A Phase 2, Randomized, Double-blind, Placebo-controlled, Dose-ranging Trial to Evaluate Pharmacokinetics, Pharmacodynamics, and Safety of AT-752 in Patients With Dengue Infection
Phase: PHASE2
Conditions: Dengue Fever
Sponsor: Atea Pharmaceuticals, Inc.

CLINICAL STUDY PROTOCOL
A PHASE 2, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, DOSE-RANGING TRIAL TO EVALUATE 
PHARMACOKINETICS, PHARMACODYNAMICS, AND SAFETY OF 
AT-752 IN PATIENTS WITH DENGUE INFECTION 
PROTOCOL NO. AT-02A-002
Sponsor:
Atea Pharmaceuticals, Inc.
125 Summer Street
Boston, MA 02110 USA
Sponsor Contact:
Atea Pharmaceuticals, Inc.
Version of Protocol:
Protocol version 1.0
Date of Protocol: 
20 September 2021
CONFIDENTIAL
The concepts and information contained in this document or generated during the study are 
considered proprietary and may not be disclosed in whole or in part without the expressed, 
written consent of Atea Pharmaceuticals, Inc.
The study will be conducted according to this Protocol, the International Council for 
Harmonisation Guideline E6(R2): Good Clinical Practice and applicable Regulatory 
Requirements.
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
PPD
PPD

Atea Pharmaceuticals, Inc.
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Protocol No. AT-02A-002
Clinical Study Protocol Version 1.0
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INVESTIGATOR PROTOCOL AGREEMENT PAGE 
I agree to conduct the study as outlined in the protocol titled “A Phase 2, Randomized, 
Double-Blind, Placebo-Controlled Dose-Ranging Trial to Evaluate Pharmacokinetics, 
Pharmacodynamics, and Safety of AT-752 in Patients with Dengue Infection” in accordance 
with the Protocol, ICH Guideline E6(R2): Good Clinical Practice and all applicable Health 
Authority requirements and national laws. I have read and understand all sections of the 
protocol.
Investigator’s Signature
Investigator’s Name (Please Print)
Date

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AT-752
Protocol No. AT-02A-002
Clinical Study Protocol Version 1.0
 
20 SEP 2021 
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PROTOCOL SYNOPSIS 
PROTOCOL NO.: AT-02A-002
TITLE: A Phase 2 randomized, double-blind, placebo-controlled, dose-ranging trial to 
evaluate pharmacokinetics, pharmacodynamics, and safety of AT-752 in patients with dengue 
infection  
STUDY PHASE: 2 
STUDY SITE: 25-30 sites  
INDICATION: Dengue fever 
RATIONALE: Dengue fever is a mosquito-borne illness that impacts an estimated 
100 million people each year. There are close to 400 million infections annually, 500,000 of 
which develop into severe disease. Severe forms of the disease, including dengue 
hemorrhagic fever and dengue shock syndrome, cause significant morbidity and mortality 
worldwide. The disease is now endemic in over 100 countries, and its global prevalence 
continues to grow. Dengue fever is caused by 4 distinct types of ribonucleic acid (RNA)
viruses (DENV-1, DENV-2, DENV-3, and DENV-4) belonging to the flavivirus genus. 
Although a vaccine is available, its efficacy is variable between the different viral serotypes 
and it is only indicated for individuals with a history of previous dengue virus (DENV) 
infection. There are no effective therapeutics for dengue, and treatment options are limited to 
supportive care such as fluid replacement and clinical monitoring. A safe and effective 
antiviral therapy that targets all DENV serotypes is greatly needed to reduce the global 
burden of this disease and meet this unmet medical need. 
Atea Pharmaceuticals has developed a novel purine nucleotide prodrug, AT-752, which is 
designed to treat patients that have been infected with the DENV. When dissolved, AT-752 
releases the freebase AT-281, which in a series of steps is converted to the active metabolite, 
AT-9010. A first-in-human study (Protocol AT-02A-001) is being conducted in approximately 
64 healthy adults in Australia to investigate the safety and pharmacokinetics (PK) (with 
embedded food effect), of AT-752. Part A of this study, assessing single ascending doses 
(SAD) in 40 subjects, has been completed. Part B of this study, assessing multiple ascending 
doses (MAD) is ongoing. 
The Phase 2 study described herein will be conducted in adult patients with confirmed 
DENV infection and will investigate safety, PK, and pharmacodynamics (PD) in this 
population. The study will be conducted in several dosing cohorts to enable dose selection 
for subsequent trials. 
OBJECTIVES: 
The primary objective of this study is: 
To investigate the antiviral activity of AT-752 versus placebo in terms of reduction of DENV 
RNA from baseline in adult subjects with confirmed DENV infection 

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Protocol No. AT-02A-002
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The secondary objectives of this study include PK and safety objectives as outlined below:
The PK objective of this study is:
To evaluate the PK of AT-752 (AT-281) and metabolites in adult subjects with confirmed 
DENV infection. AT-281, the free base of AT-752, is a nucleotide prodrug that requires 
multistep metabolic activation to the pharmacologically active entity
The safety objective of this study is: 
To evaluate safety of AT-752 versus placebo assessed by treatment-emergent adverse 
events (TEAEs), serious adverse events (SAEs), physical exams, vital signs, clinical 
laboratory assessments (including serum chemistry, coagulation, and hematology), and 
electrocardiogram (ECG) results in adult subjects with confirmed DENV infection
The exploratory objectives of this study include PD objectives as outlined below:
To describe the effect of AT-752 on viremia, DENV nonstructural protein 1 (NS1) levels, 
fever, and biomarkers (See list in Section 8.3.4) compared to placebo in adult subjects
with confirmed DENV infection  
STUDY DESIGN: 
This study evaluates the safety, PK, and PD of AT-752 and will enroll approximately 
60 subjects that meet the inclusion/exclusion criteria. Following screening and informed 
consent, eligible subjects will be randomized to receive either AT-752 or matching placebo 
orally 3 times a day (TID) for 5 days in Cohort 1 of the study. Subsequent cohorts will 
receive AT-752/placebo either twice a day (BID) or TID, as described below. Randomization 
will be stratified by geographic region. Standard of care treatment, including acetaminophen,
will be permitted during the study.  
At screening, information including demographics, medical history (including time since 
illness onset), and concomitant medications will be gathered from potential subjects. Any 
clinical care necessary throughout the study, such as supportive care, will be at the discretion 
of the investigator and institutional guidelines. Subject eligibility will be confirmed at the 
screening visit. Randomization and the initial dosing should occur on the same day as 
screening, if possible. Initial dosing should occur no later than 24 hours after screening.
Upon randomization, subjects will be confined to the clinic and will receive their first dose. 
For TID dosing, subjects will receive doses in the morning, at mid-day, and in the evening. 
Doses will be separated by approximately 8 hours. Subjects will be discharged on Day 6 
(after end of treatment) and asked to return on Day 7, Day 8, and Day 14 (± 1 day) with a 
final safety follow-up performed on Day 28 (± 3 days). For clinical sites that decide to use
mobile nursing, subjects may be discharged from the clinic on Day 2 and some of the 
additional visits (Days 4-5, Days 7-8, and Day 14) may be performed at investigator 
discretion through mobile nursing. The Day 1, Day 2, Day 3, Day 6, and Day 28 visits must 
be conducted at the clinical site. 
 
 
 

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Protocol No. AT-02A-002
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The dose level for Cohort 1 has been determined based on review of PK and safety data from 
Part A (SAD) of the Phase 1 healthy volunteer study (Protocol AT-02A-001) in addition to 
preliminary data from Part B (MAD) of the study. Specific doses for Cohort 2 and Cohort 3 
will be determined by a Safety Review Committee (SRC) after a review of all prior cohorts. 
Subjects who are enrolled in cohorts that are receiving BID dosing will receive doses in the 
morning and the evening. In those cohorts, doses will be separated by approximately 12 
hours. 
 Cohort 1: 750 mg AT-752/placebo TID for 5 days 
 Cohort 2: up to 1000 mg AT-752/placebo BID or TID for 5 days 
 Cohort 3: up to 1500 mg AT-752/placebo BID for 5 days 
In each blinded, randomized cohort, subjects will receive AT-752 and placebo at a 3:1 ratio. 
Each cohort will include 20 subjects (15 subjects receive AT-752 and 5 receive placebo). 
Prior to the initiation of each cohort after Cohort 1, all safety and PK data through at least 
5 days in the current dose cohort will undergo a blinded review by the SRC.  
STUDY POPULATION: 
Inclusion Criteria: 
A patient must meet the following criteria to be eligible for participation in this study: 
1. 18-55 years of age at time of screening
2. F
 (or feeling feverish) with onset during the previous 48 hours 
3. Live/work in or recent travel to dengue endemic area
4. Positive test confirming DENV on a NS1 antigen test or reverse transcription-polymerase 
chain reaction (RT-PCR) assay 
5. Negative rapid diagnostic test result for SARS-CoV-2 and Influenza A and B
6. Body mass index (BMI) of 18 to 30 kg/m2
7. Provides written informed consent prior to initiation of any study procedures
8. Able to understand and agrees to comply with planned study procedures and be available 
for all study visits
9. Males and females of childbearing potential must agree to use protocol-specified methods 
of contraception as described in Section 4.1.1
10. Male subjects must agree to not donate sperm from the first dose through 90 days after 
the last dose of study drug
Exclusion Criteria:
A patient who meets any of the following criteria will be excluded from participation in this 
study: 
1. Pregnant at screening or plans to become pregnant within 90 days of screening
2. Female patient who is breastfeeding or plans to breastfeed during the study period
 
 
 
 

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3. Has previously received any investigational or approved vaccine for dengue 
4. Previous history of HIV, chronic hepatitis B infection, or current hepatitis C infection
(from medical history)
5. Use of any antiviral drug within 30 days or within 5 half-lives of the active drug or 
metabolite (for long-acting antivirals) 
6. Currently enrolled in or plans to participate in another clinical trial with an 
investigational agent or device that will be received during the study-reporting period 
7. Exposure to another investigational agent within 30 days or 5 half-lives, whichever is 
longer, prior to study drug administration 
8. Use of herbal or dietary supplements or grapefruit juice within 7 days of screening (eg, 
chamomile, raspberry, peppermint, lemon, ginger, hibiscus, echinacea, rooibos, sage, 
lemon balm, rose hip, or passionflower tea, turmeric, ginger, bitter gourd, mangosteen, 
Blumea balsamifera, banaba [Lagerstroemia speciosa], soursop, bignay [Wild cherry], or 
horseradish [Moringa oleifera], artichoke, lotus, and other herbal cough treatments or 
herbal headache relievers in case of fever or cough)
9. Patients with chronic medical conditions that put them at risk for severe dengue, 
including uncontrolled diabetes mellitus, severe asthma requiring oral steroids, or
admission to the hospital in the previous 6 months for cardiac disease. 
10. Current use of anticoagulant or antiplatelet drugs or documented medical history of 
bleeding disorders
11. Current use of medications for treatment of inflammatory bowel disease or documented 
medical history of chronic gastrointestinal disease including inflammatory bowel disease
12. Immunocompromised due to use of immunosuppressive drugs including systemic 
corticosteroids (inhaled or topical corticosteroids are allowed) or any current disease or 
condition 
13. Evidence of severe dengue disease including: 
 Severe plasma leakage leading to shock or fluid accumulation with respiratory 
distress 
 Severe bleeding 
 
consciousness, or heart impairment)
14. Suspected or confirmed acute illness thought to be caused by a pathogen other than 
DENV 
15. Confirmed or suspected SARS-CoV-2 infection or contact with patients with confirmed 
SARS-CoV2 infection within 7 days prior to screening 
16. ALT or AST > 5x upper limit of normal (ULN) or total bilirubin > 1.5x ULN (Gilbert’s 
syndrome is exempt), or platelet count <80,000/mm3 at the time of screening 
17. Has any other medical disease or condition that in the opinion of the site principal 
investigator or appropriate sub-investigator, precludes study participation. This includes 
any acute, subacute, intermittent, or chronic disease or condition that would place the 
 
 
 
 
 
 
 
 
 
 
 
 

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patient at an unacceptable risk of injury, render the patient unable to meet the 
requirements of the protocol, or interfere with the evaluation of responses or the patient's 
successful completion of the trial 
ESTIMATED STUDY DURATION: 
Subject participation in this study will be up to 32 days. After screening (within 48 hours of 
onset of a fever), each subject will receive the investigational drug or placebo on Day 1 and 
should continue on the regimen-specific schedule until all planned doses are completed (10 
doses if BID dosing and 15 doses if TID dosing)). If possible, screening and Day 1 visits 
should occur on the same day. After dosing is complete (on Day 5 or Day 6 depending on 
what time of day dosing starts on Day 1), subjects will have additional assessments on Days 
6-8 and will have follow-up visits on Days 14 (± 1 day) and 28 (± 3 days). The maximum 
duration that any patient will be involved is 32 days (screening day plus 28 - 31 days from 
beginning of treatment to end of follow-up). 
STUDY PROCEDURES: 
Primary Endpoint 
 Change in DENV viral load from baseline  
Secondary Endpoints: PK Endpoints 
Pharmacokinetic endpoints will be characterized as subject numbers and PK data permit. 
 Plasma concentrations of AT-281 (and metabolites AT-551, AT-229, and AT-273) for 
each cohort at: 
o
Day 1 at time 0 (pre-dose; before the first dose on Day 1) 
o 24 hours after Dose 1 (before Dose 4 for TID dosing and before Dose 3 for 
BID dosing) 
o A day of intensive PK sampling: 
 For TID dosing, samples will be obtained before Dose 7 and 0.5, 1, 2, 
4, and 6 hours after Dose 7. This serial PK sampling may be done for 
Dose 7, 8, or 9, based on site/patient convenience 
 For BID dosing, samples will be obtained before Dose 5 and 0.5, 1, 2, 
4, 6, and 8 hours after Dose 5. This serial PK sampling may be done 
for Dose 5, 6, or 7, based on site/patient convenience 
For blood samples (both TID and BID dosing), a ±10 minute window 
4 hours; ±15 minute for time points between 4 and 
12 hours  
o At any early study discontinuation visits. The timing of these PK samples 
relative to the last 2 (most recent) doses will be recorded 
 Noncompartmental analysis will be performed for the following plasma PK 
parameters, when applicable and if data permit. Other PK parameters may also be 
calculated. PK parameters will be calculated based on actual times: 
 
 
 
 
 
 
  
 

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o
AUClast (area under the plasma concentration versus time curve from time 0 to 
the last quantifiable concentration)
o AUCtau (area under the plasma concentration versus time curve over the 
dosing interval)
o AUCinf (area under the plasma concentration versus time curve from time 0 to 
extrapolated to infinity)
o Cmax (maximum observed plasma concentration)
o Tmax (time to maximum observed plasma concentration) 
o  t1/2z (apparent terminal elimination half-life)
o
CL/F (apparent oral clearance)
o Vz/F (apparent volume of distribution) 
o Ctrough (trough concentration)
Secondary Endpoints: Safety Endpoints
 Incidence and grade of any TEAEs from first dose through Day 28 or withdrawal 
from the study 
 Incidence and grade of any SAEs through Day 28 or withdrawal from the study 
 Vital sign measurements 
 Physical examination findings
 Clinical laboratory (serum chemistry, hematology, coagulation, and urinalysis 
findings)
 ECG
Exploratory Endpoints: PD Endpoints
 Area under the log10-transformed viral load curve (AUC) from first dose to the end 
of treatment or study
 Time to viral RNA clearance, which is defined as the first of 2 consecutive 
undetectable DENV viral RNA measurements 
 Time to clearance of NS1 protein using a NS1 antigen test. Clearance is defined as 
time from start of treatment until the first of 2 consecutive plasma samples are NS1-
negative. 
 Change of DENV viral load from baseline, viral load AUC, time to viral RNA, or 
NS1 clearance by DENV serotype
 Time to resolution or duration of fever  
 Exploratory biomarkers on immunological response to dengue (See list in Section 
8.3.4) 
 
 
 
 
 
 
 
 
 
 
 
 

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 Exploratory analyses may be performed to evaluate exposure-response relationship. 
The relationship between the exposure of AT-752 (and its metabolites) and DENV 
viral RNA measurement may be explored using graphical displays 
STUDY DRUG, DOSAGE, AND ROUTE OF ADMINISTRATION: 
Oral dose levels of AT-752 will be evaluated across 3 sequential dosing cohorts: 
Cohort 1: 750 mg AT-752/placebo TID for 5 days
Cohort 2: up to 1000 mg AT-752/placebo BID or TID for 5 days
Cohort 3: up to 1500 mg AT-752/placebo BID for 5 days
STATISTICAL ANALYSIS PLANS:
Sample Size:
In Low et al (Low 2014), the observed standard deviations (SD) for VLR, defined as mean 
change from baseline viral load on days 2, 3, and 4, ranged from 0.75 (N=26) to 1.07 (N=24). 
Taking into account that the VLR endpoint in that study was based on an average of 3 
measurements and assuming that there is some correlation between measurements on days 2 
through 4, we consider power to detect a true effect at a single time point using a one-sided 
0.10 level test (unadjusted for multiple comparisons) with N=15 per arm for SD in a range 
from 1 to 1.75: 
True standard deviation 
Effect (log10 copies/mL) with 80% power
1
0.8 
1.25
1 
1.5
1.2 
1.75
1.4 
Based on the above table, there is 80% power to detect a true treatment effect (versus 
placebo) on change-from-baseline viral load of 1 log10 at a time point if the true SD is 1.25. 
Furthermore, if true SD is in the range from 1 to 1.75, the probability that the observed effect
would be 0.5 log10 or larger is low (in range from 0.09 to 0.22) if there is no treatment effect, 
ie, an observed effect of 0.5 or larger might be considered suggestive of a signal. 
Interpretation of results will consider the totality of the data.
Statistical Methods:
The primary objective of this study is to evaluate the antiviral activity of AT-752 compared 
with placebo on change from baseline in viral load based on the log-10 scale at specified 
timepoints.
Change from baseline viral load will be compared between each AT-752 arm and a combined 
placebo group. Viral load will be analyzed using repeated measures mixed model with 
treatment, time, and treatment-by-time interaction as fixed factors. The treatment group least 
squares mean (LSM) estimates for mean change from baseline and treatment group 
differences at a time point, with 80% confidence interval (CI) and p-value will be presented. 
 
 
 
 

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Additionally, descriptive summaries for the change from baseline will also be presented by 
treatment group. Further details will be provided in a separate statistical analysis plan.
Safety, PK, and PD data will be presented in statistical summaries in tabular and/or graphical 
format by active dose treatment arms and one-pooling placebo treatment arm. Continuous 
data will be summarized in descriptive statistics (n, mean, SD, median, 95% CI) and 
categorical data will be presented in counts and percentages. All subject-level data will be 
presented in listings. Dose proportionality in PK will be assessed by a power model, if data 
permit. 
The population for PK analysis will include subjects who receive at least 1 dose of the study 
drug and have sufficient concentration data to support accurate estimation of at least 1 PK 
parameter. The safety population will include all subjects who receive at least 1 dose of the 
study drug. The population for PD analysis will include subjects who received at least 1 dose 
of study drug and have baseline and at least 1 post-baseline virology measurement. 

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TABLE OF CONTENTS 
SIGNATURE PAGE ................................................................................................................2
INVESTIGATOR PROTOCOL AGREEMENT PAGE ......................................................3
PROTOCOL SYNOPSIS ........................................................................................................4
TABLE OF CONTENTS.......................................................................................................12
1. 
BACKGROUND .................................................................................................16
1.1 
DENGUE VIRUS.............................................................................................16
1.2
AT-752 ..............................................................................................................17
1.2.1
Clinical Studies.............................................................................................19
1.3 
RATIONALE FOR STUDY ............................................................................27
1.4 
RATIONALE FOR DOSE SELECTION.........................................................28
2. 
STUDY OBJECTIVES.......................................................................................29
3. 
STUDY DESIGN .................................................................................................29
3.1 
SCHEDULE OF ASSESSMENTS ..................................................................32
3.1.1 
Screening/Day 1 ...........................................................................................33
3.1.2 
Timing of TID Dosing ..................................................................................35
3.1.3 
Timing of BID Dosing..................................................................................36
3.1.4 
Timing of Samples for PK, Viral Load, and NS1 .........................................37
4. 
STUDY POPULATION......................................................................................43
4.1 
INCLUSION CRITERIA .................................................................................43
4.1.1 
Protocol Specified Methods of Contraception .............................................44
4.2 
EXCLUSION CRITERIA ................................................................................45
4.3 
WITHDRAWAL OF SUBJECTS FROM THE STUDY .................................47
4.3.1
Reasons for Withdrawal................................................................................47
4.3.2 
Handling of Withdrawals ..............................................................................47
4.3.3 
Replacements ................................................................................................48
5. 
STUDY TREATMENTS ....................................................................................48
5.1 
TREATMENTS ADMINISTERED .................................................................48
5.1.1 
Safety Review Committee ............................................................................48
5.2 
INVESTIGATIONAL PRODUCTS ................................................................49
5.2.1 
Study Drug Packaging and Storage ..............................................................49
5.2.2 
Study Drug Accountability ...........................................................................49
5.3 
METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS.........50
5.4 
BLINDING .......................................................................................................50
5.4.1 
Blinding Procedures .....................................................................................50
5.4.2 
Breaking the Blind ........................................................................................50
5.5 
TREATMENT COMPLIANCE .......................................................................50

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5.5.1
Prior and Concomitant Medications.............................................................51
Prior Medications......................................................................................51
Concomitant Medications.........................................................................51
6.
STUDY ENDPOINTS.........................................................................................51
6.1
PRIMARY ENDPOINT ...................................................................................51
6.2
SECONDARY ENDPOINTS: PHARMACOKINETIC ENDPOINTS...........51
6.3
SECONDARY ENDPOINTS: SAFETY ENDPOINTS ..................................52
6.4
EXPLORATORY ENDPOINTS: PHARMACODYNAMIC ENDPOINTS ...53
7.
STUDY ASSESSMENTS ...................................................................................53
7.1
PHARMACOKINETIC ASSESSMENTS.......................................................54
7.1.1
Pharmacokinetic Sample Collection.............................................................54
7.1.2
Pharmacokinetic Sample Analysis................................................................54
7.2
PHARMACODYNAMIC ASSESSMENTS....................................................54
7.3
SAFETY ASSESSMENTS ..............................................................................55
7.3.1
Adverse Events.............................................................................................55
Adverse Event Definitions........................................................................55
Eliciting and Documenting Adverse Events.............................................57
Reporting Adverse Events ........................................................................57
Assessment of Severity.............................................................................59
Assessment of Causality...........................................................................59
Follow-up of Adverse Events ...................................................................60
7.3.2
Clinical Laboratory Testing..........................................................................60
7.3.3
Vital Sign Measurements..............................................................................61
7.3.4
12-Lead Safety Electrocardiogram...............................................................62
7.3.5
Physical Examinations..................................................................................62
8.
STATISTICAL ANALYSIS................................................................................62
8.1
SAMPLE SIZE CALCULATIONS..................................................................62
8.2
ANALYSIS SETS ............................................................................................63
8.3
PLANNED STATISTICAL ANALYSIS..........................................................63
8.3.1
Primary Endpoint Analyses ..........................................................................64
8.3.2
Pharmacokinetic Analyses............................................................................64
8.3.3
Safety Analyses ............................................................................................64
8.3.4
Pharmacodynamic Analyses.........................................................................65
8.4
HANDLING OF MISSING DATA..................................................................65
9.
REFERENCE LIST............................................................................................66
10.
APPENDICES.....................................................................................................68
10.1
APPENDIX 1: LIST OF ABBREVIATIONS..................................................68
 
 
 
 
 
 
 
 

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10.2
APPENDIX 2: STUDY GOVERNANCE .......................................................70
10.2.1
Data Quality Assurance ................................................................................70
10.2.2
Investigator Obligations ...............................................................................70
Confidentiality ..........................................................................................70
Institutional Review..................................................................................70
Subject Consent ........................................................................................71
Study Reporting Requirements.................................................................72
Financial Disclosure and Obligations.......................................................72
Investigator Documentation......................................................................72
Study Conduct ..........................................................................................72
Case Report Forms and Source Documents .............................................72
Adherence to Protocol ..............................................................................73
Reporting Adverse Events ........................................................................73
Investigator’s Final Report .......................................................................73
Records Retention.....................................................................................73
Publications...............................................................................................74
10.2.3
Study Management.......................................................................................74
Monitoring of the Study............................................................................74
Study Digital Options ...............................................................................74
Inspection of Records ...............................................................................75
10.2.4
Management of Protocol Amendments and Deviations ...............................75
Protocol Amendments...............................................................................75
Protocol Deviations ..................................................................................75
Study Termination.....................................................................................76
Final Report ..............................................................................................76
LIST OF TABLES
 
 
 
 
 
 
23
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 3-1
Schedule of events .......................................................................................... 32
Table 3-2
TID dosing beginning before 10 AM, with 3 doses given on Day 1: Timing of 
samples for PK, viral load, and NS1 ............................................................... 39
Table 3-3 
TID dosing beginning between 10 AM and 4 PM, with 2 doses given on Day 
1: Timing of samples for PK, viral load, and NS1.......................................... 40
Table 3-4 
TID dosing beginning in the evening, with 1 dose given on Day 1: Timing of 
samples for PK, viral load, and NS1 ............................................................... 41
Table 3-5 
BID dosing beginning before 4 PM, with 2 doses given on Day 1: Timing of 
samples for PK, viral load, and NS1 ............................................................... 42
Table 3-6 
BID dosing beginning between 6 PM and 10 PM, with 1 dose given on Day 1: 
Timing of samples for PK, viral load, and NS1 .............................................. 43
LIST OF FIGURES
 
 
 
 
 
 
 
 
Figure 3-1
AT-02A-002 Study design ............................................................................... 30
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1.
BACKGROUND
1.1 
DENGUE VIRUS 
Flaviviruses are single-stranded, positive-sense ribonucleic acid (RNA) viruses. Medically 
important mosquito -borne flaviviruses include dengue virus (DENV), West Nile virus, 
Japanese encephalitis virus, yellow fever virus, and Zika virus. Among these viruses, DENV 
produces the highest incidence of illness, with an estimated 400 million infections each year, 
of which approximately 100 million with clinical manifestations, including dengue 
hemorrhagic fever and about 25 000 deaths (CDC2020, WHO 2020, Low 2018). The recent 
decades have witnessed a drastic resurgence of DENV with over 8-fold increase of dengue
cases reported to WHO in the past 20 years (WHO 2020) with large outbreaks, while mostly 
in tropical and sub-tropical regions including Africa, Southeast Asia, and South America, also 
occurred in parts of Europe (Wilder-Smith 2012). Dengue is now endemic in more than 
100 countries/regions worldwide (Low 2018). Dengue fever is also on the rise in United 
States with over 5000 cases, mostly travel-associated, reported between 2010 and 2017 
(Rivera 2020). 
There are 4 antigenically distinct but closely related DENV serotypes (DENV 1-4). Isolation 
of a fifth serotype (DENV-5) was reported in 2013, although it has yet to be officially 
recognized. Recovery from infection is believed to provide lifelong immunity against that 
specific serotype. However, cross-immunity to the other serotypes after recovery is only 
partial and transient. Secondary infection by other serotypes increases the risk of developing 
severe dengue (WHO 2020). 
There are no direct-acting antivirals (DAAs) or broadly indicated vaccines for DENV. The 
only licensed vaccine (Dengvaxia®) has a restricted indication only for individuals who have 
had at least one documented previous DENV infection. Moreover, protection by Dengvaxia 
against DENV is not complete with an efficacy of approximately 80% (Dengvaxia 2020). 
Efficacy is variable for each of the 4 DENV serotypes and appears to quickly wane (Thomas 
2017). Therefore, in view of the global re-emergence of DENV, in addition to vaccines, 
parallel efforts have to be urgently devoted to developing effective DAAs to treat DENV 
infection.  
The viral replication cycle offers multiple targets for DAAs. Among those targets, viral 
polymerase, a critical enzyme in viral replication, has proven to be a valid target for RNA
and deoxyribonucleic acid (DNA) viruses including among others hepatitis B virus, hepatitis 
C virus, and human immunodeficiency virus-1 (HIV). Many nucleoside/nucleotides viral 

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polymerase inhibitors have successfully been developed and become a cornerstone in treating 
major human viral diseases.
The nonstructural protein 5 is the largest nonstructural protein and functions as the viral 
RNA-dependent RNA polymerase (RdRp). The highly conserved nature of DENV RdRp 
potentially allows for a single agent to be active against all viral serotypes. Similarly, to other 
viruses, the DENV RdRp has been the target of many investigational DAAs, mostly 
nucleoside/nucleotide analogues as expected (Troost 2020). Yet, to date, only one nucleoside 
analogue, balapiravir, has been tested clinically; however, it showed no difference between 
active and placebo regarding antiviral response, cytokine profile, and time to fever clearance 
(Nguyen 2012). 
1.2 
AT-752 
Atea Pharmaceuticals, Inc. is developing AT-752, an orally administered guanosine 
nucleotide prodrug with potent inhibitory activity against the replication of DENV in vitro
and in vivo in preclinical evaluations. A comprehensive non-clinical program and data 
package, including chronic 14-day repeat-dose Good Laboratory Practice toxicology studies 
in 2 species (rat and monkey), was completed to support clinical studies in human subjects. 
 
 
 
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In the current study, the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of 
AT-752 will be assessed in adult patients with confirmed DENV infection to support dose 
selection for future studies.  
Further information on the study drug can be found in the investigator’s brochure (Atea 
Pharmaceuticals). 
1.2.1
Clinical Studies
A first-in-human study (Protocol AT-02A-001) is currently being conducted in approximately 
64 healthy adults in Australia to investigate the safety and PK (with embedded food effect) of 
AT-752. This Phase 1 first-in human, randomized, double-blind, placebo-controlled study is 
evaluating the safety, tolerability, and PK of AT-752 in healthy subjects. The study consists of 
2 sequential parts: SAD (single ascending dose; Part A) and MAD (multiple ascending doses; 
Part B). Part A (SAD) includes a food effect cohort and both Part A (SAD) and Part B 
(MAD) cohorts are evaluating the potential effect of AT-752 on the QTc interval.  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
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PK (with embedded food effect), of AT-752. Part A of this study (Protocol AT-02A-001), 
assessing single ascending doses (SAD) in 40 subjects, has been completed. Part B of this 
study, assessing multiple ascending doses (MAD) is ongoing. 
The Phase 2 study described herein will be conducted in adult patients with confirmed 
DENV infection and will investigate safety, PK, and PD in this population. The study will be 
conducted in several dosing cohorts to enable dose selection for subsequent trials. 
1.4 
RATIONALE FOR DOSE SELECTION 
Based on the rat and monkey no observed adverse effect level (NOAEL) of 1000 mg/kg/day 
of AT-752 (expressed as AT-281 free base) determined after 14 days of dosing, margins of 
safety have been calculated per FDA guidance for human doses of 1000 mg BID and 
1000 mg TID (Table 1-7) (DHHS 2005). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
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The dose level for Cohort 1 has been determined based on review of PK and safety data from 
Part A (SAD) of the Phase 1 healthy volunteer study (Protocol AT-02A-001) in addition to 
preliminary data from Part B (MAD) of the study. Specific doses for Cohort 2 and Cohort 3 
will be determined by a Safety Review Committee (SRC) after a review of all prior cohorts. 
Based on the results of the AT-02A-001 study, the dose levels selected for the study described 
herein are:  
 Cohort 1: 750 mg AT-752/placebo 3 times a day (TID) for 5 days 
 Cohort 2: up to 1000 mg AT-752/placebo twice a day (BID) or TID for 5 days 
 Cohort 3: up to 1500 mg AT-752/placebo BID for 5 days 
2. 
STUDY OBJECTIVES 
The primary objective of this study is: 
 To investigate the antiviral activity of AT-752 versus placebo in terms of reduction of 
DENV RNA from baseline in adult subjects with confirmed DENV infection 
 
The secondary objectives of this study include PK and safety objectives as outlined below.  
The PK objective of this study is: 
 To evaluate the PK of AT-752 (AT-281) and metabolites in adult subjects with 
confirmed DENV infection. AT-281, the free base of AT-752, is a nucleotide prodrug 
that requires multistep metabolic activation to the pharmacologically active entity 
The safety objective of this study is: 
 To evaluate safety of AT-752 versus placebo assessed by TEAEs, serious adverse 
events (SAEs), physical exams, vital signs, clinical laboratory assessments (including 
serum chemistry, coagulation, hematology), and ECG results in adult subjects with 
confirmed DENV infection 
The exploratory objectives of this study include PD objectives as outlined below: 
 To describe the effect of AT-752 on viremia, DENV nonstructural protein 1 (NS1) 
levels, fever, and biomarkers (see list in Section 8.3.4) compared to placebo in adult 
subjects with confirmed DENV infection 
3. 
STUDY DESIGN 
This study evaluating the safety, PK, and PD of AT-752 will enroll approximately 60 subjects 
that meet the inclusion/exclusion criteria. Following screening and informed consent, eligible 
subjects will be randomized to receive either AT-752 or matching placebo orally TID for 
 
 
 
 
 
 
 

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5 days in Cohort 1 of the study. Subsequent cohorts will receive AT-752/placebo either BID 
or TID, as described in Figure 3-1. Randomization will be stratified by geographic region.
Standard of care treatment, including acetaminophen, will be permitted during the study.  
A schematic of the study design is provided in Figure 3-1.
Figure 3-1
AT-02A-002 Study design
At screening, information including demographics, medical history (including time since 
illness onset), and concomitant medications will be gathered from potential subjects. 
Additional assessments and collection of data will be conducted as indicated in the schedule 
of events (SOE; Table 3-1). Any clinical care necessary throughout the study, such as 
supportive care, will be at the discretion of the investigator and institutional guidelines. After 
subjects are confirmed eligible at screening, randomization and the initial dosing should 
occur within 24 hours, and if possible, the initial dose should be given on the same day as 
screening.
Upon randomization, subjects will be confined to the clinic and will receive their first dose of 
study drug. Subjects in Cohort 1 will receive doses that are separated by approximately 8 
hours (± 2 hours; morning, mid-day, and evening). Subjects will be discharged on Day 6
(after end of treatment) and asked to return on Day 7, Day 8, and Day 14 (± 1 day) with a 
final safety follow-up performed on Day 28 (± 3 days). For clinical sites that decide to use
mobile nursing, subjects may be discharged from the clinic on Day 2 and some of the 
additional visits (Days 4-5, Days 7-8, and Day 14) may be performed at investigator 
discretion through mobile nursing. The Day 1, Day 2, Day 3, Day 6, and Day 28 visits must 
be conducted at the clinical site. The Day 6 end of treatment visit will occur 8 to 24 hours 
after the last dose of study medication is administered.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Note that if the initial dose of study drug is administered on the same day as screening (at 
mid-day or in the evening), the last dose of study drug will be administered on Day 6. See 
Section 3.1.2 and Section 3.1.3 for detailed descriptions of TID and BID dosing, respectively.  
The initial dose level for Cohort 1 has been determined based on review of PK and safety 
data from Part A (SAD) of the Phase 1a healthy volunteer study (Protocol AT-02A-001). 
Specific doses for Cohort 2 and Cohort 3 will be determined by the SRC after a review of all 
prior cohorts. Subjects receiving BID dosing will receive doses that are separated by 12 
hours (± 2 hours; morning and evening). The 3 planned sequential dosing cohorts are:
• 
Cohort 1: 750 mg AT-752/placebo TID for 5 days 
• 
Cohort 2: up to 1000 mg AT-752/placebo BID or TID for 5 days 
• 
Cohort 3: up to 1500 mg AT-752/placebo BID for 5 days 
In each blinded, randomized cohort, subjects will receive active drug, and placebo at a 3:1 
randomization. Each cohort will include 20 subjects (15 subjects receive AT-752 and 
5 subjects receive placebo).  
Prior to the initiation of each cohort after Cohort 1, all safety data through at least 5 days in 
the current dose cohort will undergo a blinded review by the SRC. Following each SRC 
review, the next cohort will be enrolled and proceed according to schedule outlined in the 
SOE (Table 3-1).  

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3.1
SCHEDULE OF ASSESSMENTS
Table 3-1
Schedule of events 
Assessment
Screening
Treatment Period 
Follow-up
 
Day
1
Days
2-4
Day 
5
Day
6
Day
7
Day 
8
Day
14±1
Day
28 ±3
Visit Type 
Site
Site
Site
or 
Mobile
Site
or 
Mobile
Site
Site
or 
Mobile
Site
or 
Mobile
Site
or 
Mobile
Site
Eligibility criteria
X
Informed consenta
X
Demographics
X
Medical history
X 
 
 
 
 
 
Concomitant medications 
X 
X 
X
X
X 
X
X 
X
X
Physical examinationb 
X
X
X
X
X
X
X
X
X
Vital signsc 
X 
X 
X
X
X 
 
 
12-lead ECG (triplicate-consecutive)
X 
 
 
X 
 
X
Chemistry/hematology/coagulationd
X 
X 
Day 2,
4 
X 
 
X 
X
X
Urinalysis w/ microscopyd
X 
X 
 
X 
 
X 
 
SARS-CoV-2 rapid test, RIDTe 
X 
 
 
X 
 
 
Pregnancy testingf
X 
 
 
 
 
 
NS1 rapid testg
X 
 
 
 
 
 
Pharmacokinetic assessmentsh 
 
X 
Day 2
and 
Day 3 
or 4 
 
 
 
DENV serotype testingi
X 
 
 
 
 
 
Viral loadj
X 
X 
X
X
X 
X
X 
X
X
NS1 antigen test
X 
X 
X
X
X 
X
X 
X
X
Adverse eventsk 
X 
X 
X
X
X 
X
X 
X
X
Randomization
Prior to dosing
 
 
 
 
Study drug administration 
 
X 
X
X
 
 
 
Abbreviations: DENV = dengue virus; ECG = electrocardiogram; ELISA = enzyme-linked immunosorbent 
assay; NS1 = nonstructural protein 1; RIDT = rapid influenza diagnostic test 
a. 
Informed consent will be performed before any study procedures are conducted. Results from standard 
of care evaluations that are available prior to informed consent are accepted if performed within 24 
hours of screening 
b. A full physical examination, including height and weight, will be performed at screening and Day 28, 
except height will not be collected at Day 28. Symptom-directed physical examinations will be 
performed at the remaining visits.  
c. 
On Day 1, vital signs should be collected pre-administration of study drug. Vital sign measurements 
should be performed before any scheduled blood collections. On subsequent days (Days 2-6), vital signs 
can be collected at any time. 
In addition, temperature readings will be performed at least 4 times daily, in the morning, mid-day, late 

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Determining eligibility criteria
Obtaining informed consent
Recording demographics, medical history, and concomitant medications
Complete physical examination. If the initial dose of study drug is administered on 
the same day as screening, the results of the complete physical examination at 
screening will be substituted for symptom-directed physical examination on Day 1
Vital signs. On Day 1, vital sign measurements should be performed before any 
scheduled blood collections and prior to administration of study drug. If possible, the 
initial dose of study drug should be administered on the same day as screening; if this 
is possible then the results of the vital signs obtained at screening will be used for the 
Day 1 vital sign results. Note that temperature is also to be collected during the 
dosing period at least 4 times a day (morning, mid-day, late afternoon, evening; 
approximately every 4 hours while subjects are awake)  
 Triplicate consecutive12-lead ECG. If the initial dose of study drug is administered 
on the same day as screening, results of the screening ECG will be used for the Day 1 
ECG results  
 Chemistry, hematology, coagulation, and urinalysis (with microscopy). At screening, 
samples should be collected for urinalysis (with microscopy), but subjects can begin 
treatment with study drug before the results are obtained unless medically required to 
establish eligibility (at investigator’s discretion). If the initial dose of study drug is 
administered on the same day as screening, the screening results for these tests will be 
used for the Day 1 results. Results from standard of care evaluations that are available 
prior to informed consent are accepted if performed within 24 hours of screening 
 SARS-CoV-2 rapid test, rapid influenza diagnostic test, and urine pregnancy testing  
 DENV serotype testing. Subjects can begin treatment with study drug before the 
DENV-serotype results are obtained, but the samples should be obtained before 
dosing 
 Viral load. Measurement of plasma viremia using a serotype-specific, real-time RT-
PCR assay. Subjects can begin treatment with study drug before the DENV-serotype 
results are obtained, but the sample should be obtained prior to dosing. If the initial 
 
 
 
 
 
 
 
 
 
 

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dose of study drug is administered on the same day as screening, the screening results 
for viral load will be used for the Day 1 values
NS1 antigen detection test. If the initial dose of study drug is administered on the 
same day as screening, the screening results for viral load will be used for the Day 1 
values 
 Adverse events. AEs will be collected from screening to end of study (EOS) 
 Randomization. Randomization will be stratified by geographic region 
3.1.2 
Timing of TID Dosing 
If possible, the first dose of study medication should be administered on the same day as 
screening.  
The first dose of study medication (on Day 1) must be taken under observation at the study 
site. All other doses will be administered at the study site for subjects who are confined to the 
site during the study or will be self-administered outside the study site (eg, at home) for 
subjects at sites that choose to use  mobile nursing, except that the dose for PK evaluation 
(Dose 7, 8, or 9; see Section 3.1.4) must be taken under observation at the study site. The 
timing of the doses will be recorded in a patient diary. 
The first dose of study medication should be administered between 6 AM and 4 PM, 
inclusive or between 8 PM and 10 PM, inclusive. Dosing after 4 PM but before 8 PM would 
make scheduling for the second dose difficult, considering the later hours. 
The second dose of study medication must be taken after at least 6 hours and no later than 
10 hours after the first dose, allowing the participant to select a convenient 8-hour (± 2 hours)
dosing schedule thereafter to complete a total of 15 doses.  
For example, if a patient intends to choose a 6 AM, 2 PM, 10 PM dosing schedule: 
 Then if the first dose is administered between 6 AM and 8 AM on Day 1, the second 
dose should be administered at 2 PM on Day 1 and the third dose at 10 PM on Day 1, 
and the subject can then proceed with the 6 AM, 2 PM, and 10 PM dosing schedule 
on Day 2 and thereafter. 
 
 
 
 

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Or if the first dose is administered between 8 AM and 10 AM on Day 1, the second 
dose should be administered at 4 PM on Day 1 and the third dose at 10 PM on Day 1, 
and the subject can then proceed with the 6 AM, 2 PM, and 10 PM dosing schedule 
on Day 2 and thereafter.
Or if the first dose is administered between 10 AM and noon on Day 1, then the 
second dose should be administered at 8 PM on Day 1, and the subject can then 
proceed with the 6 AM, 2 PM, and 10 PM dosing schedule on Day 2 and thereafter.
Or if the first dose is administered between noon and 4 PM on Day 1, the second dose 
should be administered at 10 PM on Day 1, and the subject can then proceed with the 
6 AM, 2 PM, and 10 PM dosing schedule on Day 2 and thereafter.
 Or if the first dose is administered between 8 PM and 10 PM on Day 1, the subject 
can then proceed with the 6 AM, 2 PM, and 10 PM dosing schedule on Day 2 and 
thereafter. 
Doses of AT-752 and matching placebo should be separated by 8 hours (±2 hours). After Day 
1, if a dose is delayed, it should be taken as soon as possible, but must be taken at least 6 
hours before the next scheduled dose. Otherwise, the dose must be skipped, and the next dose 
taken as scheduled. Dosing will be stopped at the end of the 15-dose treatment period. At the 
end of the treatment period, the tablets from any missed doses should be returned to the site. 
Treatment adherence will be assessed by a study medication log (patient diary), which will be 
completed by the clinic staff for in clinic doses and by the participant for out of clinic doses.  
3.1.3 
Timing of BID Dosing 
If possible, the first dose of study medication should be administered on the same day as 
screening.  
The first dose of study medication (on Day 1) must be taken under observation at the study 
site. The doses for PK evaluation (for Dose 5, 6, or 7; see Section 3.1.4) must also be taken 
under observation at the study site.
All other doses may be administered either at the study site or will be self-administered 
outside the study site (eg, at home). The timing of the doses will be recorded in a patient 
diary. 
 
 
 
 

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The second dose of study medication must be taken after at least 6 hours and no later than 
12 hours after the first dose, allowing the participant to select a convenient 12-hour (± 2 
hours) dosing schedule thereafter to complete a total of 10 doses. For example,  
If the first dose of study medication is administered between 6AM and 1 PM on Day 
1, the second dose should be administered between 6 PM and no later than 10PM on 
Day 1, and then the subject can begin their preferred 12-hour dosing schedule on Day 
2 (eg, 6 AM and 6 PM, OR 7 AM and 7 PM, OR 8 AM or 8 PM,  etc), as long as the 
12 hours (± 2 hours) timing of doses is adhered to. 
 Or if the first dose of study medication is administered between 1 PM and 4 PM on 
Day 1, the second dose should be administered at 10 PM on Day 1, and then the 
subject can begin their preferred 12-hour dosing schedule on Day 2 (eg, 6 AM and 6 
PM, OR 7 AM and 7 PM, OR 8 AM or 8 PM, etc), as long as the 12 hours (± 2 hours) 
timing of doses is adhered to. 
 Or if the first dose of study medication is administered between 6 PM and 10 PM on 
Day 1, the subject can then begin their preferred 12-hour dosing schedule on Day 2 
(eg, 6 AM and 6 PM, OR 7 AM and 7 PM, OR 8 AM or 8 PM, etc), as long as the 12 
hours (± 2 hours) timing of doses is adhered to. 
Doses of study drug should be separated by 12 hours (±2 hours). After Day 1, if a dose is 
delayed, it should be taken as soon as possible, but must be taken at least 6 hours before the 
next scheduled dose. Otherwise, the dose must be skipped, and the next dose taken as 
scheduled. Dosing will be stopped at the end of the 10-dose treatment period. At the end of 
the treatment period, the tablets from any missed doses should be returned to the site.
Treatment adherence will be assessed by a study medication log (patient diary), which will be 
completed by the clinic staff for in clinic doses and by the participant for out of clinic doses.  
3.1.4 
Timing of Samples for PK, Viral Load, and NS1 
The timing of samples for PK analyses, viral load determination, and NS1 levels are outlined 
below for TID and for BID dosing. As shown in the tables below, the timing will vary 
depending on the time of day that the patient received Dose 1 of study medication and how 
many doses of study medication they received on Day 1. 
 
 
 

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Timing of sample collections for patients who begin TID dosing at different times on Day 1 
and thus receive either 3 doses, 2 doses, or 1 dose of study medication on Day 1, are
provided in Table 3-2, Table 3-3, and Table 3-4, respectively. In these tables, Day 1 is the day 
of dosing. Some of the PK sample times are fixed (pre-dose on Day 1, 24 hours after Dose 
1), and some are flexible (serial PK samples for TID dosing may be obtained at either dose 7, 
8, or 9). Some of the virology sample times are fixed (pre-dose on Day 1, 24 hours after Dose 
1, 48 hours after Dose 1, and 8-24 hours after Dose 15). Other virology sample times are 
flexible, with samples collected anytime on each of 6 days (Days 4, 5, 7, 8, 14, and 28). 
Timing of sample collections for patients who begin BID dosing at different times on Day 1 
and thus receive either 2 doses or 1 dose of study medication on Day 1, are provided in Table 
3-5 and Table 3-6, respectively. In these tables, Day 1 is the day of dosing. Some of the PK 
sample times are fixed (pre-dose on Day 1, 24 hours after Dose 1), and some are flexible 
(serial PK samples for BID dosing may be obtained at either dose 5, 6, or 7). Some of the 
virology sample times are fixed (pre-dose on Day 1, 24 hours after Dose 1, 48 hours after 
Dose 1, and 8-24 hours after Dose 15). Other virology sample times are flexible, with 
samples collected anytime on each of 6 days (Days 4, 5, 7, 8, 14, and 28).   

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Table 3-2
TID dosing beginning before 10 AM, with 3 doses given on Day 1: 
Timing of samples for PK, viral load, and NS1 
 
For TID Dosing (with 3 doses given on Day 1) 
Day
Dose #
PK draw
Viral load and NS1
Day 1
1
Predose
Predose
 
2 
  
  
  
3 
  
  
Day 2  
4 
24 hrs post Dose #1 (prior to Dose #4) 
24 hrs post Dose #1 (prior to Dose #4) 
 
5 
  
  
  
6 
  
  
Day 3 
7 
Predose #7 AND 0.5, 1, 2, 4, and 6 hrs post 
dose #7 
48 hrs post Dose #1 (prior to Dose #7) 
 
8 
NOTE:  Serial PK can be done at Dose 7, 8, 
or 9 (based on site/patient convenience). 
  
  
9 
  
  
Day 4 
10 
  
One sample anytime Day 4 
 
11 
  
  
12 
  
Day 5 
13 
  
One sample anytime Day 5 
 
14 
  
  
15 
  
Day 6 
  
  
8-24 hrs post Dose #15 
Day 7 
  
  
Any time 
Day 8 
  
  
Any time  
Day 14 
  
  
Any time  
Day 28
Any time 

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Table 3-3
TID dosing beginning between 10 AM and 4 PM, with 2 doses 
given on Day 1: Timing of samples for PK, viral load, and NS1 
 
For TID Dosing (with 2 doses given on Day 1) 
Day
Dose #
PK draw
Viral load and NS1
Day 1
1
Predose
Predose
 
2 
  
  
Day 2  
3 
  
  
 
4 
24 hrs post Dose #1 (prior to Dose #4) 
24 hrs post Dose #1 (prior to Dose #4) 
  
5 
  
  
Day 3 
6 
  
  
 
7 
Predose #7 AND 0.5, 1, 2, 4, and 6 hrs post 
dose #7 
48 hrs post Dose #1 (prior to Dose #7) 
  
8 
NOTE:  Serial PK can be done at Dose 7, 8, 
or 9 (based on site/patient convenience. 
  
Day 4 
9 
  
One sample anytime Day 4 
 
10 
  
 
  
11 
  
 
Day 5 
12 
  
One sample anytime Day 5 
 
13 
  
 
  
14 
  
 
Day 6 
15 
  
  
 
  
  
8-24 hrs post Dose #15 
Day 7 
  
  
Any time 
Day 8 
  
  
Any time  
Day 14 
  
  
Any time  
Day 28 
  
  
Any time  

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Table 3-4
TID dosing beginning in the evening, with 1 dose given on Day 1: 
Timing of samples for PK, viral load, and NS1
 
For TID Dosing (with 1 dose given on Day 1)
Day
Dose #
PK draw
Viral load and NS1
Day 1
1
Predose
Predose
Day 2 
2
3
 
4 
24 hrs post Dose #1 (prior to Dose #4) 
24 hrs post Dose #1 (prior to Dose #4) 
Day 3 
5 
 
 
6 
 
 
 
7 
Predose #7 AND 0.5, 1, 2, 4, and 6 hrs post 
dose #7 
48 hrs post Dose #1 (prior to Dose #7) 
Day 4 
8 
NOTE:  Serial PK can be done at Dose 7, 8, 
or 9 (based on site/patient convenience). 
One sample anytime Day 4 
9 
 
 
 
10 
 
 
Day 5 
11 
 
One sample anytime Day 5 
12 
 
 
 
13 
 
 
Day 6 
14 
 
 
15 
 
 
 
 
 
8-24 hrs post Dose #15 
Day 7 
 
 
Any time 
Day 8 
 
 
Any time  
Day 14 
 
 
Any time  
Day 28 
 
 
Any time  
 

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Table 3-5
BID dosing beginning before 4 PM, with 2 doses given on Day 1: 
Timing of samples for PK, viral load, and NS1 
 
For BID Dosing (with 2 doses given on Day 1) 
Day
Dose #
PK draw
Viral load and NS1
Day 1
1
Predose
Predose
 
2 
  
  
Day 2  
3 
24 hrs post Dose #1 (prior to Dose #3) 
24 hrs post Dose #1 (prior to Dose #3) 
 
4 
  
  
Day 3 
5 
Predose #5 AND 0.5, 1, 2, 4, 6, and 8 hrs 
post dose #5
48 hrs post Dose #1 (prior to Dose #5)
6
NOTE:  Serial PK can be done at Dose 5, 6 
or 7 (based on site/patient convenience.
Day 4 
7 
  
One sample anytime Day 4 
 
8 
  
 
Day 5 
9 
  
One sample anytime Day 5 
 
10 
  
 
Day 6 
  
  
8-24 hrs post Dose #10 
7 
  
  
Any time 
8 
  
  
Any time  
14
  
  
Any time  
28
  
  
Any time  
 

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Table 3-6
BID dosing beginning between 6 PM and 10 PM, with 1 dose given 
on Day 1: Timing of samples for PK, viral load, and NS1
For BID Dosing (with 1 doses given on Day 1)
Day
Dose #
PK draw
Viral load and NS1
Day 1
1
Predose
Predose
Day 2 
2
3
24 hrs post Dose #1 (prior to Dose #3)
24 hrs post Dose #1 (prior to Dose #3)
Day 3
4
5
Predose #5 AND 0.5, 1, 2, 4, 6 and 8 hrs 
post dose #5
48 hrs post Dose #1 (prior to Dose #5)
Day 4
6
NOTE:  Serial PK can be done at Dose 5, 6 
or 7 (based on site/patient convenience.
One sample anytime Day 4
7
Day 5
8
One sample anytime Day 5
9
Day 6
10
8-24 hrs post Dose #10
Day 7
Any time
Day 8
Any time 
Day 14
Any time 
Day 28
Any time 
4.
STUDY POPULATION
Approximately 60 subjects will be enrolled in the study at approximately 25 study sites.
Subjects will be adults with confirmed DENV infection. 
4.1
INCLUSION CRITERIA
A patient must meet the following criteria to be eligible for participation in this study: 
18-55 years of age at time of enrollment
(or feeling feverish) with onset during the previous 48 hours
Live/work in or recent travel to dengue endemic area
Positive test confirming DENV on a NS1 antigen test or RT-PCR assay
Negative rapid diagnostic test result for SARS-CoV-2 and Influenza A and B
 
 
 
 
 
 
 

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Body mass index (BMI) of 18 to 30 kg/m2
Provides written informed consent prior to initiation of any study procedures
Able to understand and agrees to comply with planned study procedures and be available 
for all study visits
Males and females of childbearing potential must agree to use protocol-specified methods 
of contraception as described in Section 4.1.1
Male subjects must agree to not donate sperm from the first dose through 90 days after 
the last dose of study drug
4.1.1
Protocol Specified Methods of Contraception
Female subjects of childbearing potential must agree to use one of the following 
methods of birth control from screening through 30 days after the last dose of study 
drug:
o
intrauterine device (IUD)
o
bilateral tubal occlusion
o
vasectomized partner
o
sexual abstinence
o
hormonal contraception (including combined, progesterone only or 
intrauterine hormone-releasing system [IUS]) together with a barrier method 
such as (i) male or female condom with or without spermicide or (ii) cap, 
diaphragm or sponge with spermicide
Note:  A female subject of non-
female of any age who had a hysterectomy, bilateral oophorectomy, or bilateral 
tubal ligation.
Male subjects must agree to use a condom from the first dose through 90 days after 
the last dose of the study drugs. If their female partner is of childbearing potential, the 
male subject must agree to discuss with his female partner the importance of using 
 
 
 
 
  
 
 
 
  
 
  
  
 
 
 
 
 
 
  
 
 
 
 
 
  

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one of the additional contraceptive methods listed above from the first dose through 
90 days after the last dose of study drug.   
Male subjects must have agreed not to donate sperm from the first dose through 90 
days after the last dose of study drug.
4.2
EXCLUSION CRITERIA
A patient who meets any of the following criteria will be excluded from participation in this 
study: 
Pregnant at screening or plans to become pregnant within 90 days of screening
Female patient who is breastfeeding or plans to breastfeed during the study period
Has previously received any investigational or approved vaccine for dengue
Previous history of HIV, chronic hepatitis B infection, or current hepatitis C infection
(from medical history)
Use of any antiviral drug within 30 days or within 5 half-lives of the active drug or 
metabolite (for long-acting antivirals)
Currently enrolled in or plans to participate in another clinical trial with an 
investigational agent or device that will be received during the study-reporting period
Exposure to another investigational agent within 30 days or 5 half-lives, whichever is 
longer, prior to study drug administration
Use of herbal or dietary supplements or grapefruit juice within 7 days of screening (eg, 
chamomile, raspberry, peppermint, lemon, ginger, hibiscus, echinacea, rooibos, sage, 
lemon balm, rose hip, or passionflower tea, turmeric, ginger, bitter gourd, mangosteen, 
Blumea balsamifera, banaba [Lagerstroemia speciosa], soursop, bignay [wild cherry], or 
horseradish [Moringa oleifera], artichoke, lotus, and other herbal cough treatments or 
herbal headache relievers in case of fever or cough)
Patients with chronic medical conditions that put them at risk for severe dengue, 
including uncontrolled diabetes mellitus, severe asthma requiring oral steroids, and 
admission to the hospital in the previous 6 months for cardiac disease
Current use of anticoagulant or antiplatelet drugs or documented medical history of 
bleeding disorders
 
 
 
 
 
 
 
 
 
 
 

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Current use of medications for treatment of inflammatory bowel disease or documented 
medical history of chronic gastrointestinal disease including inflammatory bowel disease
Immunocompromised due to use of immunosuppressive drugs including systemic 
corticosteroids (inhaled or topical corticosteroids are allowed) or any current disease or 
condition
Evidence of severe dengue disease including:
Severe plasma leakage leading to shock or fluid accumulation with respiratory 
distress
Severe bleeding
Severe organ impairment (eg, 
consciousness, or heart impairment)
Suspected or confirmed acute illness thought to be caused by a pathogen other than 
DENV
Confirmed or suspected SARS-CoV-2 infection or contact with patients with confirmed 
SARS-CoV2 infection within 7 days prior to screening
ALT or AST > 5x upper limit of normal (ULN) or total bilirubin > 1.5x ULN (Gilbert’s 
syndrome is exempt) or platelet count <80,000/mm3 at the time of screening
Has any other medical disease or condition that in the opinion of the site principal 
investigator or appropriate sub-investigator, precludes study participation. This includes 
any acute, subacute, intermittent, or chronic disease or condition that would place the 
patient at an unacceptable risk of injury, render the patient unable to meet the 
requirements of the protocol, or interfere with the evaluation of responses or the patient's 
successful completion of the trial
One-time retests of individual screening laboratory parameters or assessments may be 
permitted in certain scenarios. Such scenarios may include lab processing error, results 
inconsistent with subject’s historical values/medical history, or other extenuating 
circumstances such as a recent or intercurrent illness potentially affecting screening 
laboratory results
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 

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4.3 
WITHDRAWAL OF SUBJECTS FROM THE STUDY 
4.3.1 
Reasons for Withdrawal 
Subjects can withdraw consent and discontinue from the study at any time, for any reason, 
without prejudice to further treatment. 
The investigator may withdraw a subject from the study if the subject is:
1. Noncompliant with the protocol requirements;
2. Experiences an SAE or intolerable AE(s) that in the investigator’s opinion requires 
withdrawal from the study;
3. Pregnant;
4. Required to take a medication prohibited by the protocol; or
5. Requesting an early discontinuation for any reason. 
The investigator can also withdraw a subject upon the request of the sponsor, or if the 
sponsor terminates the study. Upon occurrence of an SAE or intolerable AE, the investigator 
will confer with the sponsor. If a subject is discontinued because of an AE, the event will be 
followed until it is resolved, stable, or judged by the investigator to be not clinically 
significant.
4.3.2 
Handling of Withdrawals 
Subjects are free to withdraw from the study at any time upon request. Subject participation 
in the study may be stopped at any time at the discretion of the investigator or at the request 
of the sponsor. 
When a subject withdraws from the study, the reason(s) for withdrawal shall be recorded by 
the investigator on the relevant page of the eCRF. Whenever possible, any subject who 
withdraws from the study prematurely will undergo all EOS assessments. Any subject who 
fails to return for final assessments will be contacted by the site in an attempt to have them 
comply with the protocol. The status of subjects who fail to complete final assessments will 
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4.3.3 
Replacements 
At the discretion of the investigator, subjects who have been randomized, but withdraw prior 
to dosing, may be automatically replaced. Additionally, after consultation with the medical 
monitor from the Contract Research Organization (CRO) for this study (
) and the 
sponsor, subjects who were dosed, but withdraw for reasons not related to safety of the study 
drug (eg, becoming infected with Covid) or who were lost to follow-up) before completing 
the study, may be replaced. Any replacement subject will be assigned to the same cohort and 
receive the same study drug as the subject being replaced.
5. 
STUDY TREATMENTS 
5.1 
TREATMENTS ADMINISTERED 
All subjects will receive the study treatments as described in Section 3. The time of the initial 
study drug administration will be called “0” hours. The study drug will be administered with 
approximately 240 mL of water. Up to an additional 240 mL of water will be allowed, if 
necessary, to aid in swallowing of the study drugs. Subjects will not engage in strenuous 
activity at any time during the treatment period. When morning blood draws are required, 
study drug will be administered after blood sample collection. Study drug may be taken with 
or without food. The timing of TID dosing is provided in Section 3.1.2 and the timing of BID 
dosing is provided in Section 3.1.3. Doses of AT-752 and matching placebo should be 
separated by 8 hours (± 2 hours) for TID dosing and by 12 hours (±2 hours) for BID dosing. 
After Day 1, if a dose is delayed, it should be taken as soon as possible, but must be taken at 
least 6 hours before the next scheduled dose. Otherwise, the dose must be skipped and the 
next dose taken as scheduled.  
Dosing will be stopped at the end of the 15-dose (TID) or 10-dose (BID) treatment period. At
the end of treatment period, tablets corresponding to any missed doses should be returned to 
the site. 
Treatment adherence will be assessed by a study medication log (patient diary), which will be 
completed by the clinic staff for in clinic doses and by the participant for out of clinic doses.  
5.1.1 
Safety Review Committee 
This study is designed such that moving to the next dosing cohort is allowed only after a 
blinded safety data review of the previous cohort by the SRC.  
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Study assessments (eg, AEs, clinical laboratory test results, vital sign measurements, and 
12-lead ECG results) will be used to evaluate safety and tolerability of a given dose.
Initiation of additional cohorts will occur based on an initial safety review by the SRC of 
available safety data (through Day 5) and PK data of the prior cohort. 
SRC charter will include safety related considerations.
5.2
INVESTIGATIONAL PRODUCTS
The study drugs that will be used are as follows:
Product 
Supplied Formulation 
AT-752 tablet 
250 mg of AT-281, free base of the drug substance AT-752 
Matching placebo tablet 
0 mg of AT-281, free base of the drug substance AT-752 
Further information on the study drug can be found in the investigator’s brochure (Atea 
Pharmaceuticals 2020). 
5.2.1 
Study Drug Packaging and Storage 
ATEA Pharmaceuticals, Inc. will provide the investigator and clinical unit with adequate 
quantities of AT-752 and matching placebo. Detailed instructions for the preparation of study 
treatments will be provided separately to the pharmacy. 
All study drugs must be stored according to the labeled instructions in a secure cabinet or 
room with access restricted to necessary clinic personnel. The site will be required to keep a 
temperature log to establish a record of compliance with storage conditions.
The storage condition for AT-752 and Placebo is: 15 -
.
5.2.2 
Study Drug Accountability 
The investigator will maintain accurate records of receipt of all study drugs, including dates 
of receipt. Accurate records will be kept regarding when and how much study drug is 
dispensed and used by each subject in the study. Reasons for departure from the expected 
dispensing regimen must also be recorded. At the completion of the study, and to satisfy 
regulatory requirements regarding drug accountability, all study drugs will be reconciled and 
retained or destroyed according to applicable regulations. 
 

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5.3 
METHOD OF ASSIGNING SUBJECTS TO TREATMENT 
GROUPS 
 will generate the randomization schedule. Eligible subjects will be enrolled into the 
current dose cohort at a ratio of 3:1 (active:placebo). Each cohort will be independently 
randomly assigned by a qualified person who is not directly involved in study conduct, data 
management, or data analysis. Randomization will be stratified by geographic region.
5.4 
BLINDING 
5.4.1 
Blinding Procedures 
This study will employ a double-blind study design. The study drug and matching placebo 
tablets will be identical in appearance. The unblinded pharmacist will be responsible for 
dispensing the study drug in a manner consistent with maintaining the blind. 
As this is an early phase study, the Sponsor may perform unblinded interim reviews of the 
data during the course of the study. Interim study database locks may be performed after 
completion of the clinical conduct of each cohort and completion of the bioanalysis of 
samples from the corresponding treatment arm.
5.4.2 
Breaking the Blind 
 will be responsible for maintaining the blind throughout the study. 
If a subject becomes seriously ill or pregnant during the study, the blind will be broken (via 
code break envelopes) only if knowledge of the administered study drug will affect that 
subject’s available treatment options. In the event of a medical emergency requiring 
identification of the study drug administered to an individual subject, the investigator will 
make every attempt to contact 
 to explain the need for opening the 
code within 24 hours of opening the code. The investigator will be responsible for 
documenting the time, date, reason for the code break, and the names of the personnel 
involved.
5.5 
TREATMENT COMPLIANCE 
Treatment adherence will be assessed by a study medication log (patient diary), which will be 
completed by the clinic staff for in clinic doses and by the participant or mobile nursing staff 
for out of clinic doses.   
CCI
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The date and time of study drug administration will be recorded on the appropriate page of 
the eCRF. If a subject is not administered study drug, the reason for the missed dose will be 
recorded.
5.5.1
Prior and Concomitant Medications
Restrictions for prior and concomitant medications and therapies are provided in Sections 4.1
and 4.2. Prior and concomitant medications and therapies will be coded using the latest 
version of the World Health Organization Drug Dictionary.
Prior Medications
Information regarding prior medications taken by the subject within the 30 days before 
signing the informed consent form (ICF) will be recorded in the subject’s eCRF.
Concomitant Medications
Any concomitant medication deemed necessary for the welfare of the subject during the 
study may be given at the discretion of the investigator. If a concomitant medication is taken, 
except for those specified in the protocol, a joint decision will be made by the investigator 
and the sponsor to continue or discontinue the subject based on the time the medication was 
administered, its pharmacology and PK, and whether the use of the medication will 
compromise the safety of the subject or the interpretation of the data. The investigator is 
responsible for ensuring that details regarding the medication are adequately recorded in the 
eCRF.
6.
STUDY ENDPOINTS
6.1
PRIMARY ENDPOINT
Change in DENV viral load from baseline
6.2
SECONDARY ENDPOINTS: PHARMACOKINETIC 
ENDPOINTS
Plasma concentrations of AT-281 (and metabolites AT-551, AT-229, and AT-273) for 
each cohort at the following timepoints:
o
Day 1: Pre-dose (before the first dose, time 0)
 
 
 
 

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o
24 hours after Dose 1 (before Dose 4 for TID dosing and before Dose 3 for 
BID dosing)
o
A day of intensive PK sampling:
i. For TID dosing, samples will be obtained before Dose 7 and 0.5, 1, 2, 
4, and 6 hours after Dose 7. This serial PK sampling may be done for 
Dose 7, 8, or 9, based on site/patient convenience
ii. For BID dosing, samples will be obtained before Dose 5 and 0.5, 1, 2, 
4, 6, and 8 hours after Dose 5. This serial PK sampling may be done 
for Dose 5, 6, or 7, based on site/patient convenience
For blood samples (both TID and BID dosing), a ±10-minute window 
hours; ±15 minute for time points between 4 and 12 
hours 
o
At any early study discontinuation visits. The timing of these PK samples 
relative to the last 2 (most recent) doses will be recorded
Noncompartmental analysis will be performed for the following plasma PK 
parameters, when applicable and if data permit. Other PK parameters may also be 
calculated. PK parameters will be calculated based on actual times:
o
AUClast (area under the plasma concentration versus time curve from time 0 to 
the last quantifiable concentration)
o
AUCtau (area under the plasma concentration versus time curve over the 
dosing interval)
o
AUCinf (area under the plasma concentration versus time curve from time 0 to 
extrapolated to infinity)
o
Cmax
o
Tmax
o
t1/2z (apparent terminal elimination half-life)
o
CL/F for AT-281 only (apparent oral clearance)
o
Vz/F for AT-281 only (apparent volume of distribution)
o
Ctrough
6.3
SECONDARY ENDPOINTS: SAFETY ENDPOINTS
Incidence and grade of any TEAEs from first dose through Day 28 or withdrawal 
from the study
Incidence and grade of any SAEs through Day 28 or withdrawal from the study
 
 
 
 
 
 
 

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Vital sign measurements
Physical examination findings
Clinical laboratory (serum chemistry, hematology, coagulation, and urinalysis 
findings)
ECG
6.4
EXPLORATORY ENDPOINTS: PHARMACODYNAMIC
ENDPOINTS
Area under the log10-transformed viral load curve (AUC) from first dose to the end 
of treatment or study
Time to viral RNA clearance, which is defined as the first of 2 consecutive 
undetectable DENV viral RNA measurements
Time to clearance of NS1 protein using NS1 antigen test. Clearance is defined as time 
from start of treatment until the first of 2 consecutive plasma samples are NS1-
negative.
Change of DENV viral load from baseline, viral load AUC, time to viral RNA or NS1 
clearance by DENV serotype
Time to resolution or duration of fever 
Exploratory biomarkers on immunological response to dengue (See list in Section
8.3.4)
Exploratory analyses may be performed to evaluate exposure-response relationship. 
The relationship between the exposure of AT-752 (and its metabolites) and DENV 
viral RNA measurement may be explored using graphical displays
7.
STUDY ASSESSMENTS
Before performing any study procedures, all potential subjects will sign an ICF as outlined in 
Section 9.2.2.3. Subjects will undergo study procedures at the time points specified in the 
 
 
 
 
 
 
 
 
 
 
 

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SOE (Section 3). The total amount of blood collected from each subject over the duration of 
the study, including any extra assessments that may be required, will not exceed 500 mL.
7.1 
PHARMACOKINETIC ASSESSMENTS 
PK plasma samples will be collected as described in Section .6.2. For blood samples, there is 
a ±10
and a ±15 minute window for time points 
between 4 and 12 hours. 
Pharmacokinetic endpoints will be characterized as subject numbers and PK data permit. 
7.1.1
Pharmacokinetic Sample Collection
Details for the collection, processing, storage, and shipping of PK samples will be provided 
to the clinical sites in the study manual. 
7.1.2 
Pharmacokinetic Sample Analysis 
Pharmacokinetic samples will be analyzed using a validated liquid chromatography coupled 
with tandem mass spectrometry assays for AT-752 and metabolites AT-551, AT-229, and AT-
273 in human plasma. Assay results and validation details will be provided in a separate 
bioanalytical report. 
7.2 
PHARMACODYNAMIC ASSESSMENTS 
Temperature readings will be performed at least 4 times daily through the end of treatment 
(morning, mid-day, late afternoon, and evening; approximately every 4 hours during waking 
hours). Temperature will be measured orally and recorded in a patient diary (and given to the 
site coordinator for entry in the eCRF). 
A rapid point of care (POC) test for DENV NS1 antigen and a DENV serotype test will be 
performed at screening. Viral load will be assessed by measuring plasma viremia with a 
serotype-specific, real-time reverse transcription PCR assay at screening and on Days 1-8, 
Day 14, and Day 28. DENV NIS will be measured by ELISA at screening and on Days 1-8, 
Day 14, and Day 28.  See Section 3.1.4 for a description of the timing for collection of these 
samples. 
 
 
 
 
 
 
 

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7.3
SAFETY ASSESSMENTS
Safety will be assessed by monitoring and recording of AEs, vital sign measurements, 12-
lead ECG results, physical examination findings, and clinical laboratory test results 
(hematology, coagulation, serum chemistry, and urinalysis).
For all safety assessments, the investigator will determine whether results are clinically 
significant, which is defined as any variation in a result that has medical relevance and may 
result in an alteration in medical care (eg, active observation, diagnostic measures, or 
therapeutic measures). If clinical significance is noted, the result and reason for significance 
will be documented and an AE reported on the AE page of the subject’s eCRF. The 
investigator will monitor the subject until the result has reached the reference range or the 
result at screening, or until the investigator determines that follow-up is no longer medically 
necessary.
7.3.1
Adverse Events
Adverse events will be assessed from the time of screening until EOS and should be followed 
until they are resolved, stable, or judged by the investigator to be not clinically significant.
The investigator is responsible for ensuring that all AEs and SAEs are recorded in the eCRF 
and reported to the sponsor, regardless of their relationship to study drug or clinical 
significance. If there is any doubt as to whether a clinical observation is an AE, the event 
should be reported.
Adverse Event Definitions
An AE is defined as any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. Subjects will be instructed to contact the 
investigator at any time after randomization if any symptoms develop.
A treatment emergent AE is defined as any event not present before exposure to study drug or 
any event already present that worsens in intensity or frequency after exposure.
A suspected adverse reaction is any AE for which there is a reasonable possibility that the 
study drug caused the AE. For the purposes of investigational new drug safety reporting, 
“reasonable possibility” means that there is evidence to suggest a causal relationship between 
the study drug and the AE. A suspected adverse reaction implies a lesser degree of certainty 
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An adverse reaction is any AE caused by a study drug. Adverse reactions belong to a subset 
of all suspected adverse reactions and indicate that there are reasons to conclude that the 
study drug caused the event.
An AE or suspected adverse reaction is considered “unexpected” if it is not listed in the 
investigator brochure or if it occurs with specificity or severity that has not been previously 
observed with the study drug being tested; or, if an investigator brochure is not required or 
available, the AE or suspected adverse reaction is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application. For 
example, under this definition, hepatic necrosis would be unexpected (by virtue of greater 
severity) if the investigator brochure referred only to elevated hepatic enzymes or hepatitis. 
Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by virtue 
of greater specificity) if the investigator brochure listed only cerebral vascular accidents. 
“Unexpected,” as used in this definition, also refers to AEs or suspected adverse reactions 
that are mentioned in the investigator brochure 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.
An AE or suspected adverse reaction is considered an SAE/suspected unexpected serious 
adverse reaction if, in the view of either the investigator or sponsor, it results in any of the 
following outcomes:
Death
Life-threatening AE
Inpatient hospitalization or prolongation of existing hospitalization
Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions
Congenital anomaly or birth defect
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the 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 
 
 
 
 
 

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dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse.
An AE or suspected adverse reaction is considered “life threatening” if, in the view of either 
the investigator or sponsor, its occurrence places the subject at immediate risk of death. It 
does not include an AE or suspected adverse reaction that might have caused death if it had 
been more severe.
Eliciting and Documenting Adverse Events
Subjects will be asked a standard question to elicit any medically related changes in their 
well-being. They will also be asked if they have been hospitalized, had any accidents, used 
any new medications, or changed concomitant medication regimens (both prescription and 
over-the-counter medications).
In addition to subject observations, AEs will be documented from any data collected on the 
AE page of the eCRF (eg, laboratory values, physical examination findings, and ECG 
changes) or other documents that are relevant to subject safety.
Reporting Adverse Events
All AEs reported or observed during the study will be recorded on the AE page of the eCRF. 
Information to be collected includes drug treatment, type of event, time of onset, dosage, 
investigator-specified assessment of severity and relationship to study drug, time of 
resolution of the event, seriousness, any required treatment or evaluations, and outcome. Any 
AEs resulting from concurrent illnesses, reactions to concurrent illnesses, reactions to 
concurrent medications, or progression of disease states must also be reported. The Medical 
Dictionary of Regulatory Activities (MedDRA) will be used to code all AEs.
Any medical condition that is present at the time that the subject is screened but does not 
deteriorate should not be reported as an AE. However, if it deteriorates at any time during the 
study, it should be recorded as an AE.
Any AE that is considered serious by the investigator or which meets SAE criteria 
(Section 6.3.1.1) must be reported to the sponsor within 24 hours of awareness (after the 
investigator has confirmed the occurrence of the SAE). The investigator will assess whether 
there is a reasonable possibility that the study drug caused the SAE. The sponsor will be 
responsible for notifying the relevant regulatory authorities of any SAE. The investigator is 
 
 
 

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status of mother and child, even if the subject was discontinued from the study. Pregnancy 
complications and elective terminations for medical reasons should not be reported as AEs or 
SAEs. Spontaneous miscarriages must be reported as an SAE.
Assessment of Severity
The severity (or intensity) of an AE refers to the extent to which it affects the subject’s daily 
activities. Severity of AEs will be graded according to the grading scales modified from 
DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DHHS 2017).
The determination of severity not listed in the AIDS Table for Grading the Severity of Adult 
and Pediatric Adverse Events (DHHS 2017) should be made by the investigator based upon 
medical judgment and the definitions of severity as follows:
Grade 1 (Mild): Mild symptoms causing no or minimal interference with usual social 
and functional activities with intervention no indicated
Grade 2 (Moderate): Moderate symptoms causing greater than minimal interference
with usual social and functional activities with intervention indicated
Grade 3 (Severe): Severe symptoms causing inability to perform usual social and 
functional activities with intervention or hospitalization indicated
Grade 4 (Potentially life-threatening): Potentially life-threatening symptoms causing 
inability to perform basic self-care functions with intervention indicated to prevent 
permanent impairment, persistent disability, or death
Grade 5 (Death)
Changes in the severity of an AE should be documented to allow the duration of the event at 
each level of intensity to be assessed. An AE characterized as intermittent does not require 
documentation of the onset and duration of each episode.
Assessment of Causality
The investigator’s assessment of an AE’s relationship to study drug is part of the 
documentation process
 
 
 
 
 
 
 

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The investigator will assess causality (ie, whether there is a reasonable possibility that the 
study drug caused the event) for all AEs and SAEs. The relationship will be classified as 
follows:
Not related: There is not a reasonable possibility of relationship to study drug. The 
AE does not follow a reasonable temporal sequence from study drug administration, 
or can be reasonably explained by the subject’s clinical state or other factors (eg, 
disease under study, concurrent diseases, and concomitant medications).
Related: There is a reasonable possibility of relationship to study drug. The AE 
follows a reasonable temporal sequence from study drug administration and cannot be 
reasonably explained by the subject’s clinical state or other factors (eg, disease under 
study, concurrent diseases, or concomitant medications), represents a known reaction 
to the study drug or other drugs in its class, is consistent with the known 
pharmacological properties of the study drug, and/or resolves with discontinuation of 
the study drug (and/or recurs with re-challenge, if applicable).
Follow-up of Adverse Events
All AEs must be reported in detail on the appropriate page of the eCRF and followed until 
they are resolved, stable, or judged by the investigator to be not clinically significant.
7.3.2
Clinical Laboratory Testing
Clinical laboratory tests will be performed by the study sites’ local laboratories. Blood and 
urine samples will be collected, as per the SOE (Section 3) and will be prepared using 
standard procedures. 
A repeat measurement of clinical laboratory testing is permitted for eligibility determination. 
Other clinical laboratory retests may be permitted once in certain scenarios with 
 
 approval. Such scenarios may include laboratory processing error, results 
inconsistent with subject’s historical values/medical history, or other extenuating 
circumstances such as a recent or intercurrent illness potentially affecting screening 
laboratory results. The clinical laboratory that will perform the tests will provide the 
reference ranges for all clinical laboratory parameters. Abnormal clinical laboratory values 
will be flagged as either high or low (or normal or abnormal) based on the reference ranges 
for each laboratory parameter.
 
 
 
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The following clinical laboratory assessments will be performed:
Hematology 
Complete blood count (CBC) including white blood cell (WBC)
count with differential count, red blood cell (RBC) count, platelet
count, hematocrit, hemoglobin, red blood cell indices
Coagulation
Prothrombin time, partial thromboplastin time, and international 
normalized ratio (INR) 
Serum chemistry
Alanine aminotransferase (ALT), alkaline phosphatase, aspartate 
aminotransferase (AST), bilirubin (total and direct), blood urea 
nitrogen (BUN), creatinine, lipase, serum creatinine kinase
Urinalysis
Urinalysis will be performed with microscopy at indicated. 
Additional urinalysis may be performed as clinically indicated. It is 
not required to have the results from the urinalysis performed at 
screening before beginning study drug dosing, unless medically 
necessary to establish eligibility (at investigator’s discretion)
Serology
DENV serotype testing (screening only) 
Direct viral tests
SARS-CoV-2 rapid test, rapid influenza diagnostic test
Other analyses
Female subjects: 
Follicle-stimulating hormone, pregnancy test ( -HCG; urine at 
screening and urine or serum after screening)  
 
7.3.3 
Vital Sign Measurements 
Vital signs will be measured after the subject has been in the seated position for at least 
5 minutes. A repeat measurement of vital sign measurements is permitted for eligibility 
determination. On Day 1, vital signs will be measured before study drug administration and 
before any scheduled blood collections (Section 3). Subsequent measurements of vital signs 
(once a day on Days 2-6) may occur anytime during the day, either in the clinic or with 
mobile nursing staff.   
Vital signs will include systolic and diastolic blood pressure, pulse rate, respiratory rate, and 
body temperature.  
In addition, temperature will be measured orally at least every 4 hours during the study 
treatment period (morning, mid day, late afternoon, evening, while the subject is awake) and 
will be recorded in a patient diary. 
 

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7.3.4 
12-Lead Safety Electrocardiogram 
Triplicate 12-lead ECG recordings will be performed as listed in the SOEs (Section 3) after 
the subject has been in the supine position for at least 5 minutes. 
Measurements of the following intervals will be reported: RR interval, PR interval, QRS 
width, QT interval, and QTcF. Assessments should include comments on whether the tracings 
are normal or abnormal; rhythm; presence of arrhythmia or conduction defects; morphology; 
any evidence of myocardial infarction; or ST-segment, T Wave, and U Wave abnormalities. 
7.3.5
Physical Examinations
A complete physical examination will include, at minimum, assessment of skin, head, ears, 
eyes, nose, throat, neck, thyroid, lungs, heart, cardiovascular, abdomen, lymph nodes, and 
musculoskeletal system/extremities. A symptom-targeted physical examination will include, 
at minimum, assessment of skin, lungs, cardiovascular system, and abdomen (liver and 
spleen). Interim physical examinations may be performed at the discretion of the investigator, 
if necessary, to evaluate AEs or clinical laboratory abnormalities. 
8. 
STATISTICAL ANALYSIS 
Details of all statistical analyses will be described in a separate statistical analysis plan.
8.1 
SAMPLE SIZE CALCULATIONS 
The sample size for this study is approximately 60 subjects. Each of the 3 cohorts will 
include 20 subjects (15 subjects receive AT-752 and 5 subjects receive placebo). 
In Low et al (Low 2014) , the observed standard deviations for VLR, defined as mean change 
from baseline viral load on days 2, 3, and 4, ranged from 0.75 (N=26) to 1.07 (N=24). Taking 
into account that the VLR endpoint in that study was based on an average of 3 measurements
and assuming that there is some correlation between measurements on days 2 through 4, we 
consider power to detect a true effect at a single time point using a one-sided 0.10 level test 
(unadjusted for multiple comparisons) with N=15 per arm for standard deviations in a range 
from 1 to 1.75:
True standard deviation 
Effect (log10 copies/mL) with 80% power 
1 
0.8 
1.25 
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1.5 
1.2 
1.75 
1.4 
Based on the above table, there is 80% power to detect a true treatment effect (versus 
placebo) on change-from-baseline viral load of 1 log10 at a time point if the true standard 
deviation is 1.25. Furthermore, if true standard deviation is in the range from 1 to 1.75, the 
probability that the observed effect would be 0.5 log10 or larger is low (in range from 0.09 to 
0.22) if there is no treatment effect, ie, an observed effect of 0.5 or larger might be 
considered suggestive of a signal. Interpretation of results will consider the totality of the 
data.
8.2 
ANALYSIS SETS 
The analysis populations are as follows: 
 The PK population will include subjects who receive at least 1 dose of the study drug and 
have sufficient concentration data to support accurate estimation of at least 1 PK 
parameter. 
 The safety population will include all subjects who receive at least 1 dose of study drug.
 The PD population will include subjects who received at least 1 dose of study drug and 
have baseline and at least 1 post-baseline virology measurement. 
8.3 
PLANNED STATISTICAL ANALYSIS  
Safety, PK, and PD data will be presented in statistical summaries in tabular and/or graphical 
format by active dose treatment arms and one-pooling placebo treatment arm. Continuous 
data will be summarized in descriptive statistics (n, mean, standard deviation [SD], median, 
95% confidence interval [CI]) and categorical data will be presented in counts and 
percentages. All subject-level data will be presented in listings. Dose proportionality in PK 
will be assessed by a power model, if data permit.
Baseline demographic and background variables will be summarized overall for all subjects. 
The number of subjects who enroll in the study and the number and percentage of subjects 
who complete the study will be presented. Incidence and percentage of subjects who 
withdraw or discontinue from the study, and the reason for withdrawal or discontinuation, 
will also be summarized.  
 
 
 

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Baseline is the last measurement prior to the start of study drug.
8.3.1
Primary Endpoint Analyses
The primary objective of this study is to evaluate the antiviral activity of AT-752 compared 
with placebo on change from baseline in viral load based on the log-10 scale at specified 
timepoints.
Change from baseline viral load will be compared between each AT-752 arm and a combined 
placebo group. Viral load will be analyzed using repeated measures mixed model with 
treatment, time, and treatment-by-time interaction as fixed factors, with more details to be 
provided in the SAP. The treatment group least squares mean (LSM) estimates for mean 
change from baseline and treatment group differences at a time point, with 80% CI and p-
value will be presented. Additionally, descriptive summaries for the change from baseline 
will also be presented by treatment group. Further details will be provided in a separate 
statistical analysis plan. 
8.3.2 
Pharmacokinetic Analyses 
Plasma concentrations will be listed and summarized descriptively (number of subjects, 
arithmetic mean, SD, coefficient of variation (CV), geometric mean, geometric CV, median, 
minimum, and maximum). Plasma concentration versus time profiles for each subject will be 
presented graphically. The mean plasma concentration versus scheduled time profiles will be 
presented graphically. 
Pharmacokinetic parameters derived from plasma samples using noncompartmental methods 
with Phoenix® WinNonlin® (Certara USA Inc., Princeton, New Jersey) Version 8.0 or higher 
or SAS Version 9.3 or higher (SAS Institute Inc., Cary, North Carolina) will be summarized 
by treatment and ethnicity using descriptive statistics (number of subjects, mean, SD, CV, 
geometric mean, geometric mean CV, median, minimum, and maximum). The parameter 
Tmax will be summarized by treatment using the number of subjects, median, minimum, and 
maximum values. 
8.3.3 
Safety Analyses 
Adverse events will be coded by preferred term and system organ class using the latest 
version of the MedDRA. Severity of AEs will be graded according to the grading scales 
modified from DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events 

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(DHHS 2017). All AE data will be presented in a data listing. Treatment--emergent AEs will 
be summarized by treatment and overall, as well as by severity and relationship to study 
drug. Serious AEs and AEs leading to discontinuation of study drug will also be presented in 
the data listings and summarized by treatment and overall.
Relevant laboratory, vital sign (pulse rate, respiratory rate, blood pressure, SpO2, and 
temperature), and ECG data will be displayed by time. Where appropriate, graded laboratory 
abnormalities will be summarized by treatment (DHHS 2017). Shift tables will be generated 
to summarize baseline and post-baseline severity grades. Physical examination findings will 
be presented in a data listing.
8.3.4
Pharmacodynamic Analyses
Area under the log10-transformed viral load curve (AUC) from first dose to the end 
of treatment (Day 5-6) and to study end (Day 28)
Time to viral RNA or NS1 clearance, defined as time to first of 2 consecutive 
undetectable viral RNA or NS1, will be described using Kaplan-Meier methods. The 
median time to viral clearance and the estimated proportions of patients with viral 
clearance will be summarized by treatment group. Patients who do not receive a 
record a negative test result by RT-PCR or NS1 antigen assay by the last observation 
timepoint will be treated as censored at the final scheduled evaluation time point.
Methods for analysis of time to resolution or duration of fever will be presented in the 
SAP
Exploratory biomarkers may include plasma concentrations of cytokines (for 
example, TNF-
IFN-
IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-1
IP-10 and 
MCP-1)
Exploratory analyses may be performed to evaluate exposure-response relationship. 
The relationship between the exposure of AT-752 (and its metabolites) and DENV 
viral RNA measurement may be explored using graphical displays
8.4
HANDLING OF MISSING DATA
Strategies for handling missing data will be described in the SAP.
 
 
 
 
 
 
 

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9.
REFERENCE LIST
Atea Pharmaceuticals, Inc. AT-752. Investigator’s brochure, edition No. 1 Boston (MA). 
2020.
Center for Disease Control and Prevention (CDC). Dengue. July 2020 [cited 03 Dec 2020] 
[13 screens]. Available from: https://www.cdc.gov/dengue/index.html. 
Dengvaxia Package Insert. Jun 2019 [cited 03 Dec 2020] [16 pages] Available from: 
https://www.fda.gov/media/124379/download.  
Department of Health and Human Services (DHHS), Food and Drug Administration 
(DHHS), Center for Drug Evaluation and Research (US). Guidance for industry: Food-effect 
bioavailability and fed bioequivalence studies. December 2002 [03 Dec 2020] [12 screens]. 
Available from: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance
s/UCM070241.pdf
Department of Health and Human Services (DHHS), Food and Drug Administration, Center 
for Drug Evaluation and Research (US). Guidance for Industry: Estimating the maximum 
safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers. July 
2005 [cited 03 Dec 2020] [30 screens]. Available from: 
http://www.fda.gov/downloads/Drugs/Guidances/UCM078932.pdf
Department of Health and Human Services (DHHS), National Institutes of Health, National 
Institute of Allergy and Infectious Diseases, Division of AIDS. Division of AIDS (DAIDS) 
table for grading the severity of adult and pediatric adverse events. Version 2.1. July 2017 
[cited 2020 Dec 10] [35 screens]. Available from: 
https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf
Levey AS, Coresh J, Greene T, et al; Chronic Kidney Disease Epidemiology Collaboration. 
Using standardized serum creatinine values in the modification of diet in renal disease study 
equation for estimating glomerular filtration rate. Ann Intern Med. 2006;145(4):247-54.
Low JG, Sung C, Wijaya L, et al. Efficacy and safety of celgosivir in patients with dengue 
fever (CELADEN): a phase 1b, randomised, double-blind, placebo-controlled, proof-of-
concept trial. Lancet Infect Dis. 2014;14:706-715. 

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Low JG, Gatsinga R, Vasudevan SG, et al. Dengue Antiviral Development: A Continuing 
Journey. Adv Exp Med Biol. 2018;1062:319-32.
 
 
 
 
 
Nguyen NM, Tran CN, Phung LK, et al. A randomized, double-blind placebo controlled trial 
of balapiravir, a polymerase inhibitor, in adult dengue patients. J Infect Dis. 
2013;207(9):1442-50.
Rivera A, Adams LE, Sharp TM, et al. Travel-associated and locally acquired dengue 
cases-United States, 2010–2017. MMWR Morb Mortal Wkly Rep. 2020;69:149-154. 
Thomas SJ and Yoon I-K. Hum A review of Dengvaxia®: development to deployment. 
Vaccin Immunother. 2019; 15(10): 2295–2314.Troost B and Smit JM. Recent advances in 
antiviral drug development towards dengue virus. Curr Opin Virol. 2020;43:9-21 
Wilder-Smith A, Quam M, Sessions O, et al. The 2012 dengue outbreak in Madeira: 
exploring the origins. Euro Surveill. 2014; 19:20718. 
World Health Organization (WHO). Dengue and severe dengue. June 2020 [cited 03 Dec 
2020] [1 screen]. Available from: https://www.who.int/news-room/fact-sheets/detail/dengue-
and-severe-dengue. 
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10. 
APPENDICES 
10.1 
APPENDIX 1: LIST OF ABBREVIATIONS 
Abbreviation
Term
AE 
adverse event
ALT 
alanine aminotransferase
AST
aspartate transaminase
AUC
area under the plasma concentration versus time curve
AUCinf
area under the plasma concentration versus time curve from time 0 
extrapolated to infinity
AUClast
area under the plasma concentration versus time curve from time 0 
to the last quantifiable concentration
AUCtau 
area under the plasma concentration versus time curve over the 
dosing interval
BID 
twice a day
BMI 
body mass index
BUN 
blood urea nitrogen 
CBC 
complete blood count
CI 
confidence interval 
CL/F 
apparent oral clearance
Cmax 
maximum observed plasma concentration 
C-QTc 
concentration-QTc
CRO 
Contract Research Organization 
Ctrough
trough concentration
CV 
coefficient of variation 
DAA 
direct-acting antiviral 
DENV
dengue virus 
DNA
deoxyribonucleic acid
DtP
direct to patient
EC
Ethics Committee
ECG 
electrocardiogram
eConsent 
electronic consent 
eCRF 
electronic case report form 
ELISA 
enzyme-linked immunosorbent assay 
EOS 
end of study 
FDA 
Food and Drug Administration
GMR
geometric mean ratio 
HCV 
hepatitis C virus 
HED 
human equivalent dose
HHC
home health care 
HIV 
human immunodeficiency virus
ICF 
informed consent form
ICH 
International Council for Harmonisation 
INR 
international normalized ratio 

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Abbreviation 
Term 
IRB
Institutional Review Board
IUD
intrauterine device
IUS
intrauterine hormone-releasing system 
LSM
least squares mean 
MAD
multiple ascending doses
MedDRA
Medical Dictionary for Regulatory Activities
NOAEL
no observed adverse effect level 
NS1 
nonstructural protein 1
PD 
pharmacodynamic(s) 
PBMC
peripheral blood mononuclear cell
PK
pharmacokinetic(s)
POC 
point of care
QD 
once daily
QTc
QT interval corrected for heart rate 
RBC
red blood cell  
RdRp 
RNA-dependent RNA polymerase
RIDT
rapid influenza diagnostic test
RNA
ribonucleic acid
RT-PCR
reverse transcription-polymerase chain reaction
SAD 
single ascending dose
SAE 
serious adverse event
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SD 
standard deviation(s)
SOE 
schedule of events 
SRC 
Study Review Committee 
t1/2, z 
apparent terminal elimination half-life 
TEAE 
treatment-emergent adverse event
TID 
3 times a day
Tmax
time to maximum observed plasma concentration
TP 
triphosphate 
ULN
upper limit of normal
Vz/F 
apparent volume of distribution 
WBC
white blood cell 

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10.2
APPENDIX 2: STUDY GOVERNANCE
10.2.1
Data Quality Assurance
This study will be conducted using the quality processes described in applicable procedural 
documents. The quality management approach to be implemented will be documented and 
will comply with current ICH guidance on quality and risk management. All aspects of the 
study will be monitored for compliance with applicable government regulatory requirements, 
current Good Clinical Practice, the protocol, and standard operating procedures.
Important protocol deviations (Section 9.2.3.2), should they occur during the study, will be 
presented in Section 10.2 of the clinical study report.
10.2.2
Investigator Obligations
The following administrative items are meant to guide the investigator in the conduct of the 
study and may be subject to change based on industry and government standard operating 
procedures, working practice documents, or guidelines. Changes will be reported to the 
IRB/EC but will not result in protocol amendments.
Confidentiality
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain subject confidentiality. All records will be kept in a secure 
storage area with limited access. Clinical information will not be released without the written 
permission of the subject (or the subject’s legal guardian), except as necessary for monitoring 
and auditing by the sponsor, its designee, or the IRB/EC.
The investigator and all employees and coworkers involved with this study may not disclose 
or use for any purpose other than performance of the study, any data, record, or other 
unpublished, confidential information disclosed to those individuals for the purpose of the 
study. Prior written agreement from the sponsor or its designee must be obtained for the 
disclosure of any said confidential information to other parties.
Institutional Review
ICH guidelines require that approval be obtained from an IRB/EC before participation of 
human subjects in research studies. Before study onset, the protocol, ICF, advertisements to 
be used for the recruitment of study subjects, and any other written information regarding 
 
 

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this study that is to be provided to the subject or the subject’s legal guardian must be 
approved by the IRB/EC. Documentation of all IRB/EC approvals and of the IRB/EC
compliance with the ICH harmonised tripartite guideline E6(R2): Good Clinical Practice will 
be maintained by the site and will be available for review by the sponsor or its designee.
All IRB/EC approvals should be signed by the IRB/EC chairperson or designee and must 
identify the IRB/EC name and address, the clinical protocol by title or protocol number or 
both, and the date approval or a favorable opinion was granted.
Ethical Conduct of the Study
The Study will be performed in accordance with ethical principles that have their origin in 
the Declaration of Helsinki and are consistent with ICH/GCP and applicable regulatory
requirements.
Subject Consent
Written informed consent in compliance with IRB/EC requirements shall be obtained from 
each subject before he or she enters the study or before performing any nonroutine procedure 
that involves risk to the subject. Prior to a subject’s participation in the trial, the written ICF 
should be signed and personally dated by the subject/legal acceptable representative and by 
the person conducting the informed consent discussions. If any institution-specific 
modifications to study-related procedures are proposed or made by the site, the consent 
should be reviewed by the sponsor or its designee or both before IRB/EC submission. Once 
reviewed, the investigator will submit the ICF to the IRB/EC for review and approval before 
the start of the study. If the ICF is revised during the course of the study, all active 
participating subjects must sign the revised form.
Before recruitment and enrollment, each prospective subject or his/her legal guardian will be 
given a full explanation of the study and will be allowed to read the approved ICF, ask any 
questions they have, and have adequate time to consider the information provided. Once the 
investigator is assured that the subject/legal guardian understands the implications of 
participating in the study, the subject/legal guardian will be asked to give his or her consent 
to participate in the study by signing the ICF. The investigator must maintain the original and 
signed ICF. A copy of the ICF will be provided to the subject/legal guardian.
 

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Study Reporting Requirements
By participating in this study, the investigator agrees to submit reports of SAEs according to 
the time line and method outlined in this protocol. In addition, the investigator agrees to 
submit annual reports to his or her IRB/EC as appropriate.
Financial Disclosure and Obligations
The investigator is required to provide financial disclosure information to allow the sponsor 
to submit the complete and accurate certification or disclosure statements required as per
IRB/EC and prior to subject enrollment. In addition, the investigator must provide to the 
sponsor a commitment to promptly update this information if any relevant changes occur 
during the course of the investigation and for 1 year following the completion of the study.
Investigator Documentation
Prior to beginning the study, the investigator will be asked to comply with this Protocol, ICH 
E6(R2) Section 8.2 and all applicable regulatory requirements by providing essential 
documents. The investigator will also provide all required essential documents during trial 
conduct and at trial termination in accordance with ICH E6 Guidelines.
Study Conduct
The investigator agrees to perform all aspects of this study in accordance with the ICH 
E6(R2): Good Clinical Practice; the protocol; and all national, state, and local laws or 
regulations.
Case Report Forms and Source Documents
Site personnel will maintain source documentation, enter subject data into the electronic case 
report form (eCRF) as accurately as possible, and will rapidly respond to any reported 
discrepancies.
eCRFs and electronic data capture will be utilized. Each person involved with the study will 
have an individual identification code and password that allows for record traceability. The
system, and any investigative reviews, can identify coordinators, investigators, and 
individuals who have entered or modified records, as well as the time and date of any 
modifications.
 
 
 
 
 

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Each eCRF is presented as an electronic copy, allowing data entry by site personnel, who can 
add and edit data, add new subjects, identify and resolve discrepancies, and view records. 
This system provides immediate direct data transfer to the database, as well as immediate 
detection of discrepancies, enabling site coordinators to resolve and manage discrepancies in 
a timely manner.
Paper copies of the eCRFs and other database reports may be printed and signed by the 
investigator. This system provides site personnel, monitors, and reviewers with access to 
hardcopy audits, discrepancy reviews, and investigator comment information.
Adherence to Protocol
The investigator agrees to conduct the study as outlined in this protocol, in accordance with 
ICH E6(R2) and all applicable guidelines and regulations.
Reporting Adverse Events
By participating in this study, the investigator agrees to submit reports of SAEs according to 
the timeline and method outlined in this protocol. In addition, the investigator agrees to 
submit annual reports to the IRB/EC as appropriate. The investigator also agrees to provide 
the sponsor with an adequate report, if applicable, shortly after completion of the 
investigator’s participation in the study.
Investigator’s Final Report
Upon completion of the study, the investigator, where applicable, should inform the 
institution; the investigator/institution should provide the IRB/EC with a summary of the 
study’s outcome and the sponsor and regulatory authorities with any reports required.
Records Retention
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or until at least 2 years have elapsed since the 
formal discontinuation of clinical development of the study drug. These documents should be 
retained for a longer period; however, if required by applicable regulatory requirements or by 
an agreement with the sponsor. The sponsor is responsible for informing the 
investigator/institution when these documents no longer need to be retained.
 
 
 
 

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Publications
After completion of the study, the data may be considered for reporting at a scientific 
meeting or for publication in a scientific journal. In these cases, the sponsor will be 
responsible for these activities and will work with the investigators to determine how the 
manuscript is written and edited, the number and order of authors, the publication to which it 
will be submitted, and any other related issues. The sponsor has final approval authority over 
all such issues.
Data are the property of the sponsor and cannot be published without their prior 
authorization, but data and any publication thereof will not be unduly withheld.
10.2.3
Study Management
Monitoring of the Study
The clinical monitor, as a representative of the sponsor, is obligated to follow the study 
closely. In doing so, the monitor will visit the investigator and study site at periodic intervals 
in addition to maintaining necessary telephone and email contact. The monitor will maintain 
current personal knowledge of the study through observation, review of study records and 
source documentation, and discussion of the conduct of the study with the investigator and 
staff.
All aspects of the study will be carefully monitored by the sponsor or its designee for 
compliance with applicable government regulation with respect to current ICH E6(R2) 
guidelines and standard operating procedures.
Study Digital Options
eConsent (electronic consent): It is the responsibility of the Investigator or designee 
to obtain signed (written or electronic signature) informed consent
HHC (home health care): Home visits are allowed at certain visits as well as under 
reasonable occasional circumstances where the participant is unable to attend a clinic 
visit during the treatment period (see SOE; Section 3.1). Home visits will be 
conducted by qualified medical professionals with the permission of the Investigator 
and in accordance with all national, state, and local laws or regulations of the 
pertinent regulatory authorities.
 
 
 
 
 

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Televisits can replace study phone calls with participants
DtP (direct to patient): If allowed by country regulation/IRBs/ECs, study drug can be 
shipped DtP from the investigation site to the patient’s home address via courier if 
needed.
Inspection of Records
The investigator and sites involved in the study will permit study-related monitoring, audits, 
IRB and EC review, and regulatory inspections by providing direct access to investigation 
facilities including drug storage and direct access to all original and/or certified copies of 
medical records and all study records. In the event of a sponsor audit, or a regulatory 
inspection, the investigator agrees to allow the sponsor, their representatives, the FDA, or 
other regulatory agencies access to all study records.
The investigator should promptly notify the sponsor and study site(s) of any audits scheduled 
by any regulatory authorities and promptly forward copies of any audit reports related to this 
study received to the sponsor.
10.2.4
Management of Protocol Amendments and Deviations
Protocol Amendments
Any protocol amendments will be prepared by the Sponsor. Protocol amendments will be 
submitted to the IRB/EC and to regulatory authorities in accordance with local regulatory 
requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally required) 
before implementation of any changes, except for changes necessary to eliminate an 
immediate hazard to subjects or changes that involve logistical or administrative aspects only 
(eg, change in Medical Monitor or contact information).
Protocol Deviations
The investigator should document and explain any protocol deviations. The investigator
should promptly report any deviations that might have an impact on patient safety and data 
integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC policies 
and procedures. The Sponsor will review all protocol deviations and assess whether any 
represent a serious breach of Good Clinical Practice guidelines and require reporting to 
 
 
 
 
 

Atea Pharmaceuticals, Inc.
AT-752
Protocol No. AT-02A-002
Clinical Study Protocol Version 1.0
20 SEP 2021
CONFIDENTIAL
Page 76
health authorities. As per the Sponsor's standard operating procedures, prospective requests 
to deviate from the protocol, including requests to waive protocol eligibility criteria, are not 
allowed.
Study Termination
Although the sponsor has every intention of completing the study, they reserve the right to 
discontinue it at any time for clinical or administrative reasons.
The end of the study is defined as the date on which the last subject completes the last visit 
(including the EOS visit and any additional long-term follow-up). Any additional long-term 
follow-up that is required for monitoring of the resolution of an AE or finding may be 
appended to the clinical study report.
Final Report
Regardless of whether the study is completed or prematurely terminated, the sponsor will 
ensure that clinical study reports are prepared and provided to regulatory agency(ies) as 
required by the applicable regulatory requirement(s). The sponsor will also ensure that 
clinical study reports in marketing applications meet the standards of the ICH harmonised 
tripartite guideline E3: Structure and content of clinical study reports.