A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial to Demonstrate Lot-to-Lot Consistency of 3 Lots of a Tetravalent Dengue Vaccine Candidate in Healthy Adults in Non-Endemic Country(Ies) for Dengue
Phase: PHASE3
Conditions: Dengue Fever
Sponsor: Takeda




Title: A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial to Demonstrate Lot-to-
Lot Consistency of 3 Lots of a Tetravalent Dengue Vaccine Candidate in Healthy Adults in Non-
Endemic Country(ies) for Dengue 
NCT Number: NCT03423173
Protocol Approve Date: 29 October 2018
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.

 TITLE PAGE 
TITLE PAGE 
PROTOCOL 
A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial to Demonstrate Lot-to-Lot 
Consistency of 3 Lots of a Tetravalent Dengue Vaccine Candidate in Healthy Adults in 
Non-Endemic Country(ies) for Dengue 
Lot-to-lot Consistency of 3 Lots of TDV in Non-Endemic Country(ies) for Dengue 
Sponsor: 
Takeda Vaccines, Inc. 
40 Landsdowne Street, 
Cambridge, MA 02139, 
USA 
Trial Identifier: 
DEN-304 
IND Number: 
014292 
EudraCT Number: 
Not available 
Vaccine Names: 

Investigational vaccine: tetravalent dengue vaccine candidate (TDV)
comprised of a molecularly characterized, attenuated dengue
serotype 2 strain (TDV-2), a dengue serotypes 2/1 chimeric strain
(TDV-1), a dengue serotypes 2/3 chimeric strain (TDV-3), and a
dengue serotypes 2/4 chimeric strain (TDV-4).

Placebo: saline solution.
Date: 
29 October 2018 
Version: 
Version 4.0 
Proper
f Takeda: For non-commercial use only and subject to the applicable Terms of Use

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Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-304 
Page 5 of 79 
Protocol Version 4.0 
29 October 2018 
 
 
1.3 
Protocol Amendment Summary of Changes 
This document describes the changes in reference to the Protocol incorporating Amendment No. 2. 
The primary purpose of this amendment is to remove the planned Day 120 (Month 4 [M4]) interim 
analysis. Minor grammatical and editorial changes are included for clarification purposes only. 
Full details on changes of text are given in Section 1.3.2. 
1.3.1 Amendment History 
Date 
Amendment Number 
Amendment Type 
Region 
26 September 2016 
Initial Protocol 
Not applicable 
Global 
21 July 2017 
1 
Substantial 
Global 
29 October 2018 
2 
Non-substantial 
Global 
1.3.2 Summary of Changes 
Amendment to Protocol Version 3.0, 21 July 2017 
Rationale for the Amendment: 
The rationale for removing the planned Day 120 (M4) interim analysis is that it is no longer 
required.  
The removal of this interim analysis has no impact on the final statistical analyses planned for 
this study, the scientific value of the study, the study conduct, or the safety of subjects enrolled.  
The administrative trial information has been updated and the reference list has been checked 
and updated as needed.  
Details of the changes are outlined below. In this section only (ie, not in the protocol body) all 
new text is shown in bold italics and any redundant text is marked using strikethrough. 
 
 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

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Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-304 
Page 7 of 79 
Protocol Version 4.0 
29 October 2018 
 
 
TABLE OF CONTENTS 
1.0 
ADMINISTRATIVE INFORMATION ..............................................................................2 
1.1 
Contacts..........................................................................................................................2 
1.2 
Approval ........................................................................................................................3 
1.3 
Protocol Amendment Summary of Changes..................................................................5 
1.3.1 Amendment History .................................................................................................5 
1.3.2 Summary of Changes ...............................................................................................5 
2.0 
TRIAL SUMMARY ..........................................................................................................11 
2.1 
Schedule of Trial Procedures .......................................................................................20 
3.0 
TRIAL REFERENCE INFORMATION ...........................................................................22 
3.1 
Trial-Related Responsibilities ......................................................................................22 
3.2 
Signatory Principal Investigator ..................................................................................22 
3.3 
List of Abbreviations ...................................................................................................23 
3.4 
Corporate Identification ...............................................................................................24 
4.0 
INTRODUCTION .............................................................................................................25 
4.1 
Background ..................................................................................................................25 
4.2 
Rationale for the Proposed Trial ..................................................................................26 
5.0 
TRIAL OBJECTIVES AND ENDPOINTS ......................................................................28 
5.1 
Objectives ....................................................................................................................28 
5.1.1 Primary Objective ..................................................................................................28 
5.1.2 Secondary Objectives.............................................................................................28 
5.2 
Endpoints .....................................................................................................................28 
5.2.1 Primary Endpoint ...................................................................................................28 
5.2.2 Secondary Endpoints .............................................................................................28 
6.0 
TRIAL DESIGN AND DESCRIPTION ...........................................................................30 
6.1 
Trial Design .................................................................................................................30 
6.2 
Justification for Trial Design, Dose, and Endpoints ....................................................32 
6.3 
Duration of Subject’s Expected Participation in the Entire Trial ................................32 
6.4 
Premature Termination or Suspension of Trial or Investigational Site .......................32 
6.4.1 Criteria for Premature Termination or Suspension of the Trial .............................32 
6.4.2 Criteria for Premature Termination or Suspension of Investigational Sites ..........33 
6.4.3 Procedures for Premature Termination or Suspension of the Trial or the 
Participation of Investigational Site(s)...................................................................33 
7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS ...............34 
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Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-304 
Page 8 of 79 
Protocol Version 4.0 
29 October 2018 
 
 
7.1 
Inclusion Criteria .........................................................................................................34 
7.2 
Exclusion Criteria ........................................................................................................34 
7.3 
Criteria for Delay of Vaccination and/or Blood Sampling ..........................................36 
7.4 
Criteria for Early Trial Termination of a Subject ........................................................37 
7.5 
Criteria for Premature Discontinuation of Trial Vaccine Application .........................38 
8.0 
CLINICAL TRIAL MATERIAL MANAGEMENT .........................................................40 
8.1 
Trial Vaccines and Materials .......................................................................................40 
8.1.1 Dosage Form, Packaging, and Labeling ................................................................40 
8.1.2 Storage ...................................................................................................................40 
8.1.3 Dose and Regimen .................................................................................................41 
8.2 
Trial Vaccine Assignment and Dispensing Procedures ...............................................41 
8.3 
Randomization Code Creation and Storage .................................................................42 
8.4 
Trial Vaccine Blind Maintenance ................................................................................42 
8.5 
Unblinding Procedure ..................................................................................................42 
8.6 
Accountability and Destruction of Sponsor-Supplied Vaccines ..................................43 
9.0 
TRIAL PLAN ....................................................................................................................45 
9.1 
Trial Procedures ...........................................................................................................45 
9.1.1 Informed Consent Form .........................................................................................45 
9.1.2 Demographics, Medical History and Prior Medications ........................................45 
9.1.3 Documentation of Trial Entrance/Randomization .................................................46 
9.1.4 Physical Examination.............................................................................................46 
9.1.5 Vital Signs ..............................................................................................................47 
9.1.6 Immunogenicity Assessments ................................................................................47 
9.1.7 Safety Assessments ................................................................................................47 
9.1.8 Contraception and Pregnancy Avoidance Procedure .............................................47 
9.1.9 Pregnancy ...............................................................................................................47 
9.1.10 Documentation of Subjects who are not Randomized ...........................................48 
9.2 
Monitoring Subject Compliance to TDV or Placebo Administration .........................48 
9.3 
Schedule of Observations and Procedures ...................................................................48 
9.3.1 Pre-Vaccination Procedures (Day 1 [M0] and Day 90 [M3]) ................................48 
9.3.2 Vaccination Procedures (Day 1 [M0] and Day 90 [M3]) ......................................49 
9.3.3 Post Vaccination Procedures (Day 1 [M0] and Day 90 [M3]) ..............................49 
9.3.4 Clinic Visits after Vaccination (Day 30 [M1], Day 120 [M4], and Day 270 
[M9]) ......................................................................................................................51 
9.3.5 Final (End of Trial) Visit .......................................................................................52 
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Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-304 
Page 9 of 79 
Protocol Version 4.0 
29 October 2018 
 
 
9.3.6 Post-Trial Care .......................................................................................................52 
9.4 
Biological Sample Retention and Destruction .............................................................52 
10.0 
ADVERSE EVENTS .........................................................................................................53 
10.1 
Definitions....................................................................................................................53 
10.1.1 Adverse Events ......................................................................................................53 
10.1.2 Solicited Adverse Events .......................................................................................53 
10.1.3 Medically Attended Adverse Events .....................................................................55 
10.1.4 Serious Adverse Events .........................................................................................55 
10.2 
Causality of Adverse Events ........................................................................................55 
10.2.1 Relationship to Trial Procedures ............................................................................55 
10.3 
Additional Points to Consider for Adverse Events ......................................................56 
10.4 
Procedures ....................................................................................................................57 
10.4.1 Collection and Reporting of Adverse Events.........................................................57 
10.4.2 Collection and Reporting of Solicited Adverse Events .........................................58 
10.4.3 Collection and Reporting of Medically Attended Adverse Events ........................58 
10.4.4 Collection and Reporting of Serious Adverse Events............................................58 
10.5 
Follow-up Procedures ..................................................................................................59 
10.5.1 Adverse Events ......................................................................................................59 
10.5.2 Serious Adverse Events .........................................................................................59 
10.5.3 Safety Reporting to Investigators, Institutional Review Boards, and Regulatory 
Authorities..............................................................................................................59 
10.5.4 Post-Trial Events ....................................................................................................59 
11.0 
TRIAL-SPECIFIC REQUIREMENT(S) ...........................................................................60 
11.1 
Trial-Specific Committees ...........................................................................................60 
11.1.1 Data Monitoring Committee ..................................................................................60 
12.0 
DATA HANDLING AND RECORDKEEPING ..............................................................61 
12.1 
Electronic CRFs (eCRF) ..............................................................................................61 
12.2 
Record Retention .........................................................................................................61 
13.0 
STATISTICAL METHODS ..............................................................................................63 
13.1 
Statistical and Analytical Plans ....................................................................................63 
13.1.1 Analysis Sets ..........................................................................................................63 
13.1.2 Analysis of Demographics and Other Baseline Characteristics ............................63 
13.1.3 Immunogenicity Analysis ......................................................................................63 
13.1.4 Safety Analysis ......................................................................................................64 
13.2 
Interim Analysis and Criteria for Early Termination ...................................................65 
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Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-304 
Page 10 of 79 
Protocol Version 4.0 
29 October 2018 
 
 
13.3 
Determination of Sample Size .....................................................................................65 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................66 
14.1 
Trial-Site Monitoring Visits .........................................................................................66 
14.2 
Protocol Deviations ......................................................................................................66 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections ..................................66 
15.0 
ETHICAL ASPECTS OF THE TRIAL .............................................................................67 
15.1 
Institutional Review Board ..........................................................................................67 
15.2 
Subject Information, Informed Consent, and Subject Authorization ..........................68 
15.3 
Subject Confidentiality ................................................................................................69 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy ..................................69 
15.4.1 Publication and Disclosure ....................................................................................69 
15.4.2 Clinical Trial Registration......................................................................................69 
15.4.3 Clinical Trial Results Disclosure ...........................................................................70 
15.5 
Insurance and Compensation for Injury .......................................................................70 
16.0 
REFERENCES ..................................................................................................................71 
 
LIST OF IN-TEXT TABLES 
Table 8.a 
Sponsor-Supplied Vaccines and Placebo ...............................................................41 
Table 10.a 
Local and Systemic AEs ........................................................................................54 
Table 10.b 
Solicited Safety Parameters ...................................................................................54 
Table 16.a 
Serology Plan .........................................................................................................79 
 
LIST OF IN-TEXT FIGURES 
Figure 2.a 
Schematic of Trial Design .....................................................................................13 
Figure 6.a 
Schematic of Trial Design .....................................................................................31 
 
LIST OF APPENDICES 
Appendix A 
Responsibilities of the Investigator ........................................................................73 
Appendix B 
Investigator Consent to Use of Personal Information ............................................75 
Appendix C 
Elements of the Subject Informed Consent Form ..................................................76 
Appendix D 
Serology Plan .........................................................................................................79 
 
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Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-304 
Page 11 of 79 
Protocol Version 4.0 
29 October 2018 
 
 
2.0 
TRIAL SUMMARY 
Name of Sponsor: 
Takeda Vaccines, Inc 
40 Landsdowne Street, Cambridge, MA 02139, USA 
Product Name: 
Tetravalent Dengue Vaccine Candidate (TDV) 
Trial Title: A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial to Demonstrate Lot-to-Lot Consistency 
of 3 Lots of a Tetravalent Dengue Vaccine Candidate in Healthy Adults in Non-Endemic Country(ies) for Dengue. 
IND No.: 014292 
EudraCT No.: Not applicable 
Trial Identifier: DEN-304 
Phase: 3 
Trial Blinding Schema: Double-Blind 
Background and Rationale: 
Dengue fever is caused by infection with the wild type dengue virus (DENV), a ribonucleic acid virus that occurs as 
4 recognized serotypes, DENV-1, DENV-2, DENV-3, or DENV-4. These dengue viruses are transmitted from human 
to human by mosquitoes (primarily Aedes aegypti). The 4 dengue viruses are endemic in Asia, Central and South 
America, the Caribbean, the Pacific Islands, and parts of Africa. There are an estimated 390 million dengue infections 
per year worldwide, which is more than 3 times the previous World Health Organization (WHO) estimate of 50 to 
100 million cases. Every year, around 500,000 cases of dengue hemorrhagic fever (DHF) require hospitalization with 
an estimated death rate of 2.5%, primarily in children. It is estimated that 3.9 billion people are at risk of dengue 
infection. 
Dengue fever is clinically defined as an acute febrile illness with 2 or more of the following manifestations: headache, 
retro-orbital pain, myalgia, arthralgia, rash, hemorrhagic manifestations, or leucopenia, and occurrence at the same 
location and time as other confirmed cases of dengue fever. The most severe forms of dengue infection – DHF and 
dengue shock syndrome (DSS) – are life threatening. Primary infection with any one of the 4 dengue serotypes is 
thought to result in life-long protection from re-infection by the same serotype, but does not protect against a 
secondary infection by one of the other 3 dengue serotypes and may lead to an increased risk of severe disease 
(DHF/DSS). 
Treatment of dengue fever is based solely on signs and symptoms, with fluid replacement required for hemorrhagic or 
shock cases. An antiviral therapy for dengue virus infection is not available. Preventive measures that rely on 
mosquito control and individual protection are of limited efficacy, complex to implement and questionable in terms of 
cost-effectiveness. There is a great unmet global public health need for a safe and effective vaccine to reduce the 
morbidity and mortality associated with dengue disease. Vaccine development has focused on tetravalent vaccines 
that provide protection against all 4 dengue serotypes simultaneously since all 4 dengue serotypes commonly 
co-circulate in endemic areas. A first tetravalent dengue vaccine (CYD-TDV) has been recently approved in some 
countries in Asia and Latin America. However, the initial findings suggest an unfavorable risk-benefit profile for 
younger subjects with the approved vaccine. Additionally, vaccine efficacy was different between serotypes and 
depended on dengue pre-exposure status. Hence, there is a continued unmet public health need for safer and more 
efficacious dengue vaccines. 
Tetravalent Dengue Vaccine Candidate (TDV) - Background: 
Takeda’s TDV consists of 1 molecularly characterized, attenuated dengue serotype 2 virus strain and 3 chimeric 
recombinant dengue virus strains expressing surface antigens corresponding to dengue serotypes 1–4. The dengue 
serotype 2 strain (TDV-2) is based upon the attenuated laboratory-derived virus, DENV-2 Primary Dog Kidney 
(PDK)-53, originally isolated at Mahidol University, Bangkok, Thailand. The chimeric, attenuated vaccine strains for 
dengue serotypes 1, 3 and 4 were engineered by substituting the structural genes, pre-membrane (prM) and envelope 
(E), of TDV-2 with the prM and E genes of the wild type (DENV) virus strains, DENV-1 16007, DENV-3 16562 or 
DENV-4 1036 virus, respectively. Thus TDV is comprised of 4 dengue virus strains: a molecularly characterized, 
attenuated dengue serotype 2 strain (TDV-2), a dengue serotypes 2/1 chimeric strain (TDV-1), a dengue serotypes 
2/3 chimeric strain (TDV-3), and a dengue serotypes 2/4 chimeric strain (TDV-4). 
Nonclinical studies carried out in mice and nonhuman primates have demonstrated an acceptable safety, 
immunogenicity, and efficacy profile of Takeda’s TDV. Additionally, data from completed phase 1 and phase 2 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

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Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-304 
Page 18 of 79 
Protocol Version 4.0 
29 October 2018 
 
 
analyses will be based on the PPS; additional immunogenicity analyses may be provided based on the FAS. 
Analysis of demographics and other Baseline characteristics 
Age, gender, race, and other Baseline characteristics will be summarized descriptively by trial group for all 
randomized subjects. 
Immunogenicity analysis (immunogenicity subset) 
An immunogenicity subset of 616 subjects (TDV groups: 176 subjects each and placebo group: 88 subjects) will be 
randomly selected for the immunogenicity analyses (i.e., the immunogenicity subset). 
For the primary and secondary immunogenicity endpoints (i.e., GMTs of neutralizing antibodies and seropositivity 
rates for each of the 4 dengue serotypes), descriptive statistics and 95% CIs will be provided by trial group for each 
applicable visit (Day 120 [M4] and Day 270 [M9]). Seropositivity is defined as a reciprocal neutralizing titer ≥10. 
The primary endpoint will evaluate lot-to-lot consistency at Day 120 (M4). For each serotype, an analysis of variance 
(ANOVA) model on the natural logarithms of titers of dengue neutralizing antibodies will include data from the 
subjects in Groups 1-3 with trial group as a factor. A 95% CI will be provided for the 3 pairwise comparisons of 
log-transformed GMTs. The CIs will be back-transformed in order to report 95% CIs of the ratios in the original scale. 
For each pairwise comparison, equivalence of immune responses will be established if the 95% CI for the ratio is 
contained between equivalence margins of 0.5 and 2.0. Lot-to-lot consistency will be concluded if equivalence of 
immune responses is established for all pairwise comparisons and all 4 dengue serotypes. For the secondary endpoint 
of GMT at Day 270 (M9), a similar model will be fit. 
For the secondary endpoint of seropositivity, 95% CIs for the difference in proportions between groups of interest for 
each dengue serotype at each applicable visit will be constructed using the Newcombe and Wilson method. 
The primary immunogenicity analyses will be based on the PPS; other immunogenicity analyses may be provided 
based on the FAS. 
Safety analysis (all subjects) 
All safety data will be summarized by trial group using the safety set. 
Solicited AEs 
In all subjects, the presence and severity (Grade) of solicited local AEs (injection site pain, injection site erythema and 
injection site swelling) and solicited systemic AEs (fever, asthenia, malaise, headache and myalgia) will be collected 
for 7 days and 14 days, respectively, following each vaccination (including the day of vaccination) via collection of 
diary cards. 
For each solicited AE, the number and percentage of subjects with local (injection site) and systemic AEs will be 
summarized by trial group and event severity for each day after each vaccination (ie, Day 1 through Day 7 for local 
[injection site] AEs and Day 1 through Day 14 for systemic AEs), and overall. Summaries of first onset of each event 
and the number of days subjects reported experiencing each event will also be provided. For subjects with more than 
1 episode of the same event, the maximum severity will be used for tabulations. 
Persistent/prolonged solicited local or systemic AEs continuing on Day 8 and Day 15, respectively, following each 
trial vaccination will be assessed separately. Unless otherwise specified these AEs will not be included in the 
analyses/tabulations of unsolicited AEs and will have separate listings.  
Unsolicited AEs 
Unsolicited AEs will be assessed for 28 days following each TDV/placebo dose (day of vaccination + 27 days).  
In all subjects, unsolicited AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) and 
summarized by System Organ Class (SOC) and Preferred Term (PT) for each trial group. AEs leading to trial or 
vaccine withdrawal will also be summarized for the duration of the trial. 
Unsolicited AEs will be summarized as follows: by PT including events with frequency greater than a pre-defined 
frequency (the percentage will be specified in the statistical analysis plan); by SOC and PT; by SOC, PT, and severity; 
and by SOC, PT, and relationship to the investigational vaccine. Subjects reporting more than 1 occurrence for the 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-304 
Page 19 of 79 
Protocol Version 4.0 
29 October 2018 
 
 
term (level) being summarized will be counted only once. 
MAAEs 
In all subjects, MAAEs will be collected throughout the trial. MAAEs will be coded using MedDRA, and summarized 
by SOC and PT for each trial group. 
SAEs 
In all subjects, SAEs will be collected throughout the trial. SAEs will be coded using MedDRA, and summarized by 
SOC and PT for each trial group. 
Sample Size Justification: 
It is assumed that the natural logarithms of titers of neutralizing antibodies for each of the 4 dengue serotypes are 
distributed as independent normal distributions, with standard deviations of 1.35, 0.86, 1.21, and 1.27, respectively. A 
sample size of 137 evaluable subjects in each of the 3 TDV groups (ie, Groups 1-3) is sufficient to achieve 
approximately 90% overall power for establishing lot-to-lot consistency in terms of equivalence of immune responses 
to 3 consecutive TDV lots based on the 95% CIs of the titer ratios, using equivalence margins of 0.5 and 2.0. This 
sample size assumes no variation among the 3 TDV lots; that is, for each serotype, the true ratio of GMT is 1.0 
between the first and second lots and between the second and third lots. 
Further adjusted for approximately 20% dropouts and non-evaluable subjects, the required sample size to evaluate 
lot-to-lot consistency is approximately 176 subjects for each TDV group (ie, Groups 1-3) and 88 subjects for the 
placebo group, given 2:2:2:1 randomization ratio between trial groups and taking into account ratio between the 
immunogenicity subset and its complement. Therefore, the immunogenicity subset will include 616 subjects. 
To ensure sufficient size of the safety database in the dengue non-endemic regions, overall sample size for the trial is 
924 subjects: 264 for each TDV group and 132 for placebo group.  
Interim Analysis: 
No interim analyses are planned. 
Data Monitoring Committee: 
A Data Monitoring Committee (DMC) will have oversight of this clinical trial. The DMC functions at a Takeda 
dengue program level and further information are available in the DMC Charter. 
DEN-304 Version 4.0 (29 October 2018) 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

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Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-304 
Page 22 of 79 
Protocol Version 4.0 
29 October 2018 
 
 
3.0 
TRIAL REFERENCE INFORMATION 
3.1 
Trial-Related Responsibilities 
The Sponsor will perform all trial-related activities with the exception of those identified in the 
Trial-Related Responsibilities template. The identified vendors in the template for specific 
trial-related activities will perform these activities in full or in partnership with the Sponsor. 
3.2 
Signatory Principal Investigator 
The Sponsor will select a Signatory Principal Investigator from the Investigators who participate 
in the trial. Selection criteria for this Investigator will include significant knowledge of the trial 
protocol, the investigational vaccine, their expertise in the therapeutic area and the conduct of 
clinical research as well as trial participation. The Signatory Principal Investigator will be required 
to review and sign the clinical trial report and by doing so agrees that it accurately describes the 
results of the trial. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-304 
Page 23 of 79 
Protocol Version 4.0 
29 October 2018 
 
 
3.3 
List of Abbreviations 
AE 
Adverse Event 
BMI 
Body Mass Index 
CFR 
Code of Federal Regulations 
CSR 
Clinical Study Report 
DENV 
Wild Type Dengue Virus 
DENV-1, -2, -3, -4 
Wild Type Dengue Virus Serotypes 1, 2, 3, and 4 
DHF 
Dengue Hemorrhagic Fever 
DMC 
Data Monitoring Committee 
DSS 
Dengue Shock Syndrome 
E 
Envelope 
eCRF 
electronic Case Report Form 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMT 
Geometric Mean Titer 
ICH 
International Council for Harmonization of Technical Requirements for Pharmaceuticals 
for Human Use 
Inc 
Incorporated 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
JE 
Japanese Encephalitis 
M0, -1, -3, -4, -9 
Month 0, 1, 3, 4, and 9 
MAAE 
Medically Attended Adverse Event 
MedDRA 
Medical Dictionary for Regulatory Activities 
MNT50 
Microneutralization Test 50% 
PPS 
Per-Protocol Set 
prM 
pre-Membrane 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SOC 
System Organ Class 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TDV 
Tetravalent Dengue Vaccine Candidate 
TDV-4 
Dengue Serotypes 2/4 Chimeric Strain 
TDV-1 
Dengue Serotypes 2/1 Chimeric Strain 
TDV-3 
Dengue Serotypes 2/3 Chimeric Strain 
TDV-2 
Molecularly Characterized, Attenuated Dengue Serotype 2 Strain 
WHO 
World Health Organization 
WN 
West Nile 
YF 
Yellow Fever 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-304 
Page 24 of 79 
Protocol Version 4.0 
29 October 2018 
 
 
3.4 
Corporate Identification 
TV 
Takeda Vaccines, Inc. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-304 
Page 25 of 79 
Protocol Version 4.0 
29 October 2018 
 
 
4.0 
INTRODUCTION 
4.1 
Background 
Dengue fever is caused by infection with the wild type dengue virus (DENV), a ribonucleic acid 
virus that occurs as 4 recognized serotypes, DENV-1, DENV-2, DENV-3, or DENV-4. These 
dengue viruses are transmitted from human to human by mosquitoes (primarily Aedes aegypti). 
The 4 dengue viruses are endemic in Asia, Central and South America, the Caribbean, the Pacific 
Islands, and parts of Africa. There are an estimated 390 million dengue infections per year 
worldwide, which is more than 3 times the previous World Health Organization (WHO) estimate 
of 50 to 100 million cases. Every year, around 500,000 cases of dengue hemorrhagic fever (DHF) 
require hospitalization with an estimated death rate of 2.5%, primarily in children. It is estimated 
that 3.9 billion people are at risk of dengue infection [1-4]. 
Dengue fever is clinically defined as an acute febrile illness with 2 or more of the following 
manifestations: headache, retro-orbital pain, myalgia, arthralgia, rash, hemorrhagic 
manifestations, or leucopenia, and occurrence at the same location and time as other confirmed 
cases of dengue fever. The most severe forms of dengue infection – DHF and dengue shock 
syndrome (DSS) – are life threatening. Primary infection with any one of the 4 dengue serotypes is 
thought to result in life-long protection from re-infection by the same serotype, but does not 
protect against a secondary infection by one of the other 3 dengue serotypes and may lead to an 
increased risk of severe disease (DHF/DSS) [3-6]. 
Treatment of dengue fever is based solely on signs and symptoms, with fluid replacement required 
for hemorrhagic or shock cases. An antiviral therapy for dengue virus infection is not available. 
Preventive measures that rely on mosquito control and individual protection are of limited 
efficacy, complex to implement and questionable in terms of cost-effectiveness. There is a great, 
unmet global public health need for a safe and effective vaccine to reduce the morbidity and 
mortality associated with dengue disease [1-7]. Vaccine development has focused on tetravalent 
vaccines that provide protection against all 4 dengue serotypes simultaneously since all 4 dengue 
serotypes commonly co-circulate in endemic areas. A first tetravalent dengue vaccine 
(CYD-TDV) has been recently approved in some countries in Asia and Latin America [8]. 
However, the initial findings suggest an unfavorable risk-benefit profile for younger subjects with 
the approved vaccine. Additionally, vaccine efficacy was different between serotypes and 
depended on dengue pre-exposure status. Hence, there is a continued unmet public health need for 
safer and more efficacious dengue vaccines [9, 10]. 
Tetravalent Dengue Vaccine Candidate (TDV) - Background: 
Takeda’s TDV consists of 1 molecularly characterized, attenuated dengue serotype 2 virus strain 
and 3 chimeric recombinant dengue virus strains expressing surface antigens corresponding to 
dengue serotypes 1–4. The dengue serotype 2 strain (TDV-2) is based upon the attenuated 
laboratory-derived virus, DENV-2 Primary Dog Kidney (PDK)-53, originally isolated at Mahidol 
University, Bangkok, Thailand [11]. The chimeric, attenuated vaccine strains for dengue serotypes 
1, 3 and 4 were engineered by substituting the structural genes, pre-membrane (prM) and envelope 
(E), of TDV-2 with the prM and E genes of the wild type (DENV) virus strains, DENV-1 16007, 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-304 
Page 26 of 79 
Protocol Version 4.0 
29 October 2018 
 
 
DENV-3 16562 or DENV-4 1036 virus, respectively [12]. Thus TDV is comprised of 4 dengue 
virus strains: a molecularly characterized, attenuated dengue serotype 2 strain (TDV-2), a dengue 
serotypes 2/1 chimeric strain (TDV-1), a dengue serotypes 2/3 chimeric strain (TDV-3), and a 
dengue serotypes 2/4 chimeric strain (TDV-4). 
Nonclinical studies carried out in mice and nonhuman primates have demonstrated an acceptable 
safety, immunogenicity, and efficacy profile of Takeda’s TDV. Additionally, data from completed 
phase 1 and phase 2 clinical trials in humans have shown satisfactory reactogenicity, safety and 
immunogenicity profiles of Takeda’s TDV in healthy adults in non-endemic areas as well as in 
healthy adults and children in endemic areas in Asia and Latin America. Ongoing and completed 
phase 2 clinical trials have enabled the selection of a final TDV dose (lyophilized formulation) and 
a 2-dose vaccination regimen 3 months apart by subcutaneous (SC) injection for use in the pivotal 
program. 
The current Investigator’s Brochure contains additional product information and a more detailed 
review of pre-clinical and clinical trials [14]. 
4.2 
Rationale for the Proposed Trial 
Different production lots of TDV will be used in upcoming clinical trials. The WHO guidelines for 
independent lot release of vaccines specify that no new biological substance should be released 
until consistency of manufacturing and quality, as demonstrated by a consistent release of batches, 
has been established [14]. In addition, the WHO recommends assessment of lot-to-lot consistency 
with the specific aim of comparing immunogenicity and safety between equal numbers of subjects 
who receive different lots [15]. The primary objective of this trial is to investigate lot-to-lot 
consistency in terms of equivalence of the immune responses induced by 3 consecutive TDV lots 
in a healthy adult population in country(ies) non-endemic for dengue. It is anticipated that the 
conclusion from this trial can be extrapolated to age groups other than adults. This trial will also 
contribute to the safety database of dengue naive adult subjects included in the dengue clinical 
development program. 
To minimize bias, the trial will be randomized, placebo-controlled and double-blind. Subjects with 
a history of flavivirus infection or vaccination, or prolonged (≥1 year) habitation in a dengue 
endemic area will be excluded to minimize confounding factors. There will be 4 trial groups, 3 
TDV groups and a placebo group. In each group, 2 doses of either TDV (Lots 1, 2, or 3) or placebo 
(0.9% saline) will be administered 3 months apart (ie, Day 1 [Month 0; M0] and Day 90 [Month 3; 
M3]). 
Approximately 924 subjects are planned to be enrolled in the trial. Immunogenicity will be 
assessed in subjects included in the immunogenicity subset (TDV groups: 176 subjects each and 
placebo group: 88 subjects) and safety will be assessed in all subjects in each group (TDV groups: 
264 subjects each and placebo group: 132 subjects). The immunogenicity assessment for the 
primary endpoint is planned at 1 month post second dose (Day 120 [M4]) to coincide with the 
anticipated peak in post-vaccination antibody titers. As the trial will be conducted in region(s) 
non-endemic for dengue, 6 months follow-up duration after the last dose is considered adequate. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-304 
Page 27 of 79 
Protocol Version 4.0 
29 October 2018 
 
 
This trial will be conducted in accordance with the protocol, the International Council for 
Harmonization of Technical Requirements for Pharmaceuticals and Good Clinical Practice 
(ICH-GCP) Guidelines and applicable local laws and regulations, including, but not limited to 
those related to data privacy and clinical trial disclosure. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

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Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-304 
Page 42 of 79 
Protocol Version 4.0 
29 October 2018 
 
 
Prior to vaccination, a subject must be determined to be eligible for trial vaccination and it must be 
clinically appropriate in the judgment of the Investigator to vaccinate. Eligibility for vaccination 
prior to first trial vaccine administration is determined by evaluating the entry criteria outlined in 
this protocol (Section 7.1 and Section 7.2). 
Eligibility for subsequent trial vaccination is determined by the criteria outlined in Section 7.3. 
Trial vaccines should not be administered to individuals with known hypersensitivity to any 
component of the vaccines. 
Standard immunization practices are to be observed and care should be taken to administer the 
injection by the SC route. In addition, the WHO recommendations to reduce anxiety and pain at 
the time of vaccination should be followed [16]. Before administering the vaccine, the vaccination 
site is to be disinfected with a skin disinfectant (eg, 70% alcohol). Allow the skin to dry. DO NOT 
inject intravascularly. 
As with all injectable vaccines, trained medical personnel and appropriate medical treatment 
should be readily available in case of anaphylactic reactions following vaccination. For example, 
epinephrine 1:1000, diphenhydramine, and/or other medications for treating anaphylaxis should 
be available. These rescue medications will not be supplied by the Sponsor. 
8.3 
Randomization Code Creation and Storage 
Randomization personnel of the Sponsor or designee will generate the randomization schedule(s). 
Randomization information will be stored in a secured area, accessible only by authorized 
personnel. 
8.4 
Trial Vaccine Blind Maintenance 
The trial will be conducted in a double-blind manner meaning that the subject, those responsible 
for the evaluation of any trial endpoint and the Sponsor will be all unaware of which trial vaccine 
was administered. The investigational vaccine blind will be maintained using IRT. The subjects, 
data collectors (eg, Investigator), and data evaluators (eg, trial statisticians) are blinded. One or 
more designated pharmacist’s/vaccine administrators at the site will be unblinded. These 
unblinded personnel will be responsible for receiving and storing the trial vaccines to ensure that 
the trial blind is not broken. They will also be responsible for the trial vaccine accountability. The 
unblinded personnel will have no role in data collection or evaluation. 
8.5 
Unblinding Procedure 
The trial vaccine blind shall not be broken by the Investigator unless information concerning the 
trial vaccine is necessary for the medical treatment of the subject or is requested by the subject in 
case of pregnancy. In the event of a pregnancy or medical emergency, if possible, the medical 
monitor should be contacted before the trial vaccine blind is broken to discuss the need for 
unblinding. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

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9

Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-304 
Page 44 of 79 
Protocol Version 4.0 
29 October 2018 
 
 
The pharmacist (or designated individual) at each site must record the current inventory of all 
Sponsor-supplied vaccines (TDV and placebo) including TDV diluent on a Sponsor-approved 
vaccine accountability log. The following information will be recorded at a minimum: protocol 
number and title, name of Investigator, site identifier and number, description of Sponsor-supplied 
vaccines, expiry date and amount. The log (IRT) should include all required information as a 
separate entry for each subject to whom Sponsor-supplied vaccine is administered. 
Prior to site closure or at appropriate intervals throughout the trial, before any clinical trial 
materials are returned to the Sponsor or designee for destruction, a representative from the Sponsor 
or designee will perform clinical trial material accountability and reconciliation. The Investigator 
will retain a copy of the documentation regarding clinical trial material accountability, return, 
and/or destruction, and originals will be sent to the Sponsor or designee. 
The pharmacist (or designated individual) at each site will be responsible for vaccine 
accountability and will document receipt, use, return, or destruction of trial vaccines (TDV and 
placebo) including TDV diluent.  
Vaccine accountability documentation will be reviewed by the unblinded monitor during clinical 
monitoring visits. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-304 
Page 45 of 79 
Protocol Version 4.0 
29 October 2018 
 
 
9.0 
TRIAL PLAN 
9.1 
Trial Procedures 
The following sections describe the trial procedures and data to be collected. For each procedure, 
subjects are to be assessed by the same Investigator or site personnel whenever possible. The 
Schedule of Trial Procedures is located in Section 2.1. 
9.1.1 Informed Consent Form 
The requirements of the informed consent form are described in Section 15.2. 
Informed consent must be obtained prior to the subject entering into the trial (up to 28 days prior to 
first administration of the trial vaccine), and before any protocol-directed procedures are 
performed. 
A unique subject number will be assigned to each subject after informed consent is obtained from 
the IRT. If all eligibility criteria are fulfilled, this subject number will be used throughout the trial. 
Subject numbers assigned to subjects who fail screening should not be reused (see Section 9.1.10). 
9.1.2 Demographics, Medical History and Prior Medications 
Demographic information to be obtained will include age, sex, race and ethnicity as described by 
the subject. 
Medical history will also be collected, including but not limited to any medical history that may be 
relevant to subject eligibility for trial participation such as prior vaccinations, concomitant 
medications, and previous and ongoing illnesses or injuries. Relevant medical history can also 
include any medical history that contributes to the understanding of an AE that occurs during trial 
participation, if it represents an exacerbation of an underlying disease/preexisting problem. 
All medications and vaccine history from 1 month (minimum 28 days) prior to administration of 
each trial vaccine dose up to 1 month (minimum 28 days) thereafter, steroids and 
immunostimulants within 60 days prior to Day 1 (M0), immunoglobulins and blood products 
within 3 months prior to Day 1 (M0), and immunosuppressive therapy within 6 months prior to 
Day 1 (M0). Concomitant medication/vaccination will be collected throughout the trial conduct 
and are to be recorded on the “Medication History/Concomitant Medications” eCRF and in the 
subject’s source document. The use of antipyretics and/or analgesic medications within 24 hours 
prior to vaccination must be identified and the reason for their use (prophylaxis versus treatment) 
must be described in the source documents or the eCRF. Medications taken for prophylaxis are 
those intended to prevent the onset of AEs following vaccination. Medications taken for treatment 
are intended to reduce or eliminate the presence of symptoms that are present. Trial vaccination 
should be delayed if subjects have used antipyretics and/or analgesic medication within 24 hours 
prior to vaccine administration. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

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Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-304 
Page 47 of 79 
Protocol Version 4.0 
29 October 2018 
 
 
Clinically significant changes from the Baseline assessment must be recorded in the subject’s 
source documents and the eCRF. 
Symptom-directed physical examinations may be performed if deemed necessary. 
9.1.5 Vital Signs 
Vital signs will be measured on Day 1 (M0), Day 30 (M1), Day 90 (M3), Day 120 (M4), and Day 
270 (M9). These will include (but are not limited to) the measurement of systolic blood 
pressure/diastolic blood pressure, heart rate, and body temperature. 
9.1.6 Immunogenicity Assessments 
Blood samples for immunogenicity assessments will be collected from subjects in the 
immunogenicity subset randomly selected using IRT prior to administration of the first 
vaccination (TDV or placebo) (Day 1 [M0]), at 1 month (Day 120 [M4]) and at 6 months (Day 270 
[M9]) after the second vaccination. Refer to Appendix D. 
All samples will be collected in accordance with acceptable laboratory procedures. All blood 
samples will be processed and stored at the trial site as detailed in the Laboratory Guidelines. 
9.1.7 Safety Assessments 
Safety assessments will include collection and recording of solicited local (injection site) and 
systemic AEs, unsolicited AEs (non-serious AEs and SAEs), and MAAEs. Refer to Section 10.1 
for safety definitions. Details on collection and reporting of AEs are in Section 10.5. 
9.1.8 Contraception and Pregnancy Avoidance Procedure 
For female subjects of childbearing potential, serum or urine pregnancy testing will be performed 
prior to vaccination at Day 1 (M0) and Day 90 (M3). Additional pregnancy tests may be performed 
during the trial if deemed necessary by the Investigator. Females of childbearing potential who are 
sexually active will be reminded during trial visits to adhere to acceptable contraceptive methods 
up to 6 weeks post second trial vaccination at Day 90 (M3). Subjects will be provided with 
information on acceptable methods of contraception as part of the subject informed consent 
process and will be asked to sign a consent form stating that they understand the requirements for 
avoidance of pregnancy and donation of ova. During the course of the trial, subjects of 
childbearing potential will receive continued guidance with respect to the avoidance of pregnancy 
as part of the trial procedures (Section 2.1); see also Section 7.2. 
9.1.9 Pregnancy 
To ensure subject safety and the safety of the unborn child, each pregnancy in a subject having 
received a trial vaccine must be reported to the Sponsor within 24 hours of the site learning of its 
occurrence. If the subject becomes pregnant during the trial, she will not receive any further doses 
of any Sponsor-supplied trial vaccine. The pregnancy must be followed to determine outcome, 
including spontaneous or voluntary termination, details of birth, and the presence or absence of 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

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11.0 
TRIAL-SPECIFIC REQUIREMENT(S) 
11.1 
Trial-Specific Committees 
11.1.1 Data Monitoring Committee 
A DMC will have oversight of this clinical trial. The DMC functions at a Takeda dengue program 
level and further information is available in the DMC Charter. 
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12.0 
DATA HANDLING AND RECORDKEEPING 
The full details of procedures for data handling will be documented in the Data Management Plan. 
AEs, medical history, and concurrent conditions will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA, System Organ Class [SOC], High Level Group Term, High 
Level Term, Low Level Term, Preferred Term [PT], and their corresponding descriptive terms). 
Drugs will be coded using the WHO Drug Dictionary. 
12.1 
Electronic CRFs (eCRF) 
Completed eCRFs are required for each subject who provides a signed informed consent. 
The Sponsor or designee will supply investigative sites with access to eCRFs. The Sponsor will 
make arrangements to train appropriate site staff in the use of the eCRF. eCRFs must be completed 
in English. 
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Sponsor 
personnel (or designees) and will be answered by the site. 
Corrections to eCRFs are recorded in an audit trail that captures the old information, the new 
information, identification of the person making the correction, the date the correction was made, 
and the reason for change. 
The Principal Investigator or designee must review the eCRFs for completeness and accuracy and 
must sign and date the appropriate eCRFs as indicated. Furthermore, the Investigator must retain 
full responsibility for the accuracy and authenticity of all data entered on the eCRFs. 
eCRFs will be reviewed for completeness and acceptability at the trial site during periodic visits by 
trial monitors. The Sponsor or designee will be permitted to review the subject’s medical and 
hospital records pertinent to the trial to ensure accuracy of the eCRFs. The completed eCRFs are 
the sole property of the Sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the Sponsor. 
12.2 
Record Retention 
The Investigator agrees to keep the records stipulated in Section 12.0 and those documents that 
include (but are not limited to) the trial-specific documents, the identification log of all 
participating subjects, medical records. Temporary media such as thermal sensitive paper should 
be copied and certified, source worksheets, all original signed and dated informed consent forms, 
subject authorization forms regarding the use of personal health information (if separate from the 
informed consent or forms), electronic copy of eCRFs, including the audit trail, and detailed 
records of vaccine disposition to enable evaluations or audits from regulatory authorities, the 
Sponsor or designees. Furthermore, ICH E6 Section 4.9.5 requires the Investigator to retain 
essential documents specified in ICH E6 (Section 8) until at least 2 years after the last approval of 
a marketing application for a specified vaccine indication being investigated or, if an application is 
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not approved, until at least 2 years after the investigation is discontinued and regulatory authorities 
are notified. In addition, ICH E6 Section 4.9.5 states that the trial records should be retained until 
an amount of time specified by applicable regulatory requirements or for a time specified in the 
Clinical Trial Site Agreement between the Investigator and Sponsor. 
Refer to the Clinical Trial Site Agreement for the Sponsor’s requirements on record retention. The 
Investigator should contact and receive written approval from the Sponsor before disposing of any 
such documents. 
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13.0 
STATISTICAL METHODS 
13.1 
Statistical and Analytical Plans 
A statistical analysis plan (SAP) will be prepared and finalized prior to the database lock and 
unblinding of subject’s trial vaccine assignment. This document will provide further details 
regarding the definition of analysis variables and analysis methodology to address all trial 
objectives. 
A blinded review of data will be conducted prior to unblinding of subject’s trial vaccine 
assignment. This review will assess the accuracy and completeness of the trial database, subject 
evaluability, and appropriateness of the planned statistical methods. 
13.1.1 Analysis Sets 
Safety set: The safety set will consist of all subjects who received at least 1 dose of trial vaccine. 
Full analysis set (FAS): The FAS will include all randomized subjects in the immunogenicity 
subset who received at least 1 dose of trial vaccine and for whom a valid pre-dose and at least one 
valid post-dose blood sample is taken. 
Per–protocol set (PPS): The PPS will exclude all subjects seropositive for dengue virus at 
Baseline and will include all subjects in the FAS who have no major protocol violations. The 
major protocol violation criteria will be defined as part of the blinded data review prior to the 
unblinding of the trial vaccine assignment. The categories of major protocol violations include: 
(1) not meeting selected entry criteria, (2) not receiving a the correct randomly assigned trial 
vaccine or placebo, (3) receiving prohibited therapies, (4) not receiving 2 doses of trial vaccine or 
receiving the second trial dose inadmissibly outside of the visit window, and (5) other major 
protocol violations that may be identified during blinded data reviews. 
All summaries and analyses of safety data will be based on subjects in the safety set. The primary 
immunogenicity analyses will be based on the PPS; additional immunogenicity analyses may be 
provided based on the FAS. 
13.1.2 Analysis of Demographics and Other Baseline Characteristics 
Age, gender, race, and other Baseline characteristics will be summarized descriptively by trial 
group for all randomized subjects. 
13.1.3 Immunogenicity Analysis  
An immunogenicity subset of 616 subjects (TDV groups: 176 subjects each and placebo group: 
88 subjects) will be randomly selected for the immunogenicity analyses (ie, the immunogenicity 
subset). 
For the primary and secondary immunogenicity endpoints (ie, GMTs of neutralizing antibodies 
and seropositivity rates for each of the 4 dengue serotypes), descriptive statistics and 95% CIs will 
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be provided by trial group for each applicable visit (Day 120 [M4] and Day 270 [M9]). 
Seropositivity is defined as a reciprocal neutralizing titer ≥10. 
The primary endpoint will evaluate lot-to-lot consistency at Day 120 (M4). For each serotype, an 
analysis of variance (ANOVA) model on the natural logarithms of titers of dengue neutralizing 
antibodies will include data from subjects in Groups 1-3 with trial group as a factor. A 95% CI will 
be provided for the 3 pairwise comparisons of log-transformed GMTs. The CIs will be 
back-transformed in order to report 95% CIs of the ratios in the original scale. For each pairwise 
comparison, equivalence of immune responses will be established if the 95% CI for the ratio is 
contained between equivalence margins of 0.5 and 2.0. Lot-to-lot consistency will be concluded if 
equivalence of immune responses is established for all pairwise comparisons and all 4 dengue 
serotypes. For the secondary endpoint of GMT at Day 270 (M9), a similar model will be fit. 
For the secondary endpoint of seropositivity, 95% CIs for the difference in proportions between 
groups of interest for each dengue serotype at each applicable visit will be constructed using the 
Newcombe and Wilson method. 
The primary immunogenicity analyses will be based on the PPS; other immunogenicity analyses 
may be provided based on the FAS. 
13.1.4 Safety Analysis 
All safety data will be summarized by trial group using the safety set. 
Solicited AEs 
In all subjects, the presence and severity (Grade) of solicited local AEs (injection site pain, 
injection site erythema and injection site swelling) and solicited systemic AEs (fever, asthenia, 
malaise, headache and myalgia) will be collected for 7 days and 14 days, respectively, following 
each vaccination (including the day of vaccination) via collection of diary cards. 
For each solicited AE, the number and percentage of subjects with local AEs (injection site) and 
systemic AEs will be summarized by trial group and event severity for each day after each 
vaccination (ie, Day 1 through Day 7 for local AEs [injection site] AEs and Day 1 through Day 14 
for systemic AEs), and overall. Summaries of first onset of each event and the number of days 
subjects reported experiencing each event will also be provided. For subjects with more than 
1 episode of the same event, the maximum severity will be used for tabulations. 
Persistent/prolonged solicited local or systemic AEs continuing on Day 8 and Day 15, 
respectively, following each trial vaccination will be assessed separately. Unless otherwise 
specified these AEs will not be included in the analyses/tabulations of unsolicited AEs and will 
have separate listings. 
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Unsolicited AEs 
Unsolicited AEs will be assessed for 28 days following each TDV/placebo dose (day of 
vaccination + 27 days). 
In all subjects, unsolicited AEs will be coded using the MedDRA and summarized by SOC and PT 
for each trial group. AEs leading to trial or vaccine withdrawal will also be summarized for the 
duration of the trial. 
Unsolicited AEs will be summarized as follows: by PT including events with frequency greater 
than a pre-defined frequency (the percentage will be specified in the SAP); by SOC and PT; by 
SOC, PT, and severity; and by SOC, PT, and relationship to the investigational vaccine. Subjects 
reporting more than 1 occurrence for the term (level) being summarized will be counted only once. 
MAAEs 
In all subjects, MAAEs will be collected throughout the trial. MAAEs will be coded using 
MedDRA and summarized by SOC and PT for each trial group. 
SAEs 
In all subjects, SAEs will be collected throughout the trial. SAEs will be coded using MedDRA, 
and summarized by SOC and PT for each trial group.  
13.2 
Interim Analysis and Criteria for Early Termination 
No interim analyses are planned. 
13.3 
Determination of Sample Size 
It is assumed that the natural logarithms of titers of neutralizing antibodies for each of the 4 dengue 
serotypes are distributed as independent normal distributions, with standard deviations of 1.35, 
0.86, 1.21, and 1.27, respectively. A sample size of 137 evaluable subjects in each of the 3 TDV 
groups (ie, Groups 1-3) is sufficient to achieve approximately 90% overall power for establishing 
lot-to-lot consistency in terms of equivalence of immune responses to 3 consecutive TDV lots 
based on the 95% CIs of the titer ratios, using equivalence margins of 0.5 and 2.0. This sample size 
assumes no variation among the 3 TDV lots; that is, for each serotype, the true ratio of GMT is 1.0 
between the first and second lots and between the second and third lots. 
Further adjusted for approximately 20% dropouts and non-evaluable subjects, the required sample 
size to evaluate lot-to-lot consistency is approximately 176 subjects for each TDV group and 88 
subject for the placebo group, given 2:2:2:1 randomization ratio between trial groups and taking 
into account ratio between the immunogenicity subset and its complement. Therefore, the 
immunogenicity subset will include 616 subjects. 
To ensure sufficient size of the safety database in the dengue non-endemic regions, overall sample 
size for the trial is 924 subjects: 264 for each TDV group and 132 for the placebo group.  
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14.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 
Trial-Site Monitoring Visits 
Monitoring visits to the trial site will be made periodically during the trial to ensure that all aspects 
of the protocol are followed. Source documents will be reviewed for verification of data recorded 
on the eCRFs. Source documents are defined as original documents, data, and records. The 
Investigator and institution guarantee access to source documents by the Sponsor or designee 
(contract research organization) and by the IRB. 
All aspects of the trial and its documentation will be subject to review by the Sponsor or designee 
(as long as blinding is not jeopardized), including but not limited to the Investigator’s Binder, trial 
vaccine, subject medical records, informed consent form documentation, documentation of subject 
authorization to use personal health information (if separate from the informed consent forms), 
and review of eCRFs and associated source documents. It is important that the Investigator and 
other trial personnel are available during the monitoring visits and that sufficient time is devoted to 
the process. 
14.2 
Protocol Deviations 
The Investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to trial subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the Investigator should consult with the medical 
monitor (and IRB, as required) to determine the appropriate course of action. There will be no 
exemptions (a prospective approved deviation) from the inclusion or exclusion criteria. 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections 
The trial site also may be subject to quality assurance audits by the Sponsor or designees. In this 
circumstance, the Sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the vaccine is stored and prepared, and any other facility used during the trial. In addition, 
there is the possibility that this trial may be inspected by regulatory agencies, including those of 
foreign governments (eg, the Food and Drug Administration [FDA], the United Kingdom 
Medicines and Healthcare Products Regulatory Agency, the Pharmaceuticals and Medical Devices 
Agency of Japan). If the trial site is contacted for an inspection by a regulatory body, the Sponsor 
should be notified immediately. The Investigator and institution guarantee access for quality 
assurance auditors to all trial documents as described in Section 14.1. 
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15.0 
ETHICAL ASPECTS OF THE TRIAL 
This trial will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonized Tripartite Guideline for GCP. Each Investigator will conduct 
the trial according to applicable local or regional regulatory requirements and align his or her 
conduct in accordance with the “Responsibilities of the Investigator” that are listed in Appendix A. 
The principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and Investigator responsibilities. 
15.1 
Institutional Review Board 
IRBs must be constituted according to the applicable local requirements of each participating 
region. The Sponsor or designee will require documentation noting all names and titles of 
members who make up the respective IRB If any member of the IRB has direct participation in this 
trial, written notification regarding his or her abstinence from voting must also be obtained. Those 
US sites unwilling to provide names and titles of all members due to privacy and conflict of 
interest concerns should instead provide a Federal Wide Assurance Number or comparable 
number assigned by the Department of Health and Human Services. 
The Sponsor or designee will supply relevant documents for submission to the respective IRB for 
the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of the 
informed consent form, and, if applicable, subject recruitment materials and/or advertisements and 
other documents required by all applicable laws and regulations, must be submitted to a central or 
local IRB for approval. The IRB’s written approval of the protocol and subject informed consent 
form must be obtained and submitted to the Sponsor or designee before commencement of the trial 
(ie, before shipment of the Sponsor-supplied vaccine or trial specific screening activity). The IRB 
approval must refer to the trial by exact protocol title, number, and version date; identify versions 
of other documents (eg, informed consent form) reviewed; and state the approval date. The 
Sponsor will notify the site once the Sponsor has confirmed the adequacy of site regulatory 
documentation and, when applicable, the Sponsor has received permission from the competent 
authority to begin the trial. Until the site receives [notification] no protocol activities, including 
screening may occur. 
Sites must adhere to all requirements stipulated by their respective IRB. This may include 
notification to the IRB regarding protocol amendments, updates to the informed consent form, 
recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports and updates regarding the ongoing review of the trial at intervals specified by the 
respective IRB, and submission of the Investigator’s final status report to IRB. All IRB approvals 
and relevant documentation for these items must be provided to the Sponsor or designee. 
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB and Sponsor. 
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15.2 
Subject Information, Informed Consent, and Subject Authorization 
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) describe the planned and permitted uses, 
transfers, and disclosures of the subject’s personal and personal health information for purposes of 
conducting the trial. The informed consent form and the subject information sheet (if applicable) 
further explain the nature of the trial, its objectives, and potential risks and benefits, as well as the 
date informed consent is given. The informed consent form will detail the requirements of the 
participant and the fact that he or she is free/ to withdraw at any time without giving a reason and 
without prejudice to his or her further medical care. 
The Investigator is responsible for the preparation, content, and IRB approval of the informed 
consent form and if applicable, the subject authorization form. The informed consent form, subject 
authorization form (if applicable), and subject information sheet (if applicable) must be approved 
by both the IRB and the Sponsor prior to use. 
The informed consent form, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective subject. 
It is the responsibility of the Investigator to explain the detailed elements of the informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) to the 
subject. Information should be given in both oral and written form whenever possible and in the 
manner deemed appropriate by the IRB. 
The subject must be given ample opportunity to: (1) inquire about details of the trial and (2) decide 
whether or not to participate in the trial. If the subject determines he or she will participate in the 
trial, then the informed consent and subject authorization form (if applicable) must be signed and 
dated by the subject at the time of consent and prior to the subject entering into the trial. The 
subject should be instructed to sign using their legal names, not nicknames, using blue or black 
ballpoint ink. The Investigator must also sign and date the informed consent form and subject 
authorization (if applicable) at the time of consent and prior to subject entering into the trial; 
however, the Sponsor may allow a designee of the Investigator to sign to the extent permitted by 
applicable law. 
Once signed, the original informed consent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) will be stored in the Investigator’s site file. The 
Investigator must document the date the subject signs the informed consent form in the subject’s 
medical record and eCRF. Copies of the signed informed consent form, the signed subject 
authorization form (if applicable), and subject information sheet (if applicable) shall be given to 
the subject. 
All revised informed consent forms must be reviewed and signed by the relevant subject in the 
same manner as the original informed consent form. The date the revised consent was obtained 
should be recorded in the subject’s medical record and eCRF, and the subject should receive a 
copy of the revised informed consent form. 
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15.3 
Subject Confidentiality 
The Sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this trial, a subject’s source data will only be linked to the 
Sponsor’s clinical trial database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth, and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number. 
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the Sponsor 
requires the Investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the Sponsor’s designated auditors, and the 
appropriate IRBs to review the subject’s original medical records (source data or documents), 
including, but not limited to, laboratory test result reports, electrocardiogram (ECG) reports, 
admission and discharge summaries for hospital admissions occurring during a subject’s trial 
participation, and autopsy reports. Access to a subject’s original medical records requires the 
specific authorization of the subject as part of the informed consent form process (see 
Section 15.2). 
Copies of any subject source documents that are provided to the Sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF). 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy 
15.4.1 Publication and Disclosure 
The results of this trial are expected to be published in a scientific journal. It is anticipated that 
clinical and laboratory co-Investigators will participate in authorship. The order of authorship and 
choice of journal will be proposed by the Sponsor to the Principal Investigators, to be eventually 
agreed upon by all authors. The data analysis center for this trial will provide the analyses needed 
for publication. Information regarding this trial will be posted on ClinicalTrials.gov. 
15.4.2 Clinical Trial Registration 
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable law, regulation and guidance, the Sponsor will, at a minimum register all 
clinical trials conducted in subjects that it Sponsors anywhere in the world on ClinicalTrials.gov or 
other publicly accessible websites before trial initiation. The Sponsor contact information, along 
with Investigator’s city, country, and recruiting status will be registered and available for public 
viewing. 
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15.4.3 Clinical Trial Results Disclosure 
The Sponsor will post the results of this clinical trial, regardless of outcome, on ClinicalTrials.gov 
or other publicly accessible websites, as required by applicable laws and/or regulations. 
Trial completion corresponds to the date on which the final subject was examined or received an 
intervention for the purposes of final collection of data for the primary outcome, whether the 
clinical trial concluded according to the pre-specified protocol or was terminated. 
15.5 
Insurance and Compensation for Injury 
Each subject in the trial must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the Sponsor or Sponsor’s 
designee will obtain clinical trial insurance against the risk of injury to clinical trial subjects. Refer 
to the Clinical Trial Site Agreement regarding the Sponsor’s policy on subject compensation and 
treatment for injury. If the Investigator has questions regarding this policy, he or she should 
contact the Sponsor or Sponsor’s designee. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

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Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-304 
Page 79 of 79 
Protocol Version 4.0 
29 October 2018 
 
 
APPENDIX D SEROLOGY PLAN 
Table 16.a 
Serology Plan 
Timing 
Blood volume 
Assessments 
Day 1 (M0), Day 120 (M4), and Day 270 (M9) 
5 mL 
Dengue neutralizing antibodies (by MNT50) 
M=month, MNT50=microneutralization test 
Note: Blood samples for immunogenicity testing will only be collected from subjects included in the immunogenicity subset. Blood 
sampling at Day 1 (M0) should be taken prior to administration of the first trial dose. The blood sample at Day 120 (M4) should be 
taken at least 29 days after the second trial dose at Day 90 (M3). 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

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