Conditions: Dengue
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1595
Healthy volunteers: yes

Brief summary:
The purpose of this study is to evaluate the prophylactic effect of JNJ-64281802 with respect to the prevention of laboratory-confirmed dengue virus (DENV) infection up to the last day of dosing among participants who have no evidence of current DENV infection at baseline.

Detailed description:

Arms:
arm 1: Participants will receive JNJ-64281802 400 milligrams (mg) loading dose (LD) twice daily for 48 hours (2 days), followed by JNJ-64281802 150 mg maintenance dose (MD) once daily for 26 days in fed conditions. arm 2: Participants will receive JNJ-64281802 150 mg LD twice daily for 48 hours (2 days), followed by JNJ-64281802 50 mg MD once daily for 26 days in fed conditions. arm 3: Participants will receive JNJ-64281802 matching placebo LD and MD from Day 1 to Day 28.

Interventions: intervention 1: JNJ-64281802 intervention 2: Placebo
Intervention descriptions: intervention 1: JNJ-64281802 tablets will be administered orally as per the defined regimens. intervention 2: Matching placebo for each dose level as tablet will be administered orally.

Protocol document:
Prot_000.pdf: 
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
1
Status: Approved, Date: 19 July 2023
Janssen Research & Development *
Clinical Protocol
Protocol Title
A Phase 2, Randomized, Double-blind, Placebo-controlled, Double-dummy, Multicenter
Trial Assessing the Efficacy and Safety of Two Dose Regimens of JNJ-64281802 for the
Prevention of Dengue Infection.
Protocol 64281802DNG2004; Phase 2
AMENDMENT 3
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.
United States (US) sites of this study will be conducted under US Food & Drug Administration
Investigational New Drug (IND) regulations (21 CFR Part 312).
IND: 143525
Status: 
Approved
Date: 
19 July 2023
Prepared by: Janssen Research & Development, a division of Janssen Pharmaceutica NV
EDMS number: 
EDMS-RIM-145705, 4.0
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.
NCT05201794


JNJ-64281802  
Clinical Protocol 64281802DNG2004
AMENDMENT 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
2
Status: Approved, Date: 19 July 2023
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document 
Date
Amendment 3 
18 July 2023
Amendment 2 
02 December 2022
Amendment 1 
04 October 2022
Original Protocol 
09 November 2021
Amendment 3 (18 July 2023)
Overall Rationale for the Amendment: The main purpose of this amendment is to clarify and simplify
some operational aspects of the study, to avoid potential confusion or misinterpretation, and to facilitate
study conduct.
Clarifications were provided with regards to the timing of study intervention dosing and the term household
contact (HHC). Updates were made to some inclusion and exclusion criteria, the discontinuation criteria,
and the lists of allowed and disallowed concomitant therapy and contraceptives. The US FDA toxicity
grading Table was replaced with information obtained from the Division of Acquired Immunodeficiency
Syndrome (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events and
supplemented with WHO toxicity grading scales where values were absent, and further clarifications and
corrections were made. The changes made to the clinical protocol 64281802DNG2004 as part of Protocol
Amendment 3 are listed below, including the rationale of each change and a list of all applicable sections.
Changes made in the previous protocol amendments are listed in Section 10.12Appendix 12: Protocol
Amendment History.
Section number 
and Name
Description of Change 
Brief Rationale
Synopsis 
1.3.2.2 Double-blind Prophylactic 
Dosing of HHCs: Day 1 to Day 13 
1.3.2.3 Double-blind Prophylactic
Dosing of HHCs (Day 14 to Day
28) and Follow-up Phase4.1
Overall Design
6.1 Study Intervention(s)
Administered
6.4 Study Intervention Compliance
8 STUDY ASSESSMENTS AND
PROCEDURES
The timing of the loading dose
and maintenance dose
administrations was clarified.
For clarification.
Synopsis 
4.1 Overall Design  
5 STUDY POPULATION  
It was clarified that HHCs may
include family members,
acquaintances, co-workers, and
community contacts of the index
case.
For clarification.
5.1 Inclusion Criteria 
It was clarified that abnormal
blood pressure results are only
exclusionary for HHCs if the
investigator judges the deviations
from normal blood pressure are
clinically significant.
For clarification.
5.2 Exclusion Criteria 
It was clarified that clinically
relevant skin diseases are
exclusionary for HHCs ifthe
clinically relevant skin disease
To allow enrollment of participants
with any clinically relevant skin
disease ≥ 3 months prior to
enrollment, instead of ≥ 5 years.
NCT05201794


JNJ-64281802  
Clinical Protocol 64281802DNG2004
AMENDMENT 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
3
Status: Approved, Date: 19 July 2023
Section number 
and Name
Description of Change 
Brief Rationale
occurred within 3 months prior to
study enrollment.
5.2 Exclusion Criteria 
It was clarified that prior 
treatment with 
immunomodulation therapy is 
exclusionary for HHCs if the 
therapy was taken within the past
6 months.
To allow enrollment of participants
with a history of immunomodulatory
therapy ≥ 6 months prior to
enrollment.
5.2 Exclusion Criteria 
It was clarified that prior receipt 
of an investigational intervention 
or prior use of an invasive 
investigational medical device is 
exclusionary for HHCs if the 
investigational intervention or 
invasive investigational medical
device was used within 3 months
before the planned first dose of
study intervention.
To allow enrollment of participants
with a history of using investigational
intervention or invasive
investigational medical device
products ≥3 months prior to
enrollment.
2.3.1 Risks for Study Participation  
5.2 Exclusion Criteria 
6.8 Concomitant Therapy  
10.4 Appendix 4: COVID-19 
Appendix
Participants will be allowed to 
receive a COVID-19 vaccine 
during the study. 
To allow participants to receive a
COVID-19 vaccine and adhere to
national/local vaccination
recommendations.
5.2 Exclusion Criteria 
6.8 Concomitant Therapy  
10.10 Appendix 10: Examples of 
Disallowed Medications 
The concomitant use of CYP3A4
inhibitors, inducers, and
substrates, as well as BCRP
substrates, was clarified.
CYP3A4 substrates were limited
to those with narrow therapeutic
index, and CYP3A4 inhibitors
and CYP3A4 inducers were
limited to strong ones. Examples
of disallowed medications were
provided.
In addition, some inconsistencies
between Exclusion Criterion 11
and the concomitant therapy
section were corrected.
JNJ-64281802 is a weak inhibitor of
CYPs 2C8, 2C9, 2C19, and 3A4
based on a cocktail drug interaction
study (64281802DNG1004) using
repaglinide, warfarin, omeprazole,
and midazolam respectively as
probes. Substrates of CYP2C8, 2C9,
and 2C19 do not warrant exclusion
but should be appropriately
monitored if coadministered.
5.2 Exclusion Criteria 
It was specified that the medical
history of participants should be
evaluated based on clinical
significance by the investigator.
For clarification.
5.2 Exclusion Criteria 
6.8 Concomitant Therapy  
A change was made in the time
period for administration of
licensed (not live) vaccines.
To facilitate participant enrollment
and for clarification.
6.8 Concomitant Therapy  
Details regarding the use of
paracetamol/acetaminophen were
added.
To broaden the use of co-medication
and to add more detailed instructions
regarding their use.
5.1 Inclusion Criteria 
10.5 Appendix 5: Contraceptive 
and Barrier Guidance 
It was clarified that the use of
estrogen and/or progestogen
hormonal contraception is not
The interaction between JNJ-
64281802 and hormone-based
contraceptives has not been assessed.
The efficacy of hormone-based
NCT05201794


JNJ-64281802  
Clinical Protocol 64281802DNG2004
AMENDMENT 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
4
Status: Approved, Date: 19 July 2023
Section number 
and Name
Description of Change 
Brief Rationale
allowed as sole method of 
contraception during the study. 
contraceptives may be decreased
when coadministered with
JNJ-64281802 and therefore should
not be considered a highly effective
contraceptive method during dosing
with JNJ-64281802. A woman using
any type of hormonal contraception
must use an additional barrier-based
contraceptive method.
7.1 Discontinuation of Study 
Intervention  
Discontinuation criteria based on 
laboratory abnormalities were 
updated. 
To accommodate laboratory values
that can be expected in the diverse
population included in this global
study and that are not anticipated to
pose a safety risk.
8.3.2 Method of Detecting Adverse 
Events and Serious Adverse Events 
Laboratory events were removed 
from the list of solicited AEs. 
Since laboratory assessments are an
objective measurement, it is incorrect
to categorize them as solicited AEs.
Solicited AEs are predefined events
for which the participant is
specifically questioned.
1.3.2.2 Double-blind Prophylactic 
Dosing of HHCs: Day 1 to Day 13 
1.3.2.3 Double-blind Prophylactic 
Dosing of HHCs (Day 14 to Day 
28) and Follow-up Phase 
1.3.2.4 Discontinuation From 
Study Intervention or Study  
8 STUDY ASSESSMENTS AND 
PROCEDURES
10.8 Appendix 8: Clinical
Laboratory Tests
It was clarified that baseline 
laboratory assessments for clinical 
chemistry and coagulation should, 
in addition to being performed 
centrally, be performed locally.
Local testing at subsequent visits
is at the discretion of the PI and if
requested by the Sponsor.
To facilitate evaluation and
monitoring ofparticipant safety
regarding discontinuation criteria in a
timelier manner at baseline.
Synopsis 
8.3.2 Method of Detecting Adverse 
Events and Serious Adverse Events 
9.4.4.1 Safety Analyses 
10.7.3 Severity Criteria 
10.9 Appendix 9: Toxicity 
Grading Scale for Determining the 
Severity of Adverse Events 
The US FDA toxicity grading 
Table was replaced with 
information obtained from the 
DAIDS table for Grading the 
Severity of Adult and Pediatric 
Adverse Events and supplemented 
with WHO toxicity grading scales
where values were absent.
The DAIDS Toxicity Grading Scale
supplemented with WHO toxicity
grading scales was considered more
appropriate, given the global nature of
this study, including a diverse
population.
1.3.2.4 Discontinuation From 
Study Intervention or Study  
8.2.5 Pregnancy Testing 
10.8 Appendix 8: Clinical 
Laboratory Tests 
It was clarified that a pregnancy 
test will be performed at
screening, on Days 28 and 50, and
during a withdrawal visit, and that
additional pregnancy tests may be
performed as determined
necessary by the investigator or
required by local regulations.
To correct an inconsistency.
5.4 Screen Failures 
It was clarified that the 
investigator will not generate 
screening and enrollment logs. 
To align with the company’s most
recent protocol template per company
policy.
7.1.2 Participant Stopping Criteria 
due to Liver Chemistry 
Liver chemistry stopping criteria 
were added. 
To provide guidelines for actions
required for participants who develop
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JNJ-64281802  
Clinical Protocol 64281802DNG2004
AMENDMENT 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
5
Status: Approved, Date: 19 July 2023
Section number
and Name
Description of Change 
Brief Rationale
10.11 Appendix 11: Liver Safety:
Suggested Actions and Follow-up
Assessments
ALT and AST elevations during the
participation of the study.
1.1 Synopsis
1.3.1 Index Cases
4.1 Overall Design
5.1 Inclusion Criteria
8.1.1.1 Antiviral Activity
8.7.1  NS1 Test and RT-PCR/anti-
DENV IgM test ofIndex Cases
Removal of ‘rapid’ test. 
To not restrict inclusion based on
diagnostic test.
1.1 Synopsis
4.1 Overall Design
Informed consent from ICs may
be obtained remotely.
For clarification.
1.1 Synopsis
4.1 Overall Design
Confirmation of baseline DENV
infection is to be performed at a
central laboratory.
For clarification.
1.1 Synopsis
1.3.2.1 Screening Phase
1.3.2.2 Double-blind Prophylactic
Dosing of HHCs: Day 1 to Day 13
1.3.2.3 Double-blind Prophylactic
Dosing of HHCs (Day 14 to Day
28) and Follow-up Phase
1.3.2.4 Discontinuation From
Study Intervention or Study
8 STUDY ASSESSMENTS AND
PROCEDURES
8.2.2 Vital Signs
8.3.2 Method of Detecting Adverse
Events and Serious Adverse Events
10.3 Appendix 3: WHO Clinical
Classification of Dengue Disease
Measurement of body temperature
should be performed orally. No
antipyretic medications are
allowed prior to body temperature
measurement for at least 4 hours.
For clarification.
1.3.1 Index Cases 
It was added that AEs related to
blood sampling from ICs will be
collected.
To include the need to report AEs
related to blood sampling.
Throughout the protocol 
Minor grammatical, formatting, or
spelling changes and clarifications
were made.
Minor errors were corrected.
NCT05201794


JNJ-64281802  
Clinical Protocol 64281802DNG2004
AMENDMENT 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
6
Status: Approved, Date: 19 July 2023
TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................... 2
TABLE OF CONTENTS ............................................................................................................................... 6
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 8
1. 
PROTOCOL SUMMARY..................................................................................................................... 9
1.1. 
Synopsis........................................................................................................................................... 9
1.2. 
Schema.......................................................................................................................................... 23
1.3. 
Schedule of Activities..................................................................................................................... 24
1.3.1. 
Index Cases................................................................................................................................ 24
1.3.2. 
Household Contacts ................................................................................................................... 25
2. 
INTRODUCTION................................................................................................................................ 37
2.1. 
Study Rationale.............................................................................................................................. 39
2.2. 
Background.................................................................................................................................... 39
2.3. 
Benefit-risk Assessment................................................................................................................. 44
2.3.1. 
Risks for Study Participation....................................................................................................... 44
2.3.2. 
Benefits for Study Participation .................................................................................................. 46
2.3.3. 
Benefit-risk Assessment for Study Participation......................................................................... 46
3. 
OBJECTIVES AND ENDPOINTS ..................................................................................................... 46
4. 
STUDY DESIGN ................................................................................................................................ 48
4.1. 
Overall Design................................................................................................................................ 48
4.2. 
Scientific Rationale for Study Design............................................................................................. 51
4.2.1. 
Study-specific Ethical Design Considerations ............................................................................ 52
4.3. 
Justification for Dose...................................................................................................................... 53
4.4. 
End of Study Definition................................................................................................................... 55
5. 
STUDY POPULATION ...................................................................................................................... 55
5.1. 
Inclusion Criteria............................................................................................................................ 56
5.2. 
Exclusion Criteria........................................................................................................................... 58
5.3. 
Lifestyle Considerations................................................................................................................. 61
5.3.1. 
Meals and Dietary Restrictions................................................................................................... 61
5.3.2. 
Caffeine, Alcohol, and Drugs of Abuse....................................................................................... 61
5.4. 
Screen Failures.............................................................................................................................. 62
6. 
STUDY INTERVENTION AND CONCOMITANT THERAPY............................................................ 62
6.1. 
Study Intervention(s) Administered................................................................................................ 62
6.2. 
Preparation/Handling/Storage/Accountability ................................................................................ 66
6.3. 
Measures to Minimize Bias: Randomization and Blinding............................................................. 67
6.4. 
Study Intervention Compliance...................................................................................................... 68
6.5. 
Dose Modification........................................................................................................................... 69
6.6. 
Continued Access to Study Intervention After the End of the Study ............................................. 69
6.7. 
Treatment of Overdose .................................................................................................................. 69
6.8. 
Concomitant Therapy..................................................................................................................... 69
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL............................................................................................... 71
7.1. 
Participant Discontinuation Criteria................................................................................................ 71
7.1.1. 
Participant Stopping Criteria due to DENV infection .................................................................. 72
7.1.2. 
Participant Stopping Criteria due to Liver Chemistry................................................................. 72
7.1.3. 
Study Pausing Criteria................................................................................................................ 72
7.2. 
Participant Discontinuation/Withdrawal From the Study................................................................ 74
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JNJ-64281802  
Clinical Protocol 64281802DNG2004
AMENDMENT 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 19 July 2023
7.2.1. 
Withdrawal From the Use of Research Samples ....................................................................... 74
7.3. 
Lost to Follow-up............................................................................................................................ 75
8. 
STUDY ASSESSMENTS AND PROCEDURES ............................................................................... 76
8.1. 
Efficacy........................................................................................................................................... 78
8.1.1. 
Virology....................................................................................................................................... 78
8.1.2. 
Immune Assessments ................................................................................................................ 79
8.2. 
Safety Assessments....................................................................................................................... 79
8.2.1. 
Physical Examinations................................................................................................................ 79
8.2.2. 
Vital Signs................................................................................................................................... 80
8.2.3. 
Electrocardiograms..................................................................................................................... 80
8.2.4. 
Clinical Safety Laboratory Assessments .................................................................................... 80
8.2.5. 
Pregnancy Testing...................................................................................................................... 81
8.3. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting ....................................... 81
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event
Information.................................................................................................................................. 81
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events .......................................... 82
8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events ....................................................... 83
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events ............................................. 84
8.3.5. 
Pregnancy................................................................................................................................... 84
8.3.6. 
Disease-related Events and Disease-related Outcomes Not Qualifying as Adverse
Events or Serious Adverse Events ............................................................................................. 84
8.4. 
Pharmacokinetics........................................................................................................................... 84
8.4.1. 
Evaluations ................................................................................................................................. 85
8.4.2. 
Analytical Procedures................................................................................................................. 85
8.4.3. 
Pharmacokinetic Parameters and Evaluations........................................................................... 85
8.5. 
Pharmacogenomics ....................................................................................................................... 86
8.6. 
Biomarkers..................................................................................................................................... 86
8.7. 
Other Virology Assessments.......................................................................................................... 86
8.7.1. 
NS1 Test and RT-PCR/anti-DENV IgM test of Index Cases...................................................... 86
8.8. 
Health Economics .......................................................................................................................... 86
8.9. 
Pharmacokinetic Substudy ............................................................................................................ 86
9. 
STATISTICAL CONSIDERATIONS.................................................................................................. 87
9.1. 
Statistical Hypotheses.................................................................................................................... 87
9.2. 
Sample Size Determination ........................................................................................................... 87
9.3. 
Populations for Analysis Sets ........................................................................................................ 88
9.4. 
Statistical Analyses ........................................................................................................................ 89
9.4.1. 
General Considerations.............................................................................................................. 89
9.4.2. 
Primary Endpoint(s).................................................................................................................... 90
9.4.3. 
Key Secondary Endpoint............................................................................................................ 91
9.4.4. 
Secondary Endpoint(s)............................................................................................................... 92
9.4.5. 
Exploratory Endpoint(s).............................................................................................................. 94
9.4.6. 
Other Analyses ........................................................................................................................... 94
9.5. 
Interim Analysis.............................................................................................................................. 96
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ............................ 98
10.1. 
Appendix 1: Abbreviations ............................................................................................................. 98
10.2. 
Appendix 2: Rash Management................................................................................................... 101
10.3. 
Appendix 3: WHO Clinical Classification of Dengue Disease...................................................... 107
10.4. 
Appendix 4: COVID-19 Appendix ................................................................................................ 108
10.5. 
Appendix 5: Contraceptive and Barrier Guidance ....................................................................... 111
10.6. 
Appendix 6: Regulatory, Ethical, and Study Oversight Considerations....................................... 113
10.6.1. 
Regulatory and Ethical Considerations .................................................................................... 113
10.6.2. 
Financial Disclosure.................................................................................................................. 116
10.6.3. 
Informed Consent Process and Assent Form .......................................................................... 117
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JNJ-64281802  
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Status: Approved, Date: 19 July 2023
10.6.4. 
Data Protection ......................................................................................................................... 118
10.6.5. 
Long-term Retention of Samples for Additional Future Research............................................ 119
10.6.6. 
Committees Structure............................................................................................................... 119
10.6.7. 
.......................................................... 120
10.6.8. 
Data Quality Assurance............................................................................................................ 121
10.6.9. 
Monitoring ................................................................................................................................. 122
10.6.10. Case Report Form Completion................................................................................................. 122
10.6.11. Source Documents ................................................................................................................... 123
10.6.12. On-site Audits ........................................................................................................................... 124
10.6.13. Record Retention...................................................................................................................... 124
10.6.14. Study and Site Start and Closure ............................................................................................. 125
10.7. 
Appendix 7: Adverse Events, Serious Adverse Events, Product Quality Complaints, and
Other Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up,
and Reporting............................................................................................................................... 126
10.7.1. 
Adverse Event Definitions and Classification ........................................................................... 126
10.7.2. 
Attribution Definitions................................................................................................................ 127
10.7.3. 
Severity Criteria........................................................................................................................ 127
10.7.4. 
Special Reporting Situations .................................................................................................... 127
10.7.5. 
Procedures ............................................................................................................................... 128
10.7.6. 
Product Quality Complaint Handling......................................................................................... 129
10.7.7. 
Contacting Sponsor Regarding Safety, Including Product Quality........................................... 130
10.8. 
Appendix 8: Clinical Laboratory Tests ......................................................................................... 131
10.9. 
Appendix 9:  Toxicity Grading Scale for Determining the Severity of Adverse Events................ 134
10.10. Appendix 10: Examples of Disallowed Medications .................................................................... 138
10.11. Appendix 11: Liver Safety: Suggested Actions and Follow-up Assessments.............................. 140
10.11.1. Stopping Criteria....................................................................................................................... 140
10.11.2. Follow-up Assessments............................................................................................................ 140
10.12. Appendix 12: Protocol Amendment History................................................................................. 144
11. REFERENCES................................................................................................................................. 151
INVESTIGATOR AGREEMENT............................................................................................................... 153
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1: 
.............................................................................. 55
Table 2: 
Description of Study Intervention.............................................................................................. 64
Table 3: 
Solicited Adverse Events .......................................................................................................... 83
Table 4: 
Grading of Solicited Adverse Events ........................................................................................ 83
Table 5: 
Management of Rash Events by Severity Grade ................................................................... 102
FIGURES
Figure 1: Schematic Overview of the Study............................................................................................. 23
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CCI
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JNJ-64281802  
Clinical Protocol 64281802DNG2004
AMENDMENT 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 19 July 2023
1. 
PROTOCOL SUMMARY
1.1. 
Synopsis
A Phase 2, Randomized, Double-blind, Placebo-controlled, Double-dummy, Multicenter Trial Assessing
the Efficacy and Safety of Two Dose Regimens of JNJ-64281802 for the Prevention of Dengue Infection.
JNJ-64281802 is a novel antidengue virus (DENV) small molecule targeting DENV nonstructural protein
(NS)4B. It has shown potent antiviral activity against all 4 DENV serotypes in nonclinical studies. By
disrupting the DENV viral replication, JNJ-64281802 could potentially reduce the viral load (VL) and/or
prevent viremia from emerging and thereby reduce or even prevent DENV infection-associated morbidity
and mortality.
This study has 4 sequential phases: DENV-infected index case identification, screening of the household
contacts (HHCs) which may include family members, acquaintances, co-workers, and community contacts
of the index case, double-blind prophylactic dosing of HHCs, and follow-up phases.
This study will include index cases ≥1 years of age who will participate for one visit only and HHCs aged
16 or 18 (depending on the legal age of consent in the jurisdiction in which the study is taking place) to
≤65 years who are eligible to be included in the intervention part of the study. HHCs must not have DENV-
associated clinical signs and symptoms at baseline.
"Participant" refers to HHCs, unless index cases are explicitly mentioned. When "participant" is referred to
in relation to the informed consent form (ICF), this can be either a HHC or an index case; when "participant"
is referred to in relation to the informed assent form, this refers to an index case.
OBJECTIVES AND ENDPOINTS
Objectives 
Endpoints
Primary
 
To 
evaluate 
the 
prophylactic 
effect 
of
JNJ-64281802 with respect to the prevention of
laboratory-confirmed DENV infection up to the
last day of dosing among HHC  who have no
evidence of current DENV infection at baseline.
 
Laboratory-confirmed DENV infectiona between
baseline and the last day of dosing.
Key Secondary
 
To 
evaluate 
the 
prophylactic 
effect 
of
JNJ-64281802 with respect to the prevention of
symptomatic 
DENV 
infection 
through
development of signs and symptoms up to the last
day of dosing (see Safety Evaluations section)
among all HHC.
 
Laboratory-confirmed 
symptomatic 
DENV
infectionb between baseline and the last day of
dosing.
Secondary
 
To 
evaluate 
the 
prophylactic 
effect 
of
JNJ-64281802 with respect to the prevention of
symptomatic 
DENV 
infection 
through
development of signs and symptoms up to the last
day of dosing (see Safety Evaluations section)
among HHC who have no evidence of current
DENV infection at baseline.
 
Laboratory-confirmed 
symptomatic 
DENV
infectionb between baseline and the last day of
dosing.
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JNJ-64281802  
Clinical Protocol 64281802DNG2004
AMENDMENT 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 19 July 2023
Objectives 
Endpoints
 
To assess the safety and tolerability of 2 dose 
regimens (high and low) of JNJ-64281802 among 
HHC. 
 
Safety and tolerability as measured by recording of
adverse events (AEs), serious adverse events
(SAEs), physical examinations, vital signs,
electrocardiograms 
(ECGs), 
and 
clinical
laboratory assessments.
 
To assess the pharmacokinetics (PK) of 
JNJ-64281802 following repeated oral dosing 
among HHC. 
 
PK parameters for JNJ-64281802 (area under the
concentration curve during one dosing interval
[AUCτ], observed analyte concentration just prior
to the beginning or at the end of a dosing interval
[Ctrough], 
and 
maximum 
observed 
analyte
concentration [Cmax]).
 
To assess the relationship between the PK and 
pharmacodynamics 
(PD); selected 
antiviral 
activity of JNJ-64281802, clinical outcome, and
safety parameters) after repeated dosing of
JNJ-64281802 among HHC.
 
Laboratory-confirmed DENV infectiona between
baseline and the last day of dosing.
 
PK 
(plasma 
concentrations 
or 
exposure
parameters) of JNJ-64281802.
 
Safety parameters.
 
Laboratory-confirmed 
symptomatic 
DENV
infectionb between baseline and the last day of
dosing.
Exploratory
 
To 
evaluate 
the 
prophylactic 
effect 
of 
JNJ-64281802 with respect to the prevention of 
DENV infection up to the last day of dosing as
measured by DENV ribonucleic acid (RNA)
among HHC who have no evidence of current
DENV infection at baseline.
 
Presence or absence of a positive DENV RNA test
result between baseline and the last day of dosing.
 
To 
evaluate 
the 
prophylactic 
effect 
of 
JNJ-64281802 with respect to the reduction of 
DENV RNA among enrolled HHC who have no
evidence of current DENV infection at baseline
and who are infected post baseline.
 
The maximum DENV RNA  levels between
baseline and last day of dosing.
 
To 
evaluate 
the 
prophylactic 
effect 
of 
JNJ-64281802 with respect to the prevention of 
DENV infection up to the last day of dosing as 
measured by detection of DENV NS1 protein
among HHC who have no evidence of current
DENV infection at baseline.
 
Presence or absence of a positive DENV NS1
protein test result between baseline and the last day
of dosing.
 
To 
evaluate 
the 
prophylactic 
effect 
of 
JNJ-64281802 with respect to the prevention of 
DENV infection as measured by increase in anti-
DENV antibodies among HHC who have no
evidence of current DENV infection at baseline.
 
Increase in anti-DENV antibody between baseline
and Day 40.

Increase in anti-DENV antibody between baseline
and Day 50.
 
Increase in anti-DENV antibody between baseline
and Day 90.
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Status: Approved, Date: 19 July 2023
Objectives 
Endpoints
 
To 
evaluate 
the 
prophylactic 
effect 
of
JNJ‑64281802 with respect to the prevention of
symptomatic DENV infection up to Day 40, 50,
and 90 among all HHC who completed study
intervention (28 days).
 
Laboratory-confirmed 
symptomatic 
DENV
infectionb between baseline and Day 40.
 
Laboratory-confirmed 
symptomatic 
DENV
infectionb between baseline and Day 50.
 
Laboratory-confirmed 
symptomatic 
DENV
infectionb between baseline and Day 90.
 
To evaluate the antiviral effect of JNJ-64281802 as
early treatment among HHC who have evidence of
DENV infection at baseline.
 
Time to end of detectable DENV RNA and/or
reduction in DENV RNA load.
 
Time to end of detectable DENV NS1 protein.
 
DENV-associated signs and symptoms.
 
To 
identify  
circulating 
DENV
serotypes/genotypes and genetic variants among
index cases and HHC.
 
Serotype/genotype of DENV based on viral
genome sequence analysis.
 
Genetic variation of viral genome sequence based
on changes at the amino acid level
 
Emergent JNJ-64281802 resistance-associated
mutations in HHC using index case sequence as
reference.
AE = adverse event; DENV = dengue virus; ECG = electrocardiogram; HHC = household contact;
nAb = neutralizing antibody; NS = non-structural protein; PCR = polymerase chain reaction;
PD = pharmacodynamics; PK = pharmacokinetic(s); RNA = ribonucleic acid; SAE = serious adverse event.
a Laboratory-confirmed DENV infection is defined as a positive DENV RNA or DENV NS1 protein test result.
b Laboratory-confirmed symptomatic DENV infection is defined as having at least 2 solicited systemic AEs (see
Safety Evaluations section), of which at least one is a most common dengue symptom (ie, fever,
headache/retro-orbital pain, myalgia, arthralgia, rash), lasting for ≥1 day and occurring within a +/-2-day
window around the positive PCR or NS1 test, between baseline and the last day of dosing.
HYPOTHESIS
The primary hypothesis of this study is that JNJ-64281802 is superior to placebo with respect to prevention
oflaboratory-confirmed DENV infection between baseline and the last day of dosing in study participants
who are DENV RNA and NS1 protein negative at baseline. Laboratory-confirmed DENV infection is
defined as a positive DENV RNA and/or DENV NS1 protein test result.
OVERALL DESIGN
This is a Phase 2 randomized, double-blind, placebo-controlled, double-dummy, multicenter, interventional
study, assessing the efficacy and safety of 2 dose regimens of JNJ-64281802 for the prevention of dengue
infection in HHCs of a DENV-infected index case.
The study will be conducted in approximately 10 countries in South-East Asia and the American continent.
The study has 4 sequential phases: DENV-infected index case identification, screening of the HHCs which
may include family members, acquaintances, co-workers, and community contacts of the index case,
double-blind prophylactic dosing of HHCs, and follow-up phases.
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CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 19 July 2023
The study consists of 2 stages, with an interim analysis (IA) planned at the end of Stage 1 and the final
analysis (FA) planned at the end of Stage 2 (i.e., at the end of the study). The IA will be performed by an
independent statistical support group and will be reviewed by the Independent Data Monitoring Committee
(IDMC) who will receive unblinded safety and efficacy data. After the review, the IDMC will make
recommendations to the Sponsor Committee regarding the continuation of the study (see Interim Analysis
section). A Sponsor Committee, consisting of senior sponsor personnel not involved in the conduct of the
study, will be established and will be responsible for decision making considering the IDMC
recommendation. The FA will be performed by the sponsor who will be fully unblinded to the treatment
allocation at that time.
This study consists of a main study (see below) and a PK substudy (see Pharmacokinetic Substudy section).
Assessments and visits to the site will be performed as indicated in the Schedule of Activities.
DENV-infected Index Case Identification
An index case is a patient (≥1 years old) with laboratory-confirmed dengue identified in the community
(ie, hospital and/or health care center [HCC]/health care provider [HCP]). Laboratory-confirmed dengue
for an index case is defined as:
1. 
Any DENV-associated signs and symptoms ≤72 hours of onset (according to World Health
Organization [WHO] clinical classification of dengue disease), AND
2. 
A positive DENV NS1 test at screening. Results from tests performed as part of the local standard-of-
care ≤72 hours of screening can  be used for screening for this study. If a DENV NS1 test is not
available, a DENV polymerase chain reaction (PCR) test or anti-DENV immunoglobulin M (IgM) test
can also be used.
After informed consent/assent is obtained, either at the site or remotely (eg, at the index case’s home), a
blood sample for viral assessments will be collected, and the person's HHCs will be contacted. If the index
case is a minor according to the local laws and regulations, assent and informed consent from the parent(s)
or legal guardian(s) or legally acceptable representative(s) will be obtained.
Screening of the Household/Community Contacts of the Index Case
An HHC is a person who lives, spends the night, or regularly attends/shares/consumes cooking/meals in
the same dwelling or housing complex as the index case. A household can include one or more families, ,
or community contacts in a single or in multiple houses or dwellings, depending on the country, site,
social-economic, and cultural characteristics. Co-workers and acquaintances can also be considered HHCs,
if they spend time together with the index case (eg, during early morning hours or twilight hours).
HHCs aged 16 or 18 (depending on the legal age of consent in the jurisdiction in which the study is taking
place) to ≤65 years can be included in the intervention part of the study. HHCs must be asymptomatic at
screening and can include participants with no evidence of current DENV infection (consisting of naïve
and historical DENV-infected participants) or with evidence of current DENV infection as confirmed by
laboratory assessments, performed at a central laboratory on samples taken at baseline (see Section 1.2,
Schema).
Screening for eligible HHC(s) will be performed within 48 hours of obtaining informed consent/assent of
the index case. For this purpose, HHCs will be invited to the study site. Informed consent of the HHC will
be obtained on site or remotely.
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Status: Approved, Date: 19 July 2023
Double-blind Prophylactic Dosing of HHCs
Participants will be randomized in a 1:1:1 ratio to receive a high- or low-dose study intervention, or
matching placebo in a double-dummy fashion (see table below) for 28 days. The study will use
randomization at the individual participant level, stratified by country.
 
High-dose JNJ-64281802 regimen (HDR):
 
400 mg JNJ-64281802 loading dose (LD) twice daily for 48 hours, followed by
 
150 mg JNJ-64281802 maintenance dose (MD) once daily for 26 days.
 
Low-dose JNJ-64281802 regimen (LDR):
 
150 mg JNJ-64281802 (LD) twice daily for 48 hours, followed by
 
50 mg JNJ-64281802 (MD) once daily for 26 days.
 
Placebo (double-dummy; see table below).
LDs need to be taken twice daily, approximately around the same timepoints. MDs will start after the last
LD and need to be taken once daily, approximately around the same timepoint, until Day 28.
The study intervention is to be taken in fed conditions (for details, see table below). Study intervention can
be taken with water.
Development of DENV-associated clinical signs and symptoms (according to WHO clinical classification
of dengue disease) will be evaluated and recorded, virologic and serologic testing, and safety assessments
will be performed.
A PK substudy will be performed (see Pharmacokinetic Substudy section below).
Follow-up Phase
Double-blind prophylactic dosing of HHCs will be followed by intensive follow-up until Day 50 and a last
visit on Day 90. At the end-of-study visit, assessments will be performed as indicated in Section 1.3.2.3.
Stopping Criteria
HHCs who develop DENV-associated clinical warning signs and symptoms (according to WHO clinical
classification of dengue disease [WHO 2022]) during the study and require hospitalization will be
withdrawn from study intervention. The participant will perform a withdrawal and safety follow-up visit as
described in Section 1.3.2.4, Discontinuation From Study Intervention or Study.
The participant will receive medical care according to local standards. Hospitalization is classified as SAE
and should be reported accordingly.
NUMBER OF PARTICIPANTS
The study is event driven, with a target number of 36 DENV infections observed in HHCs without evidence
of DENV infection at baseline (ie, primary study population) and 24 symptomatic DENV infections
observed in all HHCs (ie, complete study population). Under the current assumptions, between 1,250 and
1,850 participants are expected to be enrolled in the study.
This study will include index cases ≥1 years of age with laboratory-confirmed dengue infection and HHCs
16 or 18 (depending on the legal age of consent in the jurisdiction in which the study is taking place) to
65 years of age, inclusive, with a body mass index (BMI) between 18.0 and 35.0 kg/m2 (inclusive), and
body weight ≥40.0 kg at screening without DENV signs and symptoms at baseline.
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A PK substudy will be performed in 30 to 40 participants (see Pharmacokinetic Substudy section below).
INTERVENTION GROUPS AND DURATION
HHCs will receive the study interventions as described above in the Overall Design section. Total study
duration will be approximately 13 weeks for HHCs.
Index case participation in the study will involve only one visit.
DESCRIPTION OF INTERVENTIONS
Route of 
Administration
Oral 
Oral
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AMENDMENT 3
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Status: Approved, Date: 19 July 2023
Intervention Name 
JNJ-64281802 
Placebo
Food/Fasting 
Requirement 
The study intervention is to be taken in 
fed conditions, ie, within 30 minutes after 
the start of the participant’s regular meal 
(eg, breakfast, lunch, snack, and/or 
dinner). 
The study intervention is to be taken in
fed conditions, ie, within 30 minutes
after the start of the participant’s regular
meal (eg, breakfast, lunch, snack, and/or
dinner).
Use 
Experimental 
Placebo
LD = loading dose; MD = maintenance dose.
EFFICACYEVALUATIONS
Virology
Antiviral Activity
Antiviral activity will be assessed by measuring DENV RNA levels and DENV NS1 protein levels in serum
of the HHCs. Serum DENV RNA levels will be assessed using a validated quantitative DENV reverse
transcriptionPCR (RT-qPCR) assay and serum DENV NS1 protein levels will be assessed using an ELISA-
based assay.
Viral Genome Sequencing and Dengue Virus Serotyping
Blood sampling for viral genome sequence analysis on index cases and HHCs will be performed. Viral
sequencing will only be performed on DENV RNA positive samples at the discretion of the sponsor’s
virologist. Sequencing of the DENV genome will be performed to monitor DENV variants. Viral genome
sequence analysis will be performed by sequencing the NS4B gene and other regions of the DENV genome
(if warranted) to characterize DENV variants associated with resistance to JNJ-64281802. Additional
exploratory virology analyses may be performed with these samples.
Circulating DENV serotypes/genotypes and genetic variants among index cases and HHCs will be assessed
by RT-qPCR and DENV whole genome sequencing at the discretion of the sponsor’s virologist.
Immune Assessments
Blood samples for detection of DENV infection as measured by increase in anti-DENV antibodylevels will
be performed. The level of anti-DENV antibodies will be measured using an ELISA-based assay. The
presence of nAbs against DENV and other flaviviruses will be determined using an assay such as
microneutralization assay.
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.
Safety assessments will include the monitoring of AEs, physical examinations, vital signs measurements,
ECGs, and clinical laboratory tests. DENV-associated signs and symptoms (systemic solicited AEs; see
table below), AEs, and concomitant medication will be recorded by the participant in a diary. For oral
measurement of body temperature at home to assess fever, participants will be provided with a thermometer.
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Status: Approved, Date: 19 July 2023
Solicited Adverse Events
Systemic Reactogenicity
- Retro-orbital pain
- Abdominal pain
- Arthralgia
- Fever
- Headache
- Nausea
- Fatigue
- Myalgia
- Loss of appetite
- Vomiting
- Diarrhea
- Rash
PHARMACOKINETIC EVALUATIONS
Based on the individual plasma concentration-time data, using the actual dose taken and the actual sampling
times, the following PK parameters and exposure information of JNJ-64281802 can  be derived using
population PK modeling: AUCτ (if data allow), Ctrough, and Cmax  (if data allow).
PHARMACOKINETIC/PHARMACODYNAMIC EVALUATIONS
Pharmacokinetic-pharmacodynamic evaluations may be performed to evaluate the relationship between the
PK and the antiviral activity of JNJ-64281802 and clinical outcome, 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.
PHARMACOGENOMIC (DNA) EVALUATIONS
Participant participation in pharmacogenomic research is optional.
Optional blood samples for pharmacogenomic (deoxyribonucleic acid [DNA]) research may be collected,
preferably before the first dose of study intervention. If necessary, the sample may be collected at a later
time point without constituting a protocol deviation. This DNA sample can be used to investigate the
potential association ofhost genetic factors with PK, antiviral activity, safety of JNJ-64281802, the DENV
infection or dengue disease, or may be used to develop tests/assays related to JNJ-64281802 or DENV
infection.
BIOMARKER EVALUATIONS
Blood samples for exploratory analysis of biomarkers will be obtained. These samples may be assessed for
serum proteins, RNA expression profiling, immune cell components, proteomics, metabolomics, or
microbiome. Samples can only be used for research related to JNJ-64281802, DENV infection, or dengue
disease, or may be used to develop tests/assays related to JNJ-64281802 or DENV infection. Results may
be reported separately from the Clinical Study Report.
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OTHER VIROLOGY ASSESSMENTS
NS1 Test and RT-PCR of Index Cases
An acute DENV infection of the index case will be assessed by the detection of the NS1 protein using a
diagnostic NS1 test, DENV RNA using DENV RT-PCR, or anti-DENV IgM using an anti-DENV IgM test.
PHARMACOKINETIC SUBSTUDY
In a PK substudy, rich serial PK blood sampling for the measurement of plasma concentrations of
JNJ-64281802 will be performed. This substudy will be conducted at selected study sites in
30-40 participants who will be evenly distributed (1:1:1 ratio) over HDR, LDR, and placebo regimen (see
Overall Design section). Participants included in the PK substudy will also undergo all assessments in the
main study.
At selected study sites participating in the PK substudy, the ICF will contain a separate section explaining
the substudy and separate consent will be given for this substudy.
Participants in the substudy will undergo rich serial PK sampling as indicated in Section 1.3.2.5,
Pharmacokinetic Substudy.
STATISTICAL METHODS
The study has an event-driven design where study recruitment will continue until the required number of
events is reached. The study consists of 2 stages with an IA at the end of Stage 1 and a FA at the end of
Stage 2 (ie, the end of the study). The objective of Stage 1 is to obtain proof-of-concept (PoC) for the
primary hypothesis. The objectives of Stage 2 are to select the dose for future development and to confirm
superiority of the selected dose above placebo.
The IA will be scheduled when 24 laboratory-confirmed DENV infections are observed between baseline
and the last day of dosing for the primary hypothesis in the primary analysis population. Based on the results
from the IA and other available information from other studies (eg, human challenge), the LDR can be
dropped in Stage 2.
The IA will be performed by an independent statistical support group and will be reviewed by the IDMC
who will receive unblinded safety and efficacy data. After the review, the IDMC will make
recommendations to the Sponsor Committee regarding the continuation of the study. Refer to the Interim
Analysis section for more information on the planned IA.
Unless stopped for futility at the IA, the study will continue till 36 DENV infections are observed between
baseline and the last day of dosing in the primary study population and 24 symptomatic DENV infections
are observed between baseline and the last day of dosing in the complete study population. Both conditions
need to be satisfied before recruitment is considered complete.
Sample Size Calculation
The targets of 36 DENV infection events between baseline and the last day of dosing in the primary study
population and 24 symptomatic DENV infections between baseline and the last day of dosing in the
complete study population were selected to ensure at least 80% power for the primary and key secondary
analyses for the HDR assuming a 75% prophylactic efficacy against DENV infection in the primary study
population (using a 2.5% one-sided significance level) and 72.5% prophylactic efficacy against
symptomatic DENV infection in the complete study population (using a 20% one-sided significance level).
These targets and resulting sample size were estimated through Monte Carlo simulation. More details of
the sample size calculations, including sample size simulation programs, will be provided in the Statistical
Analysis Plan and a separate Modeling and Simulation report.
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As a consequence of the event-driven design of the study, the study has no fixed sample size.
Populations for Analysis Sets
Population 
Description
Enrolled 
All participants (index cases and HHCs) who signed the ICF.
Index Case 
population
All participants enrolled as an index case, with a laboratory-confirmed DENV infection.
Randomized 
All participants (HHCs) who are randomized in the study.
Safety  
All randomized participants who received at least one dose of study intervention.
This population will be used for the safety analysis.
Primary study 
population  
All randomized participants who received at least one dose of study intervention and who had
no evidence of current DENV infection (based on negative results for DENV RNA and NS1
protein assays) at baseline.
This population will be used for the primary, secondary, and exploratory efficacy analyses.
Secondary study 
population  
All randomized participants who received at least one dose of study intervention, who had
evidence of current DENV infection (based on positive results for DENV RNA or NS1
protein assays) but without DENV signs and symptoms at baseline.
This population will be used to evaluate the exploratory objective of an antiviral effect of
JNJ-64281802 as early treatment.
Complete study 
population  
All randomized participants who received at least one dose of study intervention and without
DENV signs and symptoms at baseline.
This population will be used to investigate the key secondary endpoint of the effect of
JNJ-64281802 on the prevention of symptomatic DENV infection.
PK 
All participants who received at least one dose of study intervention and who have at least
one plasma concentration value after dosing.
This population will be used to the assess the PK and the relationship between PK and the
antiviral activity of JNJ-64281802.
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Status: Approved, Date: 19 July 2023
DENV = dengue virus; HHC = household contact; ICF = informed consent/assent form; PCR = polymerase chain
reaction; PK = pharmacokinetic(s).
Primary Endpoint
The primary endpoint is defined as presence or absence of a laboratory-confirmed DENV infection between
baseline and the last day of dosing. Laboratory-confirmed DENV infection is defined as a positive DENV
RNA or DENV NS1 protein test result. Missing results between baseline and last day of dosing will not be
considered for the primary endpoint.
The primary estimand attributes are as follows.
Population: Healthy HHCs, aged 16 or 18  (depending on the legal age of consent in the jurisdiction in
which the study is taking place) to 65 years inclusive, who have negative results for DENV RNA and NS1
protein assay at baseline. HHCs for which only one of both assays is available will be included on condition
that this assay has a negative result.
Interventions: Participants will receive a high- or low-dose JNJ-64281802 regimen, or matching placebo
in a double-dummy fashion under fed conditions (see Description of Interventions section).
Intercurrent Events:
 
Fasted intake of study intervention.
 
Prohibited medication.
 
Missed doses and treatment discontinuation: Missing a LD, 2 consecutive MDs, or 2 nonconsecutive
MDs within a week.
These intercurrent events will be handled using a "treatment policy strategy" (ie, data will be used as
observed).
Population-level Summary: Calculated prophylactic efficacy (= 1 - odds ratio ≈1-relative risk rate).
The primary hypothesis of this study is that JNJ-64281802 is superior to placebo with respect to prevention
of laboratory-confirmed DENV infection between baseline and the last day of dosing.
The primary hypothesis will be evaluated based on the comparison between intervention groups using
confidence intervals (CIs), estimates, and p-values obtained from an exact logistic regression model with
intervention group and the stratification factor (country) as independent variables. The odds-ratio from the
logistic regression model will be used to estimate prophylactic efficacy. Given the expected low incidence,
this is thought to be similar to the prophylactic efficacy estimated using relative risk. The calculated
prophylactic efficacy (= 1 - odds ratio ≈1 - relative risk rate) will be used as the population-level summary.
For the PoC stage (Stage 1), the superiority of JNJ-64281802 above placebo will be tested at 20% one-
sided significance level. In the confirmatory stage (Stage 2) a 2.5% one-sided significance level will be
used. The individual 2-sided CIs (2 x one-sided significance level) for the prophylactic efficacy will be
calculated from the regression model described above. This is the primary efficacy analysis. As a secondary
estimator, the Mantel-Haenszel stratum-weighted estimator of the risk difference, adjusted for the
stratification factor (country) will be calculated together with the associated CIs.
At the IA, the HDR and LDR will be tested hierarchically: First HDR will be tested and if PoC is reached
for HDR, the LDR will be tested. Based on these results and other available information (refer to Interim
Analysis section), the LDR can be dropped in Stage 2.
At the FA, the primary objective will be assessed using the following hierarchical hypothesis testing
approach:
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1. 
In the first step, the HDR will be compared with placebo.
2. 
If the LDR is not dropped at the IA and a significant reduction in laboratory-confirmed DENV
infections is established for the HDR, the LDR will be compared with placebo with regards to the
primary endpoint.
Key Secondary Endpoint
The key secondary endpoint is defined as presence or absence of laboratory-confirmed symptomatic DENV
infection between baseline and last day of dosing. Laboratory-confirmed symptomatic DENV infection is
defined as having at least 2 solicited systemic AEs (see Safety Evaluations section), of which at least one
is a most common dengue symptom (ie, fever, headache/retro-orbital pain, myalgia, arthralgia, rash), lasting
for ≥1 day and occurring within a +/-2-day window around the positive PCR or NS1 test, between baseline
and the last day of dosing.
The key secondary objective will only be assessed at the FA if a significant reduction in the number of
laboratory-confirmed DENV infections in the primary study population is established for the HDR. The
key secondary objective will be assessed by estimating the prophylactic efficacy of the intervention
group(s) in preventing laboratory-confirmed symptomatic DENV infection in the complete study
population together with the 80% one-sided lower confidence limit for this prophylactic efficacy.
Depending on the result of the primary analysis for the LDR, the key secondary objective will be assessed
by:
1. 
Comparing the pooled number of events on HDR and LDR with the placebo regimen, if both active
intervention groups showed a significant effect in the primary study analysis population.
2. 
Comparing the number of events of the HDR with the placebo regimen, if only the HDR showed a
significant effect in the primary study analysis population.
Laboratory-confirmed symptomatic DENV infections will be analyzed similarly as the primary endpoint
with the model adjusted for DENV infection at baseline as well.
Secondary Endpoints
All secondary endpoints will be analyzed graphically and descriptively as described in the Statistical
Analysis Plan (SAP). For continuous variables, descriptive statistics (n, mean, standard deviation [SD],
median, minimum, maximum, and 95% CIs) will be calculated. For categorical variables, frequency tables
and corresponding 95% CIs will be presented.
Safety Analyses
Adverse Events
For each AE, the percentage of participants who experience at least 1 occurrence of the given event will be
summarized by intervention group. Solicited AEs will be summarized by intervention group. All AEs will
be analyzed descriptively.
Summaries, listings, datasets, or participant narratives may be provided, as appropriate, for those
participants who die, who discontinue intervention due to an AE, who experience a severe or a serious AE,
or who experience rashes requiring rash-management procedures (Section 10.2).
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Frequency tabulations of the laboratory
abnormalities will be made either by grading according to the modified Division of Acquired
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Immunodeficiency Syndrome (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse
Events, supplemented with WHO toxicity grading scales t, or with classes for below, within, and above
normal ranges for parameters that are not graded for either DAIDS and WHO grading scales. 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 (Grade 3 or Grade 4) will also be provided.
Electrocardiograms
The effects on cardiovascular variables will be evaluated by means of descriptive statistics. These tables
will include observed values and changes from baseline values (the last observed ECG prior to the first
study intervention administration will be used as baseline).
The ECG variables that will be analyzed are heart rate, PR interval, QRS interval, QT interval, and QT
corrected for heart rate (QTc) interval using the following correction methods: QTc according to Bazett's
formula (QTcB) and QTc according to Fridericia's formula (QTcF).
Descriptive statistics of QTc intervals and changes from baseline will be summarized at each scheduled
time point. The percentage of participants with QTc interval >450 milliseconds, >480 milliseconds, or
>500 milliseconds will be summarized, as will the percentage of participants with QTc interval increases
from baseline >30 milliseconds or >60 milliseconds.
Vital Signs
Vital signs including pulse/heart rate and systolic and diastolic blood pressure (supine) 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.
Pharmacokinetic Analyses
The JNJ-64281802 plasma PK samples taken from all participants in the study (see Sections 1.3.2.2 to
1.3.2.4), as well as the rich serial PK samples collected in the PK substudy (Section 1.3.2.5) can be used
for population PK model development and/or population PK model update using nonlinear mixed-effects
modeling. Population PK modeling can be used to describe the concentration-time profiles and estimate the
exposure parameters (AUCτ, Ctrough, and Cmax, if data allow) of JNJ-64281802. Available baseline
participant characteristics may be explored as potential covariates affecting PK parameters of
JNJ-64281802.
For the intensive PK samples of the rich PK substudy, noncompartmental PK analysis of JNJ-64281802
will be performed using actual sampling time and plasma concentrations obtained from rich serial PK blood
sampling for 30-40 participants. Descriptive statistics will be provided for the PK parameters (Ctrough, Cmax,
time to maximum concentration [tmax], Cmin, and AUCτ) derived, including graphical analyses of the data.
Pharmacokinetic/Pharmacodynamic Analyses
Relationships of PK parameters for JNJ-64281802 with selected antiviral activity, clinical outcome, and
safety endpoints may be evaluated, applying graphical tools and, if feasible, statistical models, as data
allow.
Exploratory Endpoints
The statistical analysis of the exploratory endpoints will be described in the SAP.
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Interim Analysis
After the review of the IA results, the IDMC will make recommendations to the Sponsor Committee
regarding the continuation of the study (see below for details). An IDMC charter will be prepared before
start of the study with more details on the IDMC and Sponsor Committee composition and organization.
The aim of the IA at the end of Stage 1 is to assess PoC of the HDR and LDR for the primary objective. In
this analysis, PoC is defined as a statistically significant reduction in the number of laboratory-confirmed
DENV infections on active prophylactic dosing compared with placebo at the 20% one-sided significance
level. The HDR and LDR will be tested hierarchically: First HDR will be tested and if PoC is reached for
the HDR, the LDR will be tested. Based on these results, the IDMC can advise to:
 
Stop the study for futility, or
 
Drop the LDR and continue the study with placebo regimen and the HDR, or
 
Continue the study with both active intervention groups (HDR and LDR) and placebo.
If the study continues, the IDMC may advise to open study recruitment to adolescent HHCs via protocol
amendment.
The IDMC advice will be based on the following decision rule:
 
If PoC is not reached for the HDR, the IDMC can advise to stop the study.
 
If PoC is reached for the HDR but not for the LDR, the IDMC can advise to continue the study with
only the HDR and placebo regimen and drop the LDR from the study.
 
If PoC is reached for both HDR and LDR, the IDMC can advise to continue the study with both active
intervention groups and placebo.
However, this rule is non-binding and based on a full review of all safety, efficacy, and exposure-response
data available for the current study. In addition, data from other studies (eg, human challenge) may be
available to guide the decision.
As the study design only allows for futility assessment at the IA, no multiplicity correction will be
performed for the IA. In addition, the impact of potentially dropping the LDR at the IA on the comparison
of the HDR with the placebo regimen at the FA was assessed through analytical derivation of the Type I
error rate. This analysis showed the Type I error was well controlled (Type I error rate <2.5%).
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1.2. 
Schema
Figure 1: 
Schematic Overview of the Study
* Based on negative results for DENV RNA and NS1 protein assays
° Based on positive results for DENV RNA or NS1 protein assays
For the definition of index case and HHC, refer to the Overall Design section in the Synopsis.
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1.3. 
Schedule of Activities
1.3.1. 
Index Cases
Visit Day  Day 1
StudyProcedure 
Notes
Screening / Administrative
ICF  
X 
Must be signed before any study-related activity. Informed consent may be
obtained remotely.
Inclusion/exclusioncriteria 
X
Blood sample collection to confirm dengue infection: 
DENV NS1 testa in local laboratory 
X 
Test results of a NS1 testa that were performed outside the study by
local standard-of-care ≤72 hours of screening may be used for
screening of this study.
Antiviral Activity Assessments
Blood sample collection for DENV VL determination: 
RT-qPCR in central laboratory
X
Viral Genome Sequencing
Blood sample collection for viral genome sequencing 
X
Ongoing Participant Review
AEsb 
X
DENV = dengue virus; ICF = informed consent/assent form; NS = nonstructural protein; RT-(q)PCR = (quantitative) reverse transcription polymerase chain
reaction; VL = viral load.
a. IfDENV NS1 test is not available, RT-PCR or anti-DENV IgM test in a local laboratory can be used.
b. Only AEs that are related to blood sample procedures will be captured from signing ICF until Day 7. Index cases should actively contact the site if AEs related to the
blood sample procedure should occur between the visit day and Day 7.
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1.3.2. 
Household Contacts
1.3.2.1. 
Screening Phase
Visit Day  -12 hoursa
StudyProcedure 
Notes
Study Visit / Contact
On-site visit 
X
Screening / Administrative
ICF  
X 
Must be signed before any study-related activity. Informed consent may be obtained remotely.
At selected study sites participating in the PK substudy, the ICF will contain a separate section explaining the
substudy and separate consent will be given for this substudy.
Demographics 
X
Medical history and concomitant diseases 
X
Inclusion/exclusioncriteria 
X
BMI 
X
Height 
X
Bodyweight 
X
Urine pregnancy test 
X 
For all women.
Safety Assessments
12-lead ECG  
X 
Should be performed after ≥5 minutes rest in supine position.
ECGs are recommended to be performed before vital signs.
Vital signs 
X 
Systolic and diastolic blood pressure and pulse/heart rate (supine after ≥5 minutes rest). Vital signs are
recommended to be assessed after 12-lead ECG.
Physicalexamination  
X 
The physical examination  includes a review of the following systems: head/neck/thyroid,
eyes/ears/nose/throat, respiratory, cardiovascular, lymph nodes, abdomen, skin, musculoskeletal, and
neurological.
Body temperature 
X 
Body temperature is to be measured orally in the absence ofantipyretic medication, or at least 4 hours after the
last intake of antipyretic medication (if applicable).
Ongoing Participant Reviewb
Concomitant therapy  
X
AEs 
X
AE = adverse event; BMI = body mass index; ECG = electrocardiogram; HHC = household contact; ICF = informed consent form.
Notes:
Refer to Section 1.3.2.4 for assessments to be performed in case of discontinuation of study intervention or the study.
a. 
Screening for eligible HHC(s) will be performed within 48 hours of obtaining informed consent of the index case. HHCs should start study intervention intake
within 12 hours of signing their ICF.
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b. 
Throughout the study from signing of the ICF (AEs) and from the screening visit (concomitant therapy) 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.
1.3.2.2. 
Double-blind Prophylactic Dosing of HHCs: Day 1 to Day 13
Phase 
Double-blind Prophylactic Dosing
Visit Day  1 
2 3 4 
5 
6 7 8 
9 10 11 12 13
Visit Window  
± 1d  
± 1d 
± 1d
StudyProcedure 
Notes
Study Visit / Contact
On-site visit or visit at homea,b  
X X X 
X 
X 
X
Distribution ofwallet (study) card 
X
Distribution of paper diary and 
thermometer 
X 
Oral body temperature, DENV-associated signs and symptoms
(systemic solicited AEs, including fever by oral measurement of body
temperature), AEs, and concomitant medication, whether a meal was
taken prior to administration of study intervention, and date/time of
study intervention intake will be recorded by the participant in a diary,
except for the assessments specified in Section 1.3.2.4,
Discontinuation From Study Intervention or Study, that will be
collected by study site personnel.
Study Intervention Administration
Randomization 
 
HDR, LDR, or placebo regimen.
Administer study interventionb 
Xc Xc X X 
X 
X X X X X X X X LD twice daily for 48 hours, followed by a MD once daily for 26
days, under fed conditions (for details, refer to the Description of
Interventions section).
Whether a meal was taken prior to administration of study
intervention, and date/time of study intervention intake will be
recorded by the participant in a diary. Administration of study
intervention will either be at home (including remote supervision of
study intervention intake, if feasible) or participants may come to
the site.
Dispense study interventionf 
X X
Accountability of study intervention  
X X 
X 
X 
X
AntiviralActivity Assessments
Blood sample collection  for DENV  VL 
determination (RT-qPCR, NS1 testing)
 
X 
 
 
 
X 
 
 
 
X
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Phase 
Double-blind Prophylactic Dosing
Visit Day  1 
2 3 4 
5 
6 7 8 
9 10 11 12 13
Visit Window  
± 1d  
± 1d 
± 1d
StudyProcedure 
Notes
Immune Assessments
Blood sample collection for humoral 
immunity (IgG and IgM)
 
X 
 
X 
X
Blood sample collection for humoral 
immunity (nAb)
 
 
 
Viral Genome Sequencing
Blood sample collection for viral 
genomesequencing 
 
X 
X 
 
X Viral sequencing will only be performed on DENV RNA positive
samples.
SafetyAssessments
Suspected DENV-associated signs and 
symptoms (systemic solicited AEs) 
X X X X 
X 
X X X X X X X X DENV-associated signs and symptoms will be recorded daily
in a diary by the participant. In case a particular systemic
solicited AE was not observed at time of recording but occurs
later that day, the participant should record this. In case the
systemic solicited AE is fever, oral body temperature should
also be recorded.
Body temperature 
X X X X 
X 
X X X X X X X X Body temperature is to be measured orally in the absence of
antipyretic medication, or at least 4 hours after the last intake
of antipyretic medication (if applicable).
Will be recorded daily in a diary by the participant (preferably
at the same time each day) and in case of feeling feverish.
Will be added to the CRF by study site personnel in case the
oral body temperature is ≥37.5°C (99.5°F).
Clinical Laboratory Tests
Blood sample collection for hematology  
g 
X
Blood sample collection for serum  
chemistry
e, g 
X
Blood sample collection for coagulation  
e, g 
X
Urine sample collection for urinalysis 
 
X Urinalysis including dipstick, microscopic sediment
examination, and quantitative protein determination.
Pharmacokinetics
Blood sample collection for PK 
 
 
X 
X 
 
X 
 
X Blood collections for PK assessments should be kept as close to the
specified time as possible.
For participants in the PK Substudy, see also Section 1.3.2.5,
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participant has been deemed lost to follow-up after demonstration of due diligence of follow-up efforts.
e. Two samples will be obtained: one sample to be analyzed by the local laboratory and the other sample to be analyzed by the central laboratory.
f. 
For Days 1 and 2, blisters will be provided with LD and MD, respectively.
g. If a participant reports with 2 or more ≥ Grade 2 laboratory abnormalities at baseline (Day 1) for ALT, AST, creatinine, lipase, absolute neutrophil count,
platelet count, or hemoglobin, the investigator should assess whether the study intervention discontinuation criteria are met (Refer to section 7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT DISCONTINUATION/WITHDRAWAL), since laboratory results will not be
available at randomization. Discontinuation of study intervention should only occur after a confirmatory retesting result.
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1.3.2.3. 
Double-blind Prophylactic Dosing of HHCs (Day 14 to Day 28) and Follow-up Phase
Phase 
Double-blind Prophylactic Dosing 
Follow-up
Visit Day  14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 
EOD  
40a 50a 60, 
70,
80
90a
Visit Window  
± 1d  
± 1d  
± 1d  
± 1d  ± 2d ± 2d±2d ± 2d
StudyProcedure 
Notes
Study Visit / Contact
On-site visit or visit at 
homeb
X 
X 
X 
X 
X 
X 
X
Phone call visit 
X
Return of paper diary and 
thermometer
X
Study Intervention Administration
Administer study  
interventionc 
X X X X X X X X X X X X X X 
X 
MD once daily under fed conditions (for details, refer
to the Description of Interventions section).
Whether a meal was taken prior to administration of
study intervention and date/time of study intervention
intake will be recorded by the participant in a diary.
Administration of study intervention will either be at
home (including remote supervision of study
intervention intake, if feasible) or participants may
come to the site.
Return of study intervention 
X 
On Day 28, all study intervention dispensed to the
participant should be returned to the site.
Accountability of study 
intervention
X 
X 
X 
X
Antiviral Activity Assessments
Blood sample collection for 
DENV VL determination  
(RT-qPCR, NS1 testing)d 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
X 
X 
If a participant shows signs and symptoms of DENV
infection between Day 28 and Day 90, they must
contact the study site and additional blood will be
drawn at the study site or their home for antiviral
activity assessment and viral genome sequencing,
Immune Assessments
Blood sample collection  
for humoral immunity
(IgG and IgM)d
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X
Blood sample collection for 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X
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Phase 
Double-blind Prophylactic Dosing 
Follow-up
Visit Day  14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 
EOD  
40a 50a 60, 
70,
80
90a
Visit Window  
± 1d  
± 1d  
± 1d  
± 1d  ± 2d ± 2d±2d ± 2d
StudyProcedure 
Notes
humoral immunity(nAb)d
Viral Genome Sequencing
Blood sample collection for 
viral genome sequencingd 
 
 
X 
 
 
X  
 
X 
 
 
X 
X 
X 
X 
Viral sequencing will only be performed on DENV
RNA positive samples.
SafetyAssessments
Physical examination  
X 
The physical examination includes a review ofthe
followingsystems: head/neck/thyroid,
eyes/ears/nose/throat, respiratory, cardiovascular,
lymph nodes, abdomen, skin, musculoskeletal, and
neurological.
Suspected DENV- 
associated signs and 
symptoms (systemic 
solicited AEs) f 
X X X X X X X X X X X X X X 
X 
X 
X 
X X 
Will be recorded daily in a diary by the participant
until Day 28. In case a particular systemic solicited
AE was not observed at time of recording but occurs
later that day, the participant should record this. In
case the systemic solicited AE is fever, body
temperature should also be recorded.
Vital signsd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Systolic and diastolic blood pressure and pulse/heart
rate (supine after ≥5 minutes rest).
Body temperaturef 
X X X X X X X X X X X X X X 
X 
X 
X 
Oral body temperature is to be measured in the
absence ofantipyretic medication, or at least 4 hours
after the last intake of antipyretic medication (if
applicable) until Day 28.
Will be recorded daily in a diary by the participant
(preferably at the same time each day) and in case
of feeling feverish.
Will be added to the CRF by study site personnel in
case the body temperature is ≥37.5°C (99.5°F).
12-lead ECGd 
 
X 
Should be performed after ≥5 minutes rest in supine
position.
See also Section 1.3.2.5, Pharmacokinetic
Substudy.
Urine pregnancy test 
 
X 
X 
For all women.
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a. If participants show signs or symptoms of DENV infection between Day 28 and Day 90, they must contact the study site. Additional blood for anti-viral activity
assessment and viral sequencing will be drawn at the study site or at their home. Safety will be monitored through AE reporting.
b. Visiting the site is required on Days 1, 2, and 28. All other visits may either be performed at the site or by designated study site personnel who visits the participant
at home. A time window of +/- 1 day from Day 1 to Day 28 and +/- 2 days after Day 28 for both site and home visits is allowed as indicated, to ensure at least 2
visits per week at least 2 days apart and maximally 4 days in between blood samples.
c. Between on-site visits as indicated in this Schedule of Activities, administration of study intervention will either be at home (including remote supervision of study
intervention intake, if feasible) or participants may come to the site. MDs need to be taken approximately at the same timepoint every day.
d. If multiple assessments are scheduled for the same time point, it is recommended that procedures be performed in the following sequence: 12-lead ECGs, vital signs,
blood draw. Compared to Day 1, where parallel testing is mandatory, parallel (central and local lab analysis) testing is allowed at other timepoints at the discretion of
the local PI and Sponsor.
e. Throughout the study from signing of the ICF (for both AEs and concomitant therapy) 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.
f. After Day 28, the participant should contact the site in case any solicited AE, fever, or suspected DENV-associated signs and symptoms (systemic AEs) are
experienced, and an additional follow-up visit should be scheduled.
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1.3.2.4. 
Discontinuation From Study Intervention or Study
Visit Day  Withdrawal 
Visita
Follow-up Visita
Visit Window
StudyProcedure 
Notes
Study Visit / Contact
On-site visit or visit at homeb 
X 
X
Return of diary and thermometer 
X
Study Intervention Administration
Return of study intervention 
X 
At the withdrawal visit, all study intervention dispensed to
the participant should be returned to the site.
Accountability of study intervention  
X
Antiviral Activity Assessments
Blood sample collection for DENV VL determination (RT-qPCR, 
NS1 testing)c
X 
X
Immune Assessments
Blood sample collection for humoral immunity (IgG and IgM)c 
X 
X
Blood sample collection for humoral immunity (nAb)c 
X 
X
Viral Genome Sequencing
Blood sample collection for viral genomesequencing 
X 
X 
Viral sequencing will only be performed on DENV RNA
positive samples.
SafetyAssessmentsd
Physical examination  
X 
X 
The physical examination includes a review ofthe following
systems: head/neck/thyroid, eyes/ears/nose/throat,
respiratory, cardiovascular, lymph nodes, abdomen, skin,
musculoskeletal, and neurological.
Vital signsc 
X 
X 
Systolic and diastolic blood pressure and pulse/heart rate
(supine after ≥5 minutes rest).
Body temperature 
X 
X 
Body temperature is to be measured orallyin the absence of
antipyretic medication, or at least 4 hours after the last
intake of antipyretic medication (if applicable) and will be
assessed by study site personnel.
12-lead ECGc 
X 
X 
Should be performed after ≥5 minutes rest in supine position.
Urine pregnancy testf 
X 
For all women.
Clinical Laboratory Testsd
Blood sample collection for hematologyc 
X 
X
Blood sample collection for serumchemistryc 
X 
X
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2. 
INTRODUCTION
Dengue is caused by any of the 4 antigenically distinct dengue virus (DENV) serotypes (DENV-1,
-2, -3, and -4), which belong to the genus Flavivirusin the family of the Flaviviridae. The DENVs
are human pathogens which are 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
(Carrington 2014). Dengue is endemic in more than 125 countries, and it has also again become
endemic in the United States of America (USA) and its territories of American Samoa, Puerto
Rico, and the US Virgin Islands (CDC 2019a). 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 (WHO 2019a,b).
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 manifest clinically (with any severity of the disease) (Bhatt 2013).
On average, each year about 500,000 dengue cases require hospitalization due to severe and
life-threatening diseases and up to 25,000 patients die due to dengue.
During a DENV infection, 1 in 4 infections are symptomatic and 1 in 20 cases develop severe
dengue (CDC 2019b) 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 infection usually occurs within 4 to 7 days due to a robust innate
and adaptive immune response (Whitehorn 2011). However, less than 1% of DENV infections
result in severe dengue outcomes such as dengue hemorrhagic fever (DHF) and dengue shock
syndrome (DSS).
People with asymptomatic/pre-symptomatic dengue infection play a key role in dengue
transmission dynamics leading to outbreaks and epidemics. Mosquitoes can become infected from
people who are viremic with DENV. This can be someone who has a symptomatic dengue
infection, someone who is yet to have a symptomatic infection (they are pre-symptomatic), but
also people who show no signs of illness as well (they are asymptomatic) (Duong 2015). People
with asymptomatic infections are approximately 80% as infectious to mosquitoes as symptomatic
people and, at a population level, approximately 88% of infections result from people who display
no apparent symptoms at the time of transmission (asymptomatic/pre-symptomatic)
(Ten Bosch 2018). These asymptomatic individuals continue to perform their daily activities and
thereby play a major role in dengue transmission dynamics. Factors such as population movement,
DENV transmission from infected (but asymptomatic) humans to resident mosquitoes and from
infected mosquitoes to susceptible humans eventually lead to dengue outbreaks and dengue
epidemic expansion at both a local/regional and international level (Grunnill 2018).
Patients with symptomatic dengue have a limited role in dengue transmission dynamics. A study
in Iquitos (Peru) compared 2 groups of febrile individuals (dengue-positive and dengue-negative)
with an afebrile control group. Compared to participants with no fever, febrile participants spent
more time at home and visited fewer locations and were therefore less likely to transmit the virus
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(Perkins 2016). It has been estimated that only 1% of DENV transmission is attributable to people
with symptomatic infections (Ten Bosch 2018).
The risk of developing DHF/DSS is especially increased after secondary DENV infection with a
different serotype than that of the primary infection, due to a process called antibody-dependent
enhancement. The non-neutralizing, cross-reactive antibodies generated during the primary
infection partially interact with the virus of a different serotype. Consequently, these partially
antibody-coated viruses have a higher likelihood to be taken up by crystallizable fragment
(Fc)-receptor-bearing cells (Guzman 2010). Overall, this leads to a higher number of infected
target cells, a higher viral load (VL), and a higher probability to develop DHF/DSS. Therefore, it
is critical to develop an antiviral small molecule which has equipotent efficacy against all
4 serotypes of DENV.
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 from the Philippine market because of safety concerns, which led to
revocation of the vaccine’s licensure in the Philippines in February 2019. In December 2018, the
vaccine was approved in the European Union for the prevention of dengue disease caused by all
DENV serotypes (DENV-1, -2, -3, and -4) in individuals 9 to 45 years of age who have been
infected with DENV before and who live in areas where this infection is endemic. 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 World Health Organization (WHO) working group
for immunization, as a number of factors need further consideration  (WHO 2019a,
FDA dengvaxia website). 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.
Study 64281802DNG2004 (further referred to as DNG2004) is a Phase 2, randomized,
double-blind, placebo-controlled, double-dummy, multicenter trial assessing the efficacy and
safety of 2 dose regimens of JNJ-64281802 for the prevention of dengue infection. JNJ-64281802
is a novel, potent, pan-serotypic small-molecule inhibitor of DENV targeting DENV nonstructural
protein (NS)4B.
For the most comprehensive nonclinical and clinical information regarding JNJ-64281802, refer
to the latest version of the Investigator's Brochure (IB) for JNJ-64281802 (IB JNJ-64281802
2022).
The term "study intervention" throughout the protocol, refers to JNJ-64281802 or placebo.
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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". "Participant"
refers to household contacts (HHCs), unless index cases are explicitly mentioned. When
"participant" is referred to in relation to the informed consent form (ICF), this can be either a HHC
or an index case; when "participant" is referred to in relation to the informed assent form, this
refers to an index case.
2.1. 
Study Rationale
Currently, there is no effective prevention or treatment against dengue infection. Due to limitations
on the current dengue approved vaccine, the development of drugs for prophylactic use is getting
renewed interest as potential alternatives to prevent dengue (Whitehorn 2014). Prophylaxis could
be beneficial for travelers to dengue-endemic regions (eg, aid workers, tourists, business and
military travelers, and expatriates), as well as for vulnerable populations living in dengue-endemic
regions. By preventing viremia and/or reducing VL, DENV infection-associated morbidity and
mortality could be reduced remarkably or even prevented (Bhatt 2013).
JNJ-64281802 is a novel anti-DENV small molecule targeting DENV NS4B. It has shown potent
antiviral activity against all 4 DENV serotypes in nonclinical studies (IB JNJ-64281802 2022). By
disrupting the DENV viral replication, JNJ-64281802 could potentially reduce the VL and/or
prevent viremia from emerging and thereby reduce or even prevent DENV infection-associated
morbidity and mortality.
Phase 1 first-in-human (FIH) study 64281802DNG1001, further referred to as DNG1001, has been
completed. The 2 dose regimens the study is bringing forward, high and low dose, are based on
the results from the Phase 1 FIH study DNG1001 and the available in vitro antiviral activity data
of JNJ-64281802.
Study DNG2004 is a randomized, double-blind, placebo-controlled Phase 2 study with an index
case-based event-driven design that will evaluate the prophylactic efficacy and safety of
JNJ-64281802 for the prevention of dengue in dengue-endemic areas. The study is conducted in
asymptomatic HHC at baseline. The study consists of 2 stages. The objective of Stage 1 is to obtain
proof-of-concept (PoC) for the primary hypothesis. The objectives of Stage 2 for the primary
hypothesis are to select the dose for future development and to confirm superiority of the selected
dose above placebo.
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
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fluorescent protein (eGFP). JNJ-64281802 exhibited a median EC50 of 0.05 nM with a selectivity
index of 48,000 against DENV-2/16681/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 quantitative reverse transcription polymerase
chain reaction (RT-qPCR) against a panel of DENV strains belonging to the 4 major serotypes,
including laboratory-adapted strains and clinical isolates obtained from several sources.
JNJ-64281802 exhibited potent antiviral activity against all 4 DENV serotypes
(laboratory-adapted strains and clinical isolates) with sub-nanomolar or low nanomolar median
EC50 values against most strains, and a high specificity toward DENV.
In Vivo Pharmacology
In DENV-2 inoculated mice treated with JNJ-64281802, dose-dependent viral ribonucleic acid
(RNA) reductions in serum 
 compared with vehicle treated
mice were observed and were associated with a significant effect on survival. In a non-human
primate model, no viral RNA was detected at the highest doses of JNJ-64281802 
 against DENV-2/16681 and at 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
Toxicology
In rats, the no observed adverse effect level (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, non-adverse 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 andhigh 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.
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Pharmacokinetics and Metabolism
 
 
Absorption: JNJ-64281802 was generally slowly absorbed, with moderate oral
bioavailability across species (absolute bioavailability: 25% - 66%). In male dogs withheld
from food, 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 semi-solid
hard gelatin capsule (Gelure 44/14); 1.2-fold increase compared with a 100% polyethylene
glycol 400 (PEG400) solution. 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: 
 
 
 
 via uridine diphosphate-glucuronosyltransferase
(UGT)1A9 and possibly UGT1A4, UGT1A8, and UGT1A10. There was no indication of
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 (PK) 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 toward CYP1A2 and CYP2D6
(50% inhibitory concentration [IC50] >30 µM), and inhibition of CYP2C9 (IC50 = 3.7 µM),
CYP2C8 (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.
Clinical Studies
Study 64281802DNG1001
The Phase 1, double-blind, randomized, placebo-controlled, FIH  study 64281802DNG1001
(EudraCT number: 2018-002201-62) examined the safety, tolerability, and PK of increasing single
(in 39 participants) and multiple oral doses (in 47 participants) of JNJ-64281802 in healthy adult
participants. An open-label, randomized, crossover, relative oral bioavailability part (in 36
participants) was included to study the PK and safety following 2
 formulation concepts
compared with an oral solution, 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 was based on time-matched QT interval corrected for heart rate (QTc).
Holter data supports the absence of an effect of JNJ-64281802 on cardiac repolarization at the
JNJ-64281802 concentration range investigated in Study DNG1001.
Human Pharmacokinetics
Following single-dose administration with JNJ-64281802 (50-1,200 mg), formulated as oral
solution, 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 elimination
half-life (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%.
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64281802DNG1006
64281802DNG1005
In study 64281802DNG1005, 
64281802DNG1004
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2.3. 
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 (IB JNJ-64281802 2022).
2.3.1. 
Risks for Study Participation
All therapies have the potential to cause adverse experiences. To date, clinical data with
JNJ-64281802 are available from the Phase 1 FIH  study DNG1001, study DNG1004, study
DNG1005, and study DNG1006, in healthy adult participants. 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, 400 mg once daily for 31 days, or 800 mg twice daily
for 2 days.
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Potential Risks of 
Clinical Significance 
Summary of Data/
Rationale for Risk  
Mitigation Strategy
Risks Due to Study Intervention
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.
Refer to Inclusion
Criteria 6, 7, 8 and
Exclusion Criterion 14
for women, and
Inclusion Criteria 9 and
10 and Exclusion
Criterion 15 for men in
this study.
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. A causal 
relationship between the events of rash and the study 
intervention cannot be excluded. 
Additional safety
follow-up procedures
will apply, as described
in the rash management
protocol in Appendix 2:
Rash Management.
Concomitant 
vaccination  
Concomitant vaccination might have an influence on the 
safety profile of JNJ-64281802. Likewise, JNJ-64281802 
might have an influence on both safety profile and 
immunogenicity of any concomitant vaccination. 
Licensed live attenuated
vaccines, except for
COVID-19 vaccines and
boosters, are disallowed
from 28 days before first
dose of study
intervention until 90 days
after last dose of study
intervention. Other
licensed (not live)
vaccines are disallowed,
from 7 days before first
dose of study
intervention until 90 days
after last dose of study
intervention (refer to
Exclusion Criterion 12
and Appendix 4:
COVID-19 Appendix).
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 Due to Study Procedures
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.
All assessments will be
performed by qualified
study site personnel.
COVID-19 = Coronavirus Disease 2019.
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2.3.2. 
Benefits for Study Participation
Participants taking part in this study might have the benefit of prevention of dengue infection
during the course of JNJ-64281802 administration. Results from the proposed study may be useful
in developing a new prophylactic compound for dengue.
2.3.3. 
Benefit-risk Assessment for Study Participation
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 risk ofdengue infection.
3. 
OBJECTIVES AND ENDPOINTS
The design of this study is detailed in Section 4.1. This study will include index cases ≥1 years of
age who will participate for one visit only, and HHCs aged 16 or 18 (depending on the legal age
of consent in the jurisdiction in which the study is taking place) to ≤65 years who are eligible be
included in the intervention part of the study (see Section 5.1, Inclusion Criteria). HHCs must not
have DENV-associated clinical signs and symptoms at baseline (see Section 5.2, Exclusion
Criteria).
Objectives 
Endpoints
Primary
 
To evaluate the prophylactic effect of
JNJ-64281802 with respect to the prevention
of laboratory-confirmed DENV infection up
to the last day of dosing among HHC who
have no evidence of current DENV infection
at baseline.
 
Laboratory-confirmed 
DENV 
infectiona
between baseline and the last day of dosing.
Key Secondary
 
To evaluate the prophylactic effect of
JNJ-64281802 with respect to the prevention
of symptomatic DENV infection through
development of signs and symptoms up to the
last day of dosing (see Table 3) among all
HHC.
 
Laboratory-confirmed symptomatic DENV
infectionb between baseline and the last day of
dosing.
Secondary
 
To evaluate the prophylactic effect of
JNJ-64281802 with respect to the prevention
of symptomatic DENV infection through
development of signs and symptoms up to the
last day of dosing (see Table 3) among HHC
who have no evidence of current DENV
infection at baseline.
 
Laboratory-confirmed symptomatic DENV
infectionb between baseline and the last day of
dosing.
 
To assess the safety and tolerability of 2 dose
regimens (high and low) of JNJ-64281802
among HHC.
 
Safety and tolerability as measured by
recording of adverse events (AEs), serious
adverse 
events 
(SAEs), 
physical
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Objectives 
Endpoints
examinations, vital signs, electrocardiograms
(ECGs), and clinical laboratory assessments.
 
To assess the PK of JNJ-64281802 following 
repeated oral dosing among HHC. 
 
PK parameters for JNJ-64281802 (area under
the concentration curve during one dosing
interval 
[AUCτ], 
observed 
analyte
concentration just prior to the beginning or at
the end of a dosing interval [Ctrough], and Cmax).
 
To assess the relationship between the PK and 
pharmacodynamics (PD), selected antiviral 
activity of JNJ-64281802, clinical outcome
and safety parameters) after repeated dosing
of JNJ-64281802 among HHC.
 
Laboratory-confirmed 
DENV 
infectiona
between baseline and the last day of dosing.
 
PK (plasma concentrations or exposure
parameters) of JNJ-64281802.
 
Safety parameters.
 
Laboratory-confirmed symptomatic DENV
infectionb between baseline and the last day of
dosing.
Exploratory
 
To evaluate the prophylactic effect of
JNJ-64281802 with respect to the prevention
of DENV infection up to the last day of dosing
as measured by  DENV RNA among HHC
who have no evidence of current DENV
infection at baseline.
 
Presence or absence of a positive DENV RNA
test result between baseline and the last day of
dosing.
 
To evaluate the prophylactic effect of
JNJ-64281802 with respect to the reduction of
DENV RNA among enrolled HHC who have
no evidence of current DENV infection at
baseline and who are infected post baseline.
 
Maximum DENV RNA levels between
baseline and last day of dosing.
 
To evaluate the prophylactic effect of
JNJ-64281802 with respect to the prevention
of DENV infection up to the last day of dosing
as measured by  detection of DENV NS1
protein among HHC who have no evidence of
current DENV infection at baseline.
 
Presence or absence of a positive DENV NS1
protein test result between baseline and the
last day of dosing.
 
To evaluate the prophylactic effect of
JNJ-64281802 with respect to the prevention
of DENV infection as measured by increase in
anti-DENV antibodies among HHC who have
no evidence of current DENV infection at
baseline.
 
Increase in anti-DENV antibody between
baseline and Day 40
 
Increase in anti-DENV antibody between
baseline and Day 50
 
Increase in anti-DENV antibody between
baseline and Day 90
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Objectives 
Endpoints
 
To evaluate the prophylactic effect of
JNJ‑64281802 with respect to the prevention
of symptomatic DENV infection up to Day
40, 50, and 90 among all HHC who completed
study intervention (28 days).
 
Laboratory-confirmed symptomatic DENV
infectionb between baseline and Day 40.
 
Laboratory-confirmed symptomatic DENV
infectionb between baseline and Day 50.
 
Laboratory-confirmed symptomatic DENV
infectionb between baseline and Day 90.
 
To 
evaluate 
the 
antiviral 
effect 
of
JNJ-64281802 as early treatment among HHC
who have evidence of DENV infection at
baseline.
 
Time to end of detectable DENV RNA and/or
reduction in DENV RNA load.
 
Time to end of detectable DENV NS1 protein.
 
DENV-associated signs and symptoms.
 
To 
identify  
circulating 
DENV
serotypes/genotypes and genetic variants
among index cases and HHC.
 
Serotype/genotype of DENV based on viral
genome sequence analysis.
 
Genetic variation of viral genome sequence
based on changes at the amino acid level
 
Emergent 
JNJ-64281802 
resistance-
associated mutations in HHC using index case
sequence as reference.
AE = adverse event; DENV = dengue virus; ECG = electrocardiogram; HHC = household contact;
nAb = neutralizing antibody; NS = non-structural protein; PCR = polymerase chain reaction;
PD = pharmacodynamics; PK = pharmacokinetic(s); RNA = ribonucleic acid; SAE = serious adverse event.
a 
Laboratory-confirmed DENV infection is defined as a positive DENV RNA or DENV NS1 protein test result.
b 
Laboratory-confirmed symptomatic DENV infection is defined as having at least 2 solicited systemic AEs
(see Table 3), of which at least one is a most common dengue symptom (ie, fever, headache/retro-orbital pain,
myalgia, arthralgia, rash), lasting for ≥1 day and occurring within a +/-2 day-window around the positive PCR
or NS1 test, between baseline and the last day of dosing.
Refer to Section 8, Study Assessments and Procedures for evaluations related to endpoints.
HYPOTHESIS
See Section 9.1, Statistical Hypotheses.
4. 
STUDY DESIGN
4.1. 
Overall Design
This is a Phase 2 randomized, double-blind, placebo-controlled, double-dummy, multicenter,
interventional study, assessing the efficacy and safety of 2 dose regimens of JNJ-64281802 for the
prevention of dengue infection in HHCs of a DENV-infected index case.
The study will be conducted in approximately 10 countries in South-East Asia and the American
continent.
There are 4 sequential phases in the study: DENV-infected index case identification, screening of
the HHCs which may include family members, acquaintances, co-workers, and community
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contacts of the index case, double-blind prophylactic dosing of HHCs, and the follow-up phase.
Stopping criteria are listed in Section 7.1.1.
The study consists of 2 stages with an interim analysis (IA) planned at the end of Stage 1 and the
final analysis (FA) planned at the end of Stage 2 (ie, at the end of the study). The IA will be
performed by an independent statistical support group and will be reviewed by the Independent
Data Monitoring Committee (IDMC) who will receive unblinded safety and efficacy data (see
Section 10.6.6, Committees Structure). After the review, the IDMC will make recommendations
to the Sponsor Committee regarding the continuation of the study (see Section 9.5, Interim
Analysis). A Sponsor Committee, consisting of senior sponsor personnel not involved in the
conduct of the study, will be established and will be responsible for decision making considering
the IDMC recommendation. The FA will be performed by the sponsor who will be fully unblinded
to the treatment allocation at that time.
This study consists of a main study (see below) and a PK substudy (see Section 8.9,
Pharmacokinetic Substudy).
Assessments and visits to the site will be performed as indicated in the Schedule of Activities.
Please refer to Appendix 4: COVID-19 Appendix  for guidance on study conduct during the
Coronavirus Disease 2019 (COVID-19) pandemic.
DENV-infected Index Case Identification
An index case is a patient (≥1 years old) with laboratory-confirmed dengue identified in the
community (ie, hospital and/or health care center [HCC]/health care provider [HCP]).
Laboratory-confirmed dengue for an index case is defined as:
1. Any DENV-associated signs and symptoms ≤72 hours of onset (according to Appendix 3:
WHO Clinical Classification of Dengue Disease), AND
2. A positive DENV NS1 test at screening. Results from tests performed as part of the local
standard-of-care ≤72 hours of screening may be used for screening for this study. If a DENV
NS1 test is not available, a DENV PCR test or anti-DENV immunoglobulin M (IgM) test can
also be used.
After informed consent/assent is obtained, either at the site or remotely (eg, at the index case’s
home), a blood sample for viral assessments will be collected, and the person's HHCs will be
contacted. If the index case is a minor according to the local laws and regulations, assent and
informed consent from the parent(s) or legal guardian(s) or legally acceptable representative(s)
will be obtained.
Screening of the Household/Community Contacts of the Index Case
A HHC is a person who lives, spends the night, or regularly attends/shares/consumes
cooking/meals in the same dwelling or housing complex as the index case. A household can
include one or more families, or community contacts in a single or in multiple houses or dwellings,
depending on the country, site, social-economic, and cultural characteristics. Co-workers and
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acquaintances can also be considered HHCs, if they spend time together with the index case (eg,
early morning hours or twilight hours) can also be considered as HHCs.
HHCs aged 16 or 18 (depending on the legal age of consent in the jurisdiction in which the study
is taking place) to ≤65 years can be included in the intervention part of the study. HHC must be
asymptomatic at screening and can include participants with no evidence of current DENV
infection (consisting of naïve and historical DENV-infected participants) or with evidence of
current DENV infection as confirmed by laboratory assessments, performed at a central laboratory
on samples taken at baseline (see Section 1.2, Schema).
Screening for eligible HHC(s) will be performed within 48 hours of obtaining informed
consent/assent of the index case. For this purpose, HHCs will be invited to the study site. Informed
consent of the HHC will be obtained on site or remotely (see Section 10.6.3, Informed Consent
Process and Assent Form).
Double-blind Prophylactic Dosing of HHCs
The study is event driven, with a target number of 36 DENV infections observed in the primary
study population and a target number of 24 symptomatic DENV infections observed in the
complete study population (see Section 9.3, Populations for Analysis Sets). Both conditions need
to be satisfied before recruitment is considered complete. Under the current assumptions, between
1,250 and 1,850 participants are expected to be enrolled in the study (see Section 9.2, Sample Size
Determination).
Participants will be randomized in a 1:1:1 ratio to receive a high- or low-dose study intervention,
or matching placebo in a double-dummy fashion (see Table 2 for details) for 28 days. The study
will use randomization at the individual participant level, stratified by country.
 
High-dose JNJ-64281802 regimen (HDR):
 
400 mg JNJ-64281802 loading dose (LD) twice daily for 48 hours, followed by
 
150 mg JNJ-64281802 maintenance dose (MD) once daily for 26 days.
 
Low-dose JNJ-64281802 regimen (LDR):
 
150 mg JNJ-64281802 (LD) twice daily for 48 hours, followed by
 
50 mg JNJ-64281802 (MD) once daily for 26 days.
 
Placebo (double-dummy; see Table 2).
LDs need to be taken twice daily, approximately around the same timepoints. MDs will start after
the last LD and need to be taken once daily, approximately around the same timepoint, until Day
28.
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The study intervention is to be taken in fed conditions (for details, see Table 2). Study intervention
can be taken with water.
All participants will complete 2 days of LD and 26 days of MD. This is to cover the estimated 3 to
4 weeks A. Aegypti lifespan with 10 to 18 days infective life and DENV transmission risk,
depending on environmental temperature (Goindin 2015).
Development of DENV-associated clinical signs and symptoms (according to Appendix 3: WHO
Clinical Classification of Dengue Disease) will be evaluated and recorded, virologic and serologic
testing, and safety assessments will be performed.
In a PK substudy, rich serial PK blood sampling for the measurement of plasma concentrations of
JNJ-64281802 will be performed. This substudy will be conducted at selected study sites in
30-40 participants who will be evenly distributed (1:1:1 ratio) over HDR, LDR, and placebo
regimen (see Section 8.9, Pharmacokinetic Substudy). Participants included in the PK substudy
will also undergo all assessments in the main study.
The study intervention will be dispensed directly to the participants at the site (see Section 6.2,
Preparation/Handling/Storage/Accountability).
Follow-up Phase
Double-blind prophylactic dosing of HHCs will be followed by intensive follow-up until Day 50
and a last visit on Day 90. At the end-of-study visit, assessments will be performed as indicated in
Section 1.3.2.3. Total study duration will be approximately 13 weeks for HHCs.
4.2. 
Scientific Rationale for Study Design
Population
Asymptomatic HHCs aged 16 or 18 (depending on the legal age of consent in the jurisdiction in
which the study is taking place) to ≤65 years can be included in the intervention part of the study.
People in dengue-endemic areas older than 65 years would have already been infected with all
4 dengue serotypes at any time in their lives. As there can be up to 4 DENV serotypes circulating
at any time in dengue-endemic regions, the conduct of the study in dengue-naïve as well as
dengue-past exposed study participants in endemic regions allows for the assessment of the
efficacy of the 2 dose regimens and of the ultimate decision on one dose selection.
Blinding, Control, 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 that known and unknown participant attributes (eg, demographic
and baseline characteristics) are evenly balanced across intervention groups, and to enhance the
validity of statistical comparisons across intervention groups.
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Blinded intervention will be used to reduce potential bias during data collection and evaluation of
clinical endpoints. Administration of study intervention will be in a double-dummy fashion to
maintain the blind between the HDR and LDR.
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 (deoxyribonucleic acid [DNA]) 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 is to collect DNA to allow the
identification of host genetic factors that may influence the PK, antiviral activity, safety of
JNJ-64281802, the DENV infection or dengue disease, or may be used to develop tests/assays
related to JNJ-64281802 or DENV infection. An optional blood sample for pharmacogenomic
research may be collected (where local regulations permit), preferably at baseline (ie, before first
dose of study intervention). Participation in the pharmacogenomic research is voluntary  and
requires a separate consent.
Biomarker samples will be collected to evaluate the mechanism of action ofJNJ-64281802, to help
analyze interindividual variability in clinical outcomes, or help to potentially 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 intervention-clinical response relationship. Samples can
only be used for research related to JNJ-64281802 or DENV infection, or they 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. Analyses of the
DNA and biomarker samples are at the discretion of the sponsor and results may be reported
separately.
4.2.1. 
Study-specific Ethical Design Considerations
This study will also include index cases ≥1 years of age. When "participant" is referred to in
relation to the ICF, this can be either a HHC or an index case; when "participant" is referred to in
relation to the informed assent form, this refers to an index case.
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/assent 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/assentvoluntarily will be enrolled.
Written consent/assent may be obtained through various sources (eg, paper or electronic such as
eConsent, eSignature, or digital signature) as determined by regulations as well as study and/or
patient preferences.
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The primary ethical concern is that this study will be performed in asymptomatic HHCs aged 16 or
18 (depending on the legal age of consent in the jurisdiction in which the study is taking place) to
≤65 years without clinical signs and symptoms of dengue. Participants taking part in the study might
have the benefit of dengue infection prevention during JNJ-64281802 administration. They will
receive financial compensation to a comparable fair market value for the time and inconveniences
that may arise from participation in the study per local regulations. Refer to Section 2.3 for details
on benefits and risks, and for the safety measures taken to minimize risk to participants.
When referring to the signing of the ICF, the terms legal guardian and legally acceptable
representative refer to the legally appointed guardian of the child with authority to approve
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. Assent must be obtained
from children (minors) capable of understanding the nature of the study, typically participants
7 years of age and older, depending on the institutional policies. For the purposes of this study, all
references to participants who have provided consent (and assent as applicable) 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/assent according to this process. Minors who assent to
a study and later withdraw that assent should not be maintained in the study against their will, even
if their parent(s) still want them to participate.
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 (American Red Cross 2021).
4.3. 
Justification for Dose
The dosing regimen selection was based on final data from the Phase 1 FIH study DNG1001,
interim data from the Phase 1 study DNG1006, final data from the Phase 1 human challenge
characterization studies with DENV-1 (CSR DENV-1-LVHC 2021; Endy 2021), Good Laboratory
Practice toxicity studies, final data from the non-human primate challenge studies, and in vitro
antiviral activity data of JNJ-64281802.
A population PK model was developed using pooled data from DNG1001 (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) and DNG1006 Panels 1-5 (single doses of 50 to 800 mg). 
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The 2 days twice daily administered LDs will be followed by 26 days once daily administered
MDs. 
 
 The following LD/MD regimens
were selected:
 
High-dose JNJ-64281802 regimen:
 
400 mg JNJ-64281802 (LD) twice daily for 48 hours, followed by
 
150 mg JNJ-64281802 (MD) once daily for 26 days.
 
Low-dose JNJ-64281802 regimen:
 
150 mg JNJ-64281802 (LD) twice daily for 48 hours, followed by
 
50 mg JNJ-64281802 (MD) once daily for 26 days.
The 28-day dosing period will cover the estimated 3 to 4 weeks A. Aegypti lifespan with 10 to
18 days infective life and DENV transmission risk, depending on environmental temperature
(Goindin 2015).
Based on population PK simulations, a mean Cmax and mean AUC0-24h at Day 2 (end of LD period)
and Day 28 (end of dosing period) were derived for the selected JNJ-64281802 dosing regimens
(Table 1).
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Table 1: 
4.4. 
End of Study Definition
Index Case
Index case participation in the study will involve only one visit.
Household Contact
End of Study Definition
The end of study is considered as the last visit 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
visit 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 the participant has completed
assessments at Day 90.
5. 
STUDY POPULATION
Patients with laboratory-confirmed dengue (index case) will first be identified (see Section 4.1,
Overall Design). HHCs (which may include family members, acquaintances, co-workers, and
community contacts) of the index case who have no DENV-associated clinical signs and symptoms
at baseline will be enrolled in this study. Screening for eligible HHC(s) will be performed within
48 hours of obtaining informed consent/assent of the index case. HHCs should start study
intervention intake within 12 hours of signing their ICF. Refer to Section 5.4, Screen Failures for
conditions under which the repeat of any screening procedures is allowed.
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.
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5.1. 
Inclusion Criteria
Index Cases
Each potential participant must satisfy all of the following criteria to be enrolled in the study:
Age
1. 
≥1 years of age.
Type of Participant and Disease Characteristic
2. 
Criterion modified per Amendment 1.
2.1 Criterion modified per Amendment 3.
2.2 Must have laboratory-confirmed dengue infection:
a. Any DENV-associated signs and symptoms ≤72 hours of onset (according to
Appendix 3: WHO Clinical Classification of Dengue Disease), AND
b.   A positive DENV NS1 test at screening. Test results performed by local standard-
of-care ≤72 hours of screening may be used for screening for this study. If a
DENV NS1 test is not available, a DENV PCR test or anti-DENV IgM test could
also be used.
Informed Consent/Assent
3. 
Must sign an ICF (or their legally acceptable representative must sign) indicating that the
participant understands the purpose of, and procedures required for, the study and is
willing to participate in the study.
In case the index case has not reached the legal adult age per the local regulation, the
signature of a legal representative of the index case will be required. Parent(s) (preferably
both if available or as per local requirements) (or their legally acceptable representative)
must sign an ICF indicating that they understand the purpose of, and procedures required
for, the study and is willing to allow the child to participate in the study. Assent is also
required of children capable of understanding the nature of the study as described in
Section 10.6.3, Informed Consent Process and Assent Form.
Household Contacts
Each potential participant must satisfy all of the following criteria to be enrolled in the study:
Age
1. 
16 or 18 (depending on the legal age of consent in the jurisdiction in which the study is
taking place) to 65 years of age, inclusive.
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Type of Participant and Disease Characteristic
2. 
Healthy on the basis of physical examination, medical history, and vital signs performed
at screening. If there are abnormalities, the participant may be included only if the
investigator judges the abnormalities to be not clinically relevant. This determination
must be recorded in the participant's source documents.
3. 
Criterion modified per Amendment 3.
3.1 Must have a blood pressure (participant must be supine for ≥5 minutes):
For a participant between 16 and 18 years old: between 90 and 120 mmHg systolic,
extremes included, and ≤80 mmHg diastolic at screening.
For a participant >18 years old: between 90 and 140 mmHg systolic, extremes included,
and ≤90 mmHg diastolic at screening.
Two repeat measurements are allowed in the absence of any other concerning health
screening issues. If the results of blood pressure are outside these ranges, the participant
may be included only if the investigator judges the deviations from normal blood pressure
to be not clinically significant or to be appropriate and reasonable for the population under
study.
Weight
4. 
Criterion modified per Amendment 1.
4.1 Must have a body mass index (BMI, weight in kg divided by the square of height in
meters) between 18.0 and 35.0 kg/m2 inclusive, and a body weight of ≥40.0 kg at
screening.
Sex and Contraceptive/Barrier Requirements
5. 
Man or woman.
6. 
A woman must have a negative highly sensitive urine pregnancy test at screening.
7. 
Criterion modified per Amendment 3
7.1 A woman must be (as defined in Appendix 5: Contraceptive and Barrier Guidance)
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 ≥90 days after the last dose,
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the end of relevant systemic exposure. The investigator should evaluate the
potential for contraceptive method failure (eg, noncompliance, recently
initiated) in relationship to the first dose of study intervention.
Examples of highly effective methods of contraception are provided in
Appendix 5: Contraceptive and Barrier Guidance.
A woman using hormonal contraception must use an additional barrier-based
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 coadministered with JNJ-64281802 and
therefore they should not be considered as a highly effective contraceptive
method during dosing with JNJ-64281802.
8. 
A woman must agree not to donate eggs (ova, oocytes) or freeze for future use for the
purposes of assisted reproduction during the study and for a period of 6 months after the
last dose of study intervention.
9. 
During the study and for ≥90 days after last dose of 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.
10. 
A male participant must agree not to donate sperm for the purpose of reproduction during
the study and for ≥90 days after receiving the last dose of study intervention.
Informed Consent
11. 
Must sign an ICF (or their legally acceptable representative must sign) indicating that the
participant understands the purpose of, and procedures required for, the study and is
willing to participate in the study.
12. 
Must sign a separate ICF  (or their legally acceptable representative must sign) if the
participant agrees to provide an optional DNA sample for research (where local
regulations permit). Refusal to give consent for the optional DNA research sample does
not exclude a participant from participation in the study.
13. 
Must be willing and able to adhere to the study requirements and lifestyle restrictions
specified in this protocol.
5.2. 
Exclusion Criteria
Any potential HHC who meets any of the following criteria will be excluded from participating in
the study:
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Medical Conditions
1. 
Having any DENV-associated clinical signs and symptoms (according to Appendix 3:
WHO Clinical Classification of Dengue Disease).
2. 
Criterion modified per Amendment 1.
2.1 Criterion modified per Amendment 3.
2.2. History of liver or renal insufficiency, 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, neoplastic, autoimmune, or
metabolic disturbance, if deemed clinically significant by the investigator.
3. 
Known allergies, hypersensitivity, or intolerance to JNJ-64281802 or its excipients
(refer to the IB for JNJ-64281802 [IB JNJ-64281802 2022]).
4. 
Criterion modified per Amendment 3.
4.1 Any clinically relevant skin disease (as assessed by the investigator) in the past 3
months such as, but not limited to, dermatitis, eczema, drug rash, psoriasis, food allergy,
and urticaria.
5. 
Having donated or lost >1 unit of blood (500 mL) within 60 days or >1 unit of plasma
(250 mL) within 7 days before the planned first dose of study intervention, or having
the intention to donate blood or blood products during the study or within 6 months
after last dose of study intervention.
6. 
Criterion modified per Amendment 3.
6.1 Reduced immune function due to:
a. Known or suspected congenital or acquired immunodeficiency; or
b. Receipt of immunomodulation therapy  within the last 6 months (such as
anticancer chemotherapy or radiation therapy).
7. 
History of risk factors for Torsades de Pointes (eg, heart failure, hypokalemia, family
history of Long QT Syndrome).
8. 
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.
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Prior/Concurrent Clinical Study Experience
9. 
Criterion modified per Amendment 1.
9.1 Criterion modified per Amendment 3.
9.2 Received an investigational intervention (including investigational vaccines other
than a COVID-19 vaccine) or used an invasive investigational medical device within 3
months before the planned first dose of study intervention or received an investigational
biologic product within 3 months prior to enrollment or 5 half-lives, whichever is
longer, before the planned first dose of study intervention, or is currently enrolled in an
investigational study.
Prior/Concomitant Therapy
10. 
Taken any disallowed therapies as noted in Section 6.8, Concomitant Therapy before
the planned first dose of study intervention.
11. 
Criterion modified per Amendment 3.
11.1 Use of any strong CYP3A4 inhibitors, strong CYP3A4 inducers, substrates for
CYP3A4 with a narrow therapeutic index, or sensitive BCRP substrates within 7 days
before first dose of study intervention. Refer to Appendix 10 for examples of such
disallowed medications.
12. 
Criterion modified per Amendment 1
12.1 Criterion modified per Amendment 3.
12.2 Received or plans to receive any of the following vaccines:
a. Licensed live attenuated vaccines are disallowed 28 days before first dose of
study intervention until 90 days after last dose of study intervention.
b. Other licensed (not live) vaccines are disallowed from 7 days before first dose
of study intervention until 90 days after last dose of study intervention.
Any prior vaccinations against DENV virus are not allowed until 90 days after last dose
of study intervention. Vaccinations against all other flaviviruses are not allowed from
28 days before first dose of study intervention until 90 days after last dose of study
intervention.
Participants will be allowed to receive a COVID-19 vaccine (see Appendix 4:
COVID-19 Appendix ).
13. 
Use of any immunosuppressive corticosteroids (excluding topical and nasal) or
immunosuppressive drugs within 28 days before first dose of study intervention. An
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immunosuppressive dose of corticosteroids is defined as ≥10 mg prednisone equivalent
per day for ≥14 days.
Other Exclusions
14. 
Pregnant, breastfeeding, or planning to become pregnant while enrolled in this study or
within 90 days after the last dose of study intervention.
15. 
Plans to father a child while enrolled in this study or within 90 days after the last dose
of study intervention.
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.
The required source documentation to support meeting the enrollment criteria are noted in
Appendix 6: 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 6.8, 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. 
Must refrain from consumption of grapefruit or grapefruit juice from screening until the
last PK sample has been taken.
5.3.2. 
Caffeine, Alcohol, and Drugs of Abuse
1. 
Must limit the use of food or drinks/beverages containing alcohol to the absolute
minimum from screening until the last PK sample has been taken. If any alcohol is taken,
≤2 standard drink consumptions daily will be allowed. A standard drink is defined as a
350-mL glass of 5% alcohol-by-volume (ABV) beer, a 150-mL glass of 12% ABV wine,
or a 45-mL glass of 40% ABV (80 proof) spirit.
2. 
Must refrain from all use of energy drinks and avoid excessive use of caffeine from
screening until the last PK sample has been taken. Limited use of caffeinated
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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).
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 investigator will not generate screening and
enrollment logs directly from the interactive web response system (IWRS).
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/assent. In cases where the participant is not
randomized into the study, the date seen and age at initial informed consent/assent will be used.
Individuals who do not meet the criteria for participation in this study (screen failure) may be
rescreened. Rescreened participants must be assigned new participant numbers.
6. 
STUDY INTERVENTION AND CONCOMITANT THERAPY
6.1. 
Study Intervention(s) Administered
HHCs should start study intervention intake within 12 hours of signing their ICF.
Participants will be randomized to study intervention as described in Section 4.1, Overall Design
and receive study intervention in a double-dummy fashion under fed conditions as presented in
Table 2. Study intervention can be taken with water.
Study intervention will be dispensed at the site or by designated study site personnel who visits
the participant at home as indicated in the Schedule of Activities. Study site personnel will instruct
participants on how to store study intervention for at-home use as indicated for this protocol. All
intakes of study intervention from Day 1 to Day 28 will take place at the study site or at home.
On Day 1, the first administration of study intervention will take place at the site. The second
administration of study intervention will take place at home. Administration of the third dose of
study intervention will be at the site and the fourth dose will be taken at home.
Participants in the PK substudy must take the first dose of study intervention on site in the morning
to allow for the hourly PK sample collection. The second dose of study intervention should be
taken in the evening at the site.
MD starts after LD (on Day 3) and should be taken once daily, at approximately the same time of
the day, until Day 28.
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Whether a meal was taken prior to administration of study intervention and date/time of study
intervention intake must be captured in the diary  and the case report form (CRF). See also
Section  6.2, Preparation/Handling/Storage/Accountability  and Section 6.4, Study Intervention
Compliance.
JNJ-64281802 will be manufactured and provided under the responsibility of the sponsor. Refer
to the IB for JNJ-64281802 for a list of excipients (IB JNJ-64281802 2022).
For a definition of study intervention overdose, refer to Section 6.7, Treatment of Overdose.
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Table 2: 
Description of Study Intervention
Intervention Name 
JNJ-64281802 
Placebo
Dose Formulation 
Unit Dose Strength(s) 
Dosage Level(s) and Frequency  
 High-dose regimen: 
o 400 mg JNJ-64281802 (LD) twice daily for 48 hours, 
followed by  
o 150 mg JNJ-64281802 (MD) once daily for 26 days 
 Low-dose regimen:
o 150 mg JNJ-64281802 (LD) twice daily for 48 hours,
followed by
o 50 mg JNJ-64281802 (MD) once daily for 26 days
Placebo will be administered in a double-dummy fashion so
that there is only one placebo group with administration of
study intervention at the same frequency as the active
intervention groups.
Number 
 
Route of Administration 
Oral 
Oral
Food/Fasting Requirement 
The study intervention is to be taken in fed conditions, ie, 
within 30 minutes after the start of the participant’s regular 
meal (eg, breakfast, lunch, snack, and/or dinner). 
The study intervention is to be taken in fed conditions, ie,
within 30 minutes after the start of the participant’s regular
meal (eg, breakfast, lunch, snack, and/or dinner).
Use 
Experimental 
Placebo
Investigational Medicinal Product 
(IMP) and Non-Investigational
Medicinal Product
IMP  
IMP
Sourcing 
Provided centrally by the Sponsor 
Provided centrally by the Sponsor
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Table 2: 
Description of Study Intervention
Packaging and Labeling 
(Labels will contain information to 
meet the applicable regulatory
requirements.)
JNJ-64281802 will be provided in blisters in child resistant
packaging.
Placebo will be provided in blisters in child resistant
packaging.
IMP = investigational medicinal product; LD = loading dose; MD = maintenance dose.
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6.2. 
Preparation/Handling/Storage/Accountability
Study intervention will be self-administered and/or administered by designated study  site
personnel when the participant visits the site or is visited at home. For details, see Section 6.4,
Study Intervention Compliance.
Preparation/Handling/Storage
The study intervention will be dispensed directly to the participants at the site by designated study
site personnel who will adhere to privacy requirements approved by the Independent Ethics
Committee/Institutional Review Board (IEC/IRB).
All study intervention must be stored at controlled temperatures as indicated on the
product-specific labeling. On Day 1, participants will be instructed on how to store the study
intervention at home.
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 dispensing of study intervention to the
participant, and the return of study intervention from the participant (if applicable), must be
documented on the intervention accountability form. Participants, or their legally acceptable
representatives where applicable, must be instructed to return all blisters, whether empty or
containing study intervention. The study intervention administered to the participant must be
documented on the intervention accountability form. Participants will note study intervention
administration in a diary. All study intervention will be stored and disposed of according to the
sponsor's instructions.
Study intervention must be handled in strict accordance with the protocol, and the study
intervention 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 sponsors study site monitor
during on-site monitoring visits. 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.
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. Whenever a participant brings his or her study
intervention to the study site for pill count, this is not seen as a return of supplies. Study
intervention may not be relabeled or reassigned for use by other participants. For administration
of study intervention at the site, the investigator agrees to not store the study intervention at any
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site other than the study sites agreed upon with the sponsor. The investigator agrees to administer
the study intervention only at the study site or at the participants' home. Further guidance and
information for the final disposition of unused study interventions are provided in the pharmacy
manual/study-site investigational product and procedures manual.
6.3. 
Measures to Minimize Bias: Randomization and Blinding
Intervention Allocation
Procedures for Randomization
Central randomization will be implemented in this study. Participants will be assigned to 1 of
3 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. A separate randomization list will be
created for the PK substudy.
The IWRS will assign a unique intervention code, which will dictate the intervention assignment
and matching study intervention kit for the participant. The requestor must use his or her own user
identification and personal identification number when contacting the IWRS and will then give the
relevant participant details to uniquely identify the participant.
Blinding
The investigator will not be provided with randomization codes. The codes will be maintained
within the IWRS, which has the functionality to allow the investigator to break the blind for an
individual participant.
Data that may potentially unblind the intervention  assignment (ie, study intervention  serum
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.
Under normal circumstances, the blind should not be broken until all participants have completed
the study and the database is finalized. The investigator may in an emergency determine the
identity of the intervention  by contacting the IWRS. 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 IWRS and in the appropriate section of the CRF. The documentation received from the
IWRS indicating the code break must be retained with the participant's source documents in a
secure manner.
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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, for the IA (see Section 9.5, Interim Analysis), 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
IA. Sponsor personnel involved in the PK and exposure-response modeling will have access to the
PK and PD data before formal unblinding. Sponsor personnel involved in study conduct, data
management, and statistics will not have access to these data.
6.4. 
Study Intervention Compliance
Study intervention will be self-administered and/or administered by designated study  site
personnel when the participant visits the site or is visited at home. Visits to the study site are
indicated in the Schedule of Activities:
 
For the main study:
 
Visiting the site is required on Days 1, 2, and 28. All other visits as indicated in the
Schedule of Activities may either be performed at the site or by designated study site
personnel who visits the participant at home. Between on-site visits, administration of
study intervention will either be at home (including remote supervision of study
intervention intake, if feasible) or participants may come to the site. MDs need to be taken
approximately at the same timepoint every day.
 
For the PK substudy:
 
Participants will remain at the site during the first 12 hours on Days 1 and 28. Visiting
the site is required on Day 2 and Day 3. All other visits (Day 29 and Day 32) may either
be performed at the site or by designated study site personnel who visits the participant
at home.
Study intervention will be administered orally, and date/time of study intervention intake will be
recorded by the participant in a diary.
When the participant visits the site, study intervention will be administered by designated study
site personnel who will check the participant's mouth to confirm that the dose was swallowed. The
date and time of each dose administered in the study site will be recorded in the source documents
for on-site administration and recorded in the CRF. The intake 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.
When participants self-administer study intervention at home, compliance with study intervention
will be assessed as indicated in the Schedule of Activities. Administration of study intervention
will either be at home (including remote supervision of study intervention intake, if feasible) or
participants may come to the site (also see Section 8, Study Assessments and Procedures).
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Participants will receive instructions on compliance with study intervention administration on
Day 1. During the study, the investigator or designated study site personnel will be responsible for
providing additional instruction to reeducate any participant who is not compliant with taking the
study intervention.
Compliance will be assessed by counting returned tablets and review of the diary during the site
or home visits and documented in the source documents and CRF. Deviation(s) from the prescribed
dosage regimen should be recorded in the CRF.
The number of study intervention tablets dispensed will be recorded and compared with the
number returned. A record of the number of study intervention tablets dispensed to and taken by
each participant must be maintained and reconciled with study intervention and compliance
records. Intervention start and stop dates, including dates for intervention delays and/or dose
reductions will also be recorded in the CRF.
6.5. 
Dose Modification
Not applicable.
6.6. 
Continued Access to Study 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.
6.7. 
Treatment of Overdose
For this study, any dose of JNJ-64281802 greater than the assigned daily dose within a 24-hour
time period (Table 2) will be considered an overdose. The sponsor does not recommend specific
treatment for an overdose.
In the event of an overdose, the investigator or treating physician should:
 
Contact the Medical Monitor immediately.
 
Evaluate need to discontinue study intervention in consultation with the Medical Monitor.
 
Closely monitor the participant for AE/SAE and laboratory abnormalities until
JNJ-64281802 can no longer be detected systemically (at least 46 days).
 
Document the quantity of the excess dose as well as the duration of the overdosing in the
source documents and the CRF.
Decisions regarding dose discontinuation will be made by the investigator in consultation with the
Medical Monitor based on the clinical evaluation of the participant.
6.8. 
Concomitant Therapy
Prestudy therapies administered up to 14 days before first dose of study intervention must be
recorded at screening.
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Concomitant therapies must be recorded in the CRF throughout the study from the screening visit
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.
In case any comedications are used, the dose and dosing regimen must be recorded in the
Concomitant Therapy Section of the CRF. 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 following medications other than the study intervention are allowed during (a part of) the
study:
 
The investigator may permit the use of paracetamol/acetaminophen from 3 days before first
dose of study intervention until the last PK sample has been taken at ≤3 x 500 mg per day,
and ≤3 grams per week. In case paracetamol/acetaminophen is 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. In order to minimize the antipyretic effects of
paracetamol/acetaminophen  on body temperature outcome readings, participants are
recommended not to take paracetamol/acetaminophen within 4 hours before the next body
temperature measurement, except those with high fever (≥39°C). In this case, the body
temperature before taking paracetamol/acetaminophen, the dose taken, and the body
temperature one hour after taking paracetamol/acetaminophen should be recorded in the
daily dairy. In addition, the Medical Monitor should be informed about this occurrence.
 
Stable HRT (ie, same dose and not starting or stopping HRT for 2 weeks before first dose of
study intervention until the end of the study) in postmenopausal women is allowed. It should
be noted that JNJ-64281802 may affect the effectiveness of HRT  agents when
coadministered. The use of HRT must be recorded in the Concomitant Therapy Section of
the CRF. Applicable procedures and treatment guidance based on package inserts should be
respected.
Other co-medication allowed include the following:
 
H1 receptor antagonists (with exception of mizolastine), topical corticosteroids, or
antipruritic agents in the recommended dose scheme.
 
H2 receptor antagonists.
 
The use of antiemetics in case of severe nausea.
For vaccinations:
 
Participants will be allowed to receive an authorized/licensed COVID-19 vaccine throughout
this study (see Appendix 4: COVID-19 Appendix), including attenuated COVID-19
vaccines and boosters.
 
Other licensed live attenuated vaccines are not allowed from 28 days before first dose of
study intervention until 90 days after last dose of study intervention. Furthermore, other
licensed (not live) vaccines, are disallowed from 7 days before first dose of study
intervention until 90 days after last dose of study intervention.
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 
Any prior vaccinations against DENV virus are not allowed until 90 days after last dose of
study intervention. Vaccinations against all other flaviviruses are not allowed from 28 days
before first dose of study intervention until 90 days after last dose of study intervention.
Participants must not use any immunosuppressive corticosteroids (excluding topical and nasal) or
immunosuppressive drugs from 28 days before first dose of study intervention until 28 days after
last dose of study intervention. 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 indication, the dose, and
the dosing regimen must be recorded in the Concomitant Therapy Section of the CRF.
Participants must not use any anticoagulant medication or NSAIDs including aspirin, from
screening until the last study visit. Aspirin and NSAIDs can interfere with the ability of the blood
to clot. It is not anticipated that any participants will have severe DENV infection with bleeding
problems, however, it is still recommended to avoid these drugs. The investigator may recommend
paracetamol/acetaminophen or an equivalent at doses described above.
Use of any strong CYP3A4 inhibitors, strong CYP3A4 inducers, substrates for CYP3A4 with a
narrow therapeutic index, or sensitive BCRP substrates from 7 days before first dose of study drug
until 28 days after last dose of study drug is not permitted. 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.
Refer to 10.10 Appendix 10: Examples of Disallowed Medications for examples of such
disallowed medications.
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in
which prohibited therapies are administered.
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL
7.1. 
Participant Discontinuation Criteria
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, AE) it is in the
best interest of the participant to discontinue study intervention.
 
The participant becomes pregnant.
 
As baseline (Day 1) laboratory results will not be available at randomization, any participant
who reports with 2 or more ≥Grade 2 laboratory abnormalities for ALT, AST, creatinine,
lipase, absolute neutrophil count, platelet count, or hemoglobin  at baseline, must be
discontinued. Discontinuation of study intervention should only occur after a confirmatory
retesting result and if deemed clinically significant by the investigator.
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 
Noncompliance with study intervention  administration occurs, defined as missing a LD,
2 consecutive MDs, or 2 nonconsecutive MDs within a week (judged case-by-case after
discussion between the Sponsor and investigator).
 
In case of abnormal liver tests as outlined in 10.11 Appendix 11: Liver Safety: Suggested
Actions and Follow-up Assessments and Section 7.1.2 Participant Stopping Criteria due to
Liver Chemistry .
If a participant discontinues study intervention prematurely for any reason other than withdrawal
of consent before the end of the double-blind prophylactic dosing phase, a withdrawal visit should
be scheduled as soon as possible after the decision for discontinuation, followed by a follow-up
visit, which is preferably scheduled 13 to 17 days after the last dose study intervention intake, if
the condition of participant allows (see Section 1.3.2.4, Discontinuation From Study Intervention
or Study). Blood sample should be collected at the withdrawal and follow-up visits for immune
assessments, viral analysis, viral genome sequencing, and safety assessments (at the follow-up
visit, safety assessments should occur at the discretion of the investigator).
Study intervention assigned to the participant who discontinued study intervention may not be
assigned to another participant. Additional participants will be entered to ensure the
protocol-specified number of participants complete the study.
Please refer to Appendix 4: COVID-19 Appendix  for guidance on study conduct during the
COVID-19 pandemic.
7.1.1. 
Participant Stopping Criteriadue to DENV infection
In addition to the discontinuation criteria outlined in Section 7.1 above, HHCs who develop
DENV-associated clinical warning signs and symptoms (according to Appendix 3: WHO Clinical
Classification of Dengue Disease) during the study and require hospitalization will be withdrawn
from study intervention. The participant will perform a withdrawal and safety follow-up visit as
described in Section 7.1, Discontinuation of Study Intervention.
The participant will receive medical care according to local standards. Hospitalization is classified
as SAE and should be reported accordingly (see Section 8.3, Adverse Events, Serious Adverse
Events, and Other Safety Reporting).
7.1.2. 
Participant Stopping Criteria due to Liver Chemistry
Stopping of study intervention for abnormal liver tests is required by the investigator when a
participant meets one of the conditions outlined in 10.11 Appendix 11: Liver Safety: Suggested
Actions and Follow-up Assessments, after consultation with the sponsor, or in the presence of
abnormal liver chemistries not meeting protocol-specified stopping rules if the investigator
believes that it is in best interest of the participant.
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7.1.3. 
Study Pausing Criteria
If significant safety concerns arise following administration of study intervention (and a specific
set of study pausing criteria have been met), further randomization and dosing of participants may
be paused.
The reasons for pausing the study are listed below. The list only applies for events that are
considered by the investigator to be related to study intervention and unrelated to dengue disease
or an associated infection (eg, COVID-19).
 
Death of a participant, considered related to study intervention or if the causal relationship
to the study intervention cannot be excluded; OR
 
Three or more participants at one study site or six or more participants at all study sites
experience a ≥Grade 3 unsolicited AE of the same type (as per medical judgment of the
sponsor) that is considered related to study intervention;
Note: An AE report based on a ≥Grade 3 laboratory abnormality will only be considered if
the laboratory abnormality is clinically significant and persistent (upon repeated testing) per
the investigator. Elevations of total cholesterol will not be considered.
OR
 
Any safety findings that in the opinion of the sponsor or the IDMC warrants pausing (or
cessation) of dosing.
To enable a prompt response to a situation that could trigger the study pausing criteria, the
investigator should notify the sponsor’s medical monitor (or designee) immediately and no later
than 24 hours after becoming aware of any ≥Grade 3 unsolicited AE considered related to study
intervention (and update the CRF with relevant information on the same day the AE information
is collected). A thorough analysis of all reported ≥Grade 3 unsolicited AEs will initially be carried
out by the sponsor’s medical monitor (or designee). Based on the available data, the sponsor’s
medical monitor (or designee) will determine whether a safety data review by the IDMC is
warranted, to assess whether the study pausing criteria are met.
If the IDMC judges that the study pausing criteria have been met, the IDMC will recommend to
either pause the study or to implement modifications to the study conduct and/or to the safety
assessments. If safety concerns would occur only with the HDR, the IDMC may recommend to
pause randomization and dosing in the HDR group but continue randomization and dosing in the
LDR and placebo groups.
In case the IDMC recommends a study pause, all sites/investigators will be notified immediately
of the pause by the sponsor’s medical monitor (or designee).
In case a safety data review by the IDMC was triggered because three or more participants at one
study site or six or more participants at all study sites experienced a ≥Grade 3 unsolicited AE of
the same type (as per medical judgment of the sponsor) that is determined to be related to study
intervention, the IDMC will indicate the conditions under which it requires further notification and
review of the subsequent similar AEs.
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At any point during the study, the IDMC has the authority to recommend modifications to the
study conduct and/or to the safety assessments to the Sponsor Committee to ensure the safety of
enrolled participants. The IDMC can recommend to the Sponsor Committee to halt a dose arm or
to pause or stop the study due to safety concerns.
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
 
Failure to comply with the protocol requirements or to cooperate with the study  site
personnel
When a participant withdraws before study  completion, the reason for withdrawal is to be
documented in the CRF and in the source document.
For participants who discontinue the study prematurely for reasons other than withdrawal of
consent, a withdrawal visit and a follow-up will be performed (see Section 7.1, Discontinuation of
Study Intervention and Section 1.3.2.4, Discontinuation From Study Intervention or Study).
HHCs who withdraw consent from the study will be offered a follow-up visit. Index cases who
withdraw consent/assent during screening (ie, their only visit in the study) will not be followed up.
Withdrawal of Consent/Assent
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
A participant who withdraws from the study will have the following options regarding the optional
research samples (only applicable to pharmacogenomic research samples; see Section 8.5):
 
The collected samples will be retained and used in accordance with the participant's original
separate informed consent for optional research samples.
 
The participant may withdraw consent for the optional research samples, ie, samples for
pharmacogenomic analysis, in which case, the samples will be destroyed, and no further
testing will take place. To initiate the sample destruction process, the investigator must notify
the sponsor study site contact of withdrawal of consent for the optional research samples and
to request sample destruction. The sponsor study site contact will, in turn, contact the
biomarker representative to execute sample destruction. If requested, the investigator will
receive written confirmation from the sponsor that the samples have been destroyed.
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Withdrawal From the Optional Research Samples While Remaining in the Main Study
The participant may withdraw consent for the optional pharmacogenomic research samples while
remaining in the study. In such a case, the optional research samples will be destroyed. The sample
destruction process will proceed as described above.
Withdrawal From the Use of Samples in Future Research While Remaining in the Main
Study
The participant may withdraw consent for use of samples for additional future research (refer
Section 10.6.5, Long-term Retention of Samples for Additional Future Research). 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 the optional
pharmacogenomics research samples.
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 the participant 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 futile. 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.
 
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), and to determine the reason for
discontinuation/withdrawal. 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.
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8. 
STUDY ASSESSMENTS AND PROCEDURES
Overview
The Schedule of Activities summarizes the frequency and timing of sampling to enable assessment
of antiviral activity, viral genome sequencing, PK, immune, biomarker, pharmacogenomic, and
safety measurements applicable to this study.
If multiple assessments are scheduled for the same time point, it is recommended that procedures
be performed in the following sequence: 12-lead ECGs, vital signs, blood draw. Compared to Day
1, where parallel testing is mandatory, parallel (central and local lab analysis) testing is allowed at
other time points at the discretion of the local PI and Sponsor. Blood collections for antiviral
activity and PK assessments should be kept as close to the specified time as possible. Other
measurements may be done earlier/later than specified time points if needed. Actual dates and
times of assessments will be recorded in the source documentation and CRF.
The total blood volume to be collected from each HHC will not exceed 450 mL. For index cases,
the total blood volume collected will be approximately 5 mL for those <18 years old and
approximately 10 mL for those ≥18 years old.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the
samples.
A urine drug screen (including amphetamine, barbiturate, benzodiazepine, cannabinoids, cocaine,
methadone, opiates, and tricyclic antidepressants) and alcohol test may be performed throughout
the study at the discretion of the investigator.
Oral body temperature (daily and in case of feeling feverish), DENV-associated signs and
symptoms (systemic solicited AEs, including fever by oral measurement of body temperature),
AEs, and concomitant medication, whether a meal was taken prior to administration of study
intervention, and date/time of study intervention intake will be recorded by the participant in a
diary  (except for the assessments specified in Section 1.3.2.4, Discontinuation From Study
Intervention or Study, that will be collected by study site personnel) and will be added to the CRF
by study site personnel. Body temperature will only be added to the CRF in case the oral body
temperature is ≥37.5°C (99.5°F). If the participant is unable to read or write, an acceptable
representative of the participant may complete the diary (which includes reading and explaining
all written information).
Telehealth Visits
Refer to Section 6.4, Study Intervention Compliance and Schedule of Activities.
Telehealth visits (conducted via phone or video conference) may be implemented by or with
approval from the sponsor and per the clinical judgment of the investigator, where feasible and
permissible by local policy.
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How the assessments performed at each visit are collected (via on-site visit, home health care, or
telehealth visit) must be recorded in the CRF.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the CRF, laboratory requisition
form, and the source documents.
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.
Refer to the Schedule of Activities for the timing and frequency of all sample collection, and visits
to the study site:
 
For the main study:
 
Visiting the site is required on Days 1, 2, and 28. All other visits as indicated in the
Schedule of Activities may either be performed at the site or by designated study site
personnel who visits the participant at home. A time window of +/- 1 day for both site
and home visits is allowed as indicated in the Schedule of Activities, to ensure at least 2
visits per week at least 2 days apart and maximally 4  days in between blood samples.
Between on-site visits, administration of study intervention will either be at home
(including remote supervision of study interventionintake, if feasible) or participants may
come to the site. MDs need to be taken approximately at the same timepoint every day.
Follow-up visits on Days 40, 50, and 90 should take place within a window of +/- 2 days.
 
For the PK substudy:
 
Participants will remain at the site during the first 12 hours on Days 1 and 28. Visiting
the site is required on Day 2 and Day 3. All other visits (Day 29 and Day 32) may either
be performed at the site or by designated study site personnel who visits the participant
at home.
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 for JNJ-64281802 (IB JNJ64281802 2022)
 
Study protocol
 
Sample ICF
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 
Participant (paper) diary
 
Pharmacy manual/study site investigational product and procedures manual
 
Laboratory manual
 
Electronic data capture (eDC) manual
 
Contact Information page(s)
 
Any other manual, as applicable
8.1. 
Efficacy
8.1.1. 
Virology
8.1.1.1. 
Antiviral Activity
Blood sampling for DENV VL determination will be performed at the time points indicated in the
Schedule of Activities.
Antiviral activity will be assessed by measuring DENV RNA levels and DENV NS1 protein levels
in serum of the HHCs. Serum DENV RNA levels will be assessed using a validated quantitative
DENV RT-PCR assay  and serum DENV NS1 protein levels will be assessed using an
enzyme-linked immunosorbent assay (ELISA)-based assay. For a subset of samples (including but
not limited to RNA positive samples), the NS1 serum levels may be analyzed by a diagnostic assay
at the discretion of the sponsor’s virologist. Details of the assays used will be provided in the
laboratory manual.
Samples may be used by the sponsor for additional assessments analyzing the serologic and
virologic characteristics of DENV infection and antiviral activity of JNJ-64281802.
8.1.1.2. 
Viral Genome Sequencing and Dengue Virus Serotyping
Blood sampling for viral genome sequence analysis on index cases and HHCs will be performed
at the time points indicated in the Schedule of Activities. Viral sequencing will only be performed
on DENV RNA positive samples at the discretion of the sponsor’s virologist.
Sequencing of the DENV genome will be performed to monitor DENV variants. Viral genome
sequence analysis will be performed by sequencing the NS4B gene and other regions of the DENV
genome (if warranted) to characterize DENV variants associated with resistance to JNJ-64281802.
Additional exploratory virology analyses may be performed with these samples.
Samples may be used by the sponsor for additional assessments analyzing the serologic and
virologic characteristics of DENV infection and antiviral activity of JNJ-64281802.
Circulating DENV serotypes/genotypes and genetic variants among index cases and HHCs will be
assessed by RT-qPCR and DENV whole genome sequencing at the time points indicated in the
Schedule of Activities, at the discretion of the sponsor’s virologist.
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8.1.2. 
Immune Assessments
Blood samples for detection of DENV infection as measured by increase in anti-DENV antibody
levels will be performed at the time points indicated in the Schedule of Activities. The level of
anti-DENV antibodies will be measured using an ELISA-based assay. The presence of nAb against
DENV and other flaviviruses maybe determined using an assay such as micro-neutralization assay
for a subset of samples at the time points indicated in the Schedule of Activities and at the
discretion of the sponsor’s virologist. Details of the assays used will be provided in the laboratory
manual.
Samples may be used by the sponsor for additional assessments analyzing the serologic and
virologic characteristics of DENV infection and antiviral activity of JNJ-64281802.
8.2. 
Safety Assessments
Details regarding the IDMC are provided in Section 10.6.6, Committees Structure.
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.
Safety assessments will include the monitoring of AEs, physical examinations, vital signs, ECGs,
and clinical laboratory tests. In addition, DENV-associated clinical signs and symptoms will be
recorded as solicited AEs (see Section 8.3.2, Method of Detecting Adverse Events and Serious
Adverse Events).
Adverse events will be reported and followed by the investigator as specified in Section 8.3,
Adverse Events, Serious Adverse Events, and Other Safety Reporting, and Appendix 7: Adverse
Events, Serious Adverse Events, Product Quality Complaints, and Other Safety Reporting:
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.
Any clinically significant abnormalities persisting at the end of the study/early withdrawal will be
followed by the investigator until resolution (return to baseline), until a clinically stable condition
is reached, or until the participant has been deemed lost to follow-up after demonstration of due
diligence of follow-up efforts.
The study will include the following evaluations of safety and tolerability according to the time
points provided in the Schedule of Activities. Additional safety assessments may be performed at
the discretion of the investigator.
8.2.1. 
Physical Examinations
Physical examination and height and body weight measurements will be conducted.
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Physical examination includes a review of the following systems: head/neck/thyroid,
eyes/ears/nose/throat, respiratory, cardiovascular, lymph nodes, abdomen, skin, musculoskeletal,
and neurological.
To obtain the actual body weight, participants must be weighed lightly clothed and barefoot.
The height should be measured barefoot. The same weighing scale will preferably be used.
8.2.2. 
Vital Signs
Oral body temperature (in the absence of antipyretic medication or at least 4 hours after the last
intake of antipyretic medication (if applicable)), pulse/heart rate, and systolic and diastolic blood
pressure will be assessed. Vital signs are recommended to be assessed before blood draw and after
12-lead ECG.
Blood pressure and pulse/heart rate measurements will be assessed in supine position, if possible
with a completely automated device consisting of an inflatable cuff and an oscillatory detection
system. 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).
Body temperature will be recorded by the participant in a diary daily (preferably at the same time
each day) and in case of feeling feverish, and will be added to the CRF by study site personnel in
case the oral body temperature is ≥37.5°C (99.5°F).
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.
For eligibility determination, the machine-read ECG results, printed on the ECG device print-out
of the ECG tracing, will be taken into account. These ECGs need to be interpreted for clinical
significance, signed, and dated by the investigator and filed in participant's source documents.
Clinically relevant abnormalities occurring during the study should be recorded by the investigator
in the Adverse Event Section of the CRF.
Central ECG readings will be performed by a central ECG laboratory. Instructions for ECG
acquisition and ECG transmission will be described in the manual provided by the ECG laboratory.
There will be 2 ECG reports: A preliminary report and a final report.
8.2.4. 
Clinical Safety Laboratory Assessments
Blood samples for serum chemistry, hematology and coagulation, and a urine sample for other
tests will be collected as noted in Appendix 8: Clinical Laboratory Tests. The investigator must
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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.
8.2.5. 
Pregnancy Testing
All women must have a negative highly sensitive urine pregnancy test at screening and on Days
28 and 50. A pregnancy test will also be performed during the withdrawal visit. Additional serum
or urine pregnancy tests may also 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.
8.3. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting
Timely, accurate, and complete reporting and analysis of safety information, including AEs, SAEs,
and product quality complaint (PQC), 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. Adverse events
and concomitant medication will be recorded by the participant in a diary, except in case of
discontinuation of study intervention or study (see Section 1.3.2.4) where they will be collected
by study site personnel.
For further details on AEs, SAEs, and PQC refer to Appendix 7: Adverse Events, Serious Adverse
Events, Product Quality Complaints, and Other Safety Reporting: 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 AEs and special 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, or until the participant has been
deemed lost to follow-up after demonstration of due diligence of follow-up efforts.
For any ≥Grade 3 unsolicited AE, whether serious or non-serious, the investigator will as soon as
possible assess the possible relationship to study intervention. If the investigator considers the
≥Grade 3 unsolicited AE to be related to study intervention, the investigator will notify the
sponsor’s medical monitor (or designee) immediately and no later than 24 hours after becoming
aware ofthe AE.
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Serious Adverse Events
All SAEs occurring during the study must be reported to the appropriate sponsor contact person
by study site personnel immediately, but no later than 24 hours of their knowledge of the event.
Serious adverse events, including those spontaneously reported to the investigator within 30 days
after the last dose of study intervention, must be reported. The sponsor will evaluate any safety
information that is spontaneously reported by an investigator beyond the time frame specified in
the protocol.
Information regarding SAEs 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 an SAE should be transmitted electronically or by facsimile (fax). Telephone reporting
should be the exception and the reporter should be asked to complete the appropriate form(s) first.
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events
Care will be taken not to introduce bias when detecting AEs or SAEs. Open-ended and nonleading
verbal questioning of the participant is the preferred method to inquire about AE occurrence.
Solicited Adverse Events
Solicited AEs are predefined events for which the participant is specifically questioned. Signs and
symptoms of DENV infection (DENV-infection associated AEs) will be collected by the
investigator or designee as solicited AEs (Table 3). DENV-associated signs and symptoms
(systemic solicited AEs) will be recorded daily by the participant in a diary. In case a particular
systemic solicited AE was not observed at time of recording but occurs later that day, the
participant should record this. In case the systemic solicited AE is fever, oral body temperature
should also be recorded. For oral measurement of body temperature at home to assess fever,
participants will be provided with a thermometer.
All AEs are evaluated using the gradings presented in Table 4, the modified DAIDS Table for
Grading the Severity of Adult and Pediatric Adverse Events supplemented with WHO toxicity
grading scales in Section 10.9 , or the rash management protocol in Section 10.2.
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Table 3: 
Solicited Adverse Events
Systemic Reactogenicity
- Retro-orbital pain a
- Abdominal pain a
- Arthralgia a
- Fever b
- Headache b
- Nausea b
- Fatigue b
- Myalgia b
- Loss of appetite a
- Vomiting b
- Diarrhea b
- Rash c
a. Grading according to Table 4.
b. Grading according to the modified DAIDS Table for Grading the Severity of Adult and Pediatric Adverse
Events supplemented with WHO toxicity grading scales in Section 10.9.
c. Grading according to the rash management protocol in Section 10.2.
Table 4: 
Grading of Solicited Adverse Events
Reaction to 
Intervention 
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 
(eg inadequate oral 
caloric intake and/or
fluid intake); tube
feeding or total
parenteral nutrition
indicated
Life-threatening
consequences; urgent
intervention
indicated
Unsolicited Adverse Events
Unsolicited AEs are all AEs for which the participant is not specifically questioned.
8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events
The investigator is obligated to perform or arrange for the conduct of supplemental measurements
and evaluations as medically indicated to elucidate the nature and causality of the AE, SAE, or
PQC as fully as possible. This may include additional laboratory tests or investigations,
histopathological examinations, or consultation with other health care professionals.
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Adverse events and the special reporting situation of pregnancy will be followed by the
investigator as specified in Appendix 7: Adverse Events, Serious Adverse Events, Product Quality
Complaints, and Other Safety Reporting: 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 AEs 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 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 SAEs andmust be reported using an SAE reporting form.Any participant who becomes
pregnant during the study must be promptly withdrawn from study intervention but can continue
to participate in the follow-up period.
Follow-up information regarding the outcome of the pregnancy  for female participants who
become pregnant, or where the pregnancy was the result of male participant and his partner, will
be required.
8.3.6. 
Disease-related Events and Disease-related Outcomes Not Qualifying
as Adverse Events or Serious Adverse Events
All events that meet the definition of an SAE will be reported as SAEs, regardless of whether they
are protocol-specific assessments.
The cause of death of a participant in a study, whether or not the event is expected or associated
with the study intervention, is considered an SAE.
8.4. 
Pharmacokinetics
Venous blood samples will be used to evaluate the PK ofJNJ-64281802. Plasma collected for PK
may additionally be used to evaluate safety or antiviral activity aspects that address concerns
arising during or after the study period. Samples may also be used for the analysis of metabolites
of JNJ-64281802 or endogenous markers for enzymes or transporters involved in the metabolism
and distribution of JNJ-64281802, at the discretion of the sponsor. Genetic analyses will not be
performed on these samples. Participant confidentiality will be maintained.
See also Section 8.9, Pharmacokinetic Substudy.
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8.4.1. 
Evaluations
Venous blood samples will be collected for measurement of plasma concentrations of
JNJ-64281802.
Samples collected for analyses of JNJ-64281802 plasma concentration may additionally be used
to evaluate safety or antiviral activityaspects that address concerns arising during or after the study
period or for the evaluation of relevant biomarkers. Genetic analyses will not be performed on
these plasma samples. Participant confidentiality will be maintained. Additional information about
the collection, handling, and shipment of biologic samples can be found in the laboratory manual.
8.4.2. 
Analytical Procedures
Pharmacokinetics
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 assigned to placebo (except for samples taken predose
on Day 1) will not be analyzed unless unexpected results should occur. All plasma PK samples
from participants receiving JNJ-64281802 will be analyzed for JNJ-64281802 concentrations.
To allow selection of samples, the bioanalytical laboratory will receive randomization lists per
study intervention. 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.
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.
8.4.3. 
Pharmacokinetic Parameters and Evaluations
Parameters
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 can be derived using
population PK modeling:
 
AUCτ (if data allow)
 
Ctrough, and
 
Cmax (if data allow).
Pharmacokinetic/Pharmacodynamic Evaluations
Pharmacokinetic-pharmacodynamic evaluations may be performed to evaluate the relationship
between the PK and the antiviral activity of JNJ-64281802 and clinical outcome, as data allow. In
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addition, the relationship between the PK and selected safety endpoints may be explored, as data
allow and at the discretion of the sponsor.
8.5. 
Pharmacogenomics
A pharmacogenomic blood sample will be collected from participants who consent separately to
this component of the study to allow for pharmacogenomic research, as necessary (where local
regulations permit).
Participant participation in pharmacogenomic research is optional.
Optional blood samples for pharmacogenomic (DNA) research maybe collected, preferably before
the first dose of study intervention. If necessary, the sample may be collected at a later time point
without constituting a protocol deviation. This DNA sample can be used to investigate the potential
association of host genetic factors with PK, antiviral activity, safety of JNJ-64281802, the DENV
infection or dengue disease, or may be used to develop tests/assays related to JNJ-64281802 or
DENV infection.
These analyses may be conducted under the supervision of the sponsor and may be reported
separately from the main study report.
8.6. 
Biomarkers
Blood samples for exploratory analysis of biomarkers will be obtained at the time points indicated
in the Schedule of Activities. These samples may be assessed for serum proteins, humoral
immunity profiling, RNA expression profiling, immune cell components, proteomics,
metabolomics, or microbiome. Samples can only be used for research related to JNJ-64281802,
DENV infection, or dengue disease, or may be used to develop tests/assays related to JNJ-
64281802 or DENV infection. Results may be reported separately from the Clinical Study Report.
8.7. 
Other Virology Assessments
8.7.1. 
NS1 Test and RT-PCR/anti-DENV IgM test of Index Cases
An acute DENV infection of the index case will be assessed at the local laboratory or site by the
detection of the NS1 protein using a diagnostic NS1 test. If a DENV NS1 test is unavailable, a
DENV RT-PCR or anti-DENV IgM test can be used. Detection of DENV RNA will be confirmed
by RT-qPCR at the central laboratory. If anti-DENV IgM and IgG antibodies are included in the
NS1 test, these data should be captured.
8.8. 
Health Economics
Health Economics/Medical Resource Utilization and Health Economics parameters are not
evaluated in this study.
8.9. 
Pharmacokinetic Substudy
In a PK substudy, rich serial PK blood sampling for the measurement of plasma concentrations of
JNJ-64281802 will be performed. This substudy will be conducted at selected study sites in
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30-40 participants who will be evenly distributed (1:1:1 ratio) over HDR, LDR, and placebo
regimen (see Section 4.1, Overall Design).
At selected study sites participating in the PK substudy, the ICF will contain a separate section
explaining the substudy and separate consent will be given for this substudy.
Participants included in the PK substudy will also undergo all assessments in the main study.
Participants in the substudy will undergo rich serial PK sampling as indicated in Section 1.3.2.5.
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 efficacy and safety data are outlined
below. Specific details will be provided in the Statistical Analysis Plan (SAP).
9.1. 
Statistical Hypotheses
The primary hypothesis of this study is that JNJ-64281802 is superior to placebo with respect to
prevention of laboratory-confirmed DENV infection between baseline and the last day of dosing
in study participants who are DENV RNA  and NS1 protein negative at baseline.
Laboratory-confirmed DENV infection is defined as a positive DENV RNA orDENV NS1 protein
(ELISA) test result.
9.2. 
Sample Size Determination
The study has an event-driven design where study recruitment will continue until the required
number of events is reached. Unless stopped for futility at the IA, the study will continue till
36 DENV infections are observed between baseline and the last day of dosing in the primary study
population and 24 symptomatic DENV infections are observed between baseline and the last day
of dosing in the complete study population (see Section 9.3, Populations for Analysis Sets). Both
conditions need to be satisfied before recruitment is considered complete.
The targets of 36 DENV infection events in the primary study population and 24 symptomatic
DENV in the complete study population were selected to ensure at least 80% power forthe primary
and key secondary analyses for the HDR assuming a 75% prophylactic efficacy against DENV
infection in the primary study population (using a 2.5% one-sided significance level) and
72.5% prophylactic efficacy against symptomatic DENV infection in the complete study
population (using a 20% one-sided significance level). These targets and resulting sample size
were estimated through Monte Carlo simulation. More details of the sample size calculations,
including sample size simulation programs, will be provided in the SAP and a separate Modeling
and Simulation report.
As a consequence of the event-driven design of the study, the study has no fixed sample size.
However, the planned recruitment total is estimated based on the following information:
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9.3. 
Populations for Analysis Sets
For purposes of analysis, the following populations are defined:
Population 
Description
Enrolled 
All participants (index cases and HHCs) who signed the ICF.
Index Case 
population
All participants enrolled as an index case, with a laboratory-confirmed DENV infection.
Randomized 
All participants (HHCs) who are randomized in the study.
Safety  
All randomized participants who received at least one dose of study intervention.
This population will be used for the safety analysis.
Primary study 
population  
All randomized participants who received at least one dose of study intervention and who had
no evidence of current DENV infection (based on negative results for DENV RNA and NS1
protein assays) at baseline.
This population will be used for the primary, secondary, and exploratory efficacy analyses.
Secondary study 
population  
All randomized participants who received at least one dose of study intervention, who had
evidence of current DENV infection (based on positive results for DENV RNA or NS1
protein assays) but without DENV signs and symptoms at baseline.
This population will be used to evaluate the exploratory objective of an antiviral effect of
JNJ-64281802 as early treatment.
Complete study 
population  
All randomized participants who received at least one dose of study intervention and without
DENV signs and symptoms at baseline.
This population will be used to investigate the key secondary endpoint of the effect of
JNJ-64281802 on the prevention of symptomatic DENV infection.
PK 
All participants who received at least one dose of study intervention and who have at least
one plasma concentration data value after dosing.
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Population 
Description
This population will be used to the assess the PK and the relationship between PK and the
antiviral activity of JNJ-64281802.
DENV = dengue virus; HHC = household contact; ICF = informed consent/assent form; PCR = polymerase chain
reaction; PK = pharmacokinetic(s).
9.4. 
Statistical Analyses
The SAP 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.
9.4.1. 
General Considerations
The study has an event-driven design where study recruitment will continue until the required
number of events is reached. The study consists of 2 stages with an IA after Stage 1 and a FA after
Stage 2 (ie, the end of the study). The objective of Stage 1 is to obtain  PoC  for the primary
hypothesis. The objectives of Stage 2 are to select the dose for future development and to confirm
superiority of the selected dose above placebo.
The IA will be scheduled when 24 laboratory-confirmed DENV infections are observed between
the baseline and the last day of dosing in the primary analysis population. Based on the results
from the IA and other available information, the LDR can be dropped in Stage 2.
The IA will be performed by an independent statistical support group and will be reviewed by the
IDMC who will receive unblinded safety and efficacy data (see Section 10.6.6, Committees
Structure). After the review, the IDMC will make recommendations to the Sponsor Committee
regarding the continuation of the study. Refer to Section 9.5, Interim Analysis for more
information on the planned IA.
Unless stopped for futility at the IA, the study will continue till 36 DENV infections are observed
between baseline and the last day of dosing in the primary study population and 24 symptomatic
DENV infections are observed between baseline and the last day of dosing in the complete study
population (see Section 9.2, Sample Size Determination). Both conditions need to be satisfied
before recruitment is considered complete.
All demographic characteristics (eg, age, race, ethnicity, height, body weight, BMI) and other
initial participant characteristics (eg, medical and surgical history, concomitant diseases) will be
tabulated and analyzed descriptively for the index case population (when applicable), the safety
population, the primary, secondary, and the complete study populations.
Descriptive statistics will be provided for the disease characteristics of the index case population.
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9.4.2. 
Primary Endpoint(s)
Definition
The primary endpoint is defined as the presence or absence of a laboratory-confirmed DENV
infection between baseline and the last day of dosing. Laboratory-confirmed DENV infection is
defined as a positive DENV RNA or DENV NS1 protein (ELISA) test result. Missing results
between baseline and last day of dosing will not be considered for the primary endpoint.
Estimand
The primary estimand attributes are as follows.
Population
Healthy HHCs, aged 16 or 18 (depending on the legal age of consent in the jurisdiction in which
the study is taking place) to 65 years inclusive, who have negative results for DENV RNA and
NS1 protein assay at baseline. HHCs for which only one of both assays is available will be included
on condition that this assay has a negative result.
Interventions
Participants will receive a high- or low-dose JNJ-64281802 regimen, or matching placebo in a
double-dummy fashion under fed conditions (see Table 2).
Intercurrent Events
 
Fasted intake of study intervention.
 
Prohibited medication.
 
Missed doses and treatment discontinuation: Missing a LD, 2 consecutive MDs, or
2 nonconsecutive MDs within a week.
These intercurrent events will be handled using a "treatment policy strategy" (ie, data will be used
as observed).
Population-level Summary
Calculated prophylactic efficacy (=1 - odds ratio ≈1-relative risk rate).
Primary Estimator
The primary hypothesis of this study is that JNJ-64281802 is superior to placebo with respect to
prevention of laboratory-confirmed DENV infection between baseline and last day of dosing.
The primary hypothesis will be evaluated based on the comparison between intervention groups
using CIs, estimates, and p-values obtained from an exact logistic regression model with
intervention group and the stratification factor (country) included as independent variables. The
odds-ratio from the logistic regression model will be used to estimate the prophylactic efficacy.
Given the expected low incidence, this is expected to be similar to the prophylactic efficacy
estimated using the relative risk. The calculated prophylactic efficacy(= 1 - odds ratio ≈1 - relative
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risk rate) will be used as the population-level summary. For the PoC stage (Stage 1), the superiority
of JNJ-64281802 above placebo will be tested at 20% one-sided significance level. In the
confirmatory stage (Stage 2) a 2.5% one-sided significance level will be used. The individual
2-sided CIs (2 x one-sided significance level) for the prophylactic efficacy will be calculated from
the regression model described above. This is the primary efficacy analysis. As a secondary
estimator, the Mantel-Haenszel stratum-weighted estimator of the risk difference, adjusted for the
stratification factor (country) will be calculated together with the associated CIs.
At the IA, the HDR and LDR will be tested hierarchically: First the HDR will be tested and if PoC
is reached for the HDR, the LDR will be tested. Based on these results and other available
information (refer to Section 9.5, Interim Analysis), the LDR can be dropped in Stage 2.
At the FA, the primary objective will be assessed using the following hierarchical hypothesis
testing approach:
1. In the first step, the HDR will be compared with placebo.
2. If the LDR is not dropped at the IA and a significant reduction in laboratory-confirmed DENV
infections is established for the HDR, the LDR will be compared with placebo with regards
to the primary endpoint.
Sensitivity Estimators
Sensitivity estimators will be calculated as follows:
 
Handling the intercurrent events in a ‘while on treatment strategy’: Only laboratory
assessments prior to the occurrence of the intercurrent events are considered.
 
Restricting the population to the HHCs who completed treatment up to Day 28.
 
Early dropout and intermediate missing values: Fitting an exact Poisson regression with the
event rate, defined as the number of cases over the number of samples (offset) as dependent
variable and the intervention group and country as independent variables. For cases, the
number of samples is defined as the number of samples between start of study intervention
and the occurrence of the first event (first laboratory-confirmation of the DENV infection),
for non-cases, it is the number of samples between start of study intervention and the last
available sample before or at the last day with study intervention. Thus, all participants are
included in the analysis according to their number of available samples.
9.4.3. 
Key Secondary Endpoint
The key secondary endpoint is defined as presence or absence of laboratory-confirmed
symptomatic DENV infection between baseline and last day of dosing. Laboratory-confirmed
symptomatic DENV infection is defined as having at least 2 solicited systemic AEs (see Table 3),
of which at least one is a most common dengue symptom (ie, fever, headache/retro-orbital pain,
myalgia, arthralgia, rash), lasting for ≥1 day and occurring within a +/-2-day window around the
positive PCR or NS1 test, between baseline and the last day of dosing.
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The key secondary objective will only be assessed at the FA if a significant reduction in the number
of laboratory-confirmed DENV infections in the primary study population is established for the
HDR. The key secondary objective will be assessed by estimating the prophylactic efficacy of the
intervention group(s) in preventing laboratory-confirmed symptomatic DENV infection in the
complete study population together with the 80% one-sided lower confidence limit for this
prophylactic efficacy. Depending on the result of the primary analysis for the LDR, the key
secondary objective will be assessed by:
1. Comparing the pooled number of events on the HDR and LDR with the placebo regimen, if
both active intervention groups showed a significant effect in the primary study analysis
population.
2. Comparing the number of events on the HDR with the placebo regimen, if only the HDR
showed a significant effect in the primary study analysis population.
Laboratory-confirmed symptomatic DENV infections will be analyzed similarly as the primary
endpoint with the model adjusted for DENV infection at baseline as well.
9.4.4. 
Secondary Endpoint(s)
All secondary endpoints will be analyzed graphically and descriptively as described in the SAP.
For continuous variables, descriptive statistics (n, mean, SD, median, minimum, maximum, and
95% CIs) will be calculated. For categorical variables, frequency tables and corresponding 95%
CIs will be presented.
9.4.4.1. 
Safety Analyses
All safety analyses will be made on the safety population. Participants in this population will be
defined by the study intervention actually received, not by randomization assignment.
Adverse Events
The verbatim terms used in the CRF  by investigators to identify AEs 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 last day of study participation is considered to be
treatment-emergent. All reported AEs will be included in the analysis. For each AE, the percentage
of participants who experience at least 1 occurrence of the given event will be summarized by
intervention group. All AEs will be analyzed descriptively.
Summaries, listings, datasets, or participant narratives may be provided, as appropriate, for those
participants who die, who discontinue intervention due to an AE, who experience a severe or a
serious AE, or who experience rashes requiring rash-management procedures (Section 10.2).
Solicited AEs will be summarized by intervention group. The number and percentages of
participants with at least one solicited AE will be presented. The frequencies by intervention group,
as well as frequencies according to severity will be described for solicited AEs. Frequencies of
unsolicited AEs will be presented by system organ class and preferred term, while those of solicited
AEs will be presented only by preferred term.
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All AEs are evaluated using the gradings presented in Table 4, the modified DAIDS Table for
Grading the Severity of Adult and Pediatric Adverse Events supplemented with WHO toxicity
grading scales in Section 10.9 , or the rash management protocol in Section 10.2.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Frequency tabulations of the
laboratory abnormalities will be made either by grading according to the modified DAIDS Table
for Grading the Severity of Adult and Pediatric Adverse Events supplemented with WHO toxicity
grading scales (Section 10.9), or with classes for below, within, and above normal ranges for
parameters that are not graded for either DAIDS and WHO grading scales. 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 (Grade 3 or Grade 4) will also be provided.
Electrocardiogram
Electrocardiogram data will be summarized by ECG parameter. The ECG variables that will be
analyzed are heart rate, PR interval, QRS interval, QT interval, and QTc interval using the
following correction methods: QTc according to Bazett's formula (QTcB) and QTcF (Bazett 1920,
Fridericia 1920, Hodges 1983, ICH guidelines 2005).
Descriptive statistics of QTc intervals and changes from baseline will be summarized at each
scheduled time point. The percentage of participants with QTc interval >450 milliseconds,
>480 milliseconds, or >500 milliseconds will be summarized, as will the percentage of participants
with QTc interval increases from baseline >30 milliseconds or >60 milliseconds. The last observed
ECG prior to the first study intervention administration will be used as baseline.
All clinically relevant abnormalities in ECG waveform that are changes from the baseline readings
will be reported (eg, changes in T-wave morphology or the occurrence of U-waves).
For the safety substudy, ECGs will be analyzed similarly to ECG statistical analysis as described
above.
Vital Signs
Vital signs including pulse/heart rate and systolic and diastolic blood pressure (supine) 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.
9.4.4.2. 
Pharmacokinetic Analyses
The JNJ-64281802 plasma PK samples taken from all participants in the study (see Section 1.3.2.2
to Section 1.3.2.4), as well as the rich serial PK samples collected in the PK substudy
(Section 1.3.2.5) can be used for population PK model development and/or population PK model
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update using nonlinear mixed-effects modeling. The PK samples taken from participants in the
rich serial PK substudy will also be analyzed by noncompartmental PK analysis as specified below.
Population PK modeling can be used to describe the concentration-time profiles and estimate the
exposure parameters (AUCτ, Ctrough, and Cmax, if data allow) of JNJ-64281802. Available baseline
participant characteristics (demographics, body weight, laboratory variables, genotype, etc) may
be explored as potential covariates affecting PK parameters of JNJ-64281802. 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 population PK report. For operational reasons, a snapshot date for PK
samples to be analyzed will be defined, if required. Samples collected before this date will be
analyzed for JNJ-64281802 and included in the population PK analysis. Samples collected after
the snapshot date will be analyzed at a later date and may be included in a population PK
re-analysis when they become available after database lock.
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 an
SAE.
Pharmacokinetic Substudy Analyses
For the intensive PK samples of the rich PK substudy, noncompartmental PK analysis of
JNJ-64281802 will be performed using actual sampling time and plasma concentrations obtained
from rich serial PK blood sampling for 30-40 participants. Descriptive statistics will be provided
for the PK parameters (Ctrough, Cmax, tmax, Cmin, and AUCτ) derived, including graphical analyses of
the data. Results will be presented in a separate PK report.
9.4.4.3. 
Pharmacokinetic/Pharmacodynamic Analyses
Relationships of PK parameters for JNJ-64281802 with selected antiviral activity, clinical
outcome, and safety endpoints may be evaluated, applying graphical tools and, if feasible,
statistical models, as data allow. If conducted, details of the analysis will be provided in a separate
analysis plan and results will be presented in a separate report.
9.4.5. 
Exploratory Endpoint(s)
The statistical analysis of the exploratory endpoints will be described in the SAP.
9.4.6. 
Other Analyses
An IDMC will be established as noted in Section 10.6.6, Committees Structure.
Viral Genome Sequence Analyses
DENV viral genome sequence analysis will be performed to evaluate the presence of
polymorphisms and genetic variations on the amino acid level and to define the serotype/genotype
of the DENV virus.
Sequencing is focused on a predefined list of positions of interest. Data will be described in the
CSR or in a separate virology report.
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Samples for viral sequencing are taken throughout the study as shown in the Schedule of Activities,
but sequencing is triggered at the discretion of the virologist considering the DENV VL levels and
the limitations of the sequencing assay.
Polymorphisms, ie, genetic variations, are defined as amino acid changes from serotype-specific
DENV reference sequences.
Wild type: If at certain position the amino acid in the participant sequence matches the reference
sequence, that is no genetic variation is present at that position, the virus is considered to be wild
type at that position.
Number (%) of participants with a specific substitution and number (%) of participants with a
specific DENV serotype/genotype will be analyzed.
Frequencies and percentages will be presented for the specified parameters. The denominator is
the number of participants with sequencing data. Summaries will be provided by subgroup and
intervention group.
Pharmacogenomic Analyses
The statistical approach for analyzing 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 and will always be under the
supervision of the sponsor. Results will be presented in the main study report or a separate report.
DNA samples may  be used for pharmacogenomic analyses. Host genetic analyses may be
conducted if it is hypothesized that this may help resolve issues with the clinical data, and for
research related to JNJ-64281802 and comedications, if applicable, or dengue infection or dengue
disease. They may also be used to develop tests/assays related to JNJ-64281802 and comedications
in the protocol, if applicable, and dengue infection. Pharmacogenomic research may consist of the
analysis of one or more candidate genes or of the analysis of genetic markers throughout the
genome (as appropriate) in relation to JNJ-64281802 and comedications, if applicable, or dengue
clinical endpoints.
Results will be presented in the main study report or a separate report.
Biomarker 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 and will always be under the supervision of the sponsor. Results will be presented in the
main study report or a separate report.
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9.5. 
Interim Analysis
The SAP will describe the planned IA in greater detail.
The IA will be performed at a predetermined analysis time point. This time point is defined when
24 laboratory  -confirmed DENV infections (see Section 9.4.1, General Considerations) are
detected between baseline and the last day of dosing in the primary study population as defined in
Section 9.3, Populations for Analysis Sets.
The IA will be performed by an independent statistical support group and will be reviewed by the
IDMC who will receive unblinded safety and efficacy data (see Section 10.6.6, Committees
Structure). After the review, the IDMC will make recommendations to the Sponsor Committee
regarding the continuation of the study (see below for details). A Sponsor Committee, consisting
of senior sponsor personnel not involved in the conduct of the study, will be established and will
be responsible for decision making, considering the IDMC recommendation. An IDMC charter
will be prepared before start of the study with more details on the IDMC and Sponsor Committee
composition and organization.
Unblinded exposure response analyses will be performed by independent sponsor
pharmacometricians using data available based on a predefined snapshot date at the IA, with
adequate firewalls so the study team will remain blinded.
The aim of the IA at the end of Stage 1 is to assess PoC of the HDR and LDR for the primary
objective. In this analysis, PoC is defined as a statistically significant reduction in the number of
laboratory-confirmed DENV infections on active prophylactic dosing compared with placebo at
the 20% one-sided significance level. The HDR and LDR will be tested hierarchically: First the
HDR will be tested and if PoC is reached for the HDR, the LDR will be tested. Based on these
results, the IDMC can advise to:
 
Stop the study for futility, or
 
Drop the LDR and continue the study with the placebo regimen and the HDR, or
 
Continue the study with both active intervention groups (HDR and LDR) and placebo.
If the study continues, the IDMC may advise to open study recruitment to adolescent HHCs via
protocol amendment.
The IDMC advice will be based on the following decision rule:
 
If PoC is not reached for the HDR, the IDMC can advise to stop the study.
 
If PoC is reached for the HDR but not for the LDR, the IDMC can advise to continue the
study with only the HDR and placebo regimen and drop the LDR from the study.
 
If PoC is reached for both HDR and LDR, the IDMC can advise to continue the study with
both active intervention groups and placebo.
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However, this rule is non-binding and based on a full review of all safety, efficacy, and
exposure -response data available for the current study. In addition, data from other studies
(eg, human challenge) may be available to guide the decision.
As the study design only allows for futility assessment at the IA, no multiplicity correction will be
performed for the IA. In addition, the impact of potentially dropping the LDR at the IA on the
comparison of the HDR with the placebo regimen at the FA was assessed through analytical
derivation of the Type I error rate. This analysis showed the Type I error was well controlled
(Type I error rate <2.5%).
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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Abbreviations
ABV  
alcohol-by-volume
AE 
adverse event
AIH  
autoimmune hepatitis
ALP  
alkaline phosphatase
ALT  
alanine aminotransferase
APTT  
activated partial thromboplastin time
AST  
aspartate aminotransferase
BCRP  
breast cancer resistance protein
BMI 
body mass index
BUN  
blood urea nitrogen
CFR  
Code of Federal Regulations
CI 
confidence interval
COVID-19 
Coronavirus Disease 2019
CPK  
creatine (phospho)kinase
CRF  
case report form
CV  
coefficient of variation
CYD-TDV  
chimeric yellow fever –dengue virus tetravalent dengue vaccine
CYP  
cytochrome P450
DAIDS  
Division of Acquired Immunodeficiency Syndrome
DENV  
dengue virus
DHF  
dengue hemorrhagic fever
DMID  
Division of Microbiology and Infectious Diseases
DNA  
deoxyribonucleic acid
DSS  
dengue shock syndrome
EC50 
50% effective concentration
ECG  
electrocardiogram
eDC  
electronic Data Capture
eGFP  
enhanced green fluorescent protein
ELISA  
enzyme-linked immunosorbent assay
FA 
final analysis
Fc 
crystallizable fragment
FDA  
Food and Drug Administration
FIH  
first-in-human
GCP  
Good Clinical Practice
GGT  
gamma-glutamyltransferase
GLDH  
glutamate dehydrogenase
HCC  
health care center
HCP  
health care provider
HDR  
high-dose JNJ-64281802 regimen
HHC  
household contact
 
HRT  
hormonal replacement therapy
IA  
interim analysis
IB  
Investigator’s Brochure
IC50 
50% inhibitory concentration
ICF  
informed consent(/assent) form
ICH  
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for
Human Use
ICMJE  
International Committee of Medical Journal Editors
IDMC  
Independent Data Monitoring Committee
IEC  
Independent Ethics Committee
Ig 
immunoglobulin
IMP  
investigational medicinal product
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INR  
international normalized ratio
IRB  
Institutional Review Board
IUD  
intrauterine device
IUS  
intrauterine hormone-releasing system
IWRS  
interactive web response system
LAM  
lactational amenorrhea method
LC-MS/MS 
liquid chromatography-mass spectrometry/mass spectrometry
LD  
loading dose
LDH  
lactate dehydrogenase
LDR  
low-dose JNJ-64281802 regimen
LDL 
low density lipoprotein
LLN  
lower limit of laboratory normal range
MD  
maintenance dose
MDR1 
multidrug resistance protein 1
MedDRA  
Medical Dictionary for Regulatory Activities
nAb 
neutralizing antibody
NOAEL 
no observed adverse effect level
NS  
nonstructural protein
NSAID  
nonsteroidal anti-inflammatory drug
PCC  
protocol clarification communication
PCR  
polymerase chain reaction
PEG400 
polyethylene glycol 400
PI 
principal investigator
PK 
pharmacokinetic(s)
PoC 
proof-of-concept
PQC  
product quality complaint
PT  
prothrombin time
PTT  
partial thromboplastin time
QTc 
QT corrected for heart rate
QTcB  
QT corrected for heart rate according to Bazett's formula
QTcF  
QT corrected for heart rate according to Fridericia's formula
RBC  
red blood cell
RNA  
ribonucleic acid
RT-qPCR  
quantitative reverse transcription polymerase chain reaction
SAE  
serious adverse event
SAP  
Statistical Analysis Plan
SD 
standard deviation
SUSAR  
suspected unexpected serious adverse reaction
TOC  
table of content
UGT  
uridine diphosphate-glucuronosyltransferase
ULN  
upper limit of laboratory normal range
US  
United States
USA  
United States of America
USP  
United States Pharmacopeia
VKM  
viral kinetic model
WBC  
white blood cell
WHO  
World Health Organization
VL 
viral load
Definitions of Terms
AUC0-24h  
area under the plasma concentration-time curve from 0 to 24 hours
AUC0-∞ 
area under the plasma concentration-time curve from 0 hours to infinity
AUCτ 
area under the concentration curve during one dosing interval
Cmax  
maximum plasma concentration
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Ctrough  
observed analyte concentration just prior to the beginning or at the end of a dosing interval
t1/2 
elimination half-life
tmax  
time to maximum concentration
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10.2. Appendix 2: Rash Management
Dengue symptomatic infection is known to result in skin rashes in most patients. Rashes may
potentially also be related to the study intervention, and it may not be possible to differentiate
between a rash secondary to DENV infection and one related to the study intervention. In all cases
of rash that are not related to DENV infection, the below rash management should be followed.
In case a causal relationship between the rash and the study intervention 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.
If a causal relationship between the rash and the study intervention cannot be excluded, safety
blood samples need to be taken during the (unscheduled) visits as described below. The following
parameters need to be tested: aspartate aminotransferase (AST), ALT, creatinine, erythrocyte
sedimentation rate, and a complete blood cell count (including hemoglobin, hematocrit, red blood
cell [RBC] count, white blood cell [WBC] count, neutrophils, lymphocytes, monocytes,
eosinophils, basophils, and platelet count).
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.
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. The skin
reaction should be evaluated at the study site the same day (if possible) or the next day.
Participants should be advised to contact the investigator immediately if there is any
worsening of the rash, if any systemic signs or symptoms appear, or if mucosal involvement
develops.
Grading of rash events will be based on the Division of Acquired Immunodeficiency Syndrome
(DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS 2017).
Monitoring of the evolution of rash events will be performed as described in Table 5 below.
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Table 5: 
Management of Rash Events by Severity Grade
Definition 
Study  
Intervention 
Action 
Activities by Day  
a
Referral to Dermatologist
and  Dermatology
Activities
Grade 1 
rashb 
Localized rash that 
is easily tolerated 
and/or may require 
one dose of 
medication. 
Study intervention 
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 laboratory assessments 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 and 7: 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 CRF should be completed.
Not required
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Definition 
Study
Intervention
Action
Activities by Daya
Referral to Dermatologist
and  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 intervention
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 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 CRF should be completed
Not required
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Definition 
Study
Intervention
Action
Activities by Daya
Referral to Dermatologist
and  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
oral body
temperature
≥39.3°C to <40.0°C
(≥102.7°F to
<104.0°F),
OR
eosinophils
>1,000/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: Regardlessof 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 CRF should be completed.
Requiredc
Biopsy required within
24 hours after onset of
rash.
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Definition 
Study
Intervention
Action
Activities by Daya
Referral to Dermatologist
and  Dermatology
Activities
Grade 4
rashb
Potentially 
life-threatening rash 
with: 
Extensive or 
generalized bullous 
lesions, 
OR 
ulceration of
mucous membrane
involving 2 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: Regardlessof 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 CRF should be completed.
Requiredc
Biopsy required within
24 hours after onset of
rash.
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Definition 
Study  
Intervention 
Action 
Activities by Day  
a
Referral to Dermatologist
and  Dermatology
Activities
AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CRF = case report form; IDMC = Independent Data Monitoring
Committee; ULN = upper limit of normal.
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 at the study site and on the sponsor’s secure server. Only the sponsor team members and the IDMC members will
have access to the sponsor’s secure server.
Per investigator’s discretion, the participant may be treated symptomatically until the rash resolves.
a. Day0 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.
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10.4. Appendix 4: COVID-19 Appendix
Guidance on Study Conduct During the COVID-19 Pandemic
It is recognized that the 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; travel
restrictions/limited access to public places, including hospitals; study site personnel being
reassigned to critical tasks.
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 or the clinical judgment 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 efficacy endpoint assessments
should be performed if required and as feasible. Participants will also be questioned regarding
general health status to fulfill any physical examination requirement.
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 COVID-19 Appendix after consultation with the participant, investigator, and the
sponsor. Missed assessments/visits will be captured in the clinical trial management system for
protocol deviations. Discontinuations of study interventions and withdrawal from the study should
be documented with the prefix “COVID-19-related” in the CRF.
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 health authorities according to local guidance.
If a participant has tested positive for COVID-19, the investigator should contact the sponsor’s
responsible medical officer 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.
Guidance Specific to This Protocol
The following emergency provisions are meant to ensure participant and staff safety while site
capabilities are compromised by COVID-19-related restrictions. Remote medical consultation and
alternatives to clinical laboratory assessments and study intervention administration may allow
continued study participation for participants in this study.
As local restrictions are lifted and the acute phase of the COVID-19 pandemic resolves, sites
should revert to the original protocol conduct as soon as feasible and in accordance with any
country-specific regulatory requirements.
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Study Visits and Procedures
 
In case visits to the study site are not possible, mitigations include; remote (eg, by
phone/telemedicine) visits and referral of participants to health care services for safety
evaluation, if deemed necessary.
 
In case assessments cannot be performed per protocol at the study site, alternatives may be
possible after discussion and agreement with the sponsor.
 
If certain assessments cannot be performed or are to be performed differently, this is to
be documented in the source documents and the (electronic) CRF.
 
There are some assessments that could be conducted remotely via telephone (or
videoconference). This methodology can only be used in accordance with applicable
(including local) laws, regulations, guidance, and procedures. These remote assessments
include review of AEs, concomitant therapy, and questions regarding general health
status to fulfill any physical examination requirement.
 
All visits/assessments need to be performed by trained and delegated site staff.
 
Other procedures, eg, imaging, may be conducted at an appropriate facility.
Administration of Study Intervention
Procurement of study intervention by participants (or designee) or shipment of study intervention
from the study site directly to participants for at-home administration (including the potential for
self-administration of study intervention) could be a possible mitigation.
Exposure to Coronavirus/Development of COVID-19
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
laboratory test kits, eg, a diagnostic kit using RT-qPCR. This should be reported to the local health
authorities as required.
In addition, the investigator needs to evaluate and discuss with the sponsor’s Medical Monitor
whether enrollment of a participant with acute COVID-19 infection is in line with the eligibility
criteria and whether enrollment of a participant in the study is compromising the participant’s
safety or the data collection, quality, and interpretation. Special precaution should be taken for
those who may carry a higher risk for severe COVID-19 illness.
Impact on Study Data
The sponsor will evaluate the totality ofimpact of COVID-19 on collection of key study data and
additional data analyses will be outlined in study SAP(s).
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Monitoring/Audits/Consent/Ethics
Monitoring
Depending on local restrictions, routine on-site monitoring visits may be postponed. The site
monitor may set up remote visits in accordance with site and local requirements instead. Additional
monitoring visits may be needed in the future to catch up on monitoring activities that can only be
performed on-site.
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
Consenting and re-consenting of participants for the measures taken (including also remote
consenting by phone or video consultation) will be performed as applicable and according to local
guidance for informed consent applicable during the COVID-19 pandemic. The process is to be
documented in the source documents.
Ethics
In case of any protocol deviations related to COVID-19, the investigator should notify these to the
local IEC/IRB/health authorities per local requirements.
Study Conduct Related to COVID-19 Vaccine Deployment for NonCOVID-19 Clinical Trials
 
Participants will be allowed to receive an authorized/licensed COVID-19 vaccine throughout
this study, including attenuated COVID-19 vaccines and boosters. 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 judgment of the principal investigator of the study.
 
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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10.5. Appendix 5: Contraceptive and Barrier Guidance
Participants must follow contraceptive measures as outlined in Section 5.1, Inclusion Criteria.
Pregnancy information will be collected and reported as noted in Section 8.2.5, Pregnancy Testing,
Section 8.3.5, Pregnancy  and Appendix 7: Adverse Events, Serious Adverse Events, Product
Quality Complaints, and Other Safety Reporting: Definitions and Procedures for Recording,
Evaluating, Follow-up, and Reporting.
Definitions
Woman of Childbearing Potential
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.
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.
 
permanently sterile (for the purpose of this study)
 
Permanent sterilization methods include hysterectomy, or bilateral salpingectomy, or
bilateral oophorectomy.
 
Has congenital abnormalities resulting in sterility.
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 must 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 must 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.
 Intrauterine device (IUD)
 Tubal closure (eg, bilateral tubal occlusion, bilateral tubal ligation)
 Azoospermic partner (vasectomized or due to medical cause)
(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 must 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.
 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)
 Any hormonal (estrogen and/or progestogen) contraceptives (oral, injectables, implants, patches,
intrauterine hormone-releasing system (IUS), etc.)b
 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)
a) Typical use failure rates may differ from those when used consistently and correctly. Use must be
consistent with local regulations regarding the use of contraceptive methods for participants in
clinical studies.
b) The interaction between JNJ-64281802 and hormone-based contraceptives has not been assessed.
The efficacy of hormone-based contraceptives may be decreased when coadministered with
JNJ-64281802 and therefore should not be considered a highly effective contraceptive method
during dosing with JNJ-64281802. A woman using any type of hormonal contraception must use an
additional barrier-based contraceptive method.
c) Male condom and female condom must not be used together (due to risk of failure with friction).
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10.6. Appendix 6: Regulatory, Ethical, and Study Oversight Considerations
10.6.1. 
Regulatory and Ethical Considerations
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the
protocol, current International Council for Harmonisation of Technical Requirements for
Pharmaceuticals for Human Use (ICH) guidelines on 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 Clarification Communications
If text within a final approved protocol requires clarification (eg, current wording is unclear or
ambiguous) that does not change any aspect of the current study conduct, a protocol clarification
communication (PCC) may be prepared. The PCC Document will be communicated to the
Investigational Site, Site Monitors, Local Trial Managers, Clinical Trial Managers, and/or Contract
Research Organizations who will ensure that the PCC explanations are followed by the
investigators.
The PCC Document may be shared by the sites with IECs/IRBs per local regulations.
The PCC Documents must NOT be used in place of protocol amendments, but the content of the
PCC Document must be included in any future protocol amendments.
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.
In situations where a departure from the protocol is unavoidable during the study, 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
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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:
 
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.
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 
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
participation in the study, if applicable.
 
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 research and for the corresponding ICF 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.
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 
Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at
least annually).
 
Reports of AEs 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
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.
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, Study-specific Ethical
Design Considerations.
10.6.2. 
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.
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10.6.3. 
Informed Consent Process and Assent Form
This study will include index cases ≥1 years of age and HHCs aged 16 or 18 (depending on the
legal age of consent in the jurisdiction in which the study is taking place) to ≤65 years can  be
included in the intervention part of the study.
When "participant" is referred to in relation to the ICF, this can be either a HHC or an index case;
when "participant" is referred to in relation to the informed assent form, this refers to an index
case.
Each participant, or a legally acceptable representative, must give written consent/assent 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) and assent form 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/assent should be in accordance
with principles that originated in the Declaration of Helsinki, current ICH and GCP guidelines,
applicable regulatory requirements, and sponsor policy.
Informed consent or assent may be obtained remotely. Refer to the Monitoring Guideline.
Before enrollment in the study, the investigator or an authorized member of the study site personnel
must explain to potential participants, or their legally acceptable representative, 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/assent to participate at any time. They will be
informed that choosing not to participate will not 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, or legally
acceptable representative, 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/assent for
additional safety evaluations, and subsequent disease-related treatments, if needed.
The participant or legally acceptable representative 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/assent should be appropriately recorded by means of the participant's or his or her legally
acceptable representative's personally dated signature. After having obtained the consent/assent, a
copy of the ICF must be given to the participant.
Participants will be asked for consent/assent to provide optional samples for research (where local
regulations permit). After informed consent/assent for the study is appropriately obtained, the
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participant or his or her legally acceptable representative will be asked to sign and personally date
a separate 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.
If the participant or legally acceptable representative is unable to read or write, an impartial witness
should be present for the entire informed consent/assent process (which includes reading and
explaining all written information) and should personally date and sign the ICF after the oral
consent/assent of the participant or legally acceptable representative is obtained.
Children (minors) or participants who are unable to comprehend the information provided can be
enrolled only after obtaining consent of a legally acceptable representative. Assent must be
obtained from children (minors) capable of understanding the nature of the study, typically
participants 7 years of age and older, depending on the institutional policies. Written assent should
be obtained from participants who are able to write. A separate assent form written in language the
participant can understand should be developed for adolescents. After having obtained the assent,
a copy of the assent form must be given to the participant, and to the participant's parent(s) or if
applicable legally acceptable representative.
See also Section 4.2.1, Study-specific Ethical Design Considerations.
10.6.4. 
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.
The informed consent/assent obtained from the participant (or his or her legally acceptable
representative) includes explicit consent/assent 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.
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Exploratory DNA, biomarker, PK, and immune 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.
10.6.5. 
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
DENV infection, to understand differential intervention responders, and to develop tests/assays
related to JNJ-64281802 and DENV infection. 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).
10.6.6. 
Committees Structure
Independent Data Monitoring Committee
An IDMC will be established to monitor data on an ongoing basis in an unblinded manner to ensure
the continuing safety of the participants enrolled in this study. The committee will meet
periodically to review these safety data.
This committee will consist of at least one medical expert in the relevant therapeutic area and at
least one statistician; committee membership responsibilities, authorities, and procedures will be
documented in its charter.
Any deaths, admission to the intensive care unit or severe dengue (DHF/DSS) will trigger a safety
data review by the IDMC. A safety data review by the IDMC will also be triggered when the
sponsor’s medical monitor (or designee) judges, based on a thorough analysis of all reported
≥Grade 3 unsolicited AEs, that the study pausing criteria may have been met (see Section 7.1.3).
If, in the judgment of the investigator and/or the sponsor’s study-responsible physician, a
significant or unexpected safety event occurs, the IDMC  will review unblinded safety data.
Regular safety checks will be performed by the IDMC during the course of the study.
At any point during the study, the IDMC has the authority to recommend modifications to the
study conduct and/or to the safety assessments to the Sponsor Committee to ensure the safety of
enrolled participants. The IDMC can recommend to the Sponsor Committee to halt a dose arm or
to pause or stop the study due to safety concerns.
In addition, the IDMC  will review the IA  data. After the review, the IDMC  will make
recommendations to the Sponsor Committee regarding the continuation of the study  (see
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Section 9.5, Interim Analysis). In case the timing of the IDMC safety review coincides with that
of the scheduled IA, it may be performed as part of the IA.
Modifications recommended by the IDMC and endorsed by the Sponsor Committee will be
communicated in writing to investigators, health authorities, and IEC/IRB and may be
implemented without amendment to this protocol. Details will be provided in the IDMC charter.
Sponsor Committee
A Sponsor Committee will be established for the formal decision taking after IDMC
recommendations on modifications to the study conduct and further continuation of the study.
The Sponsor Committee must be independent of the study conduct and include senior medical and
statistical members who can make scientific and business decisions based on the IDMC
recommendations.
One of the members of the Sponsor Committee will serve as the Chairperson. The Chairperson
will serve as the point of contact between the IDMC and sponsor.
The roles and responsibilities of the Sponsor Committee will be detailed in the IDMC charter.
10.6.7. 
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Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence of the results of clinical studies as required by
law. The disclosure of the final study results will be performed after the end of study to ensure the
statistical analyses are relevant.
10.6.8. 
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, periodic monitoring visits by the sponsor, and direct
transmission of clinical laboratory, PK, antiviral activity, immune, and viral genome sequencing
data from the central (or local for hematology and microscopic urinalysis) laboratory into the
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sponsor's database. 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.
10.6.9. 
Monitoring
The sponsor will use a combination of monitoring techniques (central, remote, and 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.
10.6.10. 
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.
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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.
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.
10.6.11. 
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/assent; dates of visits; results of safety and efficacy parameters as required by
the protocol; record of all AEs and follow-up  of AEs; 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 other equivalent document).
The following data will be recorded directly into the CRF and will be considered source data:
 Race
 History ofsmoking 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
 Discharge summaries
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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.
The participant’s paper diary used to collect information as specified in Section 8, Study
Assessments and Procedures will be considered source data.
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. These 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.
10.6.12. 
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
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 the participant
has been contacted by a regulatory agency concerning an upcoming inspection.
10.6.13. 
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.
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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.
10.6.14. 
Study and Site Start and Closure
First Act of Recruitment
The first participant screened is considered the first act of recruitment and it becomes the study
start date.
Study/Site 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.
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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10.7. Appendix 7: Adverse Events, Serious Adverse Events, Product Quality
Complaints, and Other Safety Reporting: Definitions and Procedures for
Recording, Evaluating, Follow-up, and Reporting
10.7.1. 
Adverse Event Definitions and Classification
Adverse Event
An AE is any untoward medical occurrence in a clinical study participant administered a
pharmaceutical (investigational or non-investigational) product. An AE does not necessarily have
a causal relationship with the intervention. An AE 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 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 AEs starting with the signing of the ICF (refer to All Adverse Events
under Section 8.3.1, Time Period and Frequency for Collecting Adverse Event and Serious
Adverse Event Information, for time of last AE recording).
Serious Adverse Event
An SAE based on ICH and European Union  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.
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If a serious and unexpected AE occurs for which there is evidence suggesting a causal relationship
between the study intervention and the event (eg, death from anaphylaxis), the event 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 AE 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 AE will be determined by
whether or not it is listed in the IB for JNJ-64281802 (IB JNJ-64281802 2022).
10.7.2. 
Attribution Definitions
Assessment of Causality
The causal relationship to study intervention is assessed by the investigator. The following
selection must be used to assess all AEs.
Related
There is a reasonable causal relationship between study intervention administration and the AE.
Not Related
There is not a reasonable causal relationship between study intervention administration and the
AE.
The term "reasonable causal relationship" means there is evidence to support a causal relationship.
10.7.3. 
Severity Criteria
An assessment of severity grade will be made using the general categorical descriptors outlined in
the modified DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events
supplemented with WHO toxicity grading scales in Section 10.9 and using the rash management
protocol in Section 10.2.The investigator should use clinical judgment in assessing the severity of
events not directly experienced by the participant (eg, laboratory abnormalities).
10.7.4. 
Special Reporting Situations
Safety events of interest on a sponsor study intervention in an interventional study that 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.
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 
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.
 
Reporting of participant pregnancy or participant partner(s) pregnancy.
Special reporting situations must be recorded in the CRF. Any special reporting situation that
meets the criteria of an SAE must be recorded on the SAE page of the CRF.
10.7.5. 
Procedures
All Adverse Events
All AEs, 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
AE to study therapy. All measures required for AE 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 SAEs that have not resolved by the end of the study, or that have not resolved upon the
participant's discontinuation from 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.
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 
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).
Suspected transmission of an infectious agent by a medicinal product will be reported as an SAE.
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during
participation in the study must be reported as an SAE, except hospitalizations for the following:
 
Hospitalizations not intended to treat an acute illness or AE (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 SAEs. Any AE that results in a prolongation of the originally planned
hospitalization is to be reported as a new SAE.
 
For convenience the investigator may choose to hospitalize the participant for the duration
of the intervention period.
The cause of death of a participant in a study, whether or not the event is expected or associated
with the study intervention, is considered an SAE.
Information regarding SAEs will be transmitted to the sponsor using an SAE reporting form and
safety report form of the CRF, which must be completed and reviewed by a physician from the
study site, and transmitted in a secure manner to the sponsor within 24 hours. The initial and
follow-up reports of an SAE should be transmitted in a secure manner electronically or by
facsimile (fax). Telephone reporting should be the exception and the reporter should be asked to
complete the appropriate form(s) first.
10.7.6. 
Product Quality Complaint Handling
Definition
A 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, reliability, or
performance of a distributed product, including its labeling, drug delivery system, or package
integrity. A PQC may have an impact on the safety and efficacy of the product. In addition, it
includes any technical complaints, defined as any complaint that indicates a potential quality issue
during manufacturing, packaging, release testing, stability monitoring, dose preparation, storage
or distribution of the product or the drug delivery system.
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.
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A sample of the suspected product should be maintained under the correct storage conditions until
a shipment request is received from the sponsor.
10.7.7. 
Contacting Sponsor Regarding Safety, Including Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted
regarding safety issues, PQC, or questions regarding the study are listed in the Contact Information
page(s), which will be provided as a separate document.
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Systemic (General) Mild (Grade 1) 
Moderate (Grade
2)
Severe (Grade 3) 
Potentially Life
Threatening
(Grade 4)
Nausea/Vomiting 
Transient (< 24 hours) 
or intermittent AND 
no or minimal 
interference with oral 
intake
Persistent nausea
resulting in decreased
oral intake for 24 to
48 hours
Persistent nausea resulting 
in minimal oral intake for 
> 48 hours OR
Rehydration indicated (eg,
IV fluids)
Life-threatening consequences
(eg, hypotensive shock)
Diarrhea 
Transient or 
intermittent episodes 
of unformed stools 
OR increase of ≤ 3 
stools over baseline 
per 24-hour period 
Persistent episodes of
unformed to watery
stools OR increase of
4 to 6 stools over
baseline per 24-hour
period
Increase of ≥ 7 stools per 
24-hour period OR IV 
fluid replacement 
indicated
Life-threatening consequences
(eg,
hypotensive shock)
Headache 
Symptoms causing no 
or minimal 
interference with 
usual social & 
functional activities 
Symptoms causing
greater than minimal
interference with
usual social &
functional activities
Symptoms causing 
inability to perform usual 
social & functional 
activities 
Symptoms causing inability to
perform basic self-care
functions OR Hospitalization
indicated OR Headache with
significant impairment of
alertness or other neurologic
function
Fatigue or Malaise 
Report only one 
Symptoms causing no 
or minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities
Symptoms causing 
inability to perform usual 
social & functional 
activities 
Incapacitating symptoms of
fatigue or malaise causing
inability to perform basic self-
care functions
Myalgia 
Muscle pain causing 
no or minimal 
interference with 
usual social & 
functional activities 
Muscle pain causing 
greater than minimal 
interference with 
usual social & 
functional activities
Muscle pain causing 
inability to perform usual 
social & functional 
activities
Disabling muscle pain causing
inability to perform basic self-
care functions
Rasha 
Specify type, if 
applicable 
Localized rash that is 
easily tolerated and/or 
may require one dose 
of medication  
Diffuse, 
maculopapular rash, 
or target lesions. 
Symptomatic 
(pain/pruritus) but 
does not interfere with 
function and/or 
requires more than 
one dose of
medication
Diffuse rash AND 
vesicles or limited number 
of bullae or superficial 
ulcerations of mucous 
membrane limited to one 
site 
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
Systemic Illness 
Mild (Grade 1) 
Moderate (Grade 
2) 
Severe (Grade 3) 
Potentially
Life -threatening
(Grade 4)
Illness or clinical adverse 
event not identified 
elsewhere in the grading 
table. 
Mild symptoms causing 
no or minimal 
interference with usual 
social & functional 
activities with 
intervention not 
indicated 
Moderate symptoms 
causing greater than 
minimal interference 
with usual social & 
functional activities 
with intervention 
indicated 
Severe symptoms 
causing inability to 
perform usual social & 
functional activities with 
intervention or 
hospitalization indicated 
Potentially life-
threatening symptoms
causing inability to
perform basic self-care
functions with
intervention indicated to
prevent permanent
impairment, persistent
disability, or death
a 
Please refer to Section 10.2 for the rash management protocol details.
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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.
Biochemistrya 
Mild
(Grade 1)
Moderate
(Grade 2)
Severe
(Grade 3)
Potentially Life
Threatening
(Grade 4)
Sodium - Hyponatremia mEq/L  
130 to < 135 
125 to < 130 
121 to < 125 
≤ 120
Sodium - Hypernatremia mEq/L  
146 to < 150 
150 to < 154 
154 to < 160 
≥ 160
Potassium - Hyperkalemia mEq/L  
5.6 to < 6.0 
6.0 to < 6.5 
6.5 to < 7.0 
≥ 7.0
Potassium - Hypokalemia mEq/L  
3.0 to < 3.4 
2.5 to < 3.0 
2.0 to < 2.5 
< 2.0
Glucose - Hypoglycemia mg/dL  
55 to 64 
40 to < 55 
30 to < 40 
< 30
Glucose
  Fasting mg/dL
  Non-Fasting - mg/dL
110 to 125 
116 to 160 
> 125 to 250 
> 160 to 250 
> 250 to 500 
> 250 to 500 
≥ 500
≥ 500
Uric Acid mg/dl 
7.5 to <10.0 mg/dL 
10.0 to <12.0 mg/dL 
12.0 to <15.0 mg/dL 
≥15.0 mg/dL
Blood Urea Nitrogen (BUN) increase by
factor
≥1.25 to ≤2.50 x ULN  
>2.50 to ≤5.00 x ULN  >5.00 to ≤10.00 x ULN  >10.00 x ULN
Creatinine 
1.1 to 1.3 x ULN 
> 1.3 to 1.8 x ULN 
> 1.8 to < 3.5 x ULN 
≥ 3.5 x ULN
Calcium - hypocalcemia mg/dL  
7.8 to < 8.4 
7.0 to < 7.8 
6.1 to < 7.0 
< 6.1
Calcium - hypercalcemia mg/dL  
10.6 to < 11.5 
11.5 to < 12.5 
12.5 to < 13.5 
≥ 13.5
Magnesium - hypomagnesemia mEq/l 
1.2 to < 1.4 
0.9 to < 1.2 
0.6 to < 0.9 
< 0.6
Phosphorous - hypophosphatemia mg/dL  2.0 to < LLN 
1.4 to < 2.0 
1.0 to < 1.4 
< 1.0
Creatine (phospho)kinase (CPK) 
3 to < 6 x ULN 
6 to < 10x ULN 
10 to < 20 x ULN 
≥ 20 x ULN
Albumin - Hypoalbuminemia g/dL  
3.0 to < LLN 
≥ 2.0 to < 3.0 
< 2.0 
--
Alkaline phosphate High 
1.25 to < 2.5 x ULN 
2.5 to < 5.0 x ULN 
5.0 to < 10.0 x ULN 
≥ 10.0 x ULN
Gamma-glutamyltransferase GGT  
≥1.25 to ≤2.50 x ULN  
>2.50 to ≤5.00 x ULN  >5.00 to ≤10.00 x ULN  >10.00 x ULN
AST increase by factor 
1.1 to 2.5x ULN  
2.6 to 5.0x ULN  
5.1 to 10x ULN  
> 10x ULN
ALT increase by factor 
1.1to- 2.5x ULN  
2.6 to 5.0x ULN  
5.1 to 10x ULN  
> 10x ULN
Total Bilirubin 
1.1 to < 1.6 x ULN 
1.6 to < 2.6 x ULN 
2.6 to < 5.0 x ULN 
≥ 5.0 x ULN
Total Cholesterol mg/dl
≥ 18 years of age
200 to < 240 
240 to < 300 
≥ 300 
NA
< 18 years of age 
170 to < 200 
200 to < 300 
≥ 300 
NA
LDL, Fasting, High
≥ 18 years of age
130 to < 160 mg/dL 
160 to < 190mg/dL 
≥ 190mg/dL  
N/A
LDL, Fasting, High
< 18 years of age
110 to < 130mg/dL  
130 to < 190mg/dL 
≥ 190 mg/dL  
N/A
Triglycerides, Fasting, High  
150 to 300mg/dL 
>300 to 500mg/dL 
>500 to <1000md/dL 
> 1000mg/dL
Lipase 
1.1 to < 1.5 x ULN 
1.5 to < 3.0 x ULN 
3.0 to < 5.0 x ULN 
≥ 5.0 x ULN
Amylase 
1.1-1.5x 1.1 to < 1.5 x ULN  1.5 to < 3.0 x ULN 
3.0 to < 5.0 x ULN  
≥ 5.0 x ULN
a 
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
of the normal range.
Hematologya 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe
(Grade 3)
Potentially Life
Threatening
(Grade 4)
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Hemoglobin (Female) - gm/dL  
9.5 to 10.4 
8.5 to < 9.5 
6.5 to < 8.5 
< 6.5
Hemoglobin (Male) - gm/dL  
10.0 to 10.9 
9.0 to < 10.0 
7.0 to < 9.0 
< 7.0
WBC Decrease - cell/mm3 
2,000 to 2,499 
1,500 to 1,999 
1,000 to 1,499 
< 1,000
Lymphocytes Decrease - cell/mm3 
600 to < 650 
500 to < 600 
350 to < 500 
< 350
Neutrophils Decrease - cell/mm3 
800 to 1,000 
600 to 799 
400 to 599 
< 400
Platelets Decrease - cell/mm3 
100,000 to < 125,000 
50,000 to < 100,000 
25,000 to < 50,000 
< 25,000
PT - increase by factor (prothrombin
time)
1.1 to < 1.25 x ULN 
1.25 to < 1.50 x ULN 1.50 to < 3.00 x ULN 
≥ 3.00 x ULN
aPTT - increase by factor (activated
partial thromboplastin time)
≥1.01 to ≤1.66 x ULN  
>1.66 to ≤2.33 x ULN  >2.33 to ≤3.00 x ULN  >3.00 x ULN
Fibrinogen decrease - mg/dL  
100 to < 200 
75 to < 100 
50 to < 75 
< 50
INR, High (not on anticoagulation 
therapy)
1.1 to < 1.5 x ULN 
1.5 to < 2.0 x ULN 
2.0 to < 3.0 x ULN 
≥ 3.0 x ULN
a 
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 of the normal range.
Urinea 
Mild  
(Grade 1) 
Moderate
(Grade 2)
Severe 
(Grade 3) 
Potentially Life-threatening
(Grade 4)
Protein 
1+ 
2+ 
3+ or higher 
Hospitalization or dialysis
Glucose 
Trace to 1+ or 
≤ 250 mg 
2+ or 
˃ 250 to ≤ 500 
mg
> 2+ or 
> 500 mg
Hospitalization for Hyperglycemia
Blood (microscopic) - 
red blood cells per 
high power field (rbc/hpf) 
6 to < 10 RBCs per 
high power field 
≥ 10 RBCs per 
high power field 
Gross, with or without 
clots OR With RBC 
casts OR Intervention
indicated
Hospitalization or packed red blood
cells (PRBC) transfusion
a 
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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Status: Approved, Date: 19 July 2023
10.10. Appendix 10: Examples of Disallowed Medications
Please note that the below list is not a definitive list of disallowed medications, investigators are
advised to ensure any medications being prescribed are not metabolized by the prohibited
enzymatic pathways.
Strong CYP3A4 inhibitors
Amiodarone 
Idelalisimib 
Posaconazole
Ceritinib 
Itraconazole 
Ribociclib
Clarithromycin  
Lonafarnib 
Ritonavir
Cobicistat 
Methimazole 
Stiripetol
Danazol 
Midostaurin  
Telithromycin
Delavirdine 
Nefazodone 
Troleandomycin
Ditiocarb 
Nelfinavir 
Voriconazole
Econazole 
Nilotinib
Strong CYP3A4 inducers
Apalutamide 
Lumacaftor/Ivacaftor 
Rifampin
Carbamazepine 
Mitotane 
St. John’s wort (Hypericum
perforatum)
Enzalutamide 
Phenobarbital
Ivosidenib 
Phenytoin
CYP3A4 substrates with a narrow therapeutic index
Benzodiazepines (eg, clonazepam, midazolam, triazolam)
Chemotherapeutic agents
Ergot derivatives
Opioids (eg, fentanyl, hydrocodone)
Bosentan  
Flecainide 
Tacrolimus
Clopidogrel 
Ivabradine 
Tadalafil
Clozapine 
Lurasidone 
Temsirolimus
Cyclosporine 
Pimozide 
Tianeptine
Digoxin  
Primidone 
Tolvaptan
Disopyramide 
Propafenone 
Vardenafil
Dofetilide 
Quinidine 
Voclosporin
Eplerenone 
Sildenafil 
Warfarin
Everolimus
Sensitive BCRP substrates
Folic acid 
Pravastatin
Anticoagulants
Apixiban  
Heparin  
Warfarin
Dabigatran  
Rivaroxaban
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Status: Approved, Date: 19 July 2023
NSAIDs
Celexocib 
Ibuprofen  
Naproxen
Diclofenac 
Indomethacin  
Piroxicam
Corticosteroids (systemica)
Cortisone 
Methylprednisolone 
Prednisolone
Dexamethasone 
Prednisone
a 
Topical administration is allowed.
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Status: Approved, Date: 19 July 2023
10.11. Appendix 11: Liver Safety: Suggested Actions and Follow-up
Assessments
10.11.1. 
Stopping Criteria
10.11.1.1. 
ALT or AST
Liver Chemistry Stopping Criteria
ALT or AST- 5xULN, or
ALT or AST- 3xULN persists for 4 weeks, or
ALT or AST- 3xULN and total bilirubin 2xULN (or at least a doubling of direct bilirubin
in known Gilbert’s syndrome), or
ALT or AST- 3xULN and international normalized ratio (INR) >1.5, if INR measured, or
ALT or AST- 3xULN associated with symptoms (new or worsening) believed to be related to
liver injury or hypersensitivity
Dengue infection can alter/increase liver enzymes in the infected individual.  For this reason, if
any of the above liver chemistry stopping criteria are met, investigator together with sponsor will
decide on the discontinuation of the study intervention. If a participant is discontinued, they will
not be restarted or rechallenged again.
10.11.2. 
Follow-up Assessments
 Repeat testing to confirm laboratory abnormalities within 24 hours prior to stopping, unless
safety is considered at risk by the sponsor and/or investigator
 Report the event to the sponsor within 24 hours to decide on discontinuing study
intervention
10.11.2.1. 
Liver Follow-up Assessments with discontinued Study Intervention
If liver chemistry stopping are deemed to be possibly related to the drug intervention  by the
investigator and sponsor, the below monitoring and follow up assessments apply:
Suggested Actions, Monitoring and Follow-up Assessments
Actions 
Follow-up Assessmentsf
 Complete the CRF according to CRF 
completion guidelines, and complete an SAE 
data collection tool if the event also met the 
criteria for an SAEb
 Perform follow-up assessments as described in 
the Follow Up Assessment column  
 Monitor the participant until liver chemistry 
test abnormalities resolve, stabilize, or return 
to baseline (see MONITORING) 
 Viral hepatitis serologyd
 Obtain INR and recheck with each
liver chemistry assessment until the
transaminases values show downward
trend
 Obtain blood sample for PK analysis
after the most recent dosee
 Obtain serum CPK, lactate
dehydrogenase (LDH), GGT,
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Status: Approved, Date: 19 July 2023
MONITORING:
If ALP <2 x ULN, ALT or AST- 3xULN AND
total bilirubin 2xULN (or at least a doubling
of direct bilirubin in known Gilbert’s
syndrome) or INR >1.5 (if measured):
 Repeat liver chemistry tests (include ALT,
AST, ALP, total and direct bilirubin and INR)
and perform liver event follow-up assessments
within 24 hours
 Monitor participant twice weekly until liver
chemistry test abnormalities resolve, stabilize,
or return to baseline
 A specialist or hepatology consultation is
recommended
If ALT or AST- 3xULN AND total bilirubin
<2xULN and INR 1.5:
 Repeat liver chemistry tests (include ALT,
AST, alkaline phosphatase, total and direct
bilirubin and INR) and perform liver chemistry
follow-up assessments within 24 to 72 hours
 Monitor participants weekly until liver
chemistry abnormalities resolve, stabilize, or
return to baseline
glutamate dehydrogenase (GLDH),
and serum albumin
 Fractionate bilirubin
 Obtain complete blood count with
differential to assess eosinophilia
 Record the appearance or worsening of
clinical symptoms of liver injury, or
hypersensitivity, on the CRF as per
CRF completion guidelines
 Record use of concomitant
medications (including
acetaminophen, herbal remedies,
recreational drugs and other over-the-
counter medications)
 Record alcohol use on the CRF as per
CRF completion guidelines
If ALT or AST 3xULN AND total
bilirubin 2xULN or INR >1.5 (if
measured) obtain the following in
addition to the assessments listed above:
 Anti-nuclear antibody, anti-smooth
muscle antibody, Type 1 anti-liver
kidney microsomal antibodies, and
quantitative total IgG or gamma
globulins
 Serum acetaminophen adduct assay,
when available, to assess potential
acetaminophen contribution to liver
injury in participants with definite or
likely acetaminophen use in the
preceding week
 Depending on availability, liver
imaging (ultrasound, magnetic
resonance, or computerized
tomography) and/or liver biopsy to
evaluate liver disease; complete CRF
as per CRF completion guidelines
 Liver biopsy may be considered and
discussed with local specialist if
available:
 In participants when serology raises
the possibility of autoimmune
hepatitis (AIH)
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 In participants when suspected
DILI progresses or fails to resolve
on withdrawal of study intervention
 In with acute or chronic atypical
presentation
 If liver biopsy conducted complete
CRF as per CRF completion
guidelines
a 
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not
immediately available, discontinue study intervention if ALT 3xULN and total bilirubin 2xULN.
Additionally, if serum bilirubin fractionation testing is unavailable, record the absence/presence of detectable
urinary bilirubin on dipstick which is indicative of direct bilirubin elevations suggesting liver injury.
b 
All events of ALP <2 x ULN, ALT or AST 3 x ULN and total bilirubin 2xULN (or at least a doubling of
direct bilirubin in known Gilbert’s syndrome) or ALP <2 x ULN , ALT or AST 3 x ULN and INR >1.5 (if
measured) may indicate severe liver injury (possible ‘Hy’s Law’) and must be reported to sponsor in an
expedited manner and as an SAE if SAE criteria are met (excluding studies of hepatic impairment or cirrhosis).
The INR stated threshold value will not apply to participants receiving anticoagulants.
c 
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right
upper quadrant pain or tenderness, or jaundice) or hypersensitivity (such as fever, rash or eosinophilia).
d 
Includes: hepatitis A IgM antibody; HBsAgG and HBcAB; hepatitis C RNA; cytomegalovirus IgM antibody;
Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, heterophile antibody or monospot testing);
and hepatitis E IgM antibody.
e 
PK sample may not be required for participants. record the date/time of the PK blood sample draw and the
date/time of the last dose of study intervention prior to the blood sample draw on the CRF. If the date or time of
the last dose is unclear, provide the participant’s best approximation. If the date/time of the last dose cannot be
approximated OR a PK sample cannot be collected in the time period indicated above, do not obtain a PK
sample. Instructions for sample handling and shipping are in the Study Reference Manual.
f 
Local laboratories can perform the follow-up assessments where available to allow a rapid turnaround in these
assessments.
10.11.2.2. 
Liver Chemistry Increased Monitoring Criteria with Continued Study
Intervention
Liver Chemistry Increased Monitoring Criterion and Actions with Continued Study
Intervention
Criterion 
Actions
ALT or AST- 3xULN and <5xULN 
and total bilirubin <2xULN or 
INR<1.5 (if measured), without 
symptoms believed to be related to 
liver injury or hypersensitivity, and  
who can be monitored weekly for 4 
weeks 
 Notify the sponsor within 24 hours of learning of
the abnormality to discuss participant safety
PARTICIPANT CAN CONTINUE STUDY
INTERVENTION.
 Participant must return weekly for repeat liver
chemistry tests (ALT, AST, alkaline phosphatase,
total bilirubin) until the abnormalities resolve,
stabilize or return to baseline
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Status: Approved, Date: 19 July 2023
 If at any time, the participant meets liver chemistry
stopping criteria, proceed as described in Section
10.11.2.1 Liver Follow-up Assessments
 If, after 4 weeks of monitoring, ALT or AST -
<3xULN and total bilirubin <2xULN, monitor
participants twice monthly until liver chemistry
tests resolve, stabilize, or return to baseline
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Status: Approved, Date: 19 July 2023
10.12. Appendix 12: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located
directly before the Table of Contents (TOC).
Amendment 2 (2 December 2022)
Overall Rationale for the Amendment: The main purpose of this amendment is to implement regulatory
feedback with regards to study pausing in case of safety concerns. In addition, it was clarified that
participants with certain laboratory abnormalities at baseline (Day 1) will be discontinued from study
intervention. Serum lipase was added to the blood chemistry panel and a clarification concerning the
recording of body temperature was added.
The changes made to the clinical protocol 64281802DNG2004 as part of Protocol Amendment 2 are listed
below, including the rationale of each change and a list of all applicable sections.
Section number 
and Name
Description of Change 
Brief Rationale
7.1.2 Study Pausing Criteria;
8.3.1 Time Period and
Frequency for Collecting
Adverse Event and Serious
Adverse Event Information;
10.6.6 Committees Structure
Study pausing criteria were added.
The sponsor’s medical monitor (or
designee) will do a thorough analysis of
all reported ≥Grade 3 unsolicited AEs to
determine whether a safety data review by
the IDMC is warranted. If the IDMC
judges that the study pausing criteria have
been met, the IDMC will recommend to
either pause the study or to implement
modifications to the study conduct and/or
to the safety assessments.
In addition, it was clarified that the
investigator should notify the sponsor’s
medical monitor (or designee)
immediately and no later than 24 hours
after becoming aware of any ≥Grade 3
unsolicited AE considered related to study
intervention.
Upon Health Authority request
7.1 Discontinuation of Study
Intervention
It was clarified that participants who
report with 2 or more ≥Grade 2 laboratory
abnormalities for elevations of
triglycerides, low-density lipoprotein
cholesterol, and/or total cholesterol,
and/or 2 or more ≥Grade 2 laboratory
abnormalities for other laboratory
parameters at baseline (Day 1) will be
discontinued from study intervention.
To ensure that participants with
clinically significant laboratory
abnormalities at baseline
discontinue treatment with study
intervention.
10.8 Appendix 8: Clinical
Laboratory Tests
Serum lipase will be monitored during the
dosing and follow-up phases.
Upon Health Authority request
1.3.2.2 Double-blind
Prophylactic Dosing: Day 1
to Day 13;
1.3.2.3 Double-blind
Prophylactic Dosing (Day 14
to Day 28) and Follow-up
Phase;
8 STUDY ASSESSMENTS
AND PROCEDURES;
It was clarified that body temperature will
be recorded by the participant in a diary
daily (preferably at the same time each
day) and in case of feeling feverish, and
that it will be added to the CRF by study
site personnel only in case the body
temperature is ≥37.5°C (99.5°F).
Clarification
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Section number 
and Name
Description of Change 
Brief Rationale
8.2.2 Vital Signs
Throughout the protocol 
Minor grammatical, formatting, or 
spelling changes and clarifications were
made.
Minor errors were corrected.
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Amendment 1 (04 October 2022)
Overall Rationale for the Amendment: The main purpose of this amendment is to remove serology as a
criterion for identifying dengue virus (DENV) infection in household contacts (HHC) for the evaluation of
the prophylactic effect of JNJ-64281802 for the primary endpoint. In addition, the measurement of anti-
DENV antibodies was moved from a secondary to an exploratory endpoint. Other changes in this
amendment include the following:
 
The diagnosis of DENV infection in index cases was clarified, and the possibility of using anti-DENV
IgM test if necessary was added.
 
The follow-up period was extended to 62 days following the last dose.
 
The calculation of the prophylactic efficacy was adjusted.
 
The requirement to have energy bars along with the study intervention was removed.
 
The other changes, such as performing clinical laboratory analyses in local laboratories, were made
for logistical reasons.
Section number
and Name
Description of Change 
Brief Rationale
1.1 Synopsis: Hypothesis;
primary endpoint;
9.1 Statistical Hypotheses;
9.4.2 Primary Endpoint(s)
- Removed serology as a criterion for
identifying laboratory-confirmed DENV
infection in HHC.
- Specified the definition of laboratory-
confirmed DENV infection.
- To restrict the identification of
lab-confirmed DENV infection to
detection of the DENV virus itself
(either viral RNA and/or NS1
antigen) as detection of anti-DENV
antibodies can be hampered by
many variable factors such as cross
reactivity with other flaviviruses.
- To clarify what is meant by
laboratory-confirmed DENV
infection.
1.1 Synopsis: Objectives and
Endpoints; Statistical
Methods;
3 OBJECTIVES AND
ENDPOINTS
Measurement of anti-DENV antibodies
was moved from a secondary objective to
an exploratory objective.
As the detection of anti-DENV
antibodies can be hampered by
many variable factors, this analysis
was moved to exploratory
objective.
1.1 Synopsis: Objectives and
Endpoints;
3 OBJECTIVES AND
ENDPOINTS
Removal of the analysis of neutralizing
antibodies as an exploratory objective. It
will be analyzed in an exploratory
research.
Detection of neutralizing antibodies
can be hampered by many
variables.
1.1 Synopsis;
1.3.1 Index Cases;
4.1 Overall Design;
5.1 Inclusion Criteria
8.7.1 NS1 Rapid Test and
RT-PCR of Index Cases
The criteria for identifying index cases
were modified to include the possibility of
using anti-DENV IgM test.
To allow for the possibility to use
an alternative anti-DENV IgM test
when a DENV NS1 or DENV PCR
test is not available.
1.3.2.2 Double-blind
Prophylactic Dosing: Day 1
to Day 13;
1.3.2.3 Double-blind
Prophylactic Dosing (Day 14
to Day 28) and Follow-up
Phase
Blood samples should be taken prior to
the first drug intake only on Day 1.
Day 1 predose blood sample
required as baseline sample, other
sampling points can be done at any
time points of the visit day to
facilitate operational conduct of the
trial.
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JNJ-64281802  
Clinical Protocol 64281802DNG2004
AMENDMENT 3
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Section number
and Name
Description of Change 
Brief Rationale
1.1 Synopsis: Overall Design
- Follow-up Phase;
1.3.2.3 Double-blind
Prophylactic Dosing (Day 14
to Day 28) and Follow-up
Phase;
4.1 Overall Design Follow-
up Phase;
4.4 End of Study Definition
Study Completion Definition;
8 STUDY ASSESSMENTS
AND PROCEDURES
- A follow-up visit and immune
assessments on Day 90, and phone follow-
ups between Day 50 and Day 90 were
added.
- The approximate duration of the study
was changed from 7 weeks to 13 weeks to
reflect the additional follow-up.
- Clarified in footnote that concomitant
medications and AEs will be reviewed
throughout the follow-up period until
Day 90.
To assess post-treatment DENV
serology and to document and
review any cases of symptomatic
dengue during an extended follow-
up period.
1.3.2.3 Double-blind
Prophylactic Dosing (Day 14
to Day 28) and Follow-up
Phase
- Specified that participants showing signs
or symptoms of DENV infection between
Day 28 and Day 90 had to come to the
study site.
- Specified that after Day 28 the
occurrence of AEs will be based on phone
monitoring in addition to the site visits on
Days 40, 50, and 90.
- Added a window of +/- 1 day to the
Day 28 visit.
- To ensure that blood would be
drawn for antiviral activity
assessment and viral sequencing for
infections that occur after the last
dose.
- To ensure safety is regularly
monitored between participants’
site visits.
- To allow for the Day 28 blood
sampling to occur on a Monday in
case Day 28 is a Sunday.
1.2 Schema Figure 1: 
Schematic Overview of the 
Study
The number of days between the end of
treatment and follow-up was modified.
To account for the additional
Day 90 follow-up.
1.1 Synopsis: Description of 
Intervention; 
1.3.2.2 Double-blind
Prophylactic Dosing: Day 1
to Day 13;
4.3 Justification for Dose
6.1 Study Intervention(s)
Administered;
Table 2;
8 STUDY ASSESSMENTS
AND PROCEDURES
The requirement to have an energy bar
was removed.
The impact of additional energy on
bioavailability was minimal based
on data from the relative
bioavailability study
64281802DNG1006.
2.2 Background 
An additional result from Part 2 of study
64281802DNG1006 was added.
To explain why energy bars were
no longer required with dosing.
6.8 Concomitant Therapy  
- Domperidone was removed from the list
of concomitant medications that are not
allowed.
- Concomitant medications that are
prohibited were updated.
Newly collected information on
JNJ-64281802 as an inhibitor and
inducer of various CYP enzymes
and transporter proteins obtained in
Study DNG1005 has led to the
revision of disallowed concomitant
medication.
2.2 Background;
2.3.1 Risks for Study
Participation
Summary of study 64281802DNG1004
was added.
The safe doses were updated based on
study 64281802DNG1004.
For completeness since the final
64281802DNG1004study report
became available.
2.2 Background Study
DNG1001
In the Background section, the safety
summary of Study 64281802DNG1001
was modified for consistency with the text
in other documents.
For consistency with other Phase 2
protocols and the Investigator’s
Brochure.
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Status: Approved, Date: 19 July 2023
Section number
and Name
Description of Change 
Brief Rationale
1.3.2.3 Double-blind
Prophylactic Dosing (Day 14
to Day 28) and Follow-up
Phase
An additional pregnancy test was added
on Day 28.
To increase the likelihood of
detecting a pregnancy while on the
study intervention.
1.1 Synopsis: Statistical
Methods;
9.4.4.1 Safety Analyses
10.2 Appendix 2: Rash
Management
Rash was added as an event that requires
narrative reporting. Clarified that rashes
are to be assessed by investigators at their
discretion. All rashes that are not related
to DENV infection are to undergo rash
management assessment.
To generate more comprehensive
clinical data and better assess
rashes that are not related to dengue
infection.
1.1 Synopsis: Statistical
Methods;
9.4.2 Primary Endpoint(s)
- Clarified the calculation of prophylactic
efficacy: The odds-ratio from the logistic
regression model will be used to estimate
prophylactic efficacy.
- The statement referring to interim
analysis in the sensitivity analysis was
deleted.
- Given the expected low incidence,
the odds ratio will be a very good
approximation of the relative risk.
- The reference to the Interim
Analysis section is not needed as no
sensitivity estimators are planned
for the interim analysis.
1.1 Synopsis: Statistical
Methods;
4.1 Overall Design;
9.2 Sample Size
Determination
The number of participants expected to be
enrolled was updated from 1,300–1,850 to
1,250–1,850.
The number of expected
participants was recalculated.
10.6.8 Data Quality
Assurance;
10.8 Appendix 8: Clinical
Laboratory Tests
- Clarification made that hematology and
microscopic urinalysis must be performed
by local laboratories and results entered
by the clinical site staff.
- Lactose dehydrogenase (LDH) and
bicarbonate were removed from the list of
analytes for clinical chemistry.
- For protocols performed in remote
settings, sample shipment times can
exceed the specimen viability time,
and central laboratory analysis
cannot be performed due to sample
degradation. This directly impacts
monitoring of participant safety.
Therefore, for perishable samples,
hematology testing and
microscopic urinalysis will be
performed locally.
- Analysis of LDH and bicarbonate
were not deemed medically
necessary for the analysis and
assessment of safety for this study.
8 STUDY ASSESSMENTS
AND PROCEDURES
Overview;
10.8 Appendix 8: Clinical
Laboratory Tests
Alcohol test was kept general and not
limited to a breath test.
Some study sites do not use alcohol
breath test.
1.1 Synopsis: Number of
participants;
5.1 Inclusion Criteria
The maximum body mass index in the
inclusion criteria was increased from 33 to
35.
To reduce screen failures due to
BMI. No implications for safety are
expected.
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Section number
and Name
Description of Change 
Brief Rationale
2.3.1 Risks for Study
Participation;
5.2 Exclusion Criteria;
6.8 Concomitant Therapy
10.4 Appendix 4: COVID 19
Appendix
- The vaccination exclusion criterion was 
modified so that it excluded attenuated 
COVID-19 vaccination.
- Clarification regarding COVID-19 
vaccinations in the exclusion criteria. 
- To allow for vaccination against
COVID-19.
- Attenuated COVID-19 vaccines
and boosters (if these become
available during the study) were
included in the exclusion criteria
since information on the type of
vaccine (live or non-live
attenuated) taken may not be
readily available. Once the study
intervention has stopped, receiving
COVID-19 vaccination is up to the
discretion of the investigator.
1.1 Synopsis: Objectives and
Endpoints;
3 OBJECTIVES AND
ENDPOINTS
Modification of the exploratory endpoints. The exploratory endpoints were
phrased more precisely.
1.1 Synopsis: Objectives and
Endpoints;
3 OBJECTIVES AND
ENDPOINTS
Removal of the exploratory objective to
evaluate the prophylactic effect of
JNJ-64281802 with respect to the
prevention of laboratory-confirmed
DENV infection up to Day 50 among
HHC who have no evidence of current
DENV infection at baseline and who
completed study intervention.
Laboratory-confirmed DENV
infection is defined as a positive
result on the DENV RNA and/or
DENV NS1 protein assay. In order
not to miss the detection of a
laboratory-confirmed DENV
infection, at least twice weekly
sampling is necessary, which is
only planned up to Day 28.
1.1 Synopsis: Description of
Study Intervention;
Table 2
1.3.2.4 Discontinuation From
Study Intervention or Study;
7.1 Discontinuation of Study
Intervention
Addition that immune assessments, viral
analysis, and viral sequencing will be
performed at withdrawal and follow-up
visits when participant discontinues from
the study or study intervention.
Sequencing at these time point
added (consistent with other
sampling time points) to
characterize DENV variants
associated with resistance to
JNJ-64281802.
1.3.2.4 Discontinuation From
Study Intervention or Study
- Clarified that upon the visit at
discontinuation, participants will come to
the study site.
- Added footnote (d)
- Modified the description of the follow-
up visit (removed “Safety” and made
clarifications in footnote d)
- Since ECG measurements will
have to be taken, the withdrawal
visit needs to be at the study site.
- To specify that safety assessments
and clinical laboratory tests at
follow-up will be performed at the
discretion of investigators.
- To clarify that the follow-up visit
is performed mainly for antiviral
and immune assessments. No safety
issues are expected.
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Status: Approved, Date: 19 July 2023
Section number 
and Name
Description of Change 
Brief Rationale
1.3.2.5 Pharmacokinetic 
Substudy; 
6.4 Study Intervention 
Compliance; 
8 STUDY ASSESSMENTS 
AND PROCEDURES 
Sample Collection and
Handling
- Requirement for study site visit on Days 
29 and 32 in the PK Substudy was made 
optional. 
- The requirement to visit study site on 
Days 2 and 3 was specified in the
footnote.
- Visit can be performed at the site
or at home.
- To maintain consistency with the
table.
7.2.1 Withdrawal From the 
Use of Research Samples 
Clarified that the only optional research 
samples are for pharmacogenomics. 
To clarify that the only optional
samples are for pharmacogenomics.
1.1 Synopsis: Safety Analysis 
1.3.2.2 Double-blind 
Prophylactic Dosing: Day 1 
to Day 13; 
1.3.2.3 Double-blind
Prophylactic Dosing (Day 14
to Day 28) and Follow-up
Phase;
8 STUDY ASSESSMENTS
AND PROCEDURES
8.2.2 Vital Signs
- Removed body temperature from vital 
signs. 
- Specified that body temperature needs to 
be recorded only in case of fever.
To clarify that normal body
temperature does not need to be
recorded.
5.2 Exclusion Criteria 
Removed the specification that 
constipation is considered as an exclusion 
criterion if it lasts >2 days. 
To consider any occurrence of
constipation as an exclusion
criterion.
6.7 Treatment of Overdose 
The option for the decision to be taken in 
case of overdose was changed to continue 
(or discontinue) study intervention. 
No study treatment interruption or
modification is allowed in the
study.
Throughout the protocol 
Minor grammatical, formatting, or 
spelling changes and clarifications were 
made.
Minor errors were corrected, and
clarifications added.
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11. 
REFERENCES
(CDC 2019a). Centers for Disease Control and Prevention. Dengue statistics and maps: 2019 data.
https://www.cdc.gov/dengue/statistics-maps/index.html. Accessed 12 April 2021.
(CDC 2019b). Centers for Disease Control and Prevention. Dengue for Healthcare Providers.
ttps://www.cdc.gov/dengue/healthcare-providers/clinical-presentation.html. Accessed 06 July 2021.
American Red Cross (2021). Blood needs & blood supply. http://www.redcrossblood.org/learn-about-blood/blood-
facts-and-statistics. Accessed 13 April 2021.
Bazett HC (1920). An analysis of the time-relationship of electrocardiograms. Heart. 1920;7:353-380.
Bhatt S (2013), Gething PW, Brady OJ, et al. The global distribution and burden of dengue. Nature.
2013;496(7446):504-507.
Carrington LB (2014), Simmons CP. Human to mosquito transmission of dengue viruses. Front Immunol.
2014;5:290.
Clinical study report (2021). Phase one, open label expansion of a dengue-1-virus-live virus human challenge -
(DENV-1-LVHC) virus strain. The Research Foundation for the State University of New York, 11 February 2021.
DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, corrected version 2.1, dated
July 2017. https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf. Accessed 12 April 2021.
Duong V (2015), Lambrechts L, Paul RE, et al. Asymptomatic humans transmit dengue virus to mosquitoes.
Proceedings of the National Academy of Sciences of the USA. 2015;112(47):14688-14693.
Endy TP (2021), Wang D, Polhemus ME, et al. A Phase 1, open-label assessment of a dengue virus-1 live virus
human challenge strain. J Infect Dis. 2021;223(2):258-267.
Fridericia LS (1920). The duration of systole in the electrocardiogram of normal subjects and patients with heart
disease. Acta Med Scand. 1920;57:469-486.
Goindin D (2015), Delannay C, Ramdini C, Gustave J, Fouque F. Parity and longevity of Aedes aegypti according
to temperatures in controlled conditions and consequences on dengue transmission risks. PLoS One.
2015;10(8):e0135489.
Grunnill M (2018). An exploration of the role of asymptomatic infections in the epidemiology of dengue viruses
through susceptible, asymptomatic, infected and recovered (SAIR) models. J Theor Biol. 2018;439:195-204.
Guzman MG (2010), Vazquez S. The complexity of antibody-dependent enhancement of dengue virus infection.
Viruses. 2010;2(12):2649-2662.
Hodges M (1983), Salerno D, Erlien D. Bazett’s QT correction reviewed: evidence that a linear QT correction for
heart rate is better. J Am Coll Cardiol. 1983;1:694.
International Councel for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human
Use. ICH Harmonized Tripartite Guideline E14: Clinical evaluation of QT/QTc interval prolongation and
proarrhythmic potential for non-antiarrhythmic drugs. ICH 12 May 2005.
Investigator's Brochure: JNJ-64281802. Edition 5. Janssen Research & Development (October 2022).
James LP, Letzig L, Simpson PM, et al, Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
Muller DA (2017), Depelsenaire ACI, Young PR. Clinical and Laboratory Diagnosis of Dengue Virus Infection.
J Infect Dis. 2017(1);215(suppl_2):S89-S95. doi: 10.1093/infdis/jiw649.
Perkins TA (2016), Paz-Soldan VA, Stoddard ST, et al. Calling in sick: impacts of fever on intra-urban human
mobility. Proc R Soc B. 2016;283(1834):20160390.
Ten Bosch Q (2018), Clapham HE, Lambrechts L, et al. Contributions from the silent majority dominate dengue
virus transmission. Plos Pathog. 2018;14(5):e1006965.
US Food and Drug Administration. Dengvaxia. https://www.fda.gov/vaccines-blood-biologics/dengvaxia. Accessed
12 April 2021.
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Whitehorn J (2011), Simmons CP. The pathogenesis of dengue. Vaccine. 2011;29(42):7221-7228.
Whitehorn J (2014), Yacoub S, Anders KL, et al. Dengue therapeutics, chemoprophylaxis, and allied tools: state of
the art and future directions. PLoS Negl Trop Dis. 2014;8(8):e3025.
World Health Organization (WHO 2019a). Dengue and severe dengue.
http://www.who.int/mediacentre/factsheets/fs117/en/. Updated June 2020. Accessed 12 April 2021.
World Health Organization (WHO 2019b). Ten threats to global health in 2019. https://www.who.int/news-
room/spotlight/ten-threats-to-global-health-in-2019. Accessed 12 April 2021.
World Health Organization (WHO 2022). Dengue and Severe dengue.  https://www.who.int/news-room/fact-
sheets/detail/dengue-and-severe-dengue. Accessed 29 August 2022.
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Status: Approved, Date: 19 July 2023
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.
NCT05201794
PPD


Signature
User 
Date 
Reason
 
19-Jul-2023
05:12:57
(GMT)
Document Approval
NCT05201794
PPD

SAP_001.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved, Date: 21 October 2024
Janssen Research & Development
Statistical Analysis Plan
A Phase 2, Randomized, Double-blind, Placebo-controlled, Double-dummy, 
MulticenterTrial Assessing the Efficacy and Safety of Two Dose Regimens of JNJ-
64281802 for thePrevention of Dengue Infection.
Protocol 64281802DNG2004; Phase 2
JNJ-64281802 (Monsnodenvir)
Status:
Approved
Date:
21 October 2024
Prepared by:
Janssen Research & Development, a division of Janssen Pharmaceutica NV
Document No.: EDMS-RIM-609281, 1.0
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.
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JNJ-64281802 (Monsnodenvir)
Statistical Analysis Plan 64281802DNG2004
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
2
Status: Approved, Date: 21 October 2024
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 4
VERSION HISTORY..................................................................................................................................... 5
1.
INTRODUCTION.................................................................................................................................. 6
1.1.
Objectives and Endpoints ................................................................................................................ 6
1.2.
Study Design.................................................................................................................................... 8
2.
STATISTICAL HYPOTHESES.......................................................................................................... 10
3.
SAMPLE SIZE DETERMINATION.................................................................................................... 10
4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS..................................................................... 12
5.
STATISTICAL ANALYSES............................................................................................................... 13
5.1.
General Considerations ................................................................................................................. 13
5.1.1.
Analysis Phase Definition ........................................................................................................... 13
5.1.2.
Visit Windows ............................................................................................................................. 13
5.2.
Participant Dispositions.................................................................................................................. 15
5.3.
Primary Endpoint(s) Analysis......................................................................................................... 15
5.3.1.
Definition of Endpoint(s) ............................................................................................................. 15
5.3.3.
Estimand..................................................................................................................................... 16
5.3.4.
Analysis Methods........................................................................................................................ 17
5.4.
Secondary Endpoint(s) Analysis .................................................................................................... 17
5.4.1.
Key Secondary Endpoint(s)........................................................................................................ 17
5.4.1.1.
Definition of Endpoint(s) .......................................................................................................... 17
5.4.1.2.
Level of Significance................................................................................................................ 18
5.4.1.3.
Estimand.................................................................................................................................. 18
5.4.1.4.
Analysis Methods .................................................................................................................... 19
5.4.2.
Supportive Secondary Analysis.................................................................................................. 20
5.4.2.1.
Symptomatic DENV infections................................................................................................. 20
5.5.
Exploratory Endpoint(s) Analysis ................................................................................................... 20
5.5.1.1.
DENV infections ...................................................................................................................... 20
5.5.1.2.
Analyses by Serotype.............................................................................................................. 21
5.5.1.3.
Quantitative DENV RNA VL Levels......................................................................................... 21
5.5.1.4.
DENV-associated signs and symptoms .................................................................................. 23
5.5.1.5.
DENV Infections in Follow-up.................................................................................................. 23
5.6.
Safety Analyses ............................................................................................................................. 24
5.6.1.
Extent of Exposure ..................................................................................................................... 24
5.6.2.
Adverse Events........................................................................................................................... 24
5.6.3.
Additional Safety Assessments (if applicable)............................................................................ 25
5.6.3.1.
Clinical Laboratory Tests......................................................................................................... 25
5.6.3.2.
Vital Signs and Physical Examination Findings....................................................................... 26
5.6.3.3.
Electrocardiogram ................................................................................................................... 27
5.7.
Other Analyses............................................................................................................................... 29
5.7.1.
Pharmacokinetics ....................................................................................................................... 29
5.7.2.
Viral Genome Sequencing.......................................................................................................... 29
5.7.3.
Biomarkers.................................................................................................................................. 29
5.7.4.
Data Monitoring Committee (DMC) or Other Review Board ...................................................... 30
6.
SUPPORTING DOCUMENTATION .................................................................................................. 31
6.1.
Appendix 1 List of Abbreviations.................................................................................................... 31
6.2.
Appendix 2 Changes to Protocol-Planned Analyses ..................................................................... 32
6.3.
Appendix 3 Index Cases ................................................................................................................ 34
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JNJ-64281802 (Monsnodenvir)
Statistical Analysis Plan 64281802DNG2004
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Status: Approved, Date: 21 October 2024
6.4.
Appendix 4 Demographics and Baseline Characteristics of the HHCs ......................................... 35
6.5.
Appendix 5 Protocol Deviations ..................................................................................................... 36
6.6.
Appendix 6 Prior and Concomitant Medications............................................................................ 37
6.7.
Appendix 7 Medical History ........................................................................................................... 38
6.8.
Appendix 8 Laboratory Related Adverse Events Coded Terms .................................................... 39
7.
REFERENCES................................................................................................................................... 42
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JNJ-64281802 (Monsnodenvir)
Statistical Analysis Plan 64281802DNG2004
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Status: Approved, Date: 21 October 2024
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:
Construction of analysis phases............................................................................................... 13
Table 2:
Visit Windows............................................................................................................................ 14
Table 3:
Solicited systemic AEs.............................................................................................................. 18
Table 4:
Data Handling Rules for anti DENV IgG Immunology Assessments........................................ 20
Table 5:
Data Handling Rules for DENV RT-qPCR levels (copies/mL).................................................. 22
Table 6:
Graded Abnormal Vital Signs ................................................................................................... 27
Table 7:
Criteria for Abnormal QTc Values and Changes from Baseline ............................................... 28
Table 8:
Demographic Variables............................................................................................................. 35
FIGURES
Figure 1:
Schematic Overview of the Study............................................................................................... 9
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JNJ-64281802 (Monsnodenvir)
Statistical Analysis Plan 64281802DNG2004
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Status: Approved, Date: 21 October 2024
VERSION HISTORY
Table [xx] – SAP Version History Summary
SAP Version
Approval Date
Change
Rationale
1
21 October 2024
Not Applicable
Initial release
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JNJ-64281802 (Monsnodenvir)
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Status: Approved, Date: 21 October 2024
1.
INTRODUCTION
This statistical analysis plan (SAP) contains definitions of analysis sets, derived variables and 
statistical methods for the analysis of efficacy and safety of study drug JNJ-64281802. A separate 
document, the data presentation specifications (DPS), for mock shells and a table of contents for 
tables, figures and listings is also produced. The SAP is to be interpreted in conjunction with the 
protocol1(amendment 3).
The study was prematurely ended on 02 October 2024 when 21 laboratory confirmed dengue
infections between baseline and last day of dosing (+1 day) were observed in the primary analysis 
population and 14 symptomatic dengue infection between baseline and last day of dosing (+1 day) 
were observed in the complete study population. This decision was taken by Johnson & Johnson 
based on portfolio reprioritization and was not based on any safety concerns. The current SAP will 
cover the final analysis (FA). Changes to the per protocol planned analysis are described in 
section 6.2, Appendix 2.
1.1.
Objectives and Endpoints
The primary, secondary and exploratory objectives and endpoints covered in this SAP are listed 
below.
Objectives
Endpoints
Primary

To evaluate the prophylactic effect of 
JNJ-64281802 with respect to the prevention 
of laboratory-confirmed DENV infection 
among household contacts (HHCs) who have 
no evidence of current DENV infection at 
baseline.

Laboratory-confirmed 
DENV 
infectiona
between baseline and the last day of dosing + 
1 day.
Key Secondary

To evaluate the prophylactic effect of 
JNJ-64281802 with respect to the prevention 
of symptomatic DENV infection through 
development of signs and symptoms (see 
Safety Evaluations section) among all HHCs.

Laboratory-confirmed symptomatic DENV 
infectionb between baseline and the last day of 
dosing + 1 day.
Secondary

To evaluate the prophylactic effect of 
JNJ-64281802 with respect to the prevention 
of symptomatic DENV infection through 
development of signs and symptoms (see 
Safety Evaluations section) among HHCs
who have no evidence of current DENV 
infection at baseline.

Laboratory-confirmed symptomatic DENV 
infectionb between baseline and the last day of 
dosing + 1 day.

To assess the safety and tolerability of 2 dose 
regimens (high and low) of JNJ-64281802 
among HHCs.

Safety and tolerability as measured by 
recording of adverse events (AEs), serious 
adverse 
events 
(SAEs), 
physical 
examinations, vital signs, electrocardiograms 
(ECGs), and clinical laboratory assessments.
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Status: Approved, Date: 21 October 2024
Objectives
Endpoints

To assess the pharmacokinetics (PK) of 
JNJ-64281802 following repeated oral dosing 
among HHCs.

Observed analyte concentrations over time.
Exploratory

To evaluate the prophylactic effect of 
JNJ-64281802 with respect to the prevention 
of DENV infection as measured through 
increase of anti-DENV antibodies among 
HHCs who have no evidence of current 
DENV infection at baseline.

Increase in anti-DENV antibodies between 
baseline and Day 40.

Increase in anti-DENV antibodies between 
baseline and Day 50.

Increase in anti-DENV antibodies between 
baseline and Day 90.

To 
identify
circulating 
DENV 
serotypes/genotypes and genetic variants 
among index cases and HHCs.

Serotype/genotype of DENV based on viral 
genome sequence analysis.

Genetic variation of viral genome sequence 
based on changes at the amino acid level.

Emergent 
JNJ-64281802 
resistance-
associated mutations in HCC using index case 
sequence as reference.
AE = adverse event; DENV = dengue virus; ECG = electrocardiogram; HHC=household contact; 
RNA=ribonucleic acid; NS = non-structural protein; PCR = polymerase chain reaction; SAE = serious adverse 
event.
a
DENV infection is defined as a positive DENV RNA or DENV NS1 protein test result.
b
Laboratory-confirmed symptomatic DENV infection is defined as having at least 2 solicited systemic AEs 
(see Safety Evaluations section), of which at least one is a most common dengue symptom (ie, fever, 
headache/retro-orbital pain, myalgia, arthralgia, rash), lasting for ≥1 day and occurring within a +/-2 days 
time window around the positive PCR or NS1 test.
The statistical analysis for the following exploratory objectives might be performed, but will 
depend on the unblinded results of the primary and secondary endpoints, for hypothesis generating 
purposes:
Objectives
Endpoints
Exploratory

To evaluate the prophylactic effect of 
JNJ-64281802 with respect to reduction of 
DENV RNA among enrolled HHCs who have 
no evidence of current DENV infection at 
baseline and who are infected post baseline.

The maximum DENV RNA levels between 
baseline and the last day of dosing + 1 day.

To 
evaluate 
the 
antiviral 
effect 
of 
JNJ-64281802 as early treatment among 
HHCs who have evidence of DENV infection 
at baseline.

Time to end of detectable DENV RNA and/or 
reduction in DENV RNA load.

DENV-associated signs and symptoms.
HYPOTHESIS
See Section 2, Statistical Hypotheses.
NCT05201794


JNJ-64281802 (Monsnodenvir)
Statistical Analysis Plan 64281802DNG2004
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
8
Status: Approved, Date: 21 October 2024
1.2.
Study Design
Study 64281802DNG2004 (further referred to as DNG2004) is Phase 2 randomized, double-blind, 
placebo-controlled, double-dummy, multicenter, interventional trial with an event-driven design
that will evaluate the prophylactic efficacy (PE) and safety of 2 dose regimens of JNJ-64281802 
for the prevention of dengue infection in HHCs of a DENV-infected index case.
As there can be up to 4 DENV serotypes circulating at any time in dengue-endemic regions, the 
conduct of the study in dengue-naïve as well as in dengue-post exposed study participants in 
endemic regions allows for the assessment of the efficacy of the 2 dose regimens and of the 
ultimate decision on one dose selection. 
There are 4 sequential phases in the study: DENV-infected index case identification, screening of 
the household contacts (HHCs) of the index case, double-blind prophylactic dosing, and the 
follow-up phase.
The study included index cases ≥1 years of age who participated for one visit only, and HHCs 
aged 16 or 18 (depending on the legal age of consent in the jurisdiction in which the study is taking 
place) to ≤65 years who were included in the intervention part of the study.
An index case is a patient (≥1 years old) with laboratory-confirmed dengue identified in the 
community (ie, hospital and/or health care center/health care provider). If the index case was a 
minor according to the local laws and regulations, assent and informed consent from the parent(s) 
or legal guardian(s) or legally acceptable representative(s) was obtained. After informed 
consent/assent was obtained from the patient or from the legal guardian(s), a blood sample for viral 
assessments was collected, and the person's HHCs were contacted. 
A HHC is a person who lives, spends the night, or regularly attends/shares/consumes 
cooking/meals in the same dwelling or housing complex as the index case. A household can 
include one or more families, or community contacts in a single or in multiple houses or dwellings, 
depending on the country, site, social-economic, and cultural characteristics. Co-workers and 
acquaintances can also be considered HHCs, if they spend time together with the index case (eg, 
during early morning hours or twilight hours). HHCs had to be asymptomatic at screening and 
could include participants with no evidence of current DENV infection (consisting of naïve and 
historical DENV infected participants) or with evidence of current DENV infection as confirmed 
by laboratory assessments on samples taken at baseline.
Participants (ie. HHCs) were randomized in a 1:1:1 ratio to receive the study intervention as high 
dose regimen (HDR), low dose regimen (LDR), or as matching placebo in a double-dummy 
fashion. The study used randomization at the individual participant level. Participants were
assigned to 1 of 3 intervention groups based on a computer-generated randomization schedule 
prepared before the study by or under the supervision of the sponsor. The randomization was
balanced by using randomly permuted blocks and was stratified by country. A separate 
randomization list was created for the PK substudy.
NCT05201794


JNJ-64281802 (Monsnodenvir)
Statistical Analysis Plan 64281802DNG2004
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
9
Status: Approved, Date: 21 October 2024
Figure 1:
Schematic Overview of the Study
* Based on negative results for DENV RNA and NS1 protein assays
°
Based on positive results for DENV RNA or NS1 protein assays
The interactive web response system (IWRS) assigned a unique intervention code, which dictated
the intervention assignment and matching study intervention kit for the participant. The 
investigator will not be provided with randomization codes. The codes will be maintained within 
the IWRS, which has the functionality to allow the investigator to break the blind for an individual 
participant.
Data that may potentially unblind the intervention assignment (ie, study intervention serum 
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.
The primary hypothesis of this study is that JNJ-64281802 is superior to placebo with respect to 
prevention of laboratory-confirmed DENV infection (further referred to as DENV infection) from 
baseline until the last day of dosing + 1 day in study participants who are DENV RNA and NS1 
protein negative at baseline (further referred to as the primary analysis population). DENV 
infection will be measured by a positive result on a DENV RNA assay and/or a DENV NS1 protein 
assay.
The study is an event-driven design where study recruitment was planned until the required 
number of events was reached. The study consists of 2 stages with an IA at the end of Stage 1 and 
the FA at the end of Stage 2 (ie, the end of the study). The objective of Stage 1 was to obtain proof-
of-concept (PoC) on the primary hypothesis. The objectives of Stage 2 were to select the dose for 
future development and to confirm superiority of the selected dose above placebo.
The IA was scheduled when 24 DENV infections were observed in the primary analysis 
population. All HHCs with an enrollment date before or at the date of this 24th laboratory 
confirmed DENV infection would be included in the IA. The IA data base should have been
NCT05201794


JNJ-64281802 (Monsnodenvir)
Statistical Analysis Plan 64281802DNG2004
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
10
Status: Approved, Date: 21 October 2024
cleaned and locked and should have contained all data of the included HHCs that is needed to 
derive the primary endpoint, all PK data and all safety and tolerability data up to their last day of 
dosing (day 28 or earlier, in case of discontinuation) + 1 day.
Based on the results from the IA and other available information from other studies (eg, human 
challenge), the LDR could be dropped in Stage 2.
Unless stopped for futility at the IA, the study would continue till 36 DENV infections were 
observed in the primary study population and 24 symptomatic DENV infections were observed in 
the complete study population. Symptomatic DENV infections are defined as having at least 2 
solicited systemic AEs (see protocol1), of which at least one is a most common dengue symptom 
(ie, fever, headache/retro-orbital pain, myalgia, arthralgia, rash), lasting for ≥1 day and occurring 
within a +/-2 days’ time window around the positive PCR or NS1 test, between baseline and the 
last day of dosing + 1 day. Both conditions on DENV infections and symptomatic DENV 
infections needed to be satisfied before recruitment was considered complete.
The study was prematurely ended before the IA on 02 October 2024 due to portfolio
reprioritization., therefore no IA is performed and the analysis after this premature end will be 
considered as FA. This decision was not based on any safety concerns.
2.
STATISTICAL HYPOTHESES
The primary hypothesis of this study is that JNJ-64281802 is superior to placebo with respect to 
prevention of laboratory-confirmed DENV infection from baseline until the last day of dosing + 1 
day in study participants who are DENV RNA and NS1 protein negative at baseline.
Laboratory-confirmed DENV infection is defined as a positive DENV RNA or a DENV NS1 
protein (ELISA) test result. The primary efficacy endpoint is the presence or absence of a 
laboratory-confirmed DENV infection between baseline and the last day of dosing + 1 day. The 
primary analysis population consists of study participants who are DENV RNA and NS1 protein 
negative at baseline. The null hypothesis is that the DENV infection rate from baseline until the 
last day of dosing + 1 day in the primary analysis population is at least as high in participants on 
prophylactic dosing with JNJ-64281802 than in participants on placebo. 
3.
SAMPLE SIZE DETERMINATION
The study is an event-driven design where study recruitment would continue until the required 
number of events was reached. Unless stopped for futility at the IA, the study would continue till 
36 DENV infections were observed in the primary study population and 24 symptomatic DENV 
infections were observed in the complete study population (see Section 4, Populations for 
Analysis). Both conditions needed to be satisfied before recruitment could be considered complete.
An IA for PoC was planned when 24 DENV infections were observed in the primary study 
population. The targets of 24/36 DENV infection events in the primary study population and 24 
symptomatic DENV in the complete study population were determined through simulation based 
on the following requirements and assumptions. 
NCT05201794


JNJ-64281802 (Monsnodenvir)
Statistical Analysis Plan 64281802DNG2004
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
11
Status: Approved, Date: 21 October 2024
Requirements

at the IA 90% power is required, using a 20% one-sided significance level, to obtain PoC on
the primary endpoint (DENV infections in the primary study population) for HDR and LDR 
if they reach the target PE of 75%;

at the FA 80% power is required, using a 2.5% one-sided significance level, to test the primary 
hypothesis of the study for HDR and LDR if they reach the target PE of 75%;

in addition, at the FA, 80% power is required, using a 20% one-sided significance level, for 
PoC for the key secondary endpoint (symptomatic DENV infections in the complete study 
population) if at least HDR reaches the target PE against symptomatic DENV infection of 
72.5%;
Assumptions

the number of eligible and recruited HHC per index case was hypothesized to be 1.5;

the proportion of unevaluable subjects (drop-outs, missing data) was hypothesized to be 20%;

the proportion of recruited HHC NS1+ and/or PCR+ at recruitment was hypothesized to be 
20%;

the incidence of DENV infection events in the primary study population was hypothesized to 
be 7.5% during the 28-day dosing period. This assumption is based on the 15 to 18% incidence 
of DENV infection in Nha Thrang (unpublished data), Vietnam, as observed during an 
epidemiologic study of HHCs using seroconversion over a 1-month period after identification 
of the index case. An incidence of ~50% of the observed seroconversion rate was assumed to 
cover variations in incidence rates across sites and countries and to allow for potential false 
positive seroconversion results;

the proportion of incident DENV infections that become symptomatic in the primary study 
population was hypothesized to be 20% during the 28-day dosing period;

the proportion of prevalent DENV infections that become symptomatic in the secondary study 
population was hypothesized to be 10% during the 28-day dosing period.
The simulations are fully described in the modelling and simulation report (MSR)2, which also 
contains the simulation programs.
The simulations showed that at the FA and under the protocol assumptions, the study design results 
in at least 85% power for the primary objective assessed for the HDR and at least 80% power for 
the key secondary analysis, irrespective of the PE LDR. If the PE LDR is at least 90% of the PE 
HDR, the study also has at least 80% power for the primary objective assessed for the LDR and 
has at least 90% power for the key secondary objective. The expected recruitment of the study 
ranges from 1250 (assuming the PE of LDR is 0%) to 1850 (assuming the PE of LDR is equal to 
the PE of HDR, ie. 75%). If the PE of LDR is 50% of the PE of HDR, the expected study 
recruitment is 1455. If 1.5 eligible HHC can be recruited/index case, this requires the identification 
of nearly 1000 index cases 
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JNJ-64281802 (Monsnodenvir)
Statistical Analysis Plan 64281802DNG2004
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
12
Status: Approved, Date: 21 October 2024
The study design is robust to minor deviations from the protocol assumption. If the PE of HDR is 
5 percentage points lower than the protocol assumptions, the power for the primary analysis (HDR) 
is maintained to ≥77%. If the incidence or prevalence of (symptomatic) DENV infections is 
different from protocol assumptions, the proposed design generally maintains a power for the 
primary analysis ≥80% and for the key secondary analysis ≥75%. However, if incidence of 
(symptomatic) DENV infections is lower than expected the total study recruitment will be 
increased.
The study ended prematurely when 21 laboratory confirmed dengue infections between baseline 
and last day of dosing (+1 day) were observed in the primary analysis population and 14 
symptomatic dengue infection between baseline and last day of dosing (+1 day) were observed in 
the completed study population.
4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled
All participants (index cases and HHCs) who sign the ICF.
Index 
Case 
population
All participants enrolled as an index case, with a laboratory-confirmed DENV infection.
Test results of a NS1 rapid test and/or RT-PCR test that were performed outside the study by 
local standard-of care ≤72 hours of screening may be used to confirm the DENV infection.
Randomized
All participants (HHCs) who are randomized in the study.
Safety
All randomized participants who received at least one dose of study intervention.
This population will be used for the safety analysis. 
Primary 
study 
population
All randomized participants who received at least one dose of study intervention, who had no 
evidence of current DENV infection at baseline (based on target not detected (TND) results for 
DENV RNA assay and, if available, a negative/borderline result for NS1 protein assays) and 
with at least 1 result for DENV RNA or NS1 protein assay available post baseline up to and 
including the last day of dosing + 1 day
This population will be used for the primary, secondary, and exploratory efficacy analyses.
Secondary study 
population
All randomized participants who received at least one dose of study intervention, who had 
evidence of current DENV infection (based on positive results for DENV RNA or NS1 protein 
assays at baseline) but without DENV signs and symptoms at baseline.
This population will be used to evaluate the exploratory objective of an antiviral effect of JNJ-
64281802 as early treatment.
Complete study 
population
All participants included in the primary or secondary study population.
This population will be used to investigate the key secondary endpoint of the effect of 
JNJ-64281802 on the prevention of symptomatic DENV infection.
PK
All participants who received at least one dose of study intervention and who have at least one 
plasma concentration data value after dosing.
This population will be used to the assess the plasma concentrations of JNJ-64281802.
NCT05201794


JNJ-64281802 (Monsnodenvir)
Statistical Analysis Plan 64281802DNG2004
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
13
Status: Approved, Date: 21 October 2024
5.
STATISTICAL ANALYSES
5.1.
General Considerations
All analysis dataset preparations and statistical analyses will be performed using SAS® version 9.4
or higher. Figures can be generated in R.
Index cases participated for one visit only, therefore the next sections are only applicable to the 
HHCs. Descriptive statistics that will be provided for the index cases can be found in Appendix 3,
Index Cases. 
5.1.1.
Analysis Phase Definition
The Prophylactic Dosing phase used for the safety evaluation and as defined below is extended 
compared to the Prophylactic Dosing phase as defined in the protocol considering the long half-
life (~10 days) of the study intervention.
Following analysis phases are defined:
Table 1:
Construction of analysis phases
Analysis phase
Start date
End date
Screening
(phase 1)
The date & time of signing the 
informed consent*
1 minute before date & time of first study drug intake**.
Prophylactic Dosing
(phase 2)
Date & time of first study drug intake**
(JNJ - 64281802 or Placebo)
Minimum of:
a.
Date of Day 50 Visit at 23.59h***
b.
Date of study termination at 23.59h
Follow-up
(phase 3) ***
End of the Prophylactic Dosing phase
+1 minute
Study termination date (date of last contact) at 23.59h
*: if no time is available then impute with 00:00
** If no time is available and randomization happened on the same day, then impute with randomization time.
*** If no Day 50 Visit was performed, the date of first study intervention intake + 49 days will be used. Participants 
recruited under protocol version 1 (dd. 09NOV2021) or earlier will not have a Follow-up phase and will have 
their prophylactic phase ending at Study termination date (date of last contact) at 23:59h.
5.1.2.
Visit Windows
As participants do not always adhere to the protocol visit schedule, the following rules are applied 
to assign actual visits to analysis visits. Listed below are the visit windows and the target days for 
each visit. The reference day is the date of first study intervention intake. The relative day (reldy) 
of each visit will be defined as:

reldy = visit date – reference date + 1 for visits on or after Day 1,

reldy= visit date – reference date for visits before Day 1.
Consequently, there is no ‘Day 0’ defined.
If a participant has 2 or more actual visits in 1 visit window, the visit closest to the target day will 
be used as the protocol visit for that visit window. The other additional visit(s) will not be used in 
the summaries or analyses, but they can be used for determination of clinically important 
endpoints. If 2 actual visits are equidistant from the target day within a visit window, the later visit 
is used.
NCT05201794


JNJ-64281802 (Monsnodenvir)
Statistical Analysis Plan 64281802DNG2004
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
14
Status: Approved, Date: 21 October 2024
All assignments will be made in chronological order. Once a visit date is assigned to a visit 
window, it will no longer be used for a later time point. Listed below (Table 2]) are the analysis
visit windows and the target days for each visit defined in the protocol.
Table 2:
Visit Windows
Parameter
Analysis 
Phase
Scheduled 
Visit Number
Time Interval
(label on output)
Time Interval
(Day)*
Target Time 
Point (Day)
[Antiviral 
Activity/
Immune]
[Screening]
[2]
[Baseline]
[<= 1]
[1]
[Prophylactic]
[6]
[Day 5]
[1 to 7]
[5]
[Prophylactic]
[10]
[Day 9]
[8 to 11]
[9]
[Prophylactic]
[14]
[Day 13]
[12 to 15]
[13]
[Prophylactic]
[18]
[Day 17]
[16 to 19]
[17]
[Prophylactic]
[22]
[Day 21]
[20 to 23]
[21]
[Prophylactic]
[26]
[Day 25]
[24 to 26]
[25]
[Prophylactic]
[29]
[Day 28]
[27 to 34]
[28]
[Prophylactic]
[30]
[Day 40]
[35 to 45]
[40]
[Prophylactic]
[31]
[Day 50]
> 45
[50]
[Follow-up]
[35]
[Day 90]
>45
[90]
[Clinical 
Laboratory]
[Screening]
[2]
[Baseline]
[<= 1]
[1]
[Prophylactic]
-
[Unscheduled]
[1 to 11]
-
[Prophylactic]
[14]
[Day 13]
[12 to 15]
[13]
[Prophylactic]
-
[Unscheduled]
[16 to 26]
-
[Prophylactic]
[29]
[Day 28]
[27 to 34]
[28]
[Prophylactic]
-
[Unscheduled]
[35 to 45]
-
[Prophylactic]
[31]
[Day 50]
> 45
[50]
[Vital Signs]
[Screening]
[1]
[Baseline]
[<= 1]
[1]
[Prophylactic]
-
[Unscheduled]
[1 to 26]
-
[Prophylactic]
[29]
[Day 28]
[27 to 34]
[28]
[Prophylactic]
[Unscheduled]
[35 to 45]
[Prophylactic]
[31]
[Day 50]
> 45
[50]
[ECG]
[Screening]
[1]
[Baseline]**
[<= 1]
[1]
[Prophylactic]
[4]/-
[Day 3]/[Unscheduled]#
[1,5]
[3]
[Prophylactic]
-
[Unscheduled]
[6 to 15]
-
[Prophylactic]
[29]
[Day 28]
[27 to 34]
[28]
[Prophylactic]
-
[Unscheduled]
>34
-
[Physical 
examination]
[Screening]
[1]
[Baseline]
[<= 1]
[1]
[Prophylactic]
-
[Unscheduled]
[1 to 44]
-
[Prophylactic]
[31]
[Day 50]
> 45
[50]
[PK]
[Screening]
[1]
[Baseline]
[<= 1]
[1]
[Prophylactic]
[4]
[Day 3]
[3]
[3]
[Prophylactic]
[6]
[Day 5]
[4 to 6]
[5]
[Prophylactic]
-
[Unscheduled]
[7]
-
[Prophylactic]
[10]
[Day 9]
[8 to 10]
[9]
[Prophylactic]
-
[Unscheduled]
[11]
-
[Prophylactic]
[14]
[Day 13]
[12 to 14]
[13]
[Prophylactic]
-
[Unscheduled]
[15 to 19]
-
[Prophylactic]
[22]
[Day 21]
[20 to 22]
[21]
[Prophylactic]
-
[Unscheduled]
[23 to 26]
-
[Prophylactic]
[29]
[Day 28]
[27 to 29]
[28]
[Prophylactic]
-
[Unscheduled]
[30 to 37]
-
[Prophylactic]
[30]
[Day 40]
[38 to 42]
[40]
[Prophylactic]
-
[Unscheduled]
[43 to 47]
-
[Prophylactic]
[31]
[Day 50]
[48 to 52]
[50]
[Prophylactic]
-
[Unscheduled]
[53 to 87]
-
NCT05201794


JNJ-64281802 (Monsnodenvir)
Statistical Analysis Plan 64281802DNG2004
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
15
Status: Approved, Date: 21 October 2024
Parameter
Analysis 
Phase
Scheduled 
Visit Number
Time Interval
(label on output)
Time Interval
(Day)*
Target Time 
Point (Day)
[Follow-up]
[35]
[Day 90]
[88,92]
[90]
*
Relative to date of first study drug intake
** Up to 60 minutes after first study intervention intake
# 
PK substudy/other participants
5.2.
Participant Dispositions
The number of HHCs in the following disposition categories will be summarized throughout the 
study by intervention group and overall:

Participants screened

Participants randomized

Participants who received study drug

Participants who discontinued study drug

Reasons for discontinuation of study drug

Participants who completed the study

Participants who terminated study prematurely

Reasons for termination of study
This summary will be created separately for the safety, the primary, the secondary and the 
complete study population.
Listings of participants will be provided for the following categories:

Participants who discontinued study drug

Participants who terminated study prematurely

Participants who were unblinded during the study period

Participants who were randomized yet did not receive study drug.
5.3.
Primary Endpoint(s) Analysis
5.3.1.
Definition of Endpoint(s)
All samples will be tested by a DENV RT-qPCR with a qualitative output. A sample is considered 
positive for DENV RNA in case the result is ‘target detected’. 
In addition, all samples will be tested by the EUROIMMUN enzyme-linked immunosorbent assay
(ELISA). The results of this test will be reported in relative units (RU)/ml and will be interpreted 
as follows:

<8 RU/ml: negative

≥8 to <11 RU/ml: borderline
NCT05201794


JNJ-64281802 (Monsnodenvir)
Statistical Analysis Plan 64281802DNG2004
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
16
Status: Approved, Date: 21 October 2024

≥11 RU/ml: positive
A sample is considered DENV NS1 positive if the qualitative DENV NS1 result is positive (ie. 
quantitative DENV NS1 result ≥11 RU/ml). Samples are considered DENV NS1 negative for 
missing ELISA results and for borderline or negative qualitative ELISA results (ie. quantitative 
DENV NS1 result <11 RU/ml).
The primary endpoint is defined as presence or absence of a laboratory-confirmed DENV infection
between baseline and the last day of dosing + 1 day. Presence of a laboratory-confirmed DENV 
infection is defined as a positive DENV RNA or DENV NS1 protein (ELISA) test result. Missing 
results between baseline and last day of dosing + 1 day will not be considered.
5.3.2.
Level of Significance
The superiority of JNJ-64281802 above placebo will be tested at 20% one-sided significance level
to assess PoC. 
5.3.3.
Estimand
The primary estimand attributes are as follows.
Population
Healthy HHCs, aged 16 or 18 (depending on the legal age of consent in the jurisdiction in which 
the study is taking place) to 65 years inclusive , with a baseline ‘target not detected (TND)’ results 
for the DENV RT-qPCR assay and, if available, a negative/borderline NS1 protein assay result
and with at least 1 post-baseline DENV RT-qPCR qualitative result up to and including the last 
day of dosing + 1 day. 
Endpoint
Binary endpoint: presence or absence of a laboratory-confirmed DENV infection between baseline 
and last day of dosing + 1 day.
Interventions
Participants will receive a high- or low-dose JNJ-64281802 regimen, or matching placebo in a 
double-dummy fashion under fed conditions.
Intercurrent Events

Prohibited medication (when considered as major protocol deviation).

Missed doses and dose interruptions: Missing a loading dose (LD), 2 consecutive maintenance 
doses (MDs), or 2 nonconsecutive MDs within a week.

Overdose of study intervention (when considered as major protocol deviation).

Wrong study intervention (when considered as major protocol deviation).
These intercurrent events will be handled using a "treatment policy strategy" (ie, data will be used 
as observed), with participants included in the study intervention group as randomized.
NCT05201794


JNJ-64281802 (Monsnodenvir)
Statistical Analysis Plan 64281802DNG2004
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
17
Status: Approved, Date: 21 October 2024
Population-level Summary
Calculated prophylactic efficacy (=1 - odds-ratio ≈1 – relative risk).
5.3.4.
Analysis Methods
Primary Estimator
The primary hypothesis of this study is that JNJ-64281802 is superior to placebo with respect to 
prevention of laboratory-confirmed DENV infection between baseline and last day of dosing.
The primary hypothesis will be evaluated based on the comparison between intervention groups 
using CIs, estimates, and p-values obtained from an exact logistic regression model adjusted for 
stratification factor region. The odds-ratio from the logistic regression model will be used to 
estimate the PE. Given the expected low incidence, this is expected to be similar to the PE 
estimated using the relative risk. The calculated prophylactic efficacy (= 1 - odds ratio ≈ 1 - relative 
risk rate) will be used as the population-level summary. The superiority of JNJ-64281802 above 
placebo will be tested at 20% one-sided significance level as a PoC. The individual 1-sided CIs  
for the prophylactic efficacy will be calculated from the regression model described above. This 
is the primary efficacy analysis. As a secondary estimator, the Mantel-Haenszel stratum-weighted 
estimator of the risk difference, adjusted for the stratification factor region will be calculated 
together with the associated CIs.
The primary objective will be assessed using the following hierarchical hypothesis testing 
approach: 
1.
In the first step, the HDR will be compared with placebo. 
2.
If a significant reduction in laboratory-confirmed DENV infections is established for the 
HDR, the LDR will be compared with placebo with regards to the primary endpoint.
Subgroup Analyses
Subgroup analyses will be performed by geographic region (American Continent, Southeast Asia), 
country, serostatus at baseline (seronegative, defined as IgG <22 RU/mL, seropositive defined as 
IgG ≥22 RU/mL) and age (<40 years, >=40 years) upon the condition that at least 6 cases are 
observed in the subgroup and over the combined placebo and active study intervention group for 
which the comparison is done.
5.4.
Secondary Endpoint(s) Analysis
5.4.1.
Key Secondary Endpoint(s)
5.4.1.1.
Definition of Endpoint(s)
The key secondary endpoint is defined as presence or absence of laboratory-confirmed 
symptomatic DENV infection between baseline and last day of dosing + 1 day. Laboratory-
confirmed symptomatic DENV infection is defined as having at least 2 solicited systemic AEs, of 
which at least one is a most common dengue symptom (see Table 3), lasting for ≥1 day and 
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Interventions
Depending on the result of the primary analysis:

If a significant reduction in laboratory-confirmed DENV infections is established for the LDR
in the primary study population: Participants on a high- or low-dose JNJ-64281802 regimen
(combined), or matching placebo in a double-dummy fashion under fed conditions.

If no significant reduction in laboratory-confirmed DENV infections is established for the 
LDR in the primary study population: Participants on a high-dose JNJ-64281802 regimen, or 
matching placebo in a double-dummy fashion under fed conditions.
Intercurrent Events

Prohibited medication (when considered as major protocol deviation).

Missed doses and dose interruptions: Missing a LD, 2 consecutive MDs, or 2 nonconsecutive 
MDs within a week.

Overdose of study intervention.

Wrong study intervention (when considered as major protocol deviation)
These intercurrent events will be handled using a "treatment policy strategy" (ie, data will be used 
as observed), with participants included in the study intervention group as randomized.
Population-level Summary
Calculated prophylactic efficacy (=1 - odds-ratio ≈ 1 – relative risk).
5.4.1.4.
Analysis Methods
The key secondary hypothesis in this study is that JNJ-64281802 is superior to placebo with respect 
to prevention of laboratory-confirmed symptomatic DENV infection between baseline and last day 
of dosing + 1 day in the complete study population.
Depending on the result of the primary analysis for the LDR, the key secondary objective will be 
assessed by: 
1.
Comparing the pooled number of events on HDR and LDR with the placebo regimen, if both 
active intervention groups showed a significant effect on the primary endpoint (as described 
in Section 5.3). 
2.
Comparing the number of events of the HDR with the placebo regimen, if only the HDR 
showed a significant effect on the primary endpoint.
Laboratory-confirmed symptomatic DENV infections will be analyzed similarly as the primary 
endpoint with the model adjusted for both the stratification factor (region) and DENV infection at 
baseline (primary/secondary study population). This includes the subgroup analyses as described 
in section 5.3.4.
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5.4.2.
Supportive Secondary Analysis
5.4.2.1.
Symptomatic DENV infections
Supportive analysis will be done with the objective to evaluate the prophylactic effect of 
JNJ-64281802 with respect to the prevention of symptomatic DENV infection between baseline 
and last day of dosing + 1 day among HHC who have no evidence of current DENV infection at 
baseline (ie. the primary study population).
The same definition, significance level, attributes and analysis methods as for the key secondary 
endpoint will be used (see 5.4.1), with exception of the population attribute as the population is 
restricted to the primary study population.
No subgroup analyses will be done for this endpoint.
5.5.
Exploratory Endpoint(s) Analysis
5.5.1.1.
DENV infections 
For IgG antibodies the actual values (RU/mL) will be available. Collected unquantifiable data of 
apassessments on anti DENV IgG Immunology will be handled according to the rules summarized 
in Table 4. 
Table 4:
Data Handling Rules for anti DENV IgG Immunology Assessments
DENV Parameter
Quantitative Limits
LOD/
LLOQ
ULOQ
Imputed Values
TND/
<LLOQ, TD (1)
>ULOQ(2)
IgG antibodies (RU/mL) (4)
2 (LLOQ)
280
1 (<LLOQ, TD)
308
(1)
LOD/2 or LLOQ/2
(2)
ULOQ+(ULOQ/10)
Exploratory analysis will be done to evaluate the prophylactic effect of JNJ-64281802 with respect 
to the prevention of DENV infection among HHC who have no evidence of current DENV 
infection at baseline (ie. the primary study population) using different definitions of DENV 
infection:

through increase of 1.5 in anti-DENV antibody between baseline and Day 40 ,

through increase of 1.5 in anti-DENV antibody between baseline and Day 50,

through increase of 1.5 in anti-DENV antibody between baseline and Day 90,
on condition that the increase results in a value > 22 RU/mL (=cut-off level).
The cut-off for the increase in anti-DENV antibody might be updated during the analysis.
The same significance level, attributes and analysis methods as for the primary endpoint will be 
used (see 5.4.1).
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No subgroup analyses will be done for this endpoint.
5.5.1.2.
Analyses by Serotype
Analyses by serotype to evaluate the prophylactic efficacy against DENV infection and against 
symptomatic DENV infection will be done upon the condition that at least 6 cases of the same 
serotype are observed over the JNJ-64281802 and placebo in group that will be compared.
In this analysis, a laboratory confirmed DENV infection is defined through the detection of DENV 
RNA of a specific serotype between baseline and the last day of dosing + 1 day. Infections with 
other serotypes will be excluded from this analysis.
The same significance level, attributes and analysis methods as for the primary and key secondary 
endpoint will be used (see sections 5.3 and 5.4.1).
No sensitivity or subgroup analyses will be done for these analyses.
5.5.1.3.
Quantitative DENV RNA VL Levels
Descriptive analyses will be done to evaluate

the prophylactic effect of JNJ-64281802 with respect to reduction of DENV RNA among 
enrolled HHC who have no evidence of current DENV infection at baseline and who are 
infected post baseline

the antiviral effect of JNJ 64281802 as early treatment among HHC who have evidence of 
DENV infection at baseline.
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Data Handling Rules
Serum DENV RT-qPCR levels will be assessed using a validated quantitative DENV RT - qPCR
assay.
Measurements collected from screening visit to the end of study below the lower limit of detection 
(LOD) and below/above the lower/upper limit of quantification (LLOQ/ULOQ) for each of the 4 
serotypes on this assay will be handled according to the rules summarized in Table 5.
Table 5:
Data Handling Rules for DENV RT-qPCR levels (copies/mL)
Serotype
LOD
LLOQ
ULOQ
Imputed Values
target not 
detected(1)
<LLOQ target 
detected(2)
>ULOQ(3)
DENV-1
29
1000
1 000 000 000
15
500 
1 100 000 000
DENV-2
60
1000
1 000 000 000
15
500 
1 100 000 000
DENV-3
36
1000
1 000 000 000
15
500 
1 100 000 000
DENV-4
55
1000
1 000 000 000
15
500 
1 100 000 000
(1)
LOD (from DENV-1)/2 rounded to the nearest integer
(2)
LLOQ/2
(3)
ULOQ+(ULOQ/10)
Before any other rule is applied, the value for each day is defined as the maximum value of
assessments performed on that day for each assay (DENV-1, DENV-2, DENV-3 and DENV-4). 
This is applied for each day separately.
Endpoint Definitions
Measurement
Formula/Definition
Reduction of DENV RNA among HHC who have no evidence of current DENV infection at 
baseline and who are infected post baseline
Peak of detectable DENV RNA
Maximum of all measured DENV RNA values
Antiviral effect of JNJ 64281802 as early treatment among HHC who have evidence of 
current DENV infection at baseline
Peak of post baseline detectable 
DENV RNA
Maximum of all post-baseline measured DENV RNA 
values
Time to end of detectable DENV RNA
Minimum of (days with undetectable DENV RNA after the last 
detectable DENV RNA result) – Day 1 + 1
If the last measured DENV RNA result is still detectable, the 
value will be censored at the last available sample.
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Analysis Methods
Reduction of DENV RNA among HHC who have no evidence of current DENV infection at 
baseline and who are infected post baseline:
Descriptive statistics on peak of detectable DENV RNA will be calculated for each study
intervention group separately. Statistics include sample size (n), mean, SD, median, minimum, and 
maximum.
Antiviral effect as early treatment among HHC who have evidence of current DENV infection 
at baseline:
Descriptive statistics on peak of post-baseline detectable DENV RNA will be calculated for each 
study intervention group separately. Statistics include sample size (n), mean, SD, median, 
minimum, and maximum.
Time-to end of detectable DENV RNA will be analyzed using Kaplan-Meier (KM) estimates. A 
summary table including number of participants included in the analysis, number of participants 
censored, 25th and 75th percentiles, and median time-to-event, with 95% CIs 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 study drug.
5.5.1.4.
DENV-associated signs and symptoms
To evaluate the antiviral effect of JNJ-64281802 as early treatment among HHC who have 
evidence of DENV infection at baseline, descriptive analyses will be done on the DENV-
associated signs and symptoms.
DENV-associated signs and symptoms are defined as the reported solicited adverse events 
(Table 3). Tabulations will be provided showing the proportion of subjects per reported adverse 
events.
Time to end of end of DENV Infection-associated AEs will be defined as the time between the 
minimum of all start dates and the maximum of all end dates+1 day and will be censored if there 
are still signs & symptoms present at Day 28. Time to end of end of DENV Infection-associated 
AEs will be analyzed using Kaplan-Meier (KM) estimates. A summary table including number of 
participants included in the analysis, number of participants censored, 25th and 75th percentiles, 
and median time-to-event, with 95% CIs 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 study drug.
5.5.1.5.
DENV Infections in Follow-up
Individual data on DENV Infections observed in follow-up period will be provided.
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5.6.
Safety Analyses
All safety analyses will be based on the safety analysis set and actual intervention received, unless 
otherwise specified.
For all continuous safety variables, descriptive statistics by intervention group will include: N, 
mean, standard deviation, median, minimum, and maximum. Categorical variables will be 
summarized by intervention group using frequency counts and percentages.
5.6.1.
Extent of Exposure
The number and percentage of participants who received study intervention will be summarized
by study intervention group. 
Study intervention duration is defined as:
date of last dose of study intervention – date of first dose of study intervention +1
(including days off study intervention).
Duration of intervention will be summarized in the following duration categories: 
[<1 week, 1-<2 weeks, 2-<3 weeks, 3-<4 weeks, 4 weeks].
Total dosing days of intervention is defined as:
total number of days that study intervention
was taken by
the participant 
(excluding days off study intervention).
Compliance is defined as:
Compliance (%) = 100 x Total dosing days of intervention/Study intervention duration 
Study intervention compliance will be summarized descriptively. In addition, compliance will be 
summarized in the following categories:
o
The number of full compliant participants,
o
The number of participants for which >= 1 LD was missed,
o
The number of participants for which >= 1 MD was missed,
o
The number of participants with 2 consecutive missed MDs,
o
The number of participants with > 1 missed MDs within a week.
Exposure and compliance will be given for each of the following population: safety, primary, 
secondary and complete study population.
5.6.2.
Adverse Events
The verbatim terms used in the CRF by investigators to report adverse events will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA version 25.0). Any AE occurring at 
or after the initial administration of study intervention until the last study-related activity, or until 
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the participant has been deemed lost to follow-up after demonstration of due diligence of follow-
up efforts will be considered as treatment emergent. If the event occurs on the day of the initial 
administration of study intervention, and either event time or time of administration are missing, 
then the event will be assumed to be treatment emergent (TE), unless the AE is reported based on 
a baseline laboratory result, in which case the AE will be assigned to the screening phase. The list 
of coded AE terms that are based on a laboratory result is included in appendix 8 (section 6.8). If 
the event date is recorded as partial or completely missing, then the event will be considered as
treatment emergent unless it is known to be prior to the first administration of study intervention
based on partial onset date or resolution date. All reported adverse events will be included in the 
analysis. For each adverse event, the number and percentage of participants who experience at 
least 1 occurrence of the given event will be summarized by intervention group.
Separate tables and participants listings will be created for solicited (see Table 3) and unsolicited 
adverse events, showing the results by study intervention group.
Summary tables by study intervention group will be provided for adverse events by phase 
(Prophylactic Dosing, Follow-up and both phases combined):

AEs

Serious AEs (SAEs)

AEs leading to discontinuation of study intervention/termination of study participation

AEs by toxicity grade assigned by the investigator, based upon protocol appendix 9.

AEs by relationship to study intervention

AEs leading to dose interruption of study intervention
In addition to the summary tables, participants listings will be provided for participants who:

Had SAEs

Had AEs leading to discontinuation/interruption of study intervention or termination of study 
participation
A listing of participants who died will be provided.
5.6.3.
Additional Safety Assessments (if applicable)
5.6.3.1.
Clinical Laboratory Tests
Clinical laboratory tests will be displayed for the participants included in the safety analysis set
and will be restricted to the laboratory tests as required by Section 10.8 appendix 8 of the protocol, 
with exception of the differential WBC counts for which the level of data cleaning was deemed 
insufficient (neutrophils, lymphocytes, monocytes, eosinophils and basophils). The analysis of 
laboratory data will be done at the level of standardized values and units.
As for some laboratory tests local labs are used for the value determination, pooled results over 
the different labs will only be provided on the categorical results, ie. based on the normal limits or 
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based on toxicity grades. The laboratory reference ranges from the lab where the samples were 
analyzed will be used to determine the laboratory abnormalities or toxicity grades.
Toxicity grades will be determined according to the Table for Laboratory Abnormalities as shown 
in the original protocol (dated 09 November 2021), or, if not available, as shown in protocol 
amendment 3 (dated 19 July 2023), Section 10.9 Appendix 9 and will be attributed to the baseline 
and postbaseline values. In case no toxicity grades are defined for a test, the abnormalities 
(below/above normal ranges) will be used.
Postbaseline abnormalities will be compared with their corresponding baseline result:

For toxicity grades, treatment emergence (TE) will be concluded if the postbaseline grade is 
worse than the baseline grade.

For abnormalities based on normal range and/or criteria: If the postbaseline value is above the 
upper limit and the baseline value is below the upper limit (eg, Normal or Low), then the 
postbaseline abnormality will be considered TE. The same applies to the postbaseline value 
being below the lower limit with the baseline value being above the lower limit (eg, Normal 
or High).

If the baseline value is missing, a postbaseline abnormality will always be considered as TE.

The worst TE grade/abnormality will be determined. The worst TE toxicity grade is the 
highest grade reached. For non-graded abnormalities, the ‘low’ and ‘high’ classes are equally 
worse, both will be considered as worst abnormality.
A summary table will show the number and percentage of participants per TE abnormality. Shift 
summaries from baseline laboratory value to the worst toxicity grade/abnormality in chemistry 
and hematology tests will be presented by intervention group.
Descriptive statistics and mean ± SE graphs by lab and by study intervention will be presented at 
scheduled time points on actual values and changes from baseline for chemistry, hematology, and 
urinalysis (pH and specific gravity) laboratory tests restricted to the laboratory tests for the labs in 
which at least 100 participants were analyzed.
In addition to the above tables, summary listings will be provided for all participants with 
treatment-emergent abnormal laboratory values of at least grade 2, or with reported clinically 
significant laboratory results whether treatment-emergent or not. This listing will include all other 
time points for the corresponding participant/parameter. 
5.6.3.2.
Vital Signs and Physical Examination Findings
Continuous vital sign parameters including pulse and blood pressure (systolic and diastolic) will 
be summarized at each scheduled assessment time point. Change from baseline will be 
summarized by intervention group. Descriptive statistics (mean, standard deviation, median, 
minimum and maximum) will be presented.
According to protocol, vital signs parameters should have been collected in supine position. 
However, if these are not available, available standing or semi-recumbent position can be used.
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Abnormality grades will be determined according to the Division of Acquired Immunodeficiency 
Syndrome (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, 
Version 2.0 (DAIDS 2017) and supplemented where values were absent (see Table 6) and will be 
attributed to the baseline and postbaseline values.
Table 6:
Graded Abnormal Vital Signs
Vital Sign
Mild (Grade 1)
Moderate (Grade 2)
Severe (Grade 3)
Pulse (bpm)
Tachycardia
>100-115
>115-130
>130
Bradycardia
50-54
<50-45
<45
Systolic blood pressure (mmHg)
Hypertension (Systolic)
141-150
>150-155
>155
Hypotension (Systolic)
85-89
80-<85
<80
Diastolic blood pressure (mmHg)
Hypertension (Diastolic)
91-95
>95-100
>100
Postbaseline values will be compared with their corresponding baseline values.

TE will be concluded if the postbaseline grade is worse than the baseline grade.

If the baseline value is missing, a postbaseline abnormality will always be considered as TE.

The worst TE grade will be determined. The worst TE toxicity grade is the highest grade 
reached.
A summary table will show the number and percentage of participants per emergent abnormality.
In addition, shift summaries from baseline value to the abnormality will be presented by 
intervention group. 
A listing of abnormal individual participant vital signs values from scheduled and unscheduled
time points will be provided. This listing will include all other time points for the corresponding
participant/parameter
All abnormal physical examination results will be listed, including clinical significance 
specifications if/as provided.
5.6.3.3.
Electrocardiogram
The ECG parameters as measured by the central monitoring that will be analyzed are heart rate, 
PR interval, RR interval, QRS interval, QT interval, and corrected QT (QTc) interval using the 
following correction methods: Bazett’s formula (QTcB) and Fridericia’s formula (QTcF)3,4.
QTcB and QTcF values will be used as reported by central ECG lab, they will not be recalculated.
If ECG measurements are repeated at a visit, only the first measurement will be considered in the 
‘Visit’ ECG result. The repeat measurements can be used for the worst TE grade/abnormality as 
explained below.
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Descriptive statistics (mean, standard deviation, median and ranges) of actual ECG parameters and 
change from baseline will be summarized by intervention group at each scheduled time point.
The actual values for HR, PR, QRS, QTcB and QTcF and the changes from baseline for QTcB 
and QTcF will be categorized into abnormalities using the boundaries defined in Table 7.
Table 7:
Criteria for Abnormal QTc Values and Changes from Baseline
Abnormality class and label
ECG parameter
HR (bpm)
PR (ms)
QRS (ms)
QTcB 
and 
QTcF 
Abnormalities for actual values
Low
< 45
< 110
-
-
High
≥ 120
≥ 220
≥ 120
-
]450, 480] ms M/F (*)
> 450 - ≤ 480
]450, 480] ms M/F (*)
> 470 - ≤ 480
]480, 500] ms
> 480 - ≤ 500
> 500 ms
> 500
Abnormalities for change from baseline
]30, 60] ms
> 30 - ≤ 60
> 60 ms
> 60
(*) The boundaries for QTcB and QTcF abnormalities are different for males and females, but the same abnormality 
label will be used.
No abnormalities will be defined for uncorrected QT, but uncorrected actual QT values >500 ms 
will be flagged and only shown in listings. Actual QTc values ≤450 ms are considered as normal, 
as well as all changes ≤30 ms.
Postbaseline abnormalities will be compared with their corresponding baseline result:

TE will be concluded if the postbaseline value is above the upper limit and the baseline value 
is below the upper limit (eg, Normal or Low). The same applies to the postbaseline value 
being below the lower limit with the baseline value being above the lower limit (eg, Normal 
or High).

If the baseline value is missing, a postbaseline abnormality will always be considered as TE.

When changes from baseline are concerned (QTcB/QTcF), abnormality classes are always 
TE, per definition.

The worst TE grade/abnormality by phase will be determined. For non-graded abnormalities, 
the ‘low’ and ‘high’ classes are equally worse, both will be considered as worst abnormality.
A summary table will show the number and percentage of participants per emergent abnormality
for the prophylactic phase. A cross-tabulation of the worst abnormality versus baseline will be 
presented by intervention group. 
A tabulation of the worst QT/QTc change versus baseline will be presented by study intervention.
A listing of clinically relevant ECG abnormalities from scheduled and unscheduled time points 
will be provided. This listing will include all other time points for the corresponding 
participant/parameter.
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Subgroup Analyses
Subgroup analysis for the participants included PK substudy will be performed.
5.7.
Other Analyses
5.7.1.
Pharmacokinetics
All HHCs who received at least 1 dose of study drug and have at least 1 plasma concentration 
value after administration will be included in the analysis. Individual JNJ-64281802 plasma 
concentrations will be listed and summarized with descriptive statistics (n, mean, SD, geometric 
mean, median, minimum, maximum and interquartile ranges) by dose. Individual and summarized 
plasma concentration results may be graphically presented by dose and at selected time points. In 
this graphical presentation, special attention will be given to plasma concentration profiles of 
HHCs who have a lab-confirmed DENV infection between baseline and the last day of dosing + 1 
day. Special attention to plasma concentration-time profiles may also be given to individuals with 
SAEs.
5.7.2.
Viral Genome Sequencing
DENV viral genome sequence analysis will be performed to evaluate the presence of 
polymorphisms and genetic variations on the amino acid level and to define the serotype/genotype 
of the DENV virus.
Sequencing is focused on a predefined list of positions of interest.
The list of positions of interest might be updated during the analysis.
Polymorphisms, ie, genetic variations, are defined as amino acid changes from serotype-specific 
DENV reference sequences.
Wild type: If at certain position the amino acid in the participant sequence matches the reference
sequence, that is no genetic variation is present at that position, the virus is considered to be wild
type at that position.
Number (%) of participants with a specific substitution and number (%) of participants with a
specific DENV serotype/genotype will be analysed.
Frequencies and percentages will be presented for the specified parameters. The denominator is
the number of participants with sequencing data. Summaries will be provided by subgroups and
intervention groups.
A separate SAP and virology report may be prepared.
5.7.3.
Biomarkers
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 
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discretion and are not part of this SAP. The analyses will always be under the supervision of the 
sponsor. 
Results will be presented in the main study report or a separate report.
5.7.4.
Data Monitoring Committee (DMC) or Other Review Board
An IDMC was commissioned for this study and reviewed unblinded safety data on a regular basis 
throughout the conduct of this study to ensure participant safety. The committee did meet
periodically to review these safety data. 
At any point during the study, following any reviews of safety, PK and/or IAs data, the IDMC had
the authority to recommend to the Sponsor Committee modifications to the study conduct and/or 
to the safety assessments, or to halt a dose arm due to safety concerns. Based on the 
recommendations of the IDMC, the Sponsor Committee could decide that changes to the study 
should be implemented. 
Further details on the composition of the IDMC, the content of the data package and the frequency 
of the meetings are available in the IDMC charter.
The regular IDMC analyses followed this SAP, but data was restricted to the following:
Index Case Data
Index cases
section 6.3
General Information Data
Participant Dispositions
section 5.2
Demographics and Baseline Characteristics
section 6.4
Protocol Deviations
section 6.5
Extent of Exposure
section 5.6.1
Efficacy Data
Primary Endpoint(s) Analysis
section 5.3
Safety Data
Adverse Events
section 5.6.2
Clinical Laboratory Tests
section 5.6.3.1
Vital 
Signs 
and 
Physical 
Examination section 5.6.3.2
Electrocardiogram
section 5.6.3.3
Other Analyses Data
Pharmacokinetics
section 5.7.1
A Separate DPS specifying the outputs created for the IDMC analyses is also produced.
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Statistical Analysis Plan 64281802DNG2004
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Status: Approved, Date: 21 October 2024
6.
SUPPORTING DOCUMENTATION
6.1.
Appendix 1 List of Abbreviations
AE
adverse event
ATC
anatomic and therapeutic class
AUC
area under the curve
AUCτ
area under the concentration curve during one dosing interval
BMI
body mass index
CI
confidence interval
Cmax
maximum concentration
CPAP
Clinical pharmacology analysis plan
CRF
Case report form
Ctrough
observed analyte concentration just prior to the beginning or at the end of a dosing interval
DENV
Dengue virus
DMC
Data Monitoring Committee
DPS
Data Presentation Specifications
ECG
electrocardiogram
FA
Final analysis
FDA
Food and Drug Administration
HDR
High dose regimen
HHC
Household contact
IA
Interim Analysis
ICF
Informed consent form
IDMC
Independent data monitoring committee
Ig
Immunoglobulin
IWRS
interactive web response system
LD
Loading dose
LDR
Low dose regimen
LLOD
lower limit of detection
LLOQ
Lower limit of quantification
MD
Maintenance dose
MedDRA
Medical Dictionary for Regulatory Activities
MSR
Modelling and simulation report
NAb
neutralizing antibodies
NS
Non-structural protein
PCR
Polymerase chain reaction
PD
pharmacodynamic(s)
PE
Prophylactic efficacy
PK
pharmacokinetic(s)
PoC
Proof-of-concept
qPCR
Quantitative polymerase chain reaction
RNA
Ribonucleic acid
RT
Reverse transcription
SAE
serious adverse event
SAP
Statistical analysis plan
SAS
Statistical analysis sofware
SD
standard deviation
SE
Standard error
SMQs
standardised MedDRA queries
SSG
Statistical support group
Tmax
time to maximum concentration
VL
Viral Load
WHO
World Health Organization
WHO-DD
World Health Organization Drug Dictionary
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JNJ-64281802 (Monsnodenvir)
Statistical Analysis Plan 64281802DNG2004
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 21 October 2024
6.2.
Appendix 2 Changes to Protocol-Planned Analyses
1) Minor updates and clarifications are made to the primary estimand when compared to the 
definition in the protocol. The modifications are done based on the available data and new 
insights on the detectability of a laboratory confirmed DENV infection using different assays: 
-
1 extra day is added to the observation period of the endpoint because for some participants 
the Day 28 assessment is performed 1 day after the last dose,
-
intercurrent events are modified and clarified: fasted intake of study intervention is not 
considered as intercurrent event based on the quality of the data collected for this purpose, 
clarifications are added to the missed doses and treatment interruptions, overdose of study 
intervention and wrong IP have been added as intercurrent events.
-
the stratification factor ‘country’ is updated to ‘region’ in the logistic model used for the 
primary estimand of the prophylactic efficacy to avoid quasi-complete separation of data 
points due to the low number of events. Similarly, region is used as the stratification factor 
in the Mantel-Haenszel stratum-weighted estimator of the risk difference.
-
the 2-sided confidence interval was updated to a corresponding 1-sided confidence interval.
2) The definition of the complete study population is updated to “All participants included in the 
primary or secondary study population”: a minimum of DENV RNA and/or NS1 protein assay 
data should be available to be able to confirm by laboratory data that the signs and symptoms 
are caused by a DENV infection.
3) The study was prematurely ended on 02 October 2024 when 21 laboratory confirmed dengue 
infections between baseline and last day of dosing (+1 day) were observed in the primary 
analysis population and 14 symptomatic dengue infection between baseline and last day of 
dosing (+1 day) were observed in the complete study population. This decision was taken by 
Johnson & Johnson based on portfolio reprioritization and was not based on any safety 
concerns.
Because of this early termination, the following changes to the per protocol-planned analyses 
are done: the planned IA is skipped, the sensitivity estimators for the primary objective are not 
calculated, the PK analyses is restricted to descriptive statistics on the individual plasma 
concentration-time data, the PK/PD analyses are not done, some exploratory analyses are left 
out and the analysis is considered final.
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JNJ-64281802 (Monsnodenvir)
Statistical Analysis Plan 64281802DNG2004
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 21 October 2024
The following exploratory analysis are left out:
-
Exploratory analysis on the prophylactic effect of JNJ-64281802 with respect to the 
prevention of DENV infection as measured by DENV ribonucleic acid (RNA) 
-
Exploratory analysis on the prophylactic effect of JNJ-64281802 as measured through 
detection of DENV NS1 protein 
It is clear from the available data that all laboratory confirmed DENV infections have 
detectable RNA on at least 1 time point, while only a minority have detectable DENV NS1 
protein.
-
Exploratory analysis to evaluate the prophylactic effect of JNJ‑64281802 with respect to 
the prevention of symptomatic DENV infection up to Day 40, Day 50 and Day 90 
Only isolated cases of symptomatic DENV infections after the last dose of study intervention 
are observed.
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JNJ-64281802 (Monsnodenvir)
Statistical Analysis Plan 64281802DNG2004
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 21 October 2024
6.3.
Appendix 3 Index Cases
Index cases will participate for one visit only.
Disposition
The number of Index cases in the following disposition categories will be summarized:

Index cases enrolled

Index cases for which the DENV infection was confirmed by the central lab test
An overview will be provided by region, country and site ID, showing per index case the number 
of HHCs (1, 2, 3 or > 3) that entered in the trial.
A summary will be provided of the different serotypes per region/country and clinical site.
Viral sequencing.
Exploratory analysis will be done to determine the circulating DENV serotypes/genotypes among 
the index cases.
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JNJ-64281802 (Monsnodenvir)
Statistical Analysis Plan 64281802DNG2004
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 21 October 2024
6.4.
Appendix 4 Demographics and Baseline Characteristics of the HHCs
The number of participants in each analysis set will be summarized and listed by intervention 
group and overall. In addition, the distribution of participants by region, country, and site ID will 
be presented unless otherwise noted.
Table 8 presents a list of the demographic variables that will be summarized by intervention group 
and overall for the primary, secondary and safety analysis set.
Table 8:
Demographic Variables
Continuous Variables:
Summary Type
Age ([years])
Descriptive statistics (N, mean, 
standard deviation [SD], median 
and range [minimum and 
maximum]).
Weight (kg)
Height (cm)
Body Mass Index (BMI) (kg/m2)
Categorical Variables
Age ([≤25 years, 26-40 years, 41-55 years, and > 55 years])
Frequency distribution with the 
number and percentage of 
participants in each category.
Sex (male, female, undifferentiated)
Racea (American Indian or Alaska Native, Asian, Black or African 
American, Native Hawaiian or other Pacific Islander, White, Multiple)
Ethnicity (Hispanic or Latino, not Hispanic or Latino)
BMI ([underweight <18.5 kg/m2, normal 18.5-<25 kg/m2, overweight 25-
<30 kg/m2, obese >=30 kg/m2])
Region ((Asia-Oceania (APAC), Europe and Middle East and Africa
(EMEA), North America (NA), and Latin America and the
Caribbean (LATAM))
Country
Baseline Serology (IgG) (<16 relative units (RU)/mL (negative); ≥16 to <22 
RU/mL (borderline); ≥22 RU/mL (positive))
aIf multiple race categories are indicated, the Race is recorded as 'Multiple'
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JNJ-64281802 (Monsnodenvir)
Statistical Analysis Plan 64281802DNG2004
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 21 October 2024
6.5.
Appendix 5 Protocol Deviations
In general, the following list of major protocol deviations may have the potential to impact 
participants’ rights, safety or well-being, or the integrity and/or result of the clinical study. 
Participants with major protocol deviations will be identified prior to database lock and the 
participants with major protocol deviations will be summarized by category.

Developed withdrawal criteria but not withdrawn

Entered but did not satisfy criteria

Received a disallowed concomitant treatment

Received wrong treatment or incorrect dose

Missed doses

Other
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JNJ-64281802 (Monsnodenvir)
Statistical Analysis Plan 64281802DNG2004
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 21 October 2024
6.6.
Appendix 6 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 continued after the first dose of study intervention.
Summaries of concomitant medications will be presented by ATC1 and ATC2 term, standardized 
medication name, intervention group, and study phase (prophylactic, follow-up and combination 
of prophylactic and follow-up). The proportion of participants who receive each concomitant 
medication will be summarized as well as the proportion of participants who receive at least 1
concomitant medication. 
Prior medications will be listed.
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JNJ-64281802 (Monsnodenvir)
Statistical Analysis Plan 64281802DNG2004
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 21 October 2024
6.7.
Appendix 7 Medical History
The medical history will be listed.
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JNJ-64281802 (Monsnodenvir)
Statistical Analysis Plan 64281802DNG2004
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 21 October 2024
6.8.
Appendix 8 Laboratory Related Adverse Events Coded Terms 
The following adverse events are related to laboratory assessments and will be assigned to the 
screening phase when the start date equals the date of first study drug intake:
AEBODSYS
AEDECOD
Blood and lymphatic system disorders
Anaemia
Blood and lymphatic system disorders
Eosinophilia
Blood and lymphatic system disorders
Hypochromic anaemia
Blood and lymphatic system disorders
Iron deficiency anaemia
Blood and lymphatic system disorders
Leukocytosis
Blood and lymphatic system disorders
Lymphadenopathy
Blood and lymphatic system disorders
Microcytic anaemia
Blood and lymphatic system disorders
Neutropenia
Blood and lymphatic system disorders
Normochromic normocytic anaemia
Blood and lymphatic system disorders
Normocytic anaemia
Blood and lymphatic system disorders
Thrombocytopenia
Blood and lymphatic system disorders
Thrombocytosis
Hepatobiliary disorders
Hyperbilirubinaemia
Infections and infestations
Asymptomatic bacteriuria
Infections and infestations
Pyuria
Investigations
Activated partial thromboplastin time prolonged
Investigations
Alanine aminotransferase decreased
Investigations
Alanine aminotransferase increased
Investigations
Amylase increased
Investigations
Aspartate aminotransferase decreased
Investigations
Aspartate aminotransferase increased
Investigations
Bacterial test
Investigations
Blood alkaline phosphatase
Investigations
Blood alkaline phosphatase increased
Investigations
Blood bilirubin increased
Investigations
Blood cholesterol increased
Investigations
Blood creatine phosphokinase
Investigations
Blood creatine phosphokinase increased
Investigations
Blood glucose decreased
Investigations
Blood glucose increased
Investigations
Blood lactate dehydrogenase increased
Investigations
Blood phosphorus decreased
Investigations
Blood potassium increased
Investigations
Blood pressure increased
Investigations
Blood triglycerides increased
Investigations
Blood uric acid increased
Investigations
Blood urine present
NCT05201794


JNJ-64281802 (Monsnodenvir)
Statistical Analysis Plan 64281802DNG2004
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 21 October 2024
Investigations
Gamma-glutamyltransferase increased
Investigations
Glucose urine present
Investigations
HIV test positive
Investigations
Haemoglobin decreased
Investigations
Hepatic enzyme increased
Investigations
Lipase increased
Investigations
Low density lipoprotein increased
Investigations
Lymphocyte count decreased
Investigations
Nitrite urine present
Investigations
Platelet count decreased
Investigations
Protein urine
Investigations
Protein urine present
Investigations
Prothrombin time prolonged
Investigations
Red blood cell sedimentation rate
Investigations
Red blood cell sedimentation rate increased
Investigations
Red blood cells urine
Investigations
Red blood cells urine positive
Investigations
Transaminases increased
Investigations
Urine ketone body present
Investigations
White blood cell count
Investigations
White blood cell count increased
Investigations
White blood cells urine
Investigations
White blood cells urine positive
Metabolism and nutrition disorders
Diabetes mellitus
Metabolism and nutrition disorders
Dyslipidaemia
Metabolism and nutrition disorders
Hyperamylasaemia
Metabolism and nutrition disorders
Hypercalcaemia
Metabolism and nutrition disorders
Hypercholesterolaemia
Metabolism and nutrition disorders
Hyperglycaemia
Metabolism and nutrition disorders
Hyperkalaemia
Metabolism and nutrition disorders
Hyperphagia
Metabolism and nutrition disorders
Hypertriglyceridaemia
Metabolism and nutrition disorders
Hyperuricaemia
Metabolism and nutrition disorders
Hypoalbuminaemia
Metabolism and nutrition disorders
Hypocalcaemia
Metabolism and nutrition disorders
Hypoglycaemia
Metabolism and nutrition disorders
Hypokalaemia
Metabolism and nutrition disorders
Hyponatraemia
Metabolism and nutrition disorders
Hypophosphataemia
Metabolism and nutrition disorders
Hypoproteinaemia
Metabolism and nutrition disorders
Impaired fasting glucose
Metabolism and nutrition disorders
Type 2 diabetes mellitus
NCT05201794


JNJ-64281802 (Monsnodenvir)
Statistical Analysis Plan 64281802DNG2004
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
41
Status: Approved, Date: 21 October 2024
Renal and urinary disorders
Glycosuria
Renal and urinary disorders
Haematuria
Renal and urinary disorders
Leukocyturia
Renal and urinary disorders
Proteinuria
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JNJ-64281802 (Monsnodenvir)
Statistical Analysis Plan 64281802DNG2004
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 21 October 2024
7.
REFERENCES
1.
Janssen R&D Protocol 64281802DNG2004, A Phase 2, Randomized, Double-blind, Placebo
controlled, Double-dummy, Multicentre Trial Assessing the Efficacy and Safety of Two Dose
Regimens of JNJ-64281802 for the Prevention of Dengue Infection.
2.
Janssen R&D Modeling and Simulation Report to Support the Dengue Phase 2 Study DNG2004.
3.
Bazett HC (1920). An analysis of the time-relationship of electrocardiograms. Heart. 1920;7:353-380.
4.
Fridericia LS (1920). The duration of systole in the electrocardiogram of normal subjects and patients 
with heart disease. Acta Med Scand. 1920;57:469-486.
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