Clinical trial NCT05466240
Conditions: Dengue Fever
Keywords: Dengue Vector borne disease Infections Virus disease Viral RNA virus Hemorrhagic fevers
Sponsor: Atea Pharmaceuticals, Inc.
Start date: 2022-04-29; Completion date: 2023-01-19
Enrollment: 21 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The Phase 2 study will be conducted in adult patients with confirmed Dengue 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

Detailed description:

Arms: arm 1: Tablet; 750-mg, Three (3) times a day for 5-days arm 2: Tablet; Dose A, for 5-days arm 3: Tablet; Dose B, for 5-days
Interventions: intervention 1: AT-752 intervention 2: Placebo
Intervention descriptions: intervention 1: AT-752 for 5 days intervention 2: Placebo for 5 days

Protocol documents:
SAP_002.pdf: 
Confidential 
 
 
STATISTICAL ANALYSIS PLAN 
 
VERSION: 1.0 
DATE OF PLAN: 
15-NOV-2022 
 
BASED ON: 
Protocol Amendment 1, 29JUL2022 
 
STUDY DRUG: 
AT-752  
PROTOCOL NUMBER: 
AT-02A-002 
 
STUDY 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 
 
SPONSOR: 
Atea Pharmaceuticals, Inc. 
225 Franklin Street 
Suite 2100 
Boston, MA 02110 USA 
 
 
This study is being conducted in compliance with good clinical practice, including the archiving 
of essential documents. 
 
 
 
 
 
 
PPD




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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ...................................................................................................... 5 
1. 
INTRODUCTION ............................................................................................................ 6 
2. 
OBJECTIVES ................................................................................................................... 6 
2.1 ............................................................................................................................................... PRIMARY 
OBJECTIVE .....................................................................................................................................6 
2.2 .......................................................................................................................................... SECONDARY 
OBJECTIVES ...................................................................................................................................6 
2.3 ..................................................................................................................................... EXPLORATORY 
OBJECTIVES ...................................................................................................................................7 
3. 
STUDY DESIGN ............................................................................................................... 7 
3.1 .................................................................................................................................. OVERALL STUDY 
DESIGN ..........................................................................................................................................7 
3.2 ................................................................................................................................................... STUDY 
ENDPOINTS ....................................................................................................................................7 
3.2.1 ............................................................................................................................................ PRIMARY 
ENDPOINT ......................................................................................................................................7 
3.2.2 ....................................................................................................................................... SECONDARY 
ENDPOINTS ....................................................................................................................................7 
3.2.3 .................................................................................................................................. EXPLORATORY 
ENDPOINTS ....................................................................................................................................8 
4. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................... 9 
4.1. ................................................................................................................................................ SAMPLE 
SIZE .............................................................................................................................................10 
4.2. ........................................................................................ RANDOMIZATION, STRATIFICATION, AND 
BLINDING ....................................................................................................................................11 
4.3. .............................................................................................................................................ANALYSIS 
POPULATION ................................................................................................................................11 
5. 
SUBJECT DISPOSITION ............................................................................................. 12 
5.1 ......................................................................................................................................... DISPOSITION
 ....................................................................................................................................................12 
5.2 ............................................................................................................................................. PROTOCOL 
DEVIATIONS ................................................................................................................................12 
5.3 ............................................................................................................... INCLUSION AND EXCLUSION 
CRITERIA .....................................................................................................................................12 
6. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS .................................. 13 
6.1 ................................................................................................................................... DEMOGRAPHICS
 ....................................................................................................................................................13 
6.2 ............................................................................................................................................... MEDICAL 
HISTORY ......................................................................................................................................13 
7. 
TREATMENTS AND MEDICATIONS ....................................................................... 13 
 
 
 
 


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7.1 ................................................................................................................. PRIOR AND CONCOMITANT 
MEDICATIONS ..............................................................................................................................13 
7.2 ................................................................................................ MEDICAL OR SURGICAL TREATMENT 
PROCEDURES ...............................................................................................................................13 
7.3 ................................................................................................................................................... STUDY 
TREATMENT.................................................................................................................................13 
8. 
EFFICACY ...................................................................................................................... 14 
8.1 ............................................................................................................................................... PRIMARY 
EFFICACY ....................................................................................................................................14 
8.1.1 ............................................................................................................................................ PRIMARY 
ENDPOINT ....................................................................................................................................14 
8.1.2 ................................................................................................... PRIMARY ENDPOINT SUPPORTIVE 
ANALYSES ...................................................................................................................................14 
9. 
SAFETY ANALYSIS ..................................................................................................... 14 
9.1 ............................................................................................................................................... ADVERSE 
EVENTS ........................................................................................................................................15 
9.2 ...................................................................................................................... CLINICAL LABORATORY 
EVALUATIONS .............................................................................................................................16 
9.3 ........................................................................................................................................... VITAL SIGN 
MEASUREMENTS ..........................................................................................................................22 
9.4 .............................................................................................................................................. PHYSICAL 
EXAMINATION .............................................................................................................................23 
9.5 ...................................................................................................................... ELECTROCARDIOGRAMS
 ....................................................................................................................................................23 
10. 
MISSING DATA HANDLING ...................................................................................... 23 
11. 
PHARMACOKINETICS ............................................................................................... 24 
11.1 ................................................................................................................................................... DATA 
HANDLING ...................................................................................................................................24 
11.2 ............................................................................................................ PLASMA PHARMACOKINETIC 
PARAMETERS ...............................................................................................................................24 
12. 
PHARMACODYNAMICS ............................................................................................ 25 
13. 
INTERIM ANALYSIS ................................................................................................... 26 
14. 
CHANGES IN THE PLANNED ANALYSIS .............................................................. 26 
15. 
REFERENCES ................................................................................................................ 26 
 
 
 
 
 
 
 


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List of Abbreviations 
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 
BLQ 
Below the limit of quantification 
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 
Ctrough 
trough concentration  
CSR 
clinical study report 
CV 
coefficient of variation 
DAA 
direct-acting antiviral 
DENV 
dengue virus 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
FDA 
Food and Drug Administration 
GMR 
geometric mean ratio 
ICH 
International Council for Harmonization 
LLOQ 
Lower limit of quantification 
LSM 
Least Squares Mean 
MAD 
multiple ascending dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCA 
noncompartmental analysis 
NS1 
nonstructural protein 1 
PBMC 
peripheral blood mononuclear cell 
PD 
pharmacodynamics 
 
 
 
 


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PK 
pharmacokinetics 
PT 
preferred term 
QTcF 
QT interval 
 
RBC 
red blood cell 
RNA 
ribonucleic acid 
RT-PCR 
reverse transcription-polymerase chain reaction 
SAD 
single ascending dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SOC 
system organ class 
SRC 
Study Review Committee 
t1/2z 
apparent terminal elimination half-life 
TEAE 
treatment-emergent adverse event 
Tlast  
time of last measurable observed concentration  
TLF 
table listing figure 
Tmax 
time to maximum observed plasma concentration 
ULN 
upper limit of normal 
Vz/F 
apparent volume of distribution during the terminal phase 
WBC 
white blood cell 
 
 
 
 
 
 
 
 
 
  
 


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1. Introduction 
This Statistical Analysis Plan (SAP) provides details of the planned analyses and statistical methods 
used to evaluate antiviral activity, safety, pharmacokinetics (PK), and pharmacodynamics (PD) data 
for Study AT-02A-002. This SAP is written based on AT-02A-002 protocol Amendment 1, dated on 
29 July 2022. 
Dengue fever is a mosquito-borne illness that is caused by 4 distinct serotypes of ribonucleic acid 
(RNA) viruses (DENV-1, DENV-2, DENV-3, and DENV-4) belonging to the flavivirus genus.  
Atea Pharmaceuticals is developing a novel purine nucleotide prodrug, AT-752, which is designed to 
treat patients that have been infected with the dengue virus (DENV). When dissolved, AT-752 
releases the freebase 
, which in a series of steps is converted to the intracellular active 
triphosphate metabolite, AT-9010 (triphosphate of AT-273, and therefore plasma AT-273 is 
considered a surrogate of intracellular AT-9010). A first-in-human study (Protocol AT-02A-001) 
was completed in 65 healthy adults in Australia to investigate the safety and pharmacokinetics (PK) 
(with embedded food effect and PK ethnic sensitivity evaluation) of AT-752. 41 subjects received 
single ascending doses (SAD), and 24 subjects participated in the multiple ascending dose (MAD) 
portion of the study.  The first-in-human study supported dose selection for the current study. 
The Phase 2 study AT-02A-002 will be conducted in adult patients with confirmed DENV infection 
and will investigate antiviral activity, safety, PK, and PD in this population. This study will be 
conducted in several dosing cohorts to enable dose selection for subsequent trials. 
 
2. Objectives 
 
2.1 
Primary Objective 
 
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 
 
2.2 
Secondary Objectives 
 
To evaluate the safety of AT-752 versus placebo in adult subjects with confirmed DENV 
infection 
 
To evaluate the PK of AT-752 (
) and metabolites in adult subjects with confirmed 
DENV infection 
 
 
 
 
 
 
 
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2.3 
Exploratory Objectives 
 
To describe the effect of AT-752 on viremia (viral titre), DENV nonstructural protein 1 (NS1) 
levels, fever, and biomarkers (see list in section 12) compared to placebo in adult subjects with 
confirmed DENV infection 
3. Study Design 
3.1 
Overall Study Design 
who 
n un
 
 
 
 
 
 
 
Subjects will be discharged on Day 6 (after end of treatment) 
 
nursing. The Day 1, Day 6, and Day 28 visits must be conducted at the clinical site. 
 
3.2 
Study Endpoints 
3.2.1 Primary Endpoint 
The primary objective will be assessed by change in DENV viral load (DENV RNA as measured by 
RT-qPCR) from baseline. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
  
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
  
 
 
 
  
 
 
 
 
  
 
 
  
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
  
 
 
 
  
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 




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PD  
Change in DENV viral load (as measured by 
infectious viral titre) from baseline 
Area under the log 10-transformed viral load 
curve (AUC) from first dose to the end of 
treatment or study [as measured by DENV RNA 
and viral titre] 
load clearance, which is defined as 
the first of 2 consecutive undetectable viral load 
measurements [as measured by DENV RNA and 
viral titre] 
 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. 
Subgroup analysis by DENV serotype: Change 
of DENV viral load [as measured by DENV RNA 
and viral titre] from baseline, viral load AUC, 
time to viral load, or NS1 clearance by DENV 
serotype 
-emergent amino acid substitutions in 
DENV NS5 polymerase 
resolution or duration of fever 
 Exploratory biomarkers on immunological 
response to dengue (See list in Section 12) 
Exploratory analysis to evaluate exposure-
response relationship. The relationship between 
the exposure of AT-752 (and its metabolites) and 
DENV viral load measurement may be explored 
using graphic displays. 
 
4. General Statistical Considerations 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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4.1. 
Sample Size 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
   
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
  
 




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4.3. 
Analysis Population 
 
 
 
 
 
 
5. Subject Disposition 
5.1 
Disposition 
 
 The number of subjects who completed the study drug per protocol 
 The number of subjects who completed the study 
 The number of subjects who did not complete the study and study drug treatment (both 
overall and according to reasons for discontinuation from the study and study drug treatment) 
 The number of subjects in each analysis population. 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 


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5.2 
Protocol Deviations 
 
5.3 
Inclusion and Exclusion Criteria 
 
6. Demographics and Baseline Characteristics 
6.1 
Demographics 
 
Descriptive statistics will be calculated for the following continuous demographic characteristics:  
 Age (years) 
 Weight (kg) 
 Height (cm) 
 Body mass index (BMI) (kg/m2) 
 
 Sex 
 Race 
 Ethnicity 
 
6.2 
Medical History 
 
7. Treatments and Medications 
7.1 
Prior and Concomitant Medications 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
   
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


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7.2 
Medical or Surgical Treatment Procedures 
 
7.3 
Study Treatment 
 
 
8. Efficacy 
 
8.1 
Primary Efficacy  
8.1.1 Primary Endpoint  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 


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8.1.2 Primary Endpoint Supportive Analyses 
 
 
 Change from baseline in log10 viral load by scheduled time point (Kruskal-Wallis). Along 
with the Kruskal-Wallis test, a one-way ANOVA will be used to compare treatment effect 
separately at each time point. 
 Proportion of measurements above the lower limit of quantification (Fisher exact) 
All viremia data will be listed and individual profiles of viremia over time will be presented for each 
subject. Viremia levels below the lower limit of quantification will be considered as 0 in the log10 
viral load summaries and indicated as BLQ in the listings. 
 
9. Safety Analysis 
All safety summaries and analyses will be based upon the safety population. 
 
9.1 
Adverse Events 
 
 
 
 
 
   
 
  
 
 
 
  
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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 Any TEAE 
 Any treatment related TEAE 
 Any TEAE of grade 2 or higher 
 Any treatment related TEAE of grade 2 or higher 
 Any TEAE of grade 3 or higher 
 Any treatment related TEAE of grade 3 or higher 
 Any SAE 
 Any treatment related SAE 
 Any treatment related AE leading to early study drug discontinuation 
 Any treatment related AE leading to early study discontinuation 
 Any death 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 




















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11. Pharmacokinetics 
 
 
 
11.1 
Data handling 
 
Plasma concentrations that are BLQ will be treated as zero for calculation of concentration 
descriptive statistics; if <3 values are above the lower limit of quantification (LLOQ) at one time 
point, the arithmetic mean, SD, and CV will not be reported at that time point. For PK parameter 
analysis, all BLQ values will be treated as zero, with the exception of BLQ values observed between 
2 quantifiable concentrations which will be set to missing. For the estimation of geometric mean and 
geometric CVs, all BLQ values will be set to missing. 
 
11.2 
Plasma Pharmacokinetic Parameters 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
    
  
 
 
  
 
 
 
 
 
 
 
 
   
  
 
 
 
 
 
 
 
 
 
 
 
 
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Noncompartmental analysis will be used to estimate the following PK parameters, when applicable 
and if data permit:  
, AT-551, AT-229, AT-219 and AT273:  
Ctrough 
Observed trough (predose) concentration (TID on Dose 7, BID on Dose 
5). AT-273  
Cmax 
Maximum observed concentration. 
Tmax 
Time of maximum observed concentration. 
AUClast 
AUC from time 0 to the last measurable observed concentration (Ct), 
calculated using the linear trapezoidal rule. 
AUCtau 
AUC within a dosing interval, calculated using the linear trapezoidal 
rule. 
 
 
 
 
12. 
Pharmacodynamics 
 
 
 
 
 
 
  
 
  
   
  
 
 
  
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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AUCD5 and AUCD28 refer to area under the log 10-tranformed viral load curve (AUC) from first dose 
to the end of treatment (Day 5) and to study end (Day 28) respectively. The following rules will be 
followed for the area under the curve derivation. 
 A time-scaled trapezoidal rule will be used for AUC calculation. 
 AUC will be calculated from the log 10-tranformed viral load curve connecting baseline or 
the first available viral load measurement time point before Day 5 till Day 5 for 
AUCD5   Similarly, connecting the baseline or the first available viral load measurement time 
point before Day 28 till Day 28 for AUCD28   
 Subjects with missing Day 5 measurements will have Day 5 viral load imputed from last and 
next available viral loads by linear interpolation for AUCD5 calculation. If viral load 
measurement is missing for Day 5 and all subsequent measurement days beyond Day 5,  the 
subject will not have AUCD5 calculated and will be excluded from AUC analyses.   
 Subjects with missing Day 28 measurements will not have AUCD28 calculated and will be 
excluded from AUC analyses. 
Intermediate missing log 10-tranformed viral loads (between baseline and the last day) will be 
linearly interpolated using the last and next available viral loads for AUC calculation for both 
AUCD5 and  AUCD28. Subjects with intermediate missing values will be included in AUC analysis. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Exploratory biomarkers may include plasma concentrations of cytokines (for example, TNF-
-
IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-
-10 and MCP-1). Data will be presented in 
descriptive statistics by treatment. 
 
Exploratory analyses may be performed to evaluate exposure-response relationship. The relationship 
between the exposure of AT-752 (AT-281 and its metabolites AT-551, AT-229, and AT-273) and DENV 
viral load may be explored using graphical displays. Scatter plots of drug exposure versus change in 
DENC viral load will be provided.   
13. 
Interim Analysis 
 
14. 
Changes in the Planned Analysis 
 
15. 
References 
 Schedule of Events  
Assessment 
Screeni
ng 
Treatment Period 
Follow-up 
 
 
Day 
1 
Days 
2-4 
Day 
5 
Day 
6 
Day 
7 
Day 
8 
Day 
14±1 
Day 
28 ±3/ EOS 
(Early 
Terminatio
n) 
Visit Type 
Site 
Site 
Site 
or 
Mobile 
Site 
or 
Mobi
le 
Site 
Site 
or 
Mobil
e 
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 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 


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12-lead ECG 
(triplicate-
consecutive) 
X 
 
 
 
X 
 
 
 
X 
Chemistry/ 
hematology/coa
gulationd 
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 
 
 
 
 
 
 
 
 
Pharmacokineti
c assessmentsh 
 
X 
Day 2 
and 
Day 3 
or 4 
 
 
 
 
 
 
DENV serotype 
testingi 
X 
 
 
 
 
 
 
 
 
Viral loadj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(Day 28 
only) 
NS1 antigen 
test 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(Day 28 
only) 
Plasma 
Biomarker 
X 
X 
Day 2, 
4 
 
X 
 
X 
X 
X 
(Day 28 
only) 
Adverse eventsk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
Prior to dosing 
 
 
 
 
 
 
 
Study drug 
administration 
 
X 
X 
X 
 
 
 
 
 
Accountability 
of 
returned drug, 
and 
review of 
patient diary 
 
 
 
 
X 
 
 
 
X 
(Early 
Termination 
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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. 
 
 
 
 
 
 
 
 
 

Prot_001.pdf: 




Atea Pharmaceuticals, Inc. 
AT-752 
Protocol No. AT-02A-002 
Clinical Study Protocol Amendment 1 
29 JUL 2022 
CONFIDENTIAL 
Page 3 
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 


Atea Pharmaceuticals, Inc. 
AT-752 
Protocol No. AT-02A-002 
Clinical Study Protocol Amendment 1 
 
29 JUL 2022 
CONFIDENTIAL 
Page 4 
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: Approximately 40 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 serotypes 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 is developing 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 intracellular active 
triphosphate metabolite, AT-9010 (triphosphate of AT-273, and therefore plasma AT-273 is 
considered a surrogate of intracellular AT-9010).  
In preclinical studies, AT-752 showed potent in vitro antiviral activity against dengue 
serotypes 1-4, as well as potent in vivo antiviral activity in small animal models. A first-in-
human study (Protocol AT-02A-001) was completed in 65 healthy adults to investigate the 
safety and pharmacokinetics (PK) (with embedded food effect and PK ethnic sensitivity 
evaluation) of AT-752. 41 subjects received single ascending doses (SAD) and 24 subjects 
participated in the multiple ascending dose (MAD) portion of the study.  The first-in-human 
study supported dose selection for the current study. 
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. 


Atea Pharmaceuticals, Inc. 
AT-752 
Protocol No. AT-02A-002 
Clinical Study Protocol Amendment 1 
 
29 JUL 2022 
CONFIDENTIAL 
Page 5 
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.  
The safety objective of this study is:  
• To evaluate safety of AT-752 versus placebo 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 (viral titre), 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. 
For TID dosing, subjects will receive doses in the morning, at mid-day, and in the evening. 
TID doses will be separated by approximately 8 hours. [For BID dosing, subjects will receive 
doses in the morning and in the evening. BID doses will be separated by approximately 12 
hours.] Subjects can continue participation even if hospitalized or using mobile nursing 
during the study, depending on site availability and subject decision. Subjects will be 
discharged on Day 6 (after end of treatment) if hospitalized, 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, some of the subsequent visits (Days 2-5, 


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Days 7-8, and Day 14) may be performed at investigator discretion through mobile nursing. 
The Day 1, Day 6, and Day 28 visits must be conducted at the clinical site. 
The dose level for Cohort 1 (750 mg TID) was determined based on review of PK and safety 
data from the Phase 1 healthy volunteer study (Protocol AT-02A-001). In healthy subjects, 
this dose was able to rapidly achieve and maintain AT-273 troughs plasma concentrations 
above 200 ng/mL (in vitro EC90 of AT-281 against DENV-2 is 0.64 µM or approximately 
200 ng/mL equivalent of AT-273) and was well-tolerated. Specific doses for Cohort 2 and 
Cohort 3 will be endorsed by the Safety Review Committee (SRC) after an unblinded review 
of the previous cohort by the SRC.     
• 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 cohort, subjects will be randomized to receive AT-752 or placebo in 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 available PK data through 
at least 5 days in the current dose cohort will undergo an unblinded review by the SRC. 
Following each SRC review, the dose for the next cohort will be endorsed by the SRC and 
the cohort enrolled. 
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. Fever ≥38°C (or feeling feverish) with onset during the previous 60 hours 
3. Positive test confirming DENV on a NS1 antigen test or reverse transcription-
polymerase chain reaction (RT-PCR) assay 
4. Negative rapid diagnostic test results for SARS-CoV-2 and Influenza A and B 
5. Body mass index (BMI) of 18 to 30 kg/m2 
6. Provides written informed consent prior to initiation of any study procedures 
7. Able to understand and agrees to comply with planned study procedures and be 
available for all study visits 
8. Males and females of childbearing potential must agree to use protocol-specified 
methods of contraception as described in Section 4.1.1 
9. Male subjects must agree to not donate sperm from the first dose through 90 days after 
the last dose of study drug 


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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 
3. Has previously received any investigational or approved vaccine for dengue 
4. Previous history of HIV, active 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 (whichever is longer) of 
the active drug or metabolite (for long-acting antivirals) of screening 
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. Concomitant use of herbal or natural supplements (e.g. St. John’s Wort, echinacea, milk 
thistle) or grapefruit juice. These should be discontinued at screening if the investigator 
feels that they can be safely discontinued or substituted for the duration of the study.  
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. Malabsorption syndrome or other conditions that would interfere with enteral absorption  
12. Immunocompromised due to use of immunosuppressive drugs including systemic 
corticosteroids (inhaled or topical corticosteroids are allowed) or immunocompromised 
due to any current disease or condition 
13. Use of P-glycoprotein (P-gp) inducers and inhibitors as described in Section 5.6.1.  Note:  
hydroxychloroquine and amiodarone are prohibited within 3 months prior to screening 
and during the study. 
14. Evidence of severe dengue disease including: 
• Severe plasma leakage leading to shock or fluid accumulation with respiratory distress 
• Severe bleeding (including any subjects with hemoglobin levels <13.0g/dL in males and 
<11.0g/dL in females). 
• Severe organ impairment (e.g., elevated transaminases ≥1,000 IU/L, impaired 
consciousness, renal failure [including any subjects with creatinine clearance < 60 
mL/min {Cockcroft Gault formula}], or heart impairment [including any subjects with 
clinically significant abnormal ECG at Screening]) 
15. Suspected or confirmed acute illness thought to be caused by a pathogen other than 
DENV 


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16. Confirmed or suspected SARS-CoV-2 infection or contact with patients with confirmed 
SARS-CoV2 infection within 7 days prior to screening 
17. 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 
18. 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 
ESTIMATED STUDY DURATION: 
Subject participation in this study will be up to 32 days. After screening (within 60 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 for BID dosing and 15 doses for 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 (DENV RNA as measured by RT-qPCR) 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, AT-219 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 


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For blood samples (both TID and BID dosing), a ±10 minutes window 
for time points ≤4 hours; ±15 minute for time points between 4 and 
24 hours  
o At any early study discontinuation visit: 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, where applicable, 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 (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 treatment-emergent adverse events (TEAEs) from first 
dose through Day 28 or withdrawal from the study 
• Incidence and grade of any serious adverse events (SAEs) through Day 28 or 
withdrawal from the study 
• Vital sign measurements 
• Physical examination findings 
• Clinical laboratory (serum chemistry, hematology, coagulation, and urinalysis) 
findings 
• Electrocardiogram (ECG) findings 
Exploratory Endpoints: PD Endpoints 
• Change in DENV viral load (as measured by infectious viral titre) from baseline  
• Area under the log10-transformed viral load curve (AUC) from first dose to the end 
of treatment or study (as measured by DENV RNA and viral titre) 


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• Time to viral load clearance, which is defined as the first of 2 consecutive 
undetectable viral load measurements [as measured by DENV RNA and viral titre] 
• 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 (as measured by DENV RNA and viral titre) from 
baseline, viral load AUC, time to viral load or NS1 clearance by DENV serotype 
• Treatment-emergent amino acid substitutions in DENV NS5 polymerase 
• 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 load may be explored using graphical displays 
STUDY DRUG, DOSAGE, AND ROUTE OF ADMINISTRATION: 
Dose levels of AT-752 will be evaluated across 3 sequential cohorts dosed orally: 
• 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 (log 10 copies/ml) with 
80% power (N=15 vs. 15) 
Comparison versus placebo pooled 
across 3 planned cohorts 
Effect (log 10 copies/ml) with 
80% power (N=15 vs. 5) 
Comparison versus placebo within 
a cohort 
1 
0.8 
1.1 
1.25 
1 
1.4 
1.5 
1.2 
1.7 
1.75 
1.4 
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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 
for comparison of groups with N=15 each. The analogous power to detect a 1 log10 effect for 
a within cohort comparison is 59%. 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, i.e., 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 investigate the antiviral activity of AT-752 versus 
placebo in terms of reduction of DENV RNA from baseline.  
Change from baseline in viral load based on the log10 scale will be compared between each 
AT-752 arm and a combined placebo group at specific timepoints. 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. 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 (SAP). 
Safety, PK, and PD data will be summarized in tabular and/or graphical format by active 
dose treatment arms and a pooled placebo arm. Continuous data will be summarized using 
descriptive statistics (n, mean, SD, median, 95% CI) and categorical data will be summarized 
using counts and percentages. All subject-level data will be presented in listings.  
The primary analysis population is the modified intent-to-treat (mITT) population, which will 
include all randomized subjects who received at least 1 dose of study drug and have baseline 
and at least 1 post-baseline virology measurement. The primary analysis will also be 
performed on the per-protocol population of patients who completed treatment without a 
major protocol deviation. 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 be the mITT 
population. A per protocol population will include the subset of the modified intent-to-treat 
population who completed study drug treatment without a major protocol violation. 


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TABLE OF CONTENTS 
SIGNATURE PAGE ................................................................................................................2 
INVESTIGATOR PROTOCOL AGREEMENT PAGE ......................................................3 
PROTOCOL SYNOPSIS ........................................................................................................4 
TABLE OF CONTENTS .......................................................................................................12 
1.
BACKGROUND .................................................................................................15 
1.1 
DENGUE VIRUS .............................................................................................15 
1.2 
AT-752 ..............................................................................................................16 
1.2.1 
Clinical Studies .............................................................................................17 
1.3 
RATIONALE FOR STUDY ............................................................................19 
1.4 
RATIONALE FOR DOSE SELECTION.........................................................19 
2.
STUDY OBJECTIVES .......................................................................................21 
3.
STUDY DESIGN .................................................................................................22 
3.1 
SCHEDULE OF ASSESSMENTS ..................................................................24 
3.1.1 
Screening/Day 1 ...........................................................................................26 
3.1.2 
Timing of TID Dosing ..................................................................................27 
3.1.3 
Timing of BID Dosing ..................................................................................29 
3.1.4 
Timing of Samples for PK, Viral Load, and NS1 .........................................30 
4.
STUDY POPULATION......................................................................................35 
4.1 
INCLUSION CRITERIA .................................................................................35 
4.1.1 
Protocol Specified Methods of Contraception .............................................36 
4.2 
EXCLUSION CRITERIA ................................................................................36 
4.3 
WITHDRAWAL OF SUBJECTS FROM THE STUDY .................................39 
4.3.1 
Reasons for Withdrawal................................................................................39 
4.3.2 
Handling of Withdrawals ..............................................................................39 
4.3.3 
Replacements ................................................................................................40 
5.
STUDY TREATMENTS ....................................................................................40 
5.1 
TREATMENTS ADMINISTERED .................................................................40 
5.1.1 
Safety Review Committee ............................................................................41 
5.2 
INVESTIGATIONAL PRODUCTS ................................................................41 
5.2.1 
Study Drug Packaging and Storage ..............................................................42 
5.2.2 
Study Drug Accountability ...........................................................................42 
5.3 
METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS .........42 
5.4 
BLINDING .......................................................................................................43 
5.4.1 
Blinding Procedures .....................................................................................43 
5.4.2 
Breaking the Blind ........................................................................................43 
5.5 
TREATMENT COMPLIANCE .......................................................................44 


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5.6 
PRIOR AND CONCOMITANT MEDICATIONS ..........................................44 
5.6.1 
Prohibited Therapy .......................................................................................45 
5.6.2 
Cautionary Therapy ......................................................................................46 
6. 
STUDY ENDPOINTS .........................................................................................47 
6.1 
PRIMARY ENDPOINT ...................................................................................47 
6.2 
SECONDARY ENDPOINTS: PHARMACOKINETIC ENDPOINTS ...........47 
6.3 
SECONDARY ENDPOINTS: SAFETY ENDPOINTS ..................................48 
6.4 
EXPLORATORY ENDPOINTS: PHARMACODYNAMIC ENDPOINTS ...48 
7. 
STUDY ASSESSMENTS ...................................................................................49 
7.1 
PHARMACOKINETIC ASSESSMENTS .......................................................49 
7.1.1 
Pharmacokinetic Sample Collection .............................................................49 
7.1.2 
Pharmacokinetic Sample Analysis................................................................49 
7.2 
PHARMACODYNAMIC ASSESSMENTS ....................................................50 
7.3 
SAFETY ASSESSMENTS ..............................................................................50 
7.3.1 
Adverse Events .............................................................................................50 
 
Adverse Event Definitions ........................................................................51 
 
Eliciting and Documenting Adverse Events .............................................52 
 
Reporting Adverse Events ........................................................................53 
 
Assessment of Severity .............................................................................54 
 
Assessment of Causality ...........................................................................55 
 
Follow-up of Adverse Events ...................................................................56 
7.3.2 
Clinical Laboratory Testing ..........................................................................56 
7.3.3 
Vital Sign Measurements ..............................................................................57 
7.3.4 
12-Lead Safety Electrocardiogram ...............................................................58 
7.3.5 
Physical Examinations ..................................................................................58 
8. 
STATISTICAL ANALYSIS ................................................................................58 
8.1 
SAMPLE SIZE CALCULATIONS..................................................................58 
8.2 
ANALYSIS SETS ............................................................................................59 
8.3 
PLANNED STATISTICAL ANALYSIS ..........................................................60 
8.3.1 
Primary Endpoint Analyses ..........................................................................60 
8.3.2 
Pharmacokinetic Analyses ............................................................................61 
8.3.3 
Safety Analyses ............................................................................................61 
8.3.4 
Pharmacodynamic Exploratory Analyses .....................................................61 
8.4 
HANDLING OF MISSING DATA ..................................................................62 
9. 
REFERENCE LIST............................................................................................63 
10. 
APPENDICES .....................................................................................................65 
10.1 
APPENDIX 1: LIST OF ABBREVIATIONS ..................................................65 
 
 
 
 
 
 






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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 approved 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 
polymerase inhibitors have successfully been developed and become a cornerstone in treating 
major human viral diseases. 
The virus’ 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 


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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. 
AT-752 is the hemisulfate salt of AT-281, a phosphoramidate protide, which undergoes 
multistep activation to the intracellular active 5’-triphosphate metabolite (AT-9010) of the 
nucleoside 2’-fluoro-2’-C-methylguanosine (AT-273). 
 
 
 
 
 
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, randomized, double-blind, placebo-controlled study (Protocol AT-02A-001) 
was conducted in 65 healthy adults to investigate the safety, tolerability, and PK of AT-752. 
Single doses up to 1500 mg and multiple doses (1000 mg QD x 7 days; 750 mg BID x 4.5 
days; 750 mg BID x 4.3 days) were evaluated.  Based on the human PK results obtained from 
this study, an AT-752 dose of 750 mg TID (starting dose for the current study) is anticipated 
to demonstrate antiviral activity in dengue patients. In healthy subjects, this regimen rapidly 
achieved plasma concentrations of AT-273, considered plasma surrogate for the intracellular 
active triphosphate metabolite AT-9010, in excess of 200 ng/mL (in vitro EC90 of AT-281 
against DENV-2 is 0.64 µM or approximately 200 ng/mL equivalent of AT-273) and 
maintained through concentrations consistently above this threshold throughout the treatment 
duration (Figure 1-2). 
CCI


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Figure 1-1  
Mean (+SD) Plasma Concentration-Time Profile of AT-273, Surrogate of 
the Intracellular Active Triphosphate Metabolite AT-9010, Following Oral 
Administration of 750 Mg TID of AT-752 Under Fasted Conditions in 
Healthy Participants (AT-02A-001 Cohort 3b; N=6) 
 
Furthermore, a high-fat/high-calorie meal did not impact the total exposure of AT-281 while 
slightly increasing plasma exposure of AT-273. Therefore, AT-752 can be dosed without or 
with a meal.  Also, plasma exposure of AT-273 was similar between a separately enrolled 
ethnic cohort of healthy participants with southeast Asian origins and the general population 
(Cohort 3a), whereas plasma exposure of AT-281, AT-551, and AT-229 was numerically 
higher by 20-30%, which is within the expected variability for the drug. Dose adjustment is 
not expected for this ethnic group. 
AT-752 was well tolerated after either single or multiple doses in healthy subjects. Other 
than a single subject who withdrew consent, all other subjects completed the study. There 
were no SAEs reported. Most AEs were Grade 1 (mild) in intensity and no AEs of ≥ Grade 3 
severity were reported. The most common AEs across both parts of the study were headache, 
nausea, and vomiting. GI-related events (e.g., nausea, vomiting, abdominal pain, diarrhea, 
and constipation) were observed more commonly with AT-752 as compared to placebo. 
Vomiting appeared to increase with increasing AT-752 dose level (≥750 mg), although cases 
were mild/moderate in intensity and were self-limiting or managed with ondansetron. Most 
changes in laboratory parameters were mild (Grade 1) with no apparent relationship between 
 
 
 
  
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 


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the incidence of any laboratory toxicity and AT-752 dose level. Clinically significant 
changes were not reported for ECG parameters. 
Additional details on this study can be found in the investigator’s brochure v 2.0 (Atea 
Pharmaceuticals). 
1.3 
RATIONALE FOR STUDY 
Dengue is caused by 4 distinct types of 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 serotypes and it is only indicated for individuals with a history 
of previous 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 is developing a novel purine nucleotide prodrug, AT-752, which is 
designed to treat patients that have been infected with the DENV. Supported by 
tolerability/safety and PK in healthy subjects (see Section 1.2.1), the next logical 
development step for a dengue treatment is to evaluate safety, antiviral activity and PK/PD 
relationships of differing doses of AT-752 in DENV-infected patients.  This study will 
evaluate the safety, PK, and PD of AT-752 in adult patients with confirmed DENV infection 
and further support dose selection for subsequent, later phase trials. 
1.4 
RATIONALE FOR DOSE SELECTION 
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 
 
Based on the PK results of the AT-02A-001 study (see Section 1.2.1), the AT-752 starting 
dose of 750 mg TID (2250 mg total daily dose) is anticipated to demonstrate antiviral activity 
in dengue patients. This dose rapidly achieved and maintained plasma AT-273 troughs above 
the target 200 ng/mL (in vitro EC90 of AT-281 against DENV-2 is 0.64 μM or approximately 




Atea Pharmaceuticals, Inc. 
AT-752 
Protocol No. AT-02A-002 
Clinical Study Protocol Amendment 1 
29 JUL 2022 
CONFIDENTIAL 
Page 21 
 
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.  
The safety objective of this study is: 
CCI


Atea Pharmaceuticals, Inc. 
AT-752 
Protocol No. AT-02A-002 
Clinical Study Protocol Amendment 1 
 
29 JUL 2022 
CONFIDENTIAL 
Page 22 
• To evaluate safety of AT-752 versus placebo 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 (viral titre), 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 evaluates 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 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Atea Pharmaceuticals, Inc. 
AT-752 
Protocol No. AT-02A-002 
Clinical Study Protocol Amendment 1 
 
29 JUL 2022 
CONFIDENTIAL 
Page 23 
occur within 24 hours, and if possible, the initial dose should be given on the same day as 
screening. 
Upon randomization, subjects 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 receiving BID dosing will receive doses that are separated by 12 
hours (± 2 hours; morning and evening)]. Subjects can continue participation even if 
hospitalized or using mobile nursing during the study, depending on site availability and 
subject decision. Subjects will be discharged on Day 6 (after end of treatment) if 
hospitalized, 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, some of the subsequent visits (Days 2-5, Days 7-8, and Day 14) may be performed 
at investigator discretion through mobile nursing. The Day 1, 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. 
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 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 cohort, subjects will be randomized to receive active drug or placebo in a 3:1 
randomization. Each cohort will include 20 subjects (15 subjects receive AT-752 and 
5 subjects receive placebo).  
Specific doses for Cohort 2 and Cohort 3 will be endorsed by the SRC) after an unblinded 
review of the previous cohort by the SRC. Prior to the initiation of each cohort after Cohort 
1, all safety and available PK data through at least 5 days in the current dose cohort will 
undergo an unblinded review by the SRC. Following each SRC review, the dose for the next 
cohort will be endorsed by the SRC and the cohort enrolled according to schedule outlined in 
the SOE (Table 3-1).  


Atea Pharmaceuticals, Inc. 
AT-752 
Protocol No. AT-02A-002 
Clinical Study Protocol 
20 SEP 2021 
CONFIDENTIAL 
Page 24 
 
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/ EOS 
(Early 
Termination) 
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/coagu
lationd 
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 
(Day 28 only) 
NS1 antigen test 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(Day 28 only) 


Atea Pharmaceuticals, Inc. 
AT-752 
Protocol No. AT-02A-002 
Clinical Study Protocol Amendment 1 
 
29 JUL 2022 
CONFIDENTIAL 
Page 25 
Plasma Biomarker 
X 
X 
Day 2, 4 
 
X 
 
X 
X 
X 
(Day 28 only) 
Adverse eventsk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
Prior to dosing 
 
 
 
 
 
 
 
Study drug 
administration 
 
X 
X 
X 
 
 
 
 
 
Accountability of 
returned drug, and 
review of patient 
diary 
 
 
 
 
X 
 
 
 
X 
(Early 
Termination 
only) 
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 afternoon, 
and evening (approximately every 4 hours while the subject is awake) through the end of treatment. Temperature 
will be measured orally and will be recorded in a patient diary (and given to the site coordinator for entry in the 
eCRF). 
d. Hematology/ chemistry/ coagulation to include complete blood count (CBC) including white blood cell (WBC) 
count with differential count, red blood cell (RBC) count, platelet count, hemoglobin, hematocrit, and RBC 
indices; aspartate transaminase (AST), alanine aminotransferase (ALT), total and direct bilirubin, alkaline 
phosphatase, blood urea nitrogen (BUN), creatinine, serum creatine kinase, lipase, bicarbonate or total carbon 
dioxide, sodium, potassium, chloride, glucose,  total protein, albumin, phosphate, calcium, and amylase; 
international normalized ratio (INR), prothrombin time, and partial thromboplastin time. Urinalysis will be 
performed with microscopy at indicated visits but treatment with study drug may begin before the screening 
results have been obtained unless medically required to establish eligibility (at investigator’s discretion). 
Additional urinalysis may be performed as clinically indicated. 
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. Standard of care laboratory results prior to informed consent are accepted if 
performed within 24 hours of screening. 
e. 
SARS-CoV-2 rapid test performed at screening and Day 6. RIDT performed only at screening. 
f. 
A dipstick pregnancy test is required at screening. Additional pregnancy tests may be performed locally as 
clinically indicated. 
g. Rapid point of care (POC) test for DENV NS1 antigen. See Section 3.1.4 for details about assay timing. 
h. Pharmacokinetic (PK) plasma samples will be collected on Day 1 at time 0 (pre-dose; before the first dose on Day 
1) and 24 hours after Dose 1. 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 for TID dosing 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 for BID dosing may be done for Dose 5, 6, or 7, based on site/patient convenience. For 
blood samples, a ± 10-minute window for time points ≤4 hours; ± 15 minute for time points between 4 and 24 
hours. PK samples will also be obtained at any early study discontinuation visits. The timing of these PK samples 
relative to the last 2 (most recent) doses will be recorded. See Section 3.1.4. 
i. 
Subjects can begin treatment with study drug before the DENV-serotype results are obtained. 


Atea Pharmaceuticals, Inc. 
AT-752 
Protocol No. AT-02A-002 
Clinical Study Protocol Amendment 1 
 
29 JUL 2022 
CONFIDENTIAL 
Page 26 
j. 
Measurement of plasma viremia by viral titre and using a serotype-specific, real-time reverse transcription 
polymerase chain reaction (RT-PCR) assay. Subjects can begin treatment before the viral load results are obtained. 
See Section 3.1.4 for details about the timing of this assay. 
k. Adverse events are collected beginning at screening. Treatment-emergent adverse events and serious adverse 
events will be assessed from the time of study drug dosing until end of study and should be followed until they are 
resolved, stable, or judged by the investigator to be not clinically significant. 
l. 
After subjects are confirmed eligible at screening, randomization and the initial dosing should occur within 24 
hours, the initial dose should be given on the same day as screening, if possible. TID dosing at screening/Day 1 
can begin in the morning, at mid-day, or in the evening (see Section 3.1.2. BID dosing on Screening/Day 1 can 
begin in the morning or the evening (See Section 3.1.3). 
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(s) of study drug will be administered on Day 6.  
 
3.1.1 
Screening/Day 1 
After eligibility is determined at screening, the initial dose of study drug can be administered 
after randomization and within 24 hours of screening. This can occur before obtaining the 
results of the DENV serotype testing and viral load assessments. If possible, administer the 
initial dose of study drug on the same day as screening. 
Evaluations that must be completed before administering the initial dose include: 
• 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  the initial 
dose of study drug is administered on the same day as screening,  the results of the 
vital signs obtained at screening will be used for the Day 1 vital sign results. Note that 
oral 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.  


Atea Pharmaceuticals, Inc. 
AT-752 
Protocol No. AT-02A-002 
Clinical Study Protocol Amendment 1 
 
29 JUL 2022 
CONFIDENTIAL 
Page 27 
• 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 by viral titre and 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 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 NS1 antigen 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 (e.g., at home) for 
subjects at sites that choose to use  mobile nursing ( except  the doses administered prior to 
PK evaluation [Dose 7, 8, or 9; see Section 3.1.4], which must be taken under observation at 


Atea Pharmaceuticals, Inc. 
AT-752 
Protocol No. AT-02A-002 
Clinical Study Protocol Amendment 1 
 
29 JUL 2022 
CONFIDENTIAL 
Page 28 
the study site, or under observation by mobile nursing staff as applicable). 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. 
• 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 


Atea Pharmaceuticals, Inc. 
AT-752 
Protocol No. AT-02A-002 
Clinical Study Protocol Amendment 1 
 
29 JUL 2022 
CONFIDENTIAL 
Page 29 
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, or under observation by mobile nursing staff as 
applicable. 
All other doses may be administered either at the study site or will be self-administered 
outside the study site (e.g., at home). The timing of the doses will be recorded in a patient 
diary. 
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 (e.g., 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 


Atea Pharmaceuticals, Inc. 
AT-752 
Protocol No. AT-02A-002 
Clinical Study Protocol Amendment 1 
 
29 JUL 2022 
CONFIDENTIAL 
Page 30 
(e.g., 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.  
 
10. 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 Table3-2, 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). 
11. 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 10). Other virology 
sample times are flexible, with samples collected anytime on each of 6 days (Days 4, 5, 
7, 8, 14, and 28).  
 
 
 


Atea Pharmaceuticals, Inc. 
AT-752 
Protocol No. AT-02A-002 
Clinical Study Protocol Amendment 1 
 
29 JUL 2022 
CONFIDENTIAL 
Page 31 
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  
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  
 


Atea Pharmaceuticals, Inc. 
AT-752 
Protocol No. AT-02A-002 
Clinical Study Protocol Amendment 1 
 
29 JUL 2022 
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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  
 


Atea Pharmaceuticals, Inc. 
AT-752 
Protocol No. AT-02A-002 
Clinical Study Protocol Amendment 1 
 
29 JUL 2022 
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Page 33 
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  
 
 


Atea Pharmaceuticals, Inc. 
AT-752 
Protocol No. AT-02A-002 
Clinical Study Protocol Amendment 1 
 
29 JUL 2022 
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Page 34 
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 40 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 screening 
 Fever ≥38°C (or feeling feverish) with onset during the previous 60 hours 
 Positive test confirming DENV on a NS1 antigen test or RT-PCR assay 
 Negative rapid diagnostic test results for SARS-CoV-2 and Influenza A and B 
 Body mass index (BMI) of 18 to 30 kg/m2 
 
 
 
 
 


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 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-childbearing potential is defined as a female ≥ 54 
years old with menses cessation for ≥ 12 months since previous menses, or a 
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 
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:  
 
 
 
 


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 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, active 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 (whichever is longer) of 
the active drug or metabolite (for long-acting antivirals) of screening 
 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 
 Concomitant use of herbal or natural supplements or grapefruit juice (e.g. St. John’s 
Wort, echinacea, milk thistle) or grapefruit juice. These should be discontinued at 
screening if the investigator feels that they can be safely discontinued or substituted for 
the duration of the study. 
 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 
 Malabsorption syndrome or other conditions that would interfere with enteral absorption  
 Immunocompromised due to use of immunosuppressive drugs including systemic 
corticosteroids (inhaled or topical corticosteroids are allowed) or any current disease or 
immunocompromised due to any current disease or condition 
 Use of P-glycoprotein (P-gp) inducers and inhibitors as described in Section 5.6.1.  Note:  
hydroxychloroquine and amiodarone are prohibited within 3 months prior to screening 
and during the study. 
 
 
 
 
 
 
 
 
 
 
 
 
 


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 Evidence of severe dengue disease including: 
 Severe plasma leakage leading to shock or fluid accumulation with respiratory 
distress 
 Severe bleeding (including any subjects with hemoglobin levels <13.0g/dL in males 
and <11.0g/dL in females) 
 Severe organ impairment (e.g., elevated transaminases ≥1,000 IU/L, impaired 
consciousness, renal failure [including any subjects with creatinine clearance < 60 
mL/min {Cockcroft Gault formula}, or heart impairment) [including any subjects 
with clinically significant abnormal ECG at Screening] 
 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 or from treatment at any time, 
for any reason, without prejudice to further treatment. 
The investigator may withdraw a subject from the study or from treatment if the subject: 
1. Is 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. Becomes pregnant; 
4. Is required to take a medication prohibited by the protocol; or 
5. Requests 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 
be documented in the eCRF. 


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All subjects who prematurely discontinue study treatment should be encouraged to remain in 
the study and maintain the same protocol schedule and assessments as described in Table 3-1.  
This will allow for continued subject follow-up for key outcome data. 
4.3.3 
Replacements 
In the event there is at least one subject who withdraws without post-baseline virology data, 
with the exception of those who withdraw for safety or tolerability, enrollment may remain 
open or extended at each dose level/cohort to enroll additional randomization block(s) of 4 
patients (3:1) to increase the likelihood that at least 15 active and 5 placebo subjects with 
evaluable virology data are included in each cohort.  Any additional patients will be 
randomized through the same centralized randomization process.  
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. Study drug dose modifications are not permitted in the study.   
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. 
Subjects must take the dose that was assigned at randomization, unless they discontinue for 
one of the reasons noted in Section 4.3.1. 
 


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5.1.1 
Safety Review Committee 
This study is designed such that moving to the next dosing cohort is allowed only after an 
unblinded safety data review of the previous cohort by the SRC.  
Unblinded safety summaries (e.g., AEs, clinical laboratory test results, vital sign 
measurements, and 12-lead ECG results) will be reviewed by the SRC 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 available PK data of the prior cohort.  
  
 
 
 
 
 
 
 
 
 
 
 
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). 
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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 - 25°C. 
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. 
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 subject will be randomly assigned 
to a treatment assignment through a centralized randomization process and will receive a 
unique randomization number linked to the blinded treatment assignment. Randomization 
will be stratified by geographic region. 
   
 
 
 
 
 
 
 
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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.  
As this is an early phase study, the Sponsor may perform unblinded interim reviews of the 
data during the course of the study. An interim snapshot of the study database may be taken 
after completion of the clinical conduct of each cohort 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 
IRT) 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 unblinding. The investigator will be 
responsible for documenting the time, date, reason for the code break, and the names of the 
personnel involved. 
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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.   
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.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.6 
PRIOR AND CONCOMITANT MEDICATIONS 
Information regarding prior medications taken by the subject within the 30 days before 
signing the informed consent form (ICF) as well as concomitant medications taken after 
starting study drug will be recorded in the subject’s eCRF.  Any concomitant medication 
deemed necessary for the welfare of the subject during the study may be given at the 
discretion of the investigator. This includes standard-of-care treatments/therapies for dengue 
should subjects deteriorate on-study due to their dengue infection. If a prohibited 
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and kidneys; and 2) do not involve concomitant use of prohibited medications discussed 
above that may interfere with the PK AT-752. 
6. 
STUDY ENDPOINTS 
6.1 
PRIMARY ENDPOINT 
 Change in DENV viral load (DENV RNA as measured by RT-qPCR) from baseline 
6.2 
SECONDARY ENDPOINTS: PHARMACOKINETIC 
ENDPOINTS 
• Plasma concentrations of AT-281 (and metabolites AT-551, AT-229, AT-219, and AT-
273) for each cohort at the following timepoints: 
o Day 1: Pre-dose (before the first dose, time 0) 
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 
for time points ≤4 hours; ±15 minute for time points between 4 and 24 
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, where applicable, 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) 
 


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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 
 Vital sign measurements 
 Physical examination findings 
 Clinical laboratory (serum chemistry, hematology, coagulation, and urinalysis 
findings) 
 ECG findings 
6.4 
EXPLORATORY ENDPOINTS: PHARMACODYNAMIC 
ENDPOINTS 
 Change in DENV viral load (as measured by infectious viral titre) from baseline  
 Area under the log10-transformed viral load curve (AUC) from first dose to the end 
of treatment or study (as measured by DENV RNA and viral titre) 
 Time to viral load clearance, which is defined as the first of 2 consecutive 
undetectable viral load measurements (as measured by DENV RNA and viral titre) 
 
 
 
 
 
 
 
 
 


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 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 (as measured by DENV RNA and viral titre) from 
baseline, viral load AUC, time to viral load or NS1 clearance by DENV serotype 
 Treatment-emergent amino acid substitutions in DENV NS5 polymerase 
 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 load 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 10.2.2.3. Subjects will undergo study procedures at the time points specified in the 
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 minutes window for time points ≤4 hour and a ±15 minutes window for time points 
between 4 and 24 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, AT-219 
 
 
 
 
 


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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 by viral 
titre and with a serotype-specific, real-time reverse transcription PCR assay at screening and 
on Days 1-8, Day 14, and Day 28. DENV NS1 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. 
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 (e.g., 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 


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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 
about causality than an adverse reaction. 
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. 
 


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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 
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 (e.g., laboratory values, physical examination findings, and ECG 
changes) or other documents that are relevant to subject safety. 
 
 
 
 
 
 


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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 7.3.1.1) 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 
responsible for notifying the Institutional Review Board (IRB) or Ethics Committee (EC) 
directly as applicable per institutional policy. The sponsor or designee will provide regulatory 
authorities, IRB/ECs, and the investigator with clinical safety updates/reports according to 
local requirements  
In addition to entering the AE details in the eCRF, the study site should also complete the 
SAE eCRF page within 24 hours of awareness. In the event that EDC entry is not possible 
(e.g., eCRF system failure or access problems), the study site should complete/fax the paper 
SAE report form and fax the form within 24 hours of awareness and update the EDC as soon 
as it is available.  
For this study, the following contact information will be used for SAE reporting:  
Email (primary):  
 
 
 
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The determination of severity not listed in the DAIDS 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 no intervention 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. 
The investigator will assess causality (i.e., 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 (e.g.,
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
 


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reasonably explained by the subject’s clinical state or other factors (e.g., 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. 
The following clinical laboratory assessments will be performed at site or laboratory 
appointed by site: 
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 creatine kinase, 
bicarbonate or total carbon dioxide, sodium, potassium, chloride, 
glucose, total protein, albumin, phosphate, calcium, and amylase  
 
 
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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) 
 
 
Direct viral tests 
SARS-CoV-2 rapid test, rapid influenza diagnostic test 
Other analyses 
Female subjects:  
Pregnancy test (β-HCG; urine at screening and urine or serum after 
screening)  
Samples for the following laboratory tests will be sent to the sponsor or a designee for 
analysis: 
• Viral Load (as measured by RT-PCR and viral titre) 
• Treatment-emergent amino acid substitutions in DENV NS5 polymerase 
• DENV Serotype Testing 
• NS1 Antigen 
• Plasma Biomarker 
• Pharmacokinetic Assessment 
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 Fridericia’s corrected QT interval (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 be 
conducted based on the specific symptoms targeted. 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 
(SAP). 
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). 
InLow 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:  


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True standard deviation 
Effect (log 10 copies/ml) with 
80% power (N=15 vs. 15) 
Comparison versus placebo 
pooled across 3 planned 
cohorts 
Effect (log 10 copies/ml) with 
80% power (N=15 vs. 5) 
Comparison versus placebo 
within a cohort 
1 
0.8 
1.1 
1.25 
1 
1.4 
1.5 
1.2 
1.7 
1.75 
1.4 
2.0 
 
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 
for comparison of groups with N=15 each. The analogous power to detect a 1 log10 effect for 
a within cohort comparison is 59%. 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, i.e., 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 primary analysis population is the modified intent-to-treat (mITT) population, 
which will include all randomized subjects who received at least 1 dose of study drug and 
have baseline and at least 1 post-baseline virology measurement. The primary analysis will 
also be performed on the per-protocol population of patients who completed treatment 
without a major protocol deviation.   
 


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• 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. 
• A per protocol population will include the subset of the modified intent-to-treat 
population who completed study drug treatment without a major protocol violation. 
8.3 
PLANNED STATISTICAL ANALYSIS  
Safety, PK, and PD data will be summarized in tabular and/or graphical format by active 
dose treatment arms and a-pooled placebo arm. Continuous data will be summarized using 
descriptive statistics (n, mean, standard deviation [SD], median, 95% confidence interval 
[CI]) and categorical data will be summarized using counts and percentages. All subject-level 
data will be presented in listings.  
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 fromtreatment, and the reason for withdrawal or 
discontinuation, will also be summarized.  
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 (DENV RNA as measured by RT-PCR) 
based on the log-10 scale at specified timepoints. 
Change from baseline in viral load will be compared between each AT-752 arm and the 
pooled placebo arm. 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 the SAP. 


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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 
(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, 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 Exploratory Analyses 
 Change in DENV viral load (as measured by viral titre) from baseline 
 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) (as measured by DENV RNA and 
viral titre) 
 
 


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 Time to viral load (as measured by DENV RNA and viral titre) or NS1 clearance, 
defined as time to first of 2 consecutive undetectable viral load 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/viral titre or NS1 antigen assay by the last observation timepoint will be treated 
as censored at the final scheduled evaluation time point. 
 Change of DENV viral load (as measured by DENV RNA and viral titre) from 
baseline, viral load AUC, time to viral load or NS1 clearance by DENV serotype  
 Treatment-emergent amino acid substitutions in DENV NS5 gene 
  
 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-α, IFN-γ, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-1β, 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 load may be explored using graphical displays 
 
8.4 
HANDLING OF MISSING DATA 
In general, observed data will be used in statistical analysis without imputation, unless 
missing data will jeopardize the integrity of the study or pose a problem in the validity of the 
analysis. A data-as-observed (DAO) approach will be used to evaluate the primary 
endpoint.  Uncertain viral load measurements that are below the lower limit of quantification 
(LLOQ) will be set to 0.5 × LLOQ in the viral load summaries and indicated as BLQ in the 
listings. Impact of missing data will be assessed, and sensitivity analysis will be performed 
when deemed appropriate. Details will be described in the SAP. 
 
 
 
 
 
 
 


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9.
REFERENCE LIST
Atea Pharmaceuticals, Inc. AT-752. Investigator’s brochure, edition No. 2 Boston (MA). 
2021. 
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 
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 Harmonization 
INR 
international normalized ratio 
IRB 
Institutional Review Board 


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Abbreviation 
Term 
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) 
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 10.2.4), 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/legally 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 timeline 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. 
 
 
 
 


Atea Pharmaceuticals, Inc. 
AT-752 
Protocol No. AT-02A-002 
Clinical Study Protocol Amendment 1 
 
29 JUL 2022 
CONFIDENTIAL 
Page 71 
 
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 
• 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. 
• Televisits can support the completion of symptom-directed physical exams performed 
by HHC medical professionals via study phone calls with participants 
 
 
 


Atea Pharmaceuticals, Inc. 
AT-752 
Protocol No. AT-02A-002 
Clinical Study Protocol Amendment 1 
 
29 JUL 2022 
CONFIDENTIAL 
Page 72 
 
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 
(e.g., change in Medical Monitor or contact information). 
 
 
 
CCI
CCI
CCI


Atea Pharmaceuticals, Inc. 
AT-752 
Protocol No. AT-02A-002 
Clinical Study Protocol Amendment 1 
 
29 JUL 2022 
CONFIDENTIAL 
Page 73 
 
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 
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. 
 
 
 
 

Prot_000.pdf: 
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.
AT-752
Protocol No. AT-02A-002
Clinical Study Protocol Version 1.0
20 SEP 2021 
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Page 3
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


Atea Pharmaceuticals, Inc.
AT-752
Protocol No. AT-02A-002
Clinical Study Protocol Version 1.0
 
20 SEP 2021 
CONFIDENTIAL
Page 4
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 


Atea Pharmaceuticals, Inc.
AT-752
Protocol No. AT-02A-002
Clinical Study Protocol Version 1.0
20 SEP 2021 
CONFIDENTIAL
Page 5
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
Clinical Study Protocol Version 1.0
 
20 SEP 2021 
CONFIDENTIAL
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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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Protocol No. AT-02A-002
Clinical Study Protocol Version 1.0
 
20 SEP 2021 
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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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Protocol No. AT-02A-002
Clinical Study Protocol Version 1.0
 
20 SEP 2021 
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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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Protocol No. AT-02A-002
Clinical Study Protocol Version 1.0
 
20 SEP 2021 
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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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Protocol No. AT-02A-002
Clinical Study Protocol Version 1.0
 
20 SEP 2021 
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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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Protocol No. AT-02A-002
Clinical Study Protocol Version 1.0
 
20 SEP 2021 
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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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Protocol No. AT-02A-002
Clinical Study Protocol Version 1.0
 
20 SEP 2021 
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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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Protocol No. AT-02A-002
Clinical Study Protocol Version 1.0
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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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Protocol No. AT-02A-002
Clinical Study Protocol Version 1.0
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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
 
 
 
 
 
 
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Protocol No. AT-02A-002
Clinical Study Protocol Version 1.0
 
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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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AT-752
Protocol No. AT-02A-002
Clinical Study Protocol Version 1.0
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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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AT-752
Protocol No. AT-02A-002
Clinical Study Protocol Version 1.0
 
20 SEP 2021 
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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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Protocol No. AT-02A-002
Clinical Study Protocol Version 1.0
 
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Protocol No. AT-02A-002
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AT-752
Protocol No. AT-02A-002
Clinical Study Protocol Version 1.0
20 SEP 2021 
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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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AT-752
Protocol No. AT-02A-002
Clinical Study Protocol Version 1.0
 
20 SEP 2021 
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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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Protocol No. AT-02A-002
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20 SEP 2021 
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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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Protocol No. AT-02A-001
Clinical Study Protocol
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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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AT-752
Protocol No. AT-02A-002
Clinical Study Protocol Version 1.0
 
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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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Protocol No. AT-02A-002
Clinical Study Protocol Version 1.0
 
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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
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 
about causality than an adverse reaction.
 


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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 
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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 
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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 
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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 
 
 
 
 
 


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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.