakova et al., 2018). Multi-log decreases in virus yields were observed after 
treatment with EIDD-1931. Additionally, it was demonstrated for VEEV that the infectivity of 
virions formed in the presence of EIDD-1931 decreases from ~20% to <0.2%, and that the 
infectious virions are significantly Impaired in their replication ability (Urakova et al., 2018). As 
a consequence of this mechanism of action, the generation of drug-resistant escape mutants is 
practically impossible. This same effect was demonstrated for CoV (Agostini et al., 2019) and 
influenza virus (Toots et al., 2019). Furthermore, given the unique mechanism of action, 
EIDD-2801 is expected to be active against viruses resistant to other antiviral agents which have 
a different mechanism of action. The only data generated to date regarding the activity of 
EIDD-1931 against viruses resistant to other nucleoside analogs found that EIDD-1931 was 


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active against CoV resistant to remdesivir in cell culture assays (T. Sheahan et al, preprint 
available at https://www.biorxiv.org/content/10.1101/2020.03.19.997890v1). 
As an alternative or additional mechanism of action, it has been theorized that incorporation of 
EIDD-2061 into viral genomic RNA can change the thermodynamics of RNA secondary 
structure and thus decrease the efficiency of the promoter regions involved in RNA genome 
replication (Stuyver et al., 2003). 
1.3.2. 
In Vitro Pharmacology 
1.3.2.1. 
Antiviral Activity in Tissue Culture and in Human Airway Epithelium 
The ribonucleoside analog EIDD-1931 is the parent of the prodrug EIDD-2801. EIDD-1931 
shows specific antiviral activity in different tissue culture cells and in the differentiated organoid 
model of human airway epithelium (HAE) with a selectivity index (SI) ranging from 21 to >100 
for all influenza viral isolates tested. It is active against IAV (pandemic and seasonal) and IBV 
strains, as well as against highly pathogenic H5N1 and H7N9 strains (Table 1). 
Table 1: 
EIDD-1931 Antiviral Activity Against Influenza A and B Viruses in Tissue 
Culture and Primary Human Bronchial/Tracheal Epithelial Cells 
Virus 
Strain 
Cell line 
EC50* 
(µM) 
CC50 
(µM) 
SI 
Reference 
IAV H1N1 
Ca/07/2009 
MDCK 
1.24 
68 
55 
NIAID Antiviral Testing Program 
IAV H1N1 
WSN/33 
MDCK 
1.1 
299.8 
275 
Yoon et al., 2018 
IAV H1N2 
WSN/33 
primary hBTEC 
5.4 
- 
- 
Yoon et al., 2018 
IAV H2N3 
Perth/16/2009 
MDCK 
0.88 
52 
59 
NIAID Antiviral Testing Program 
IAV H2N3 
Ohio/sw-10-132/2010 
MDCK 
3.2 
299.8 
94 
Yoon et al., 2018 
IAV H5N1 
Duck/MN/1525/81 
MDCK 
1.28 
27 
21 
NIAID Antiviral Testing Program 
IAV H5N1 
Vietnam/1203/2004 
MDCK 
0.14 
299.8 
2100 
Yoon et al., 2018 
IAV H7N9 
Anhui/1/2013 
MDCK 
0.13 
299.8 
2300 
Yoon et al., 2018 
IBV 
Florida/4/2006 
MDCK 
<0.4 
76 
>190 
NIAID Antiviral Testing Program 
IBV 
Brisbane/60/08 
MDCK 
0.006 
299.8 
50000 
Yoon et al., 2018 
IAV H1N1 
Ca/07/2009 
HAE-3D* 
0.08 
50 
625 
Toots et al., 2019 
IAV H1N1 
WSN/33 
HAE-3D* 
0.08 
50 
625 
Toots et al., 2019 
IBV 
Brisbane/60/08 
HAE-3D* 
0.06 
50 
833 
Toots et al., 2019 
* Human Airway Epithelium organoid model. 
EIDD-1931 also showed specific antiviral activity against human SARS-CoV, MERS-CoV 
(Table 2) and SARS-CoV-2 (Figure 2), against togaviruses VEEV, EEEV and CHKV (Table 3) 
 


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EIDD-1931 (NHC) antiviral activity (closed circles) and 
cytotoxicity (open squares) in Vero Cells infected with SARS- 
CoV-2. Vero cells were infected in duplicate with SARS-CoV- 
2 clinical isolate virus at a multiplicity of infection (MOI) of 0.05 
in the presence of a dose response of EIDD-2801 for 48 hours 
after which replication was measured through quantitation of 
cell viability by Cell-Titer-Glo assay. Cytotoxicity was 
measured in similarly treated but uninfected cultures. 
Reproduced from Sheahan et al 2020. 
Table 2: 
EIDD-1931 Antiviral Activity Against SARS and MERS Coronaviruses in Tissue 
Culture and Primary Human Bronchial/Tracheal Epithelial Cells 
Virus 
Strain 
Cell line 
EC50 
(µM) 
CC50 
(µM) 
SI 
Reference 
SARS-CoV-1 Urbani 
Vero76 
<0.4 
144 
>360 NIAID Antiviral Testing Program 
SARS-CoV-1 SARS-CoV-GFP(†) 
HAE-3D(*) 
<1 
>100 
>100 Tech. Report 25.038 
MERS-CoV 
GenBank Ac.No JX869059** DBT-9 
0.56 
>200 
>357 Agostini et al., 2019 
MERS-CoV 
Human ß-CoV C, Novel 2912 Vero E6 
<0.8 
20 
>25 
NIAID Antiviral Testing Program 
* Human Airway Epithelium organoid model; ** cDNA Derived clone 
Figure 2: Inhibition of SARS-CoV-2 by EIDD-1931 
 
Table 3: 
EIDD-1931 Antiviral Activity Against Togaviruses in Tissue Culture 
Virus 
Strain 
Cell line 
EC50 (µM) 
CC50 (µM) 
SI 
Reference 
VEEV 
TC-83 
Vero 
0.43 
>200 
>930 Urakova et al., 2018 
VEEV 
TC-83 
Vero76 
1.92 
32 
17 
NIAID Antiviral Testing Program 
EEEV 
FL93-939 
Vero76 
1.08 
84 
78 
NIAID Antiviral Testing Program 
CHKV 
S27 (VR-64) 
Vero76 
1.8 
96 
53 
NIAID Antiviral Testing Program 


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1.3.2.2. 
Cytotoxicity of EIDD-1931 in Tissue Culture Utilizing Cells from 
Different Organs and Species 
EIDD-1931 was tested for cytotoxicity in human hepatic origin Huh7 and HepG2 cells, in human 
lymphoid CEM, human pancreatic BxPC-3, human prostate cancer PC-3, human muscle A204, 
human lung A549, human epithelial hEp-2, rat heart muscle H9c2, monkey kidney Vero, and 
canine kidney MDCK cell lines (Table 5). The compound exhibits low cytotoxicity in the 
majority of cells tested (half-maximal effective concentration [EC50] values are in the range of 40 
to >100 µM) except in lymphoid origin CEM cells where the compound shows a 7.5 µM EC50 
value (Sticher et al., 2020; Urakova et al., 2018; Yoon et al., 2018). 
Table 5: 
Cytotoxicity (CC50) of EIDD-1931 in Mammalian Cell Lines 
Cell Line 
CEM 
HepG2 
PC-3 
A204 
A549 
BxPC-3 
Huh-7 
H9c-2 
Vero 
hEp-2 
MDCK 
CC50 
(µM) 
7.5 
42.3 
267.1 
84 
46 
48 
165.5 
81 
53 
272.4 
299.8 
Sources: Sticher et al., 2020, Yoon et al., 2018 
EIDD-2801 typically showed 2-4× lower activity and cytotoxicity than EIDD-1931 due to 
slightly slower uptake and anabolism in tissue culture. 
1.3.2.3. 
Assessment of Mitochondrial Toxicity 
Since EIDD-1931 is a nucleoside analog, additional investigations were performed to analyze 
whether observed cytotoxicity of EIDD-1931 is caused by mitochondrial toxicity. It was 
demonstrated that the prolonged treatment (14 days) with the compound does not result in 
selective killing of mitochondria or in mitochondrial dysfunction in CEM and HepG2 cells 
(Sticher et al., 2020). 
1.3.3. 
In Vivo Pharmacology 
The prodrug EIDD-2801 or its parent EIDD-1931 have been tested in animal models of RNA 
viral infection. An overview of results from the animal studies in indications to be pursued are 
described below. Additional detail is provided in the Investigator’s Brochure (IB). 
1.3.3.1. 
Coronavirus: SARS-CoV and MERS-CoV 
In mouse models of SARS and MERS infection and disease, coronaviral disease was assessed by 
changes in body weight, measured daily, and lung hemorrhage, assessed in the large left lobe of 
the lung following sacrifice on Day 5 (SARS-CoV) or Day 6 (MERS-CoV). To assess 
production of infectious virions, virus was isolated from the lower left lobe of the lung following 
sacrifice on Day 5 (SARS-CoV) or Day 6 (MERS-CoV) and quantified using a plaque assay. 
The results demonstrated that, in mice infected with either SARS- or MERS-CoV, both 
prophylactic and therapeutic treatment with EIDD-2801 resulted in a reduction in virus 
replication, improvements in pulmonary function, and improvements in maintaining body weight 


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(i.e., reduced body weight loss). While EIDD-2801 doses of 50, 150 and 500 mg/kg BID were 
assessed in the CoV mouse experiments, 500 mg/kg BID yielded the most consistent therapeutic 
effect. 
A prophylactic, dose-escalation study was conducted in C57BL/6 mice infected with 
mouse-adapted SARS-CoV (SARS-MA15). Prophylactic oral treatment with EIDD-2801 was 
initiated 2 hours before intranasal infection and continued every 12 hours thereafter through the 
end of the study (Day 5; Figure 3). 
In mice treated BID with EIDD-2801, body weight loss observed with vehicle treatment was 
diminished in the 50 mg/kg treatment group, beginning on Day 3 post-infection. No body weight 
loss was seen in the 150 and 500 mg/kg treatment groups (Figure 3, Panel A). Lung hemorrhage 
was also significantly reduced on Day 5 post-infection, following treatment with 500 mg/kg 
EIDD-2801 (Figure 3, Panel B). When compared to vehicle control, a dose-dependent reduction 
in SARS-CoV lung titers at Day 5 was seen across all 3 treatment groups (Figure 3, Panel C) 
with significant differences among the vehicle, 150 mg/kg and 500 mg/kg groups. Thus, 
prophylactic treatment with EIDD-2801 resulted in a robust antiviral effect that was able to 
prevent SARS-CoV replication and disease. 
Figure 3: EIDD-2801 Prophylactic Treatment of SARS-CoV Infected Mice 
 
The antiviral activity of EIDD-2801 against SARS-CoV was compared when treatment was 
initiated at -2 hours (pre-infection) and 12, 24, or 48 hours post-infection. After initiation of 
treatment, all groups were dosed every 12 hours for the duration of the study (Figure 4). For 
SARS-challenged mice, initiating treatment at 12 hours post-infection significantly prevented 
body weight loss beginning on Day 2, a result similar to that seen when dosing prophylactically 


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(i.e., beginning at 2 hours pre-infection). Initiation of treatment with EIDD-2801 at 24 hours 
post-infection also significantly reduced body weight loss on Days 3 through5 post-infection. 
When EIDD-2801 treatment was initiated at 48 hours post-infection, body weight loss was only 
statistically different from vehicle on Day 4 post-infection (Figure 4, Panel A). Significant 
reductions in lung hemorrhage were seen when EIDD-2801 treatment was initiated before 
(-2 hours) and up to 24 hours after infection; a result that mirrored body weight loss data 
(Figure 4, Panel B). All mice treated with EIDD-2801 had significantly reduced viral loads in the 
lungs, even in the group where treatment was initiated 48-hour post-infection (Figure 4, 
Panel C). Pulmonary function, measured via whole body plethysmography, was assessed using 
the PenH metric which is a surrogate marker for bronchoconstriction or pulmonary obstruction. 
The administration of EIDD-2801 prior to infection (-2 hours) and at 12 hour post-infection 
completely abrogated the loss of pulmonary function observed in vehicle-treated animals 
(Figure 4, Panel D). Improved pulmonary function was also seen in the group where treatment 
was initiated 24 hours after virus challenge. 
Figure 4: EIDD-2801 Treatment of SARS-CoV Infected Mice 
 
EIDD-2801 was also tested to determine if it is active in vivo against MERS-CoV as described 
by Sheahan et. al (draft manuscript). The murine ortholog of the MERS-CoV receptor, dipeptidyl 
peptidase 4 (DPP4), does not support viral binding and entry. Thus, all in vivo studies described 
below were performed in genetically modified hDPP4 mice permissive for MERS infection. 
Prophylactic treatment starting at 2 hours before viral challenge with either 50, 150, or 


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500 mg/kg EIDD-2801 prevented body weight loss on Days 2 through 6 post-infection (Figure 5, 
Panel A), prevented lung hemorrhage measured on Day 6 (Figure 5, Panel B), and reduced virus 
lung titer on Day 6 to the limit of detection (Figure 5, Panel C). 
Figure 5: EIDD-2801 Prophylactic Treatment of MERS-CoV Infected Mice 
 
The effect of EIDD-2801 treatment on MERS-CoV infected mice is shown in Figure 6. When 
EIDD-2801 treatment was initiated 12 hours post-infection, there was no loss in body weight 
from Days 2 through 6 post-infection (Figure 6, Panel A) and no evidence of lung hemorrhage 
on Day 6 post-infection (Figure 6, Panel B). However, protection was not observed in groups 
where treatment was initiated either 24- or 48-hours post-infection. Conversely, virus lung titer 
on Day 6 post-infection was significantly reduced to the limit of detection in all treatment 
groups, regardless of the time treatment began (Figure 6, Panel C). To gauge the effect of the 
timing of EIDD-2801 treatment initiation on physiologic measures of lung disease, pulmonary 
function was assessed by whole body plethysmography. As expected, a loss of pulmonary 
function, as determined by measuring the PenH metric, was observed in vehicle-treated animals 
infected with MERS-CoV beginning on Day 2 post-infection (Figure 6, Panel D). Mirroring the 
body weight loss data, normal pulmonary function was observed in groups where treatment was 
initiated prior to or at 12 hours post-infection (Figure 6, Panel D). 


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Figure 6: EIDD-2801 Treatment of MERS-CoV Infected Mice 
 
1.3.3.2. 
Influenza Virus 
EIDD-2801 was tested in a ferret model of influenza virus infection and disease. Ferrets 
recapitulate hallmarks of human influenza infection, providing a clinically relevant animal model 
to investigate therapeutic intervention. Therapeutic oral dosing of influenza virus-infected ferrets 
reduced shed levels of pandemic and seasonal IAV by multiple orders of magnitude, and 
alleviated fever and inflammation while improving airway epithelium histopathology. 
Post-exposure prophylactic dosing was sterilizing (Toots et al., 2019). 
Ferrets infected with pandemic IAV and treated with EIDD-2801 at a dose of 7 mg/kg 
demonstrated significantly less viral shedding and inflammatory cellular infiltrates in nasal 
lavages, but mounted a normal humoral antiviral response (Toots et al., 2019). 
When examining the effect of delayed dosing, Toots et. al. (2019) demonstrated that treatment 
with 20 mg/kg of EIDD-2801 initiated 24 hours after challenge with IAV (H1N1) resulted in a 
rapid decrease in both shed virus and fever relative to control, with fever returning to baseline at 
24 hours. When oseltamivir (20 mg/kg) was dosed prophylactically as a positive control, a 
modest suppression of fever was observed; however, there was no reduction in shed virus titer. 


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1.3.3.3. 
Venezuelan Equine Encephalitis Virus 
Treatment with EIDD-1931 was evaluated in a mouse model of lethal VEEV infections. To be 
truly effective as a therapeutic agent for VEEV infection, a drug must penetrate the blood brain 
barrier and arrest virus replication in the brain. High plasma levels of EIDD-1931 are rapidly 
achieved in mice after oral dosing. Once in the plasma, EIDD-1931 is efficiently distributed into 
organs important in the pathology of VEEV infection, including the brain, where it is rapidly 
converted to its active 5’-triphosphate (EIDD-2061). EIDD-1931 showed a good safety profile in 
mice after 7 days of dosing with up to 1,000 mg/kg/day. In mouse model studies of VEEV 
infection, EIDD-1931 was 90-100% effective in protecting mice against lethal intranasal 
infection when therapeutic treatment was started as late as 24 hours post-infection, and partial 
protection was achieved when treatment was delayed for 48 hours post-infection (Painter et al., 
2019). 
 
 
 
 
 
 
 
 
 
1.4. 
Safety and Secondary Pharmacology 
The standard battery of safety pharmacology studies including studies assessing the 
cardiovascular, respiratory and central nervous systems have been conducted. The studies are 
discussed in the IB; results indicated that there were no adverse pharmacologic effects of 
EIDD-2801 on the cardiovascular, respiratory or central nervous systems. 
1.5. 
Nonclinical Pharmacokinetics and Metabolism 
1.5.1. 
Overview 
The uptake, metabolism and protein binding of EIDD-2801 and EIDD-1931 have been studied in 
plasma, microsomes, and non-hepatic cells from several species as outlined below. The PK and 
tissue distribution of prodrug EIDD-2801 and its active parent EIDD-1931 have been studied 
extensively in rats, dogs and ferrets. Key results from these studies are presented below; 
additional detail can be found in the IB. 
1.5.2. 
Absorption 
EIDD-1931 is parent of the prodrug EIDD-2801. The appearance of EIDD-1931 is dependent on 
the absorption of EIDD-2801 and the rate of its conversion to EIDD-1931. 


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EIDD-2801 PK studies have been completed in dog, rat, mouse, ferret, and monkey. EIDD-2801 
was efficiently absorbed and rapidly converted to EIDD-1931 in each species. The tmax for 
EIDD-2801 (not observed in rodents) occurred at 0.5-1 hours, while the tmax for EIDD-1931 
occurred at 1-2 hours. 
1.5.3. 
Distribution 
 
 
 
 
 
 
 
 
 
1.5.3.2. 
Tissue Distribution Studies 
EIDD-2801 is rapidly absorbed in the gut and converted to EIDD-1931 reaching Cmax in 
1-3 hours in mice, rats, ferrets, dogs and monkeys. EIDD-1931 is then widely distributed to 
tissues including lungs and brain, where it is rapidly taken up into cells and converted to 
EIDD-2061. Figure 7 shows the concentration of EIDD-1931 and EIDD-2061 in ferret brain and 
lung following single doses of 20 (Panels A and B) and 128 (Panels C and D) mg/kg. 


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Figure 7: Tissue Distribution of EIDD-1931 and EIDD-2061 in Ferret Brain and Lung 
 
1.5.4. 
Metabolism 
1.5.4.1. 
Metabolic Stability of EIDD-1931 and EIDD-2801 
EIDD-2801 was designed to be converted to EIDD-1931 by esterases in plasma or in cells. 
Stability has been assessed in plasma and liver microsomes from mouse, rat, dog, monkey and 
humans. The stability of EIDD-2801 in mouse, rat and monkey plasma is relatively short 
(≤0.4 hours) while the stability is longer in human and dog plasma (1-3 hours). EIDD-2801 
stability in mouse, rat, dog and monkey liver microsomes is very short, ranging from 0.02 to 
0.08 hours while the stability in human liver microsomes is 1.2 hours (Table 6). 


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Table 6: 
Metabolic Stability of EIDD-2801 in Plasma and Liver Microsomes 
Species 
Plasma stability 
LM stability 
t1/2 (h) 
t1/2 (h) 
Mouse 
0.017 
0.033 
Rat 
0.033 
0.017 
Dog 
3.2 
0.083 
Monkey 
0.40 
0.017 
Human 
1.05 
1.22 
EIDD-2801 is stable in simulated gastric and intestinal fluids (Table 7). 
Table 7: 
Metabolic Stability of EIDD-2801 in Simulated Gastric and Intestinal Fluids and 
in Buffered Saline with Fetal Bovine Serum 
Matrix 
t1/2 (hr) 
Simulated Gastric Fluid 
>24 
Simulated Intestinal Fluid 
>24 
Phosphate Buffered Saline plus 10% Fetal Bovine Serum* 
>24 
EIDD-1931 was found to be stable when incubated with all tested plasmas, whole blood, liver 
microsomes and liver S9 extracts and intestinal microsomes (Table 8). 
Table 8: 
Metabolic Stability of EIDD-1931 in Plasma, Whole Blood and Liver and 
Intestinal Microsomes 
Medium 
Plasma 
Whole Blood 
Liver Microsomes 
Liver S9 Stability 
Intestinal Microsomes 
Species 
t1/2 (h) 
t1/2 (h) 
t1/2 (h) 
t1/2 (h) 
t1/2 (h) 
Mouse 
 
>24 
>24 
 
>24 
Rat 
17 
 
>24 
>24 
 
Dog 
>24 
 
 
>24 
 
Monkey 
6.5 
>24 
>24 
>24 
>24 
Human 
10 
7 
>24 
20 
>24 
1.5.4.2. 
Uptake and Anabolism of EIDD-1931 in Tissue Culture and Primary 
Cells 
EIDD-1931 is efficiently taken up by tissue culture cells and converted to its pharmacologically 
active metabolite EIDD-2061 (EIDD-1931-5’-triphosphate). Intracellular EIDD-2061 
accumulates dose-dependently, with Cmax levels ~200-2000 pmol/106 cells (at 10-20 µM dose) in 
different cell lines. It reaches high levels relatively quickly, typically within 1-3 hours, though 
the tmax values vary widely between 1 and 24 hours depending on the cell line and dose 
concentration tested. Detailed data on the uptake and anabolism of EIDD-2801 is presented in 
the IB. 


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EIDD-2801 is also taken up by tissue culture cells and is converted to EIDD-1931 and then to 
EIDD-2061, but the process is slightly delayed compared to dosing with EIDD-1931. 
EIDD-1931 is also taken up and metabolized to EIDD-2061 by primary cells. EIDD-2061 is 
accumulated in all primary cells tested except in mouse primary hepatocytes where EIDD-1931 
is apparently extensively metabolized to cytidine and uridine which, in turn, quickly metabolize 
into CTP and UTP. The quick metabolism of EIDD-1931 consequently results in low levels of 
EIDD-2061 in mouse hepatocytes. The intracellular stability (t1/2) of EIDD-2061 is 4-5 hours in 
human astrocytes and hBTEC and is significantly shorter (0.2-1.1 hours) in primary hepatocytes. 
1.5.5. 
Excretion 
Currently, there is no data on excretion of EIDD-2801 or EIDD-1931. Excretion will be 
measured in urine during this study. 
1.5.6. 
Pharmacokinetic Drug Interactions 
1.5.6.1. 
Cytochrome P450 (CYP) Inhibition 
The purpose of this non-GLP in vitro study was to determine the time-dependent inhibitory 
potential of EIDD-2801 and EIDD-1931 on human cytochromes P450 (CYP) 1A2, 2B6, 2C8, 
2C9, 2C19, 2D6, and 3A4 (midazolam and testosterone substrates) enzyme activity, using pooled 
human liver microsomes in an half-maximal inhibitory concentration (IC50) shift assay. 
Neither EIDD-2801 nor EIDD-1931 demonstrated inhibition greater than 31.4% for any of the 
CYP isozymes tested nor could the data for each assay condition be curve fit to determine 
time-dependent inhibition by these compounds. Full dose-response curves were not achieved at 
concentrations ranging from 0.00545 to 50.0 µM indicating EIDD-2801 and EIDD-1931 have no 
CYP inhibition potential at concentrations ranging from 0.00545 to 50.0 µM. Assay performance 
was acceptable based on the results for the positive control inhibitors. 
1.5.6.2. 
CYP Induction 
An assay was performed to determine the induction potential of EIDD-2801 on human CYP 
isoenzyme (1A2, 2B6, and 3A4) activity using 3 single-donor lots of inducible, cryopreserved 
human hepatocytes. Both enzyme activity and mRNA results demonstrated that EIDD-2801 did 
not show induction for any of the CYP isozymes. 
 
 
 
 
 
 
 


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1.7. 
Potential Risks and Benefits 
1.7.1. 
Potential Benefits 
As this is a FIH study in healthy volunteers, there is no direct benefit to subjects enrolled in the 
study. However, given the current pandemic situation and in vitro antiviral activity of 
EIDD-2801 against SARS-CoV-2, and the activity against several other viruses of public health 
concern, it is possible that participants may benefit from future availability of the drug. 
1.7.2. 
Potential Risks 
EIDD-2801 has never been administered to humans; therefore, the risks from EIDD-2801 to 
subjects participating in this trial are unknown. Although toxicology studies have been done, 
unexpected AEs may occur.
 
 
 
. Subjects will also be monitored for other end-organ 
effects through a range of safety assessments. 


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2. 
OBJECTIVES 
2.1. 
Study Objectives 
2.1.1. 
Primary Objectives 
The primary objective of Part 1 of the study is to determine the safety and tolerability of single 
ascending doses of EIDD-2801. 
The primary objective of Part 2 of the study is to assess the effect of food on the PK on 
EIDD-2801 and EIDD-1931 following a single oral dose. 
The primary objective of Part 3 of the study is to determine the safety and tolerability of multiple 
ascending doses of EIDD-2801. 
2.1.2. 
Secondary Objectives 
The secondary objectives of Part 1 and Part 3 of the study is to define the PK of EIDD-2801 and 
EIDD-1931 in plasma and urine following single and multiple doses administered to healthy 
volunteers. 
The secondary objective of Part 2 of the study is to determine the safety and tolerability of single 
doses of EIDD-2801. 
2.1.3. 
Exploratory Objectives 
The exploratory objectives of Parts 1 and 3 are to collect data to assess the relationship between 
EIDD-2801/EIDD-1931 concentrations and QTc. 
2.2. 
Study Outcome Measures 
2.2.1. 
Primary Outcome Measures 
The primary outcome measures for Parts 1 and 3 of are results of safety evaluations including 
safety laboratory assessments, PEs, ECGs, vital signs, and AEs. 
The primary outcome measures for Part 2 of the study are plasma PK parameters including Cmax, 
tmax, t1/2, CL/F, λz, Vz/F, AUC0-inf and AUClast as appropriate. 
2.2.2. 
Secondary Outcome Measures 
The secondary outcome measures are as follows: 
 Single-dose plasma PK parameters, including Cmax, tmax, t1/2, CL/F, λz, Vz/F, 
AUC0-inf and AUClast as appropriate (Part 1) 
 Multiple-dose plasma PK parameters, including Ctrough, Cmax, tmax, t1/2, CL/F, λz, 


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Vz/F, AUCτ, AUC0-inf (Day 1 dose only), RAAUCτ and RACmax, as appropriate (Part 3) 
 Urinary excretion of EIDD-2801 and EIDD-1931 following single- and 
multiple-dose administration (Parts 1 and 3). 
 Results of safety evaluations including safety laboratory assessments, PEs, ECGs, 
vital signs, and AEs (Part 2). 


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3. 
STUDY DESIGN 
3.1. 
Overview 
EIDD-2801-1001-UK is a Phase 1, randomized, double-blind, placebo-controlled, FIH, SAD, 
and MAD study of the safety, tolerability and PK of EIDD-2801 and EIDD-1931 following oral 
administration of single and multiple doses of EIDD-2801 to healthy volunteers. In addition, for 
a minimum of one cohort, the effect of food on the single-dose EIDD-2801 and EIDD-1931 PK 
parameters will be assessed in subjects taking open-label EIDD-2801. The overall objective of 
the study is to identify a starting dose for future safety and therapeutic intervention trials. 
The study is composed of 3 parts; P1 is the SAD study, P2 is the FE cohort study, and P3 is the 
MAD study.  
This study will be conducted at 1 site in the United Kingdom and up to 3 sites in the United 
States. 
3.1.1. 
Part 1 (Single Ascending Dose) 
A single oral dose of EIDD-2801 or PBO will be administered to subjects. Subjects will be 
randomized in a 3:1 ratio to receive either EIDD-2801 or PBO. 
Following dosing on Day 1, subjects will remain in the clinic through completion of study 
assessments on Day 4, returning to the clinic on Day 9 for study assessments, and Day 15 for the 
EOS visit. 
The first cohort will be divided into 2 groups. The first group, a sentinel group, will include 
2 subjects. On Day 1, one subject in the sentinel group will be administered PBO and one will be 
administered EIDD-2801. Analysis of the safety results for the sentinel group will be reviewed 
24 hours postdose. If no halting criteria (Section 9) have been met, the remainder of the subjects 
in Cohort 1 (the second group) will be dosed. There will be no sentinel groups for the remaining 
cohorts. 
After completion of each dosing cohort, safety and tolerability data will be reviewed to 
determine if any of the halting rules have been met. If not, then the subsequent cohort may be 
dosed following review of the 72-hour safety data. As PK data become available, these data may 
be used for dose-escalation decisions. 
The proposed dose-escalation scheme is shown in Figure 1, however, planned dose escalations 
will be determined based on ongoing review of the safety, tolerability, and available PK data. 
The starting dose in the first SAD cohort will be 50 mg. Dose levels will not increase by more 
than 3-fold for predicted nonpharmacologically active dose levels and by 2-fold for predicted 
pharmacologically active dose levels. The highest total daily dose to be studied under this 
protocol will not exceed 1600 mg (Section 9.2). 


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Three cohorts are initially planned for P1; however, up to an additional 7 cohorts may be 
enrolled. 
3.1.2. 
Part 2 (Food-Effect) 
Two single oral doses of EIDD-2801 will be administered to subjects, in an open-label manner. 
The dose for the P2/FE cohort is planned to be 100 mg but may be adjusted based on safety, 
tolerability, and/or PK data from P1. The dose assessed in the P2 cohort will have been given 
previously to subjects in a P1 cohort successfully (i.e., no halting rules were met following 
dosing).  
Subjects will be randomized to a treatment sequence; i.e., to receive drug in the fed then fasted 
state (Sequence 1) versus fasted then fed state (Sequence 2; Figure 1). Half of the subjects in the 
cohort will be randomized to Sequence 1 and the other half will be randomized to Sequence 2.  
Following dosing on Day 1, subjects will remain in the clinic through completion of study 
assessments on Day 4, returning to the clinic on Day 9 for study assessments, and Day 14 to 
begin the second dosing sequence on Day 15. Subjects will then be discharged from the clinic on 
Day 18, returning to the clinic on Day 23 for study assessments, and Day 30 for the EOS visit. 
There will be a 14-day (minimum) washout period between doses. 
One cohort of 10 subjects is planned for P2. However, if PK results obtained are equivocal, 
additional subjects may be enrolled into the P2/FE cohort at the previously tested dose or an 
additional P2/FE cohort may be added at a different dose. 
3.1.3. 
Part 3 (Multiple Ascending Dose) 
Subjects in P3 will be randomized in a 3:1 ratio to receive either EIDD-2801 or PBO. 
Twice-daily dosing will be administered to subjects on Day 1 through Day 5, inclusive, and a 
final dose will be administered on the morning of Day 6 for collection of steady-state PK 
samples during waking hours. Depending on ongoing review of the safety, tolerability, and PK 
data, the number of days of dosing may be reduced and the dosing frequency may be changed; 
the dosing frequency will be no less than once-daily or no greater than three-times daily.  
The proposed dose-escalation scheme is shown in Figure 1. The total daily dose will not exceed 
a dose shown to be safe and well-tolerated in P1. Doses in P3 may be administered in the fed 
state, following review of the PK data obtained from P2. Part 3 may run in parallel with P1, 
providing that the total daily dose to be administered does not exceed a dose already shown to be 
safe and well-tolerated in P1. 
Subjects will remain domiciled at the site during the dosing period and until Day 9, returning to 
the clinic on Day 14 for completion of study assessments, and Day 20 for the EOS visit. If the 
number of days of dosing are reduced, the timepoints for subsequent assessments and the period 
for which subjects are domiciled at the clinic will similarly be changed (subjects will be 
domiciled for 3 days post final dose). 


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Three cohorts are initially planned for P3; however, up to an additional 6 cohorts may be 
enrolled, or the number of cohorts may be reduced if the study objectives are met. Dose levels in 
P3 may be repeated for collection of PBMCs, providing that the dose level did not meet the 
dose-escalation halting criteria. 
Additional parts may be added to this study, including a SAD part in elderly healthy 
subjects and a study of the safety, tolerability, and PK in Japanese subjects. These 
additional parts are not described in this protocol, but may be added via a protocol 
amendment. 
3.2. 
Rationale and Justification 
3.2.1. 
Justification of Design 
The FIH study is a typical dose-escalation study designed to provide the maximum amount of 
data in the minimum number of subjects. The cohort size in P1 and P3 is planned to be 8 subjects 
(6 active:2 PBO). This number of subjects allows for a sufficient PK analysis, considered to be 
important because dose extrapolation from efficacious animal models to humans will be based 
on exposure. The duration of participation for each subject following dosing well exceeds 5 drug 
half-lives (up to 9.1 hours in dogs; 5 hours in ferrets) 
 
The FE cohort is considered to be important to maximize exposure 
based on fed vs. fasted condition and obtaining this information early in Phase 1 will minimize 
study drug dose in all future studies. This design follows the FDA guidance document on 
assessing FE in clinical studies. 
3.2.2. 
Justification of Starting Dose 
 
 
 
The FDA guidance document 
(“Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult 
Healthy Volunteers”) provides guidance for when a safety factor smaller than 10 may be used to 
calculate the starting dose: 
 A smaller safety factor might also be used when toxicities produced by the 
therapeutic are easily monitored, reversible, predictable, and exhibit a 
moderate-to-shallow dose-response relationship with toxicities that are consistent 
across the tested species (both qualitatively and with respect to appropriately scaled 
dose and exposure). 
 A safety factor smaller than 10 could be justified when the NOAEL was determined 
based on toxicity studies of longer duration compared to the proposed clinical 
schedule in healthy volunteers. In this case, a greater margin of safety should be built 


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into the NOAEL, as it was associated with a longer duration of exposure than that 
proposed in the clinical setting. This assumes that toxicities are cumulative, are not 
associated with acute peaks in therapeutic concentration (e.g., hypotension), and did 
not occur early in the repeat dose study. 
EIDD-2801 satisfies both of these criteria as follows: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
Importantly, given the activity of EIDD-2801 versus SARS-CoV-2 (cause of COVID-19), the 
Sponsor thinks it is most prudent to start with a dose that is predicted to be a safe starting dose 
and is also as close as possible to a potential therapeutic dose that would allow the Sponsor to 
move into COVID-19 patients as safely and expeditiously as possible. Based on modeling to 
animal data, a dose of 100 mg BID is projected to be an active dose in humans. 
3.2.3. 
Justification of Study Population 
Healthy volunteers are considered to be the appropriate population for conduct of the FIH study. 
Healthy volunteers without confounding medical conditions that may obscure the interpretation 
of AEs or affect absorption, distribution, metabolism and excretion of study drug will provide the 
most valuable data regarding the tolerability, safety, and plasma exposures observed and 
expected following single doses and multiple doses up to 10 days. EIDD-2801 is intended for 
eventual study in patients with potential CoV-2 infection as defined by the Centers for Disease 
Control and Prevention (CDC) in whom a range of AEs are expected based on the disease under 
study. Understanding the safety and PK profile in a normal population will better inform the use 
of EIDD-2801 in disease settings where complications are frequent, and AEs will need to be 
interpreted in context.  


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4. 
STUDY POPULATION 
This study will enroll healthy volunteers; 8 subjects will be enrolled into each SAD and MAD 
cohort in P1 and P3, and 10 subjects will be enrolled into the FE cohort in P2. 
The site is strongly encouraged to ensure that women are represented in each cohort. 
4.1. 
Subject Inclusion Criteria 
Subjects who meet all of the criteria at Screening will be eligible for study participation 
1. Male or female between the ages of 18 and 60, inclusive. 
2. Female subjects must be of nonchildbearing potential. Nonchildbearing potential is 
defined as women who: 
 are physiologically incapable of becoming pregnant including those who are 
surgically sterile, via hysterectomy, bilateral salpingectomy, and/or bilateral 
oophorectomy by reported medical history and/or medical records. Surgical 
sterilization to have occurred a minimum of 6 weeks, or at the PI’s (or 
designee’s) discretion, prior to Screening. 
 are post-menopausal (at least 45 years of age with amenorrhea for 12 months 
without an alternative medical reason with confirmatory FSH levels of 
≥40 mIU/mL. The amenorrhea should not be induced by a medical condition 
such as anorexia nervosa, hypothyroid disease or polycystic ovarian disease, 
or by extreme exercise. It should not be due to concomitant medications that 
may have induced the amenorrhea such as oral contraceptives, hormones, 
gonadotropin-releasing hormones, anti-estrogens, or selective estrogen 
receptor modulators). 
3. Male participants must agree to the use of effective contraception for study duration, 
i.e., from Check-in until 90 days after the EOS visit. 
4. Is in generally good health as determined by medical history, PEs (at Screening 
and/or Check-in), vital signs, and other screening procedures. 
5. Has a BMI of 18 to 30 kg/m2. 
6. Is willing and able to comply with all study procedures including providing informed 
consent. 


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4.2. 
Subject Exclusion Criteria 
Subjects who meet any of the following criteria at Screening (unless otherwise stated) will not be 
eligible for participation: 
1. Females who are pregnant, planning to become pregnant, or breastfeeding. 
2. Has a clinically relevant acute or chronic medical condition or disease of the 
cardiovascular, GI, hepatic, renal, endocrine, pulmonary, neurologic, or dermatologic 
systems as determined by the PI (or designee). 
3. Has any current or historical disease or disorder of the hematological system or 
significant liver disease or family history of bleeding/platelet disorders. 
4. Has a history of cancer (other than basal cell or squamous cell cancer of the skin), 
rheumatologic disease or blood dyscrasias. 
5. Has a history of GI surgery or other condition that may interfere with absorption of 
study drug, in the option of the PI (or designee). 
6. Has a history of febrile illness within the 14 days prior to the first dose of study drug. 
7. Has a positive alcohol or drug screen at Screening or the Day -1 visit or has a history 
of alcohol or drug abuse within the past 5 years. 
8. Currently uses tobacco, nicotine or tobacco products or e-cigarettes or stopped using 
tobacco products within the past 3 months and/or has a positive cotinine test at 
Screening or Check-in. 
9. Has any abnormal laboratory value of Grade 2 or higher, which is considered to be 
clinically significant by the PI (or designee). 
10. Has a total white cell count or absolute lymphocyte count outside the normal range, 
or hemoglobin or platelet levels below the lower limit of normal, at Screening or 
Day -1. 
11. Has values above the upper limit of normal for the following laboratory analytes: 
ALT/SGPT, alkaline phosphatase (serum), AST/SGOT, at Screening or Day -1.  
12. Positive test result for HIV, HBV, or HCV. 
13. Has an autoimmune disease, is immunosuppressed or is in any way 
immunocompromised. 
14. Has any of the following: 
 QTcF >450 ms confirmed by repeat measurement 


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 QRS duration >110 ms confirmed by repeat measurement 
 PR interval >220 ms confirmed by repeat measurements 
 findings which would make QTc measurements difficult or QTc data 
uninterpretable 
 history of additional risk factors for torsades de pointes (e.g., heart failure, 
hypokalemia, family history of long QT syndrome). 
15. Except as noted, has used prescription drugs (other than hormone replacement 
therapy) within 14 days prior to the first dose of study drug unless, in the opinion of 
the PI (or designee), the drug will not interfere with study assessments. The 
following prescription drugs will be allowed: 
 Statins: Subjects who have been on a stable dose of statins for a minimum of 
6 months and who have normal creatine kinase at Screening. 
 Antihypertensives: Subjects who have been on a stable dose of 
antihypertensives for a minimum of 6 months and have controlled blood 
pressure and no active heart disease. 
16. Has received an experimental agent (vaccine, drug, biologic, device, blood product 
or medication) within 3 months prior to the first dose of study drug and agrees not to 
receive another experimental agent during the duration of this trial. 
17. Has donated blood within 30 days, plasma within 2 weeks, or platelets within 6 
weeks prior to Screening or refuses to agree to not donate blood until 3 months after 
the EOS visit. 
18. Uses OTC medications or nutritional supplements (including, e.g., gingko biloba, 
aspirin at any dose, and NSAIDs) on a routine/scheduled basis and/or is unwilling to 
abstain from such use for the duration of the study. 
19. Is unwilling to abstain from quinine containing products including quinine water, 
tonic water, bitter lemon, jello shots, any quinine preparations or Cinchona tree bark 
preparations (e.g., herbal medications containing Cinchona tree bark). 
20. Has any condition that would, in the opinion of the PI (or designee), put the subject 
at increased risk for participation in a clinical trial or confinement in a clinical 
research unit. 


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5. 
STUDY MEDICATION, RANDOMIZATION AND DOSE 
ADMINISTRATION 
5.1. 
Study Drug Description 
EIDD-2801 and matching PBO will be supplied 
 
 
 
 
 
 
 
 
 
 
 
 
5.1.1. 
Acquisition, Formulation, Packaging and Labeling 
 
 
 
 
All study drug will be labeled according to the regulatory requirements for investigational 
product. 
5.1.2. 
Product Storage and Stability 
Study drug should be stored at controlled room temperature defined as 
 
 If excursions occur which 
are outside of this range, the pharmacy staff should contact Sponsor to determine the course of 
action. Additional stability data may be available which would allow continued use of the study 
drug, or study drug may need to be replaced. 
5.2. 
Randomization 
Unmasked study drug (EIDD-2801 and matching PBO) will be supplied to the study site 
pharmacy. The pharmacy staff will be unmasked with regards to treatment assignment. A 
randomization list will be provided to the pharmacy staff who will use that list to dispense 
masked study drug for administration to each study participant. In P1 and P3, 6 subjects will 


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receive EIDD-2801 while 2 subjects will be randomized to PBO. In P2, all 10 subjects in the FE 
cohort will receive EIDD-2801. The pharmacy staff will maintain the security of the 
randomization list ensuring that no study personnel outside of the pharmacy have access to 
identify treatment assignment. In the case that it becomes necessary to know a subject’s 
treatment assignment, unmasking procedures will be followed as discussed in Section 8.4. 
5.3. 
Dosage, Preparation and Administration of Study Drug 
Detailed instructions for extemporaneous compounding (as necessary), dispensing and 
administering study drug can be found in the pharmacy manual. 
 
 
 
 
 
 
 
 
 
 
 
 
5.4. 
Drug Accountability 
The site pharmacy must maintain records of receipt and disposition of all study drug supplied to 
the site by the Sponsor. The records must be maintained according to site standard operating 
procedures (SOPs) and should include at a minimum, receipt date, lot or batch number, amount 
and formulation received, 
 date, time and amount 
dispensed, subject identifier for each aliquot of study drug dispensed. In addition, the clinic staff 
must ensure that the time of dosing is identified for each subject. 
Monitors must verify drug accountability/dispensing records during the monitoring visit. 
Unused study drug must be disposed of according to the procedures described in the pharmacy 
manual. 
5.5. 
Concomitant Medication/Treatments 
 
 In this FIH study, limited types of concomitant 
medications are permitted. Adjustment of routine medications taken by subjects should be 
avoided during study participation except when subject safety could be affected by lack of 


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adjustment. There are no restrictions on treatment medications prescribed by the PI (or designee) 
to be used for AEs that occur during study participation. For additional restrictions, see 
Section 6.1.2. 


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6. 
STUDY CONDUCT AND VISIT SCHEDULE 
All study assessments will be conducted according to the Time and Events Schedule. 
6.1. 
Study Conduct 
6.1.1. 
Study Windows and Rounding Principles 
The time schedule described in the protocol for each scheduled activity should be followed as 
closely as possible. However, if it is not possible and if it is not otherwise specifically 
contraindicated per protocol, then the time windows detailed in Table 10 are allowed without 
incurring a protocol deviation. 
Table 10: Allowable Time Windows for Study Assessments/Visits 
Protocol Specified Time 
Allowable Window 
PK Samples and Associated Assessments 
Predose 
within 2 hours prior to dosing 
<2 hours 
± 5 minutes 
≥2 hours to 24 hours 
± 15 minutes (± 2 hours for urinalysis) 
>24 hours to 48 hours 
± 30 minutes 
>48 hours 
± 1 hour (PK) and ± 2 hours (safety)  
Study Visits - Parts 1 and 2 
Day −1 to Day 4 (Part 1) 
must occur on scheduled day 
Day −1 to Day 4 and Day 14 to Day 18 (Part 2) 
must occur on scheduled day 
Day 9 (Part 1) and Days 9 and 23 (Part 2) 
± 1 day 
End-of-Study (EOS) Visit 
± 2 days 
Study Visits - Part 3 
Day −1 to Day 9 
must occur on scheduled day 
Day 14 
± 1 day 
Day 20/EOS Visit 
± 2 days 
6.1.2. 
Restrictions 
Prior to arriving at the clinic for the Day -1 visit, subjects must abstain from consumption of 
alcoholic beverages for a minimum of 72 hours prior to Check-in. Subjects must continue to 
abstain from consumption of alcoholic beverages throughout clinic confinement. Subjects 
enrolled in P2 must continue to refrain from consuming alcoholic beverages from discharge on 
Day 4 through Check-in on Day 14, and then through the second clinic confinement to Day 18. 
After discharge on Day 4 (P1), Day 18 (P2), or Day 9 (P3), subjects must minimize consumption 
of alcoholic beverages (i.e., limit of up to one serving per day) until the EOS procedures have 
been completed. 


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All subjects must refrain from the following: 
 consuming quinine containing products from 72 hours prior to Check-in through to 
completion of the EOS procedures. 
 using nutraceuticals and nutritional/vitamin supplements (e.g., gingko biloba, 
multivitamins) from 72 hours prior to Check-in through to completion of the EOS 
procedures. However, vitamin supplements required by a physician are exempt from 
this restriction. 
 taking OTC analgesics including aspirin (any dose) and NSAIDS from 72 hours 
before Check-in until completion of EOS study procedures unless prescribed by the 
PI (or designee). 
 use of tobacco, nicotine or tobacco products, or e-cigarettes from 3 months prior to 
Screening until the EOS visit. 
 strenuous exercise from 7 days before Check-in until the EOS visit. Subjects will 
otherwise maintain their normal level of physical activity during this time (i.e., will 
not begin a new exercise program nor participate in any unusually strenuous physical 
exertion). 
 Female subjects must not donate eggs/ovum from the time of Check-in until 
3 months after the EOS visit. 
All subjects in P1 should be dosed in the fasted state. Subjects should fast overnight for a 
minimum of 10 hours prior to dosing in the morning on Day 1. Following dosing, subjects may 
have water after 2 hours and food beginning 4 hours postdose. For subjects to be dosed in the fed 
state, subjects should have a high-fat breakfast as defined in the FDA guidance. Subjects must 
complete the meal within 30 minutes of starting the meal and should be dosed after 30 minutes 
of starting the meal. Doses in P3 may be administered in the fed state, following review of the 
PK data from P2. 
6.2. 
Screening 
6.2.1. 
Screening Visit 
Subjects who meet preliminary pre-screening criteria (as defined by the site) and are interested in 
participating in the study will arrive at the study site for administration of informed consent 
according to site standard operating procedures (SOPs). After the subject has signed and dated 
the ICF, screening procedures can begin. Assessments and procedures should be conducted as 
shown in the Time and Events Schedule Screening may be conducted as early as 28 days prior to 
dosing. 


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6.2.2. 
Retesting Procedures 
In the case where a parameter is outside of the acceptable limits for enrollment, measurement of 
the parameter can be repeated one time if both the following are met: 
 In the opinion of the PI (or designee), the parameter value does not represent a 
chronic condition that otherwise will preclude the volunteer from enrolling in the 
study; and 
 In the opinion of the PI (or designee), the abnormality is not likely to recur. 
6.2.3. 
Study Visits 
Subjects who satisfy entry criteria will return to the clinic for the Day -1 visit. Following review 
of I/E criteria, subjects who still qualify will be checked into the clinic and enrolled into the 
study. Following enrollment, clinical chemistry, hematology and urine samples will be collected 
to determine baseline values. Based on site standard practices, alternate subjects will also be 
enrolled into the study in case one of the selected subjects cannot be dosed. If all subjects can be 
dosed on the morning of Day 1, the alternates will be released and may be enrolled into 
subsequent cohorts. All assessments and procedures will be performed according to the 
Time and Events Schedule. 
6.2.4. 
Part 1 (Single Ascending Dose) 
Subjects will remain in the clinic through completion of study procedures on Day 4, returning to 
the clinic for procedures on Day 9. 
6.2.5. 
Part 2 (Food-Effect) 
Subjects will remain in the clinic through completion of study procedures on Day 4, returning to 
the clinic on Day 9 for study assessments, and Day 14 to begin the second dosing sequence on 
Day 15. Subjects will then be discharged from the clinic on Day 18, returning to the clinic on 
Day 23 for study assessments. 
6.2.6. 
Part 3 (Multiple Ascending Dose) 
Subjects will remain in the clinic through dosing and completion of study procedures on Day 9, 
returning to the clinic on Day 14 for study assessments. Depending on ongoing review of the 
safety, tolerability, and PK data, the number of days of dosing may be reduced. If the number of 
days of dosing are reduced, the timepoints for subsequent assessments and the period for which 
subjects are domiciled at the clinic will similarly be changed (subjects will be domiciled for 
3 days post final dose). 
6.3. 
Safety Follow-up and End-of-Study Visit 
Subjects in P1 will return to the clinic for the EOS visit on Day 15. Subjects in the FE cohort 
(P2) will return for the EOS visit on Day 30. Subjects in P3 will return for the EOS visit on 


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Day 20. Subjects with drug-related AEs at the EOS visit will be followed as discussed in 
Section 8.2.1. 
6.4. 
Subject Withdrawal and Replacement 
As this is a small study with a limited number of subjects per cohort, it is critical that all subjects 
complete the study including postdose study assessments. Site personnel should emphasize this 
to study subjects at the time of informed consent so that subjects will understand this fact before 
agreeing to participate in the study. 
Subjects may voluntarily withdraw their consent for study participation at any time without 
penalty or loss of benefits to which they are otherwise entitled. An PI (or designee) may also 
withdraw a subject from receiving study drug or participation in the study for any reason. 
Subjects who withdraw or are withdrawn from the study should undergo withdrawal procedures 
as discussed below. These procedures would include follow-up safety evaluations. 
6.4.1. 
Reasons for Withdrawal 
If a subject withdraws or is withdrawn from the study, the primary consideration must be the 
health and welfare of the subject. The reasons for withdrawal might include but are not limited to 
the following: 
 Subject no longer meets eligibility criteria including subject withdraws consent from 
study participation (with or without a reason) 
 Subject becomes noncompliant 
 Medical disease or condition, or new clinical finding(s) for which continued 
participation, in the opinion of the PI (or designee) might compromise the safety of 
the subject, interfere with the subject's successful completion of this study, or 
interfere with the evaluation of responses 
 Subject Lost-to-Follow-up 
 Subject becomes pregnant, if applicable 
 Determined by a physician's discretion to require additional therapy not indicated in 
the protocol to ensure subject's health and well-being (or treatment failure, if 
applicable) 
The PI should be explicit regarding study follow-up (e.g. safety follow-up) that might be carried 
out. If the subject consents, every attempt will be made to follow all AEs through resolution, 
return to baseline, or until stabilized with sequelae for a maximum of 30 days following 
discontinuation. The procedures that collect safety data for the purposes of research must be 
inclusive in the original ICF or the PI may seek subsequent informed consent using an 
EC-approved ICF with the revised procedures. 


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The PI will inform the subject that already collected data will be retained and analyzed even if 
the subject withdraws from this study. 
6.4.2. 
Handling of Withdrawals 
Subjects who withdraw from the study prior to receiving study drug (i.e., on Day -1 or before 
dosing on Day 1) will be discharged from the clinic and followed only if AEs are present which 
occurred due to participation in the study (e.g., AE resulting from a study procedure). In this 
case, the subject should be followed until the AE resolves or the PI determines that the AE has 
stabilized. 
Subjects who withdraw from the study after receiving study drug should have EOS assessments 
at the time of withdrawal or as quickly thereafter as possible. 
Subjects who do not return for follow-up procedures on Days 9/23 or 15/30 (P1 and P2), or 
Days 14 or 20 (P3) will be contacted by the site at least 3 times using the subject’s preferred 
method of communication (as determined at Check-in). If the site is unable to contact the person, 
then a certified letter will be sent. If the subject still cannot be reached or refuses to come back to 
the clinic after all attempts, the subject will be considered Lost-to-Follow-up and withdrawn 
from the study. 
6.4.3. 
Documentation of Withdrawals 
If a subject withdraws or is withdrawn prior to completion of the study, the reason for this 
decision must be recorded in the CRF. If the subject is Lost-to-Follow-up, the site should 
document the attempts to contact the subject in the source documents. If the subject has an 
ongoing AE at the time of withdrawal, then the AE should be followed as detailed in 
Section 8.2.1. 
6.4.4. 
Subject Replacement 
If a subject withdraws from the study prior to receiving study drug, the subject will be replaced. 
In this case, designated alternate subjects, if available, will be first in line to replace the 
withdrawn subject. 
If a subject withdraws from the study after receiving study drug, then the decision to replace the 
subject will be made by the PI (or designee) in consultation with the Sponsor. Factors to consider 
will be the timing postdose of withdrawal and the number of safety and PK assessments 
completed prior to withdrawal. Subjects who are withdrawn because of an AE related to the 
study drug will not be replaced. 
6.5. 
Unscheduled Visit(s) 
If a subject experiences an AE after discharge from the clinic but prior to the EOS visit, the 
subject should be instructed to call the site. Based on the issue, the PI (or designee) may request 
that the subject return to the site for an unscheduled visit. In this case, procedures/assessments 


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should be conducted as deemed appropriate for the situation by the PI (or designee). The visit 
should be recorded in the unscheduled visit page of the CRF. 


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7. 
STUDY PROCEDURES/EVALUATIONS 
7.1. 
Demography and Medical History 
Demographics including age, gender, race, ethnicity, and medical history will be recorded for 
each subject. All significant medical history should be recorded. In general, significant medical 
history should include all ongoing events and all events occurring within the last 6 months. 
Clinically relevant or clinically significant events occurring greater than 6 months ago should be 
recorded. All surgeries occurring in adulthood should be recorded. If surgeries occurred more 
than 2 years ago, then only the year needs to be recorded on the CRF. 
7.2. 
Clinical Evaluations 
7.2.1. 
Physical Examinations 
The PE will be performed by the PI or a designee that is licensed to perform a PE per local 
requirements. The initial PE performed at Screening and the final PE conducted at the EOS visit 
will include examination of all pertinent body systems as defined by the site standard PE body 
systems (general appearance, HEENT, lymphatic, cardiovascular, respiratory, GI, 
musculoskeletal, neurological, dermatological). 
Subsequent PEs will be performed as shown in the Time and Events Schedule and will be 
targeted to any new signs or symptoms, any change from the previous status or any body system 
deemed pertinent to that subject by the PI (or designee). Clinically significant abnormalities 
should be recorded in the CRF; those occurring prior to dosing will be included in medical 
history unless the abnormality was the direct result of study participation. 
7.2.2. 
Vital Sign Measurements and ECGs 
Vital signs include pulse rate, respiratory rate, blood pressure, and body temperature. Vital signs 
should be measured after the subject has been supine for a minimum of 5 minutes. Site standard 
ranges will be used for determining any out-of-range values. 
Height and weight should be measured, and BMI calculated at Screening as indicated in the 
Time and Events Schedule. 
Resting 12-lead ECGs should be recorded at the visits indicated in the Time and Events Schedule 
after the subject has been supine for a minimum of 5 minutes. The PI (or designee) will evaluate 
the ECG tracings to determine if there are out-of-range values; if out-or-range values are 
detected, the PI (or designee) will determine if they are clinically significant. Site standard 
ranges will be used to determine if any parameters are considered out-of-range. At the discretion 
of the PI (or designee), the ECG may be repeated if erroneous readings are suspected. 


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7.2.2.1. 
Continuous 12-lead ECG Monitoring (Parts 1 and 3 Only) 
Continuous 12-lead ECG monitoring using a digital recorder will take place at the times 
indicated in the Time and Events Schedule, in P1 and P3 only. 
All continuous 12-lead ECG data collected will be archived without extraction or analysis and 
will not be reported in the scope of this study.  
Subjects will be supine for at least 10 minutes before the extraction timepoint and for 5 minutes 
from the start of each extraction timepoint (each extraction will last for 5 minutes). 
Environmental distractions (e.g., television, radio, conversation) should be avoided during the 
pre-ECG resting period and during ECG recording. 
When coinciding, PK sampling should always be performed after the ECG extraction time 
window. If a separate ECG machine is being used for safety assessments, that machine should be 
in place prior to the extraction window to permit safety ECGs to be recorded irrespective of the 
extraction window. If the machine is not in place prior to the extraction window, safety ECGs 
must be recorded after the extraction window. If an integral system is used, safety ECGs may be 
recorded irrespective of the extraction window.  
7.2.3. 
Adverse Events and Concomitant Medications 
Adverse Events: The PI is responsible for identifying and documenting events meeting the 
definition of an AE or SAE (Section 8.1). Once each day while the subject is in the clinic and 
once during each out-patient visit, the PI (or designee) should inquire about the occurrence of 
AEs. The following are examples of open-ended questions that may be used to obtain this 
information: “How are you feeling?”; "Have you had any medical problems recently?"; "Have 
you taken any new medicines since your last visit/assessment?" 
All AEs and SAEs must be documented in the source documents and recorded in the CRF. 
Concomitant Medications: All medications (prescription or over-the-counter), nutritional 
supplements, and nutraceuticals taken by the subject from 30 days prior to dosing through the 
EOS visit must be recorded in the CRF. Medication information should include indication, dose, 
frequency, and route of administration. Any medication taken for an AE/SAE should be 
documented as such. Refer to Section 5.5 for additional information. 
7.3. 
Laboratory Evaluations 
The laboratory will perform standard routine testing, and processing of all blood samples. For the 
entire study, the amount of blood collected from any one subject will not exceed 500 mL. 
7.3.1. 
Routine Laboratory Panels 
Blood and urine samples will be collected at the times indicated in the 
Time and Events Schedule. The analytes shown in the table below (Table 11) will be assessed. 


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If a method to determine COVID-19 status becomes readily available, subjects may be tested at 
Screening and Check-in to confirm they are not positive for COVID-19 prior to dosing.  


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Table 11: Laboratory Evaluations 
CHEMISTRY PANEL 
Alanine Aminotransferase (ALT/SGPT) 
Albumin, Serum 
Albumin/Globulin (A/G) Ratio (calculation) 
Alkaline Phosphatase, Serum 
Amylase 
Aspartate Aminotransferase (AST/SGOT) 
Bilirubin, Total and Direct 
BUN 
BUN/Creatinine Ratio (calculation) 
Calcium, Serum 
Creatinine, Serum 
Creatinine Kinase (CK) 
Gamma Glutamyl Transferase (GGT) 
Lactate Dehydrogenase (LDH)  
Uric Acid 
Electrolyte Panel (Na+, K+, Cl-, Bicarb.) 
Phosphorus 
Globulin, Total  
Glucose, Serum 
Lipase 
Protein, Total, Serum 
HEMATOLOGY PANEL 
Hemoglobin 
Hematocrit 
White Blood Cell Count with differential (absolute and percentage) 
Red Blood Count 
Prothrombin Time (PT)/Partial Prothrombin Time (PTT) and International 
Normalized Ratio (INR) 
Mean cell hemoglobin (MCH), mean cell hemoglobin concentration (MCHC), 
mean cell volume (MCV), red cell distribution width (RDW; may be a 
Grade 1 abnormality) 
Platelets 
ADDITIONAL ASSESSMENTS 
Virology: Human Immunodeficiency Virus (HIV) serology, Hepatitis B Virus 
(HBV; Surface Antigen [HBsAg]), Hepatitis C Virus (HCV) 
Follicle-Stimulating Hormone (FSH; as applicable) 
PREGNANCY TEST 
Serum Pregnancy Test 
Urine Dipstick (optional blood follow-up) 
DRUG SCREENING 
Serum/urinalysis (per site SOP) 
Cotinine 
Urine Dipstick 
Alcohol Breathalyzer 
ROUTINE URINALYSIS 
Bilirubin 
Color and appearance 
Glucose 
Ketones  
Leukocytes 
Microscopic (including red blood cells [RBCs] and white blood cells [WBCs]) 
Nitrite 
Occult blood 
pH 
Protein 
Specific Gravity 
Urobilinogen 
7.3.2. 
Pharmacokinetic Sampling 
Samples for PK analysis will be collected as shown in the Time and Events Schedule. All 
samples will be analyzed to define the PK parameters for prodrug EIDD-2801 and the active 
parent, EIDD-1931. In order to preserve EIDD-2801, special handling procedures will be put in 
place. These procedures will be documented in the laboratory manual for the study. 
Depending on ongoing review of the PK data, timepoints may be modified or removed, and up to 
3 additional samples (in each period for the food-effect) may be added. 


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7.3.3. 
Peripheral Blood Mononuclear Cell Collection 
Peripheral blood mononuclear cells will be collected in P2 and P3. Blood will be collected into 
specialized tubes and processed according to procedures described in the laboratory manual. 
Depending on ongoing review of the data, timepoints may be modified or removed, and up to 
2 additional samples may be added. 
7.3.4. 
Urine Collection 
Urine will be collected over the time periods noted in the Time and Events Schedule. Samples 
will be collected for routine urinalysis and PK analysis according to site standard practices and 
as described in the laboratory manual. 


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8. 
SAFETY MONITORING, MANAGEMENT AND REPORTING 
8.1. 
Definitions 
8.1.1. 
Adverse Events 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product. 
Abnormal clinical laboratory findings (e.g. clinical chemistry, hematology) or other abnormal 
assessments that are judged by the PI (or designee) as clinically significant will be recorded as 
AEs or SAEs if they meet the definitions of an AE or an SAE as defined in this Section 8.1.2. 
Disease specific signs and symptoms which were ongoing prior to study entry will not be 
considered AEs unless they worsen (e.g. increase in frequency or severity) unexpectedly during 
the course of the trial. 
8.1.2. 
Serious Adverse Events 
An AE or suspected adverse reaction is considered “serious” if, in the view of either the PI (or 
designee) or Sponsor, it results in any of the following outcomes: 
 Death, 
 A life-threatening AE: An AE or suspected adverse reaction is considered 
“life-threatening” if, in the view of either the PI or Sponsor, its occurrence places the 
patient or subject at immediate risk of death. It does not include an AE or suspected 
adverse reaction that, had it occurred in a more severe form, might have caused 
death. 
 Inpatient hospitalization or prolongation of existing hospitalization, 
 A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions, or 
 A congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalizations may be considered serious when, based upon appropriate medical judgment they 
may jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 


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or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
Suspected adverse reaction means any AE for which there is a reasonable possibility that the 
drug caused the AE. “Reasonable possibility” means there is evidence to suggest a causal 
relationship between the drug and the adverse event. Suspected adverse reaction implies a lesser 
degree of certainty about causality than adverse reaction, which means any adverse event caused 
by a drug. 
An AE or suspected adverse reaction is considered “unexpected” if 
 It is not listed in the IB or is not listed at the specificity or severity that has been 
observed; or, if an IB is not required or available, 
 Is not consistent with the risk information described in the general investigational 
plan or elsewhere in the current application as amended. For example, under this 
definition, hepatic necrosis would be unexpected (by virtue of greater severity) if the 
IB referred only to elevated hepatic enzymes or hepatitis. Similarly, cerebral 
thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater 
specificity) if the IB listed only cerebral vascular accidents. 
 “Unexpected” as used in this definition, also refers to AE or suspected adverse 
reactions that are mentioned in the IB as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the particular drug under investigation. 
As of the date of this protocol, there are no expected events listed in the current version of the 
IB; therefore, all AEs will be considered unexpected until such a time that the reference safety 
information in the IB is updated with any identified, expected events. 
8.2. 
Documenting Adverse Events 
8.2.1. 
Timeframe for Collection and Follow-up of AEs/SAEs 
All AEs/SAEs will be collected from the time of the first study drug administration until the 
subject has completed the EOS visit and been discontinued from the study. This includes 
subjects who discontinue early. Events considered related to study drug will be followed as 
noted: 
 AEs that are related to study drug and continue beyond the normal collection period 
(i.e., are ongoing at the time a subject exits the study) will be followed until 
resolution, return to baseline or until stabilized with sequelae for a maximum of 
30 days following discontinuation. After 30 days, the AE will be closed, and the 
outcome noted (see Table 12). 
 SAEs that are related to study drug and continue beyond the normal collection period 


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(i.e., are ongoing at the time a subject exits the study) will be followed until 
resolution, return to baseline or until stabilized with sequelae. 
 Serious AEs that are reported to the site within 30 days after the subject has been 
discontinued from the study (i.e., completed the EOS visit) will be recorded. Those 
that are considered related to study drug will be followed as noted in the bullet 
above. 
Note that all events which occurred prior to dosing with study drug should be recorded as 
medical history unless the event is directly related to study procedures. 
8.2.2. 
Recording of Adverse Events/Serious Adverse Events 
AEs/SAEs must be recorded in the CRF as indicated in the CRF completion instructions. 
Information to be collected includes event description, time of onset, clinician’s assessment of 
severity (Section 8.2.3), relationship to study drug (Section 8.2.4), outcome (Section 8.2.5), and 
time of resolution/stabilization of the event. All AEs occurring while on study must be 
documented appropriately regardless of relationship and will be followed to adequate resolution 
as described above (Section 8.2.1). All SAEs will be recorded as noted above; SAEs reported to 
the site within 30 days following the EOS visit will also be recorded. All SAEs must be entered 
onto the SAE form and reported as discussed below (Section 8.3.1). 
If an AE changes in severity, the highest severity will be recorded in the CRF. AEs characterized 
as intermittent require documentation of onset and duration of each episode. 
8.2.3. 
Assessing Severity of Adverse Events 
All AEs/SAEs will be assessed by the PI or those with the training and authority to make a 
medical judgment. AEs/SAEs will be graded according to the DMID Toxicity Grading Scale. 
For any AEs not specifically listed in the tables, the following guidelines should be used to grade 
severity: 
 Mild (Grade 1); asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
 Moderate (Grade 2); minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living. 
 Severe (Grade 3); medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care activities of daily living. 
o Life-threatening; life-threatening consequences; urgent intervention 
indicated. 
o Death; death related to AE. 


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Changes in the severity of an AE should be documented to allow an assessment of the duration 
of the event at each level of intensity to be performed. Adverse events characterized as 
intermittent require documentation of onset and duration of each episode. 
8.2.4. 
Relationship to Study Drug 
The PI’s (or designee’s) assessment of an AE’s relationship to study drug is part of the 
documentation process, but it is not a factor in determining what is or is not reported in the study. 
If there is any doubt as to whether a clinical observation is an AE, the event should be reported. 
All AEs must have their relationship to study product assessed using the terms: related or not 
related. In a clinical trial, the study product must always be suspect. To help assess, the following 
guidelines are used. 
 Definite – The AE is clearly related to the study drug. 
 Probable – The AE is likely related to the study drug. 
 Possible – The AE may be related to the study drug. 
 Unlikely – The AE is doubtfully related to the study drug. 
 Unrelated – The AE is clearly NOT related to the study drug. 
8.2.5. 
Classifying Adverse Event Outcome 
All AEs/SAEs in the study must be assigned an outcome by site staff. The outcome will be 
included on the AE CRF. Possible outcomes are shown below: 
Table 12: Adverse Event Outcomes 
Outcome 
Description 
Recovered / Resolved 
AE resolved with no residual signs or symptoms; an event is considered resolved if it 
returns to baseline (pretreatment) values. 
Recovered / Resolved with sequelae 
AE stabilized but residual signs or symptoms remain; this includes stabilization of an 
event/condition with the expectation that it will remain chronic. 
Not Recovered / Not Resolved 
AE remains ongoing AND no or only minimal improvement has occurred. 
Ongoing 
AE has not yet resolved, but continues to improve/resolve and complete resolution is 
expected over time. 
Fatal 
Outcome of the AE is death. 
Unknown 
AE outcome is not known; usually because the subject has been Lost-to-Follow-up. 


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8.3. 
Reporting Procedures 
8.3.1. 
Serious Adverse Events 
The PI or clinical site personnel should notify Covance Drug Safety Services (DSS) 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 Notification 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. 
The responsibilities of Covance DSS include the following: 
 Prepare an AE reporting plan prior to the start of the study. Where this plan differs from 
the applicable site standard operating procedure on SAE reporting, the AE reporting plan 
will always take precedence. 
 Receive and review SAE report forms from the site and inform the Sponsor of the SAE 
within 1 working day of the initial notification to DSS. Drug Safety Services will delete 
any information from the SAE report forms that may identify the subject. 
 Write case narratives and enter the case into Covance’s safety database as defined in the 
AE reporting plan. 
 Produce appropriate reports of all Suspected Unexpected Serious Adverse Reactions and 
forward to the EC, Medicines and Healthcare Products Regulatory Agency, PI’s (or 
designee’s), and the Sponsor within the timeframes stipulated in the Clinical Trials 
Directive Guideline (ENTR/CT 3).  
The responsibility for reporting SAEs will be transferred to the Sponsor 28 days after the end of 
the study. 
8.3.2. 
Pregnancy 
Subjects in this study must be of non-childbearing potential. However, should a pregnancy occur 
any time from informed consent to the EOS visit, subjects must immediately report the event to 
the clinical site which in turn must immediately report the pregnancy to the Sponsor or their 
designee. The subject will be followed until the end of the pregnancy. A separate ICF will be 
used for consenting for follow-up pregnancy activities. Pregnancy will not be considered an AE 
unless deemed likely related to study drug. Pregnancy will not be considered an SAE unless there 
is an associated SAE. A spontaneous abortion (miscarriage) or abnormal outcome (including 
congenital anomalies) will be reported as an SAE. 


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8.4. 
Unmasking Treatment Assignment 
The following controls will be employed to maintain the double-blind status of the study: 
 Placebo will be identical in appearance to the EIDD-2801. 
 The PI and other members of staff involved with the study will remain blinded to the 
treatment randomization code in P1 and P3. 
 Interim bioanalytical data will be provided in a blinded manner. 
To maintain the blind, the PI will be provided with a sealed randomization code for each subject 
in P1 and P3, containing details of their treatment. These individual sealed envelopes will be 
kept in a limited access area that is accessible 24 hours a day. In order to manage subject safety 
or to support dose-escalation decisions (in the event of possibly treatment-related SAEs or severe 
AEs), the decision to unblind resides solely with the PI. Whenever possible and providing it does 
not interfere with or delay any decision in the best interest of the subject, the PI will discuss the 
intended code-break with the Sponsor. If it becomes necessary to break the code during the 
study, the date, time, and reason will be recorded in the subject’s source data and on the 
individual envelope and will be witnessed by a second person. 
The pharmacy and bioanalytical lab will have access to the treatment randomization and will be 
unblinded. Pharmacokinetic personnel may be unblinded to perform interim PK analysis and to 
ensure that PK data are provided in a blinded manner for dose-escalation decisions.  


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9. 
DOSE-ESCALATION AND HALTING RULES 
9.1. 
Guidelines for Dose-Escalation 
Doses will be administered in an escalating manner following satisfactory review by the Sponsor 
and PI of the blinded safety and tolerability data up to 72 hours post final dose.
 
 
 
 
As PK data become available, these data will be reviewed and 
may be used to assist in dose selection. 
Doses may be reduced and may be lower than the starting dose. There will be a minimum of 
4 days between dose escalations to allow sufficient time for an adequate safety review. 
 
 
 
Integrated data from all applicable sites will be used to make dose-escalation decisions. 
Dose-escalation in P1 and P3 will only occur if data from a minimum of 6 subjects (across all 
sites) have been reviewed from the previous lower dose group, such that data from a minimum of 
4 subjects (across all sites) who have received EIDD-2801 will be used to make the 
dose-escalation decision. 
The justification for this is as follows: 
 The study treatment is of a known pharmacological class for which the on-target effects 
in humans are well characterized. Based upon nonclinical data, no clinically important off 
target effects are expected within the proposed dose range. 
 A minimum of 4 subjects receiving the active drug is considered sufficient to characterize 
the safety profile of EIDD-2801. 
Between each dose-escalation, the PI will review all available data in a blinded manner to ensure 
it is safe to proceed with the planned dose-escalation. The results from all available safety 
assessments will be sent to the Sponsor prior to the start of each successive group/treatment 
period. Any clinically significant results will be discussed with the Sponsor before 
dose-escalation continues. Interim PK data may also be reviewed in terms of dose-escalation and 
to confirm that the study design remains appropriate. In the event of a disagreement between 
Sponsor and PI on the dose-escalation decision, the most conservative decision will be upheld. 
Dose levels will not increase by more than 3-fold for predicted nonpharmacologically active 
dose levels and by 2-fold for predicted pharmacologically active dose levels. The highest total 
daily dose to be studied under this protocol will not exceed 1600 mg (Section 9.2). 


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Dose levels in P3 may be repeated for collection of PBMCs, providing that the dose level did not 
meet the dose-escalation halting criteria. 
9.2. 
Rationale for Highest Dose 
9.2.1. 
Clinical Safety 
9.2.1.1. 
Single Ascending Doses 
At the time of Protocol Version 5.1, 48 healthy subjects were administered a single dose of 50, 
100, 200, 400, 600, and 800 mg EIDD-2801 or placebo in P1. There were 6 males and 2 females 
at each dose level, with the exception of the 800 mg dose level, which included 8 males. The age 
range across all dose levels was 21 to 60 years. No clinically significant abnormalities or changes 
from baseline were reported for vital signs, ECGs, laboratory safety assessments or PEs.  
Thirty-three treatment-emergent AEs were reported across the 6 dose levels; 32 of these were 
mild and 1 were moderate in severity. Two AEs were considered to be probably related, 9 were 
possibly related, 15 were unlikely related, and 6 were unrelated to EIDD-2801.  
The most frequently reported AEs were headache (13 reports), nausea (4 reports), and 
backache (3 reports).  
 Four reports of headache (1 at 100 mg, 1 at 200mg, and 2 at 600 mg) were considered 
possibly related to EIDD-2801 and 1 (at 600 mg) was considered to be probably related; 
all were mild in severity. 
o One headache (at 600 mg) that was probably related and 2 headaches (1 at 
100 mg and 1 at 200mg) that were possibly related started within 2 hours of 
dosing and resolved without treatment within 24 hours, and 2 headaches (both at 
600 mg) that were possibly related started later, but had resolved without 
treatment within 30 hours. 
o One headache (at 100 mg) resolved after a single dose of 1 g acetaminophen. 
 At 100 mg, 1 subject reported nausea that was considered possibly related to EIDD-2801 
because it started approximately 4 hours after dosing; this event was moderate in severity 
and resolved approximately 40 minutes after onset following a single episode of 
vomiting. At 200 mg, 1 subject reported nausea that was considered possibly related to 
EIDD-2801. At 600 mg, 1 subject reported 2 episodes of nausea that were considered 
unlikely related to EIDD-2801 because they started at 28 hours and nearly 36 hours 
postdose. 
 Three reports of backache were considered unrelated to EIDD-2801. 
 Other AEs of interest included 1 report of each of loose stools and abdominal pain; both 
were mild in severity and reported by the same subject at 200 mg. The loose stools were 


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considered probably related to EIDD-2801; they started approximately 13.5 hours after 
dosing and resolved 3 days after dosing. The abdominal pain started approximately 
24 hours after dosing, resolved after 4.5 hours, and was considered to be probably related 
to EIDD-2801.  
Laboratory safety data have been reviewed through Day 14 at all dose levels. There were no 
clinically significant abnormalities or changes from baseline. There was 1 decrease in platelet 
counts to below the lower limit of normal: 1 subject (at 600 mg) had a value of 147 × 103/μL 
(normal range: 150 to 357 × 103/μL) on Day 9; however, this was not considered clinically 
significant because the subject had values of 150 × 103/μL and 178 × 103/μL on Days -1 and 14, 
respectively.  
9.2.1.2. 
Multiple Ascending Doses 
At the time of Protocol Version 5.1, 32 healthy subjects were administered multiple doses of 50, 
100, 200, and 300 mg EIDD-2801 or placebo BID in P3. There were 27 males and 5 females 
across all dose levels, with ages ranging from 20 to 60 years. No clinically significant 
abnormalities or changes from baseline were reported for vital signs, ECGs, laboratory safety 
assessments, or PEs.  
Seventeen treatment-emergent AEs were reported across the 4 dose levels; 15 of these were mild 
and 2 were moderate in severity. One AE was considered to be probably related, 4 were possibly 
related, 6 were unlikely related, and 6 were unrelated to EIDD-2801.  
The most frequently reported AEs were lower back pain (4 reports), headache (2 reports), and 
loose stools (2 reports).  
 Four reports of lower back pain were mild in severity and were considered unlikely 
related or unrelated to EIDD-2801. 
 Two reports of headache (both at 300 mg BID) were mild in severity. 
o One was considered unlikely related as it started at predose on the final day of 
dosing. 
o One was considered possibly related because it started 8 hours and 40 minutes 
after the first dose on Day 1 and lasted for 4 hours. 
 Two reports of loose stools were mild in severity and considered possibly related to 
EIDD-2801. 
o One (100 mg BID) started approximately 48 hours after the final dose on Day 6 
and resolved after 5 hours and 30 minutes. 
o One (200 mg BID) started 5 hours and 30 minutes after the first dose on Day 1 
and resolved after approximately 30 hours. 


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One report of gurgling stomach was considered probably related to EIDD-2801 (200 mg BID). 
This occurred in the subject who reported loose stools, started 5 hours after the first dose on 
Day 1, and lasted for 20 minutes. 
The only other AE considered possibly related to EIDD-2801 was a report of dizziness while 
standing (200 mg BID), which started 1 hour postdose on Day 1 and lasted for 30 minutes. This 
event was not associated with any changes in vital signs or ECGs. 
Laboratory safety data have been reviewed through Day 20 at all dose levels. There were no 
clinically significant abnormalities or changes from baseline. There was 1 decrease in platelet 
counts to below the lower limit of normal: 1 subject (300 mg BID) had a value of 130 × 103/μL 
on Day 9 (normal range: 150 to 357 × 103/μL; Screening value was 171 × 103/μL); however, this 
was not considered clinically significant because the subject had a value of 149 × 103/μL on 
Day 14.  
9.2.2. 
Pharmacokinetics 
9.2.2.1. 
Single Ascending Doses 
Pharmacokinetic data 
 have been reviewed up to 72 hours postdose for doses up to 
800 mg. Concentrations of EIDD-2801 (the ester prodrug) were quantifiable in the 0.25 hours 
postdose samples only for the majority of subjects following administration of 600 and 800 mg 
doses of EIDD-2801, thus PK parameters, with the exception of Cmax and tmax, were not 
calculable for EIDD-2801. EIDD-1931 (the active drug) appeared rapidly in plasma, with a 
median tmax of 1 hour at all dose levels. EIDD-1931 exposure increased in a dose-proportional 
manner between 50 and 800 mg. EIDD-1931 concentrations declined in a monophasic manner 
and remained quantifiable until 4 to 6 hours postdose up to 100 mg, until 9 hours at 200 mg, and 
between 9 and 12 hours at 400 mg and above. The geometric mean apparent terminal elimination 
half-life was approximately 1 hour (0.945 to 1.06 hours across dose groups) at doses up to 600 
mg, and increased to 1.29 hours at 800 mg.  
Geometric mean systemic exposure is predicted to achieve an approximate area under the 
concentration versus time curve from time zero to 24 hours postdose (AUC0-24) of 
14,000 ng•h/mL and Cmax of 5480 ng/mL at 1200 mg and is predicted to achieve an approximate 
AUC0-24 of 18,700 ng•h/mL and Cmax of 7310 ng/mL at 1600 mg 
 
 
9.2.2.2. 
Multiple Ascending Doses 
Pharmacokinetic data 
 have been reviewed up to 72 hours postdose for doses up to 
300 mg BID. A single concentration of EIDD-2801 (the ester prodrug) was quantifiable in a 
single sample at each of the 100 (Day 1, 0.5 hours) and 200 mg (Day 6, 0.5 hours) BID dose 
levels; however, no concentrations of EIDD-2801 were quantifiable in any of the samples at 
300 mg BID, thus PK parameters were not calculable for EIDD-2801 at any dose level. 
EIDD-1931 (the active drug) appeared rapidly in plasma, with a median tmax on Days 1 and 6 of 


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1 hour at 50 mg BID, 1.25 hours at 100 mg BID, and 1.5 hours at 200 and 300 mg BID. 
EIDD-1931 exposure increased in a dose-proportional manner between 50 and 300 mg BID on 
Day 6. EIDD-1931 concentrations declined in a monophasic manner and remained quantifiable 
until 4 and 9 hours postdose up to 100 mg BID on Days 1 and 6, increasing to between 9 and 12 
hours at 200 mg BID and 300 mg BID on Day 1 and Day 6, with 1 subject maintaining 
quantifiable concentrations until 24 hours postdose at 300 mg BID on Day 6.  The geometric 
mean terminal elimination half-life was approximately 0.9 to 1.0 hours on Day 1 for all dose 
levels. On Day 6, the geometric mean terminal elimination half-life increased from 0.968 hours 
at 50 mg BID to 1.71 hours at 300 mg BID. There was no significant accumulation at any dose 
level. Exposure on Day 1 were generally similar to those at the corresponding dose in Part 1 
(comparable up to 200 mg), i.e., there was no clear difference in PK between the 
 
formulations. This assessment is made with the caveat that the data have not been 
formally, statistically assessed and the results are from different subjects (not crossover).  
Geometric mean systemic exposure is predicted to achieve an approximate AUCτ of 
9060 ng•h/mL and Cmax of 2900 ng/mL at 800 mg BID. 
9.2.3. 
Rationale to Exceed the Maximum Single Dose Limit of 800 mg 
 
 
  
Based on the clinical data collected to date, it is considered acceptable to exceed 800 mg because 
EIDD-2801 has been well tolerated at the single and multiple dose levels tested to date, and the 
PK has behaved in a predictable manner.  
 
 
 
 
 
 
 
 
 
 
 
 
Because of the uncertainty of the virologic course of COVID-19, it is prudent to establish a 
safety margin above the predicted effective dose to allow for maximum viral suppression, 
especially where treatment is started later in disease where a rapid reduction of viral replication 
is important. Therefore, a potential treatment of 400 and/or 800 mg BID will be investigated. In 
order to escalate to this dose level in P3, a dose level of 1600 mg must be shown to be safe and 
well tolerated in P1. Additionally, in order to allow for unpredicted differences in PK at higher 


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dose levels compared with that seen at the dose levels already evaluated, dose levels of 1200 and 
1600 mg are planned for P1; this will allow escalation to a maximum of 800 mg BID in P3 if 
required to achieve therapeutic exposures.  
 
  
9.3. 
Dose-Escalation Halting Rules 
For Group 1 in P1, sentinel dosing will occur whereby 2 subjects (1 active and 1 PBO) will be 
dosed on 1 day and, providing no safety concerns arise, the remaining 6 subjects will be dosed 
after at least 24 hours. 
The study will be halted (i.e., no further dosing will occur) if one or more subjects experience an 
SAE that is considered to be related to EIDD-2801 or 2 or more subjects in the same group 
experience severe AEs that are considered to be related to EIDD-2801. If, following an internal 
safety review, the Sponsor deems it appropriate to restart the study, this can be done following 
approval of a substantial protocol amendment.  
Additionally, if 2 or more subjects experience a reduction of platelets greater than 50% over 
baseline levels or a reduction in lymphocytes (absolute count) to Grade 3/severe levels without 
an alternate cause, the PI and Sponsor will review the data. If, after review of unblinded data, it 
is determined that these events are probably related to study drug, no further dose escalations 
will occur. In this case, additional cohorts may be enrolled at a lower dose. 
Dose-escalation will stop if clinically relevant signs or symptoms of similar nature occur in 2 or 
more subjects in a group that, in the opinion of the PI, warrant stopping of dose-escalation. 


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10. 
STATISTICAL CONSIDERATIONS 
10.1. 
General Considerations 
All summaries will be provided by study part and treatment. Continuous variables will be 
summarized using descriptive statistics including number of observations (n), mean, standard 
deviation, minimum (min), median (med), and maximum (max). Categorical variables will be 
summarized using frequency counts and percentages. Note that PBO data from each dose level in 
Parts 1 and 3 will be combined into one PBO group. 
No missing data imputation will be performed. 
Subject listings will be provided for all the data collected during the study period. 
Specific information about the statistical analysis will be provided in a SAP that will be reviewed 
and approved by the Sponsor and will be finalized before final database lock. If there is a 
discrepancy between the methods described in the protocol and final approved SAP, the SAP 
will take precedence. 
10.2. 
Sample Size Considerations 
No formal sample size calculation was conducted. The sample size of 8 per cohort 
(6 active: 2 PBO) for the SAD and MAD cohorts is considered adequate for a Phase 1 FIH study. 
The sample size of 10 subjects (all administered EIDD-2801) is in accordance with FDA 
guidelines for sample size in FE studies. 
10.3. 
Analysis Populations 
Safety Population: All subjects who receive at least one dose of study drug. 
Pharmacokinetic Population: All subjects receiving study drug who comply sufficiently with 
protocol requirements (i.e., no major protocol violations) and for whom a sufficient number of 
analyzable PK samples have been obtained to permit the determination of the PK profile for 
EIDD-2801/EIDD-1931 and the statistical analysis of the results. Subjects who experience an 
AE of vomiting before 2× the median tmax of the group may be excluded from the PK population. 
10.4. 
Analysis of Safety Data 
All safety analyses will be performed on the Safety Population as defined in Section 10.3. Safety 
will be assessed on the basis of AEs, clinical laboratory data, vital signs, ECG parameters, and 
PEs. 
10.4.1. 
Extent of Exposure 
Dosing data will be listed by study part. 


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10.4.2. 
Adverse Events 
Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
preferred term and system organ classification. Any events reported after the initiation of study 
treatment and through the EOS are defined as treatment-emergent. The occurrence of 
treatment-emergent AEs will be summarized using MedDRA preferred terms, system organ 
classifications, and severity. Separate summaries of treatment-emergent SAEs and AEs 
considered related to study treatment and AEs leading to study treatment discontinuation will be 
generated. All AEs will be listed for individual subjects showing both verbatim and preferred 
terms. 
10.4.3. 
Clinical Laboratory Results 
Laboratory abnormalities will be graded according to the DMID Toxicity Grading Scale. Any 
graded abnormality that occurs following the initiation of study treatment and represents at least 
a one-grade increase from the baseline assessment is defined as treatment-emergent. The number 
and percentage of subjects experiencing treatment-emergent graded toxicities will be 
summarized. Raw values and mean changes from baseline in clinical laboratory measures will be 
summarized. 
Listings of the clinical laboratory test results will be provided. Abnormal laboratory values will 
be flagged in the listings. 
10.4.4. 
Other Parameters 
Individual data for ECG parameters and vital sign measurements will be listed by subject and 
time point and summarized for each treatment. Individual data for PE will be listed by subject 
and time point. 
Concomitant medications will be coded using the World Health Organization-Drug Dictionary 
(WHO-DD) and summarized. 
10.5. 
Analysis of Pharmacokinetic Data 
Pharmacokinetic analysis as defined in the SAP will be conducted using the PK population 
defined in Section 10.3. In the event of discrepancies between analyses described in the SAP and 
this clinical study protocol, the SAP will supersede the protocol. 
 All samples will be analyzed and all concentrations listed. 
 Descriptive statistics will be performed for all time points available, with the 
exclusion of subjects who had any significant protocol deviation. 
 Pharmacokinetic parameters will be derived where possible for all subjects. Data 
from subjects with incomplete profiles (missed blood draws, lost samples, samples 
unable to be quantified) may be used if PK parameters can be estimated using the 
remaining data points. 


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 Descriptive statistics will be performed on all parameters available, and any missing 
parameters will be flagged. 
Plasma concentration data for EIDD-2801 and EIDD-1931 will be listed for individual subjects 
and summarized by study part and treatment. Individual and mean plasma concentration versus 
time plots for EIDD-2801 and EIDD-1931 will be provided. Urine concentration data for 
EIDD-2801 and EIDD-1931 will be listed. 
Plasma PK parameters of EIDD-2801 and EIDD-1931 for each subject will be estimated over the 
sampling interval using noncompartmental analysis and summarized by study part and treatment 
using descriptive statistics. Actual blood sampling times will be used for plasma PK analysis. 
Urine PK parameters of EIDD-2801 and EIDD-1931 will also be analyzed and summarized 
when possible. The PK parameters that will be estimated are listed in the table below.  
Table 13: Pharmacokinetic Parameters 
Plasma PK Parameter 
Description 
AUClast 
The area under the plasma concentration-time curve, from time 0 to the last measurable 
non-zero concentration, as calculated by the linear up/log down trapezoidal method (P1 and 
P2 only). 
AUC0-inf 
The area under the plasma concentration-time curve from time 0 extrapolated to infinity. 
AUC0-inf is calculated as the sum of AUClast plus the ratio of the last measurable plasma 
concentration to the elimination rate constant (λz) (P1, P2, and Day 1 dose of P3). 
Cmax 
Maximum observed concentration. 
tmax 
Time to reach Cmax. If the maximum value occurs at more than one time point, tmax is 
defined as the first time point with this value. 
λz 
Apparent terminal elimination rate constant; represents the fraction of medication 
eliminated per unit time. 
t½ 
Apparent terminal elimination half-life of medication, calculated as 0.693/λz. 
Vz/F 
Apparent volume of distribution (EIDD-2801 only). 
CL/F 
Apparent oral drug clearance (EIDD-2801 only). 
Ctrough 
Trough concentration (P3 only). 
AUCτ 
The area under the plasma concentration-time curve during a dosing interval (P3 only). 
RAAUCτ 
Observed accumulation ratio based on AUCτ (P3 only). 
RACmax 
Observed accumulation ratio based on Cmax (P3 only). 
Urine PK Parameter 
Description 
Ae 
Amount excreted in urine over the sampling interval. 
Fe 
Fraction of drug excreted in the urine over sampling interval. 
CLR 
Renal clearance, CLR = Ae/AUC where both Ae and AUC are determined over co-incident 
time ranges after dosing. 
Additional PK parameters may be analyzed as appropriate. 


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10.5.1. 
Statistical Analysis of Pharmacokinetic Data 
10.5.1.1. Dose Proportionality 
In P1, dose-proportionality for PK parameters of EIDD-2801 and EIDD-1931 (AUC0-inf, AUClast, 
and Cmax) will be assessed by the power model. The slope and the associated 90% CI based on 
the power model will be reported. 
In Part 3 on Day 6 dose-proportionality for PK parameters of EIDD-2801 and EIDD-1931 
(AUCτ, and Cmax) will be assessed by the power model. The slope and the associated 90% CI 
based on the power model will be reported. 
10.5.1.2. Food-Effect 
To assess the effect of food on the PK of EIDD-2801 and EIDD-1931, natural log transformed 
PK parameters from P2 (AUC0-inf, AUClast, and Cmax) will be analyzed using a mixed-effects 
model with fixed-effect terms for treatment (with or without food), period, and sequence and 
with subject within sequence as a random effect. Point estimates and their associated 90% CIs 
for the natural log-transformed PK parameters for the difference between EIDD-2801 
administered under fed relative to fasted conditions will be constructed. The point estimates and 
interval estimates will be back transformed to give estimates of the ratio and 90% CI for the 
geometric least squares mean ratio for fed/fasted to assess the effect of food. 
10.6. 
Peripheral Blood Mononuclear Cells 
Peripheral blood mononuclear cells will be collected from subjects following each dose in P2. 
Depending upon ongoing review of the data, PBMCs may be collected from subjects in P3; the 
collection of these samples may be omitted from some cohorts in P3. 
The PBMCs will be stored for analysis of EIDD-2061 levels at some point in the future and 
reported separately. 
10.7. 
Interim Analyses 
There are no formal interim analyses planned for this study. However, interim analyses may be 
implemented at the discretion of the Sponsor or health authority request. In addition, data from 
P1 cohorts may be locked, unblinded, and analyzed prior to conducting P2 and P3. 


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11. 
STUDY ADMINISTRATION 
11.1. 
Regulatory and Ethical Considerations 
11.2. 
Ethical Standard 
This study will be conducted in accordance with the protocol and with the following: 
 Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
International Ethical Guidelines. 
 Applicable ICH GCP Guidelines. 
 United States CRFs applicable to clinical studies (45 CFR Part 46; 21 CFR Part 50, 21 
CFR Part 56, and 21 CFR Part 312). 
 Applicable laws and regulations. 
11.2.1. 
Ethics Committee Approval 
The PI (or designee) must ensure that all required study-specific documents and/or information 
are submitted to the EC for review and approval as appropriate including but not limited to: 
 the protocol and any future protocol amendments 
 ICF and any other documents (electronic or paper) given to the subject 
 IB 
Any substantial protocol amendments, likely to affect the safety of the subjects or the conduct of 
the study, will require EC and regulatory authority (as locally required) approval before 
implementation of changes made to the study design, except for changes necessary to eliminate 
an immediate hazard to study subjects or any nonsubstantial changes, as defined by regulatory 
requirements. 
11.2.2. 
Informed Consent 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continuing throughout the individual’s study participation. Extensive discussion of 
risks and possible benefits of this therapy will be provided to the subjects and, if applicable, their 
families. Consent forms describing in detail the study interventions/products, study procedures, 
and risks are given to the subject and written documentation of informed consent is required 
prior to starting any screening procedures or intervention/administering study product. Consent 
forms will be EC-approved and the subject will be asked to read and review the document. 


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Upon reviewing the document, the PI (or designee) will explain the research study to the subject 
and answer any questions that may arise. The subjects will sign the ICF prior to any procedures 
being done specifically for the study. The subjects should have the opportunity to discuss the 
study with their surrogates or think about it prior to agreeing to participate. The subjects may 
withdraw consent at any time throughout the course of the trial. A copy of the ICF will be given 
to the subjects for their records. The rights and welfare of the subjects will be protected by 
emphasizing to them that the quality of their medical care will not be adversely affected if they 
decline to participate in this study. 
11.3. 
Financing and Insurance 
Financing and insurance will be addressed in a separate agreement. 
11.4. 
Source Documentation and Access 
The site will maintain appropriate medical and research records in compliance with ICH E6, 
Section 4.9 and regulatory and institutional requirements for the protection of confidentiality of 
subjects. The site will permit authorized representatives of the Sponsor, its designees, and 
appropriate regulatory agencies to examine (and when required by applicable law, to copy) 
clinical records for the purposes of quality assurance reviews, audits, and evaluation of the study 
safety and progress. These representatives will be permitted access to all source data and source 
documents, which include, but are not limited to, clinical and office charts, laboratory notes, 
memoranda, subjects’ memory aid or evaluation checklists, pharmacy dispensing records, 
recorded data from automated instruments, copies or transcriptions certified after verification as 
being accurate and complete, photographic negatives, microfilm or magnetic media, x-rays, and 
subject files and records kept at the pharmacy, at the laboratory, and medico-technical 
departments involved in the clinical trial. 
11.5. 
Data Collection and Record Keeping 
11.5.1. 
Data Collection 
Data collection and data entry are the responsibility of the clinical trial staff at the site. The PI is 
responsible for ensuring the accuracy, completeness, legibility, and timeliness of the data 
reported. All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data. 
A CRF must be completed for every subject who signs the ICF and has at least one 
protocol-specified assessment conducted. The CRF must be completed and processed according 
to the CRF guidelines and the SOPs of the site. All data should be entered into the CRF, where 
possible, within 3 days after each visit for any one subject. After the subject has completed the 
study, the PI must review and sign the signature page of the CRF indicating that he has reviewed 
the completed CRF and pertinent clinical data for that subject and that, to the best of his 
knowledge, all data recorded in the CRF accurately reflects the subject’s clinical performance in 
the study 


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11.5.2. 
Study Records Retention 
Study documents should be retained for a minimum of 5 years after the end of the study. These 
documents should be retained for a longer period; however, if required by local regulations. No 
records will be destroyed without the written consent of the Sponsor, if applicable. It is the 
responsibility of the Sponsor to inform the PI when these documents no longer need to be 
retained. 
11.5.3. 
Protocol Deviations 
A protocol deviation is any noncompliance with the protocol or study procedures detailed in the 
laboratory or pharmacy manuals. The noncompliance may have been the result of action by the 
PI, site staff, or subject. All deviations should be handled in accordance with site SOPs. 
It is the responsibility of the site to use continuous vigilance to identify and report deviations 
within 5 working days of identification of the protocol deviation, or within 5 working days of the 
scheduled protocol-required activity. 
11.6. 
Clinical Monitoring 
Site monitoring is conducted to ensure that the human subjects’ protections, study and laboratory 
procedures, study intervention administration, and data collection processes are of high quality 
and meet Sponsor, ICH/GCP guidelines and applicable regulations, and that this trial is 
conducted in accordance with the protocol, protocol-specific MOP and applicable Sponsor SOPs. 
Experienced clinical monitors of the Sponsor or its designee will conduct site-monitoring visits 
as detailed in the clinical monitoring plan. 
Site visits will be made at standard intervals as defined by the Sponsor and may be made more 
frequently as directed by the Sponsor. Monitoring visits will include, but are not limited to, 
review of regulatory files, accountability records, CRFs, ICFs, medical and laboratory reports, 
and protocol and GCP compliance. Clinical monitors will have access to each participating site, 
study personnel, and all study documentation according to the site monitoring plan. Clinical 
monitors will meet with the site PI to discuss any problems and actions to be taken and will 
document site visit findings and discussions. As data are entered into a CRF, data will be 
monitored to ensure accuracy as well as adherence to data entry instructions provided in the CRF 
guidelines. 
11.7. 
Quality Control and Quality Assurance 
A quality management plan will be put in place for this study. The site is responsible for 
conducting routine quality assurance and quality control activities to internally monitor study 
progress and protocol compliance. The PI will provide direct access to all study-related sites, 
source data/data collection forms, and reports for the purpose of monitoring and auditing by the 
Sponsor, and inspection by local and regulatory authorities. The PI will ensure all study 
personnel are appropriately trained and applicable documentations are maintained on site. 


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11.8. 
Study Termination and Closure Procedures 
11.8.1. 
Study Termination 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided to the site. If the study is terminated or suspended, the PI (or 
designee) will inform study participants and the EC. The Sponsor will notify appropriate 
regulatory authorities. The Sponsor will provide the reason(s) for the termination or suspension. 
Study participants will be contacted, as applicable, and be informed of changes to study visit 
schedule. 
If suspended, the study may resume once issues that caused suspension of the study are resolved. 
11.8.2. 
Termination Procedures 
If the study is prematurely terminated, then the site must return all appropriate study data, 
resolve all data queries, complete final drug accountability, return any study drug remaining on 
site, and ship all biological samples (including PK and PBMCs) to the laboratory designated by 
the Sponsor. The PI (or designee) must notify the EC of study termination. 
11.9. 
Information Disclosure 
11.9.1. 
Confidentiality 
Subject confidentiality and privacy is strictly held in trust by the PI, site staff, and the Sponsor(s) 
and their agents. The study protocol, documentation, data, and all other information generated 
will be held in strict confidence. No information concerning the study or the data will be released 
to any unauthorized third party without prior written approval of the Sponsor. 
The study monitor or other authorized representatives of the Sponsor or regulatory agencies may 
inspect all documents and records required to be maintained by the PI, including but not limited 
to, medical records (office, clinic, or hospital) and pharmacy records for the participants in this 
study. The clinical study site will permit access to such records. 
The study participant’s contact information will be securely stored at the clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by the Sponsor, site, or regulatory requirements. 
Study participant research data will be transmitted to and stored securely by the Sponsor’s 
designated data center. This will not include the participant’s contact or identifying information. 
Individual participants and their research data will be identified by a unique study identification 
number. The study data entry and study management systems used by clinical sites will be 
secured and password-protected. At the end of the study, all study databases will be de-identified 
and archived at a secure location. 


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11.9.2. 
Clinicaltrials.gov 
This clinical study will be registered on clinicaltrials.gov as required. 
11.9.3. 
Publication Policy 
All information generated from this study is the proprietary property of the Sponsor. It is the 
intent of the Sponsor to publish the results of the study in their entirety as deemed appropriate. 


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12. 
REFERENCES 
Agostini ML, Pruijssers AJ, Chappell JD, Gribble J, Lu X, Andres EL, et al. Small-Molecule 
Antiviral β-d-N4-Hydroxycytidine Inhibits a Proofreading-Intact Coronavirus with a High 
Genetic Barrier to Resistance. J Virol. 2019 Dec 15;93(24).  
Flavell RA, Sabo DL, Bandle EF, Weissmann C. Site-directed mutagenesis: generation of an 
extracistronic mutation in bacteriophage Q beta RNA. J Mol Biol. 1974 Oct 25;89(2):255–72.  
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 Dec;48(12):4636–42.  
Mullins JI, Heath L, Hughes JP, Li D, Essigmann JM, Harris KS, et al. Mutations based on viral 
decay acceleration in the HIV-1 genomes of a clinical population treated with the mutagenic 
nucleoside KP1461. Retrovirology. 2011 Oct 3;8(Suppl 2):P84.  
Painter GR, Bowen RA, Bluemling GR, DeBergh J, Edpuganti V, Gruddanti PR, et al. The 
prophylactic and therapeutic activity of a broadly active ribonucleoside analog in a murine model 
of intranasal venezuelan equine encephalitis virus infection. Antiviral Res. 2019;171:104597.  
Sticher ZM, Lu G, Mitchell DG, Marlow J, Moellering L, Bluemling GR, et al. Analysis of the 
Potential for N4-Hydroxycytidine To Inhibit Mitochondrial Replication and Function. 
Antimicrob Agents Chemother. 2020 27;64(2).  
Stuyver LJ, Whitaker T, McBrayer TR, Hernandez-Santiago BI, Lostia S, Tharnish PM, et al. 
Ribonucleoside analogue that blocks replication of bovine viral diarrhea and hepatitis C viruses 
in culture. Antimicrob Agents Chemother. 2003 Jan;47(1):244–54.  
Toots M, Yoon J-J, Cox RM, Hart M, Sticher ZM, Makhsous N, et al. Characterization of orally 
efficacious influenza drug with high resistance barrier in ferrets and human airway epithelia. Sci 
Transl Med. 2019 Oct 23;11(515):eaax5866.  
Urakova N, Kuznetsova V, Crossman DK, Sokratian A, Guthrie DB, Kolykhalov AA, et al. 
β-d-N4-Hydroxycytidine Is a Potent Anti-alphavirus Compound That Induces a High Level of 
Mutations in the Viral Genome. J Virol. 2018 01;92(3).  
Yoon J-J, Toots M, Lee S, Lee M-E, Ludeke B, Luczo JM, et al. Orally Efficacious 
Broad-Spectrum Ribonucleoside Analog Inhibitor of Influenza and Respiratory Syncytial 
Viruses. Antimicrob Agents Chemother. 2018;62(8). 


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13. 
APPENDICES 
Appendix 1: 
Time and Events Schedule 
Parts 1 and 2 
Visit 
Screening 
(Days -28 to -2) Day -1 Day 1 Day 2 
(24 hr) 
Day 3 
(48 hr) 
Day 4 
(72 hr) Day 9 
Day 15 / EOS1 
(non-FE cohorts) 
Food-Effect Cohort 
Day 14 Day 15 Day 16 
(24 hr) 
Day 17 
(48 hr) 
Day 18 
(72 hr) Day 23 
Day 30 / EOS 
ICF; Demography 
x 
 
 
 
 
 
 
 
I/E; Medical history 
x 
x 
 
 
 
 
 
 
Physical examination2 
x 
x 
 
x 
 
x 
x 
x 
Qualifying laboratory analyses3 
x 
x 
 
 
 
 
 
 
Drug screening and pregnancy test4 
x 
x 
 
 
 
 
x 
x 
Height, weight (BMI) 
x 
 
 
 
 
 
 
 
Clinic confinement5 
 
x 
x 
x 
x 
x 
 
 
Non-residential visit 
x 
 
 
 
 
 
x 
x 
Clinical chemistry and urinalysis6 
x 
x 
 
x 
 
x 
x 
x 
Hematology7 
x 
x 
 
x 
x 
x 
x 
x 
PBMC collection (FE cohort ONLY) 
 
 
x8 
x8 
 
 
 
 
ECG 
x 
 
x9 
 
 
x 
 
x 
Continuous 12-lead ECG (Part 1 only) 
 
 
x16 
x16 
 
 
 
 
Vital signs 
x 
x 
x10 
x 
x 
x 
x 
x 
Administer study drug 
 
 
x 
 
 
 
 
 
Plasma PK sample collection 
 
 
x11 
x12 
x12 
x12 
 
 
Urine PK sample collection 
 
 
x13 
x14 
x14 
 
 
 
Adverse events 
x15 
x15 
x15 
x 
x 
x 
x 
x 
Prior and/or Concomitant medications 
x 
x 
x 
x 
x 
x 
x 
x 
Abbreviations: BMI (body mass index); EOS (End of Study); FE (food-effect); ICF (Informed Consent Form); I/E 
(Inclusion/Exclusion Criteria); ECG (electrocardiogram); PBMC (peripheral blood mononuclear cell); PK (pharmacokinetic). 
1 On Day 15, conduct the EOS visit for all subjects except those in the FE cohort. 
2 A complete PE will be performed at Screening and/or Check-in, and EOS visits; on all other days, a limited PE will be 
conducted targeting any change from the previous status or any body system deemed pertinent to that subject by the PI (or 
designee).  
3 Laboratory analyses to qualify for study entry include: total white cell count or absolute lymphocyte count (values must be in 
the normal range), hemoglobin or platelet levels (values must not be below the lower limit of normal), and ALT/SGPT, alkaline 
phosphatase, AST/SGOT (values must not be above the upper limit of normal), plus virology (HIV/HCV/HBV; tested at 
Screening only; all must be negative), and FSH (if required). 
4 Drug screening (urine drug screen, UDS), including a cotinine test, should be conducted at Screening, Day -1, Days 9, 14, and 
23, and at EOS. Pregnancy tests should be conducted in serum at Screening and in urine at all other times (i.e., Days -1, 9, 14, 
and 23, and at EOS). A positive urine pregnancy test will be confirmed with a serum pregnancy test. An alcohol breath test 
should be conducted at Screening and Days -1 and 14. 
5 Participants should be admitted to the clinic following review of final I/E criteria on Day -1 and discharged from the clinic 
following completion of study specific assessments on Day 4. Subjects in the FE cohort should be readmitted to the clinic on 
Study Day 14. 
6 Safety laboratory assessments include clinical chemistry and urinalysis. Baseline samples will be collected after clinic 
admission on Day -1.  


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7 Hematology values include, but are not limited to, RBC, WBC with differential and platelets. PT/PTT and INR assessed only at 
Screening. 
8 PBMCs will be collected predose, and 2, and 8 hrs postdose on Days 1 and 15. Depending on ongoing review of the data, 
timepoints may be modified or removed, and up to 2 additional samples may be collected. 
9 The baseline ECG should be conducted prior to dosing on Day 1/15. 
10 Vital signs include pulse rate, respiratory rate, blood pressure, and body temperature; on Day 1/15, VS should be taken 
predose, and at 2, 4, 8 and 12 hr postdose.  
11 PK samples should be collected predose and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 9, 12, and 15 hr postdose on Day 1/15. 
Depending on ongoing review of the PK data, timepoints may be modified or removed, and up to 3 additional samples (in each 
period for the food-effect) may be added. 
12 PK samples should be collected at 24, 36, 48, and 72 hr postdose on Days 2/16, 3/17, 4/18 respectively. Depending on ongoing 
review of the PK data, timepoints may be modified or removed, and up to 3 additional samples (in each period for the 
food-effect) may be added. 
13 Urine samples for PK analysis should be collected predose (spot collection), and from 0 to 4, 4 to 8, 8 to 12, and 12 to 24 hr 
postdose. 
14 Urine samples for PK analysis should be collected from 24 to 36 and 36 to 48 hr postdose. 
15 Adverse events occurring prior to study drug administration should be recorded as medical history unless the event is directly 
related to a study specified procedure. 
16 Monitor for 12-lead ECG recording will be worn from approximately 2 hours prior to dosing (0 hr) to 25 hrs (Day 2) postdose. 
Extraction timepoints will be at 60, 45, and 30 minutes prior to dosing and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 9, 12, 15 and 24 hrs 
postdose. 
 
 


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Part 3 
Visit
Screening 
(Days -28 to 
-2) 
Day -1 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 Day 9 Day 14 
Day 
20 
/EOS 
ICF; Demography 
x 
 
 
 
 
 
 
 
 
 
 
 
 
I/E; Medical history 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
Physical examination1 
x 
x 
 
x 
 
 
 
 
x 
 
 
x 
x 
Qualifying laboratory 
analyses2 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
Drug screening and 
pregnancy test3 
x 
x 
 
 
 
 
 
 
 
 
 
x 
x 
Height, weight (BMI) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Clinic confinement4 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Non-residential visit 
x 
 
 
 
 
 
 
 
 
 
 
x 
x 
Clinical chemistry and 
urinalysis5 
x 
x 
 
 
x 
 
 
x 
 
 
x 
 
x 
Hematology6 
x 
x 
 
 
x 
 
 
x 
 
 
x 
x 
x 
PBMC collection7 
 
 
x 
 
 
 
 
x 
 
 
 
 
 
ECG8 
x 
 
x 
 
 
 
 
x 
 
 
x 
 
x 
Continuous 12-lead 
ECG 
 
 
x9 
 
 
 
 
x10 
x10 
 
 
 
 
Vital signs11 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Administer study 
drug12 
 
 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
Plasma PK sample 
collection13 
 
 
x 
 
 
x 
 
x 
x 
x 
x 
x 
 
Urine PK sample 
collection14 
 
 
x 
 
 
 
 
x 
x 
x 
x 
 
 
Adverse events 
x15 
x15 
x15 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Prior and/or 
Concomitant 
medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Abbreviations: BID (twice daily); BMI (body mass index); EOS (End of Study); ICF (Informed Consent Form); I/E 
(Inclusion/Exclusion Criteria); ECG (electrocardiogram); PK (pharmacokinetic). 
1 A complete PE will be performed at Screening and/or Check-in, and EOS visits; on all other days, a limited PE will be 
conducted targeting any change from the previous status or any body system deemed pertinent to that subject by the PI (or 
designee). 
2 Laboratory analyses to qualify for study entry include: total white cell count or absolute lymphocyte count (values must be in 
the normal range), hemoglobin or platelet levels (values must not be below the lower limit of normal), and ALT/SGPT, alkaline 
phosphatase, AST/SGOT (values must not be above the upper limit of normal), plus virology (HIV/HCV/HBV; tested at 
Screening only; all must be negative), and FSH (if required). 
3 Drug screening (urine drug screen, UDS), including cotinine, should be conducted at Screening, Day -1, Day 14, and at EOS. 
Pregnancy tests should be conducted in serum at Screening and in urine at all other timepoints. A positive urine pregnancy test 
will be confirmed with a serum pregnancy test. An alcohol breath test should be conducted at Screening and Day -1. 
4 Participants should be admitted to the clinic following review of final I/E criteria on Day -1 and discharged from the clinic 
following completion of study specific assessments on Day 9. 
5 Safety laboratory assessments include clinical chemistry and urinalysis. Baseline samples will be collected after clinic 
admission on Day -1. On Days 3 and 6, the assessment will be pre-am dose. On Day 9, the assessment will be 72 hrs post-am 
dose on Day 6. 


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6 Hematology values include, but are not limited to, RBC, WBC with differential and platelets. PT/PTT and INR assessed only at 
Screening. 
7 PBMCs will be collected 2 hrs postdose, relative to the first daily dose on Day 1, and pre-am dose and 2 and 8 hrs postdose 
relative to the first daily dose on Day 6. Depending on ongoing review of the data, timepoints may be modified or removed, and 
up to 2 additional samples may be collected. Additionally, PMBC collection may be omitted from some cohorts. 
8 The baseline ECG should be conducted prior to first dosing on Day 1. On Day 1, ECG should be taken predose and 2 hours 
post-am dose. On Day 6, ECG should be taken predose, 2 hrs, and 72 hrs (Day 9) postdose. 
9 On Day 1, monitor for 12-lead ECG recording will be worn from 2 hrs prior to the first of the daily doses to 12 hrs following 
the first of the daily doses. Extraction timepoints will be 60, 45, and 30 minutes prior to the first of the daily doses and at 0.25, 
0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 9, and 12 hrs following the first of the daily doses. 
10 On Day 6, monitor for 12-lead ECG recording will be worn from 2 hours prior to dosing (0 hr) to 25 hrs (Day 7) postdose. 
Extraction timepoints will be at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 9, 12, and 24 hrs postdose. 
11 Vital signs include pulse rate, respiratory rate, blood pressure, and body temperature. On Day 1, VS should be taken pre-am 
dose, and at 2, 4, and 8 hrs post-am dose. On Day 2 through 5, VS should be taken pre-am dose. On Day 6, VS should be taken 
predose, and 2, 4, 8, 24 (Day 7), 48 (Day 8), and 72 (Day 9) hrs postdose.  
12 Study drug should be administered BID, 12 hrs apart on Days 1 through 5. On Day 6, study drug should be administered once 
in the morning only (0 hr).  Depending on ongoing review of the safety, tolerability, and PK data, the number of days of dosing 
may be reduced and the dosing frequency changed; the dosing frequency will be no less than once-daily or no greater than 
three-times daily. If the number of days of dosing are reduced, the timepoints for subsequent assessments and the period for 
which subjects are domiciled at the clinic will similarly be changed (subjects will be domiciled for 3 days post final dose). 
13 On Day 1, PK samples should be collected pre-am dose and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 9, and 12 hrs post-am dose. On 
Day 4, the PK sample should be collected pre-am dose. On Day 6, PK samples should be collected predose and at 0.25, 0.5, 1, 
1.5, 2, 2.5, 3, 4, 6, 9, 12, 15, 24 (Day 7), 48 (Day 8), 72 (Day 9), and 192 (Day 14) hrs postdose. Depending on ongoing review of 
the PK data, timepoints may be modified or removed, and up to 3 additional samples may be added. 
14 On Day 1, urine samples for PK analysis should be collected predose (spot collection), and from 0 to 4, 4 to 8, and 8 to 12 hrs 
postdose. On Day 6, urine samples for PK analysis should be collected predose (spot collection), and from 0 to 4, 4 to 8, 8 to 12, 
12 to 24 (Day 7), 24 to 48 (Day 8), and 48 to 72 hrs (Day 9).  Sampling timepoints may be modified, removed, or additional 
timepoints added depending upon ongoing review of the data. The 12-hour urine collection should occur prior to the second daily 
dose administration. 
15 Adverse events occurring prior to study drug administration should be recorded as medical history unless the event is directly 
related to a study specified procedure. 
 


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Protocol Release Date: 11 June 2020  
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Appendix 2: 
DMID Toxicity Grading Scale 
Clinical Adverse Events 
VITAL SIGNS 
Mild (Grade 1) 
Moderate Grade 2) 
Severe (Grade 3) 
Fever (°C) Oral temperature; no recent hot or 
cold beverages or smoking. 
38.0 – 38.4 
38.5 – 38.9 
>39.0 
Tachycardia - beats per minute 
101 – 115 
116 – 130 
> 130 or ventricular 
dysrhythmias 
Bradycardia - beats per minute 
50 - 54 or 45 - 50 bpm if 
baseline <60 bpm 
45 - 49 or 40 - 44 if 
baseline <60 bpm 
< 45 or <40 bpm if baseline 
<60 bpm 
Hypertension (systolic) - mm Hg [Assuming 
supine position, 10 min at rest conditions, not 
sleeping subjects, measurements on the same 
arm and several concordant results.] 
 
141 - 150 
 
151 - 160 
 
> 160 
Hypertension (diastolic) - mm Hg 
91 - 95 
96 - 100 
> 100 
Hypotension (systolic) - mm Hg 
85 - 89 
80 - 84 
< 80 
Tachypnea – breaths per minute 
23 - 25 
26 - 30 
>30 
CARDIOVASCULAR 
Grade 1 
Grade 2 
Grade 3 
Arrythmia 
 
asymptomatic, transient 
signs, no Rx required 
recurrent/persistent; 
symptomatic Rx required 
Hemorrhage, Blood Loss 
Estimated blood loss 
< 100 mL 
Estimated blood loss 
> 100 mL, no 
transfusion 
required 
Transfusion required 
RESPIRATORY 
Grade 1 
Grade 2 
Grade 3 
Cough 
Transient-no treatment 
Persistent cough; 
Interferes with daily activities 
Bronchospasm, Acute 
transient; no treatment; 
71-  80% FEV1 of peak 
flow 
requires treatment; 
normalizes with 
bronchodilator; FEV1 
60 - 70% (of peak flow) 
no normalization with 
bronchodilator; FEV1 <60% of 
peak flow 
Dyspnea 
Does not interfere with 
usual and social 
activities 
Interferes with usual 
and social activities, no 
treatment 
Prevents daily and usual social 
activity or requires treatment 
GASTROINTESTINAL 
Grade 1 
Grade 2 
Grade 3 
Nausea 
No interference with 
activity 
Some interference with 
activity 
Prevents daily activities 
Vomiting 
No interference with 
activity or 1 - 2 
episodes/24 hours 
Some interference with 
activity or > 2 
episodes/24 hours 
Prevents daily activity or 
requires IV hydration 
Diarrhea 
2 - 3 loose or watery 
stools or < 400 
gms/24 hours 
4 - 5 loose or watery 
stools or 400 - 800 
gms/24 hours 
6 or more loose or watery 
stools or > 800gms/24 hours or 
requires IV hydration 


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Reactogenicity 
Local reactions 
Grade 1 
Grade 2 
Grade 3 
Pain 
Does not interfere with 
activity 
Repeated use of 
non-narcotic pain 
reliever > 24 hours or 
interferes with activity 
Any use of narcotic pain 
reliever or prevents daily 
activity 
Tenderness 
Discomfort only to touch 
Discomfort with 
movement 
Significant discomfort at rest 
Erythema/Redness * 
2.5 - 5 cm 
5.1 - 10 cm 
> 10 cm 
Induration/Swelling ** 
2.5 - 5 cm and does not 
interfere with activity 
5.1 - 10 cm or interferes 
with activity 
> 10 cm or prevents daily 
activity 
SYSTEMIC 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Allergic Reaction 
pruritus without rash 
localized urticaria 
generalized urticaria; 
angioedema or anaphylaxis 
Headache 
No interference with 
activity 
Repeated use of 
non-narcotic pain 
reliever > 24 hours or 
some interference with 
activity 
Significant; any use of narcotic 
pain reliever or prevents daily 
activity 
Fatigue 
No interference with 
activity 
Some interference with 
activity 
Significant; prevents daily 
activity 
Myalgia 
No interference with 
activity 
Some interference with 
activity 
Significant; prevents daily 
activity 
All Other conditions 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Illness or clinical adverse event (as defined 
according to applicable regulations) 
No interference with 
activity 
Some interference with 
activity not requiring 
medical intervention 
Prevents daily activity and 
requires medical intervention 
*In addition to grading the measured local reaction at the greatest single diameter, the measurement should be recorded as a 
continuous variable. 
**Induration/Swelling should be evaluated and graded using the functional scale as well as the actual 
measurement 
 
 


Clinical Study Protocol: EIDD-2801-1001-UK 
Version 5.1 (United Kingdom) 
Ridgeback Biotherapeutics 
Protocol Release Date: 11 June 2020  
Confidential 
Page 97 
Laboratory Adverse Events 
Blood, Serum, or Plasma * 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Sodium – Hyponatremia mEq/L 
132 – <LLN 
130 – 131 
<130 
Sodium – Hypernatremia mEq/L 
>ULN – 148 
149 – 150 
>150 
Potassium – Hyperkalemia mEq/L 
>ULN – 5.2 
5.3 – 5.4 
>5.4 
Potassium – Hypokalemia mEq/L 
<LLN-3.1 
<3.1 – 3.0 
<3.0 
Glucose – Hypoglycemia mg/dL 
65 – 67 
55 – 64 
<55 
Glucose – Hyperglycemia Fasting – mg/dL 
>ULN - 120 
121 – 130 
>130 
Glucose – Hyperglycemia Random – mg/dL 
140 – 159 
160 – 200 
>200 
Blood Urea Nitrogen mg/dL 
23-26 
27 – 31 
> 31 
Creatinine – mg/dL 
>ULN – 1.7 
1.8 – 2.0 
>2.0 
Calcium – hypocalcemia mg/dL 
8.0 – <LLN 
7.5 – 7.9 
<7.5 
Calcium – hypercalcemia mg/dL 
>ULN – 11.0 
11.1 – 11.5 
>11.5 
Magnesium – hypomagnesemia mg/dL 
1.3 – 1.5 
1.1 – 1.2 
<1.1 
Phosphorus – hypophosphatemia mg/dL 
2.3 – 2.5 
2.0 – 2.2 
<2.0 
CPK – mg/dL 
400-1000 
1001-1500 
>1500 
Albumin – Hypoalbuminemia g/dL 
2.8 – 3.0 
2.5 – 2.7 
< 2.5 
Total Protein – Hypoproteinemia g/dL 
5.2 – 5.4 
4.8 – 5.1 
< 4.8 
Alkaline phosphate – U/L 
132-240 
241– 360 
>360 
AST U/L 
44 – 105 
106-175 
>175 
ALT U/L 
44 – 105 
106-175 
>175 
Bilirubin (serum total) mg/dL 
1.3 - 2.0 
2.1 - 2.5 
> 2.5 
Bilirubin – when ALT >105 (Hy's law) 
1.3 -1.5 
1.6 – 2.0 
> 2.0 
Amylase- U/L 
200-270 
271-360 
>360 
Lipase- U/L 
176-270 
271-360 
>360 
Hemoglobin (Female) - g/dL 
11.0 – 11.5 
9.5 – 10.9 
< 9.5 
Hemoglobin (Male) - g/dL 
12.0 – 12.5 
10.0 – 11.9 
<10.0 
WBC Increase - cell/mm3 
11,001 – 15,000 
15,001 – 20,000 
> 20,000 
WBC Decrease - cell/mm3 
2,500 – 3,500 
1,500 – 2,499 
< 1500 
Lymphocytes Decrease - cell/mm3 
750 – 1,000 
500 – 749 
< 500 
Neutrophils Decrease - cell/mm3 
1,500 – 2,000 
1,000 – 1,499 
< 1000 
Eosinophils - cell/mm3 
500-750 
751-1500 
> 1500 
Platelets Decreased - cell/mm3 
120,000 – 130,000 
100,000 – 119,999 
<100,000 
PT – seconds (prothrombin time) 
> ULN-14.4 
14.5 – 15.7 
> 15.7 
PTT – seconds (partial thromboplastin time) 
>ULN-42.1 
42.2– 50.0 
> 50.0 
Fibrinogen increase - mg/dL 
>ULN – 500 
501 – 600 
> 600 
Fibrinogen decrease - mg/dL 
<LLN – 140 
125 – 139 
<125 
Urine * 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Protein 
1+ 
2+ 
>2+ 
Glucose 
1+ 
2+ 
>2+ 
Blood (microscopic) - red blood cells per high 
power field (rbc/hpf) 
5-10 
11-50 
> 50 and/or gross 
blood 
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal parameters. 
* Institutional normal reference ranges should be provided to demonstrate that they are appropriate. 
 


Clinical Study Protocol: EIDD-2801-1001-UK 
Version 5.1 (United Kingdom) 
Ridgeback Biotherapeutics 
Protocol Release Date: 11 June 2020  
Confidential 
Page 98 
Appendix 3: 
Contraception Guidance 
Male subjects (regardless of fertility status) with partners of childbearing potential must use a 
male barrier method of contraception (i.e., male condom with spermicide) in addition to a second 
method of acceptable contraception from Check-in until 90 days after the EOS visit. Acceptable 
methods of contraception for female partners include: 
 hormonal injection 
 combined oral contraceptive pill or progestin/progestogen-only pill 
 combined hormonal patch 
 combined hormonal vaginal ring 
 surgical method (bilateral tubal ligation or Essure® [hysteroscopic bilateral tubal 
occlusion])  
 hormonal implant 
 hormonal or non-hormonal intrauterine device 
 OTC sponge with spermicide 
 cervical cap with spermicide 
 diaphragm with spermicide. 
An acceptable second method of contraception for male subjects is vasectomy that has been 
performed at least 90 days prior to the screening visit, with verbal confirmation of surgical 
success. 
For male subjects (even with a history of vasectomy), sexual intercourse with female partners 
who are pregnant or breastfeeding should be avoided unless condoms are used from the time of 
the first dose until 90 days after the EOS visit. Male subjects are required to refrain from 
donation of sperm from Check-in until 90 days after the EOS visit. 
Sexual Abstinence and Same-sex Relationships 
Subjects who practice true abstinence, because of the subject’s lifestyle choice (i.e., the subject 
should not become abstinent just for the purpose of study participation), are exempt from 
contraceptive requirements. Periodic abstinence (eg, calendar, ovulation, symptothermal, 
postovulation methods) and withdrawal are not acceptable methods of contraception. If a subject 
who is abstinent at the time of signing the ICF becomes sexually active they must agree to use 
contraception as described previously. 


Clinical Study Protocol: EIDD-2801-1001-UK 
Version 5.1 (United Kingdom) 
Ridgeback Biotherapeutics 
Protocol Release Date: 11 June 2020  
Confidential 
Page 99 
For subjects who are exclusively in same-sex relationships, contraceptive requirements do not 
apply. If a subject who is in a same-sex relationship at the time of signing the ICF becomes 
engaged in a heterosexual relationship, they must agree to use contraception as described 
previously. 

SAP_001.pdf: 
Protocol Reference: EIDD-2801-1001-UK 
 CONFIDENTIAL  
 
 
 
 
 
 
 
Title of study: A Randomized, Double-blind, Placebo-controlled, First-in-human Study 
Designed to Evaluate the Safety, Tolerability, and Pharmacokinetics of EIDD-2801 
Following Oral Administration to Healthy Volunteers 
NCT Number: NCT04392219 
 
Document: Statistical Analysis Plan 
Date: 30 June 2020 
 


TITLE PAGE 
Statistical Analysis Plan 
A Randomized, Double-Blind, Placebo-Controlled, First-in-Human Study 
Designed to Evaluate the Safety, Tolerability, and Pharmacokinetics of 
EIDD-2801 Following Oral Administration to Healthy Volunteers 
SAP Status: Final 
SAP Version: 2.0 
SAP Date: 30JUN2020 
Investigational Product: EIDD-2801 
Protocol Reference: EIDD-2801-1001 
Covance Study: 8427402 
Sponsor: 
Ridgeback Biotherapeutics 
3162 Commodore Plaza, Suite 3E 
Miami, FL 33133-5815 
United States 
Study Sites: 
This study will be conducted at 1 site in the 
United Kingdom and up to 3 sites in the 
United States. 
Principal Investigator: 
 
 
Information described herein is confidential and may be disclosed only with the express 
written permission of the sponsor. 


SAP 
CONFIDENTIAL 
Covance Study: 8427402 
Protocol Reference: EIDD-2801-1001 
Final, Version 2.0, 30JUN2020 
Page 2 of 29 
TABLE OF CONTENTS 
TITLE PAGE ............................................................................................................................. 1 
TABLE OF CONTENTS ........................................................................................................... 2 
LIST OF ABBREVIATIONS .................................................................................................... 4 
1. INTRODUCTION ................................................................................................................. 6 
2. STUDY OBJECTIVES .......................................................................................................... 6 
2.1. Primary Objectives .......................................................................................................... 6 
2.2. Secondary Objectives ...................................................................................................... 6 
2.3. Exploratory Objectives.................................................................................................... 7 
3. STUDY ENDPOINTS ........................................................................................................... 7 
3.1. Primary Endpoints ........................................................................................................... 7 
3.2. Secondary Endpoints ....................................................................................................... 7 
4. STUDY DESIGN................................................................................................................... 7 
4.1. Overview ......................................................................................................................... 7 
4.1.1. Part 1 (Single Ascending Dose) ............................................................................... 8 
4.1.2. Part 2 (Food-Effect).................................................................................................. 8 
4.1.3. Part 3 (Multiple Ascending Dose) ............................................................................ 9 
5. SAMPLE SIZE JUSTIFICATION ...................................................................................... 10 
6. STUDY TREATMENTS ..................................................................................................... 11 
6.1. Part 1 ............................................................................................................................. 11 
6.2. Part 2 ............................................................................................................................. 11 
6.3. Part 3 ............................................................................................................................. 12 
7. DEFINITIONS OF POPULATIONS .................................................................................. 12 
7.1. All Subjects Population ................................................................................................. 12 
7.2. Safety Population .......................................................................................................... 13 
7.3. Pharmacokinetic Population ......................................................................................... 13 
8. STATISTICAL METHODOLOGY .................................................................................... 13 
8.1. General .......................................................................................................................... 13 
8.1.1. Calculation of the Summary Statistics ................................................................... 13 
8.1.2. Repeat and Unscheduled Readings ........................................................................ 14 
8.1.3. Definitions of Baseline, and Change from Baseline .............................................. 14 
8.2. Subject Disposition and Population Assignment .......................................................... 15 
8.3. Screening Demographics .............................................................................................. 15 


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Protocol Reference: EIDD-2801-1001 
Final, Version 2.0, 30JUN2020 
Page 3 of 29 
8.4. Prior and Concomitant Medication ............................................................................... 15 
8.5. Pharmacokinetic Assessments ...................................................................................... 15 
8.5.1. Pharmacokinetic Analysis ...................................................................................... 15 
8.5.2. Presentation of Pharmacokinetic Data ................................................................... 19 
8.5.3. Pharmacokinetic Statistical Methodology .............................................................. 19 
8.6. Safety and Tolerability Assessments ............................................................................ 22 
8.6.1. Adverse Events ....................................................................................................... 22 
8.6.2. Clinical Laboratory Parameters .............................................................................. 24 
8.6.3. Vital Signs Parameters ........................................................................................... 24 
8.6.4. 12-lead Electrocardiogram Parameters .................................................................. 24 
8.6.5. Other Assessments ................................................................................................. 25 
8.6.6. Safety and Tolerability Statistical Methodology .................................................... 25 
9. INTERIM ANALYSES ....................................................................................................... 25 
10. SIGNIFICANT CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES ........ 26 
11. REFERENCES .................................................................................................................. 26 
12. APPENDICES ................................................................................................................... 27 


SAP 
CONFIDENTIAL 
Covance Study: 8427402 
Protocol Reference: EIDD-2801-1001 
Final, Version 2.0, 30JUN2020 
Page 4 of 29 
LIST OF ABBREVIATIONS 
Abbreviations pertain to the statistical analysis plan (SAP) only (not the tables, figures, and 
listings [TFLs]).  
ADaM 
analysis data model 
AE 
adverse event 
Aet1-t2 
amount of the dose administered recovered in urine over the time 
interval t1 to t2 
ANOVA 
analysis of variance 
AUClast 
the area under the plasma concentration-time curve, from time 0 to the 
last measurable non-zero concentration 
AUC0-inf 
the area under the plasma concentration-time curve from time 0 
extrapolated to infinity 
AUC 
area under the plasma concentration-time curve during a dosing interval 
hours postdose 
%AUCextrap 
percentage of AUC0-inf that is due to extrapolation from the last 
quantifiable concentration to infinity 
%AUC, extrap 
percentage of AUC that is due to extrapolation from the last 
quantifiable concentration to the end of the dosing interval 
BLQ 
below the limit of quantification 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
confidence interval 
CL/F 
apparent clearance following an extravascular dose 
CLR 
renal clearance 
Cmax 
maximum observed concentration 
CSR 
clinical study report 
Ctrough 
plasma concentration at the end of the dosing interval 
CV 
coefficient of variation 
DMID 
Division of Microbiology and Infectious Diseases  
ECG 
electrocardiogram 
EOS 
end of study 
FDA 
Food and Drug Administration 
FE 
food-effect 
Fet1-t2 
percentage of the dose administered recovered in urine over the time 
interval t1 to t2 
FIH 
first-in-human 
GLSM 
geometric least squares mean 
ICH 
International Council for/Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use 
ln 
natural log 
LSM 
least squares mean 


SAP 
CONFIDENTIAL 
Covance Study: 8427402 
Protocol Reference: EIDD-2801-1001 
Final, Version 2.0, 30JUN2020 
Page 5 of 29 
MAD 
multiple ascending dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRAUC 
EIDD-1931:EIDD-2801 ratio based on AUC0-inf 
MRCmax 
EIDD-1931:EIDD-2801 ratio based on Cmax 
MW 
molecular weight 
PBMC 
peripheral blood mononuclear cells 
PE 
physical examination 
 
 
PK 
pharmacokinetic(s) 
QTc 
QT interval corrected for heart rate 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
RAAUC 
observed accumulation ratio based on AUCτ 
RACmax 
observed accumulation ratio based on Cmax 
SAD 
single ascending dose 
SAP 
statistical analysis plan 
TEAE 
treatment-emergent adverse event 
TFL 
table, figure, and listing 
tlast 
time of the last quantifiable concentration 
tmax 
time of the maximum observed concentration 
t1/2 
apparent terminal elimination half-life 
Vz/F 
apparent volume of distribution during the terminal phase following and 
extravascular dose 
WHODrug 
World Health Organization Drug Dictionary  
z 
apparent terminal elimination rate constant 
  
  
 
 


SAP 
CONFIDENTIAL 
Covance Study: 8427402 
Protocol Reference: EIDD-2801-1001 
Final, Version 2.0, 30JUN2020 
Page 6 of 29 
1. INTRODUCTION
This SAP has been developed after review of the clinical study protocols (Final Version 5.1 
(United Kingdom) dated 11 June 2020 and Final Version 5.2 (United States) dated 11 June 
2020) and electronic case report form.  
This SAP describes the planned analysis of the pharmacokinetic (PK) and safety and 
tolerability data from this study. A detailed description of the planned TFLs to be presented 
in the clinical study report (CSR) is provided in the accompanying TFL shells document.  
In general, the analyses are based on information from the protocol, unless they have been 
modified by agreement with Ridgeback Biotherapeutics. A limited amount of information 
about this study (eg, objectives, study design) is given to help the reader’s interpretation. This 
SAP must be finalized prior to the lock of the clinical database for this study. When the SAP 
and TFL shells are approved, they will serve as the template for this study’s CSR.  
This SAP supersedes any 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 this SAP, they may be performed 
and will be identified accordingly in the CSR. Any substantial deviations from this SAP will 
be agreed with Ridgeback Biotherapeutics and identified in the CSR.  
This SAP is written with consideration of the recommendations outlined in the International 
Conference on Harmonisation (ICH) E9 guideline Statistical Principles for Clinical Trials 
and ICH E3 guideline Structure and Content of Clinical Study Reports.1,2  
The document history is presented in Appendix 1. 
2. STUDY OBJECTIVES
2.1. Primary Objectives 
The primary objective of Part 1 of the study is to determine the safety and tolerability of 
single ascending doses of EIDD-2801. 
The primary objective of Part 2 of the study is to assess the effect of food on the PK on 
EIDD-2801 and EIDD-1931 following a single oral dose. 
The primary objective of Part 3 of the study is to determine the safety and tolerability of 
multiple ascending doses of EIDD-2801. 
2.2. Secondary Objectives 
The secondary objectives of Part 1 and Part 3 of the study is to define the PK of EIDD-2801 
and EIDD-1931 in plasma and urine following single and multiple doses administered to 
healthy volunteers. 
The secondary objective of Part 2 of the study is to determine the safety and tolerability of 
single doses of EIDD-2801. 


SAP 
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Covance Study: 8427402 
Protocol Reference: EIDD-2801-1001 
Final, Version 2.0, 30JUN2020 
Page 7 of 29 
2.3. Exploratory Objectives 
The exploratory objectives of Part 1 and of Part 3 are to collect data to assess the relationship 
between EIDD-2801/EIDD-1931 concentrations and QT interval corrected for heart rate 
(QTc). 
3. STUDY ENDPOINTS  
3.1. Primary Endpoints 
The primary endpoints for Parts 1 and 3 of the study are results of safety evaluations 
including safety laboratory assessments, physical examinations (PEs), electrocardiograms 
(ECGs), vital signs, and adverse events (AEs). 
The primary endpoints for Part 2 of the study are plasma PK parameters including Cmax, tmax, 
t1/2, CL/F, λz, Vz/F, AUC0-inf and AUClast as appropriate. 
3.2. Secondary Endpoints  
The secondary endpoints are as follows: 
 Single-dose plasma PK parameters, including Cmax, tmax, t1/2, CL/F, λz, Vz/F, 
AUC0-inf and AUClast as appropriate (Part 1) 
 Multiple-dose plasma PK parameters, including Ctrough, Cmax, tmax, t1/2, CL/F, λz, 
Vz/F, AUCτ, AUC0-inf (Day 1 dose only), RAAUCτ and RACmax, as appropriate 
(Part 3) 
 Urinary excretion of EIDD-2801 and EIDD-1931 following single- and 
multiple-dose administration (Parts 1 and 3). 
 Results of safety evaluations including safety laboratory assessments, PEs, ECGs, 
vital signs, and AEs (Part 2). 
4. STUDY DESIGN  
4.1. Overview 
EIDD-2801-1001 is a Phase 1, randomized, double-blind, placebo-controlled, first in human 
(FIH), single ascending dose (SAD), and multiple ascending dose (MAD) study of the safety, 
tolerability and PK of EIDD-2801 and EIDD-1931 following oral administration of single 
and multiple doses of EIDD-2801 to healthy volunteers. In addition, for a minimum of one 
cohort, the effect of food on the single-dose EIDD-2801 and EIDD-1931 PK parameters will 
be assessed in subjects taking open-label EIDD-2801. The overall objective of the study is to 
identify a starting dose for future safety and therapeutic intervention trials. 
The study is composed of 3 parts; Part 1 is the SAD study, Part 2 is the FE cohort study, and 
Part 3 is the MAD study.  


SAP 
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Covance Study: 8427402 
Protocol Reference: EIDD-2801-1001 
Final, Version 2.0, 30JUN2020 
Page 8 of 29 
This study will be conducted at 1 site in the United Kingdom and up to 3 sites in the United 
States. 
4.1.1. Part 1 (Single Ascending Dose) 
A single oral dose of EIDD-2801 or Placebo will be administered to subjects. Subjects will be 
randomized in a 3:1 ratio to receive either EIDD-2801 or Placebo. 
Following dosing on Day 1, subjects will remain in the clinic through completion of study 
assessments on Day 4, returning to the clinic on Day 9 for study assessments, and Day 15 for 
the end of study (EOS) visit. 
The first cohort will be divided into 2 groups. The first group, a sentinel group, will include 
2 subjects. On Day 1, one subject in the sentinel group will be administered Placebo and one 
will be administered EIDD-2801. Analysis of the safety results for the sentinel group will be 
reviewed 24 hours postdose. If no halting criteria have been met, the remainder of the 
subjects in Cohort 1 (the second group) will be dosed. There will be no sentinel groups for 
the remaining cohorts. 
After completion of each dosing cohort, safety and tolerability data will be reviewed to 
determine if any of the halting rules have been met. If not, then the subsequent cohort may be 
dosed following review of the 72-hour safety data. As PK data become available, these data 
may be used for dose-escalation decisions. 
The proposed dose-escalation scheme is shown in  
 


SAP 
CONFIDENTIAL 
Covance Study: 8427402 
Protocol Reference: EIDD-2801-1001 
Final, Version 2.0, 30JUN2020 
Page 9 of 29 
Figure 1, however, planned dose escalations will be determined based on ongoing review of 
the safety, tolerability, and available PK data. The starting dose in the first SAD cohort will 
be 50 mg. Dose levels will not increase by more than 3-fold for predicted 
nonpharmacologically active dose levels and by 2-fold for predicted pharmacologically active 
dose levels. The highest total daily dose to be studied under this protocol will not exceed 
1600 mg. 
Three cohorts are initially planned for Part 1; however, up to an additional 7 cohorts may be 
enrolled. 
4.1.2. Part 2 (Food-Effect) 
Two single oral doses of EIDD-2801 will be administered to subjects, in an open-label 
manner. The dose for the Part 2/food-effect cohort is planned to be 100 mg but may be 
adjusted based on safety, tolerability, and/or PK data from Part 1. The dose assessed in the 
Part 2 cohort will have been given previously to subjects in a Part 1 cohort successfully (i.e., 
no halting rules were met following dosing).  
Subjects will be randomized to a treatment sequence; i.e., to receive drug in the fed then 
fasted state (Sequence 1) versus fasted then fed state (Sequence 2;  
 


SAP 
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Covance Study: 8427402 
Protocol Reference: EIDD-2801-1001 
Final, Version 2.0, 30JUN2020 
Page 10 of 29 
Figure 1). Half of the subjects in the cohort will be randomized to Sequence 1 and the other 
half will be randomized to Sequence 2.  
Following dosing on Day 1, subjects will remain in the clinic through completion of study 
assessments on Day 4, returning to the clinic on Day 9 for study assessments, and Day 14 to 
begin the second dosing sequence on Day 15. Subjects will then be discharged from the clinic 
on Day 18, returning to the clinic on Day 23 for study assessments, and Day 30 for the EOS 
visit. There will be a 14-day (minimum) washout period between doses. 
One cohort of 10 subjects is planned for Part 2. However, if PK results obtained are 
equivocal, additional subjects may be enrolled into the Part 2/food-effect cohort at the 
previously tested dose or an additional Part 2/food-effect cohort may be added at a different 
dose. 
4.1.3. Part 3 (Multiple Ascending Dose) 
Subjects in Part 3 will be randomized in a 3:1 ratio to receive either EIDD-2801 or Placebo. 
Twice-daily dosing will be administered to subjects on Day 1 through Day 5, inclusive, and a 
final dose will be administered on the morning of Day 6 for collection of steady-state PK 
samples during waking hours. Depending on ongoing review of the safety, tolerability, and 
PK data, the number of days of dosing may be reduced and the dosing frequency may be 
changed; the dosing frequency will be no less than once-daily or no greater than three-times 
daily.  
The proposed dose-escalation scheme is shown in  
 


SAP 
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Covance Study: 8427402 
Protocol Reference: EIDD-2801-1001 
Final, Version 2.0, 30JUN2020 
Page 11 of 29 
Figure 1. The total daily dose will not exceed a dose shown to be safe and well-tolerated in 
Part 1. Doses in Part 3 may be administered in the fed state, following review of the PK data 
obtained from Part 2. Part 3 may run in parallel with Part 1, providing that the total daily dose 
to be administered does not exceed a dose already shown to be safe and well-tolerated in Part 
1. 
Subjects will remain domiciled at the site during the dosing period and until Day 9, returning 
to the clinic on Day 14 for completion of study assessments, and Day 20 for the EOS visit. If 
the number of days of dosing are reduced, the timepoints for subsequent assessments and the 
period for which subjects are domiciled at the clinic will similarly be changed (subjects will 
be domiciled for 3 days post final dose). 
Three cohorts are initially planned for Part 3; however, up to an additional 6 cohorts may be 
enrolled, or the number of cohorts may be reduced if the study objectives are met. Dose 
levels in Part 3 may be repeated for collection of peripheral blood mononuclear cells 
(PBMCs), providing that the dose level did not meet the dose-escalation halting criteria. 
Additional parts may be added to this study, including a SAD part in elderly healthy 
subjects and a study of the safety, tolerability, and PK in Japanese subjects. These 
additional parts may be added via a protocol amendment. 
 
 


SAP 
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Covance Study: 8427402 
Protocol Reference: EIDD-2801-1001 
Final, Version 2.0, 30JUN2020 
Page 12 of 29 
Figure 1: Study Design  
 
5. SAMPLE SIZE JUSTIFICATION  
No formal sample size calculation was conducted. The sample size of 8 per cohort 
(6 active: 2 Placebo) for the SAD and MAD cohorts is considered adequate for a Phase 1 FIH 
SAD Dose 1 (50 mg QD )
SAD Dose 2 (TBD)
SAD Dose 3 (TBD)
Review 
Safety Data
Review 
Safety Data
Sentinel Grp 1: 2 subjects
24 hr safety review
Grp 2: 6 subjects
PART 1: SAD Cohorts                                                                                                          
Following review of data from Part 1 cohort administered dose selected for Part 2
Sequence 1
Dose: Fed
Sequence 2
Minimum 14-Day Washout
Dose: Fasted
Dose: Fasted
Dose: Fed
PART 2: Food Effect (FE) Cohort                                                                                              
MAD Dose 1 (TBD***)
MAD Dose 2 (TBD***)
MAD Dose 3 (TBD***)
Review 
Safety Data
Review 
Safety Data
PART 3: MAD Cohorts**                                                                                                                    
Abbreviations:
FE: food effect 
SAD: single ascending dose
MAD: multiple ascending dose
** Part 3 may run in parallel with Part 1, providing that the total daily dose to be administered does not exceed 
a dose already shown to be safe and well tolerated in Part 1
***The total daily dose in Part 3 will not exceed a dose shown to be safe and well-tolerated in Part 1


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Protocol Reference: EIDD-2801-1001 
Final, Version 2.0, 30JUN2020 
Page 13 of 29 
study. The sample size of 10 subjects (all administered EIDD-2801) is in accordance with 
Food and Drug Administration (FDA) guidelines for sample size in food-effect studies. 
6. STUDY TREATMENTS  
All treatments described are the planned treatments. The TFLs will reflect the actual 
treatments received, and dose levels will be displayed in increasing order where applicable. 
Screen failure subjects will have treatment ‘Screen Failure’ presented in all applicable 
listings.  
6.1. Part 1 
The study treatment names, abbreviations, and ordering to be used in the TFLs are presented 
in Table 1.  
Table 1: 
Presentation of Study Treatments in TFLs  
Study Treatment 
Order in TFLs 
Placebo (fasted) 
1 
50 mg EIDD-2801 
 (fasted) 
2 
100 mg EIDD-2801 
 (fasted) 
3 
200 mg EIDD-2801 
 (fasted) 
4 
400 mg EIDD-2801 
 (fasted) 
5 
600 mg EIDD-2801 
 (fasted) 
6 
800 mg EIDD-2801 
 (fasted) 
7 
XXX mg EIDD-2801 
 (fasted) 
8 
 
Additional treatment labels may be added in the same format if additional cohorts are 
required. Amend the formulation as required as changes may occur throughout the study.  
All Placebo groups will be pooled 
 for summaries but in the listings the 
formulation will be indicated in the treatment label as ‘Placebo 
 (fasted)’ or ‘Placebo 
(fasted)’. 
As the capsule formulation is expected to be utilized for the latter cohorts, the 
 
EIDD-2801 treatment groups will be summarized after the 
 EIDD-2801 treatment groups.  
 
6.2. Part 2 
The study treatment names, abbreviations, and ordering to be used in the TFLs are presented 
in Table 2.  
Table 2: 
Presentation of Study Treatments in TFLs  
Study Treatment 
Order in TFLs 
200 mg EIDD-2801 
 (fasted)   
1 
200 mg EIDD-2801 
 (fed) 
2 
Additional treatment labels may be added in the same format if additional cohorts are 
required. Amend the formulation as required as changes may occur throughout the study. 


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The study treatment sequence names, abbreviations, and ordering to be used in the TFLs are 
presented in Table 3.  
Table 3: 
Presentation of Study Treatment Sequences in TFLs  
Study Treatment Sequence 
Abbreviation 
Order in TFLs 
200 mg EIDD-2801 
(fed) /  
200 mg EIDD-2801 
 (fasted) 
200 mg EIDD-2801 
 (fed/fasted)  
1 
200 mg EIDD-2801 
 (fasted) /  
200 mg EIDD-2801 
(fed) 
200 mg EIDD-2801 
(fasted/fed) 
2 
Additional treatment sequences may be added in the same format if an additional cohort at a 
different dose level is required. Amend the formulation as required as changes may occur 
throughout the study. 
 
6.3. Part 3 
The study treatment names, abbreviations, and ordering to be used in the TFLs are presented 
in Table 4.  
Table 4: 
Presentation of Study Treatments in TFLs  
Study Treatment 
Order in TFLs 
Placebo 
 BID (fasted) 
1 
50 mg EIDD-2801 
 BID (fasted) 
2 
100 mg EIDD-2801 
 BID (fasted) 
3 
200 mg EIDD-2801 
 BID (fasted) 
4 
300 mg EIDD-2801 
BID (fasted) 
5 
400 mg EIDD-2801 
BID (fasted) 
6 
XX mg EIDD-2801 
 BID (fasted) 
7 
Fasted in the treatment labels above indicates that subjects were fasted prior to the morning 
dose on PK Days 1 and 6. BID indicates twice daily dosing on Days 1 to 5 and single dose on 
Day 6. Additional treatment labels may be added in the same format if additional cohorts are 
required. Amend the frequency, formulation and dietary state as required as changes may 
occur throughout the study. 
 
7. DEFINITIONS OF POPULATIONS  
Any protocol deviations, including those related to COVID-19, will be considered prior to 
database lock for their importance and taken into consideration when assigning subjects to 
populations.  
7.1. All Subjects Population  
The all subjects population will include all subjects who signed the informed consent form 
and had any study assessment recorded in the database per the protocol.  


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7.2. Safety Population  
The safety population will include all subjects who received at least 1 dose of study drug 
(EIDD-2801 or Placebo).  
7.3. Pharmacokinetic Population  
The PK population will include all subjects receiving study drug who comply sufficiently 
with protocol requirements (i.e., no major protocol violations) and for whom a sufficient 
number of analyzable PK samples (at least 1 quantifiable postdose sample) have been 
obtained to permit the determination of the PK profile for EIDD-2801/EIDD-1931 and the 
statistical analysis of the results. Subjects who experience an AE of vomiting before 2× the 
median tmax of the group may be excluded from the PK population.  
8. STATISTICAL METHODOLOGY  
8.1. General  
Listings will be provided for all data captured in the database. Listings will include all 
subjects assigned to the all subjects population and include data up to the point of study 
completion or discontinuation. Subjects are generally considered to have completed the study 
if they completed all protocol-specified procedures and assessments for the end-of-treatment 
visit. Any subject who discontinued the study will be identified accordingly in the listings. 
Summaries and statistical analyses will include the subjects assigned to the relevant 
population based on data type.  
Data analysis will be performed using the SAS® statistical software package Version 9.4 (or 
higher if upversioned during the study).  
Analysis Data Model (ADaM) datasets will be prepared using Clinical Data Interchange 
Standards Consortium (CDISC) ADaM Version 2.1 (or higher if upversioned during the 
study) and CDISC ADaM Implementation Guide Version 1.1 (or higher if upversioned 
during the study). Pinnacle 21 Community Validator Version 2.2.0 (or higher if upversioned 
during the study) will be utilized to ensure compliance with CDISC standards.  
Caution should be used when interpreting results from the statistical analyses conducted in 
this study because the sample size is not based on power calculations.  
Where reference is made to ‘all calculations’, this includes, but is not limited to, summary 
statistics, statistical analyses, baseline derivation, changes from baseline, percentage changes 
from baseline, and any parameter derivations.   
8.1.1. Calculation of the Summary Statistics  
For continuous data the following rules will be applied:  
● Missing values will not be imputed, unless specifically stated otherwise.  
● Unrounded data will be used in the calculation of summary statistics.  


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● If the number of subjects with valid observations (n) <3, summary statistics will not be 
calculated, with the exception of n, minimum, and maximum.  
● As Early Termination data is not associated with any scheduled timepoint, it will be 
excluded from all calculations of summary statistics.  
For categorical data the following rules will be applied:  
● If the categories of a parameter are ordered (eg, AE severity), all categories between the 
possible minimum and maximum categories will be included, even if n = 0 for a given 
category. If the categories are not ordered (eg, race), only those categories for which 
there is at least 1 subject represented will be included.  
● Missing values will not be imputed, with the exception of AEs where the ‘worst-case’ 
approach will be taken (see Section 8.6.1), or unless specifically stated otherwise. A 
‘missing’ category will be included for any parameter for which information is missing. 
This will ensure that the population size totals are consistent across different 
parameters.  
All protocol deviations and data issues (eg, missing data or data outside of the protocol 
windows) that occur during the study, including those related to COVID-19, will be 
considered prior to database lock for their severity/impact on how the data will be displayed 
and analysed statistically. 
8.1.2. Repeat and Unscheduled Readings  
For vital signs and ECG data only, any predose value recorded in addition to the original 
value or a postdose value recorded within 15 minutes of the original value will be defined as 
a repeat value; any postdose value recorded more than 15 minutes after the original value will 
be defined as an unscheduled value. For all other data types (eg, laboratory parameters), any 
value recorded in addition to the original value will be defined as an unscheduled value.  
The original value will be replaced by the last associated repeat value in all calculations, with 
the exception of the ECG outlier analysis (see Section 8.6.4).  
As unscheduled values are not associated with any scheduled timepoint, they will be 
excluded from all calculations, with the exception of the baseline derivation (see 
Section 8.1.3) and ECG outlier analysis (see Section 8.6.4).  
8.1.3. Definitions of Baseline, and Change from Baseline 
The baseline will be defined as the last value recorded prior to dosing (Part 1)/dosing in each 
period (Part 2)/the first dose (Part 3). If the date/time of the value is incomplete or missing, it 
will be excluded from the baseline calculation, unless the incomplete date/time indicates the 
value was recorded prior to dosing (Part 1)/dosing in each period (Part 2)/the first dose (Part 
3).  
Individual changes from baseline will be calculated by subtracting the individual subject’s 
baseline value from the value at the timepoint. The mean change from baseline will be 
defined as the mean of the individual changes from baseline for all subjects.  


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See Section 8.1.2 for more detail on handling repeat and unscheduled readings in the 
calculations.  
8.2. Subject Disposition and Population Assignment  
Subject disposition and population assignment will be listed.  
A summary table by treatment (Part 1 and Part 3)/treatment sequence (Part 2) will be 
provided, based on the all subjects population.   
8.3. Screening Demographics  
The screening demographics including age, sex, race, ethnicity, height, body weight, and 
body mass index will be listed.  
A summary table by treatment (Part 1 and Part 3)/treatment sequence (Part 2) will be 
provided, based on the safety population.  
8.4. Prior and Concomitant Medication  
Prior medication will be defined as medication that ends prior to dosing (Part 1)/the first dose 
(Part 2 and Part 3). Concomitant medication will be defined as medication that starts during 
or after dosing (Part 1)/the first dose (Part 2 and Part 3) or starts but does not end prior to 
dosing (Part 1)/the first dose (Part 2 and Part 3).  
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHODrug) Global, Format B3, Version March 2020 (or later if upversioned 
during the study). Prior and concomitant medications will be listed.   
8.5. Pharmacokinetic Assessments  
8.5.1. Pharmacokinetic Analysis  
PK parameters will be determined using non-compartmental methods in validated software 
program, Phoenix WinNonlin (Certara, Version 8.1 or higher). 
The following parameters will be calculated where possible from the plasma concentrations 
of EIDD-2801 and EIDD-1931: 
Parameter 
Unitsa 
Definition 
AUClast 
h*ng/mL 
the area under the plasma concentration-time curve, from time 0 to 
the last measurable non-zero concentrationb, (Part 1, Part 2 and Part 
3). 
AUC0-inf 
h*ng/mL 
the area under the plasma concentration-time curve from time 0 
extrapolated to infinityb,c. (Part 1, Part 2, and Day 1 dose of Part 3). 
AUC 
h*ng/mL 
area under the plasma concentration-time curve during a dosing 
intervalb (Part 3 only) 
%AUCextrap 
% 
percentage of AUC0-inf that is due to extrapolation from the last 
quantifiable concentration to infinity 


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%AUC, extrap 
% 
percentage of AUC that is due to extrapolation from the last 
quantifiable concentration to the end of the dosing interval 
Cmax 
ng/mL 
maximum observed concentration 
tmax 
h 
time of the maximum observed concentration 
tlast 
h 
time of the last quantifiable concentration 
z 
1/h 
apparent terminal elimination rate constant 
t1/2 
h 
apparent terminal elimination half-life 
CL/F 
L/h 
apparent clearance following an extravascular dose  
(EIDD-2801 only) 
Vz/F 
L 
apparent volume of distribution during the terminal phase 
following and extravascular dose (EIDD-2801 only) 
Ctrough 
ng/mL 
plasma concentration at the end of the dosing interval (Part 3 only) 
MRAUC 
 
EIDD-1931:EIDD-2801 ratio based on AUC0-inf (Day 1) or AUC 
(Part 3 only, Day 6) 
MRCmax 
 
EIDD-1931:EIDD-2801 ratio based on Cmax 
RAAUC 
 
observed accumulation ratio based on AUCτ (Part 3 only). 
RACmax 
 
observed accumulation ratio based on Cmax (Part 3 only). 
a Units are based on concentration units (provided by bioanalytical lab) and dose units used in the study. 
b AUC will be calculated using the linear trapezoidal rule for increasing concentrations and the logarithmic rule for 
decreasing concentrations (linear up/log down rule). 
c Based on last observed quantifiable concentration 
In addition, dose normalized parameters will be calculated for AUClast, AUC0-inf, AUC and 
Cmax, calculated by dividing the parameter by the administered dose in mg. These parameters 
will follow the same naming convention as the original parameter with the prefix ‘D’, eg, 
DCmax. 
The following parameters will be where possible from the urine concentrations of 
EIDD-2801 and EIDD-1931: 
Parameter 
Unitsa 
Definition 
Aet1-t2 
mg 
amount of the dose administered recovered in urine over the time 
interval t1 to t2 (calculated by interval and cumulatively) 
Fet1-t2 
% 
percentage of the dose administered recovered in urine over the 
time interval t1 to t2 (calculated by interval and cumulatively) 
CLR 
L/h 
renal clearance  
a Units are based on concentration units (provided by bioanalytical lab) and dose units used in the study. 
Additional PK parameters may be determined where appropriate. 
Pharmacokinetic analysis will, where possible, be carried out using actual blood sampling 
times postdose. If an actual time is missing, the sample concentration result will be treated as 
missing unless there is scientific justification to include the result using the nominal time.  
Pharmacokinetic parameters will be derived where possible for all subjects. Data from 
subjects with incomplete profiles (missed blood draws, lost samples, samples unable to be 
quantified) may be used if PK parameters can be estimated using the remaining data points.  


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The following molecular weights (MW) will be used in calculations where required 
EIDD-2801  
329.31 g/mol 
EIDD-1931  
259.22 g/mol 
Cmax, tlast and tmax will be obtained directly from the concentration-time profiles. If Cmax 
occurs at more than 1 timepoint, tmax will be assigned to the first occurrence of Cmax.  
Parent : prodrug ratios will be calculated as follows: 
MRAUC = (AUC0-inf EIDD-1931/MWEIDD-1931 / (AUC0-inf, EIDD-2081/MWEIDD-2801) 
MRCmax = (Cmax, EIDD-1931/MWEIDD-1931) / (Cmax, EIDD-2801/MWEIDD-2801) 
AUClast or other common partial area may be used to determine MRAUC if AUC0-inf cannot be 
reliably calculated for the majority of subjects.  
8.5.1.1. Criteria for the Calculation of Apparent Terminal Elimination Rate Constant 
and Half-Life 
The start of the terminal elimination phase for each subject will be defined by visual 
inspection and generally will be the first point at which there is no systematic deviation from 
the log-linear decline in concentrations.  
The apparent terminal elimination rate constant (λz) will only be calculated when a reliable 
estimate can be obtained using at least 3 data points, preferably not including Cmax, and the 
adjusted coefficient for determination of exponential fit (R2-adj) of the regression line is ≥0.7. 
Parameters requiring λz in their calculation (eg, AUC0-inf, t1/2, CL/F and Vz/F) will only be 
calculated if the R2-adj value of the regression line is ≥0.7.  
The following regression-related diagnostic PK parameters will be determined:  
Parameter 
Units 
Definition 
λz 
1/h 
apparent terminal elimination rate constant 
λz Upper 
h 
end of exponential fit 
λz Lower 
h 
start of exponential fit 
λz N 
Not applicable 
number of data points included in the log-linear regression 
λz Span Ratio 
Not applicable 
time period over which λz was determined as a ratio of t1/2 
R2-adj 
Not applicable 
adjusted coefficient for determination of exponential fit 
Where possible, the span of time used in the determination of λz (ie the difference between λz 
Upper and λz Lower) should be ≥2 half-lives. If the λz Span Ratio is <2, the robustness of the 
t1/2 values will be discussed in the CSR. 


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8.5.1.2. Criteria for Calculation and Reporting of Area Under the Concentration-time 
Curve 
The minimum requirement for the calculation of AUC will be the inclusion of at least 3 
consecutive concentrations above the lower limit of quantification. If there are only 3 
consecutive concentrations, at least 1 should follow Cmax.  
If the extrapolated area is >20%, AUC0-inf (and derived parameters) may be excluded from 
summary statistics and statistical analysis at the discretion of the sponsor or PK analyst. 
If AUC0-inf cannot be determined reliably for all subjects and/or dose levels/treatments, an 
alternative AUC measure, such as AUC to a fixed timepoint or AUClast, may be used in the 
statistical analysis. 
8.5.1.3. Calculation of Urinary Parameters  
The amount of drug excreted in urine (Ae) and urine collection interval (t1-t2) will be 
calculated as the product of urine analyte concentration and urine volume. Where only urine 
sample weight is supplied, a specific gravity of 1 g/mL will be assumed, and it will be 
considered equivalent to urine volume. A total cumulative Ae0-x h will be calculated by 
summing the Aet1-t2 values over the 0-x h interval, where x = end of the last collection time 
interval.  
The percentage of the dose administered over the time interval t1 to t2 (Fet1-t2) as EIDD-2801 
will be calculated for each urine collection interval as:  
Fet1-t2 = (Aet1-t2 / Dose) × 100%. 
The Fet1-t2 excreted as EIDD-1931 will be calculated for each urine collection interval as: 
Fet1-t2 = Aet1-t2, EIDD-1931/ (DoseEIDD-2801 × [MWEIDD-1931/ MWEIDD-2801]) × 100% 
Cumulative Fe0-x h will be calculated by summing the Fet1-t2 values over the 0-x h period in 
the same manner as Ae0-x h. 
Renal clearance will be calculated as follows: 
CLR = Ae/AUC 
where both Ae and AUC are determined over co-incident time ranges after dosing. 
 
8.5.1.4. Criteria for Handling Below the Limit of Quantification or Missing 
Concentrations for Pharmacokinetic Analysis 
Plasma concentration values that are below the limit of quantification (BLQ) will be set to a 
value of zero, with the following defined exceptions which will be set to missing: 
● Any embedded BLQ value (between 2 quantifiable concentrations). 
● BLQ values following the last quantifiable concentration in a profile. 


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● If an entire concentration-time profile is BLQ, it will be excluded from PK analysis. 
Where 2 or more consecutive concentrations are BLQ at the end of a profile, the profile will 
be deemed to have terminated and any further quantifiable concentrations will be set to 
missing for the calculation of the PK parameters unless they are considered to be a true 
characteristic of the profile of the drug. 
If a predose plasma concentration is missing, it may be set to zero by default. 
Urine concentrations that are BLQ will be set to zero for the calculation of Aet1-t2.  
8.5.1.5. Treatment of Outliers in Pharmacokinetic Analysis 
If a value is considered to be anomalous due to being inconsistent with the expected PK 
profile, it may be appropriate to exclude this point from the PK analysis. However, the 
exclusion of data must have strong justification and will be documented in CSR.   
Quantifiable predose concentration values prior to the first dose will be considered 
anomalous and set to missing for the PK analysis.  
8.5.2. Presentation of Pharmacokinetic Data 
If the actual time of sample collection deviates from the nominal time by more than ±10%, 
the concentration will be flagged and excluded from summary statistics. 
Individual concentrations that are deemed to be anomalous will be flagged in the listings and 
excluded from the summary statistics.   
For PK concentration data, Cmax and Ctrough the following rules will be applied: 
● Values that are BLQ will be set to 0 for calculation of summary statistics. 
● Arithmetic mean or median that are BLQ will be presented as 0. 
For PK parameters the following rule will be applied: 
● Geometric mean and coefficient of variation will not be calculated for tmax, and tlast. 
8.5.3. Pharmacokinetic Statistical Methodology  
All PK concentrations and parameters will be listed.  
Summary tables, mean figures, overlaying individual figures, and individual figures by 
treatment and time postdose will be provided for plasma PK concentrations. All figures will 
be produced on both linear and semi-logarithmic scales.  
Summary tables by treatment will be provided for all plasma PK parameters, with the 
exception of diagnostic regression-related PK parameters. Separate summary tables by 
treatment and time interval will be provided for urine PK parameters. 


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8.5.3.1. Dose Proportionality 
In Part 1 on day 1 a statistical analysis will be conducted to investigate the dose 
proportionality of the 
 formulation for PK parameters of EIDD-2801 and EIDD-1931 
(AUC0-inf, AUClast, and Cmax). 
A statistical analysis will also be conducted to investigate the dose proportionality of the 
 formulation on day 1 for PK parameters of EIDD-2801 and EIDD-1931 (AUC0-inf, 
AUClast, and Cmax) by combining the day 1 Part 3 data with the Part 1 
 cohorts.  
In Part 3 on day 6 a statistical analysis will be conducted to investigate the dose 
proportionality for PK parameters of EIDD-2801 and EIDD-1931 (AUCτ, and Cmax). The 
dose proportionality assessments will include dose levels from a common dietary state.  
The PK parameters will be analyzed using a power model3 that will have the following form: 
parameter = intercept × dose^slope + random error 
Using the natural log (ln) transformation,4 a power model can be expressed as a linear 
regression equation: 
ln(parameter) = intercept + slope × ln(dose) + random error 
For dose proportionality, the slope of the regression line is equal to 1; for dose independence, 
it is equal to 0.  
For each PK parameter separately, a pooled estimate (across all doses) of slope, 
corresponding 90% confidence interval (CI), and between-subject coefficient of variation 
(CV) will be calculated. Figures (on the logarithmic scale) containing individual values, 
power model line (90% CI), and dose proportionality line (defined as the power model line 
with slope of 1) will be created for each PK parameter; figures (on the semi-logarithmic 
scale) containing individual values and geometric means will be created for each 
corresponding PK parameter normalized by dose administered.  
The lack of fit test will be conducted for the statistical assessment of linearity assumption, 
and thus appropriateness of a power model. The lack of fit model will be the same as the 
power model fitted, but with dose included as additional fixed effect. The statistical 
assessment will rule the linearity assumption acceptable if the diagnostic plots appear 
reasonable and the lack of fit p-value >0.05 (dose effect is not significant at the 0.05 level of 
significance). The assessment of linearity assumption may also occur via visual examination 
of the figures by the pharmacokineticist. This assessment may override the statistical 
assessment; where this occurs, it will be detailed in the CSR.  
It will be concluded that PK parameter is dose proportional for the dose range studied if the 
assumption of linearity is ruled acceptable and the 90% CI for the slope spans 1.  
In the case of lack of dose proportionality, between treatment pairwise comparisons based on 
ln-transformed dose normalized PK parameters will be performed using an analysis of 
variance (ANOVA) model.5 The model will include dose as a factor.  For each PK parameter 
separately, the least squares mean (LSM) for each dose, difference in LSMs between each 


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dose, and corresponding 90% CIs will be calculated; these values will then be 
back-transformed to give the GLSM, ratio of GLSMs, and corresponding 90% CI.  
Examples of the SAS code that will be used are as follows: 
Power Model Analysis  
proc mixed data = <data in> alpha = 0.1; 
 by parcat1n parcat1 pkday paramn param; 
 model lpk = ldose / cl residual ddfm = kr2; 
 ods output solutionf = <data out>; 
run; 
Power Model Analysis (Between-subject Variability) 
proc mixed data = <data in> covtest alpha = 0.05; 
 by parcat1n parcat1 pkday paramn param; 
 class ldose; 
 model lpk = ldose / cl residual ddfm = kr2; 
 ods output covparms = <data out>; 
run; 
(Note: Pooled Geometric CV (%) = 100*(sqrt(exp(estimate)-1))) 
Power Model Analysis (Lack of Fit Test) 
proc mixed data = <data in>; 
 by parcat1n parcat1 pkday paramn param; 
 class dose; 
 model lpk = ldose dose / htype = 1 ddfm = kr2; 
 ods output tests1 = <data out>; 
run; 
ANOVA Model Analysis  
proc mixed data = <data in> alpha = 0.1; 
 by parcat1n parcat1 pkday paramn param; 
 class dose; 
 model ldnpk = dose / cl residual ddfm = kr2; 
 lsmeans dose / cl pdiff alpha=0.1;  
 ods output lsmeans = <data out>;  
 ods output diffs = <data out>; 
 ods output tests3 = <data out>; 
run; 
8.5.3.2. Food-Effect 
For Part 2 a statistical analysis will be conducted to investigate the food-effect by comparing 
treatments EIDD-2801 (fed) to EIDD-2801 (fasted) for PK parameters of EIDD-2801 and 
EIDD-1931 (AUC0-inf, AUClast, and Cmax). If an additional cohort is enrolled with a different 
dose level then that cohort will be analyzed in a separate model. 
The natural log (ln)-transformed PK parameters will be analyzed using a mixed model.6 The 
model will include planned treatment sequence, period, and actual treatment as fixed effects, 
and subject within planned treatment sequence as a random effect.  
For each PK parameter separately, the least squares mean (LSM) for each treatment, 
difference in LSMs between the fed and fasted treatments, and corresponding 90% CIs will 


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be calculated; these values will then be back-transformed to give the GLSM, ratio of GLSMs, 
and corresponding 90% CI.  
Additionally, the pooled estimate (across all treatments) of the within-subject coefficient of 
variation (CV) will be calculated, and residual plots will be produced to assess the adequacy 
of the model(s) fitted.  
A statistical analysis using the Wilcoxon signed-rank test7 will be conducted to investigate 
the food-effect on the treatment by comparing the fed treatment to the fasted treatment for 
tmax. The median for each treatment, Hodges-Lehmann estimate of the median difference 
between the fed and fasted treatments, and corresponding 90% CIs will be calculated. 
Examples of the SAS code that will be used are as follows: 
Mixed Model Analysis  
proc mixed data = <data in>; 
 by parcat1n parcat1 pkday paramn param; 
 class trtan aperiod trtseqp usubjid; 
 model lpk = trtan aperiod trtseqp / cl residual ddfm = kr2; 
 lsmeans trtan / cl pdiff = control('1') alpha = 0.1; 
 random intercept / subject = usubjid(trtseqp);  
 ods output lsmeans = <data out>;  
 ods output diffs = <data out>; 
 ods output covparms = <data out>; 
run; 
Wilcoxon Signed-rank Test 
proc univariate data = <data in> cipctldf(alpha = 0.1);  
 by parcat1n parcat1 pkday paramn param; 
 var ref test dif;  
 ods output quantiles = <data out>; 
 ods output testsforlocation = <data out>; 
run; 
(Note: Derive Hodges-Lehmann estimates) 
 
8.6. Safety and Tolerability Assessments  
8.6.1. Adverse Events  
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
Version 23.0 (or higher if upversioned during the study). All AEs will be assigned severity 
grade using the Division of Microbiology and Infectious Diseases (DMID) toxicity scale 
(March 2014).   
A treatment-emergent adverse event (TEAE) will be defined as an AE that starts during or 
after dosing (Part 1)/the first dose (Part 2 and Part 3), or starts prior to dosing (Part 1)/the first 
dose (Part 2 and Part 3) and increases in severity after dosing (Part 1)/the first dose (Part 2 
and Part 3).  
A treatment-related TEAE will be defined as a TEAE with a relationship of possibly, 
probably, or definitely related to the study treatment, as determined by the investigator.  
The assignment of TEAEs to treatments for Part 2 will be as follows:  


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● A TEAE occurring during or after Day 1 dosing and prior to Day 15 dosing will be 
assigned to the treatment given on Day 1 (period 1) 
● A TEAE occurring during or after Day 15 dosing will be assigned to the treatment 
given on Day 15 (period 2) 
●  All AEs will be listed. In addition to the data recorded in the database, the listings will 
include derived onset time and duration. Onset time will be calculated from the time of 
dosing (Part 1)/dosing in each period (Part 2)/the last dose (Part 3) for TEAEs only.  
The frequency of subjects with TEAEs and the number of TEAEs will be summarized for the 
following categories:  
● TEAEs (overall, serious, leading to discontinuation, life-threatening, and leading to 
death) by treatment  
● TEAEs by severity and treatment  
● Treatment-related TEAEs (overall, serious, leading to discontinuation, life-threatening, 
and leading to death) by treatment  
● Treatment-related TEAEs by severity and treatment  
The frequency of subjects will be summarized separately for TEAEs and treatment-related 
TEAEs by the following:  
● System organ class, preferred term, and treatment  
● Preferred term and treatment  
● System organ class, preferred term, day of onset, and treatment (Part 3) 
For the AE data the following rules will apply:  
● For the derivation of TEAE status: If the start date/time of an AE is incomplete or 
missing, an AE will be assumed to be a TEAE, unless the incomplete start date/time or 
the end date/time indicates an AE started prior to dosing (Part 1)/the first dose (Part 2 
and Part 3).  
● For the derivation of treatment-related TEAE status: If the study treatment relationship 
for a TEAE is missing, a TEAE will be assumed to be a treatment-related TEAE.  
● For the derivation of onset time: If the start date/time of an AE is missing, onset time 
will not be calculated. If the start date/time of an AE is incomplete, where possible, the 
minimum possible onset time will be calculated and presented in ‘≥DD:HH:MM’ 
format (eg, if the date/time of dosing (Part 1) is 01MAY2019/08:00 and recorded start 
date/time of an AE is 03MAY2019, then the minimum possible onset time will be 
calculated by assuming the AE started at the first hour and minute of 03MAY2019 
[03MAY2019/00:00], thus will be presented as onset time ≥01:16:00 in the listing).  


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● For the derivation of duration: If the end date/time of an AE is missing, duration will 
not be calculated. If the start or end date/time of an AE is incomplete, where possible, 
the maximum possible duration will be calculated and presented in ‘≤DD:HH:MM’ 
format (eg, if the start of an AE date/time is 01MAY2019/08:00 and its recorded end 
date/time is 03MAY2019, then the maximum possible duration will be calculated by 
assuming the AE ended at the last hour and minute of 03MAY2019 
[03MAY2019/23:59], thus will be presented as duration ≤02:15:59 in the listing).  
● For the calculation of summary statistics: If the severity of a TEAE is missing, a TEAE 
will be counted under the maximum severity possible.  
● For the calculation of summary statistics: If a subject experienced multiple TEAEs with 
the same preferred term for the same treatment, this will be counted as 1 TEAE for that 
treatment under the maximum severity recorded.  
● If adverse events that change severity have a missing relationship, the relationship will 
be assigned to the same relationship as the original adverse event. 
8.6.2. Clinical Laboratory Parameters  
All clinical laboratory parameters, with changes from baseline, will be listed; any value 
outside the clinical reference range will be flagged.  
Separate listings will be provided for any parameter for which there is any individual subject 
value outside the respective clinical reference range.  
Summary tables and boxplots by treatment and timepoint will be provided for chemistry, and 
hematology parameters, with changes from baseline.  
Shifts from baseline tables will be provided for chemistry and hematology parameters. 
Values recorded as <x, ≤x, >x, or ≥x will be displayed in the listings as recorded. For the 
derivation of listing flags, calculation of summary statistics, and presentation in the figures, 
<x and ≤x values will be set to half of x, whereas >x and ≥x values will be set to x.  
8.6.3. Vital Signs Parameters  
All vital signs parameters, with changes from baseline, will be listed; any value outside the 
clinical reference range will be flagged.  
Summary tables and boxplots by treatment and timepoint will be provided for all vital signs 
parameters, with changes from baseline.  
8.6.4. 12-lead Electrocardiogram Parameters  
All 12-lead ECG parameters, with changes from baseline, will be listed; any value outside the 
clinical reference range will be flagged.  
Summary tables and boxplots by treatment and timepoint will be provided for all 12-lead 
ECG parameters, with changes from baseline.  


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An outlier analysis will be performed for QT interval corrected for heart rate using 
Fridericia’s formula (QTcF). The analysis will include all individual original, repeat, and 
unscheduled postdose values.  
The maximum postdose values will be summarized by treatment according to the following 
categories:  
● ≤450 ms  
● >450 and ≤480 ms (all instances flagged in the listing)  
● >480 and ≤500 ms (all instances flagged in the listing)  
● >500 ms (all instances flagged in the listing)  
The maximum increases from baseline will be summarized by treatment according to the 
following categories:  
● ≤30 ms  
● >30 and ≤60 ms (all instances flagged in the listing)  
● >60 ms (all instances flagged in the listing)  
An extra listing presenting subjects with a QTcF>500 ms and/or an increase from baseline of 
>60 ms will be produced only if at least one occurrence of either of these criterion occur. 
8.6.5. Other Assessments  
All continuous ECG data in Part 1 and Part 3 will be archived without extraction or analysis 
and will not be reported in the scope of this study. The collection timepoints will be presented 
in a listing. 
PBMCs may be collected from subjects in Part 3, depending upon ongoing review of the 
data. The collection of these samples may be omitted from some cohorts, depending on 
ongoing review of the data. The PBMCs will be stored for analysis of EIDD-2061 levels at 
some point in the future. 
All other safety and tolerability assessments not detailed in the above sections will be listed 
only.  
8.6.6. Safety and Tolerability Statistical Methodology  
No inferential statistical analyses are planned.  
9. INTERIM ANALYSES  
No formal interim analyses are planned for this study. Data from Part 1 cohorts may be 
locked, unblinded, and analyzed prior to Part 2 and Part 3. Where applicable, doses will be 


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administered in an escalating manner following satisfactory review by the Sponsor and PI of 
the blinded safety and tolerability data.   
10. SIGNIFICANT CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES  
EIDD-2801 concentration data were not quantifiable in some treatment groups and therefore 
PK parameters were not calculable. These affected groups will not have any parameter data 
presented and any analysis based upon these parameters will not be performed. Where limited 
samples were quantifiable (i.e. not a minimum of 3 consecutive concentrations with at least 
one after Cmax) Cmax and tmax may be reported. 
The protocol indicated that the DMID toxicity grading scale would be used to grade 
laboratory parameters after taking into consideration institutional normal parameter ranges. 
The decision was made to evaluate out of reference laboratory parameters in the CSR only 
rather than using the DMID grading, as for several parameters the reference ranges used at 
the site were not consistent with the toxicity grading table provided in the protocol. 
Therefore, treatment-emergent toxicities based on DMID grading will not be reported and 
shift tables will be reported instead. 
 
11. REFERENCES  
1. ICH. ICH Harmonised Tripartite Guideline: Statistical principles for clinical trials (E9). 
5 February 1998.  
2. ICH. ICH Harmonised Tripartite Guideline: Structure and content of clinical study reports 
(E3). 30 November 1995.  
3. Gough K, Hutchinson M, Keene O, et al. Assessment of dose proportionality: report from 
the statisticians in the pharmaceutical industry/Pharmacokinetics UK Joint Working 
Party. Drug Inf J. 1995;29(3):1039-1048. 
4. Keene ON. The log transformation is special. Stat Med. 1995;14(8):811-819. 
5. Snedecor GW, Cochran WG. Statistical Methods. 8th ed. Ames, IA: Iowa State University 
Press, 1989. 
6. Brown H, Prescott R. Applied Mixed Models in Medicine. Chichester: John Wiley & 
Sons, 1999. 
7. Lehmann EL. Nonparametrics: Statistical Methods Based on Ranks. San Francisco, CA: 
Holden-Day; 1975. 
 


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Protocol Reference: EIDD-2801-1001 
Final, Version 2.0, 30JUN2020 
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12. APPENDICES 
Appendix 1: 
Document History 
Status, Version 
Date of Change 
Summary/Reason for Changes 
Final, Version 1.0 
NA 
NA; the first version. 
Final, Version 2.0 
30JUN2020 
Protocol amendment changes including: 
● The total daily dose to be administered was 
increased to 1600 mg. 
● The number of additional cohorts in Part 1 was 
increased to 7. 
● The number of additional cohorts in Part 3 was 
increased to 6. 
● Continuous 12-lead ECG monitoring was added in 
Part 1. 
Updated due to awareness of further information during 
the conduct of the study: 
● Known dose levels were added to the treatment 
labels and treatment clarifications were added. 
● As the latter cohorts in Part 1 will use the 
 
rather than 
 formulation the dose 
proportionality analysis section was updated to 
specify the dose proportionality assessments will 
be formulation specific and an additional 
assessment of dose proportionality for the 
 
formulation will be performed by combining Part 1 
 cohorts with Part 3 day 1 data. 
● Changes to planned analysis section to reflect that 
certain PK parameter data may not be presented or 
analyzed and that DMID grading for laboratory 
data will not be performed. 
● In the TFL Shells the screen failure subject data is 
presented in separate listings as there is no 
distinction during data collection which part a 
subject screen failed from. 
● In the TFL Shells presenting important protocol 
deviations and any deviations related to  
COVID-19. 
Minor formatting changes 
NA = not applicable 


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