Clinical trial NCT04906980
Conditions: Dengue
Sponsor: Janssen Research & Development, LLC
Start date: 2022-01-24; Completion date: 2023-03-21
Enrollment: 5 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to investigate the antiviral activity of JNJ-64281802 versus placebo in terms of reduction of dengue virus (DENV) ribonucleic acid (RNA) in primary DENV infection.

Detailed description:

Arms: arm 1: Participants will receive 2 initial loading doses of JNJ-64281802 up to Day 2, followed by a maintenance dose on Days 3, 4, and 5. arm 2: Participants will receive oral dose of matching placebo every 8 hour (q8h) and once daily on Day 4 and Day 5.
Interventions: intervention 1: JNJ-64281802 intervention 2: Placebo
Intervention descriptions: intervention 1: JNJ-64281802 will be administered orally. intervention 2: Matching placebo (PEG400) will be administered orally.

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
1
Status: Approved,  Date:  06 June 2022
Janssen Research & Development *
Clinical Protocol
Protocol Title
A Phase 2a, Randomized, Double-blind, Placebo-controlled Trial to Evaluate the Antiviral
Activity, Safety and Tolerability, and Pharmacokinetics of JNJ-64281802 in Participants
With Confirmed Dengue Fever.
Protocol 64281802DNG2003; Phase 2
AMENDMENT 6
JNJ-64281802
*Janssen Research & Development is a global organization that operates through different legal entities in
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen
Biologics, BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Pharmaceutica NV; Janssen
Sciences Ireland UC; Janssen Biopharma Inc.; or Janssen Research & Development, LLC. The term
“sponsor” is used throughout the protocol to represent these various legal entities; the sponsor is
identified on the Contact Information page that accompanies the protocol.
Status: 
Approved
Date: 
06 June 2022
Prepared by: Janssen Research & Development, a division of Janssen Pharmaceutica NV
EDMS number: 
EDMS-ERI-205547480, 9.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory
requirements.
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company
customarily holds close and treats as confidential. The information is being provided under the assurance that the recipient
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or
otherwise.
NCT04906980


JNJ-64281802  
Clinical Protocol 64281802DNG2003
Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date:  06 June 2022
PROTOCOL AMENDMENT SUMMARY OFCHANGES TABLE
DOCUMENT HISTORY
Document 
Date
Amendment 6 
06 June 2022
Amendment 5 
28 February 2022
Amendment 4 
22 November 2021
Amendment 3 
26 March 2021
Amendment 2 
08 September 2020
Amendment 1 
4 August 2020
Original Protocol 
19 June 2020
Amendment 6 (06 June 2022)
Overall Rationale for the Amendment: The Sponsor decided to include an additional country for the
conduct of the trial (Vietnam)and to introduce a
 formulation of the study intervention for use in newly
recruited participants, when it becomes locally available.
In addition, the protocol was amended to decrease the lower age limit to 18 years of age depending on legal
age of consent in the country, to increase the time window from randomization to the first dose from
30 minutes to 
minutes, to allow an option of ambulatory visits on Days 3, 4, 5, and 6, to introduce an
additional exclusion criterion to exclude patients with past/prior dengue infections, and to include an
optional reduction of blood sample volume for cellular immunity.
Some minor corrections and/or clarifications were addressed as outlined in the table below.
Section number 
and Name
Description of Change 
Brief Rationale
1.1 Synopsis
2. Introduction
2.1. Study rationale
4.1. Overall design
4.3. Justification for
dose
Vietnam has been added as a second country. 
To facilitate recruitment.
1.1. Synopsis
1.2. Schema
1.3. Schedule of
Activities
4.1. Overall Design
4.3. Justification for
dose
6.1. Study
Intervention(s)
Administered
The use of the 
 formulation of the study
intervention and related dosing regimen have been
added.
To ensure provision of the study
drug to sites after expiry date of the
currently used 
 formulation
and to facilitate operational and
logistic aspects of the study.
1.1 Synopsis
4.1. Overall Design
5.1. Inclusion
Criteria
The lower age limit for inclusion in the study has
been decreased to 18 years of age depending on the
legal age of consent in the country.
To accommodate the investigator’s
request to be able to include
younger adult patients in countries
where the legal age of consent is
lower than 21 years.
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Section number 
and Name
Description of Change 
Brief Rationale
5.2 Exclusion 
Criteria 
A criterion to exclude patients with past/prior 
laboratory-confirmed dengue infection (any PCR, 
NS1, IgG/IgM seroconversion) was added. 
To ensure adequate numbers of
primary infected participants are
enrolled in accordance with the
assumptions made in the sample
size section.
1.1. Synopsis 
1.3. Schedule of 
Activities 
4.1. Overall Design
The time window from randomization to the first 
dose administration has been increased from 
30 minutes to 
minutes. 
To accommodate the investigator’s
request and facilitate operational
aspects of the study.
1.1. Synopsis 
4.1. Overall design  
6.3. Measures to 
Minimize Bias: 
Randomization and 
Blinding
Wording on randomization has been updated to 
include stratification by country. 
An additional stratification factor
“by country” has been included,
since the study will now be
conducted in more than one
country.
1.1. Synopsis 
8.3. Adverse Events, 
Serious Adverse 
Events and Other 
Safety Reporting 
All adverse events and special reporting situations, 
whether serious or non-serious, will be reported 
from the time a signed and dated main study ICF is 
obtained until completion of the participant's last 
study related. For participants with only a signed
pre-screening (diagnostic) ICF, no AEs will be
reported.
To emphasize that a pre-screening
(diagnostic) ICF only consents for
the diagnostic test, and no other
study related assessments.
1.3. Schedule of 
Activities 
8. Study 
assessments and
procedures
An option to reduce the blood sample volume for
cellular immunity (PBMC) from 30 mL to 10 mL
at Day 28 has been added
To accommodate the investigator’s
request and to align with local
regulations in Vietnam.
2.1. Study rationale 
Information on prevalence of dengue virus in
Vietnam has been added.
Added because of addition of
Vietnam as participating country.
1.1. Synopsis 
1.2. Schema 
1.3. Schedule of
Activities
4.1. Overall design
6.1. Study
Intervention(s)
Administered
An option for ambulatory visits on Days 3, 4, 5,
and 6 has been added.
To accommodate the investigator’s
request.
9.4. Statistical 
Analyses 
An option for exploratory subgroup analysis for the
different drug formulations used in the trial has
been added.
To provide an option of additional
analysis following addition of the
 formulation.
4.1. Overall design  
Text added: “The population will include
participants with a primary and a non-primary or
secondary infection. The difference between the 2
subpopulations will be determined before database
lock and will be based on the IgG profile.”
For clarification
Throughout the 
protocol 
Minor updates, corrections, or additions have been
made.
Correction, clarification, and
consistency.
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Status: Approved,  Date:  06 June 2022
TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................... 2
DOCUMENT HISTORY ................................................................................................................................ 2
TABLE OF CONTENTS ............................................................................................................................... 4
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 7
1. 
PROTOCOL SUMMARY..................................................................................................................... 8
1.1. 
Synopsis........................................................................................................................................... 8
1.2. 
Schema.......................................................................................................................................... 20
1.3. 
Schedule of Activities..................................................................................................................... 21
2. 
INTRODUCTION................................................................................................................................ 28
2.1. 
Study Rationale.............................................................................................................................. 29
2.2. 
Background .................................................................................................................................... 30
2.3. 
Benefit-Risk Assessment............................................................................................................... 34
2.3.1. 
Known Benefits........................................................................................................................... 34
2.3.2. 
Potential Benefits........................................................................................................................ 35
2.3.3. 
Known Risks............................................................................................................................... 35
2.3.4. 
Potential Risks............................................................................................................................ 35
3. 
OBJECTIVES AND ENDPOINTS ..................................................................................................... 36
4. 
STUDY DESIGN ................................................................................................................................ 39
4.1. 
Overall Design................................................................................................................................ 39
4.2. 
Scientific Rationale for Study Design............................................................................................. 42
4.2.1. 
Study-Specific Ethical Design Considerations ........................................................................... 43
4.3. 
Justification for Dose...................................................................................................................... 44
4.4. 
End of Study Definition................................................................................................................... 45
5. 
STUDY POPULATION ...................................................................................................................... 45
5.1. 
Inclusion Criteria............................................................................................................................ 45
5.2. 
Exclusion Criteria........................................................................................................................... 47
5.3. 
Lifestyle Considerations................................................................................................................. 50
5.3.1. 
Meals and Dietary Restrictions................................................................................................... 50
5.3.2. 
Caffeine and Alcohol................................................................................................................... 51
5.3.3. 
Activity......................................................................................................................................... 51
5.4. 
Screen Failures.............................................................................................................................. 51
6. 
STUDY INTERVENTION................................................................................................................... 51
6.1. 
Study Intervention(s) Administered................................................................................................ 51
6.2. 
Preparation/Handling/Storage/Accountability ................................................................................ 54
6.3. 
Measures to Minimize Bias: Randomization and Blinding............................................................. 55
6.4. 
Study Intervention Compliance...................................................................................................... 56
6.5. 
Concomitant Therapy..................................................................................................................... 56
6.6. 
Dose Modification........................................................................................................................... 58
6.7. 
Intervention After the End of the Study.......................................................................................... 58
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL............................................................................................... 58
7.1. 
Discontinuation of Study Intervention ............................................................................................ 58
7.2. 
Participant Discontinuation/Withdrawal From the Study................................................................ 59
7.2.1. 
Withdrawal from the Use of Research Samples......................................................................... 59
7.3. 
Lost to Follow-up............................................................................................................................ 59
8. 
STUDY ASSESSMENTS AND PROCEDURES ............................................................................... 60


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8.1. 
Antiviral activity Assessments........................................................................................................ 62
8.1.1. 
Viral Genome Sequencing.......................................................................................................... 63
8.2. 
Safety Assessments....................................................................................................................... 63
8.2.1. 
Physical Examinations................................................................................................................ 63
8.2.2. 
Vital Signs................................................................................................................................... 64
8.2.3. 
Electrocardiograms..................................................................................................................... 64
8.2.4. 
Clinical Safety Laboratory Assessments .................................................................................... 64
8.2.4.1. 
Assessment of Clinical Endpoints ........................................................................................... 64
8.3. 
Adverse Events, Serious Adverse Events and Other Safety Reporting ........................................ 65
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event
Information.................................................................................................................................. 65
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events .......................................... 66
8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events ....................................................... 67
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events ............................................. 67
8.3.5. 
Pregnancy................................................................................................................................... 67
8.4. 
Treatment of Overdose .................................................................................................................. 68
8.5. 
Pharmacokinetics........................................................................................................................... 68
8.5.1. 
Evaluations ................................................................................................................................. 68
8.5.2. 
Analytical Procedures................................................................................................................. 68
8.5.3. 
Pharmacokinetic Parameters and Evaluations........................................................................... 69
8.6. 
Genetics ......................................................................................................................................... 69
8.6.1. 
Human Leucocyte Antigen Typing and Pharmacogenomics Assessments............................... 69
8.7. 
Biomarkers..................................................................................................................................... 70
8.8. 
Immune Assessments.................................................................................................................... 70
8.8.1. 
Humoral Immune Response....................................................................................................... 70
8.8.2. 
Cellular Immune Response ........................................................................................................ 70
9. 
STATISTICAL CONSIDERATIONS.................................................................................................. 71
9.1. 
Statistical Hypotheses.................................................................................................................... 71
9.2. 
Sample Size Determination ........................................................................................................... 71
9.3. 
Populations for Analyses................................................................................................................ 72
9.4. 
Statistical Analyses ........................................................................................................................ 72
9.4.1. 
General Considerations.............................................................................................................. 72
9.4.2. 
Antiviral Activity Analysis ............................................................................................................ 72
9.4.2.1. 
Primary Endpoint(s)................................................................................................................. 73
9.4.2.2. 
Secondary Endpoint(s)............................................................................................................ 73
9.4.3. 
Safety Analyses.......................................................................................................................... 73
9.4.4. 
Immune Analysis ........................................................................................................................ 74
9.4.4.1. 
Humoral Immune Analyses ..................................................................................................... 74
9.4.4.2. 
Cellular Immune Analyses....................................................................................................... 75
9.4.5. 
Pharmacokinetic Analyses.......................................................................................................... 75
9.4.6. 
Pharmacokinetic/Pharmacodynamic Analyses .......................................................................... 76
9.4.7. 
Biomarkers Analyses.................................................................................................................. 76
9.4.8. 
Viral Genome Sequence Analyses............................................................................................. 76
9.4.9. 
Human Leukocyte Antigen Typing and Pharmacogenomic Analyses........................................ 76
9.5. 
Interim Analysis.............................................................................................................................. 76
9.6. 
Data Review Committee ................................................................................................................ 77
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ............................ 78
10.1. 
Appendix 1: Abbreviations ............................................................................................................. 78
10.2. 
Appendix 2: Clinical Laboratory Tests ........................................................................................... 80
10.3. 
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations......................................... 81
10.4. 
Appendix 4: Adverse Events: Definitions and Procedures for Recording, Evaluating,
Follow-up, and Reporting............................................................................................................... 93
10.5. 
Appendix 5: Contraceptive and Barrier Guidance and Collection of Pregnancy Information........ 98
10.6. 
Appendix 6: United States Food and Drug Administration Toxicity Grading Table ..................... 101
10.7. 
Appendix 7: Rash Management................................................................................................... 105
10.8. 
Appendix 8: Protocol Amendment History................................................................................... 111


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10.9. 
Appendix 9: COVID-19 Appendix ................................................................................................ 120
11. REFERENCES................................................................................................................................. 124
INVESTIGATOR AGREEMENT............................................................................................................... 126


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LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1: 
Volume of Blood to be Collected From Each Participant.......................................................... 61
Table 2: 
Solicited Adverse Events .......................................................................................................... 66
Table 3: 
Grading of Solicited Adverse Events ........................................................................................ 67
Table 4: 
Management of Rash Events by Severity Grade ................................................................... 106
FIGURES
Figure 1: Schematic Overview of the Study............................................................................................. 20


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Status: Approved,  Date:  06 June 2022
1. 
PROTOCOL SUMMARY
1.1. 
Synopsis
A Phase 2a, Randomized, Double-blind, Placebo-controlled Trial to Evaluate the Antiviral Activity, Safety
and Tolerability, and Pharmacokinetics of JNJ-64281802 in Participants With Confirmed Dengue Fever.
JNJ-64281802 is a novel anti-dengue small molecule targeting DENV non-structural protein (NS)4B. It has
shown potent antiviral activity across all 4 DENV serotypes in preclinical studies.A Phase 1 first-in-human
study 64281802DNG1001 (further referred to as DNG1001) to assess the safety, tolerability, and
pharmacokinetics (PK) of increasing single and multiple oral doses of JNJ-64281802 in healthy adult
participants has been performed.
This is a Phase 2a, multicenter study to be conducted in Singapore and Vietnam. The aim of the study is to
examine the antiviral activity, PK, and safety and tolerability of JNJ-64281802, compared to placebo, and
to evaluate the improvement in clinical signs and symptoms with the administration of JNJ-64281802 for
the treatment of dengue.
OBJECTIVES AND ENDPOINTS
Objectives 
Endpoints
Primary
 
Investigate 
the 
antiviral 
activity 
of
JNJ-64281802 versus placebo in terms of
reduction of DENV RNA in primary DENV
infection
 
Area under the log10-transformed DENV RNA viral
load (log10 VL) curve from baseline until Day 5
(AUCD1-D5 [log10VL]).
Secondary
 
Assess the safety and tolerability of
JNJ-64281802 in primary and secondary
DENV infection
 
AEs
 
ECGs
 
physical examinations
 
vital signs
 
clinical laboratory assessments
 
Investigate 
the 
antiviral 
activity 
of
JNJ-64281802 versus placebo based on other
virological endpoints in primary DENV
infection
 
Virologic endpoints derived from the DENV RNA,
including
 
Occurrence of detectable DENV RNA at each
time point in primary DENV infection
 
Time to undetectable DENV RNA in primary
DENV infection
 
Evaluate the PK of JNJ-64281802 
 
PK parameters for JNJ-64281802
Exploratory
 
Investigate 
the 
antiviral 
activity 
of
JNJ-64281802 versus placebo based on DENV
infectious viral titer (further referred to as
viremia) in primary DENV infection
Virologic endpoints derived from viremia, including
 
Area under the log10-transformed viremia curve
from baseline until Day 5 in primary DENV
infection
 
Occurrence of detectable viremia at each
timepoint in primary DENV infection
 
Time to undetectable viremia in primary DENV
infection


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Objectives 
Endpoints
 
To explore the relationship between the 
exposure 
and 
antiviral 
activity 
of 
JNJ-64281802
 
PK (plasma concentrations or exposure parameters) of
JNJ-64281802
 
Area under the log10-transformed viremia or DENV
RNA viral load
 
Investigate 
the 
antiviral 
activity 
of 
JNJ-64281802 versus placebo in terms of 
reduction of DENV RNA in secondary DENV
infections and in all DENV infections
 
Virologic endpoints derived from the DENV RNA, viral
load, including
 
Area under the log10-transformed DENV RNA
viral load curve from baseline until Day 5, in
secondary DENV infection
 
Occurrence of detectable DENV RNA at each
time point in secondary DENV infection
 
Time to undetectable DENV RNA in secondary
DENV infection
 
Investigate 
the 
antiviral 
activity 
of 
JNJ-64281802 versus placebo based on
viremia in secondary DENV infections and in
all DENV infections
 
Virologic endpoints derived from viremia, including
 
Area under the log10-transformed viremia curve
from baseline until Day 5 in secondary DENV
infection
 
Occurrence of detectable viremia at each
timepoint in secondary DENV infection
 
Time to undetectable viremia in secondary DENV
infection
 
Investigate the effect of JNJ-64281802 versus 
placebo on the change in hematology values 
over 
time 
(leucocytes, 
platelets, 
and
hematocrit)
 
The maximal decrease from baseline (per participant)
observed in platelet counts from Day 2 to Day 5
 
The maximal decrease from baseline (per participant)
observed in leucocyte counts from Day 2 to Day 5
 
The maximal increase from baseline (per participant)
observed in hematocrit concentration from Day 2 to Day
5
Investigate the effect of JNJ-64281802 versus 
placebo on the immunological profile 
 
The occurrence and magnitude of anti-DENV total IgM
and IgG antibody titers
To explore the effect of JNJ-64281802 versus 
placebo on DENV-related clinical signs
and symptoms
 
Time to resolution of dengue signs and symptoms
 
Severity of dengue signs and symptoms
To assess changes in the viral genome 
sequence (with a focus on NS4B) in 
participants with detectable DENV RNA
 
Changes in the viral genome sequence at and between
first viral isolation and last viral isolation
To explore the DENV  NS1 serum protein 
levels 
 
Occurrence and magnitude of DENV  NS1 serum
protein levels
To explore the impact of host and viral 
baseline factors on the antiviral activity
and safety of JNJ-64281802
 
HLA genotyping and pharmacogenomic analyses
The following additional exploratory objectives may be evaluated at the discretion of the sponsor:
 
Investigate the effect of JNJ-64281802 versus placebo on immunological profile based on occurrence and
magnitude of anti-DENV cellular immune responses


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Objectives 
Endpoints
 
To explore changes in serum protein levels (including cytokines)
 
To explore the impact of host and viral baseline factors on the antiviral activity and safety of JNJ-64281802
based on biomarker analysis via transcriptional profiling of host RNA
 
The occurrence and magnitude of an anti-DENV neutralizing antibody response
Abbreviation key: AE(s) adverse event(s), AUC  area under the curve, DENV dengue virus, ECG: electrocardiogram,
HLA human leukocyte antigen, Ig Immunoglobulin, NS non structural, PK pharmacokinetic, RNA ribonucleic acid,
VL viral load
Hypothesis
The primary hypothesis of this study is that JNJ-64281802 is superior to placebo with respect to reduction
in viral load in participants with a primary DENV infection, as measured by area under the
log10-transformed DENV RNA viral load curve from baseline until Day 5.
OVERALL DESIGN
This is a randomized, double-blind, placebo-controlled, multicenter, Phase 2a interventional study in
participants aged ≥18 or ≥21 (depending on the legal age of consent in the jurisdiction in which the study
is taking place) to ≤60 years. Participants who report with an onset of fever of <48-hour duration at
screening and who test positive for DENV infection by the NS1 assay will be randomized in the study.
Randomization will be stratified by country and by duration of dengue symptoms from onset of fever as
reported by the participant until the time of randomization (≤24 hours and >24 hours).
The population will include participants with a primary and a non-primary or secondary infection. The
difference between the 2 subpopulations will be determined before database lock and will be based on the
IgG profile.
There are three sequential phases in the study: screening/baseline, double-blind treatment and follow-up.
Study participants will complete the screening/baseline visit on Day 0 (predose), followed by a double-blind
treatment phase from Day 1 to Day 6 or Day 9 (for participants with dengue warning symptoms). During
the double-blind treatment period, participants will be admitted to an inpatient facility. At the investigator’s
discretion, ambulatory visits instead of inpatient treatment can be allowed at Days 3, 4, 5, and 6. All
participants will be followed up for a total of 6 months after the first dosing day. The entire study duration
for each participant will be approximately 6 months (±4 days). The participants will complete the study
after having completed the final remote follow-up assessment planned 6 months (±4 days) after having
received the first dose of study intervention, unless ongoing adverse events (AEs) require monitoring.
Mobile clinical teams consisting of trained and delegated site staff(eg, nurses, clinical research coordinators
[CRCs]) will visit the clinics and communities to sensitize and pre-screen potential study participants and
play an active role in participant recruitment. Individuals with a suspected DENV infection will be asked
to undergo an NS1 rapid test after signing a pre-screening ICF during an ambulatory visit at a health care
facility organized by the mobile clinical teams.
The study sites will be open to receive referrals of participants who have consulted a health care facility
(eg, clinic/polyclinic, hospital) or practitioner (eg, general practitioner [GP], medical doctor [MD], nurse)
with an onset of fever within the last 48 hours, as reported by the participant, and who tested positive for
DENV infection by the NS1 assay at the health care facility. Individuals who test positive during an
ambulatory visit or as part of Standard of Care DENV NS1 rapid testing, will be referred to the study site
to further coordinate informed consent signing and completion of eligibility assessments. In addition,
participants may also report directly to the study site. Participants identified at the study site with an onset
of fever as reported by the participant within the last 48 hours, and who test positive for DENV infection
by the NS1 assay performed at the site after signing the ICF, will undergo eligibility assessment.


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The screening/baseline assessments are to be completed as quickly as possible at the study site. Participants
who successfully meet all inclusion criteria and none of the exclusion criteria, will be enrolled and admitted
to aninpatient facility. The participants will then be randomized to receive placebo or JNJ-64281802.
 Results of screening assessments need to be
documented in the electronic case report form (eCRF).
An internal Data Review Committee (DRC) will be commissioned for this study.
NUMBER OF PARTICIPANTS
A planned target of 150 male and female participants will be randomly assigned in a ratio of 1:1 to receive
JNJ-64281802 or placebo in this study with approximately 75 participants planned per intervention group.
The sample size can be revised after an interim analysis on the proportion of primary versus secondary
DENV infections.
INTERVENTION GROUPS AND DURATION
JNJ-64281802 (in either 
 formulation) or matching placebo will be administered according
to the following dosing regimens:
The 
formulation will be introduced for use in newly recruited participants, when it becomes locally
available.
The 
formulation was selected based on the results of study 64281802DNG1006, 
When dosed in fasted condition in 16 healthy volunteers, the JNJ-64281802 Cmax  and AUC∞ were similar
between 
 and
, with geometric mean ratios of 1.06 and 1.00, respectively. The
effect of food on JNJ-64281802 exposure when formulated as 
 tablet was dose dependent.
When administered with a standardized breakfast, JNJ-64281802 Cmax  was increased by 33%, 76%, and
178% compared to fasted conditions for a single dose of 50 mg, 200 mg, and 800 mg, respectively. For
AUC∞this increase was 12%, 69%, and 143%, respectively.
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Clinical Protocol 64281802DNG2003
Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
12
Status: Approved,  Date:  06 June 2022
The participants will stay at an inpatient facility from Day 1 to Day 6, with an option of ambulatory visits
on Days 3, 4, 5, and 6 at the investigator’s discretion. Daily clinical monitoring will be conducted, and
blood samples will be collected. Oral intake of food and fluids will be recorded on Days 1, 2, 3, 4, and 5 of
dosing.
The participants will be discharged from the inpatient facility on Day 6 (on Day 2 for ambulatory visits)
after the assessments have taken place and given their clinical status is satisfactory for discharge in the
opinion of the investigator. Participants who develop dengue warning symptoms as defined by the World
Health Organization (WHO)a will remain at the inpatient facility after Study Day 6 for an additional 3 days
and planned outpatient assessments will be performed by the study team members, where required. Patients
with severe dengue (dengue hemorrhagic fever [DHF] or dengue shock syndrome [DSS]), or participants
who are hemodynamically unstable or require interventions, can be transferred to a hospital at any time
during the inpatient stay, at the investigator’s discretion. Participants with severe dengue or dengue warning
symptoms after Study Day 9 will be moved to a hospital. After discharge, the participants will be asked to
return on Days 14, 21, and 28 (±2 days) for assessments after which remote visits are scheduled every
2 weeks for the assessment of possible DENV infection associated AEs, up to 6 months after the first study
intervention intake.
a 
World Health Organization: Dengue. Guidelines for diagnosis, treatment, prevention and control 2009


JNJ-64281802  
Clinical Protocol 64281802DNG2003
Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
13
Status: Approved,  Date:  06 June 2022
Description of Interventions
Arm Name 
Intervention  
Placebo
Intervention Name 
JNJ-64281802 
Placebo
Type 
Drug 
Placebo
Dose Formulation 
Unit Dose Strength(s) 
Dosage Level(s) 
Route of Administration 
Oral 
Oral
Use 
Experimental 
Placebo
Investigational Medicinal Product (IMP) and 
Non-Investigational Medicinal Product
(NIMP)
IMP  
IMP
Sourcing 
Provided centrally by the 
Sponsor 
Provided centrally by the
Sponsor
Packaging and Labeling 
 
 
 
 
 
 
 Each container will 
contain information and be 
labeled as required per 
country regulatory 
requirements. Labels must 
remain affixed to the 
container. 
 Each container will
contain information and be
labeled as required per
country regulatory
requirements. Labels must
remain affixed to the
container.
CCI
CCI
CCI
CCI
CCI


JNJ-64281802  
Clinical Protocol 64281802DNG2003
Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
14
Status: Approved,  Date:  06 June 2022
Arm Name 
Intervention  
Placebo
 
 
 Each 
container will contain 
information and be labeled as 
required per country 
regulatory requirements. 
Labels must remain affixed to 
the container.
 Each
container will contain
information and be labeled as
required per country
regulatory requirements.
Labels must remain affixed to
the container.
Food/Fasting requirement 
CCI
CCI
CCI


JNJ-64281802  
Clinical Protocol 64281802DNG2003
Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
15
Status: Approved,  Date:  06 June 2022
ANTIVIRAL ACTIVITYEVALUATIONS
Antiviral activity will be assessed using (i) DENV RNA levels, (ii) Levels of infectious dengue virus
(viremia) and (iii) Levels of DENV NS1 protein in serum. Samples may be used by the sponsor for
additional assessments analyzing the serologic and virologic characteristics of the DENV infection and
antiviral activity of the study intervention.
DENV RNA levels will be assessed using a validated quantitative DENV RT-PCR assay.
DENV viremia (ie, level of infectious DENV) will be determined using an assay for infectious virus
quantification such as a plaque assay.
In addition, antiviral activity will be explored by assessing NS1 protein using an NS1 test. Confirmation of
DENV infection will be done retrospectively using qualitative PCR after screening.
Additionally, blood samples will be obtained for the assessment of clinical endpoints (leukocyte count,
platelet count, and hematocrit concentration).
PHARMACOKINETIC EVALUATIONS
Venous blood samples will be used to evaluate the PK of JNJ-64281802. Plasma collected for PK may
additionally be used to evaluate safety, pharmacokinetic (plasma protein binding, metabolites) or antiviral
activity aspects that address concerns arising during or after the study period. Genetic analyses will not be
performed on these plasma samples. Participant confidentiality will be maintained.
BIOMARKER EVALUATIONS
The study includes collection of blood samples for exploratory analysis.
Samples for host RNA might be used for transcriptional profiling for example using microarray technology.
Serum samples for protein analyses might be analyzed using assays such as ELISA or Luminex.
Samples can only be used for research related to JNJ-64281802 or DENV infection or may be used to
develop tests/assays related to JNJ-64281802 or DENV infection.
IMMUNE ASSESSMENTS
Blood samples will be obtained for the assessment of antibody response. Anti-DENV IgG and IgM will be
measured using commercial ELISA and the IgG pattern will be used to make a distinction between primary
and secondary dengue infection. Presence of neutralizing antibodies (IgG and IgM) against DENV will be
determined using an assay such as flow cytometry-based neutralization assay.
Peripheral blood mononuclear cell (PBMC) samples may be analyzed in a subset of participants to assess
DENV-specific T and B cell immune responses by assays such as enzyme-linked immunospot assay
(ELISpot) and/or intracellular cytokine staining (ICS) after stimulation with DENV-specific antigens.
ELISpot detects T cells that secrete gamma interferon (IFN-γ) or B cells that secreted IgG and/or IgM in
response to an antigenic stimulation, whereas ICS determines the frequency of CD4+ and CD8+ T cells
secreting cytokines such as IFN-γ, interleukin (IL)-2 and tumor necrosis factor (TNF)-α.
Additional experiments may be performed to further phenotypically and functionally characterize PBMCs
by flow cytometry or other methods including but not limited to CyTOF, to evaluate innate and adaptive
immune responses. Leftover PBMC samples may be used at the sponsor's discretion for additional
exploratory research related to DENV infection or JNJ-64281802 (safety/antiviral activity).
VIRAL GENOME SEQUENCING
Viral genome sequencing analysis will be performed by sequencing the NS4B gene and other regions of
the DENV genome (if warranted) to characterize emerging DENV variants associated with resistance to


JNJ-64281802  
Clinical Protocol 64281802DNG2003
Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
16
Status: Approved,  Date:  06 June 2022
JNJ-64281802.
Sequencing of the DENV genome will be performed to monitor DENV variants at selected timepoints at
the discretion of the sponsor’s virologist.
Samples may be used by the sponsor for additional assessments analyzing the serologic and virologic
characteristics of DENV infection and antiviral activity and safety of JNJ-64281802.
PHARMACOGENOMIC (DNA) EVALUATIONS
Human Leucocyte Antigen Typing and Pharmacogenomic Assessments
One blood sample for human leucocyte antigen (HLA) typing and for pharmacogenomics (DNA) research
will be taken, preferably at baseline (ie, before first dose of study intervention). This sample can be used to
determine the HLA type of the participant. In addition, this sample can be used to investigate the potential
association of genetic factors with PK, antiviral activity or safety of JNJ-64281802 or the DENV infection.
These analyses may be conducted under the supervision of the sponsor and may be reported separately from
the main study report. If necessary, the sample may be collected at a later time point without constituting a
protocol deviation.
SAFETY EVALUATIONS
Safety and tolerability will be evaluated throughout the study from signing of the ICF onwards until the last
study-related activity or until the participant has been deemed lost to follow-up after demonstration of due
diligence of follow-up efforts.
Any clinically relevant changes occurring during the study must be recorded on the Adverse Event Section
of the eCRF and in the source documentation.
Any clinically significant abnormalities persisting at the end of the study/early withdrawal will be followed
by the investigator until resolution (return to baseline) or until a clinically stable condition is reached (to be
agreed upon with the sponsor) or until the participant has been deemed lost to follow-up after demonstration
of due diligence of follow-up efforts.
All adverse events and special reporting situations, whether serious or non-serious, will be reported from
the time a signed and dated main study ICF is obtained until completion of the participant's last study-
related procedure. For participants with only a signed pre-screening (diagnostic) ICF (ie, for whom consent
was not given to enroll in the main study by signing the main ICF), no AEs will be reported.
The study will include evaluations of AEs, Clinical laboratory tests (including prothrombin time [PT],
international normalized ratio [INR], and activated partial thromboplastin time [APTT] as measures of
effects on blood coagulation), ECGs, vital signs and physical examination.
Additionally, dengue signs and symptoms will be monitored throughout the study.
STATISTICAL METHODS
The primary analysis will be performed when all participants reached Day 28 or discontinued earlier. The
final analysis will be performed when all participants completed the study or discontinued earlier.
Sample Size Determination:
The study will recruit in total 150 participants, with the primary objective of investigating the antiviral
activity of JNJ-64281802 versus placebo based on DENV RNA in primary DENV infection and with a
secondary objective to describe the safety and tolerability of JNJ-64281802 in participants with DENV
infection The sample size can be revised after an interim analysis on the proportion of primary versus


JNJ-64281802  
Clinical Protocol 64281802DNG2003
Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
17
Status: Approved,  Date:  06 June 2022
secondary DENV infections.
For the objective of antiviral activity in participants with a primary DENV infection, the hypothesis is that
the intervention effect is superior to placebo as measured on the DENV RNA log10 viral load curve from
baseline until Day 5.
To assess sample size requirements for this hypothesis, data of 47 DENV RNA curves were estimated
similar to the DENV RNA curves graphically presented in the balapiravir trial. All curves were considered
as balapiravir did not have an effect on the viral load. A limit of detection of 2.3 log copies/mL was assumed.
Although the majority of the population included in the balapiravir trial suffered from a secondary infection,
these estimated DENV RNA curves were considered representative for a primary infected dengue
population. As the clearance of DENV RNA occurs earlier and faster in participants with secondary dengue,
this is a conservative assumption.
The 47 estimated DENV RNA curves were used to calculate the means, standard deviations, and
correlations of the log10 viral loads over time. These calculated values were thereafter used to simulate
10,000 trials, each with a sample size of 80 participants. A treatment effect of 0.30 log10 copies/mL per day
DENV RNA clearance on top of placebo, or two-fold reduction of the viral load was applied. Based on
these 10,000 simulated trials and using a general linear model with treatment regimen as fixed factor and
baseline log10 viral load as a covariate, a sample size of 80 participants (40 per group) was estimated to
provide a power of at least 80% at the one-sided 5% significance level to detect an intervention effect of
0.30 log10 copies/day additional DENV RNA clearance when compared to placebo.
The specificity of the DENV NS1 testing at baseline is estimated to be 98% which entails that 2% of
participants that will be enrolled will not be evaluable for efficacy. Based on literature, it is estimated that
approximately 60% of the total population will have a primary infection. Furthermore, it is anticipated that
approximately 4% of the enrolled participants drop-out for other reasons. The study will therefore need to
recruit a total of 150 participants in order to achieve a sample of 84 participants to achieve >80% power on
the primary hypothesis.
For the objective of safety assessment, the probability was calculated to observe an (S)AE that has a true
incidence of 1% which would be 53% with a total sample size of 75 participants on active treatment; the
probability to observe an (S)AE with a true incidence of 0.1%, 0.5% and 0.8% is 7%, 31% and 45%,
respectively.
Antiviral Activity Analysis
Primary Endpoint: The difference in area under the log10-transformed DENV RNA viral load curves from
immediately prior to first dose (baseline) until Day 5 for JNJ-64281802 versus placebo dosing will be
derived from a mixed model with treatment regimen and the stratification factors as fixed factors and
baseline log10 viral load as a covariate, calculating least square mean differences, including the 90% 2-sided
confidence intervals in the intent-to-treat infected (ITT-i)population with a primary dengue infection based
on IgG profile.
Secondary and Exploratory Endpoints: Descriptive statistics and mean (and standard error) graphs will be
shown for the log10 DENV RNA and viremia actual values and changes from baseline over time in
participants with primary DENV infection.
In participants with primary DENV infection, the proportion of participants within the DENV RNA and
viremia categories (≥lower limit of quantification [LLOQ], <LLOQ target detected, and <limit of detection
[LOD] target not detected) will be shown in a frequency tabulation per analysis time point.
Time to undetectable DENV RNA/viremia will be analysed using Kaplan-Meier estimates analysis. A
summary table including number of participants with primary DENV infection included in the analysis,
number of participants censored, 25th  and 75th  percentiles and median time-to event, with 95% confidence


JNJ-64281802  
Clinical Protocol 64281802DNG2003
Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
18
Status: Approved,  Date:  06 June 2022
intervals based on log-log transformation method, will be presented. The data will be presented graphically
using the Kaplan-Meier estimate of the survival function by treatment.
Descriptive statistics will also be used to describe the IgM and IgG response. The proportion of participants
with antibody positivity and the titer and timing of the antibody response will be determined. Descriptive
statistics will include sample size, mean, standard deviation, coefficient of variation, geometric mean,
median, minimum, and maximum.
Safety Analysis
Safety data will be presented descriptively. No statistical testing of safety data is planned.
Immune Analysis
Humoral Immune Analysis: Descriptive statistics will be used to describe the neutralizing antibody
response. The proportion of participants with antibody positivity, including neutralizing antibodies for all
4 DENV serotypes, and the titer and timing of the antibody response will be determined. Descriptive
statistics will include sample size, mean, SD, CV, geometric mean, median, minimum, and maximum.
Cellular Immune Analyses: Descriptive statistics will be used to describe the magnitude of the IFN-γ T cell
response or the CD4+ and CD8+ T cell responses (expressing at least 1 cytokine such as IL-2, TNF-α or
IFN-γ specific to any antigen) or B cell response as defined by ELISpot and/or ICS, respectively. Changes
from baseline (if present) will also be tabulated for PBMCs during the dosing and on-site follow-up phase
(Day 28, optional). The proportion of participants with positive responses based on the magnitude of the
IFN-γ T cell response or the CD4+ or CD8+ T cells expressing at least 1 of the cytokines amongst IL-2,
TNF-α or IFN-γ for 1 of the antigens as defined by ELISpot and/or ICS, respectively, or B cells that secrete
IgG and/or IgM will be determined.
Pharmacokinetic Analysis
All participants having received at least one dose of study intervention and having at least one PK parameter
value will be included in the PK analysis. All participants having received at least one dose of study
intervention and having at least one plasma concentration data value after administration will be included
in the descriptive statistics.
Descriptive statistics will be calculated for the plasma concentrations of JNJ-64281802 and for the derived
PK parameters, as applicable. Statistics include sample size (n), mean, SD, CV, geometric mean, median,
minimum, and maximum.
For each participant, plasma concentration-time data will be graphically presented. Similarly, graphs of the
mean plasma concentration-time profiles and overlay graphs with combined individual plasma
concentration-time profiles will be produced. Pharmacokinetic parameters will be subjected to an
exploratory graphical analysis including various transformations in order to get a general overview.
Special attention will be paid to the plasma concentrations and PK parameters of those participants who
have discontinued the study for an AE, or who experienced an AE of at least grade 3, or a serious adverse
event (SAE).
Relationships of PK parameters for JNJ-64281802 as applicable, with selected antiviral activity and with
selected safety endpoints may be evaluated, applying graphical tools and, if feasible, statistical models.
Biomarker Analysis
Statistical approaches to explore correlations between clinical outcome and blood biomarkers vary and
depend on the different data types of the applied technology platforms, as well as on the extent of observed
differences between participants. Analyses will be conducted at the sponsor’s discretion, will always be
under the sponsor's supervision, and results will be presented in the clinical study report or a separate report.


JNJ-64281802  
Clinical Protocol 64281802DNG2003
Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
19
Status: Approved,  Date:  06 June 2022
Viral Genome Sequence Analysis
The results of DENV viral genome sequencing will be evaluated by the sponsor virologist. Relevant
changes in the DENV genome will be tabulated and described for participants with detectable DENV RNA
during the study period.
Pharmacogenomic Analysis
Human Leukocyte Antigen Typing and Pharmacogenomic Analysis: The statistical approach for analysing
the exploratory host DNA research may depend on the objective of the analyses (antiviral activity, safety,
and PK) and possibly relevant genes at the time of analysis. Analyses will be conducted at the sponsor’s
discretion, will always be under the sponsor's supervision, and results will be presented in the clinical study
report or a separate report.
INTERIM ANALYSIS:
An interim analysis will be performed when at least 50 participants with a primary dengue infection reached
Day 28 or discontinued earlier to check for futility. Conditional power values will be calculated using the
observed data and assuming that in the remainder of the trial the effect size used for the sample size
calculation will be present. The conditional power provides quantification of the likelihood that the study
intervention will ultimately be successful, ie, the probability of claiming a study intervention effect at the
completion of the study based on the available interim data. A futility stopping boundary of 25% for the
conditional power will be used. This is considered a conservative boundary also reflecting that in this early
stage of development it may be best to complete the study to have a larger database to draw conclusions
from. In case the probability of a successful trial is lower than the futility boundary, the DRC and study
team can take the decision to stop for futility after evaluation of all available data. Assuming the outcome
for the primary endpoint as used for the sample size calculations was true, with a treatment effect of
0.30 log10 copies/mL per day DENV RNA clearance on top of placebo, the chance of reaching the futility
stopping boundary at the time of the IA is at most 5%. Otherwise, if there is no treatment effect at all, the
chance of reaching the futility stopping boundary is at least 60%. The proportion of primary infections will
be assessed as well during this interim analysis. If the proportion is lower than expected 60%, the sample
size may be increased.




JNJ-64281802  
Clinical Protocol 64281802DNG2003
Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
21
Status: Approved,  Date:  06 June 2022
1.3. 
Schedule of Activities
Phase 
Pre- 
screeni 
ng 
(option  
al)
Scree
ning/
Baseli
nea
Double-blind Treatment b 
Follow-Up b 
Early
Exit
Visit b
During inpatient stay (or ambulatory visitsy) 
Extended stay 
at inpatient 
facility (for
participants
with dengue
warning
symptoms)
During on
Site Visits
Remotely
(every 2
Day  
0 a 
1 a 
2 
3y 
4y 
5y 
6y 
7 
8 
9 
14 21 
28
Month 
6
Screening/Administrative
Pre screening ICFc 
X
Informed consent 
form (ICF) d
X
COVID 19 testinge 
X
Demographics 
X
Medical history and 
concomitant diseases
X
Height 
X
Body Mass Index 
(BMI)
X
Inclusion/exclusion 
criteria f
X
Estimated Creatinine 
Clearance g
X
Prestudy therapy  
X
Serum pregnancy 
testh
X
CCI
CCI


JNJ-64281802  
Clinical Protocol 64281802DNG2003
Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
22
Status: Approved,  Date:  06 June 2022
Phase 
Pre-
screeni
ng
(option
al)
Scree
ning/
Baseli
nea
Double-blind Treatment b 
Follow-Up b 
Early
Exit
Visit b
During inpatient stay (or ambulatory visitsy) 
Extended stay 
at inpatient 
facility (for
participants
with dengue
warning
symptoms)
During on
Site Visits
Remotely
(every 2
Day  
0 a 
1 a 
2 
3y 
4y 
5y 
6y 
7 
8 
9 
14 21 
28
Month 
6
NS1 rapid testi 
X 
X
Study Intervention Administration
Randomization 

Safety Assessments
ECG 
X 
X 
X 
X 
X 
X 
X 
X
Physical 
examinationl 
X 
X l 
X l 
X 
Xl 
X l 
X 
X l 
X l 
X l 
X 
X 
X 
X
Clinical status 

Vital signs m 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
Body temperaturen 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
CCI
CCI
CCI


JNJ-64281802  
Clinical Protocol 64281802DNG2003
Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
23
Status: Approved,  Date:  06 June 2022
Phase 
Pre-
screeni
ng
(option
al)
Scree
ning/
Baseli
nea
Double-blind Treatment b 
Follow-Up b 
Early
Exit
Visit b
During inpatient stay (or ambulatory visitsy) 
Extended stay 
at inpatient 
facility (for
participants
with dengue
warning
symptoms)
During on
Site Visits
Remotely
(every 2
Day  
0 a 
1 a 
2 
3y 
4y 
5y 
6y 
7 
8 
9 
14 21 
28
Month 
6
DENV infection- 
associated AEso
~ Continuously ~  
X
DENV infection 
signs and symptoms
checklist
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
Clinical Laboratory Tests
Hematologyp and 
coagulationq
X 
X 
X 
X 
X 
Xv 
X 
X 
X 
X 
X 
X 
X
Chemistry  
X 
X 
X 
X 
X 
Xv 
X 
X 
X 
X 
X 
X 
X
Pharmacokinetics
Blood sample 
collection for
pharmacokinetics
(
formulation)
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X
Blood sample 
collection for
pharmacokinetics
(
formulation)
 
X 
X 
 
 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X
CCI
CCI
CCI


JNJ-64281802  
Clinical Protocol 64281802DNG2003
Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
24
Status: Approved,  Date:  06 June 2022
Phase 
Pre-
screeni
ng
(option
al)
Scree
ning/
Baseli
nea
Double-blind Treatment b 
Follow-Up b 
Early
Exit
Visit b
During inpatient stay (or ambulatory visitsy) 
Extended stay 
at inpatient 
facility (for
participants
with dengue
warning
symptoms)
During on
Site Visits
Remotely
(every 2
Day  
0 a 
1 a 
2 
3y 
4y 
5y 
6y 
7 
8 
9 
14 21 
28
Month 
6
Blood sample 
collection for plasma
protein bindingr
 
X 
X
Blood sample 
collection for alpha 1
acid glycoproteinr
 
X 
X
Antiviral activity Assessments
Blood sample 
collection for viral
load determination
(DENV RNA,
infectious virus and
NS1)
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
Immune/Viral sequencing Assessments
Blood sample 
collection for
humoral immunity
(IgG, IgM and nAb)
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
CCI


JNJ-64281802  
Clinical Protocol 64281802DNG2003
Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
25
Status: Approved,  Date:  06 June 2022
Phase 
Pre-
screeni
ng
(option
al)
Scree
ning/
Baseli
nea
Double-blind Treatment b 
Follow-Up b 
Early
Exit
Visit b
During inpatient stay (or ambulatory visitsy) 
Extended stay 
at inpatient 
facility (for
participants
with dengue
warning
symptoms)
During on
Site Visits
Remotely
(every 2
Day  
0 a 
1 a 
2 
3y 
4y 
5y 
6y 
7 
8 
9 
14 21 
28
Month 
6
Blood sample 
collection for cellular
immunity (PBMC)s
 
Xx 
X
Blood sample 
collection for viral
sequencing
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
Biomarker Assessments
Blood sample 
collection for host
RNA
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
Blood sample 
collection for serum
proteins
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
HLA Typing and Pharmacogenomics (DNA)
Blood sample 
collectiont

CCI


JNJ-64281802  
Clinical Protocol 64281802DNG2003
Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
26
Status: Approved,  Date:  06 June 2022
Phase 
Pre-
screeni
ng
(option
al)
Scree
ning/
Baseli
nea
Double-blind Treatment b 
Follow-Up b 
Early
Exit
Visit b
During inpatient stay (or ambulatory visitsy) 
Extended stay 
at inpatient 
facility (for
participants
with dengue
warning
symptoms)
During on
Site Visits
Remotely
(every 2
Day  
0 a 
1 a 
2 
3y 
4y 
5y 
6y 
7 
8 
9 
14 21 
28
Month 
6
Ongoing Participant Review
Concomitant therapy 
(including
analgesics)
~ Continuously ~ 
X
Adverse events 
~ Continuously ~ 
X
Record food and 
fluid administration
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
 predose (within 30 minutes predose), d days, DHS dengue hemorrhagic fever, DSS dengue shock syndrome, ECG electrocardiogram, FSH follicle stimulating hormone, HLA human leukocyte antigen,
h hours, ICF informed consent form, NS1 non structural 1 protein, PK pharmacokinetic, m minutes, qRT quantitative reverse transcription.
Footnotes:
a. 
Screening/baseline assessments start at signing of the ICF. All screening/baseline procedures should take place prior to intake of the first dose of study intervention
 The day of intake of the first dose of study intervention will be considered Day 1.
b. 
Participants who prematurely discontinue study intervention for any reason (except withdrawal of consent) will be asked to continue with their remaining study visits
and assessment schedule. Participants who withdraw consent during the treatment or follow-up phase will be offered an optional Early Exit Visit. The optional Early
Exit Visit will occur the day of consent withdrawal or as soon as possible thereafter.
c. 
Participants may initially sign a pre-screening ICF to allow for ambulatory NS1 rapid testing performed by a member of the mobile clinical team as a part of the
recruitment strategy.
d. 
Must be signed before first study-related activity.
e. 
COVID-19 testing can be performed at the discretion of the investigator, depending on the epidemiological situation.
CCI
CCI


JNJ-64281802  
Clinical Protocol 64281802DNG2003
Amendment 6
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f. 
Investigators should ensure that all study enrollment criteria have been met at screening.
g. 
Calculated by the Modification of Diet in Renal Disease (MDRD) formula.
h. 
Only for women of childbearing potential. Additional serum pregnancy tests may be performed, as determined necessary by the investigator or required by local
regulation, to establish the absence of pregnancy at any time during the participation in the study.
i. 
An NS1 rapid test can be performed ambulatory by a mobile clinical team member during pre-screening. Any participant who does not have a documented proof of
a positive NS1 test performed by a doctor or by a mobile clinical team member prior to presenting himself/herself at the study site, will undergo an NS1 rapid test at
screening.
j. 
k. 
l. 
A complete physical examination will be done at screening and at Day 28. At Days 3, 6, 14, and 21, a brief physical examination will be performed. At Days 1, 2, 4,
5, 7, 8, and 9, a physical examination may be performed at the investigator’s discretion.
m. Blood pressure, pulse rate, oxygen saturation (spO2) & input-output (I/O) will be measured every 6 hours during inpatient stay and once daily in case of ambulatory
visits. Systolic and diastolic blood pressure and pulse/heart rate will be measured supine after at least 5 minutes rest. I/O ratio and spO2 will not be measured at
screening.
n. 
Two-hourly temperature monitoring during inpatient stay, starting at 6 AM in the morning (temperature will not be measured between midnight and 6 AM the next
day. In case of ambulatory visits, temperature monitoring will take place once daily.
o. 
DENV infection associated AEs will be collected as solicited AEs. DENV infection signs and symptoms checklist may be compiled by any delegated study team
member, and it may be used to assist in the collection of DENV infection associated AEs.
p. 
Any participant who has a hematocrit rise with values >20% of the baseline at any timepoint will require full blood count (FBC) monitoring every 4 hours (at the
discretion of the investigator).
q. 
Prothrombin time (PT), international normalized ratio (INR), and activated partial thromboplastin time (APTT) will be used to determine the effect of JNJ 64281802
treatment on blood coagulation during the treatment and on-site follow-up periods.
r. 
Plasma protein binding and alfa-1-acid glycoprotein will be determined in a subset of 20 participants.
s. 
Peripheral blood mononuclear cell (PBMC) samples may be analyzed in a subset of participants to assess DENV-specific T and B cell immune responses.
t. 
The pharmacogenomic (DNA) sample should be collected at the specified time point, however, if necessary, it may be collected at a later time point without
constituting a protocol deviation.
u. 
After the last on-site visit at Day 28, participants will be followed up remotely (eg, phone call, text message) until 6 months after the first dosing day. During this
every-2-weeks contact, they will be inquired for any dengue-related signs and symptoms.
v. 
At Day 6, safety laboratory testing can be performed at the discretion of the investigator.
w. 
x. 
At Day 28, the volume of blood samples for PBMC isolation can be reduced from 30 mL to 10 mL, subject to the local regulations and investigator’s request.
y. 
Optional ambulatory visits on Days 3, 4, 5, and 6 at the investigator’s discretion.
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2. 
INTRODUCTION
Dengue is caused by any of the four antigenically distinct DENV serotypes (DENV -1, -2, -3,
and -4), which belong to the genus Flavivirus in the family of the Flaviviridae. The DENV is a
human pathogen transmitted through the bite of an infected female mosquito of the genus Aedes,
mainly of the species Aedes aegypti and to a lesser extent Aedes albopictus.0 After near-extinction
in the early 1970s, dengue has spread to more than 125 countries, and has again become endemic
in the United States of America and its territories.0 About half of the global population is currently
at risk of becoming infected with DENV, ranking dengue among the top 10 threats to global health
in 2019.0,0,0,0
Dengue is widespread throughout the tropics, with local variations in risk influenced by rainfall,
temperature, and rapid urbanization. The exponential growth of the number of dengue cases
reflects the global spread of the mosquito vectors, which is driven by climate changes and, more
importantly, human population growth, urbanization, and globalization. It is anticipated that
epidemic dengue will continue to increase in magnitude and frequency, as the main drivers of
DENV spread are projected to intensify.0 Major dengue outbreaks in many countries have
burdened health care systems, especially in resource-limited countries. Consequently, dengue is
considered a global health concern.
The actual numbers of dengue cases are underreported, and many cases are misclassified as other
febrile illnesses such as malaria. It is estimated that there are 390 million DENV infections globally
per year of which 96 million infections manifest clinically (with any severity of the disease).0 On
average, each year about 500,000 dengue cases require hospitalization due to severe and
life-threatening disease and up to 25,000 patients die due to dengue.0 There is, therefore, a need to
develop an anti-DENV molecule for the prevention and treatment of dengue.
During a primary DENV infection, 75% of the individuals remain asymptomatic.0 Those that show
clinical symptoms, mainly develop an acute, self-limiting febrile illness. The first clinical
symptoms occur 3 to 8 days after a bite by a DENV infected and viremic mosquito. Resolution of
symptoms usually occurs within 4 to 7 days due to a robust innate and adaptive immune response.0
A smaller percentage of DENV infections result in severe dengue outcomes such as dengue
hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Secondary DENV infections or
infections with particularly virulent viral strains are thought to be associated with an increased risk
for severe dengue.0
During classical dengue fever, an abrupt onset of fever is accompanied by a wide range of potential
symptoms, ie, myalgia, arthralgia, headache, and rash; with retro-orbital pain and lower back pain
being prototypical symptoms. Also vomiting, nausea, and anorexia are common.0 The critical
phase is characterized by an increased propensity for capillary leakage and hemorrhage, typically
manifested by petechiae, hematuria, and gastrointestinal hemorrhage.0,0 Without early diagnosis
and proper management, some patients experience shock from blood loss or plasma leakage, which
can result in a sudden deterioration of the patient’s condition. 0


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An issue of particular importance to dengue is a process called antibody-dependent enhancement.
Briefly, when a person is infected for the first time with a DENV serotype (eg, serotype 1), a
serotype-specific antibody response is generated. These antibodies bind to the dengue serotype 1
virus specifically and cover the virus completely. As a result, these antibody-covered virus
complexes are taken up by macrophages. Consequently, these complexes undergo endocytosis and
the dengue virus is destroyed. However, the risk of developing DHF/DSS is especially increased
after secondary dengue infection with a different serotype than that of the primary infection. The
non-neutralizing, cross-reactive antibodies generated during the primary infection (in this example
against DENV-1), partially interact with and cover the virus of the different serotypes.
Consequently, these partially antibody coated virus complexes are now  able to escape the
endocytic pathway, enabling them to replicate in these immune cells.0 Overall, this leads to a
higher number of infected target cells, a higher viral load, and a higher probability to develop
DHF/DSS. Antibody-dependent enhancement reinforces the critical need to develop a small
molecule which has antiviral activity against all four serotypes of DENV.
JNJ-64281802 is a novel anti-dengue small-molecule targeting DENV non-structural protein
(NS)4B. It has shown potent antiviral activity across all 4 DENV serotypes in preclinical studies.0
A Phase 1 first-in-human study 64281802DNG1001 (further referred to as DNG1001) to assess
the safety, tolerability, and pharmacokinetics (PK) of increasing single and multiple oral doses of
JNJ-64281802 in healthy adult participants has been performed. JNJ-64281802 is currently being
evaluated for the prevention and treatment of dengue infection.
This is a Phase 2a, multicenter study to be conducted in Singapore and Vietnam. The aim of the
study is to examine the antiviral activity, safety and tolerability, and PK of JNJ-64281802,
compared to placebo, and to evaluate the improvement in clinical signs and symptoms with the
administration of JNJ-64281802 for the treatment of dengue. For the most comprehensive
nonclinical and clinical information regarding JNJ-64281802, refer to the latest version of the
Investigator's Brochure (IB)and Addenda for JNJ-64281802.0,0
The term “study intervention” throughout the protocol, refers to JNJ-64281802.
The term "sponsor" used throughout this document refers to the entities listed in the Contact
Information page(s), which will be provided as a separate document.
The term "participant" throughout the protocol refers to the common term "subject".
2.1. 
Study Rationale
Currently, there is no dengue-specific treatment available and thus, clinical treatment is principally
supportive in nature.
In December 2015, the first vaccine against DENV was licensed in Mexico. The chimeric yellow
fever DENV tetravalent dengue vaccine (CYD-TDV; Dengvaxia®) is a live attenuated vaccine
developed by Sanofi Pasteur. By November 2016, the vaccine had been approved for use in
18 countries including Brazil, Mexico, El Salvador, Costa Rica, and the Philippines. In late 2017,
the vaccine was withdrawn again from the Philippine market because of safety concerns, which


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led to revocation of the vaccine’s licensure in the Philippines in February 2019. In May 2019, the
vaccine was approved in the USA for the prevention of dengue disease caused by all DENV
serotypes (DENV-1, -2, -3, and -4) in individuals, 9 through 16 years of age, who have laboratory
confirmed previous dengue infection and who live in endemic areas. The widespread use of the
vaccine, however, is not foreseen per the World Health Organization (WHO) working group for
immunization, as a number of factors need further consideration. The Strategic Advisory Group
of Experts recommended countries to consider the introduction of Dengvaxia® only in geographic
settings (national or subnational) with high dengue endemicity. According to the National
Environment Agency, Singapore had reported a total of 14,328 cases of dengue fever as of
November 2019, representing the highest number of dengue cases since the year 2016. In addition,
new cases continue to be reported every week, with 20,600 cases being reported by July 27 of
20200. Dengue virus infection is endemic in Vietnam with an estimated burden of about 2 million
yearly infections,0,0 with high rates of secondary infections with the DENV1 and DENV2
serotypes0. However, the official average number reported by the Ministry of Health is
approximately 95,000 cases per year over the period 2002 to 2020. This under-reporting may be
due to 2 main factors: (i) dengue surveillance in Vietnam is mostly passive, relying on clinical
cases reported by patients seeking healthcare0 and (ii) up to 80% of the cases may be asymptomatic
or minimally symptomatic and will likely not seek healthcare0. With the limited prophylactic
options based on one approved vaccine and the fact that there is no dengue-specific treatment
available, the present study will look into the antiviral activity of JNJ-64281802 in participants
with primary DENV infection.
Considering the higher DENV RNA viral load values and the lower variability between these
values in patients with a primary DENV infection when compared to patients with a secondary
DENV infection, the primary objective of the current study is restricted to the evaluation of the
antiviral activity of JNJ-64281802 in participants with a primary DENV infection.
2.2. 
Background
Nonclinical Studies
In vitro Pharmacology
The anti-DENV-2 activity (50% effective concentration [EC50]) of JNJ-64281802 was tested in
vitro in Vero cells infected with DENV-2/16681, which was labeled with enhanced green
fluorescent protein (eGFP). JNJ-64281802 exhibited a median 50% effective concentration
(EC50) of 0.05 nM with a selectivity index of 48,000 against dengue virus (DENV)
2/16681/enhanced green fluorescent protein (eGFP) in Vero cells. In the presence of 50% human
serum, the antiviral activity of JNJ-64281802 against DENV 2/16681/eGFP decreased 28-fold.
The antiviral activity of JNJ-64281802 was tested using reverse transcription quantitative
polymerase chain reaction (RT-PCR) against a panel of DENV strains belonging to the 4 major
serotypes, including lab-adapted strains and clinical isolates obtained from several sources.
JNJ-64281802 exhibited potent antiviral activity against all 4 DENV serotypes (lab-adapted
strains and clinical isolates) with subnanomolar or low nanomolar median EC50 values against
most strains, and a high specificity towards DENV.


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In vivo Pharmacology
In DENV-2 inoculated mice treated with JNJ-64281802, dose-dependent viral ribonucleic acid
(RNA) reductions in serum and tissues (spleen, kidney, and liver) compared with vehicle treated
mice were observed and were linked with a significant effect on survival.
In a non-human primate model, no viral RNA was detected for the highest doses of JNJ-64281802
(0.93 and 3 mg/kg/dose) against DENV-2/16681 and for the dose of 6 mg/kg against
DENV-1/45AZ5 given prophylactically, indicating that JNJ-64281802 is highly effective in
preventing infection after DENV challenge in this rhesus monkey model.
Safety Pharmacology
Cardiovascular function was not affected in dogs up to 600 mg/kg (maximum plasma
concentration [Cmax] 7,340 ng/mL). In rats, respiratory function was not affected up to
1,000 mg/kg and neurofunctional testing up to 1,000 mg/kg (Cmax 9,870 ng/mL) did not lead to
major effects.
Pharmacokinetics and Metabolism
In vitro Permeability: JNJ-64281802 demonstrated low in vitro permeability in LLC-PK1 cells
stably transfected with multidrug resistance protein 1 (MDR1) and is likely a P-glycoprotein
substrate.
Absorption: JNJ-64281802 was generally slowly absorbed with moderate oral bioavailability
across species (absolute bioavailability: 25%-66%). In fasted male dogs, the highest JNJ-64281802
exposure values (Cmax and area under the plasma concentration-time curve from 0 hours to infinity
[AUC0-∞]) were obtained with a 
 (Gelure 44/14) (1.2-fold)
compared with a 100% PEG400 
. After repeated oral dosing of JNJ-64281802 in rats and
dogs, exposure increased less than dose proportionally, and was higher than after single dosing.
Distribution: In vitro plasma protein binding of JNJ-64281802 was high across nonclinical species
and humans, with an unbound percentage ranging from 0.00472% in mice to 0.0339% in guinea
pigs, and 0.00621% in humans. In rats, distribution was wide throughout the body with highest
levels in liver.
Metabolism: Predominant routes of metabolism were through demethylation and oxidation via
cytochrome P450 (CYP)3A4 and possibly CYP2C19, subsequently glucuronidation as well as
direct N-glucuronidation via uridine diphosphate-glucuronosyltransferase (UGT)1A9 and possibly
UGT1A4, UGT1A8, and UGT1A10. There was no indication for reactive metabolite formation.
Elimination: In rats, elimination of JNJ-64281802 was almost completely via metabolism with
low/negligible excretion in bile (approximately 3%) and urine (<0.001%).
Pharmacokinetic drug-interaction: In vitro, JNJ-64281802 did not induce CYP1A2 at 1 and
10 µM, nor CYP3A4 at 1 µM. At 10 µM, JNJ-64281802 was shown to be a CYP3A4 inducer.
JNJ-64281802 showed weak inhibition potential towards CYP1A2 and CYP2D6 (50% inhibitory
concentration [IC50] >30 µM), and inhibition of CYP2C9 (IC50 3.7 µM), CYP2C8
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(IC50 7.4 µM), and CYP2C19 (IC50 10.3 µM). Due to metabolic activation of CYP3A4/5-
mediated metabolism of midazolam and CYP3A4-mediated metabolism of testosterone, no results
were available for these CYP/probe substrate combinations, and time-dependent inhibition
potential could not be assessed.
Toxicology
In rats, the NOAEL after 31 days was 1,000 mg/kg/day (area under the plasma concentration-time
curve from 0 to 24 hours [AUC0 24h] 524,000 and 706,000 ng.h/mL in male and female rats,
respectively). Minor reduction in food consumption and minor, nonadverse changes in clinical
pathology parameters were observed. Findings in liver (hypertrophy), lungs (foci, macrophage
aggregates), thyroid gland (follicular cell hypertrophy), mammary gland (atrophy), adrenal gland
(hypertrophy), and thymus (lymphocytic apoptosis) were fully reversible. There were no apparent
functional changes to these organs.
In dogs, the NOAEL after 31 days was 200 mg/kg/day (AUC0 24h 129,000 and 177,000 ng.h/mL
in male and female dogs, respectively). Minimal effects on body weight gain (female dogs) and
on some serum parameters were observed. Dosing at 400 mg/kg twice daily (800 mg/kg/day) led
to individual body weight loss and high liver enzyme increases. Good reversibility was observed.
JNJ-64281802 was not considered genotoxic or phototoxic, and there were no test article-related
effects on embryo-fetal development in pregnant rats and rabbits. JNJ-64281802 is considered
unlikely to be a primary mitochondrial toxicant under the conditions of an in vitro mitochondrial
toxicity assay.
Clinical Studies
Up to the cutoff date of 10 September 2021, a total of 223 healthy adult participants received JNJ-
64281802 and 19 healthy adult participants received placebo.
One Phase 1 study (64281802DNG1001) has been  completed. Four Phase 1 studies
(64281802DNG1004, 64281802DNG1005, 64281802DNG1006, and 64281802DNG1008) are
currently ongoing. Two Phase 2 studies (64281802DNG2001 and 64281802DNG2002) are
currently ongoing.
64281802DNG1001
The Phase 1 study (64281802DNG1001) has been completed: a total of 122 healthy adult
participants received 
either 
JNJ-64281802 (103 participants) 
or matching 
placebo
(19 participants).
The 
Phase 
1, 
double-blind, 
randomized, 
placebo-controlled, 
first-in-human 
study
64281802DNG1001 (EudraCT 
number: 
2018-002201-62), 
further 
referred 
to 
as
DNG1001examined the safety, tolerability, and PK of increasing single and multiple oral doses of
JNJ-64281802 in healthy adult participants. An open-label, randomized, crossover, relative oral
bioavailability part was included to study the PK and safety following 
 formulation
concepts compared with
, and to study the food effect on JNJ-64281802.
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Safety
JNJ-64281802 was generally safe and well tolerated. No safety concerns were identified at single
doses up to 1,200 mg and at multiple doses up to 560 mg once daily for 10 days or 400 mg once
daily for 31 days. Two Grade 2 events of rash occurred in the multiple ascending dose part that
were considered very likely related to JNJ-64281802 by the investigator. One Grade 2 rash
occurred in a participant in the 10-day 560 mg JNJ-64281802 group on the last day of dosing
(Day 10) and resolved after 35 days. The other Grade 2 rash occurred in a participant in the 31-day
400 mg JNJ-64281802 group on dosing Day 13 and resolved after 47 days. This participant
completed the 31-day dosing period as planned.
Exposure-response analysis based on time-matched QT interval corrected for heart rate (QTc)
Holter data supports that within the investigated concentration range of study 64281802DNG1001.
There is no evidence of an effect of JNJ-64281802 on cardiac repolarization.
Human Pharmacokinetics
Following single-dose administration with JNJ-64281802 (50-1,200 mg), formulated as 
, the exposure increased dose proportionally from 50 to 150 mg and less than dose
proportionally from 240 to 1,200 mg, while following multiple dosing the exposure of
JNJ-64281802 increased closer to dose proportionally over the investigated dose range
(50-560 mg) compared with single dosing.
The median time to maximum concentration (tmax) ranged from 7 to 10 hours, and the t1/2 was
6.3 to 9.2 days following single and multiple dosing. The accumulation factor varied from 4.3 to
7.3 following 10 days of daily dosing and was 14.6 following 31 days of daily dosing.
The intersubject variability in exposure, expressed as percentage coefficient of variation (CV), was
8.6% to 58%.
A single dose of the active pharmaceutical ingredient blend in 
 (200 mg, fasted)
compared with a single dose of
 (200 mg, fasted) showed a geometric mean ratio (90%
confidence interval [CI]) between 20.6% (16.2%-26.3%) and 22.1% (17.2%-28.5%). A single
dose of the
 (2x100 mg, fasted) compared with a single dose of
(200 mg, fasted) showed a geometric mean ratio (90% CI) between 81.6% (65.2%-102.1%) and
85.9% (67.1%-109.9%). An approximately 3-fold increase in exposure was observed when the
active pharmaceutical ingredient blend in 
 was administered with a high-fat,
high-calorie breakfast compared with fasted conditions, without a relevant difference in tmax or
apparent t1/2.
The food effect following administration of 
 was not investigated in the oral
bioavailability part of study DNG1001. 
64281802DNG1006
In Part 1 of study 64281802DNG1006, further referred to as DNG1006, the relative oral
bioavailability of JNJ-64281802 in healthy participants was assessed when administered as
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 formulation concepts compared with
, following a single
oral dose in fasted conditions.
 When administered
with a standardized breakfast, JNJ-64281802 Cmax  was increased by 33%, 76%, and 178%
compared to fasted conditions for a single dose of 50 mg, 200 mg, and 800 mg, respectively. For
AUC∞, this increase was 12%, 69%, and 143%, respectively.
64281802DNG1005
In study 64281802DNG1005, the potential for drug-drug interactions (DDIs) was assessed when
administering a single dose of 200 mg JNJ-64281802 concomitantly with 200 mg itraconazole
once daily, a strong CYP3A4 and P-glycoprotein inhibitor. Coadministration  with itraconazole
significantly increased the plasma exposure of JNJ-64281802 over the full profile, by 1.87-fold
for AUC0 ∞ compared with single administration of JNJ-64281802 alone. A slight increase of
1.12-fold for Cmax  was also observed. The coadministration with itraconazole increased plasma
exposure (AUC504h) of JNJ-64281802 over 504 hours by 1.53-fold.
64281802DNG1004
In part 1 of study 64281802DNG1004, the potential for DDIs was assessed when administering a
single dose of a drug cocktail including caffeine, warfarin (supplemented with  vitamin K),
omeprazole, dextromethorphan, midazolam, repaglinide and rosuvastatin concomitantly with both
a single dose and/or multiple doses of JNJ-64281802. Exposure to caffeine (CYP1A2 substrate)
was increased by 12%, warfarin (CYP2C9 substrate) by 40%, omeprazole (CYP2C19 substrate)
by 36% while dextromethorphan exposure was decreased by 12%, midazolam (CYP3A4 substrate)
was increased by 59%, repaglinide (CYP2C8 substrate) by 58%, and rosuvastatin (BCRP
substrate) by 182%. This indicates that JNJ-64281802 is a moderate inhibitor of BCRP, and a weak
inhibitor of CYP3A4, CYP2C8, CYP2C9, and CYP2C19.
For the most comprehensive nonclinical and clinical information regarding JNJ-64281802, refer
to the latest version of the IB and Addenda for JNJ-64281802.0,0
Benefit-Risk Assessment
Below, the known and potential benefits and risks of JNJ-64281802 are discussed. More detailed
information about the known and expected benefits and risks of JNJ-64281802 may be found in
the IB for JNJ-64281802.
2.3.1. 
Known Benefits
The clinical benefits of JNJ-64281802 remain to be established.
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2.3.2. 
Potential Benefits
Results from this study may be useful to support the antiviral development program for
JNJ-64281802, and thereby contribute to the development of a new anti-DENV compound for
treatment of patients with dengue infection.
2.3.3. 
Known Risks
All therapies have the potential to cause adverse experiences. To date, limited clinical data with
JNJ-64281802 are available from the Phase 1 first-in-human study DNG1001 in healthy adult
participants (Section 2.2). JNJ-64281802 was generally well tolerated, and no safety concerns were
identified at single doses up to 1,200 mg and at multiple doses up to 560 mg once daily for 10 days
or 400 mg once daily for 31 days.
2.3.4. 
Potential Risks
Reproductive Risks and Pregnancy
Animal studies with JNJ-64281802 did not indicate harmful effects with respect to reproductive
toxicity. There were no test article-related effects on embryo-fetal development in pregnant rats
up to 500 mg/kg/day and in pregnant rabbits up to 180 mg/kg/day, which were the highest dose
levels tested. Excessive maternal toxicity was evident at 180 mg/kg/day in rabbits.
The effect of JNJ-64281802 on sperm, on conception, or on a fetus or nursing baby is unknown.
In addition, no drug-drug interaction studies have been performed and hence the potential effect
of JNJ-64281802 on contraceptive efficacy of hormonal contraceptives is unknown. Therefore, the
following should be adhered to:
 
Women who are pregnant, breastfeeding, or planning to become pregnant during the study or
within 90 days after last dose of study drug cannot receive study drug. A woman must be not
of childbearing potential, or of childbearing potential and practicing a highly effective,
preferably user-independent method of contraception (refer to Section 10.5, Appendix 5 for
examples) and agrees to remain on a highly effective method while receiving study drug and
until 90 days after last dose the end of relevant systemic exposure. Use of highly effective
methods of contraception should be consistent with local regulations regarding the use of
contraceptive methods for participants in clinical studies. A woman using oral contraceptives
should use an additional barrier-based contraceptive method (on top of what is required per
Inclusion Criterion 10 in Section 5.1).
 
All women of childbearing potential must have a negative highly sensitive serum (-human
chorionic gonadotropin) pregnancy test at screening. Additional serum pregnancy tests may
be performed, as determined necessary by the investigator or required by local regulation, to
establish the absence of pregnancy at any time during the study.
 
A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted
reproduction during the study and for up to 90 days after last dose of study drug.
 
A male participant must wear a condom during the study and for up to 90 days after last dose
of study drug when engaging in any activity that allows for passage of ejaculate to another


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person. Male participants should also be advised of the benefit for a female partner to use a
highly effective method of contraception as condoms may break or leak.
 
A male participant must agree not to donate sperm for the purpose of reproduction during the
study and for up to 90 days after last dose of study drug.
Potential Genotoxicity
JNJ-64281802 was not genotoxic when tested in the Ames assay and in the in vitro and in vivo
micronucleus assays.
Carcinogenicity and Impairment of Fertility
No carcinogenicity or fertility studies have been performed.
Risks From Blood Draws
Blood drawing may cause pain/tenderness, bruising, bleeding, lightheadedness, dizziness,
vasovagal response, syncopal episodes, and, rarely, infection at the site where the blood is taken.
Concomitant Vaccination
Concomitant vaccination might have an influence on both safety profile and immunogenicity of
JNJ-64281802. Likewise, JNJ-64281802 might have an influence on both safety profile and
immunogenicity of any concomitant vaccination. As a result, vaccinations are not allowed until 30
days after the last dose of study drug. Participants will be allowed to receive an authorized/licensed
COVID-19 vaccine at any time before, during, and after the study (see Section 10.9, Appendix 9:
Guidance on Study Conduct During the COVID-19 Pandemic).
Rash
In study DNG1001, 2 Grade 2 events of rash occurred in the multiple ascending dose part (N 47)
that were considered very likely related to JNJ-64281802 by the investigator. Both events were
resolved after 35 to 47 days. If in study DNG2003, a causal relationship between the events ofrash
and the study drug cannot be excluded, additional safety follow-up procedures will apply, as
described in the rash management protocol in Section 10.7, Appendix 7.
Taking into account the measures taken to minimize risk to participants ofthis study, the potential
risks identified in association with JNJ-64281802 are justified by the anticipated benefits that may
be afforded to participants with confirmed dengue fever.
3. 
OBJECTIVES AND ENDPOINTS
Objectives 
Endpoints
Primary
 
Investigate the antiviral activity of JNJ-
64281802 versus placebo in terms of
reduction of DENV RNA in primary DENV
infection
 
Area under the log10-transformed DENV RNA
viral load (log10 VL) curve from baseline until
Day 5 (AUCD1-D5 [log10VL]).


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Objectives 
Endpoints
Secondary
 
Assess the safety and tolerability of 
JNJ-64281802 in primary and secondary
DENV infection
 
AEs
 
ECGs
 
physical examinations
 
vital signs
 
clinical laboratory assessments
 
Investigate 
the 
antiviral 
activity 
of 
JNJ-64281802 versus placebo based on 
other virological endpoints in primary
DENV infection
 
Virologic endpoints derived from the DENV
RNA, including
 
Occurrence of detectable DENV RNA at
each time point in primary DENV
infection
 
Time to undetectable DENV RNA in
primary DENV infection
 
Evaluate the PK of JNJ-64281802 
 
PK parameters for JNJ-64281802
Exploratory
 
Investigate 
the 
antiviral 
activity 
of
JNJ-64281802 versus placebo based on
DENV infectious viral titer (further referred
to as viremia) in primary DENV infection
 
Virologic endpoints derived from viremia,
including
 
Area under the log10-transformed viremia
curve from baseline until Day 5 in primary
DENV infection
 
Occurrence of detectable viremia at each
timepoint in primary DENV infection
 
Time to undetectable viremia in primary
DENV infection
 
To explore the relationship between the
exposure 
and 
antiviral 
activity 
of
JNJ-64281802
 
PK (plasma concentrations or exposure
parameters) of JNJ-64281802.
 
Area under the log10-transformed viremia or
DENV RNA viral load.
 
Investigate 
the 
antiviral 
activity 
of
JN-64281802 versus placebo in terms of
reduction of DENV RNA in secondary
DENV infections and in all DENV
infections
 
Virologic endpoints derived from the DENV
RNA, viral load, including
 
Area under the log10-transformed DENV
RNA viral load curve from baseline until
Day 5, in secondary DENV infection
 
Occurrence of detectable DENV RNA at
each time point in secondary DENV
infection
 
Time to undetectable DENV RNA in
secondary DENV infection


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Objectives 
Endpoints
 
Investigate 
the 
antiviral 
activity 
of
JNJ-64281802 versus placebo based on
viremia in secondary DENV infections and
in all DENV infections
 
Virologic endpoints derived from viremia,
including
 
Area under the log10-transformed viremia
curve from baseline until Day 5 in
secondary DENV infection
 
Occurrence of detectable viremia at each
timepoint in secondary DENV infection
 
Time to undetectable viremia in secondary
DENV infection
 
Investigate the effect of JNJ-64281802
versus placebo on the change in hematology
values over time (leucocytes, platelets and
hematocrit)
 
The maximal decrease from baseline (per
participant) observed in platelet counts from
Day 2 to Day 5
 
The maximal decrease from baseline (per
participant) observed in leucocyte counts from
Day 2 to Day 5
 
The maximal increase from baseline (per
participant) 
observed 
in 
hematocrit
concentration from Day 2 to Day 5
 
Investigate the effect of JNJ-64281802
versus placebo on the immunological profile
 
The occurrence and magnitude of anti-DENV
total IgM and IgG antibody titers
 
To explore the effect of JNJ-64281802
versus placebo on DENV-related clinical
signs and symptoms
 
Time to resolution of dengue signs and
symptoms
 
Severity of dengue signs and symptoms
 
To assess changes in the viral genome
sequence (with a focus on NS4B) in
participants with detectable DENV RNA
 
Changes in the viral genome sequence at and
between first viral isolation and last viral
isolation
 
To explore the DENV NS1 serum protein
levels
 
Occurrence and magnitude of DENV NS1
serum protein levels
 
To explore the impact of host and viral
baseline factors on the antiviral activity and
safety of JNJ-64281802
 
HLA 
genotyping 
and 
pharmacogenomic
analyses
The following additional exploratory objectives may be evaluated at the discretion of the sponsor:
 
Investigate the effect of JNJ-64281802 versus placebo on immunological profile based on
occurrence and magnitude of anti-DENV cellular immune responses
 
To explore changes in serum protein levels (including cytokines)
 
To explore the impact of host and viral baseline factors on the antiviral activity and safety of
JNJ-64281802 based on biomarker analysis via transcriptional profiling of host RNA
 
The occurrence and magnitude of an anti-DENV neutralizing antibody response
Abbreviation key: AE(s) adverse event(s), AUC  area under the curve, DENV dengue virus, ECG: electrocardiogram,
HLA human leukocyte antigen, Ig Immunoglobulin, NS non structural, PK pharmacokinetic, RNA ribonucleic acid,
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Refer to Section 8, Study Assessments and Procedures for evaluations related to endpoints.
HYPOTHESIS
The primary hypothesis of this study is that JNJ-64281802 is superior to placebo with respect to
reduction in viral load in participants with a primary DENV infection, as measured by area under
the log10-transformed DENV RNA viral load curve from baseline until Day 5.
4. 
STUDY DESIGN
4.1. 
Overall Design
This is a randomized, double-blind, placebo-controlled, multicenter, Phase 2a interventional study
in participants aged ≥18 or ≥21 (depending on the legal age of consent in the jurisdiction in which
the study is taking place)to ≤60 years. Participants who report with an onset of fever of <48-hour
duration at screening, and who test positive for DENV infection by the NS1 assay will be
randomized into the study. Randomization will be stratified by country and by duration of dengue
symptoms from onset until the time of randomization (≤24 hours and >24 hours).
The population will include participants with a primary and a non-primary or secondary infection.
The difference between the 2 subpopulations will be determined before data base lock and will be
based on the IgG profile.
A planned target of 150 male and female participants will be randomly assigned in a ratio of 1:1
to receive JNJ-64281802 or placebo in this study with approximately 75 participants planned per
intervention group. The sample size can be revised after an interim analysis on the proportion of
primary versus secondary DENV infections (refer to Section 9.5, Interim Analysis).
There are three sequential phases in the study: screening/baseline, double-blind treatment and
follow-up. Study participants will complete the screening/baseline visit on Day 0 (predose),
followed by a double-blind treatment phase from Day 1 to Day 6 or Day 9 (for participants with
dengue warning symptoms). During the double-blind treatment phase, the participants will be
admitted to an inpatient facility. At the investigator’s discretion, ambulatory visits instead of
inpatient treatment can be allowed at Days 3, 4, 5, and 6. All participants will be followed up for
a total of 6 months after the first dosing day. The entire study duration for each participant will be
approximately 6 months (±4 days). The participants will complete the study after having
completed the final remote follow-up assessmentplanned 6 months (±4 days) after having received
the first dose of study intervention, unless ongoing adverse events (AEs) require monitoring.
Mobile clinical teams consisting of trained and delegated site staff (eg, nurses, clinical research
coordinators [CRCs]) will visit the clinics and communities to sensitize and pre-screen potential
study participants and will play an active role in participant recruitment. Individuals with a
suspected DENV infection will be asked to undergo an NS1 rapid test after signing a pre-screening
ICF during an ambulatory visit at a health care facility organized by the mobile clinical teams.
The study sites will be open to receive referrals of participants who have consulted a health care
facility (eg, clinic/polyclinic, hospital) or practitioner (eg, general practitioner [GP], medical


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doctor [MD], nurse)with an onset of fever within the last 48 hours, as reported by the participant,
and who tested positive for DENV infection by the NS1 assay at the health care facility. Individuals
who test positive during an ambulatory visit or as part of Standard of Care DENV NS1 rapid
testing, will be referred to the study site to further coordinate informed consent signing and
completion of eligibility assessments. In addition, participants may also report directly to the study
site. Participants identified at the study site with an onset of fever as reported by the participant
within the last 48 hours, and who test positive for DENV infection by the NS1 assay performed at
the site after signing the ICF, will undergo eligibility assessments.
The screening/baseline assessments are to be completed as quickly as possible at the study site.
Participants who successfully meet all inclusion criteria and none of the exclusion criteria, will be
enrolled and admitted to an inpatient facility. The participants will then be randomized to receive
placebo or JNJ-64281802. 
 Results of screening assessments need to be documented in the electronic case report
form (eCRF).
Placebo or JNJ-64281802 will be administered on Days 1 to 5, starting from the day of
randomization (Day 1). The participants will stay at the inpatient facility from Day 1 to Day 6
(with an option to attend ambulatory visits on Days 3, 4, 5, and 6 instead at the investigator’s
discretion) and daily clinical monitoring will be conducted, and blood samples will be collected as
shown in Schedule of Activities. Oral intake of food and fluids will be recorded on Days 1, 2, 3,
4, and 5 of dosing.
JNJ-64281802 (in either 
 formulation) or matching placebo will be administered
according to the following dosing regimens:
The
 formulation will be introduced for use in newly recruited participants, when it becomes
locally available.
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When dosed in fasted condition in 16 healthy volunteers, the JNJ-64281802 Cmax and AUC∞were
similar between
 and
, with geometric mean ratios of 1.06 and 1.00,
respectively. 
 When administered with a standardized breakfast, JNJ-64281802 Cmax
was increased by 33, 76, and 178% compared to fasted conditions for a single dose of 50, 200 and
800 mg, respectively. For AUC∞this increase was 12, 69, and 143%, respectively.
The participants will be discharged from the inpatient facility on Day 6 (on Day for ambulatory
visits) after the assessments indicated in the Schedule of Activities have taken place and given
their clinical status is satisfactory for discharge in the opinion of the investigator. Participants who
develop dengue warning symptoms as defined by WHO0 will remain at the inpatient facility after
Study Day 6 for an additional 3 days and planned outpatient assessments will be performed by the
study team members, where required. Patients with severe dengue (DHF or DSS), or participants
who are hemodynamically unstable or require interventions, can be transferred to a hospital at any
time during the inpatient stay, at the investigator’s discretion. Participants with severe dengue or
dengue warning symptoms after Study Day 9 will be moved to a hospital. After discharge, the
participants will be asked to return on Days 14, 21, and 28 (±2 days) and, thereafter, to perform
remote follow-up visits every two weeks (±4 days) till 6 months post dosing for assessments
specified in the Schedule of Activities. If the participant remains in the inpatient facility beyond
Day 6, planned outpatient study assessments will be performed at the inpatient facility as specified
in the Schedule of Activities.
At time points specified in the Schedule of Activities, key assessments during the study will
include the antiviral activity (as measured by DENV RNA viral load, viremia, and NS1), safety
and tolerability, and PK of JNJ-64281802. Safety and tolerability will be assessed through AE
reporting, physical examinations, vital signs, ECG and clinical laboratory tests. Furthermore, the
effect of JNJ-64281802 on the clinical course of DENV infection will be explored based on the
investigator’s assessment of DENV infection-associated AEs. In addition, the study also includes
the collection of blood samples for PK analysis, viral genome sequencing, pharmacogenomic
(DNA) research, cellular immune response analysis, and exploratory biomarker analyses,
including serum protein measurements and transcriptional profiling of host RNA.
Participants who prematurely discontinue study intervention for any reason (except withdrawal of
consent) will be asked to continue with their remaining study visits and assessment schedule.
Participants who withdraw consent during the treatment or follow-up phase will be offered an
optional Early Exit Visit. The optional Early Exit Visit will occur the day of consent withdrawal
or as soon as possible thereafter.
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An Internal Data Review Committee (DRC) will be commissioned for this study. The members of
DRC will consist of a Global Medical Safety (GMS) therapeutic area safety head, a clinician, a
clinical pharmacologist, a virologist, and a statistician, none of whom will be part of the study
team or involved in the conduct of the study. Any deaths related to dengue, admission to the
intensive care unit or severe dengue (DHF/DSS) will trigger a safety data review by the DRC. If,
in the judgment of the investigator and/or the sponsor’s study-responsible physician, a significant
or unexpected safety event occurs, the DRC will review unblinded safety data. Quarterly (every
3 months or when 50 participants are enrolled, whichever comes first), a DRC safety analysis
where DRC members review unblinded data, will take place. The DRC responsibilities,
authorities, and procedures will be documented in its charter. Refer to Committees Structure in
Section 10.3, Appendix 3, Regulatory, Ethical, and Study Oversight Considerations for details.
The primary analysis will be performed when all participants reached Day 28 or discontinued
earlier. The final analysis will be performed when all participants completed the study or
discontinued earlier.
An interim analysis will be performed when at least 50 participants with a primary dengue
infection reached Day 28 or discontinued earlier to check for futility or superiority. To check for
futility, conditional power values will be calculated using the observed data and assuming that in
the remainder of the trial the effect size used for the sample size calculation will be present. The
conditional power provides quantification of the likelihood that the study intervention will
ultimately be successful, ie, the probability of claiming a study intervention effect at the
completion of the study based on the available interim data. A futility stopping boundary of 25%
for the conditional power will be used. This is considered a conservative boundary also reflecting
that in this early stage of development it may be best to complete the study to have a larger database
to draw conclusions from. In case the probability of a successful trial is lower than the futility
boundary, the DRC and study team can take the decision to stop for futility after the evaluation of
all available data. If early superiority on the primary endpoint can be established, the DRC and
study team can take the decision to open  the study for participants at risk of severe dengue.
Assuming the outcome for the primary endpoint as used for the sample size calculations was true,
with a treatment effect of 0.30 log10 copies/mL per day DENV RNA clearance on top of placebo,
the chance of reaching the futility stopping boundary at the time of the IA is at most 5%. Otherwise,
if there is no treatment effect at all, the chance of reaching the futility stopping boundary is at least
60%. As the study will proceed even if superiority is achieved, no correction for multiple testing
will be done.
A diagram of the study design is provided in Section 1.2, Schema.
4.2. 
Scientific Rationale for Study Design
Blinding, Control, Study Phase/Periods, Intervention Groups
A placebo control will be used to establish the frequency and magnitude of changes in clinical
endpoints that may occur in the absence of active intervention. Randomization will be used to
minimize bias in the assignment of participants to intervention groups, to increase the likelihood
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evenly balanced across intervention groups, and to enhance the validity of statistical comparisons
across intervention groups. Blinded intervention will be used to reduce potential bias during data
collection and evaluation of clinical endpoints.
DNA and Biomarker Collection
It is recognized that genetic variation can be an important contributory factor to interindividual
differences in intervention distribution and response and can also serve as a marker for disease
susceptibility and prognosis. Pharmacogenomic research may help to explain interindividual
variability in clinical outcomes and may help to identify population subgroups that respond
differently to an intervention. The goal of the pharmacogenomic component is to collect DNA to
determine the human leukocyte antigen (HLA) type of each participant and to allow the
identification of genetic factors that may influence the PK, antiviral activity, or safety/tolerability
of JNJ-64281802. A blood sample for HLA genotyping and for pharmacogenomic research will
be collected, preferably at baseline (ie, before first dose of study drug). Participation in the HLA
genotyping and pharmacogenomic research is mandatory.
Biomarker samples will be collected to evaluate the mechanism of action of JNJ-64281802 or to
help explain interindividual variability in clinical outcomes or may help to identify population
subgroups that respond differently to an intervention. The goal of the biomarker analyses is to
evaluate the impact of host and viral baseline factors on the antiviral activity and safety of
JNJ-64281802 and aid in evaluating the drug-clinical response relationship. Samples can only be
used for research related to JNJ-64281802 or DENV infection or may be used to develop
tests/assays related to JNJ-64281802 or DENV infection.
DNA and Biomarker samples may be used to help address emerging issues and to enable the
development of safer, more effective, and ultimately individualized therapies.
4.2.1. 
Study-Specific Ethical Design Considerations
Potential participants will be fully informed of the risks and requirements of the study, and, during
the study, participants will be given any new information that may affect their decision to continue
participation. They will be told that their consent to participate in the study is voluntary and may
be withdrawn at any time with no reason given and without penalty or loss of benefits to which
they would otherwise be entitled. Only participants who are fully able to understand the risks,
benefits, and potential AEs of the study, and provide their consent voluntarily will be enrolled.
When referring to the signing of the ICF, the terms legal guardian and legally acceptable
representative refer to the legally appointed guardian of the adolescent with authority to authorize
participation in research. For each participant, his or her parent(s) (preferably both parents, if
available) or legally acceptable representative(s), as required by local regulations, must give
written consent (permission) according to local requirements after the nature of the study has been
fully explained and before the performance of any study-related assessments. For the purposes of
this study, all references to participants who have provided consent refers to the participants and
his or her parent(s) or the participant's legal guardian(s) or legally acceptable representative(s) who
have provided consent according to this process.


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The total blood volume to be collected is considered to be an acceptable amount of blood to be
collected over this time period from the population in this study based upon the standard of the
American Red Cross.0
4.3. 
Justification for Dose
The
 dosing regimens selection was based on the final analysis of the Phase 1 first-
in-human study DNG1001, DNG1006 study, GLP toxicity studies, and in vitro and in vivo antiviral
activity data of JNJ-64281802.
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4.4. 
End of Study Definition
End of Study Definition
The end of study is considered as the last scheduled study assessment shown in the Schedule of
Activities for the last participant in the study. The final data from the study site will be sent to the
sponsor (or designee) after completion of the final participant assessment at that study site, in the
time frame specified in the Clinical Trial Agreement.
Study Completion Definition
A participant will be considered to have completed the study if he or she has completed the last
remote follow-up assessment 6 months post first dose.
Participants who prematurely discontinue study intervention for any reason (except withdrawal of
consent) will be asked to continue with their remaining study visits and assessment schedule.
Participants who withdraw consent during the treatment or follow-up phase will be offered an
optional Early Exit Visit. The optional Early Exit Visit will occur the day of consent withdrawal
or as soon as possible thereafter.
5. 
STUDY POPULATION
It is recommended that the screening/baseline assessments are completed as quickly as possible,
in order to start intake of the first dose of study intervention as soon as possible
 Refer to Section 5.4, Screen Failures for conditions under which the repeat
of any screening procedures is allowed.
Participants with primary or secondary DENV infection will be enrolled in the study. The inclusion
and exclusion criteria for enrolling participants in this study are described below. If there is a
question about these criteria, the investigator must consult with the appropriate sponsor
representative and resolve any issues before enrolling a participant in the study. Waivers are not
allowed.
For a discussion of the statistical considerations of participant selection, refer to Section 9.2,
Sample Size Determination.
5.1. 
Inclusion Criteria
Each potential participant must satisfy all of the following criteria to be enrolled in the study:
1. 
Criterion modified per Amendment 1
1.1 
Male or female.
2. 
Criterion modified per Amendment 6
2.1 
≥18 or ≥21 (depending on the legal age of consent in the jurisdiction in which the
study is taking place)to 60 years of age, inclusive, at the time of screening.
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3. 
Must have a body mass index (BMI) between 18 to 35 kg/m2 (inclusive) and a body
weight of ≥45 kg at screening.
4. 
Must have a normal 12-lead electrocardiogram (ECG) taken in triplicate at screening
(machine read and/or assessed by investigator or cardiologist), including normal sinus
rhythm (heart rate between 45 and 100 beats per minute [bpm], extremes included), QTcF
≤450 ms for male participants and ≤470 ms for female participants, QRS interval <110
ms, and PR interval ≤220 ms. If the results of the ECG are outside the normal ranges, the
participant may be included only if the investigator judges the deviations from normal to
be not clinically significant. This determination must be recorded in the participant's
source documents and initialed and dated by the investigator.
5. 
Criterion modified per Amendment 4
5.1 
Patient with  a referral note/documentation from a health care facility or
practitioner indicating NS1 positive for DENV, positive NS1 rapid test at pre-screening
during an ambulatory visit, or patient who tests NS1 positive at the site.
6. 
Participant reported a fever with an onset within the last 48 hours.
7. 
Criterion modified per Amendment 4
7.1 
Must sign an ICF indicating that he or she understands the purpose of, and
procedures required for, the study and is willing to participate in the study. Note: prior to
signing the ICF for the study, participants may specifically allow for ambulatory NS1
rapid testing performed by a member of the mobile clinical team by signing the
pre-screening ICF.
8. 
Criterion modified per Amendment 3
8.1 
Must sign a separate part of the informed consent form if he or she agrees to
provide an optional sample for future exploratory research. Where local regulations
require, a separate consent may be requested for the required DNA component of the
study.
9. 
A woman of childbearing potential must have a negative serum pregnancy test at
screening.
10. 
A woman using oral contraceptives should use an additional contraceptive method.
Note: The interaction between JNJ-64281802 and hormone-based contraceptives has not
been assessed. The efficacy of hormone-based contraceptives may be decreased when
co-administered with JNJ-64281802 and therefore they should not be considered as a
highly effective contraceptive method during dosing with JNJ-64281802.


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Contraceptive (birth control) use by men or women should be consistent with local
regulations regarding the acceptable methods of contraception for those participating in
clinical studies.
11. 
A woman must be (as defined in Section 10.5, Appendix 5, Contraceptive and Barrier
Guidance and Collection of Pregnancy Information)
a. Not of childbearing potential
b. Of childbearing potential and practicing a highly effective, preferably
user-independent method of contraception (failure rate of <1% per year when
used consistently and correctly) and agrees to remain on a highly effective
method while receiving study intervention and until at least 90 days after last
dose  the end of relevant systemic exposure. Examples of highly effective
methods of contraception are located in Section 10.5, Appendix 5, Contraceptive
and Barrier Guidance
12. 
A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted
reproduction during the study and for a period of at least 90 days after the last dose of
study intervention.
13. 
During the study and for a minimum of 90 days after receiving the last dose of the study
intervention, a male participant must wear a condom when engaging in any activity that
allows for passage of ejaculate to another person. Male participants should also be advised
of the benefit for a female partner to use a highly effective method of contraception as
condom may break or leak.
14. 
A male participant must agree not to donate sperm for the purpose of reproduction during
the study and for a minimum of 90 days after receiving the last dose of study intervention.
15. 
Criterion modified per Amendment 5
15.1 Willing and able to adhere to the lifestyle restrictions specified in this protocol.
Note: Retesting of abnormal values that may lead to exclusion will be allowed once
without prior approval from the sponsor. Retesting to replace lost samples or broken tubes
is permitted. Retesting will be performed within the screening phase. Participants with a
normal value at retest may be included.
5.2. 
Exclusion Criteria
Any potential participant who meets any of the following criteria will be excluded from
participating in the study:
1. 
Patient with any clinical signs and symptoms for severe dengue according to the WHO
criteria0(such as severe plasma leakage leading to shock [DSS], fluid accumulation with
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1.2 
Criterion added per Amendment 6
Patient who recalls past/prior laboratory-confirmed dengue infection and/or past/prior
laboratory-confirmed dengue infection per available medical records (any PCR, NS1,
IgG/IgM seroconversion).
2. 
Criterion modified per Amendment 4
2.1 
Criterion modified per Amendment 5
2.2 
Use of any CYP3A4 inducers (eg, phenytoin, rifampin), UGT1A9 inducers (eg,
rifampin), or substrates for CYP3A4 with a narrow therapeutic range (eg, alfentanil,
cyclosporin), CYP2C8 substrates (eg, repaglinide)or BCRP substrates (eg, pravastatin
and folic acid) within 14 days before first dose of study drug.
Use of any CYP3A4 inhibitors (eg, clarithromycin, itraconazole)or UGT1A9 inhibitors
(eg, probenecid, mefenamic acid)within 7 days before first dose of study drug.
2.3 Criterion modified per Amendment 6
Use of any CYP3A4 inducers (eg, phenytoin, rifampin), UGT1A9 inducers (eg,
rifampin), substrates for CYP3A4 with a narrow therapeutic range (eg, alfentanil,
cyclosporin), or sensitive BCRP substrates (eg, pravastatin and folic acid) from 14 days
before first dose of study drug until 28 days after last dose of study drug.
Systemic use of strong CYP3A4 inhibitors (eg, clarithromycin, itraconazole) or
UGT1A9 inhibitors (eg, probenecid, mefenamic acid) from 7 days before first dose of
study drug until 28 days after last dose of study drug.
3. 
Criterion modified per Amendment 4
3.1 
One or more of the following laboratory abnormalities at screening: hematocrit
>52% in males; >46% in females, aspartate aminotransferase (AST) or alanine
aminotransferase (ALT) >1000 U/L, absolute neutrophil count <1500/µL, platelet count
<80,000/ µL, hemoglobin <12.0 g/dL in males; <10.0 g/dL in females, total bilirubin
>26 µmol/L.
4. 
History of liver or renal insufficiency (estimated creatinine clearance below 60 mL/min)
calculated by the Modification of Diet in Renal Disease [MDRD] formula]0; significant
cardiac, vascular, pulmonary, gastrointestinal (such as significant diarrhea, gastric
stasis, or constipation that in the investigator’s opinion could influence drug absorption
or bioavailability), endocrine, neurologic, hematologic, rheumatologic, psychiatric,
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5. 
History of malignancy within 5 years before screening (exceptions are squamous and
basal cell carcinomas of the skin and carcinoma in situ of the cervix, or malignancy,
which is considered cured with minimal risk of recurrence).
6. 
Any history of clinically significant skin disease such as, but not limited to, dermatitis,
eczema, drug rash, psoriasis, food allergy, and urticaria during the last 5 years.
7. 
Known allergies, hypersensitivity, or intolerance to JNJ-64281802 or its excipients
(refer to the IB).0,0
8. 
Taken any disallowed therapies as noted in Section 6.5, Concomitant Therapy before
the planned first dose of study intervention.
9. 
9.1 
Criterion modified per Amendment 3
9.2 
Criterion modified per Amendment 4
Received an investigational intervention  (including investigational vaccines or
Dengvaxia) or used an invasive investigational medical device within 30 days before
the planned first dose of study intervention or is currently enrolled in an investigational
study or is planning to be enrolled in an investigational study within 90 days after the
last dose of study intervention. Participants will be allowed to receive an
authorized/licensed COVID-19 vaccine at any time before, during, and after the study
(see Section 10.9, Appendix 9: Guidance on Study Conduct During the COVID-19
Pandemic).
10. 
Pregnant, or breast-feeding, or planning to become pregnant while enrolled in this study
or within 90 days after the last dose of study intervention.
11. 
Plans to father a child while enrolled in this study or within 90 days after the last dose
of study intervention.
12. 
Any condition for which, in the opinion of the investigator, participation would not be
in the best interest of the participant (eg, compromise the well-being) or that could
prevent, limit, or confound the protocol-specified assessments (eg, in case of
coinfections).
13. 
Had major surgery, (eg, requiring general anesthesia) within 4 weeks before screening,
or will not have fully recovered from surgery, or has surgery planned during the time
the participant is expected to participate in the study.
Note: Participants with planned surgical procedures to be conducted under local
anesthesia may participate.
14. 
Having donated or lost more than 1 unit of blood (500 mL) within 60 days or more than
1 unit of plasma (250 mL) within 7 days before the planned (first) dose of study


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intervention or having the intention to donate blood or blood products within 90 days
after (the last) dose of study intervention.
15. 
Known or suspected congenital or acquired immunodeficiency; or receipt of
immunomodulation therapy such as anti-cancer chemotherapy or radiation therapy; or
long-term systemic corticosteroid therapy (prednisone or equivalent for more than 2
consecutive weeks within the past 3 months).
16. 
Employee of the investigator or study site, with direct involvement in the proposed
study or other studies under the direction of that investigator or study site, as well as
family members of the employees or the investigator.
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening.
If a participant's clinical status changes (including any available laboratory results or receipt of
additional medical records) after screening but before the first dose of study intervention is given
such that he or she no longer meets all eligibility criteria, then the participant should be excluded
from participation in the study. The required source documentation to support meeting the
enrollment criteria is noted in Appendix  3, Regulatory, Ethical, and Study Oversight
Considerations.
5.3. 
Lifestyle Considerations
Potential participants must be willing and able to adhere to the following lifestyle restrictions
during the course of the study to be eligible for participation:
1. 
Refer to Section 6.5, Concomitant Therapy  for details regarding prohibited and
restricted therapy during the study.
2. 
Agree to follow all requirements that must be met during the study as noted in the
Inclusion and Exclusion Criteria (eg, contraceptive requirements).
5.3.1. 
Meals and Dietary Restrictions
1. 
Refrain from consumption of Seville oranges, grapefruit or grapefruit juice, pomelos,
exotic citrus fruits, grapefruit hybrids, or fruit juices from enrollment until the last dose
of the study intervention.
2. 
Criterion modified per Amendment 5
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3. 
Must not consume any foods or drinks (including additional salt or sugar) other than those
provided by the study site personnel during domiciled inpatient periods.
5.3.2. 
Caffeine and Alcohol
1. 
Must refrain from the use of food or drinks/beverages containing alcohol, or the use of
energy drinks or beverages containing caffeine from enrollment until the last dose of the
study intervention.
2. 
Limited use of caffeinated methylxanthines (eg, coffee, tea, cola, and chocolate) is
allowed (≤500 mg/day, as contained in 5 cups of tea or coffee or 8 cans of cola).
3. 
May not use drugs of abuse (including amphetamine, barbiturate, cannabinoids, cocaine,
methadone, opiates, phencyclidine, and tricyclic antidepressants)from enrollment until 3
weeks after last dose of study drug.
5.3.3. 
Activity
1. 
Unusual strenuous exercise may affect study-specified assessments and safety laboratory
results; for this reason, unusual strenuous exercise (as assessed by the investigator) should
be avoided from enrollment until 30 days after last dose of study drug.
2. 
Must not participate in another investigational study during the study or within 90 days
after last dose of study drug.
3. 
Avoid donating blood for at least 90 days after (the last) dose of study intervention.
5.4. 
Screen Failures
Participant Identification, Enrollment, and Screening Logs
The investigator agrees to complete a participant identification and enrollment log to permit easy
identification of each participant during and after the study. This document will be reviewed by
the sponsor study-site contact for completeness.
The participant identification and enrollment log will be treated as confidential and will be filed
by the investigator in the study file. To ensure participant confidentiality, no copy will be made.
All reports and communications relating to the study will identify participants by participant
identification and age at initial informed consent. In cases where the participant is not randomized
into the study, the date seen and age at initial informed consent will be used.
6. 
STUDY INTERVENTION
6.1. 
Study Intervention(s) Administered
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On Study Day 1, 
. Intake of subsequent doses of study intervention should take
place according to the Schedule of Activities and at approximately the same time each day
preferably.
 All study intervention
intakes will take place at the study site.
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Description of Interventions
Arm Name 
Intervention 
Placebo
Intervention Name 
JNJ-64281802 
Placebo
Type 
Drug 
Placebo
Dose Formulation 
Unit Dose Strength(s) 
Dosage Level(s) 
Route of Administration 
Oral 
Oral
Use 
Experimental 
Placebo
Investigational Medicinal 
Product (IMP) and Non-
Investigational Medicinal
Product (NIMP)
IMP  
IMP
Sourcing 
Provided centrally by the Sponsor 
Provided centrally by the Sponsor
Packaging and Labeling 
 
 
 
 
 Each 
container will contain information and 
be labeled as required per country 
regulatory requirements. Labels must 
remain affixed to the container. 
 
 
 
 
Each container will contain 
information and be labeled as required 
per country regulatory requirements. 
Labels must remain affixed to the 
container.
 Each
container will contain information and
be labeled as required per country
regulatory requirements. Labels must
remain affixed to the container.
 Each container will
contain information and be labeled as
required per country regulatory
requirements. Labels must remain
affixed to the container.
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Arm Name 
Intervention 
Placebo
Food/Fasting requirement 
Study intervention administration must be captured in the source documents and the eCRF.
JNJ-64281802 will be manufactured and provided under the responsibility of the sponsor. Refer
to the IB for a list of excipients.0,0
6.2. 
Preparation/Handling/Storage/Accountability
Preparation/Handling/Storage
All study intervention  must be stored at controlled temperatures as indicated on the product-
specific labeling. Any temperature excursion must be reported to the sponsor’s representative within
24 hours of knowledge of the excursion. After exposure to a temperature excursion, the product will
not be used until written approval has been given by the sponsor’s representative.
Refer to the pharmacy manual/study site investigational product and procedures manual for
additional guidance on study intervention preparation, handling, and storage.
Accountability
The investigator is responsible for ensuring that all study intervention received at the site is
inventoried and accounted for throughout the study. The study intervention administered to the
participant must be documented on the intervention accountability form. All study intervention
will be stored and disposed of according to the sponsor's instructions. Study-site personnel must
not combine contents of the study intervention containers.
Study intervention must be handled in strict accordance with the protocol and the container label
and must be stored at the study site in a limited-access area or in a locked cabinet under appropriate
environmental conditions. Unused study intervention, and study intervention returned by the
participant, must be available for verification by the sponsor's study site monitor during on-site
monitoring visits. The return to the sponsor of unused study intervention, or used returned study
intervention for destruction, will be documented on the intervention return form. When the study
site is an authorized destruction unit and study intervention supplies are destroyed on-site, this
must also be documented on the intervention return form.
Potentially hazardous materials containing hazardous liquids, should be disposed of immediately
in a safe manner and therefore will not be retained for intervention accountability purposes.
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Study intervention should be dispensed under the supervision of the investigator or a qualified
member of the study-site personnel, or by a hospital/clinic pharmacist. Study intervention will be
supplied only to participants participating in the study. Returned study intervention must not be
dispensed again, even to the same participant. Study intervention may not be relabeled or
reassigned for use by other participants. The investigator agrees neither to dispense the study
intervention from, nor store it at, any site other than the study sites agreed upon with the sponsor.
Further guidance and information for the final disposition of unused study interventions are
provided in the Study Reference Manual.
6.3. 
Measures to Minimize Bias: Randomization and Blinding
Intervention Allocation
Procedures for Randomization and Stratification
Randomization will be performed within 
hours after onset of fever. Participants will be
randomly assigned to 1 of 2 intervention groups based on a computer-generated randomization
schedule prepared before the study by or under the supervision of the sponsor. The randomization
will be balanced by using randomly permuted blocks and will be stratified by country and by the
duration of dengue symptoms from onset till time of randomization (≤24 hours and >24 hours).
Blinding
To ensure participant safety while maintaining the study blind, sealed envelopes containing the
study intervention identification (eg, active, placebo) will be provided to the investigator. These
sealed envelopes will be kept together in a limited-access area that is accessible 24 hours per day.
All envelopes, whether opened or sealed, will be collected after the end of the participant’s
participation in the study. The study interventions will be identical in appearance and will be
packaged in identical containers.
Data that may potentially unblind the intervention  assignment (ie, study intervention plasma
concentrations, virologic data, study intervention preparation/accountability data, intervention
allocation, biomarker or other specific laboratory data)will be handled with special care to ensure
that the integrity of the blind is maintained and the potential for bias is minimized. This can include
making special provisions, such as segregating the data in question from view by the investigators,
clinical team, or others as appropriate until the time of database lock and unblinding.
At the time of the first interim analysis (when at least 50 participants with a primary infection
reached Day 28 or discontinued earlier) and the primary analysis (when all participants reached
Day 28 or discontinued earlier), Sponsor personnel will become unblinded to the interim analysis
and primary analysis data. Study site personnel, investigators, participants, and operational
Sponsor team members involved with the sites will have no access to any of the evaluations
performed by either the Sponsor or the DRC  so that follow-up of safety during the 6-months
follow-up period can still be performed in a blinded fashion.
Under normal circumstances, the blind should not be broken  to the study site personnel,
investigators, participants, and operational Sponsor team members until all participants have
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completed the study and the database is finalized. The investigator may in an emergency determine
the identity of the intervention by opening the sealed code. While the responsibility to break the
intervention code in emergency situations resides solely with the investigator, it is recommended
that the investigator contact the sponsor or its designee, if possible, to discuss the particular
situation before breaking the blind. Telephone contact with the sponsor or its designee will be
available 24 hours per day, 7 days per week. In the event the blind is broken, the sponsor must be
informed as soon as possible. The date, time, and reason for the unblinding must be documented
in the appropriate section of the eCRF, and in the source document.
Participants who have had their intervention assignment unblinded should continue to return for
scheduled evaluations.
In general, randomization codes will be disclosed fully only if the study is completed and the
clinical database is closed. However, if an interim analysis is specified, the randomization codes
and, if required, the translation of randomization codes into intervention and control groups will
be disclosed to those authorized and only for those participants included in the interim analysis.
6.4. 
Study Intervention Compliance
When participants are dosed at the site, they will receive study intervention directly from the
investigator or designee, under medical supervision. JNJ-64281802 will be administered orally, by
designated study-site personnel at the study sites, who will check the participant's mouth to confirm
that the dose was swallowed. The date and time of each dose administered in the clinic will be
recorded in the source documents and recorded in the CRF. The dose of study intervention and
study participant identification will be confirmed at the time of dosing by a member of the study
site personnel other than the person administering the study intervention.
6.5. 
Concomitant Therapy
Prestudy therapies administered up to 14 days before first dose of study intervention  must be
recorded at screening.
Concomitant therapies must be recorded throughout the study beginning with start of the first dose
of study intervention until the end of the study. Concomitant therapies should also be recorded
beyond the end of study only in conjunction with new or worsening AEs.
All therapies (prescription or over-the-counter medications [including analgesics], including
vaccines, vitamins, herbal supplements; non-pharmacologic therapies such as electrical
stimulation, acupuncture, special diets, exercise regimens, or other specific categories of interest)
different from the study intervention must be recorded in the CRF. Recorded information will
include a description of the type of therapy  duration of use, dosing regimen, route of
administration, and indication. Modification of an effective preexisting therapy should not be made
for the explicit purpose of entering a participant into the study.
Beyond those listed below, participants are not being asked to discontinue current medications. If
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participants are encouraged to obtain appropriate care, comply with the course of therapy as
prescribed by their physician, and inform the investigator as soon as possible.
Stable hormone replacement therapy in postmenopausal female participants (ie, same dose and not
starting or stopping hormone replacement therapy for 2 weeks prior to the planned [first] dose of
study intervention until the end of the study) is allowed. It should be noted that JNJ-64281802 may
affect the effectiveness of hormone replacement therapy agents when co-administered. The use of
hormone replacement therapy should be recorded in the Concomitant Therapy Section of the CRF.
Applicable procedures and treatment guidance based on package inserts should be respected.
Other comedication is allowed in the following cases:
 
In case of cutaneous reaction/rash and/or an allergic reaction, the use of cetirizine,
levocetirizine, topical corticosteroids, or antipruritic agents in the recommended dose scheme
is permitted.
 
In case of severe nausea, the use of anti-emetics is permitted.
 
In case of severe diarrhea, the use of loperamide is permitted (at ≤4x2 mg per day  for a
maximum of 3 consecutive days).
The following therapies are not permitted during the study and for the time period prior to
screening as noted:
 
Herbal supplements within 14 days prior to randomization and during the study with the
exception of topically administered products.
 
Participants must not use any CYP3A4 inducers (eg, phenytoin, rifampin), UGT1A9 inducers
(eg, rifampin), substrates for CYP3A4 with a narrow therapeutic range (eg, alfentanil,
cyclosporin), or sensitive BCRP substrates (eg, pravastatin and folic acid) from 14 days before
first dose of study drug until 28 days after last dose ofstudy drug. The systemic use of strong
CYP3A4 inhibitors (eg, clarithromycin, itraconazole) or UGT1A9 inhibitors (eg, probenecid,
mefenamic acid) is not allowed from 7 days before first dose of study drug until 28 days after
last dose of study drug. In case any of these inhibitors or substrates are used, the date and time
of dosing, the indication, the dose, and the dosing regimen must be recorded in the
Concomitant Therapy Section of the CRF.
 
Participants must not use any aspirin or NSAIDs, including ADVIL®, MOTRIN®, NUPRIN®,
ALEVE®, NAPROXEN®, and CELEBREX® and any anticoagulant drugs (eg, warfarin or
clopidogrel), from 7 days before first dose until 28 days after the last dose or through 7 days
after hospital discharge, whichever is later. Aspirin, NSAIDs and anticoagulants can interfere
with the ability of the blood to clot. The investigators may recommend
paracetamol/acetaminophen or an equivalent, which can be used safely for fevers and body
aches.
 
Participants must not use any immunosuppressive corticosteroids (excluding topical and
nasal) or immunosuppressive drugs from 3 months before first dose of study drug until
28 days after last dose of study drug. An immunosuppressive dose of corticosteroids is defined
as ≥10 mg prednisone equivalent per day for ≥14 days. In case immunosuppressive
corticosteroids or immunosuppressive drugs are used, the date and time of dosing, the


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indication, the dose, and the dosing regimen must be recorded in the Concomitant Therapy
Section of the CRF.
Participants will be allowed to receive an authorized/licensed COVID-19 vaccine at any time
before, during, and after the study (see Section 10.9, Appendix 9: Guidance on Study Conduct
During the COVID-19 Pandemic).For any concomitant therapy given as a treatment for a new
condition or a worsening of an existing condition (relative to the moment of signed ICF), the
condition must be documented in the Adverse Event Section of the CRF.
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in
which prohibited therapies are administered.
6.6. 
Dose Modification
Any dose/dosage adjustment not planned per protocol should be overseen by medically qualified
study-site personnel (principal or sub-investigator unless an immediate safety risk appears to be
present).
6.7. 
Intervention After the End of the Study
Participants will be instructed that study intervention will not be made available to them after they
have completed/discontinued study intervention and that they should return to their primary
physician to determine standard of care.
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL
7.1. 
Discontinuation of Study Intervention
A participant's study intervention must be discontinued if:
 
The participant withdraws consent to receive study intervention
 
The investigator believes that for safety reasons or tolerability reasons (eg, an AE) it is in the
best interest of the participant to discontinue study intervention
 
The participant becomes pregnant
If a participant discontinues study intervention for any reason (except withdrawal of consent)
before the end of the double-blind treatment phase, the participant will be asked to continue with
their remaining study visits and assessment schedule. Participants who withdraw consent during
the treatment or follow-up phase, will be offered an optional Early Exit Visit. The optional Early
Exit Visit will occur on the day of consent withdrawal or as soon as possible thereafter and will
consist of the same assessments as at the Day 28 follow-up visit.
Additional participants may be entered only for those participants who discontinued study drug
before last dose of study drug on Day 2 to ensure the protocol-specified number of participants
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7.2. 
Participant Discontinuation/Withdrawal From the Study
A participant will be withdrawn from the study for any of the following reasons:
 
Lost to follow-up
 
Withdrawal of consent
 
Death
When a participant withdraws before study  completion, the reason for withdrawal is to be
documented in the CRF and in the source document. If the reason for withdrawal from the study
is withdrawal of consent, then no additional assessments are allowed (except in the case of an
optional Early Exit Visit).
Withdrawal of Consent
A participant declining to return for scheduled visits does not necessarily constitute withdrawal of
consent. Alternate follow-up mechanisms that the participant agreed to when signing the consent
form apply (eg, consult with family members, contacting the participant’s other physicians,
medical records, database searches, use of locator agencies at study completion) as local
regulations permit.
7.2.1. 
Withdrawal from the Use of Research Samples
Withdrawal From the Use of Samples in Future Research
The participant may withdraw consent for use of samples for research (refer to Long-Term
Retention of Samples for Additional Future Research in Section 10.3, Appendix 3, Regulatory,
Ethical, and Study Oversight Considerations). In such a case, samples will be destroyed after they
are no longer needed for the clinical study. Details of the sample retention for research are
presented in the main ICF and in the separate ICF for optional research sample.
7.3. 
Lost to Follow-up
To reduce the chances of a participant being deemed lost to follow-up, prior to randomization
attempts should be made to obtain contact information from each participant, eg, home, work, and
mobile telephone numbers and email addresses for both the participant as well as appropriate
family members.
A participant will be considered lost to follow-up if he or she repeatedly fails to return for
scheduled visits and is unable to be contacted by the study site. A participant cannot be deemed
lost to follow-up until all reasonable efforts made by the study-site personnel to contact the
participant are deemed futile0. The following actions must be taken if a participant fails to return
to the study site for a required study visit:
 
The study-site personnel must attempt to contact the participant to reschedule the missed visit
as soon as possible, to counsel the participant on the importance of maintaining the assigned
visit schedule, to ascertain whether the participant wishes to or should continue in the study.


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 
Before a participant is deemed lost to follow up, the investigator or designee must make every
reasonable effort to regain contact with the participant (where possible, 3 telephone calls, e-
mails, fax, and, if necessary, a certified letter to the participant’s last known mailing address,
or local equivalent methods. Locator agencies may also be used as local regulations permit.
These contact attempts should be documented in the participant’s medical records.
 
Should the participant continue to be unreachable, they will be considered to have withdrawn
from the study.
Should a study site close, eg, for operational, financial, or other reasons, and the investigator cannot
reach the participant to inform them, their contact information will be transferred to another study
site.
8. 
STUDY ASSESSMENTS AND PROCEDURES
Overview
The Schedule of Activities summarizes the frequency and timing of antiviral activity, PK,
immunogenicity, biomarker, pharmacogenomic, and safety measurements applicable to this study.
If multiple assessments are scheduled for the same timepoint, it is recommended that procedures
be performed in the following sequence: ECG, vital signs, blood sampling (except at screening).
Blood collections for PK and antiviral activity assessments and all other assessments (eg, ECG,
vital signs, physical examination) should be performed within the time window defined in the
Schedule of Activities. Actual dates and times of assessments will be recorded in the source
documentation and CRF.
Additional serum pregnancy tests may be performed, as determined necessary by the investigator
or required by local regulation, to establish the absence of pregnancy at any time during the
participation in the study.
The total blood volume for the study is approximately 389.8 mL for males and 392.3 mL for
females.
Refer to Table 1 for details.


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Table 1: 
Volume of Blood to be Collected From Each Participant
Type of Sample 
Volume per 
Sample (mL) 
No. of Samples 
per Participant 
Approximate
Total Volume
of Blood (mL)a
Pharmacokinetics 
3 
17 
51 mL
Safety (including screening and post-intervention
assessments)
-     Hematology  
3 
9 
27 mL
-     Serum chemistryb 
8 
9 
72 mL
- Coagulation 
2.7 
9 
24.3 mL
- Serum pregnancy  
2.5 
1 
2.5 mL
- NS1 rapid testh 
0.5 
1 
0.5 mL
Viral load
10 
11 d 
110 mLe
- RT Qualitative PCR c
- RT Quantitative PCR + back-up
- Plaque assay
- NS1 testing
Humoral Immunity  
- IgG
- IgM
- nAb
Viral Genome Sequencing (Viremics)
Serum proteins (including cytokines)
Cellular Immunity  
30i 
2 
60i mL
Host RNA  
2.5 
8 
20 mL
Blood sample collection for plasma protein binding 
3 
3 
9 mL
Blood sample collection for alpha-1 acid glycoprotein 
2.5 
3 
7.5 mL
Pharmacogenomic sample 
8.5 
1 
8.5 mL
Approximate Totalf 
389.8 mL (for
males)/
392.3 mL (for
females)g
a. Calculated as number of samples multiplied by amount of blood per sample.
b. Serum chemistry includes hematology and biochemistry (including glucose).
c. Retrospective analysis of the screening samples will be performed.
d. Maximum 14 samples will be collected in case repeat required at D1 and in case prolongation stay at unit until
Day 9.
e. Includes viral load, humoral immunity, serum proteins (including cytokines) and viral genome sequencing
f. Repeat or unscheduled samples may be taken for safety reasons or technical issues with the samples.
g. Additional 87.6 mL of blood per participant will be collected in case of an extended stay at the inpatient facility
from Day 6 to Day 9.
h. At pre-screening or at screening, if not yet performed by a health care facility or practitioner as part of standard
of care.
i. Volume per blood sample can be reduced from 30 mL to 10 mL at Day 28, subject to the local regulations and
investigator’s decision.
Note: An indwelling intravenous cannula may be used for blood sample collection.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the CRF or laboratory
requisition form. If blood samples are collected via an indwelling cannula, an appropriate amount
(1 mL) of serosanguineous fluid slightly greater than the dead space volume of the lock will be
removed from the cannula and discarded before each blood sample is taken. After blood sample
collection, the cannula will be flushed with 0.9% sodium chloride, United States Pharmacopeia
(USP) (or equivalent) and charged with a volume equal to the dead space volume of the lock.


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Refer to the Schedule of Activities for the timing and frequency of all sample collections.
Instructions for the collection, handling, storage, and shipment of samples are found in the
laboratory manual that will be provided. Collection, handling, storage, and shipment of samples
must be under the specified, and where applicable, controlled temperature conditions as indicated
in the laboratory manual.
Study-Specific Materials
The investigator will be provided with the following supplies:
 
IB
 
Pharmacy manual/study site investigational product and procedures manual
 
Laboratory manual
 
eDC Manual
 
eSource Manual
 
Sample ICF
8.1. 
Antiviral activity Assessments
At time points specified in the Schedule of Activities, blood samples will be obtained for
measurement of:
 
levels of DENV RNA
 
levels of viremia (ie, infectious virus)
 
DENV NS1 protein
Samples may be used by the sponsor for additional assessments analyzing the serologic and
virologic characteristics of the DENV infection and antiviral activity of the study intervention,
including viral genotypic and phenotypic assessments.
Procedures for sample collection, processing and storage will be provided in the laboratory
manual.
DENV RNA levels will be assessed using a validated quantitative DENV RT-PCR assay.
DENV viremia (ie, level of infectious DENV) will be determined using an assay for infectious
virus quantification such as a plaque assay.
In addition, antiviral activity will be explored by assessing NS1 protein using an NS1 test.
Confirmation of DENV infection  will be done retrospectively using qualitative PCR after
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8.1.1. 
Viral Genome Sequencing
Viral genome sequencing analysis will be performed by sequencing the NS4B gene and other
regions of the DENV genome (if warranted) to characterize emerging DENV variants associated
with resistance to JNJ-64281802.
Sequencing of the DENV genome will be performed to monitor DENV variants present at the time
points indicated in the Schedule of Activities, at the discretion of the sponsor’s virologist.
Samples may be used by the sponsor for additional assessments analyzing the serologic and
virologic characteristics of DENV infection and antiviral activity and safety of JNJ-64281802,
including viral genotypic and phenotypic assessments.
8.2. 
Safety Assessments
Details regarding the internal DRC  are provided in Committees Structure in Section 10.3,
Appendix 3, Regulatory, Ethical, and Study Oversight Considerations.
Safety and tolerability will be evaluated throughout the study from signing of the ICF onwards
until the last study-related activity or until the participant has been deemed lost to follow-up after
demonstration of due diligence of follow-up efforts.
Key safety assessments will include the monitoring of AEs (including DENV infection-associated
AEs), physical examinations, vital signs, and clinical safety laboratory tests.
Adverse events will be reported and followed by the investigator as specified in Section 8.2.4.1,
Adverse Events and Serious Adverse Events and Section 10.4, Appendix  4, Adverse Events:
Definitions and Procedures for Recording, Evaluating, Follow-Up, and Reporting.
Any clinically relevant changes occurring during the study must be recorded on the Adverse Event
section of the CRF and in the source documentation.
Any clinically significant abnormalities persisting at the end of the study/early withdrawal will be
followed by the investigator until resolution or until a clinically stable condition is reached.
The study will include the following evaluations of safety and tolerability according to the time
points provided in the Schedule of Activities.
8.2.1. 
Physical Examinations
A clinical status check should be performed within 30 minutes before the first study drug
administration.
A complete physical examination  (head/neck/thyroid; eyes/ears/nose/throat; respiratory;
cardiovascular; lymph nodes; abdomen; skin; musculoskeletal; and neurological) will be
performed at screening and on Day 28. At Days 3, 6, 14, and 21, only an abbreviated physical
exam (respiratory, cardiovascular, skin, abdomen) will be performed. At Days 1, 2, 4, 5, 7, 8, and
9, a physical examination may be performed at the investigator’s discretion. Body weight will be


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measured daily from screening until Day 6 and during on site follow-up visits, and height will be
measured at screening only.
To obtain the actual body weight, participants must be weighed lightly clothed. The height should
be measured barefoot at the screening visit.
Any clinically relevant changes occurring during the study must be recorded in the Adverse Event
Section of the CRF and in the source documentation.
8.2.2. 
Vital Signs
Temperature, pulse/heart rate, respiratory rate, peripheral capillary oxygen saturation (spO2) (not
at screening), input-output (I/O) ratio (not at screening) and blood pressure will be assessed.
Blood pressure and pulse/heart rate measurements will be assessed with a completely automated
device. Manual techniques will be used only if an automated device is not available.
Blood pressure and pulse/heart rate measurements should be preceded by at least 5 minutes of rest
in a quiet setting without distractions (eg, television, cell phones).
8.2.3. 
Electrocardiograms
During the collection of ECGs, participants should be in a quiet setting without distractions (eg,
television, cell phones). Participants should rest in a supine position for at least 5 minutes before
ECG collection and should refrain from talking or moving arms or legs. If blood sampling or vital
sign measurement is scheduled for the same time point as ECG recording, the procedures should
be performed in the following order: ECG(s), vital signs, blood draw.
At each time point at which triplicate ECGs are required, 3 individual ECG tracings should be
obtained as closely as possible in succession, but no more than 2 minutes apart. The full set of
triplicates should be completed in less than 4 minutes.
8.2.4. 
Clinical Safety Laboratory Assessments
Blood samples for serum chemistry, hematology and coagulation will be collected as noted in
Section 10.2, Appendix 2, Clinical Laboratory Tests. The investigator must review the laboratory
results, document this review, and record any clinically relevant changes occurring during the
study in the adverse event section of the CRF. The laboratory reports must be filed with the source
documents.
8.2.4.1. 
Assessment of Clinical Endpoints
Leukocyte and Platelet Counts
Blood samples will be obtained for measurement of leukocyte and platelet levels at time points
specified in the Schedule of Activities.


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Hematocrit Concentration
Blood samples will be obtained for the measurement of hematocrit concentration, at time points
specified in the Schedule ofActivities.
Any participant who has a hematocrit rise with values >20% of the baseline at any timepoint will
require full blood count (FBC) monitoring every 4 hours (at the discretion of the investigator).
8.3. 
Adverse Events, Serious Adverse Events and Other Safety Reporting
Timely, accurate, and complete reporting and analysis of safety information from clinical studies
are crucial for the protection of participants, investigators, and the sponsor, and are mandated by
regulatory agencies worldwide. The sponsor has established Standard Operating Procedures in
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety
information; all clinical studies conducted by the sponsor or its affiliates will be conducted in
accordance with those procedures.
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, surrogate,
or the participant's legally acceptable representative) for the duration of the study. All adverse
events and special reporting situations, whether serious or non-serious, will be reported from the
time a signed and dated main study ICF is obtained until completion of the participant's last study-
related procedure. No AEs will be reported for participants who only signed a pre-screening
(diagnostic) ICF and who were not enrolled in the main study.
For further details on adverse events and serious adverse events (Definitions and Classifications;
Attribution Definitions; Severity Criteria; Special Reporting Situations; Procedures) as well as
product quality complaints, refer to Section 10.4, Appendix 4, Adverse Events: Definitions and
Procedures for Recording, Evaluating, Follow-Up, and Reporting.
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious
Adverse Event Information
All Adverse Events
All adverse events andspecial reporting situations, whether serious or non-serious, will be reported
from the time a signed and dated ICF is obtained until completion of the participant's last study-
related procedure, which may include contact for follow-up of safety. For participants with only a
signed pre-screening (diagnostic) ICF (ie, for whom consent was not given to enroll in the main
study by signing the main ICF), no AEs procedure will be reported. Serious AEs, including those
spontaneously reported to the investigator within 30 days after the last dose of study intervention,
must be reported using the Serious Adverse Event Form. The sponsor will evaluate any safety
information that is spontaneously reported by an investigator beyond the time frame specified in
the protocol.
Serious Adverse Events
All serious adverse events occurring during the study must be reported to the appropriate sponsor
contact person by study-site personnel within 24 hours of their knowledge of the event.


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Information regarding serious adverse events will be transmitted to the sponsor using the Serious
Adverse Event Form and Safety Report Form of the CRF, which must be completed and reviewed
by a physician from the study site and transmitted to the sponsor within 24 hours. The initial and
follow-up reports of a serious adverse event should be transmitted electronically or by facsimile
(fax).
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events
Care will be taken not to introduce bias when detecting adverse events or serious adverse events.
Open-ended and non-leading verbal questioning of the participant is the preferred method to
inquire about adverse event occurrence.
Solicited Adverse Events
Signs and symptoms of DENV infection (DENV-infection associated AEs) will be collected by
the investigator as solicited AEs. DENV infection signs and symptoms checklist may be compiled
by any delegated study team member, and it may be used to assist in the collection of DENV
infection associated AEs.
Solicited AEs are predefined events for which the participant is specifically questioned (Table 2).
All AEs are evaluated using the gradings presented in Table 3, the US FDA Toxicity Grading
Table in Section 10.6, Appendix 6, or the rash management protocol in Section 10.7, Appendix 7.
Table 2: 
Solicited Adverse Events
Systemic Reactogenicity  
Laboratory Events
- Retro-orbital pain a 
- Decreased Hemoglobin b
- Abdominal Pain a 
- Neutropenia b
- Arthralgia a 
- Elevated ALT b
- Fever b 
- Thrombocytopenia b
- Headache b 
- Leukocytosis b
- Nausea b 
- Prolonged PT/INR b
- Fatigue b 
- Prolonged PTT b
- Myalgia b
- Loss of Appetite a
- Vomiting b
- Diarrhea b
- Rash c
ALT = alanine aminotransferase; INR = international normalized ratio; PT = prothrombin time; PTT = partial
thromboplastin time.
a Grading according to Table 3
b Grading according to the FDA Toxicity Grading Table in Section 10.5, Appendix 5.
c Grading according to the rash management protocol in Section 10.7, Appendix 7.


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Table 3: 
Grading of Solicited Adverse Events
Local Reaction to 
Injectable Product 
Mild (Grade 1) 
Moderate (Grade 
2) 
Severe (Grade 3) 
Potentially Life
Threatening
(Grade 4)
Retro-orbital pain, 
Arthralgia, 
Abdominal pain, 
Event that is easily 
tolerated, may 
require 1 dose of 
medication/treatment 
Event that interferes 
with daily activity or 
requires >1 dose of
medication/treatment
Event that prevents 
daily activity
Life-threatening
Loss of appetite 
Loss of appetite 
without alteration in 
eating habits 
Oral intake altered 
without significant 
weight loss or 
malnutrition; oral 
nutritional 
supplements indicated 
Associated with 
significant weight 
loss or malnutrition 
(e.g. inadequate oral 
caloric intake and/or
fluid intake); tube
feeding or TPN
indicated
Life threatening
consequences;
urgent intervention
indicated
Unsolicited Adverse Events
Unsolicited adverse events are all adverse events for which the participant is not specifically
questioned.
8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events
Adverse events, including pregnancy, will be followed by the investigator as specified in
Section 10.4, Appendix 4, Adverse Events: Definitions and Procedures for Recording, Evaluating,
Follow-up, and Reporting.
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events
The sponsor assumes responsibility for appropriate reporting of adverse events to the regulatory
authorities. The sponsor will also report to the investigator (and the head of the investigational
institute where required) all suspected unexpected serious adverse reactions (SUSARs). The
investigator (or sponsor where required) must report SUSARs to the appropriate Independent
Ethics Committee/Institutional Review Board (IEC/IRB) that approved the protocol unless
otherwise required and documented by the IEC/IRB. A SUSAR will be reported to regulatory
authorities unblinded. Participating investigators and IEC/IRB will receive a blinded SUSAR
summary, unless otherwise specified.
8.3.5. 
Pregnancy
All initial reports of pregnancy in female participants or partners of male participants must be
reported to the sponsor by the study-site personnel within 24 hours of their knowledge of the event
using the appropriate pregnancy notification form. Abnormal pregnancy outcomes (eg,
spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are
considered serious adverse events and must be reported using the Serious Adverse Event Form.
Any participant who becomes pregnant during the study will promptly discontinue further study
intervention but will continue study visits for additional safety follow-up.
Follow-up information regarding the outcome of the pregnancy will be required.


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8.4. 
Treatment of Overdose
For this study, any dose of JNJ-64281802 greater than the assigned daily dose within a 24-hour
time period will be considered an overdose. The sponsor does not recommend specific intervention
for an overdose.
In the event of an overdose, the investigator or treating physician should:
 
Contact the Medical Monitor immediately.
 
Closely monitor the participant for AE/SAE and laboratory abnormalities until JNJ-64281802
can no longer be detected systemically (at least 46 days).
 
Obtain a plasma sample for PK analysis as soon as possible from the date of the last dose of
study intervention if requested by the Medical Monitor (determined on a case-by-case basis).
 
Document the quantity of the excess dose as well as the duration of the overdosing in the CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator in
consultation with the Medical Monitor based on the clinical evaluation of the participant.
8.5. 
Pharmacokinetics
Venous blood samples will be used to evaluate the PK ofJNJ-64281802. Plasma collected for PK
may additionally be used to evaluate safety, pharmacokinetic (plasma protein binding, metabolites)
or antiviral activity aspects that address concerns arising during or after the study period. Genetic
analyses will not be performed on these plasma samples. Participant confidentiality will be
maintained.
8.5.1. 
Evaluations
Venous blood samples will be collected for measurement of plasma concentrations of
JNJ-64281802 at timepoints specified in the Schedule of Activities, and processed, handled and
identified according to the laboratory manual, which will be provided before the start of the study.
The exact dates and times of blood sampling must be recorded in the eCRF or laboratory
requisition form.
8.5.2. 
Analytical Procedures
Plasma samples will be analyzed to determine concentrations of JNJ-64281802 using a validated,
specific, and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method by
or under the supervision of the Sponsor’s Bioanalytical Laboratory Department of Bioanalysis.
Pharmacokinetic samples from participants receiving placebo will not be analyzed unless
unexpected results should occur.
To allow selection of samples, the bioanalytical laboratory will receive randomization lists per
treatment. Unblinding of the randomization code will be performed at the bioanalytical laboratory
only and will be subjected to a procedure that will ensure that codes will not be revealed to anyone
involved in the execution of the study.


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If required, some plasma samples may be analyzed to document the presence of circulating
metabolites using a qualified research method. In addition, plasma PK samples may be stored for
future analysis of protein binding, biomarkers or the metabolite profile.
8.5.3. 
Pharmacokinetic Parameters and Evaluations
Parameters
The following PK parameters will be derived for JNJ-64281802:
 
area under the concentration curve during one dosing interval (AUCτ) (if data allows)
 
pre-dose concentration (Ctrough) and
 
maximum observed plasma concentration (Cmax) (if data allows).
Actual sampling times will be checked for major aberrations. In case a major aberration occurs for
an actual sampling time of >20.00% deviation from the scheduled time, this plasma concentration
will be excluded from descriptive statistics in the plasma concentration table.
In a subset of 20 participants, total JNJ-64281802 plasma concentration, the fraction unbound (fu)
of JNJ-64281802 and alpha-1 acid glycoprotein may be determined at selected time points, as
indicated in the Schedule of Activities to assess protein binding at the discretion of the sponsor.
Based on the individual plasma concentration-time data, using the actual dose taken and the actual
sampling times, PK parameters and exposure information of JNJ-64281802 will be derived.
Pharmacokinetic/Pharmacodynamic Evaluations
Pharmacokinetic-pharmacodynamic evaluations may be performed to evaluate the relationship
between the PK and the antiviral activity of JNJ-64281802, as data allow.
In addition, the relationship between the PK and selected safety endpoints may be explored, as
data allow and at the discretion of the sponsor.
8.6. 
Genetics
A blood sample will be collected from all participants for the pharmacogenomic component of the
study.
8.6.1. 
Human Leucocyte Antigen Typing and Pharmacogenomics
Assessments
One blood sample for human leucocyte antigen (HLA) typing and for pharmacogenomics (DNA)
research will be taken, preferably at baseline (ie, before first dose of study intervention). This
sample can be used to determine the HLA type of the participant. In addition, this sample can be
used to investigate the potential association of genetic factors with PK, antiviral activity or safety
of JNJ-64281802 or the DENV infection.


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These analyses may be conducted under the supervision of the sponsor and may be reported
separately from the main study report. If necessary, the sample may be collected at a later time
point without constituting a protocol deviation.
8.7. 
Biomarkers
The study includes collection of blood samples for exploratory analysis. Sampling will be
performed for all participants at the time points indicated in the Schedule of Activities.
Samples for host RNA might be used for transcriptional profiling for example using microarray
technology. Serum samples for protein analyses might be analyzed using assays such as ELISA or
Luminex.
Examples of analytes that could be investigated by mRNA assessment and/or protein
measurements include, but are not limited to, ISG-15, interleukin (IL)-2, IL-6, IL-8, IL-10, IL-12,
IL-15, IL-18, tumor necrosis factor (TNF)-α, IFN-γ, and chemokine (C-X-C motif) ligand 10
(CXCL10, also referred to as interferon-inducible protein 10 [IP-10]).
Samples can only be used for research related to JNJ-64281802 or DENV infection or may be used
to develop tests/assays related to JNJ-64281802 or DENV infection.
8.8. 
Immune Assessments
8.8.1. 
Humoral Immune Response
Blood samples will be obtained for the assessment of antibody response. Anti-DENV IgG and IgM
will be measured using an in-house developed or commercial ELISA and the IgG pattern will be
used to make a distinction between primary and secondary dengue infection. Presence of
neutralizing antibodies against DENV will be determined using an assay such as flow cytometry-
based neutralization assay.
8.8.2. 
Cellular Immune Response
Peripheral blood mononuclear cell (PBMC) samples may be analyzed in a subset of participants
to assess DENV-specific T and B cell immune responses by assays such as enzyme-linked
immunospot assay (ELISpot) and/or intracellular cytokine staining (ICS) after stimulation with
DENV-specific antigens. ELISpot detects T cells that secrete gamma interferon (IFN-γ) or B cells
that secreted IgG and/or IgM in response to an antigenic stimulation, whereas ICS determines the
frequency of CD4+ and CD8+ T cells secreting cytokines such as IFN-γ, interleukin (IL)-2 and
tumor necrosis factor (TNF)-α.
Additional experiments may be performed to further phenotypically and functionally characterize
PBMCs by flow cytometry or other methods including but not limited to CyTOF, to evaluate innate
and adaptive immune responses. Leftover PBMC samples may be used at the sponsor's discretion
for additional exploratory research related to DENV infection or JNJ-64281802 (safety/antiviral
activity).


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9. 
STATISTICAL CONSIDERATIONS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general
description of the statistical methods to be used to analyze the antiviral activity and safety data is
outlined below. Specific details will be provided in the Statistical Analysis Plan.
9.1. 
Statistical Hypotheses
The primary hypothesis of this study is that JNJ-64281802 is superior to placebo with respect to
reduction in viral load in participants with a primary DENV infection, as measured by area under
the log10-transformed DENV RNA viral load curve from baseline on Day 1 until Day 5.
9.2. 
Sample Size Determination
The study will recruit in total 150 participants, with the primary objective of investigating the
antiviral activity of JNJ-64281802 versus placebo based on DENV RNA in primary DENV
infection and with an objective to describe the safety and tolerability of JNJ-64281802 in
participants with DENV infection. The sample size can be revised after an interim analysis on the
proportion of primary versus secondary DENV infections (refer to Section 9.5, InterimAnalysis).
For the objective of antiviral activity in participants with a primary DENV infection, the hypothesis
is that the intervention effect is superior to placebo as measured on the DENV RNA log10 viral
load curve from baseline on Day 1 until Day 5.
To assess sample size requirements for this hypothesis, data of 47 DENV RNA curves were
estimated similar to the DENV RNA curves graphically presented in the balapiravir trial. All
curves were considered as balapiravir did not have an effect on the viral load. A limit of detection
of 2.3 log copies/mL was assumed. Although the majority of the population included in the
balapiravir trial suffered from a secondary infection0, these estimated DENV RNA curves were
considered representative for a primary infected dengue population. As the clearance of DENV
RNA occurs earlier and faster in patients with secondary dengue, this is a conservative
assumption.0
The 47 estimated DENV RNA curves were used to calculate the means, standard deviations and
correlations of the log10 viral loads over time. These calculated values were thereafter used to
simulate 10,000 trials, each with a sample size of 80 participants. A treatment effect of 0.30 log10
copies/mL per day DENV RNA clearance on top of placebo, or two-fold reduction of the viral
load was applied. Based on these 10,000 simulated trials and using a general linear model with
treatment regimen as fixed factor and baseline log10 viral load as a covariate, a sample size of
80 participants (40 per group) was estimated to provide a power of at least 80% at the one-sided
5% significance level to detect an intervention effect of 0.30 log10 copies/day additional DENV
RNA clearance when compared to placebo.
The specificity of the DENV NS1 testing at baseline is estimated to be 98% which entails that 2%
of participants that will be enrolled will not be evaluable for efficacy. Based on literature,0 it is
estimated that approximately 60% of the total population will have a primary infection.
Furthermore, it is anticipated that approximately 4% of the enrolled participants drop-out for other


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reasons. The study will therefore need to recruit a total of 150 participants in order to achieve a
sample of 84 participants to achieve >80% power on the primary hypothesis.
For the objective of safety assessment, the probability was calculated to observe an (S)AE that has
a true incidence of 1% which would be 53% with a total sample size of 75 participants on active
treatment; the probability to observe an (S)AE with a true incidence of 0.1%, 0.5% and 0.8% is
7%, 31% and 45%, respectively.
9.3. 
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population 
Description
Enrolled 
All participants who sign the informed consent form
Randomized 
All participants who were randomized into the study
Safety  
All randomized participants who take at least 1 dose of study intervention.
PK 
All participants who receive at least 1 dose of study drug and who have at least 1 plasma
concentration data value after dosing.
Intent-to-treat 
infected (ITT-i) 
All randomized participants with a DENV infection who received at least one dose of the
study intervention
Per-protocol 
All participants who are included in the ITT-I population without protocol violations that
affect the antiviral activity assessment.
9.4. 
Statistical Analyses
The statistical analysis plan will be finalized prior to interim database lock and it will include a
more technical and detailed description of the statistical analyses described in this section. This
section is a summary of the planned statistical analyses of the most important endpoints including
primary and key secondary endpoints. Exploratory subgroup analysis can be performed for the
different drug formulations used in the trial.
9.4.1. 
General Considerations
Participants will be classified prior to data base lock as being non-DENV infected, primary DENV
infected or secondary DENV infected based on all available virological information. The decision
whether the participant had a primary or secondary infection will be based on the IgG profile.
An interim analysis will be performed when at least 50 participants with a primary dengue
infection reached Day 28 or discontinued earlier. Based on the results of this analysis, the DRC
and study team can take the decision to stop the trial for futility.
The primary analysis will be performed when all participants reached Day 28 or discontinued
earlier. A one-sided test at the 5% significance level will be used for the hypothesis that
JNJ-64281802 is superior to placebo in participants with a primary infection.
The final analysis will be performed when the last visit of the last participant in the study occurred.
9.4.2. 
Antiviral Activity Analysis
The intent-to-treat infected (ITT-i) population will be used for all antiviral activity analyses.
Treatment assignment for this population will be defined by actual treatment received.


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9.4.2.1. 
Primary Endpoint(s)
The difference in area under the log10-transformed DENV RNA viral load curves from
immediately prior to first dose (baseline)until Day 5 for JNJ-64281802 versus placebo dosing will
be derived from a mixed model with treatment regimen and the stratification factors as fixed
factors and baseline log10 viral load as a covariate, calculating least square mean differences,
including the 90% 2-sided confidence intervals in the ITT-I population with a primary dengue
infection based on IgG profile.
9.4.2.2. 
Secondary Endpoint(s)
Descriptive statistics and mean (and standard error) graphs will be shown for the log10 DENV
RNA and viremia actual values and changes from baseline over time in participants with primary
DENV infection.
In participants with primary DENV infection, the proportion of participants within the DENV
RNA and viremia categories (≥lower limit of quantification [LLOQ], <LLOQ target detected and,
<limit of detection [LOD] target not detected) will be shown in a frequency tabulation per analysis
time point.
Time to undetectable DENV RNA/viremia will be analysed using Kaplan-Meier estimates
analysis. A summary table including number of participants with primary DENV infection
included in the analysis, number of participants censored, 25th  and 75th  percentiles and median
time-to event, with 95% confidence intervals based on log-log transformation method, will be
presented. The data will be presented graphically using the Kaplan-Meier estimate of the survival
function by treatment.
Descriptive statistics will also be used to describe the IgM and IgG response. The proportion of
participants with antibody positivity and the titer and timing of the antibody response will be
determined. Descriptive statistics will include sample size, mean, standard deviation, coefficient
of variation, geometric mean, median, minimum, and maximum.
9.4.3. 
Safety Analyses
All participants enrolled into the study who received at least one dose of study intervention will
be included in the safety population. Participants in this population will be defined by the study
intervention actually received, not by randomization assignment. The safety population will be
used for all safety analyses.
Safety data will be presented descriptively. No statistical testing of safety data is planned.
Adverse Events
The verbatim terms used in the CRF by investigators to identify adverse events will be coded using
the Medical Dictionary for Regulatory Activities (MedDRA). Any AE occurring at or after the
initial administration of study intervention through the day of last dose plus 20 days is considered
to be treatment emergent. All reported adverse events will be included in the analysis. For each


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adverse event, the percentage of participants who experience at least 1 occurrence of the given
event will be summarized by intervention group.
Summaries, listings, datasets, or participant narratives may be provided, as appropriate, for those
participants who die, who discontinue intervention due to an adverse event, or who experience a
severe or a serious adverse event.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Reference ranges and markedly
abnormal results (specified in the Statistical Analysis Plan) will be used in the summary of
laboratory data. Descriptive statistics will be calculated for each laboratory analyte at baseline and
for observed values and changes from baseline at each scheduled time point. Changes from
baseline results will be presented in pre- versus post-intervention cross-tabulations (with classes
for below, within, and above normal ranges). Frequency tabulations of the laboratory abnormalities
will be made. A listing of participants with any laboratory results outside the reference ranges will
be provided. A listing of participants with any markedly abnormal laboratory results will also be
provided.
Electrocardiogram
The effects on cardiovascular variables will be evaluated by means of descriptive statistics and
frequency tabulations. These tables will include observed values and changes from baseline values
(the initial ECG will be used as baseline). Electrocardiogram data will be summarized by ECG
parameter. Descriptive statistics will be calculated at baseline and for observed values and changes
from baseline at each scheduled time point. Frequency tabulations of the abnormalities will be
made.
Vital Signs
Vital signs including pulse/heart rate, respiratory rate, and blood pressure (systolic and diastolic)
will be summarized over time, using descriptive statistics and/or graphically. The percentage of
participants with values beyond clinically important limits will be summarized.
Physical Examinations
Physical examination findings will be summarized at each scheduled time point. Frequency
tabulations of the abnormalities will be made.
9.4.4. 
Immune Analysis
9.4.4.1. 
Humoral Immune Analyses
Please refer to Section 9.4.4.2 for the analysis of the IgM and IgG response.
Descriptive statistics will be used to describe the neutralizing antibody response. The proportion
of participants with antibody positivity, including neutralizing antibodies for all 4 DENV
serotypes, and the titer and timing of the antibody response will be determined.


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Descriptive statistics will include sample size, mean, SD, CV, geometric mean, median, minimum,
and maximum.
9.4.4.2. 
Cellular Immune Analyses
Descriptive statistics will be used to describe the magnitude of the IFN-γ T cell response or the
CD4+ and CD8+ T cell responses (expressing at least 1 cytokine such as IL-2, TNF-α or IFN-γ
specific to any antigen) or B cell response as defined by ELISpot and/or ICS, respectively. Changes
from baseline (if present) will also be tabulated for PBMCs during the dosing and on-site follow-
up phase (Day 28, optional). The proportion of participants with positive responses based on the
magnitude of the IFN-γ T cell response or the CD4+ or CD8+ T cells expressing at least 1 of the
cytokines amongst IL-2, TNF-α or IFN-γ for 1 of the antigens as defined by ELISpot and/or ICS,
respectively, or B cells that secrete IgG and/or IgM will be determined.
Descriptive statistics will include sample size, mean, SD, CV, geometric mean, median, minimum,
and maximum.
9.4.5. 
Pharmacokinetic Analyses
All participants having received at least one dose of study intervention and having at least one PK
parameter value will be included in the PK analysis. All participants having received at least one
dose of study intervention and having at least one plasma concentration data value after
administration will be included in the descriptive statistics.
Descriptive statistics will be calculated for the plasma concentrations of JNJ-64281802 and for the
derived PK parameters, as applicable. Statistics include sample size (n), mean, SD, CV, geometric
mean, median, minimum, and maximum.
For each participant, plasma concentration-time data will be graphically presented. Similarly,
graphs of the mean plasma concentration-time profiles and overlay graphs with combined
individual plasma concentration-time profiles will be produced. Pharmacokinetic parameters will
be subjected to an exploratory graphical analysis including various transformations in order to get
a general overview.
Special attention will be paid to the plasma concentrations and PK parameters of those participants
who have discontinued the study for an AE, or who experienced an AE of at least grade 3, or a
serious adverse event (SAE).
Endpoints and analyses related to PK are:
 
PK parameters of JNJ-64281802 in plasma
 
Relationship between one or more PK parameters and antiviral activity endpoints (eg, DENV
RNA AUC)
 
Relationship between one or more PK parameters and safety data, at the discretion of the
sponsor.


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If deemed necessary, population PK analysis of plasma concentration-time data of JNJ-64281802
may be performed using nonlinear mixed-effects modelling. A snapshot date for PK samples to be
analyzed will be defined, if required. Samples collected before this date will be included in a
population PK analysis. Samples collected after the snapshot date may be included in a population
PK re-analysis at a later date. If conducted, details will be given in a population PK analysis plan
and the results of the population PK analysis will be presented in a separate report.
9.4.6. 
Pharmacokinetic/Pharmacodynamic Analyses
Relationships of PK parameters for JNJ-64281802 as applicable, with selected antiviral activity
and with selected safety endpoints may be evaluated, applying graphical tools and, if feasible,
statistical models, as data allow. If conducted, analysis results of the relationship between the PK
and selected safety endpoints will be presented in a separate report.
9.4.7. 
Biomarkers Analyses
Statistical approaches to explore correlations between clinical outcome and blood biomarkers vary
and depend on the different data types of the applied technology platforms, as well as on the extent
of observed differences between participants. Analyses will be conducted at the sponsor’s
discretion, will always be under the sponsor's supervision, and results will be presented in the
clinical study report or a separate report.
9.4.8. 
Viral Genome Sequence Analyses
The results of DENV  viral genome sequencing will be evaluated by the sponsor virologist.
Relevant changes in the DENV genome will be tabulated and described for participants with
detectable DENV RNA during the study period.
Additional exploratory characterization of the DENV viral genome sequence and phenotype may
be performed and reported separately.
9.4.9. 
Human Leukocyte Antigen Typing and Pharmacogenomic Analyses
The statistical approach for analysing the exploratory host DNA research may depend on the
objective of the analyses (antiviral activity, safety, and PK) and possibly relevant genes at the time
of analysis. Analyses will be conducted at the sponsor’s discretion, will always be under the
sponsor's supervision, and results will be presented in the clinical study report or a separate report.
9.5. 
Interim Analysis
An interim analysis will be performed when at least 50 participants with a primary dengue
infection reached Day 28 or discontinued earlier to check for futility. Conditional power values
will be calculated using the observed data and assuming that in the remainder of the trial the effect
size used for the sample size calculation will be present. The conditional power provides
quantification of the likelihood that the study intervention will ultimately be successful, ie the
probability of claiming a study intervention effect at the completion of the study based on the
available interim data. A futility stopping boundary of 25% for the conditional power will be used.
This is considered a conservative boundary also reflecting that in this early stage of development
it may be best to complete the study to have a larger database to draw conclusions from. In case


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the probability of a successful trial is lower than the futility boundary, the DRC and study team
can take the decision to stop for futility  after evaluation of all available data. Assuming the
outcome for the primary endpoint as used for the sample size calculations was true, with a
treatment effect of 0.30 log10 copies/mL per day DENV RNA clearance on top of placebo, the
chance of reaching the futility stopping boundary at the time of the IA is at most 5%. Otherwise,
if there is no treatment effect at all, the chance of reaching the futility stopping boundary is at least
60%. The proportion of primary infections will be assessed as well during this interim analysis. If
the proportion is lower than expected 60%, the sample size may be increased.
The Statistical Analysis Plan will describe the planned interim analyses in greater detail.
9.6. 
Data Review Committee
An internal DRC will be established as noted in Committees Structure in Appendix 3, Regulatory,
Ethical, and Study Oversight Considerations.


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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Abbreviations
AE 
adverse event
ALT  
alanine aminotransferase
API 
active pharmaceutical ingredient
APTT  
activated partial thromboplastin time
AST  
aspartate aminotransferase
AUC  
area under the plasma analyte concentration-time curve
-hCG  
beta-human chorionic gonadotropin
bid 
twice daily
BMI 
body mass index
BQL 
below quantification limit
BUN  
blood urea nitrogen
CFR  
Code of Federal Regulations
CI 
confidence interval
CN  
cyanide
COVID-19 
coronavirus disease 2019
CRC  
clinical research coordinator
CRF  
Case Report Form
CTCM  
Ca2+ transient measured in human cardiomyocytes
CV  
coefficient of variation
CYP  
cytochrome P450
D 
dose
DBP  
diastolic blood pressure
DENV  
dengue virus
DHF  
dengue hemorrhagic fever
DSS  
dengue shock syndrome
DLT  
dose limiting toxicity
DMID  
Division of Microbiology and Infectious Diseases
DNA  
deoxyribonucleic acid
DRC  
data review committee
DRM  
data review meeting
DSM  
Diagnostic and Statistical Manual of Mental Disorders
EC50 
50% effective concentration
ECG  
electrocardiogram
eDC  
electronic Data Capture
EMA  
European Medicines Agency
eSource 
electronic source data
FDA  
Food and Drug Administration
FSH  
follicle-stimulating hormone
fu 
fraction unbound
GCP  
Good Clinical Practice
GGT  
gamma-glutamyltransferase
GLP  
Good Laboratory Practice
GP  
general practitioner
GSH  
glutathione
hAhR  
human aryl hydrocarbon receptor
HCC  
healthcare center
HCP  
healthcare provider
HDL 
high-density lipoprotein
hERG  
human ether-à-go-go-
HLA  
human leukocyte antigen
IB  
Investigator’s Brochure
IC50 
50% inhibitory concentration
ICF  
Informed Consent Form
ICH  
International Council on Harmonisation


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IEC  
Independent Ethics Committee
INR 
international normalized ratio
IP  
Investigational Product
IRB  
Institutional Review Board
ITT-i 
intent-to-treat infected
i.v. 
intravenous(ly)
LC-MS/MS 
liquid chromatography-mass spectrometry/mass spectrometry
LDH 
lactic dehydrogenase
LDL 
low-density lipoprotein
LOD  
limit of detection
LS  
least square
MD  
medical doctor
MDRD  
Modification of Diet in Renal Disease
MedDRA  
Medical Dictionary for Regulatory Activities
MEC  
minimal effective concentration
MTD  
maximum tolerated dose
n 
sample size
NOAEL 
no observed adverse effect level
NS1 
non-structural 1 protein
NS4B  
non-structural protein 4B
PEG400 
polyethylene glycol 400
PFU  
plaque forming units
P-gp 
P-glycoprotein
PK 
pharmacokinetic
PQC  
product quality complaint
Pre-IND  
Pre-Investigational New Drug application
PT  
prothrombin time
qd 
once daily
RBC  
red blood cell
RNA  
ribonucleic acid
SAD  
single ascending dose
SAE 
serious adverse event
SAP  
Statistical Analysis Plan
SBP 
systolic blood pressure
SD 
standard deviation
SPF  
skin protection factor
SUSAR  
suspected unexpected serious adverse reactions
UGT  
UDP-glucuronosyltransferase
ULN  
upper limit of laboratory normal range
US  
United States
UV  
ultraviolet
WBC  
white blood cell
WHO  
World Health Organization
Definitions of Terms
Electronic source
system
Contains data traditionally maintained in a hospital or clinic record to document medical
care or data recorded in a CRF as determined by the protocol. Data in this system may be
considered source documentation.
AUCτ
area under the concentration curve during one dosing interval
Cmax
maximum observed analyte concentration
Ctrough
observed analyte concentration just prior to the beginning or at the end of a dosing interval;




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10.3. Appendix 3: Regulatory, Ethical, and Study Oversight Considerations
REGULATORY AND ETHICAL CONSIDERATIONS
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and
country-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing,
conducting, recording, and reporting studies that involve the participation of human participants.
Compliance with this standard provides public assurance that the rights, safety, and well-being of
study participants are protected, consistent with the principles that originated in the Declaration of
Helsinki, and that the study data are credible.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment by
the sponsor. All protocol amendments must be issued by the sponsor and signed and dated by the
investigator. Protocol amendments must not be implemented without prior IEC/IRB approval, or
when the relevant competent authority has raised any grounds for non-acceptance, except when
necessary to eliminate immediate hazards to the participants, in which case the amendment must
be promptly submitted to the IEC/IRB and relevant competent authority. Documentation of
amendment approval by the investigator and IEC/IRB must be provided to the sponsor. When the
change(s) involve only logistic or administrative aspects of the study, the IEC/IRB (where
required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable,
the investigator or other physician in attendance will contact the appropriate sponsor representative
listed in the Contact Information page(s), which will be provided as a separate document. Except
in emergency situations, this contact should be made before implementing any departure from the
protocol. In all cases, contact with the sponsor must be made as soon as possible to discuss the
situation and agree on an appropriate course of action. The data recorded in the CRF and source
documents will reflect any departure from the protocol, and the source documents will describe
this departure and the circumstances requiring it.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities
in each respective country, if applicable. A study may not be initiated until all local regulatory
requirements are met.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study intervention
to the study site:


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 
Protocol and amendment(s), if any, signed and dated by the principal investigator
 
A copy of the dated and signed (or sealed, where appropriate per local regulations), written
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if
applicable, participant compensation programs. This approval must clearly identify the
specific protocol by title and number and must be signed (or sealed, where appropriate per
local regulations) by the chairman or authorized designee.
 
Name and address of the IEC/IRB, including a current list of the IEC/IRB members and their
function, with a statement that it is organized and operates according to GCP and the
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, from
the IEC/IRB, a general statement may be substituted for this list. If an investigator or a
member of the study-site personnel is a member of the IEC/IRB, documentation must be
obtained to state that this person did not participate in the deliberations or in the vote/opinion
of the study.
 
Regulatory authority approval or notification, if applicable
 
Signed and dated statement of investigator (eg, Form FDA 1572), if applicable
 
Documentation of investigator qualifications (eg, curriculum vitae)
 
Completed investigator financial disclosure form from the principal investigator, where
required
 
Signed and dated clinical trial agreement, which includes the financial agreement
 
Any other documentation required by local regulations
The following documents must be provided to the sponsor before enrollment of the first
participant:
 
Completed investigator financial disclosure forms from all subinvestigators
 
Documentation of subinvestigator qualifications (eg, curriculum vitae)
 
Name and address of any local laboratory conducting tests for the study, and a dated copy of
current laboratory normal ranges for these tests, if applicable
 
Local laboratory documentation demonstrating competence and test reliability
(eg, accreditation/license), if applicable
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the IEC/IRB
with current and complete copies of the following documents (as required by local regulations):
 
Final protocol and, if applicable, amendments
 
Sponsor-approved ICF (and any other written materials to be provided to the participants)
 
IB (or equivalent information) and amendments/addenda
 
Sponsor-approved participant recruiting materials
 
Information on compensation for study-related injuries or payment to participants for
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 
Investigator's curriculum vitae or equivalent information (unless not required, as documented
by the IEC/IRB)
 
Information regarding funding, name of the sponsor, institutional affiliations, other potential
conflicts of interest, and incentives for participants
 
Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final protocol,
amendments (if any, excluding the ones that are purely administrative, with no consequences for
participants, data or study conduct, unless required locally), the ICF, applicable recruiting
materials, and participant compensation programs, and the sponsor has received a copy of this
approval. This approval letter must be dated and must clearly identify the IEC/IRB and the
documents being approved.
Approval for the collection of optional samples for future research and for the corresponding
consent must be obtained from the IEC/IRB. Approval for the protocol can be obtained
independent of this optional research component.
During the study the investigator (or sponsor where required) will send the following documents
and updates to the IEC/IRB for their review and approval, where appropriate:
 
Protocol amendments (excluding the ones that are purely administrative, with no
consequences for participants, data or study conduct)
 
Revision(s) to ICF and any other written materials to be provided to participants
 
If applicable, new or revised participant recruiting materials approved by the sponsor
 
Revisions to compensation for study-related injuries or payment to participants for
participation in the study, if applicable
 
New edition(s) of the IB and amendments/addenda
 
Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at
least annually)
 
Reports of adverse events that are serious, unlisted/unexpected, and associated with the study
intervention
 
New information that may adversely affect the safety of the participants or the conduct of the
study
 
Deviations from or changes to the protocol to eliminate immediate hazards to the participants
 
Report of deaths of participants under the investigator's care
 
Notification if a new investigator is responsible for the study at the site
 
Development Safety Update Report and Line Listings, where applicable
 
Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no
consequences for participants, data or study conduct), the amendment and applicable ICF revisions


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must be submitted promptly to the IEC/IRB for review and approval before implementation of the
change(s).
At least once a year, the IEC/IRB will be asked to review and reapprove this study, where required.
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB about
the study completion (if applicable, the notification will be submitted through the head of
investigational institution).
Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise help
ensure access to the developed product if the need for the product persists, unless explicitly
addressed as a specific ethical consideration in Section 4.2.1, Study-Specific Ethical Design
Considerations.
Other Ethical Considerations
For study-specific ethical design considerations, refer to Section 4.2.1.
FINANCIAL DISCLOSURE
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial
information in accordance with local regulations to allow the sponsor to submit complete and
accurate financial certification or disclosure statements to the appropriate regulatory authorities.
Investigators are responsible for providing information on financial interests during the course of
the study and for 1 year after completion of the study.
Refer to Required Prestudy Documentation (above) for details on financial disclosure.
INFORMED CONSENT PROCESS
Each participant must give written consent according to local requirements after the nature of the
study has been fully explained. The ICF(s) must be signed before performance of any study-related
activity. The ICF(s) that is/are used must be approved by both the sponsor and by the reviewing
IEC/IRB and be in a language that the participant can read and understand. The informed consent
should be in accordance with principles that originated in the Declaration of Helsinki, current ICH
and GCP guidelines, applicable regulatory requirements, and sponsor policy.
Prior to signing the ICF  for the study, participants may specifically allow for ambulatory NS1
rapid testing performed by a member of the mobile clinical team by signing the pre-screening
(diagnostic) ICF.
Before enrollment in the study, the investigator or an authorized member of the study-site
personnel must explain to potential participants the aims, methods, reasonably anticipated benefits,
and potential hazards of the study, and any discomfort participation in the study may entail.
Participants will be informed that their participation is voluntary and that they may withdraw
consent to participate at any time. They will be informed that choosing not to participate will not


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affect the care the participant will receive for the treatment of his or her disease. Participants will
be told that alternative treatments are available if they refuse to take part and that such refusal will
not prejudice future treatment. Finally, they will be told that the investigator will maintain a
participant identification register for the purposes of long-term follow up if needed and that their
records may be accessed by health authorities and authorized sponsor personnel without violating
the confidentiality of the participant, to the extent permitted by the applicable law(s) or regulations.
By signing the ICF the participant is authorizing such access, which includes permission to obtain
information about his or her survival status. It also denotes that the participant agrees to allow his
or her study physician to recontact the participant for the purpose of obtaining consent for
additional safety evaluations, and subsequent disease-related treatments, if needed.
The participant will be given sufficient time to read the ICF and the opportunity to ask questions.
After this explanation and before entry into the study, consent should be appropriately recorded
by means of the participant's personally dated signature. After having obtained the consent, a copy
of the ICF must be given to the participant.
Participants will be asked for consent to provide optional samples for future research. After
informed consent for the study is appropriately obtained, the participant or his or her legally
acceptable representative will be asked to sign and personally date a separate part in the ICF
indicating agreement to participate in the optional research component. Refusal to participate in
the optional research will not result in ineligibility for the study. A copy of this signed ICF will be
given to the participant.
Where local regulations require, a separate consent may be requested for the required DNA
component of the study.
If the participant or legally acceptable representative is unable to read or write, an impartial witness
should be present for the entire informed consent process (which includes reading and explaining
all written information) and should personally date and sign the ICF after the oral consent of the
participant or legally acceptable representative is obtained.
DATA PROTECTION
Privacy of Personal Data
The collection and processing of personal data from participants enrolled in this study will be
limited to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality
and compliance with applicable data privacy protection laws and regulations. Appropriate
technical and organizational measures to protect the personal data against unauthorized disclosures
or access, accidental or unlawful destruction, or accidental loss or alteration must be put in place.
Sponsor personnel whose responsibilities require access to personal data agree to keep the identity
of participants confidential.


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The informed consent obtained from the participant includes explicit consent for the processing of
personal data and for the investigator/institution to allow direct access to his or her original medical
records (source data/documents) for study-related monitoring, audit, IEC/IRB review, and
regulatory inspection. This consent also addresses the transfer of the data to other entities and to
other countries.
The participant has the right to request through the investigator access to his or her personal data
and the right to request rectification of any data that are not correct or complete. Reasonable steps
will be taken to respond to such a request, taking into consideration the nature of the request, the
conditions of the study, and the applicable laws and regulations.
Exploratory DNA research is not conducted under standards appropriate for the return of data to
participants. In addition, the sponsor cannot make decisions as to the significance of any findings
resulting from exploratory research. Therefore, exploratory research data will not be returned to
participants or investigators, unless required by law or local regulations. Privacy and
confidentiality of data generated in the future on stored samples will be protected by the same
standards applicable to all other clinical data.
LONG-TERM RETENTION OF SAMPLES FOR ADDITIONAL FUTURE RESEARCH
Samples collected in this study may be stored for up to 15 years (or according to local regulations)
for additional research. Samples will only be used to understand JNJ-64281802 to understand
dengue pathology, to understand differential intervention responders, and to develop tests/assays
related to JNJ-64281802 and antiviral activity. The research may begin at any time during the
study or the post-study storage period.
Stored samples will be coded throughout the sample storage and analysis process and will not be
labeled with personal identifiers. Participants may withdraw their consent for their samples to be
stored for research (refer to Section 7.2.1, Withdrawal From the Use of Research Samples). In
such cases, the samples will be discarded after the initial sample storage and analysis process.
COMMITTEES STRUCTURE
Data Review Committee
An internal DRC will be established to ensure the continuing safety of the participants enrolled in
this study. This committee will consist of a Global Medical Safety (GMS) therapeutic area safety
head, a clinician, a clinical pharmacologist, a virologist, and a statistician, none of whom will be
part of the study team or involved in the conduct of the study.
Any deaths related to dengue, admission to the intensive care unit or severe dengue (DHF/DSS)
will trigger a safety data review by the DRC. If, in the judgment of the investigator and/or the
sponsor’s study-responsible physician, a significant or unexpected safety event occurs, the DRC
will review unblinded safety data. Quarterly (every 3 months or when 50 participants are enrolled,
whichever comes first), a DRC safety analysis where DRC members review unblinded data, will
take place. After the review, the DRC will make recommendations regarding the continuation of
the study. The DRC responsibilities, authorities, and procedures will be documented in its charter.


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PUBLICATION POLICY/DISSEMINATION OF CLINICAL STUDY DATA
All information, including but not limited to information regarding JNJ-64281802 or the sponsor's
operations (eg, patent application, formulas, manufacturing processes, basic scientific data, prior
clinical data, formulation information) supplied by the sponsor to the investigator and not
previously published, and any data, including pharmacogenomic or exploratory biomarker
research data, generated as a result of this study, are considered confidential and remain the sole
property of the sponsor. The investigator agrees to maintain this information in confidence and use
this information only to accomplish this study and will not use it for other purposes without the
sponsor's prior written consent.
The investigator understands that the information developed in the study will be used by the
sponsor in connection with the continued development of JNJ-64281802, and thus may be
disclosed as required to other clinical investigators or regulatory agencies. To permit the
information derived from the clinical studies to be used, the investigator is obligated to provide
the sponsor with all data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and
will contain data from all study sites that participated in the study as per protocol. Recruitment
performance or specific expertise related to the nature and the key assessment parameters of the
study will be used to determine a coordinating investigator for the study. Results of
pharmacogenomic or exploratory biomarker analyses performed after the Clinical Study Report
has been issued will be reported in a separate report and will not require a revision of the Clinical
Study Report.
Study participant identifiers will not be used in publication of results. Any work created in
connection with performance of the study and contained in the data that can benefit from copyright
protection (except any publication by the investigator as provided for below) shall be the property
of the sponsor as author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal
Editors (ICMJE) guidelines, the sponsor shall have the right to publish such primary data and
information without approval from the investigator. The investigator has the right to publish study
site-specific data after the primary data are published. If an investigator wishes to publish
information from the study, a copy of the manuscript must be provided to the sponsor for review
at least 60 days before submission for publication or presentation. Expedited reviews will be
arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in
writing, the investigator will withhold such publication for up to an additional 60 days to allow for
filing of a patent application. In the event that issues arise regarding scientific integrity or
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor will
not mandate modifications to scientific content and does not have the right to suppress information.
For multicenter study designs and sub-study approaches, secondary results generally should not
be published before the primary endpoints of a study have been published. Similarly, investigators
will recognize the integrity of a multicenter study by not submitting for publication data derived
from the individual study site until the combined results from the completed study have been


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submitted for publication, within 18 months after the study end date, or the sponsor confirms there
will be no multicenter study publication. Authorship of publications resulting from this study will
be based on the guidelines on authorship, such as those described in the ICMJE Recommendations
for the Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals, which
state that the named authors must have made a significant contribution to the conception or design
of the work; or the acquisition, analysis, or interpretation of the data for the work; and drafted the
work or revised it critically for important intellectual content; and given final approval of the
version to be published; and agreed to be accountable for all aspects of the work in ensuring that
questions related to the accuracy or integrity of any part of the work are appropriately investigated
and resolved.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence of and the results of clinical studies as required
by law. The disclosure of the final study results will be performed after the end of study in order
to ensure the statistical analyses are relevant.
DATA QUALITY ASSURANCE
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified
investigators and appropriate study sites, review of protocol procedures with the investigator and
study-site personnel before the study, and periodic monitoring visits by the sponsor, and direct
transmission of clinical laboratory data from a central laboratory  into the sponsor's data base.
Written instructions will be provided for collection, handling, storage, and shipment of samples.
Guidelines for CRF completion will be provided and reviewed with study-site personnel before
the start of the study.
The sponsor will review CRF for accuracy and completeness during on-site monitoring visits and
after transmission to the sponsor; any discrepancies will be resolved with the investigator or
designee, as appropriate. After upload of the data into the study database they will be verified for
accuracy and consistency with the data sources.
CASE REPORT FORM COMPLETION
Case report forms are prepared and provided by the sponsor for each participant in electronic
format. All data relating to the study must be recorded in CRF. All CRF entries, corrections, and
alterations must be made by the investigator or authorized study-site personnel. The investigator
must verify that all data entries in the CRF are accurate and correct.
The study data will be transcribed by study-site personnel from the source documents onto an
electronic CRF, if applicable. Study-specific data will be transmitted in a secure manner to the
sponsor.
Worksheets may be used for the capture of some data to facilitate completion of the CRF. Any
such worksheets will become part of the participant's source documents. Data must be entered into


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CRF in English. The CRF must be completed as soon as possible after a participant visit and the
forms should be available for review at the next scheduled monitoring visit.
All participative measurements (eg, pain scale information or other questionnaires) will be
completed by the same individual who made the initial baseline determinations whenever possible.
If necessary, queries will be generated in the eDC tool. If corrections to a CRF are needed after
the initial entry into the CRF, this can be done in either of the following ways:
 Investigator and study-site personnel can make corrections in the eDC tool at their own
initiative or as a response to an auto query (generated by the eDC tool).
 Sponsor or sponsor delegate can generate a query for resolution by the investigator and study-
site personnel.
SOURCE DOCUMENTS
At a minimum, source documents consistent in the type and level of detail with that commonly
recorded at the study site as a basis for standard medical care must be available for the following:
participant identification, eligibility, and study identification; study discussion and date of signed
informed consent; dates of visits; results of safety and antiviral activity parameters as required by
the protocol; record of all adverse events and follow-up of adverse events; concomitant
medication; intervention  receipt/dispensing/return records; study intervention administration
information; and date of study completion and reason for early discontinuation of study
intervention or withdrawal from the study, if applicable.
The author of an entry in the source documents should be identifiable.
Specific details required as source data for the study and source data collection methods will be
reviewed with the investigator before the study and will be described in the monitoring guidelines
(or another equivalent document).
The following data will be recorded directly into the CRF and will be considered source data:
 Race
 History of smoking or all nicotine use, eg, cigarettes (including e-cigarettes or the equivalent
of e-cigarettes), cigars, chewing tobacco, patch, gum
 Blood pressure and pulse/heart rate
 Height and weight
 Details of physical examination
The minimum source documentation requirements for Section 5.1, Inclusion Criteria and
Section 5.2, Exclusion Criteria that specify a need for documented medical history are as follows:
 Referral letter from treating physician or
 Complete history of medical notes at the site


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 Discharge summaries
Inclusion and exclusion criteria not requiring documented medical history must be verified at a
minimum by participant interview or other protocol required assessment (eg, physical
examination, laboratory assessment) and documented in the source documents.
An eSource system may be utilized, which contains data traditionally maintained in a hospital or
clinic record to document medical care (eg, electronic source documents) as well as the clinical
study-specific data fields as determined by the protocol. This data is electronically extracted for
use by the sponsor. If eSource is utilized, references made to the CRF in the protocol include the
eSource system, but information collected through eSource may not be limited to that found in the
CRF.
MONITORING
The sponsor will use a combination of monitoring techniques central, remote, and mainly on-site
monitoring to monitor this study.
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will
record dates of the visits in a study site visit log that will be kept at the study site. The first post-
initiation visit will be made as soon as possible after enrollment has begun. At these visits, the
monitor will compare the data entered into the CRF with the source documents
(eg, hospital/clinic/physician’s office medical records). The nature and location of all source
documents will be identified to ensure that all sources of original data required to complete the
CRF are known to the sponsor and study-site personnel and are accessible for verification by the
sponsor study-site contact. If electronic records are maintained at the study site, the method of
verification must be discussed with the study-site personnel.
Direct access to source documents (medical records) must be allowed for the purpose of verifying
that the recorded data are consistent with the original source data. Findings from this review will
be discussed with the study-site personnel. The sponsor expects that, during monitoring visits, the
relevant study-site personnel will be available, the source documents will be accessible, and a
suitable environment will be provided for review of study-related documents. The monitor will
meet with the investigator on a regular basis during the study to provide feedback on the study
conduct.
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during these
remote contacts, study-site personnel will be available to provide an update on the progress of the
study at the site.
Central monitoring will take place for data identified by the sponsor as requiring central review.
ON-SITE AUDITS
Representatives of the sponsor's clinical quality assurance department may visit the study site at
any time during or after completion of the study to conduct an audit of the study in compliance
with regulatory guidelines and company policy. These audits will require access to all study


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records, including source documents, for inspection. Participant privacy must, however, be
respected. The investigator and study-site personnel are responsible for being present and available
for consultation during routinely scheduled study-site audit visits conducted by the sponsor or its
designees.
Similar auditing procedures may also be conducted by agents of any regulatory body, either as part
of a national GCP compliance program or to review the results of this study in support of a
regulatory submission. The investigator should immediately notify the sponsor if he or she has
been contacted by a regulatory agency concerning an upcoming inspection.
RECORD RETENTION
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all CRF and
all source documents that support the data collected from each participant, as well as all study
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a Clinical
Trial, and all study documents as specified by the applicable regulatory requirement(s). The
investigator/institution will take measures to prevent accidental or premature destruction of these
documents.
Essential documents must 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 investigational product. These documents will be retained for a longer period
if required by the applicable regulatory requirements or by an agreement with the sponsor. It is the
responsibility of the sponsor to inform the investigator/institution as to when these documents no
longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the
responsibility of keeping the study records, custody must be transferred to a person who will accept
the responsibility. The sponsor must be notified in writing of the name and address of the new
custodian. Under no circumstance shall the investigator relocate or dispose of any study documents
before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any
documentation relating to this study, the investigator/institution must permit access to such reports.
STUDY AND SITE START AND CLOSURE
First Act of Recruitment
The first site open is considered the first act of recruitment and it becomes the study start date.
Study Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A
study site is considered closed when all required documents and study supplies have been collected
and a study-site closure visit has been performed.


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The investigator may initiate study-site closure at any time, provided there is reasonable cause and
sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are not
limited to:
 Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or
local health authorities, the sponsor's procedures, or GCP guidelines
 Inadequate recruitment of participants by the investigator
 Discontinuation of further study intervention development


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10.4. Appendix 4: Adverse Events: Definitions and Procedures for Recording,
Evaluating, Follow-up, and Reporting
ADVERSE EVENT DEFINITIONS AND CLASSIFICATIONS
Adverse Event
An adverse event is any untoward medical occurrence in a clinical study participant administered
a medicinal (investigational or non-investigational) product. An adverse event does not necessarily
have a causal relationship with the intervention. An adverse event can therefore be any unfavorable
and unintended sign (including an abnormal finding), symptom, or disease temporally associated
with the use of a medicinal (investigational or non-investigational) product, whether or not related
to that medicinal (investigational or non-investigational) product. (Definition per International
Conference on Harmonisation [ICH])
This includes any occurrence that is new in onset or aggravated in severity or frequency from the
baseline condition, or abnormal results of diagnostic procedures, including laboratory test
abnormalities.
Note: The sponsor collects adverse events starting with the signing of the ICF (refer to All Adverse
Events under Section 8.3.1, Time Period and Frequency for Collecting Adverse Events and Serious
Adverse Events Information, for time of last adverse event recording).
Serious Adverse Event
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for Medicinal
Products for Human Use is any untoward medical occurrence that at any dose:
 Results in death
 Is life-threatening
(The participant was at risk of death at the time of the event. It does not refer to an event that
hypothetically might have caused death if it were more severe.)
 Requires inpatient hospitalization or prolongation of existing hospitalization
 Results in persistent or significant disability/incapacity
 Is a congenital anomaly/birth defect
 Is a suspected transmission of any infectious agent via a medicinal product
 Is Medically Important*
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is
also appropriate in other situations, such as important medical events that may not be immediately
life threatening or result in death or hospitalization but may jeopardize the participant or may
require intervention to prevent one of the other outcomes listed in the definition above. These
should usually be considered serious.
If a serious and unexpected adverse event occurs for which there is evidence suggesting a causal
relationship between the study intervention and the event (eg, death from anaphylaxis), the event


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must be reported as a serious and unexpected suspected adverse reaction even if it is a component
of the study endpoint (eg, all-cause mortality).
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An adverse event is considered unlisted if the nature or severity is not consistent with the applicable
product reference safety information. For JNJ-64281802, the expectedness of an adverse event
will be determined by whether or not it is listed in the IB.
ATTRIBUTION DEFINITIONS
Assessment of Causality
The causal relationship to study treatment is determined by the Investigator. The following
selection should be used to assess all adverse events (AE).
Related
There is a reasonable causal relationship between study treatment administration and the AE.
Not Related
There is not a reasonable causal relationship between study treatment administration and the AE.
The term "reasonable causal relationship" means there is evidence to support a causal relationship.
SEVERITY CRITERIA
An assessment of severity grade will be made using the general categorical descriptors outlined in
the US FDA Toxicity Grading Table in Section 10.6, Appendix 6, and using the rash management
protocol in Section 10.7, Appendix 7.
The investigator should use clinical judgment in assessing the severity of events not directly
experienced by the participant (eg, laboratory abnormalities).
SPECIAL REPORTING SITUATIONS
Safety events of interest on a sponsor study intervention in an interventional studythat may require
expedited reporting or safety evaluation include, but are not limited to:
 Overdose of a sponsor study intervention
 Suspected abuse/misuse of a sponsor study intervention
 Accidental or occupational exposure to a sponsor study intervention
 Medication error, intercepted medication error, or potential medication error involving a
Johnson & Johnson medicinal product (with or without patient exposure to the Johnson &
Johnson medicinal product, eg, product name confusion, product label confusion, intercepted
prescribing or dispensing errors)
 Exposure to a sponsor study intervention from breastfeeding


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Special reporting situations should be recorded in the CRF. Any special reporting situation that
meets the criteria of a serious adverse event should be recorded on the serious adverse event page
of the CRF.
PROCEDURES
All Adverse Events
All adverse events, regardless of seriousness, severity, or presumed relationship to study
intervention, must be recorded using medical terminology in the source document and the CRF.
Whenever possible, diagnoses should be given when signs and symptoms are due to a common
etiology (eg, cough, runny nose, sneezing, sore throat, and head congestion should be reported as
"upper respiratory infection"). Investigators must record in the CRF their opinion concerning the
relationship of the adverse event to study therapy. All measures required for adverse event
management must be recorded in the source document and reported according to sponsor
instructions.
For all studies with an outpatient phase, including open-label studies, the participant must be
provided with a "wallet (study) card" and instructed to carry this card with them for the duration
of the study indicating the following:
 Study number
 Statement, in the local language(s), that the participant is participating in a clinical study
 Investigator's name and 24-hour contact telephone number
 Local sponsor's name and 24-hour contact telephone number (for medical personnel only)
 Site number
 Participant number
 Any other information that is required to do an emergency breaking of the blind
Serious Adverse Events
All serious adverse events that have not resolved by the end of the study, or that have not resolved
upon discontinuation of the participant's participation in the study, must be followed until any of
the following occurs:
 The event resolves
 The event stabilizes
 The event returns to baseline, if a baseline value/status is available
 The event can be attributed to agents other than the study intervention or to factors unrelated
to study conduct
 It becomes unlikely that any additional information can be obtained (participant or health care
practitioner refusal to provide additional information, lost to follow-up after demonstration of
due diligence with follow-up efforts)


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Suspected transmission of an infectious agent by a medicinal product will be reported as a serious
adverse event. Any event requiring hospitalization (or prolongation of hospitalization) that occurs
during the course of a participant's participation in a study must be reported as a serious adverse
event, except hospitalizations for the following:
 Hospitalizations not intended to treat an acute illness or adverse event (eg, social reasons such
as pending placement in long-term care facility)
 Surgery or procedure planned before entry into the study (must be documented in the CRF).
Note: Hospitalizations that were planned before the signing of the ICF, and where the
underlying condition for which the hospitalization was planned has not worsened, will not be
considered serious adverse events. Any adverse event that results in a prolongation of the
originally planned hospitalization is to be reported as a new serious adverse event.
The cause of death of a participant in a study, whether or not the event is expected or associated
with the study drug, is considered an SAE.
CONTACTING SPONSOR REGARDING SAFETY
The names (and corresponding telephone numbers) of the individuals who should be contacted
regarding safety issues or questions regarding the study are listed in the Contact Information
page(s), which will be provided as a separate document.
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality,
durability, or reliability of a product, including its labeling or package integrity. A PQC may have
an impact on the safety and antiviral activity  of the product. Timely, accurate, and complete
reporting and analysis of PQC information from studies are crucial for the protection of
participants, investigators, and the sponsor, and are mandated by regulatory agencies worldwide.
The sponsor has established procedures in conformity with regulatory requirements worldwide to
ensure appropriate reporting of PQC information; all studies conducted by the sponsor or its
affiliates will be conducted in accordance with those procedures.
Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after
being made aware of the event.
If the defect is combined with a serious adverse event, the study-site personnel must report the
PQC to the sponsor according to the serious adverse event reporting timelines (refer to
Section 8.3.1, Time Period and Frequency for Collecting Adverse Event and Serious Adverse
Event Information). A sample of the suspected product should be maintained for further
investigation if requested by the sponsor.


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Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted
regarding product quality issues are listed in the Contact Information page(s), which will be
provided as a separate document.


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10.5. Appendix 5: Contraceptive and Barrier Guidance and Collection of
Pregnancy Information
Participants must follow contraceptive measures as outlined in Section 5.1, Inclusion Criteria.
Pregnancy information will be collected and reported as noted in Section 8.3.5, Pregnancy and
Section 10.4, Appendix 4 Adverse Events: Definitions and Procedures for Recording, Evaluating,
Follow-up, and Reporting.
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless
permanently sterile (see below).
Woman Not of Childbearing Potential
 premenarchal
A premenarchal state is one in which menarche has not yet occurred.
 postmenopausal
A postmenopausal state is defined as no menses for 12 months without an alternative medical
cause. A high follicle stimulating hormone (FSH) level (>40 IU/L or mIU/mL) in the
postmenopausal range may be used to confirm a postmenopausal state in women not using
hormonal contraception or hormonal replacement therapy (HRT), however in the absence of
12 months of amenorrhea, a single FSH measurement is insufficient. If there is a question about
menopausal status in women on HRT, the woman will be required to use one of the non-
estrogen-containing hormonal highly effective contraceptive methods if she wishes to continue
HRT during the study.
Note: If the childbearing potential changes after start of the study (eg, a premenarchal woman
experiences menarche) or the risk of pregnancy changes (eg, a woman who is not heterosexually
active becomes active), a woman must begin a highly effective method of contraception, as
described throughout the inclusion criteria.
If reproductive status is questionable, additional evaluation should be considered.
Contraceptive (birth control) use by men or women should be consistent with local regulations
regarding the acceptable methods of contraception for those participating in clinical studies.
Typical use failure rates may differ from those when used consistently and correctly. Use should
be consistent with local regulations regarding the use of contraceptive methods for participants in
clinical studies.


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Examples of Contraceptives
EXAMPLES OF CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:
USER INDEPENDENT
Highly Effective Methods That Are User Independent Failure rate of <1% per year when used
consistently and correctly.
 Implantable progestogen-only hormone contraception associated with inhibition of ovulationb
 Intrauterine device (IUD)
 Intrauterine hormone-releasing system (IUS)
 Bilateral tubal occlusion
 Vasectomized partner
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the
sole sexual partner of the woman of childbearing potential and the absence of sperm has been
confirmed. If not, additional highly effective method of contraception should be used.
Spermatogenesis cycle is approximately 74 days.)
USER DEPENDENT
Highly Effective Methods That Are User Dependent Failure rate of <1% per year when used
consistently and correctly.
 Combined (estrogen- and progestogen-containing) hormonal contraception associated with
inhibition of ovulationb
oral
intravaginal
transdermal
injectable
 Progestogen-only hormone contraception associated with inhibition of ovulationb
oral
injectable
 Sexual abstinence
(Sexual abstinence is considered a highly effective method only if defined as refraining from
heterosexual intercourse during the entire period of risk associated with the study intervention.
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study
and the preferred and usual lifestyle of the participant.)
NOT ALLOWED AS SOLE METHOD OF CONTRACEPTION DURING THE STUDY (not
considered to be highly effective - failure rate of 1% per year)
 Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary
mode of action.
 Male or female condom with or without spermicidec
 Cap, diaphragm, or sponge with spermicide
 A combination of male condom with either cap, diaphragm, or sponge with spermicide (double-
barrier methods)c
 Periodic abstinence (calendar, symptothermal, post-ovulation methods)
 Withdrawal (coitus-interruptus)
 Spermicides alone
 Lactational amenorrhea method (LAM)


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EXAMPLES OF CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:
a) Typical use failure rates may differ from those when used consistently and correctly. Use should be
consistent with local regulations regarding the use of contraceptive methods for participants in
clinical studies.
b) Hormonal contraception may be susceptible to interaction with the study intervention, which may
reduce the efficacy of the contraceptive method. In addition, consider if the hormonal contraception
may interact with the study intervention.
c) Male condom and female condom should not be used together (due to risk of failure with friction).


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10.6. Appendix 6: United States Food and Drug Administration Toxicity Grading
Table
Source: the FDA Guidance document “Toxicity Grading Scale for Healthy Adult and Adolescent
Volunteers Enrolled in Preventive Vaccine Clinical Trials” (September 2007)
A: Tables for Clinical Abnormalities
Local Reaction to 
Injectable Product 
Mild (Grade 1) 
Moderate (Grade 2) Severe (Grade 3) 
Potentially Life
Threatening
(Grade 4)
Pain  
Does not interfere 
with activity  
Repeated use of 
non-narcotic pain 
reliever >24 hours or 
interferes with activity
Any use of narcotic 
pain reliever or 
prevents daily activity  
Emergency room
(ER) visit or
hospitalization
Tenderness 
Mild discomfort to 
touch  
Discomfort with 
movement 
Significant discomfort 
at rest 
ER visit or
hospitalization
Erythema/Redness* 
2.5 –5 cm  
5.1 –10 cm  
>10 cm  
Necrosis or
exfoliative dermatitis
Induration/Swelling** 2.5 –5 cm and does 
not interfere with 
activity
5.1 –10 cm or 
interferes with activity
>10 cm or prevents 
daily activity
Necrosis
* In addition to grading the measured local reaction at the greatest single diameter, the measurement should be
recorded as a continuous variable.
** Induration/Swelling should be evaluated and graded using the functional scale as well as the actual
measurement.
Vital Signs * 
Mild (Grade 1) 
Moderate (Grade 2) Severe (Grade 3) 
Potentially Life
Threatening
(Grade 4)
Fever (°C) ** 
           (°F)** 
38.0 - 38.4 
100.4 - 101.1 
38.5 - 38.9 
101.2 - 102.0 
39.0 - 40.0 
102.1 - 104.0 
>40
>104.0
Tachycardia - beats 
per minute 
101 –115 
116 –130 
>130 
ER visit or
hospitalization for
arrhythmia
Bradycardia - beats 
per minute***  
50 –54 
45 –49 
<45 
ER visit or
hospitalization for
arrhythmia
Hypertension 
(systolic) - mm Hg 
141 –150 
151 –155 
>155 
ER visit or
hospitalization for
malignant
hypertension
Hypertension 
(diastolic) - mm Hg 
91 –95 
96 –100 
>100 
ER visit or
hospitalization for
malignant
hypertension
Hypotension 
(systolic) –mm Hg 
85 –89 
80 –84 
<80 
ER visit or
hospitalization for
hypotensive shock
Respiratory Rate – 
breaths per minute
17 –20 
21 –25 
>25 
Intubation


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* Participant should be at rest for all vital sign measurements.
** Oral temperature: no recent hot or cold beverages or smoking.
*** When resting heart rate is between 60 –100 beats per minute. Use clinical judgement when characterizing
bradycardia among some healthy participant populations, for example, conditioned athletes.
Systemic (General) Mild (Grade 1) 
Moderate (Grade 2) Severe (Grade 3) 
Potentially Life
Threatening
(Grade 4)
Nausea/Vomiting 
No interference 
with activity or 1 –2 
episodes/24 hours 
Some interference 
with activity or >2 
episodes/24 hours 
Prevents daily  
activity, requires 
outpatient IV 
hydration
ER visit or
hospitalization for
hypotensive shock
Diarrhea 
2 –3 loose stools or 
<400 gms/24 hours 
4 –5 stools or 
400 –800 gms/24 
hours 
6 or more watery  
stools or 
>800 gms/24 hours or
requires outpatient IV
hydration
ER visit or
hospitalization
Headache 
No interference with 
activity 
Repeated use of 
non-narcotic pain 
reliever >24 hours or 
some interference 
with activity
Significant; any use of 
narcotic pain reliever 
or prevents daily
activity
ER visit or
hospitalization
Fatigue 
No interference with 
activity 
Some interference 
with activity 
Significant; prevents 
daily activity 
ER visit or
hospitalization
Myalgia 
No interference with 
activity 
Some interference 
with activity 
Significant; prevents 
daily activity 
ER visit or
hospitalization
Systemic Illness 
Mild (Grade 1) 
Moderate (Grade 2) Severe (Grade 3) 
Potentially Life
Threatening
(Grade 4)
Illness or clinical 
adverse event (as 
defined according to 
applicable 
regulations)
No interference with 
activity  
Some interference 
with activity not 
requiring medical 
intervention
Prevents daily 
activity and requires 
medical intervention
ER visit or
hospitalization


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B: Tables for Laboratory Abnormalities
The laboratory values provided in the tables below serve as guidelines and are dependent upon
institutional normal parameters. Institutional normal reference ranges should be provided to
demonstrate that they are appropriate.
Serum * 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life
Threatening
(Grade 4)**
Sodium –Hyponatremia mEq/L 
132 –134 
130 –131 
125 –129 
<125
Sodium –Hypernatremia mEq/L 
144 –145 
146 –147 
148 –150 
>150
Potassium –Hyperkalemia mEq/L 
5.1 –5.2 
5.3 –5.4 
5.5 –5.6 
>5.6
Potassium –Hypokalemia mEq/L 
3.5 –3.6 
3.3 –3.4 
3.1 –3.2 
<3.1
Glucose –Hypoglycemia mg/dL 
65 –69 
55 –64 
45 –54 
<45
Glucose –Hyperglycemia 
  Fasting mg/dL 
  Random –mg/dL 
100 –110 
110 –125 
111 –125 
126 –200 
>125 
>200 
Insulin
requirements or
hyperosmolar
coma
Blood Urea Nitrogen  
BUN mg/dL
23 –26 
27 –31 
>31 
Requires dialysis
Creatinine –mg/dL 
1.5 –1.7 
1.8 –2.0 
2.1 –2.5 
>2.5 or requires
dialysis
Calcium –hypocalcemia mg/dL 
8.0 –8.4 
7.5 –7.9 
7.0 –7.4 
<7.0
Calcium –hypercalcemia mg/dL 
10.5 –11.0 
11.1 –11.5 
11.6 –12.0 
>12.0
Magnesium –hypomagnesemia mg/dL 
1.3 –1.5 
1.1 –1.2 
0.9 –1.0 
<0.9
Phosphorous –hypophosphatemia mg/dL 2.3 –2.5 
2.0 –2.2 
1.6 –1.9 
<1.6
CPK –mg/dL 
1.25 –1.5x  
ULN***
1.6 –3.0x ULN  3.1 –10x ULN  
>10x ULN
Albumin –Hypoalbuminemia g/dL 
2.8 –3.1 
2.5 –2.7 
<2.5 
--
Total Protein –Hypoproteinemia g/dL 
5.5 –6.0 
5.0 –5.4 
<5.0 
--
Alkaline phosphate – 
increase by factor
1.1 –2.0x ULN  2.1 –3.0x ULN  3.1 –10x ULN  
>10x ULN
Liver Function Tests –ALT, AST  
increase by factor
1.1 –2.5x ULN  2.6 –5.0x ULN  5.1 –10x ULN  
>10x ULN
Bilirubin –when accompanied 
by any increase in Liver Function Test
increase by factor
1.1 –1.25x ULN  1.26 –1.5x ULN 1.51 –1.75x ULN >1.75x ULN
Bilirubin –when Liver Function Test 
is normal; increase by factor
1.1 –1.5x ULN  1.6 –2.0x ULN  2.0 –3.0x ULN  >3.0x ULN
Cholesterol 
201 –210 
211 –225 
>226 
---
Pancreatic enzymes –amylase, lipase 
1.1 –1.5x ULN  1.6 –2.0x ULN  2.1 –5.0x ULN  >5.0x ULN
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal
parameters. Institutional normal reference ranges should be provided to demonstrate that they are appropriate.
** The clinical signs or symptoms associated with laboratory abnormalities might result in characterization of the
laboratory abnormalities as Potentially Life Threatening (Grade 4). For example. a low sodium value that falls
within a Grade 3 parameter (125-129 mEq/L) should be recorded as a Grade 4 hyponatremia event ifthe
participant had a new seizure associated with the low sodium value.
***”ULN” is the upper limit ofthe normal range.


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Serum * 
Mild
(Grade 1)
Moderate
(Grade 2)
Severe
(Grade 3)
Potentially Life
Threatening
(Grade 4)**
Hematology * 
Mild
(Grade 1)
Moderate
(Grade 2)
Severe
(Grade 3)
Potentially Life
Threatening
(Grade 4)
Hemoglobin (Female) - gm/dL 
11.0 –12.0 
9.5 –10.9 
8.0 –9.4 
<8.0
Hemoglobin (Female) 
change from baseline value - gm/dL 
Any decrease – 
1.5
1.6 –2.0 
2.1 –5.0 
>5.0
Hemoglobin (Male)- gm/dL 
12.5 –13.5 
10.5 –12.4 
8.5 –10.4 
<8.5
Hemoglobin (Male) 
change from baseline value –gm/dL 
Any decrease – 
1.5
1.6 –2.0 
2.1 –5.0 
>5.0
WBC Increase - cell/mm3 
10,800 –15,000 15,001 –20,000 20,001 –25,000 >25,000
WBC Decrease - cell/mm3 
2,500 –3,500 
1,500 –2,499 
1,000 –1,499 
<1,000
Lymphocytes Decrease - cell/mm3 
750 –1,000 
500 –749 
250 –499 
<250
Neutrophils Decrease - cell/mm3 
1,500 –2,000 
1,000 –1,499 
500 –999 
<500
Eosinophils - cell/mm3 
650 –1,500 
1,501 –5,000 
>5,000 
Hypereosinophilic
Platelets Decreased - cell/mm3 
125,000 – 
140,000 
100,000 – 
124,000
25,000 –99,000 <25,000
PT –increase by factor 
(prothrombin time) 
1.0 –1.10x 
ULN** 
1.11 –1.20x 
ULN
1.21 –1.25x ULN >1.25x ULN
PTT –increase by factor 
(partial thromboplastin time)
1.0 –1.2x ULN  1.21 –1.4x ULN 1.41 –1.5x ULN  >1.5x ULN
Fibrinogen increase - mg/dL 
400 –500 
501 –600 
>600 
--
Fibrinogen decrease - mg/dL 
150 –200 
125 –149 
100 –124 
<100 or
associated
with gross
bleeding or
disseminated
intravascular
coagulation (DIC)
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal
parameters. Institutional normal reference ranges should be provided to demonstrate that they are appropriate.
** “ULN” is the upper limit ofthe normal range.
Urine * 
Mild  
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life
Threatening (Grade 4)
Protein  
Trace 
1+  
2+ 
Hospitalization or
dialysis
Glucose 
Trace 
1+  
2+ 
Hospitalization for
hyperglycemia
Blood (microscopic) – 
red blood cells per 
high power field (rbc/hpf) 
1 - 10 
11 –50 
>50 and/or gross 
blood 
Hospitalization or
packed red blood cells
(PRBC) transfusion
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal
parameters. Institutional normal reference ranges should be provided to demonstrate that they are appropriate.


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10.7. Appendix 7: Rash Management
Dengue symptomatic infection is known to result in skin rashes in a majority of patients.0 Rash
may potentially also be related to the study drug and it may not be possible to differentiate between
a rash secondary to DENV infection and one related to the study drug.
During the study, all rashes, where a causal relationship between the rash and the study drug cannot
be excluded, will be discussed between the investigator and the Sponsor. In case a causal
relationship between the rash and the study drug cannot be excluded, then the following
visits and assessments will be performed as indicated. Unscheduled follow-up visits for close
follow-up of rash will be performed based on the grade (severity) of the rash. At the investigator’s
discretion, additional visits and assessments can be performed.
The rash event should be captured in the Adverse Event Section of the CRF, and in more detail in
the specific rash assessment pages of the CRF.
If a causal relationship between the rash and the study drug cannot be excluded, safety blood
samples need to be taken during the (unscheduled) visits as described below. The following
parameters need to be tested: AST, ALT, creatinine, erythrocyte sedimentation rate, and a
complete blood cell count (including hemoglobin, hematocrit, red blood cell count, white blood
cell count, neutrophils, lymphocytes, monocytes, eosinophils, basophils, and platelet count).
Participants should be informed that they should contact the investigator and visit the study
site immediately (unscheduled visit, Day 0 of the rash) when they notice any rash. They
should be advised to contact the investigator immediately if there is any worsening of the
rash, if any systemic sign or symptoms appear, or if mucosal involvement develops.
Monitoring of the evolution of rash events will be performed as described in Table 4 below. The
following grades are based on the DAIDS Table for Grading the Severity of Adult and Pediatric
Adverse Events, Corrected Version 2.1. (July 2017)a with adaptations made by the sponsor.
a 
DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, corrected version 2.1, dated July
2017. Available at https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf(accessed 20 April
2019)


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Table 4: 
Management of Rash Events by Severity Grade
Definition  
Study Drug Action 
Activities by Daya
Referral to
Dermatologistand
Dermatology  Activities
Grade 1 rashb 
Localized rash that is easily
tolerated and/or may require
one dose of medication.
Study drug intake
may be continued at
the investigator’s
discretion.
Day0: required on-site unscheduled visit for initial rash
evaluation, if participant is outside the study site.
 Safety laboratoryassessments are required.
 Digital picturesd should be taken (preferred within 24
hours) after the onset of the rash.
 Cetirizine, levocetirizine, topical corticosteroids, or
antipruritic agents may be prescribed.
Day1: safety blood samples and digital picturesd should be
taken.
After Day 7: If the rash is unresolved, additional unscheduled
visits can be performed at the investigator’s discretion.
In case the rash evolves from a Grade 1 to a higher grade,
additional unscheduled visits have to be conducted according
to the guidelines for Grade 2 or Grade 3-4 rash, respectively.
Upon resolution/stabilization of the rash: digital picturesd
should be taken and the final rash assessment pages of the
eCRF should be completed.
Not required


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Definition  
Study Drug Action 
Activities by Daya
Referral to
Dermatologistand
Dermatology  Activities
Grade 2 rashb 
Diffuse, maculopapular
rash, or target lesions.
Symptomatic
(pain/pruritus) but does
not interfere with function
and/or requires more than
one dose of medication.
Study drug intake may
be continued at the
investigator’sdiscretion
Day0: required on-site unscheduled visit for initial rash
evaluation, if participant is outside the study site.
 Safety laboratory assessments are required.
 Digital picturesd ofskin lesions should be taken
(preferred within 24 hours) after the onset of the rash.
 Cetirizine, levocetirizine, topical corticosteroids, or
antipruritic agents may be prescribed.
Day 1 and 7: safety blood samples and digital picturesd
should be taken.
After Day 7: If the rash is unresolved:
 If there is an increase in AST/ALT of ≥2 times the
ULN, participants should be followed weekly (or
more frequently, at the investigator’s discretion)
with repeated local laboratory assessments and
digital picturesd until resolution of the AST/ALT
abnormalities.
 If there is no increase in AST/ALT, additional
unscheduled visits (including local laboratory
assessments and digital picturesd) can be performed
at the investigator’s discretion.
If the rash evolves from a Grade 2 to a Grade 3-4 rash,
additional unscheduled visits have to be conducted according
to the guidelines for Grade 3-4 rash
Upon resolution/stabilization of the rash: digital picturesd
should be taken and the final rash assessment pages of the
eCRF should be completed
Not required


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Definition  
Study Drug Action 
Activities by Daya
Referral to
Dermatologistand
Dermatology  Activities
Grade 3 rashb 
Diffuse rash AND
vesicles or limited
number of bullae or
superficial ulcerations of
mucous membrane
limited to 1 site,
OR elevations in
AST/ALT >2x ULN,
OR body temperature
≥39.3°C to <40.0°C
(≥102.7°F to <104.0°F),
OR eosinophils
>1000/mm3,
OR serum sickness-like
reaction.
Must permanently
discontinue and be
withdrawn from the
study; no rechallenge
allowed.
Day 0: required on-site unscheduled visit for initial rash
evaluation, if participant is outside the study site.
Day 0 and 1:
 Safety laboratory assessments are required.
 Digital picturesd of skin lesions should be taken within
24 hours after the onset of the rash and on Day 1.
Further visit(s): appropriate management and follow-up
required until resolution of rash or until clinical stability is
reached.
Days 2, 3, and 4: Only if the participant’s AST/ALT on Day 0
and/or Day 1 of rash >2x ULN and/or in case of rash
progression:
 Additional safety blood samples are required.
 Digital picturesd are to be taken.
Day 5: Regardless of the Day 0/1 AST/ALT levels or rash
progression:
 Additional safety blood samples are required.
 Digital picturesd are to be taken.
After Day 5: Weekly follow-up visits are required (or more
frequently at the investigator’s discretion) as long as Grade 3-
4 rash is present. Once Grade 3-4 rash has resolved to ≤Grade
2 rash, follow-up should be done according to the instructions
for follow-up visits for Grade 1 or Grade 2 rash, respectively.
 Only if the participant’s AST/ALT on Day 5 of rash is
still >2x ULN and/or in case of rash progression,
additional safety blood samples and digital picturesd
are required at these weekly follow-up visits, until
resolution or stabilization of the AST/ALT
elevations.
Upon resolution/stabilization of the rash: digital picturesd
should be taken and the final rash assessment pages of the
eCRF should be completed.
Requiredc
Biopsy required within
24hrs after onset of
rash.


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Definition  
Study Drug Action 
Activities by Daya
Referral to
Dermatologistand
Dermatology  Activities
Grade 4 rashb 
Potentially life-
threatening rash with:
Extensive or generalized
bullous lesions,
OR ulceration of mucous
membrane involving two
or more distinct mucosal
sites,
OR Stevens-Johnson
syndrome,
OR toxic epidermal
necrolysis.
Must permanently
discontinue and be
withdrawn from the
study; no rechallenge
allowed.
Day 0: required on-site unscheduled visit for initial rash
evaluation, if participant is outside the study site.
Day 0 and 1:
 Safety laboratory assessments are required.
 Digital picturesd of skin lesions should be taken within
24 hours after the onset of the rash and on Day 1.
Further visit(s): appropriate management and follow-up
required until resolution of rash or until clinical stability is
reached.
Days 2, 3, and 4: Only if the participant’s AST/ALT on Day 0
and/or Day 1 of rash >2x ULN and/or in case of rash
progression:
 Additional safety blood samples are required.
 Digital picturesd are to be taken.
Day 5: Regardless of the Day 0/1 AST/ALT levels or rash
progression:
 Additional safety blood samples are required.
 Digital picturesd are to be taken.
After Day 5: Weekly follow-up visits are required (or more
frequently at the investigator’s discretion) as long as Grade
3-4 rash is present. Once Grade 3-4 rash has resolved to
≤Grade 2 rash, follow-up should be done according to the
instructions for follow-up visits for Grade 1 or Grade 2 rash,
respectively.
 Only if the participant’s AST/ALT on Day 5 of rash is
still >2x ULN and/or in case of rash progression
additional safety blood samples and digital picturesd
are required at these weekly follow-up visits, until
resolution or stabilization of the AST/ALT
elevations.
Upon resolution/stabilization of the rash: digital picturesd
should be taken and the final rash assessment pages of the
eCRF should be completed.
Requiredc
Biopsy required within
24hrs after onset of
rash.
AE: adverse event; ALT: alanine aminotransferase; AST: aspartate aminotransferase


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a. Day 0 ofthe rash is the first day ofinvestigator assessment and not the first day ofrash as reported by the participant. The initial visit should be conducted as
soon as possible after the participant contacts the investigator to report the AE (ie, preferably on Day 0). The initial visit and subsequent visits to manage the rash
may require unscheduled visit(s).
b. The participant should be advised to contact the investigator immediately ifthere is any worsening ofthe rash, ifany systemic signs or symptoms appear, or if
mucosal involvement develops. In case the rash evolves to a higher grade than that first observed, management ofthe rash should follow the guidelines indicated
for the higher grade.
c. Ifapplicable, dermatologist visit should occur preferably within 24 hours after onset ofrash.
d. Digital pictures to be taken at the study site.
Notes:
Local laboratory assessments are to be used for rash management. A copy of the local laboratory reports should be de-identified and will be collected by the site
manager.
A copy of the dermatologist’s report, and biopsy if performed, should be made anonymous and will be collected by the site manager. Dermatologist fees for evaluating
participants who experience a rash will be reimbursed by the sponsor.
Digital pictures will be de-identified and stored on the sponsor’s secure server. Only the sponsor team members will have access to the sponsor’s secure server.
Per investigator’s discretion, the participant may be treated symptomatically until the rash resolves.


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10.8. Appendix 8: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located
directly before the Table of Contents (TOC).
Amendment 5 (28 February 2022)
Overall Rationale for the Amendment:
In addition, 
 to
increase the upper age limit to 60 years of age, to relax the restrictions on the use of CYP3A4 and UGT1A9
inhibitors, to remove the restrictions on the use of substrates for CYP2C9 or CYP2C19, to reschedule the
interim analysis at the originally planned time point and to add a primary analysis.
Some minor corrections and/or clarifications were addressed as outlined in the table below.
Section number 
and Name
Description of Change 
Brief Rationale
1.1 Synopsis
1.3 Schedule of
Activities
4.1 Overall Design
5.3.1 Meals and
Dietary Restrictions
6.1 Study
Intervention(s)
Administered
To facilitate cultural and
operational aspects of the study and
to protect the safety of the
participants.
1.1 Synopsis
1.3 Schedule of
Activities
4.1 Overall Design
5. Study Population
5.1 Inclusion
Criteria
6.1 Study
Intervention(s)
Administered
6.3 Measures to
Minimize Bias:
Randomization and
Blinding
The time window of 12 hours between signing ICF
and receiving the first dose of study intervention
has been removed.
Following criteria have been added:
 
Participants must be identified and screened
within 48 hours after onset of fever.
 
To accommodate the investigator’s
request.
1.1 Synopsis
4.1 Overall Design
5.1 Inclusion
Criteria
The upper age limit for inclusion in the study has
been increased to 60 years of age.
To accommodate the investigator’s
request to be able to include older
patients.
2.2 Background
5.2 Exclusion
Criteria
6.5 Concomitant
Therapy
The restriction on the use of CYP3A4 and
UGT1A9 inhibitors has been relaxed to ‘within
7 days before first dose of study drug’.
Restrictions on the use of substrates for CYP2C9
or CYP2C19 have been removed.
Based on available clinical
drug-drug interaction study data,
restrictions on concomitant
medications have been relaxed.
CCI
CCI
CCI
CCI


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Section number 
and Name
Description of Change 
Brief Rationale
1.1 Synopsis 
1.3 Schedule of 
Activities 
8. Study 
Assessments and 
Procedures 
8.2.1 Physical 
Examinations 
9.4.4 Immune
Analysis
The SoA has been updated: 
 
Physical examination during inpatient stay 
will occur only at screening, Day 3 and Day 6.
On 
the 
other 
dosing 
days, 
physical
examination will be performed ad hoc at the
discretion of the principal investigator.
Physical examination during the follow-up
visits (Days 14, 21, and 28) remains as is.
 
A clinical status check prior to the first dosing
has been added.
 
Safety laboratory tests have been added on
Day 6, at the discretion of the investigator.
The blood volume that needs to be collected for the
safety laboratory tests as well as the total blood
volume for the study have been updated.
To monitor the safety of the study
participants.
1.1 Synopsis 
4.1 Overall Design  
6.3 Measures to 
Minimize Bias: 
Randomization and 
Blinding 
9.4.1 General 
Considerations 
9.5 Interim Analysis 
The section ‘Interim Analysis’ has been updated to 
reschedule the interim analysis at the originally 
planned time point when at least 50 participants 
with a primary dengue infection reached Day 28 or 
discontinued earlier. 
A primary analysis has been added at the time
point when all participants reached Day 28 or 
discontinued earlier. 
During this interim and primary analyses, the 
database will remain blinded to the site personnel 
to ensure that the 6-months safety follow-up can be
performed in a blinded fashion.
The time point of the interim
analysis has been rescheduled to
the originally planned time point
when at least 50 participants with a
primary dengue infection reached
Day 28 or discontinued earlier.
A primary analysis has been added
to provide the originally planned
‘final analysis’ when all
participants reached Day 28 or
discontinued earlier.
10.7 Appendix 7: 
Rash Management 
The ‘Rash Management’ appendix has been 
updated to ensure that only if causal relationship is 
considered, a rash management should be started. 
The Day 7 visit and assessments in case of Grade 1 
rash have been removed. 
Majority of participants will present
with a typical dengue-related rash
to requiring initiation of the rash
management. From safety
perspective and to facilitate
operational conduct of the study,
duration to follow-up Grade 1 rash
was reduced.
1.3 Schedule of 
Activities 
The blood sample collection for cellular immunity 
(PBMC) has been made optional at Day 28. 
To accommodate the investigator’s
request to reduce the total blood
volume at Day 28.
1.1 Synopsis 
3. Objectives and 
Endpoints 
Two exploratory objectives have been updated: 
 
Investigate 
the 
antiviral 
activity 
of
JNJ-64281802 versus placebo in terms of
reduction of DENV RNA in secondary DENV
infections and in all DENV infections
 
Investigate 
the 
antiviral 
activity 
of
JNJ-64281802 versus placebo based on
viremia in secondary DENV infections and in
all DENV infections
Clarification of the objectives.
9.4.5 
Pharmacokinetic 
Analyses 
Additional wording was added to ensure that PK 
samples collected before a certain date will be 
included in a population PK analysis.
To analyze the PK profile early in
the study.


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Section number 
and Name
Description of Change 
Brief Rationale
1.1 Synopsis 
1.3 Schedule of 
Activities 
4.1 Overall Design  
6.1 Study 
Intervention(s)
Administered
Correction.
2.2 Background 
The clinical background section has been updated 
to include studies DNG1006 (food effect),
DNG1004 (drug-drug interaction) and DNG1005
(drug-drug interaction).
For completeness.
1.1 Synopsis 
1.3 Schedule of 
Activities 
4.1 Overall Design
4.4 End of Study
Definition
It has been clarified that participants will be 
followed up remotely until 6 months after the first
dose of study intervention.
Clarification of total study duration.
1.3 Schedule of 
Activities 
It has been clarified that the time window for the
study assessments is ±30 min for the assessments
at Days 1 to 3 and ±2 hours for the assessments at
Days 4 and 5.
For completeness.
8.3.5 Pregnancy  
The wording ‘and any postnatal sequelae in the
infant’ has been removed from the below sentence:
Follow-up information regarding the outcome of
the pregnancy and any postnatal sequelae in the
infant will be required.
Correction. The Sponsor follows-up
on pregnancy through birth and
status of newborn, but no additional
follow-up is required, unless safety
issues are reported.
Throughout the 
protocol 
Minor updates, corrections, or additions have been
made.
Correction, clarification, and
consistency.
Amendment 4 (22 November 2021)
Overall Rationale for the Amendment: The protocol was amended to reflect new strategies to expedite
participant enrollment, to disallow the use of UGT1A9 inhibitors or inducers before and during the study,
to accommodate COVID-19 vaccination strategies, and to extend the follow-up period until 6 months post
dosing. In addition, some minor corrections and/or clarifications were addressed as outlined in the table
below.
Section number 
and Name
Description of Change 
Brief Rationale
1.1 Synopsis
1.3 Schedule of
Activities
4.1 Overall Design
5.1 Inclusion
Criteria
10.3 Appendix 3:
Regulatory, Ethical,
and Study Oversight
Considerations
Individuals with a suspected dengue virus infection
will be asked to undergo an NS1 rapid test under a
pre-screening consent during an ambulatory visit
organized by the mobile clinical team. Patients
who test positive for dengue virus infection will be
subsequently referred to the study site.
A broader and more pro-active
strategy for participant recruitment
will be implemented in order to
expedite study enrollment.
5.2 Exclusion
Criteria
6.5 Concomitant
Therapy
The use of UGT1A9 inhibitors or inducers within
14 days before the first dose of study drug is not
permitted.
JNJ-64281802 is a substrate for
UGT1A9 based on in vitro results.
A possible drug-drug interaction
cannot be excluded at this time.
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Section number 
and Name
Description of Change 
Brief Rationale
1.3 Schedule of 
Activities 
2.3.4 Potential Risks 
5.2 Exclusion 
Criteria 
6.5 Concomitant 
Therapy  
10.9 Appendix 9: 
COVID-19 
Appendix  
An authorized/licensed COVID-19 vaccine can be 
administered at any time before, during, or after the 
study. 
COVID-19 testing can be added as a screening 
assessment at the discretion of the investigator,
depending on the epidemiological situation.
The COVID-19 appendix has been updated and
aligned with other dengue clinical study protocols.
Other concomitant vaccinations are not allowed 
until 30 days after the last dose of study drug, 
where the period was reduced from 90 to 30 days. 
To accommodate COVID-19
vaccination strategies and for
alignment within the dengue study
program.
No substantial accumulation of the
compound is expected in the
treatment study.
1.1 Synopsis 
1.3 Schedule of 
Activities 
4.1 Overall Design  
4.4 End of Study 
Definition 
7.1 Discontinuation 
of Study 
Intervention 
8.2.1 Physical 
Examinations
9.4.4.2 Cellular
Immune Analyses
Remote every-2-weeks follow-up visits until 
6 months after the last dosing day have been added 
to inquire on any dengue-related signs and 
symptoms. A distinction between on site (ie, on
Days 14, 21, and 28) and remote (ie, every-2-
weeks after Day 28 and until 6 months after the last
dosing day) follow-up visits was made. As a result,
participants will only have completed the study
after the final remote follow-up assessment at
Mont 6 post dosing.
To accommodate the investigator's
request for a longer follow-up
period.
1.1 Synopsis 
1.3 Schedule of 
Activities 
8.3.2 Method of
Detecting Adverse
Events and Serious
Adverse Events
10.2 Appendix 2:
Clinical Laboratory
Tests
International normalized ratio (INR) has been 
specified as an additional parameter in blood 
coagulation assessments. 
The INR is an international
standard for the prothrombin time
(PT).
1.1 Synopsis 
1.3 Schedule of 
Activities 
1.2 Schema 
4.1 Overall Design  
For eligibility and screening assessments, 
participants will be directed to the study site. 
During the treatment phase, participants will be 
admitted to an inpatient facility.
Participants with symptoms of severe dengue or 
with dengue warning symptoms, will be transferred 
to a hospital.
To accommodate the site's request
to allow for flexibility on where the
participant will be admitted.
To allow for flexibility on where
the participant will be hospitalized.
1.3 Schedule of 
Activities 
8 STUDY 
ASSESSMENTS
AND
PROCEDURES
It was emphasized that for all assessments the 
30-minute time window as defined in the schedule 
of activities should be adhered to.
Clarification requested by the study
site.
8 STUDY 
ASSESSMENTS 
AND 
PROCEDURES
The blood volume that needs to be collected for 
each of the assessments has been updated. 
For alignment and consistency with
laboratory manual and on-site
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Section number 
and Name
Description of Change 
Brief Rationale
1.1 Synopsis 
4.1 Overall Design  
8 STUDY 
ASSESSMENTS
AND
PROCEDURES
8.1 Antiviral activity
Assessments
Samples that tested positive for NS1 rapid test will 
no longer have to be confirmed by a qualitative 
PCR at screening.
To expedite screening assessments
and start of treatment.
1.1 Synopsis 
1.3 Schedule of 
Activities 
4.1 Overall Design  
6.1 Study 
Intervention(s)
Administered
Clarification requested by the study
site.
1.1 Synopsis 
1.2 Schema 
1.3 Schedule of 
Activities 
4.1 Overall Design  
It was emphasized that participants with signs and 
symptoms of severe dengue can be transferred to a 
hospital at any time during the study and at the
investigator's discretion.
Participants with severe dengue OR dengue
warning symptoms after Study Day 9 will also be
moved to a hospital.
Clarification requested by the study
site.
1.1 Synopsis 
9.4.2 Antiviral 
Activity Analysis
Viral load assay results below the limit of detection 
(LOD) will be described as target not detected. 
To align with the data transfer
agreement.
1.3 Schedule of 
Activities 
Review of concomitant medication and adverse 
events were indicated as 'continuously' in the 
Schedule of Activities.
Clarification as these are being
reported on occurrence.
1.1 Synopsis 
1.3 Schedule of 
Activities 
2.2 Background
4.1 Overall Design
5.3.1 Meals and
Dietary Restrictions
6.1 Study
Intervention(s)
Administered
Correction and clarification.
1.3 Schedule of 
Activities 
5.2 Exclusion 
Criteria
8.2.2 Vital Signs
Oxygen saturation has been removed as a 
screening assessment and will be measured pre- 
dose on Day 1 (vital signs).
Correction, clarification, and
consistency.
10.2 Appendix 2: 
Clinical Laboratory 
Tests
Indirect bilirubin has been removed from the safety 
laboratory assessments. 
Local laboratory cannot provide
this test.
8.3.5 Pregnancy  
Participants becoming pregnant during the study 
will discontinue study intervention but will 
continue study visits for additional safety follow-
up.
Correction, clarification, and
consistency.
1.3 Schedule of 
Activities 
One line for blood sample collection for NS1 
concentration was removed from the schedule of 
activities.
Correction, as the assessment was
duplicated.
10.7 Appendix 7: 
Rash Management 
The word 'asymptomatic' has been removed to 
describe a Grade 1 rash.
To align wording across studies.
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Section number 
and Name
Description of Change 
Brief Rationale
1.1 Synopsis 
4.1 Overall Design  
Screening and baseline assessments are completed 
on Day 0. 
Correction to align with the
Schedule of Activities.
Throughout the 
protocol 
Minor updates, corrections, or additions have been 
made. 
Correction, clarification, and
consistency.
Amendment 3 (26 March 2021)
Overall Rationale for the Amendment: The protocol was amended as specified below.
Section number 
and Name
Description of Change 
Brief Rationale
1.1 Synopsis
1.3 Schedule of
Activities
2.2 Background
4.1 Overall Design
5.3.1 Meals and
Dietary Restrictions
6.1 Study
Intervention(s)
Administered
To facilitate cultural and
operational aspects of the study.
1.1 Synopsis
1.3 Schedule of
Activities
4.1 Overall Design
To offer additional guidance to the
study site.
1.3 Schedule of
Activities
Guidance on the allowed blood sampling time
window was added to the schedule of activities.
To offer additional guidance to the
study site.
1.1 Synopsis
4.1 Overall Design
9.5 Interim Analysis
Sentence was added with regards to treatment
effect and the futility stopping boundary at the time
of the interim analysis.
To get a better understanding of
how different the observed versus
the assumed effect can be, in order
to make a well-informed sponsor
decision at the time of the interim
analysis.
1.1 Synopsis
5.1 Inclusion
Criteria
7.2.1 Withdrawal
from the Use of
Research Samples
8 STUDY
ASSESSMENTS
AND
PROCEDURES
8.6.1 Human
Leucocyte Antigen
Typing and
Pharmacogenomics
Assessments
10.3 Appendix 3:
Regulatory, Ethical,
and Study Oversight
Considerations
Because human leukocyte antigen (HLA) and
pharmacogenomic samples are required, the word
'optional' was removed. Where local regulations
require, a separate consent can be obtained for this
part of the study.
The use of leftover samples for future exploratory
research is optional and will be consented
separately in the informed consent form (ICF).
Clarification and correction of
inconsistencies.
2.2 Background
2.3.4 Potential Risks
Information on cardiovascular safety was removed 
from potential risks. Instead, a paragraph on 
exposure analysis was added to the overall safety
data.
Cardiovascular safety is not
considered to be a potential risk.
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Section number 
and Name
Description of Change 
Brief Rationale
1.3 Schedule of 
Activities 
8.2.2 Vital Signs
Input-Output (I/O) ratio will be measured from 
predose till discharge, not during screening. 
Correction of errors and
inconsistencies.
1.1 Synopsis 
1.2 Schema 
4.1 Overall Design  
10.1 Appendix 1: 
Abbreviations 
Participants with severe dengue after Day 9 will be 
transferred to the Singapore General Hospital 
(SGH), and not to the National University
Hospital.
In addition, at the investigator’s discretion,
participants who are hemodynamically unstable or
require interventions, can be transferred to the
SGH anytime during the inpatient stay at the
investigational medicine unit (IMU).
Updates made based on site-
specific input.
1.2 Schema 
1.3 Schedule of 
Activities 
10.9 Appendix 9: 
COVID-19 
Appendix
Hospitalization at the SingHealth investigational 
medicine unit (IMU) has been replaced with 
inpatient stay at IMU. 
Update in terminology to make a
clear distinction between inpatient
stay at IMU during treatment and
transfer to the hospital for
participants with severe dengue.
1.1 Synopsis 
4.1 Overall Design  
5.1 Inclusion 
Criteria
10.1 Appendix 1:
Abbreviations
The terminology healthcare clinics (HCCs) was 
changed to general practitioner clinics (GP) 
throughout the document.
Correction of errors and
inconsistencies.
8.3.4 Regulatory 
Reporting 
Requirements for 
Serious Adverse
Events
Anticipated events and Anticipated Events Safety 
Monitoring Plan were removed, because they are 
not applicable for this study.
Correction of errors and
inconsistencies.
8.5.3 
Pharmacokinetic 
Parameters and 
Evaluations
Plasma protein binding was replaced with 'protein 
binding' with regards to Alpha-1 acid glycoprotein, 
because this is detected in serum not plasma.
Correction of errors and
inconsistencies.
10.2 Appendix 2: 
Clinical Laboratory 
Tests
C-reactive protein was added to the biochemistry 
assessments.
Clarification.
4.1 Overall Design  
10.3 Appendix 3: 
Regulatory, Ethical, 
and Study Oversight 
Considerations 
It was clarified that the data review committee 
(DRC) will be consulted in case of significant or
unexpected safety events and for quarterly (or
when 50 new participants are enrolled, whichever
comes first) safety analyses.
Clarification.
2.3.4 Potential Risks 
5.2 Exclusion 
Criteria 
6.5 Concomitant
Therapy
COVID-19 vaccination was added as an exception 
to be allowed as concomitant vaccination 30 days 
after the last dosing.
To accommodate for COVID-19
vaccinations during the pandemic.
1.1 Synopsis 
4.1 Overall Design  
Follow-up period has been corrected to 23 days 
(±2 days) after the last dosing day.
Alignment with the SoA.
1.1 Synopsis 
4.1 Overall Design  
Alignment with the SoA.
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Section number 
and Name
Description of Change 
Brief Rationale
1.3 Schedule of 
Activities 
6.1 Study 
Intervention(s) 
Administered 
6.3 Measures to 
Minimize Bias: 
Randomization and 
Blinding
Alignment within the protocol.
10.7 Appendix 7: 
Rash Management 
The updated rash management section has been 
added to this protocol.
Alignment between studies.
8.1 Antiviral activity 
Assessments 
8.2.4 Clinical Safety 
Laboratory
Assessments
8.6 Genetics
Paragraphs on viral genome sequencing and 
clinical endpoint assessments have been moved to
the correct and corresponding subsection.
Correction.
Throughout the 
protocol 
Minor updates, corrections, or additions have been 
made. 
Correction, clarification, and
consistency.
Amendment 2 (08 September 2020)
Overall Rationale for the Amendment: The protocol was amended to incorporate changes related to the
new study drug formulation and as specified below.
Section number 
and Name
Description of Change 
Brief Rationale
10.9 Appendix 9: 
COVID-19 
Appendix  
A COVID-19 appendix was added. 
To provide guidance on study
conduct during the COVID-19
pandemic.
8.2.1 Physical 
Examinations 
Body weight recording and physical examinations 
were aligned with the Schedule of Activities. 
To maintain consistency throughout
the protocol.
8 Study 
Assessments and 
Procedures 
The total blood volume for the study was decreased 
with 5 mL to approximately 382 mL for males and 
384.5 mL for females. 
Serology for HIV and Hepatitis was
removed from screening in the
previous amendment without
adjusting the total blood volume to
be drawn.
Throughout the 
protocol 
Minor updates, corrections, or additions have been 
made. 
Correction, clarification, and
consistency.
Amendment 1 (4 August 2020)
Overall Rationale for the Amendment: The protocol was amended to incorporate changes related to the
new study drug formulation and as specified below.
Section number
and Name
Description of Change 
Brief Rationale
1.1 Synopsis
6.1 Study
Intervention(s)
Administered
This formulation was selected based
on the findings from the
64281802DNG1001 study.
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Section number 
and Name
Description of Change 
Brief Rationale
1.1 Synopsis 
1.3 Schedule of 
Activities 
2.2 Background
4.1 Overall Design
5.3.1 Meals and
Dietary Restrictions
6.1 Study
Intervention(s)
Administered
This is a result of the changed study
drug formulation.
6.5 Concomitant 
Therapy  
The use of loperamide was restricted to a period of 
maximum 3 consecutive days. 
No maximum duration of
loperamide use was formulated.
1.3 Schedule of 
Activities 
8 Study 
Assessments and 
Procedures 
10.2 Appendix 2:
Clinical Laboratory
Tests
Serology for HIV and Hepatitis has been removed 
from screening. 
HIV and Hepatitis are no
inclusion/exclusion criteria. Results
from baseline testing might not be
received in time and will not alter
eligibility or dosing.
5.1 Inclusion 
Criteria 
Chromosomal complement to determine sex has 
been removed. 
Chromosomal complement testing
is not available.
5.2 Exclusion 
Criteria 
5.3.3 Activity
No blood donation within 90 days after last dose of 
study intervention. 
To maintain consistency throughout
and across protocol(s).
5.3.3 Activity  
No participation in other investigational studies 
within 90 days of the last dose of study drug 
intake.
To maintain consistency across the
protocol (exclusion criterion 9).
2.3.4 Potential Risks Vaccinations are not allowed until 90 days after 
the last dose of study drug intake. 
To maintain consistency across
protocols.
2.1 Study Rationale 
The number of reported dengue cases has been 
updated to the date of this amendment. 
To provide accurate and
contemporaneous data.
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10.9. Appendix 9: COVID-19 Appendix
It is recognized that the Coronavirus Disease 2019 (COVID-19) pandemic may have an impact on
the conduct of this clinical study due to, for example, self-isolation/quarantine by participants and
study-site personnel; lock-down situations imposed by (local) governments; travel
restrictions/limited access to public places, including hospitals; study site personnel being
reassigned to critical tasks; and courier/shipment restrictions.
In alignment with recent Health Authority guidance, the sponsor is providing options for study
related participant management in the event of disruption to the conduct of the study. This guidance
does not supersede any local or government requirements nor the clinical judgement of the
investigator to protect the health and well-being of participants and site staff. If, at any time, a
participant’s safety is considered to be at risk, study intervention will be discontinued, and study
follow-up will be conducted.
Scheduled visits that cannot be conducted in person at the study site will be performed to the extent
possible remotely/virtually or delayed until such time that on-site visits can be resumed. At each
contact, participants will be interviewed to collect safety data. Key endpoint assessments related
to treatment outcomes should be performed if required and as feasible. Participants will also be
questioned regarding general health status to fulfill any physical examination requirements.
Every effort should be made to adhere to protocol-specified assessments for participants on study
intervention, including follow-up. Modifications to protocol-required assessments may be
permitted via the COVID-19 appendix after consultation with the participants, investigator, and
the sponsor. Missed or modified assessments/visits, discontinuations of study intervention, and
withdrawal from the study due to COVID-19-related circumstances, should be documented as
protocol deviations with the prefix “COVID-19-related” in the electronic case report form (eCRF).
The sponsor will continue to monitor the conduct and progress of the clinical study, and any
changes will be communicated to the sites and to the relevant Health Authorities/Ethics
Committees according to local guidance. If a participant has tested positive for COVID-19, the
investigator should contact the sponsor’s medical monitor to discuss plans for study intervention
and follow-up. Modifications made to the study conduct as a result of the COVID-19 pandemic
should be summarized in the clinical study report.
The following provisions are meant to give guidance and mitigations for impacted study conduct
due to COVID-19 pandemic in order to warrant the participant's safety and data collection/quality.
Clinical Aspects
Participants
As for any other comorbidity, the investigator needs to diagnose and treat any (suspected)
COVID-19 disease per standard-of-care and per local/national guidance.
If a participant, in any phase of this study, becomes symptomatic for COVID-19 disease, the
sponsor suggests that the coronavirus infection should be confirmed by using locally approved


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laboratory test kits, eg, a diagnostic kit using RT-PCR. This should be reported to the local Health
Authorities as required.
The investigator needs to evaluate and discuss with the sponsor’s medical monitor when a
participant develops acute COVID-19 during the study. This should be reported as an Adverse
Event (AE). Withdrawal from the study due to an AE of suspected or confirmed SARS-CoV-2
infection in a participant should be documented as discontinuation due to an AE in the eCRF.
The investigator should notify the sponsor’s medical monitor as soon as he/she is aware of a
suspected or confirmed SARS-CoV-2 infection in a participant.
The investigator should notify the treating physician of the participant’s participation in the study
and details of the study.
Site Staff
The investigator is to follow any local or government requirements and exercise his or her clinical
judgement to protect the health and well-being of participants, and site staff.
Visits/Assessments
If a participant cannot visit the study site in person for the protocol-required assessments, or if
certain assessments cannot be performed (as usual), or if there are transport restrictions for
samples, the site staff/investigator should discuss with the sponsor how the participant’s safety and
data collection/quality is guaranteed as much as possible.
 
In case visits to the study site are not possible, mitigations include: remote contacts, phone
contacts, or delay of the visit if acceptable based on the investigator's clinical judgement and
approval by the sponsor.
 
In case assessments cannot be performed per protocol at the study site, alternatives may be
possible after discussion and agreement with the sponsor.
 
There are some assessments that could be conducted remotely via telephone (or
videoconference) with participants confined at home. This methodology can only be used
in accordance with applicable (including local) laws, regulations, guidance, and
procedures. These remote assessments include review of AEs and concomitant
medications. It must be documented in the participant’s source documents and eCRF if a
visit occurs remotely due to COVID-19.
 
If due to local or national guidance or regulations, for safety reasons of the participants
or site staff or to avoid spread of coronavirus infection, certain assessments cannot be
performed or are to be performed differently, this is to be documented in the source
documents and the eCRF.
 
In case transportation to the central laboratory is not possible, the PK blood samples should
be stored at -20°C until transportation of the sample is possible.
If a participant’s safety and/or data collection and integrity are not guaranteed, it may be decided
to interrupt/stop the participant follow-up as per Section 7 in the protocol.


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Study Drug
Drug administration will be discontinued when participants are not in the ability to come to the
study site (no home dosing).
Missed or Modified Assessments/Protocol Deviations
Missed or modified assessments/visits will be captured in the Electronic Data Capture (EDC) as
protocol deviations with the prefix “COVID-19-related”.
In case of any protocol deviation due to COVID-19 (eg, remote visits, missed or modified
assessments/visits, and out of window visits), it is recommended that these would be captured in
the participant’s source documents by the site personnel with the prefix “COVID-19-related”.
Monitoring/Audits/Consent/Ethics
On-site Monitoring visits
In case on-site monitoring visits are not possible due to local regulations, restrictions, and
guidance, the site monitor may conduct certain monitoring activities remotely. Additional on-site
monitoring visits may be needed in the future to catch up on source data verification.
Audits
To comply with national, local, and/or organizational social distancing restrictions due to
COVID-19, study-site Good Clinical Practices (GCP) Audits with direct impact/engagement from
the clinical investigator team may not be conducted at the impacted sites. Additional quality
assurance activities such as remote audits or focused review of study related documents may take
place with limited impact/engagement if possible.
Consent
In case any required assessments cannot be performed per protocol due to COVID-19, the
investigator should inform the participant about the changes and document the discussion in the
participant’s source notes.
Ethics
In case of any protocol deviations related to COVID-19, the investigator should notify these to the
local Ethics Committees/Health Authorities per local requirements.
Study Conduct Related to COVID-19 Vaccine Deployment for Non-COVID-19 Clinical
Trials
 
An authorized/licensed COVID-19 vaccine will be allowed at any time before, during, and
after the study. The COVID-19 vaccine will be reported as a concomitant medication.
 
Side effects of vaccination will be reported as AEs, defining the causality of AEs will rely on
the medical judgement of the principal investigator of the study.


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 
SUSAR reporting must be initiated if the serious adverse reaction is unexpected.
 
If the event is serious and considered related to both the COVID-19 vaccine and the study
intervention, it has to be recorded as a serious adverse reaction.


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11. 
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Rodriguez F, Harrison RW, Wojdyla D, Mahaffey KW. Lost to follow-up and withdrawal of consent in
contemporary global cardiovascular randomized clinical trials. Crit Pathways in Cardiol. 2015;14:150-153.
Shepard D, Undurraga E, Halasa Y, Stanaway J. The global economic burden of dengue: a systematic analysis.
Lancet Inf Dis. 2016; 16:935–41.
Tricou V, Minh NN, Farrar J, Tran HT, Simmons CP. Kinetics of viremia and NS1 antigenemia are shaped by
immune status and virus serotype in adults with dengue. PLoS Negl Trop Dis. 2011;5(9).
Whitehorn J, Simmons CP. The pathogenesis of dengue. Vaccine. 2011;29(42):7221-7228.
World Health Organization. Guidelines for plaque reduction neutralization testing of human antibodies to dengue
viruses. 2007


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Status: Approved,  Date:  06 June 2022
World Health Organization. A joint publication of the World Health Organization (WHO) and the Special
Programme for Research and Training in Tropical Diseases (TDR). Dengue guidelines for diagnosis, treatment,
prevention and control. New edition. http://whqlibdoc.who.int/publications/2009/9789241547871 eng.pdf?ua=1.
2009. Accessed 03 May 2018.
World Health Organization: Dengue. Guidelines for diagnosis, treatment, prevention and control. 2009
World Health Organization. Dengue and severe dengue. WHO website.
http://www.who.int/mediacentre/factsheets/fs117/en/. Updated November 2019. Accessed 07 November 2019.
World Health Organization. Ten threats to global health in 2019. https://www.who.int/emergencies/ten-threats-to-
global-health-in-2019. 2019. Accessed 07 November 2019.
Xie X, Zou J, Wang QY, Shi PY. Targeting dengue virus NS4B protein for drug discovery. Antiviral Res. 2015;
118:39-45.


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Status: Approved,  Date:  06 June 2022
INVESTIGATOR AGREEMENT
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will
conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully informed
regarding the study intervention, the conduct of the study, and the obligations of confidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature: 
Date:
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature: 
Date:
(Day Month Year)
Sponsor's Responsible Medical Officer:
Name (typed or printed): 
Institution: 
Janssen Research & Development
Signature: Electronic signature appended at the end of the protocol 
Date:
(Day Month Year)
Note: If the address or telephone number of the investigator changes during the course of the study, written
notification will be provided by the investigator to the sponsor, and a protocol amendment will not be required.
PPD


Signature
User 
Date 
Reason
07-Jun-2022
01:13:41
(GMT)
Document Approval
PPD

SAP_001.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Final, Date: 04 OCT 2023
Janssen Research & Development
Statistical Analysis Plan
A Phase 2a, Randomized, Double-blind, Placebo-controlled Trial to Evaluate the Antiviral 
Activity, Safety and Tolerability, and Pharmacokinetics of JNJ-64281802 in Participants 
with Confirmed Dengue Fever
Protocol 64281802DNG2003; Phase 2
JNJ-64281802
Status:
Final
Date:
04 OCT 2023
Prepared by:
Janssen Research & Development, a division of Janssen Pharmaceutica NV
Document No.: EDMS RIM-298496
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company 
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or 
otherwise.
NCT04906980


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Status: Final, Date: 04 OCT 2023
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
VERSION HISTORY..................................................................................................................................... 3
1.
INTRODUCTION.................................................................................................................................. 4
1.1.
Objectives and Endpoints ................................................................................................................ 4
1.2.
Study Design.................................................................................................................................... 6
2.
STATISTICAL HYPOTHESES............................................................................................................ 7
3.
SAMPLE SIZE DETERMINATION...................................................................................................... 7
4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS....................................................................... 8
5.
STATISTICAL ANALYSES................................................................................................................. 8
5.1.
General Considerations ................................................................................................................... 8
5.1.2.
Visit Windows ............................................................................................................................... 8
5.1.3.
Baseline Definition........................................................................................................................ 8
5.1.4.
Relative Day ................................................................................................................................. 8
5.1.5.
Definition of Subgroups ................................................................................................................ 9
5.1.6.
Demographics and Baseline Characteristics................................................................................ 9
5.1.7.
Exposure....................................................................................................................................... 9
5.1.8.
Protocol Deviations..................................................................................................................... 10
5.1.9.
Concomitant Medications ........................................................................................................... 10
5.1.10.
Medical History ........................................................................................................................... 10
5.2.
Participant Dispositions.................................................................................................................. 10
5.3.
Efficacy Endpoint(s) analysis ......................................................................................................... 11
5.4.
Safety Analyses ............................................................................................................................. 13
5.4.1.
Adverse Events........................................................................................................................... 13
5.4.2.
Additional Safety Assessments .................................................................................................. 13
5.4.2.1.
Clinical Laboratory Tests......................................................................................................... 13
5.4.2.2.
Vital Signs and Physical Examination Findings....................................................................... 14
5.4.2.3.
Electrocardiogram ................................................................................................................... 15
5.5.
Other Analyses............................................................................................................................... 15
5.5.1.
Pharmacokinetics ....................................................................................................................... 15
5.6.
Interim Analyses............................................................................................................................. 15
6.
SUPPORTING DOCUMENTATION .................................................................................................. 16
6.1.
Appendix 1 List of Abbreviations.................................................................................................... 16
6.2.
Appendix 2 Changes to Protocol-Planned Analyses ..................................................................... 17
6.3.
Appendix 3 Prior and Concomitant Medications............................................................................ 18
6.4.
Appendix 4 Laboratory Toxicity Grading........................................................................................ 19
7.
REFERENCES................................................................................................................................... 20


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VERSION HISTORY
Table 1 – SAP Version History Summary
SAP Version
Approval Date
Change
Rationale
1
04 October 2023
Not Applicable
Initial release








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The study sites will be open to receive referrals of participants who have consulted a health care 
facility (e.g., clinic/polyclinic, hospital) or practitioner (e.g., general practitioner, medical doctor, 
nurse) with an onset of fever within the last 48 hours, as reported by the participant, and who tested 
positive for DENV infection by the NS1 assay at the health care facility. Individuals who test 
positive during an ambulatory visit or as part of Standard of Care DENV NS1 rapid testing, will 
be referred to the study site to further coordinate informed consent signing and completion of 
eligibility assessments. In addition, participants may also report directly to the study site. 
Participants identified at the study site with an onset of fever as reported by the participant within 
the last 48 hours, and who test positive for DENV infection by the NS1 assay performed at the site 
after signing the Informed Consent Form (ICF), will undergo eligibility assessment. 
The screening/baseline assessments are to be completed as quickly as possible at the study site. 
Participants who successfully meet all inclusion criteria and none of the exclusion criteria, will be 
enrolled and admitted to an inpatient facility. The participants will then be randomized to receive 
placebo or JNJ-64281802. 
 
 
Results of screening assessments need to be documented in the electronic case report form 
(eCRF).
2.
STATISTICAL HYPOTHESES
The primary hypothesis of this study is that JNJ-64281802 is superior to placebo with respect to
reduction in viral load in participants with a primary DENV infection, as measured by area under
the log10-transformed DENV RNA viral load curve from baseline on Day 1 until Day 5.
3.
SAMPLE SIZE DETERMINATION
The study planned to recruit in total 150 participants, with the primary objective of investigating 
the antiviral activity of JNJ-64281802 versus placebo based on DENV RNA in primary DENV
infection and with a secondary objective to describe the safety and tolerability of JNJ-64281802 
in participants with DENV infection.
For the objective of antiviral activity in participants with a primary DENV infection, the hypothesis 
is that the intervention effect is superior to placebo as measured on the DENV RNA log10 viral 
load curve from baseline on Day 1 until Day 5.
To assess sample size requirements for this hypothesis, data of 47 DENV RNA curves were
estimated similar to the DENV RNA curves graphically presented in the balapiravir trial. All
curves were considered as balapiravir did not have an effect on the viral load. A limit of detection 
of 2.3 log copies/mL was assumed. Although the majority of the population included in the 
balapiravir trial suffered from a secondary infection2, these estimated DENV RNA curves were 
considered representative for a primary infected dengue population. As the clearance of DENV 
RNA occurs earlier and faster in patients with secondary dengue, this is a conservative 
assumption3.
The 47 estimated DENV RNA curves were used to calculate the means, standard deviations and
correlations of the log10 viral loads over time. These calculated values were thereafter used to
CCI


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simulate 10,000 trials, each with a sample size of 80 participants. A treatment effect of 0.30 log10
copies/mL per day DENV RNA clearance on top of placebo, or two-fold reduction of the viral
load was applied. Based on these 10,000 simulated trials and using a general linear model with
treatment regimen as fixed factor and baseline log10 viral load as a covariate, a sample size of 80 
participants (40 per group) was estimated to provide a power of at least 80% at the one-sided 5% 
significance level to detect an intervention effect of 0.30 log10 copies/day additional DENV RNA 
clearance when compared to placebo.
The specificity of the DENV NS1 testing at baseline is estimated to be 98% which entails that 2% 
of participants that will be enrolled will not be evaluable for efficacy. Based on literature1, it is 
estimated that approximately 60% of the total population will have a primary infection.
Furthermore, it is anticipated that approximately 4% of the enrolled participants drop-out for other 
reasons. The study will therefore need to recruit a total of 150 participants in order to achieve a 
sample of 84 participants to achieve >80% power on the primary hypothesis.
For the objective of safety assessment, the probability was calculated to observe an (S)AE that has 
a true incidence of 1% which would be 53% with a total sample size of 75 participants on active 
treatment; the probability to observe an (S)AE with a true incidence of 0.1%, 0.5% and 0.8% is 
7%, 31% and 45%, respectively.
4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS
Patient profiles will be produced for all participants who signed the ICF and who were randomized 
and treated in the study.
5.
STATISTICAL ANALYSES
5.1.
General Considerations
5.1.1.
Analysis Phase Definition
No analysis phases will be derived.
5.1.2.
Visit Windows
All values collected for the parameters listed below will be considered based on their actual date
and time.
5.1.3.
Baseline Definition
Not applicable.
5.1.4.
Relative Day
Study Day 1 is defined as the date of first study intervention intake (reference day). All complete 
dates reported in the patient profiles will be assigned a day relative to this date.
The relative day (reldy) will be defined as:












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condition is specified in the protocol, the non-fasting gradings should be used. In case no toxicity 
grades are defined for any laboratory test, then non-graded abnormalities (high/low vs. normal 
range) will be used instead.
Hematology and Chemistry laboratory tests will be plotted over time (days since first drug intake). 
All collected values will be displayed. In case of a toxicity/abnormality, the toxicity/abnormality 
will be flagged with the actual value on the plot.

Different colors are used for toxicity grades 0-4, and different colors are used for below 
the lower limit of normal / normal / above the lower limit of normal.

Different symbols are used for graded vs. non-graded laboratory tests.

Normal ranges will be indicated for each laboratory test.
5.4.2.2.
Vital Signs and Physical Examination Findings
The vital sign parameters that will be analyzed are temperature, pulse, systolic blood pressure, 
diastolic blood pressure, respiratory rate, oxygen saturation and I/O ratio.
Toxicity grades for the vital signs will be computed according to the United States Food and Drug 
Administration Toxicity Grading as presented in Table 9 (and appendix 6 of the protocol). No 
toxicity grades/abnormalities are defined for oxygen saturation and I/O ratio.
Vital signs will be plotted over time (days since first drug intake). All collected values will be 
displayed. In case of a toxicity/abnormality, the toxicity/abnormality will be flagged with the 
actual value on the plot.

Different colors are used for toxicity grades 0-4.

Different symbols are used for the direction of the toxicity grade (below/above).

Normal ranges will be indicated for each vital sign.
Table 9: Vital Signs: Abnormality Criteria
Vital Signs
Mild 
(Grade 1)
Moderate 
(Grade 2)
Severe 
(Grade 3)
Potentially Life
Threatening
(Grade 4)
Fever (°C) **
Fever (°F) **
38.0 - 38.4
100.4 - 101.1
38.5 - 38.9
101.2 - 102.0
39.0 - 40.0
102.1 - 104.0
>40
>104.0
Pulse (bpm)
Tachycardia
101-115
116-130
>130
Bradycardia
50-54
45-49
<45
Systolic blood pressure (mmHg)
Hypertension (Systolic)
141-150
151-155
>155
Hypotension (Systolic)
85-89
80-84
<80
Diastolic blood pressure (mmHg)
Hypertension (Diastolic)
91-95
96-100
>100
Respiratory rate (breaths/minute)
17-20
21-25
>25
Abnormal physical examination results will be listed in the patient profiles (date/time of examination, 
study day, body system, verbatim examination finding, clinically significant).


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5.4.2.3.
Electrocardiogram
The ECG parameters that will be analyzed are heart rate (HR), PR interval, RR interval, QRS 
interval, QT interval, and corrected QT (QTc) interval using the Fridericia’s formula (QTcF)
correction method.
QTcF values will be used as reported in the database. In case these corrected QT intervals are not 
present in the database, these will be derived for analysis using the following formula, rounding 
results to the nearest integer:
Fridericia’s formula: QTcF (msec) = QT (msec) / (RR (msec)/1000)1/3; if RR is missing, use 
QT (msec) * (HR(bpm)/60)1/3.
Table 10 presents the abnormality criteria for the ECG parameters. No abnormality criteria are 
defined for RR interval.
Table 10: Criteria for Abnormal ECG parameters
Abnormality class and label
ECG parameter
HR (bpm)
PR (msec)
QRS (msec)
QT, QTcF (msec)
Abnormalities for actual values
Low
< 45
-
-
-
High
> 100
> 220
≥ 110
> 450
ECG parameters will be plotted over time (days since first drug intake). All collected values will 
be displayed. In case of an abnormality, the abnormality (Low/High) will be flagged with the actual 
value on the plot.

Different colors are used for normal vs abnormality.

Different symbols are used for the direction of the abnormality (below/above).

Normal ranges will be indicated for each parameter.
Electrocardiogram interpretation will be listed in the patient profiles. The date/time (study day), 
evaluator [Investigator; Central laboratory], result [Abnormal; Normal] will be provided. In case 
of abnormal, clinically significant [Yes; No] information will be provided.
5.5.
Other Analyses
5.5.1.
Pharmacokinetics
A listing of individual plasma concentrations of JNJ-64281802 (ng/ml) at each collected timepoint 
will be provided. All available values will be shown.
5.6.
Interim Analyses
Not applicable.


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6.
SUPPORTING DOCUMENTATION
6.1.
Appendix 1 List of Abbreviations
AE
adverse event
AUC
area under the curve
BMI
body mass index
CRF
case report form
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events
DENV
Dengue virus
DPS
Data Presentation Specifications
ECG
electrocardiogram
eCRF
electronic case report form
HLA
human leukocyte antigen
ICF
informed consent form
Ig
Immunoglobulin
LLOQ
lower limit of quantification
LOD
limit of detection
MedDRA
Medical Dictionary for Regulatory Activities
NAb
neutralizing antibodies
PD
pharmacodynamic(s)
PI
principal investigator
PK
pharmacokinetic(s)
RT-PCR
Reverse transcription-polymerase chain reaction
SAE
serious adverse event
SAP
Statistical Analysis Plan
VL
viral load
WHO
World Health Organization
WHO-DD
World Health Organization Drug Dictionary


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6.2.
Appendix 2 Changes to Protocol-Planned Analyses
On 14-Sep-2023, the Sponsor decided to terminate study 64281802DNG2003 early due to low 
enrollment and not for any safety-related reasons. Five participants were enrolled into the study.
The last enrollment was on 19-Sep-2022. It was decided to simplify and reduce the statistical 
outputs to listings and individual patient profiles because data of only five randomized participants 
were collected. Therefore, no summary statistics across participants will be produced, and data 
will be reported as a listing generated for each participant (patient profile) and clinical narratives.
In addition, graphical representations will be created for selected virological parameters.


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6.3.
Appendix 3 Prior and Concomitant Medications
Prior and Concomitant medications will be coded using the [World Health Organization Drug 
Dictionary (WHO-DD)]. Prior medications are defined as any therapy used before the day of first 
dose (partial or complete) of study intervention. Concomitant medications are defined as any 
therapy used on or after the same day as the first dose of study intervention, including those that 
started before and continue on after the first dose of study intervention.


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6.4.
Appendix 4 Laboratory Toxicity Grading
Toxicity grades will be computed according to the United States Food and Drug Administration 
Toxicity Grading as presented in appendix 6 of the protocol.


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7.
REFERENCES
1.
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.
2.
Nguyen NM, Tran CHB, 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); 1442-1450.
3.
Tricou V, Minh NN, Farrar J, Tran HT, Simmons CP. Kinetics of viremia and NS1 antigenemia are 
shaped by immune status and virus serotype in adults with dengue. PLoS Negl Trop Dis. 2011;5(9).