A Phase II, Double-Blind, Controlled Trial to Assess the Safety and Immunogenicity of Different Schedules of Takeda's Tetravalent Dengue Vaccine Candidate (TDV) in Healthy Subjects Aged Between 2 and <18 Years and Living in Dengue Endemic Countries in Asia and Latin America
Phase: PHASE2
Conditions: Dengue Fever
Sponsor: Takeda




Title: A Phase II, double-blind, controlled trial to assess the Safety and Immunogenicity of 
different schedules of Takeda’s Tetravalent Dengue Vaccine Candidate (TDV) in healthy subjects 
aged between 2 and <18 years and living in dengue endemic countries in Asia and Latin America
NCT Number: NCT02302066
Protocol Approve Date: 21 July 2016 
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 
PROTOCOL 
A Phase II, double-blind, controlled trial to assess the Safety and Immunogenicity of different 
schedules of Takeda’s Tetravalent Dengue Vaccine Candidate (TDV) in healthy subjects aged 
between 2 and <18 years and living in dengue endemic countries in Asia and Latin America 
Safety and Immunogenicity of different schedules of TDV in healthy subjects 
Sponsor: 
Takeda Vaccines, Inc 
One Takeda Parkway 
Deerfield, IL 60015 
U.S.A. 
Trial Identifier: 
DEN-204 
IND Number: 
014292 
EudraCT Number: 
Not Applicable 
Vaccine Name: 
Takeda’s Tetravalent Dengue Vaccine Candidate (TDV) 
Date: 
21 July 2016 
Version: 
Version 4.0 
Pro 
akeda: 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-204 
Page 5 of 83 
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TABLE OF CONTENTS 
1.0 
ADMINISTRATIVE INFORMATION 
..............................................................................2 
1.1 
Contacts..........................................................................................................................2 
1.2 
Protocol Amendment #4 Summary of Changes.............................................................2 
1.2.1 Amendment History 
.................................................................................................2 
1.2.2 Summary of Changes 
...............................................................................................2 
1.3 
Approval ........................................................................................................................3 
2.0 
TRIAL SUMMARY 
..........................................................................................................10 
2.1 
Schedule of Trial Procedures .......................................................................................19
 
2.1.1 Schedule Trial Procedures for Immunogenicity Subset 
.........................................19 
2.1.2 Schedule Trial Procedures for Subjects Not Included in the Immunogenicity 
Subset 
.....................................................................................................................21
 
3.0 
TRIAL REFERENCE INFORMATION 
...........................................................................23 
3.1 
Trial-Related Responsibilities 
......................................................................................23 
3.2 
Coordinating Investigator ............................................................................................23
 
3.3 
List of Abbreviations 
...................................................................................................24 
3.4 
Corporate Identification ...............................................................................................26
 
4.0 
INTRODUCTION 
.............................................................................................................27 
4.1 
Background 
..................................................................................................................27 
4.2 
Rationale for the Proposed Trial 
..................................................................................28 
5.0 
TRIAL OBJECTIVES AND ENDPOINTS 
......................................................................30 
5.1 
Objectives ....................................................................................................................30 
5.1.1 Primary Objective 
..................................................................................................30 
5.1.2 Secondary Objectives.............................................................................................30 
5.1.3 Exploratory Objective 
............................................................................................30 
5.2 
Endpoints 
.....................................................................................................................30
 
5.2.1 Primary Endpoint 
...................................................................................................30 
5.2.2 Secondary Endpoints .............................................................................................30 
5.2.3 Exploratory Endpoints 
...........................................................................................31 
6.0 
TRIAL DESIGN AND DESCRIPTION ...........................................................................32 
6.1 
Trial Design .................................................................................................................32 
6.2 
Justification for Trial Design, Dose, and Endpoints 
....................................................36 
6.3 
Duration of Subject’s Expected Participation in the Entire Trial 
................................36 
6.4 
Premature Termination or Suspension of Trial or Investigational Site 
.......................37
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9.1.12 Documentation of Subjects who are not Randomized 
...........................................54 
9.2 
Monitoring Subject Treatment Compliance.................................................................54
 
9.3 
Schedule of Observations and Procedures 
...................................................................54 
9.3.1 Randomization Procedures (Day 1, M0) ...............................................................54 
9.3.2 Vaccination Procedures (Day 1/M0, Day 91/M3, Day 365/M12) 
.........................55 
9.3.3 Post Vaccination procedures (Day 1/M0, Day 91/M3, Day 365/M12) 
.................55 
9.3.4 Clinic Visits after Vaccination (Month 1, Month 6, Month 13, Month 18, 
Month 24, Month 36, Month 48) 
...........................................................................57 
9.3.5 Phone Contacts – Safety Call 
.................................................................................58 
9.3.6 Final Visit...............................................................................................................58 
9.3.7 Post Trial Care 
.......................................................................................................59 
9.4 
Biological Sample Retention and Destruction 
.............................................................59 
10.0 ADVERSE EVENTS 
.........................................................................................................60 
10.1 Definitions....................................................................................................................60 
10.1.1 Adverse Events (AEs) 
............................................................................................60 
10.1.2 Causality of AEs 
....................................................................................................61 
10.1.3 Relationship to Trial Procedures 
............................................................................61 
10.1.4 Additional Points to Consider for AEs 
..................................................................61 
10.1.5 Serious Adverse Events (SAEs).............................................................................62 
10.2 Procedures 
....................................................................................................................63 
10.2.1 Collection and Reporting of AEs 
...........................................................................63 
10.2.1.1 AE Reporting 
.............................................................................................63 
10.2.2 Collection and Reporting of SAEs 
.........................................................................63 
10.3 Follow-up of SAEs ......................................................................................................64 
10.3.1 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities .....64 
10.3.2 Post-Trial Events 
....................................................................................................64 
11.0 TRIAL-SPECIFIC REQUIREMENT(S) 
...........................................................................65 
11.1 Trial-Specific Committees 
...........................................................................................65 
11.1.1 Data Monitoring Committee (DMC) Board ..........................................................65 
12.0 DATA HANDLING AND RECORDKEEPING 
..............................................................66 
12.1 Electronic CRFs (eCRF) and Paper 
.............................................................................66 
12.2 Record Retention .........................................................................................................66 
13.0 STATISTICAL METHODS 
..............................................................................................68 
13.1 Statistical and Analytical Plans 
....................................................................................68
 
13.1.1 Analysis Sets 
..........................................................................................................68
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Trial No. DEN-204 
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13.1.2 Analysis of Demographics and Other Baseline Characteristics ............................68
13.1.3 Immunogenicity Analysis 
......................................................................................69
13.1.4 Safety Analysis 
......................................................................................................69
13.2 Interim Analysis 
...........................................................................................................70
13.3 Determination of Sample Size 
.....................................................................................70
14.0 QUALITY CONTROL AND QUALITY ASSURANCE 
.................................................72
14.1 Trial-Site Monitoring Visits 
.........................................................................................72
14.2 Protocol Deviations 
......................................................................................................72
14.3 Quality Assurance Audits and Regulatory Agency Inspections 
..................................72
15.0 ETHICAL ASPECTS OF THE TRIAL 
.............................................................................73
15.1 IRB and/or IEC Approval ............................................................................................73
15.2 Subject Information and Informed Consent/Informed Assent 
.....................................74
15.3 Subject Confidentiality ................................................................................................75
15.4 Publication, Disclosure, and Clinical Trial Registration Policy 
..................................75
15.4.1 Publication and Disclosure ....................................................................................75
15.4.2 Clinical Trial Registration......................................................................................75
15.4.3 Clinical Trial Results Disclosure 
...........................................................................76
15.5 Insurance and Compensation for Injury 
.......................................................................76
16.0 REFERENCES ..................................................................................................................77
LIST OF IN-TEXT TABLES 
Table 1.a
Contact Information 
.................................................................................................2
Table 6.a 
Number of Subjects Per Group 
..............................................................................32
Table 6.b 
Timing of Vaccination and Blood Sampling for Immunological Testing 
.............34
Table 6.c 
Timing of Vaccination and Blood Sampling for Immunological Testing 
.............34
Table 8.a 
Sponsor-Supplied Investigational Vaccines ..........................................................43
Table 9.a 
Solicited Local and Systemic AEs 
.........................................................................50
Table 9.b 
Intensity Scales for Solicited AEs in Infants/Toddlers (15-24 Months)/Child 
(< 6 Years) 
.............................................................................................................51
Table 9.c 
Intensity Scales for Solicited AEs in Adults/Children (≥ 6 Years) .......................52
Table 13.a 
Approximate 95% Confidence Interval in Seropositivity Rates (MNT
50)
 
Reciprocal Neutralizing Titer ≥ 10) for the Planned Sample Size in the 
Treatment Groups 
..................................................................................................70
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Table 13.b 
Approximate 95% Confidence Interval in GMT of Dengue Neutralizing 
Antibodies for the Planned Sample Size in the Treatment Group 
.........................71

Takeda’s Tetravalent Dengue Vaccine Candidate 
Trial No. DEN-204 
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Table 13.c 
Probability of Observing 1 or More Events for Assumed “True” Event Rate and 
Given Sample Size 
.................................................................................................71
LIST OF IN-TEXT FIGURES 
Figure 6.a 
Schematic of Trial Design .....................................................................................35
LIST OF APPENDICES 
Appendix A Responsibilities of the Investigator 
........................................................................78
Appendix B Investigator Consent to Use of Personal Information 
............................................80
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Appendix C Elements of the Subject Informed Consent/Informed Assent................................81

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Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-204 
Page 23 of 83 
Protocol Version 4.0 
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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 Coordinating Investigator 
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The sponsor will select a Signatory Coordinating 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 Coordinating 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. 

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Trial No. DEN-204 
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TDV 
Takeda’s Tetravalent Dengue Vaccine Candidate 
TNF 
Tumor Necrosis Factor 
WCC 
White Cell Count 
WFI 
Water For Injection
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Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-204 
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3.4 Corporate Identification 
TVI 
Takeda Vaccines, Inc 
VBD 
Vaccines Business Division 
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Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-204 
Page 27 of 83 
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4.0 INTRODUCTION 
4.1 Background 
Dengue fever is caused by infection with the dengue virus (DENV), a ribonucleic acid (RNA) 
virus that occurs as four recognized serotypes, DENV-1, DENV-2, DENV-3 or DENV-4. These 
viruses are transmitted from human to human by mosquitoes (primarily Aedes aegypti). The four 
dengue viruses have spread worldwide and are endemic in Asia, Central and South America, the 
Caribbean, the Pacific Islands, Australia, and parts of Africa. An estimated 50 - 100 million cases 
of dengue fever occur annually, which results in around 500,000 cases of dengue hemorrhagic 
fever (DHF) and an estimated 22,000 deaths, primarily in children. It is estimated that 2.5 billion 
people (40% of world’s population) live in areas at risk of dengue virus transmission [1-4]. 
Dengue fever is clinically defined as an acute febrile illness with two or more 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. Shock may cause death within 12 to 24 hours. The most severe forms of dengue infection – 
DHF and dengue shock syndrome (DSS) – are life threatening. Primary infection with any one of 
the four DENV 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 three DEN 
serotypes and may lead to an increased risk of severe disease (DHF/DSS) [4, 5, 6]. Primary 
infection with any one of the four DENV 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 three DENV serotypes and may lead to an increased risk of severe disease (DHF/DSS). 
Treatment of dengue fever is based solely on symptoms and signs, with fluid replacement required 
for severe fever and hemorrhagic or shock cases. No antiviral therapy for dengue virus infection is 
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 that will protect against 
dengue infection, and thereby reduce the morbidity and mortality associated with dengue disease 
[1-7]. A 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. Vaccine efficacy was different between 
serotypes and depended on dengue baseline seropositivity status. Hence, there is a continued 
unmet public health need for safer and more efficacious dengue vaccines. Additional vaccines are 
also important to ensure sufficient supply globally [9, 10]. 
Takeda’s Tetravalent Dengue Vaccine Candidate (TDV) Background: 
Takeda’s TDV consists of a mixture of four live, attenuated recombinant dengue virus strains 
expressing surface antigens corresponding to the four recognized dengue serotypes 1-4. The 
serotype 2 strain is based upon the attenuated laboratory-derived virus, DEN-2 Primary Dog 
Kidney (PDK)-53, originally isolated at Mahidol University, Bangkok, Thailand [11]
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. The 
chimeric, attenuated vaccine strains for dengue serotypes 1, 3 and 4 were engineered by replacing 
the DEN-2 structural genes, pre-membrane (prM) and envelope (E), with the prM and E genes of 

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unblinded at the site. These unblinded designees will maintain the investigational vaccine blind 
and will have no role in the assessment of subject safety. 
8.5 Unblinding Procedure 
The investigational vaccine blind shall not be broken by the investigator unless information 
concerning the investigational vaccine is necessary for the medical treatment of the subject. In the 
event of a medical emergency, if possible, the medical monitor should be contacted before the 
investigational vaccine blind is broken to discuss the need for unblinding. 
For unblinding a subject, the investigational vaccine blind can be obtained by the investigator by 
accessing the IWRS/IVRS. 
The sponsor’s Pharmacovigilance Department must be notified as soon as possible if the 
investigational vaccine blind is broken by the investigator for the purposes of a medical 
emergency, and if appropriate a completed SAE form must be sent within 24 hours. The date, time, 
and reason the blind was broken must be recorded in the source document and the same 
information (except the time) must be recorded on the eCRF. 
In the event of accidental unblinding of the investigational vaccine, the sponsor shall be 
immediately contacted for further decision about the subject’s eligibility to continue in the trial.  
8.6 Accountability and Destruction of Sponsor-Supplied Vaccine(s) 
Vaccine supplies will be counted and reconciled at the site before being returned to the sponsor or 
designee as noted below. Sites will maintain source documents in addition to entering data in the 
IWRS/IVRS. 
The investigator or designee must ensure that the sponsor-supplied vaccine is used in accordance 
with the approved protocol and is administered only to subjects enrolled in the trial. To document 
appropriate use of sponsor-supplied vaccine, the investigator must maintain records of all 
sponsor-supplied vaccine delivery to the site, site inventory, dispensation, and use by each subject, 
and return to the sponsor or designee as noted below. 
Upon receipt of sponsor-supplied vaccine, the investigator or designee must verify the contents of 
the shipments against the packing list. The verifier should ensure that the quantity is correct, the 
investigational vaccine is received within the labeled storage conditions, and is in good condition. 
If the quantity and conditions are acceptable, the investigator or designee will acknowledge receipt 
of the shipment by recording it in the IWRS/IVRS. 
If there are any discrepancies between the packing list and the actual product received, the Sponsor 
must be contacted to resolve the issue. The packing list should be filed in the investigator’s 
essential document file. 
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The investigator must maintain 100% accountability for all sponsor-supplied vaccines received 
and administered during his or her entire participation in the trial. Proper vaccine accountability 
includes, but is not limited to the following: 

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Table 9.a  
Solicited Local and Systemic AEs 
 
Infant/Toddler (15–24 
months)/Child (< 6 years) 
 Adult and child (≥ 6 years) 
Local AEs (injection site): 
Pain 
 Pain 
Erythema 
 Erythema 
Swelling 
 Swelling 
 
 
  
Systemic AEs: 
Fevera 
 Fevera 
Irritability/fussiness 
 Asthenia 
Drowsiness 
 Headache 
Loss of appetite 
 Malaise 
 
 Myalgia 
(a) Body temperature ≥ 38°C or 100.4°F is defined as fever irrespective of site of measurement 
Any unsolicited AEs will be collected for 28 days following each dose. 
SAEs and febrile episodes of potential dengue etiology will be collected from the time that the 
subject is first administered the investigational vaccine (Month 0) up to the end of the trial 
(Month 48). 
The intensity of solicited AEs will be assessed as described in Table 9.b and Table 9.c.
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Trial No. DEN-204 
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Protocol Version 4.0 
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Table 9.b  
Intensity Scales for Solicited AEs in Infants/Toddlers (15-24 Months)/Child 
(< 6 Years) 
Infant/Toddler (15–24 months)/Child (< 6 years) 
Adverse Event 
Intensity grade 
Severity/Intensity 
Pain at injection site 
0 
None 
 
1 
Mild: Minor reaction to touch 
 
2 
Moderate: Cries/protests on touch 
 
3 
Severe: Cries when limb is moved/spontaneously painful 
Erythema at injection site 
Record greatest surface diameter in mm 
Swelling at injection site 
Record greatest surface diameter in mm 
Fevera 
 
Record body temperature in °C/°F 
Irritability/Fussiness 
0 
Behavior as usual 
 
1 
Mild: Crying more than usual/no effect on normal activity 
 
2 
Moderate: Crying more than usual/interferes with normal activity 
 
3 
Severe: Crying that cannot be comforted/prevents normal activity 
Drowsiness 
0 
Behavior as usual 
 
1 
Mild: Drowsiness easily tolerated 
 
2 
Moderate: Drowsiness that interferes with normal activity 
 
3 
Severe: Drowsiness that prevents normal activity 
Loss of appetite 
0 
Appetite as usual 
 
1 
Mild: Eating less than usual/no effect on normal activity 
 
2 
Moderate: Eating less than usual/interferes with normal activity 
 
3 
Severe: Not eating at all 
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Table 9.c  
Intensity Scales for Solicited AEs in Adults/Children (≥ 6 Years) 
Adults/Child ( 6 years) 
Adverse Event 
Intensity grade 
Severity/Intensity 
Pain at injection site 
0 
None 
 
1 
Mild: Any pain neither interfering with nor preventing normal every day 
activities. 
 
2 
Moderate: Painful when limb is moved and interferes with every day 
activities. 
 
3 
Severe: Significant pain at rest. Prevents normal every day activities. 
Erythema at injection site 
Record greatest surface diameter in mm 
Swelling at injection site 
Record greatest surface diameter in mm 
Fevera 
 
Record body temperature in °C/°F 
Headache 
0 
Normal 
 
1 
Mild: Headache that is easily tolerated 
 
2 
Moderate: Headache that interferes with normal activity 
 
3 
Severe: Headache that prevents normal activity 
Asthenia 
0 
Normal 
 
1 
Mild: Asthenia that is easily tolerated 
 
2 
Moderate: Asthenia that interferes with normal activity 
 
3 
Severe: Asthenia that prevents normal activity 
Malaise 
0 
No symptoms 
1 
Mild: Malaise that is easily tolerated 
2 
Moderate: Malaise that interferes with normal activity 
3 
Severe: Malaise that prevents normal activity 
Myalgia 
0 
No symptoms 
 
1 
Mild: Myalgia that is easily tolerated 
 
2 
Moderate: Myalgia that interferes with normal activity 
 
3 
Severe: Myalgia that prevents normal activity 
(a) Body temperature ≥ 38°C or 100.4°F is defined as fever irrespective of site of measurement 
9.1.8 Febrile illness follow-up 
Any subject with febrile illness (defined as temperature ≥ 38°C on 2 consecutive days) or febrile 
illness clinically suspected to be dengue by the investigator will be asked to return to the site for 
dengue fever evaluation. A dengue infection will be considered virologically confirmed by either 
PCR or NS1 ELISA. 
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A febrile illness as described above will require an interval of at least 14 days from a previous 
febrile illness to avoid overlap of acute and convalescent visits from one episode with those from a 
second episode. 

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9.3.7 Post Trial Care 
No post-trial care will be provided except for the provision of a licensed vaccine to all subjects 
irrespective of their full participation in this trial and at least 18 months after the first protocol 
defined vaccination. The choice of this vaccine will be discussed between the Sponsor and the 
Investigator, and will be approved by the appropriate ethics committee. This vaccine will be used 
according to the labeling approved in the country. 
9.4 Biological Sample Retention and Destruction 
In this trial, specimens for immune response testing will be collected as described in Section 9.1.6.
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After blood draw and serum processing, the serum samples will be preserved and retained at a 
central laboratory that was contracted by the sponsor for this purpose for up to but not longer than 
20 years or as required by applicable law. The sponsor has put into place a system to protect the 
subjects’ personal information to ensure optimal confidentiality and defined standard processes for 
sample and data collection, storage, analysis, and destruction. 

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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 [SOC, HLGT, HLT, LL, PT, and their corresponding descriptive 
terms]). Drugs will be coded using the World Health Organization (WHO) Drug Dictionary. 
12.1 Electronic CRFs (eCRF) and Paper 
Completed eCRFs are required for each subject for whom an informed consent/assent is obtained. 
The sponsor or its 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. These forms are used to 
transmit the information collected in the performance of this trial to the sponsor and regulatory 
authorities. 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. 
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 its 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 12.1 
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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/informed 
assent 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 its designees. 
Furthermore, International Conference on Harmonization (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 drug indication being investigated or, if 
an application is 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. 

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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 first interim analysis at 
Month 6. This document will provide further details regarding the definition of analysis variables 
and analysis methodology to address all trial objectives. 
A blinded data review will be conducted prior to unblinding of subject’s vaccination 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 
The analysis sets are defined as follows: 
Safety Set: The Safety Set will consist of all randomized subjects who received at least one dose 
of the trial vaccine (including control vaccine). For analyses of solicited AEs and unsolicited 
non-serious AEs, only subjects in the immunogenicity subset will be included (600 subjects in 
total [groups 1 and 4: 100 subjects each; groups 2 and 3: 200 subjects each]). SAEs, virologically 
confirmed dengue and AEs leading to trial or vaccine withdrawal will be assessed for all subjects 
in the Safety Set. 
Full Analysis Set (FAS): The Full Analysis Set will consist of all randomized subjects who 
received the trial vaccine (including control vaccine) and for whom valid pre-dosing and at least 
one valid post-dosing blood sample have been received. 
Per-Protocol Set (PPS): The Per-Protocol Set will consist of 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 individual subject’s treatment assignment. The 
categories of major protocol violations include: (1) not meeting selected entry criteria, (2) 
receiving wrong trial treatment, (3) receiving prohibited therapies, and (4) other major protocol 
violations that may be identified during blinded data reviews. 
Both the FAS and PPS will include only subjects from the immunogenicity subset (600 subjects in 
total [groups 1 and 4: 100 subjects each; groups 2 and 3: 200 subjects each]), i.e., subjects for 
whom blood samples for assessment of dengue neutralizing antibodies are collected. 
The primary analysis of immunogenicity will be based on the PPS, and other supportive analysis 
may be provided for the FAS. The safety analysis will be based on the Safety Set as described 
above. 
13.1.2 Analysis of Demographics and Other Baseline Characteristics 
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For illustrative purposes, Table 13.b provides approximate 95% confidence interval for various 
different GMT and GSD (Geometric Standard Deviation), given the planned sample size per group 
in the immunogenicity subset. 
Table 13.b  Approximate 95% Confidence Interval in GMT of Dengue Neutralizing 
Antibodies for the Planned Sample Size in the Treatment Group 
 
(95% CI) 
N=100 
(95% CI) 
N=200 
GMT (GSD) 
LL 
UL 
LL 
UL 
500 (6) 
351.9 
710.4 
390.1 
640.9 
1500 (6) 
1,055.8 
2,131.1 
1,170.2 
1,922.8 
200 (8) 
133.1 
300.6 
149.9 
266.8 
50 (7) 
34.1 
73.2 
38.2 
65.5 
LL = Lower Limit, UL = Upper Limit 
Note: The GMT and GSD in the table are based on study INV-DEN-203, Day 28 results for serotypes 1-4 in subjects 
aged 1.5-11 years old (Clinical Study Report Table 15.2.2.7.2) 
Safety 
Table 13.c illustrates the probability of observing 1 or more event, (e.g., any specific type of AE 
related to vaccine) for a range of assumed true but unknown event rates in the range of 0.33% to 
4.0% (without considering the background incidence). 
Table 13.c  Probability of Observing 1 or More Events for Assumed “True” Event Rate 
and Given Sample Size 
“True” Unknown Event Rate 
Sample Sizes 
N=1,600 
N=1,000 
N=200 
0.33% 
99.5% 
96.3% 
48.4% 
0.50% 
>99.9% 
99.3% 
63.3% 
1.00% 
>99.9% 
>99.9% 
86.6% 
2.00% 
>99.9% 
>99.9% 
98.2% 
3.00% 
>99.9% 
>99.9% 
99.8% 
4.00% 
>99.9% 
>99.9% 
>99.9% 
N=number of subjects 
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Therefore, even with an event rate as low as 0.33%, there is a 99.5% chance that at least 1 such 
event will be observed in the trial. For AEs with event rate higher than 4.00%, there is a >99.9% 
chance to observe at least one such event. 

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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 its designee 
(CRO) and by the IRB or IEC. 
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, 
investigational vaccine, subject medical records, informed consent/informed assent 
documentation, documentation of subject authorization to use personal health information (if 
separate from the informed consent/informed assent 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 or IEC, 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 (e.g., the 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 (i.e., 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/informed assent and investigator responsibilities. 
15.1 IRB and/or IEC Approval 
IRBs and IECs 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 or IEC. If any member of the IRB or IEC 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 or 
IEC for the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of 
the informed consent/informed assent 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 or IEC for approval. The IRB’s or IEC’s written approval of 
the protocol and subject informed consent/informed assent must be obtained and submitted to the 
sponsor or designee before commencement of the trial (i.e., before shipment of the 
sponsor-supplied Vaccine or trial specific screening activity). The IRB or IEC approval must refer 
to the trial by exact protocol title, number, and version date; identify versions of other documents 
(e.g., informed consent/informed assent 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 competent authority to begin the 
trial. Until the site receives [vaccine/notification] no protocol activities, including screening may 
occur. 
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the informed 
consent/informed assent 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 or IEC, and submission of the investigator’s final status report to 
IRB or IEC. All IRB and IEC approvals and relevant documentation for these items must be 
provided to the sponsor or its designee. 
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Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor. 

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15.2 Subject Information and Informed Consent/Informed Assent 
Written consent documents will embody the elements of informed consent/informed assent 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/informed assent form and subject 
information sheet 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/informed assent 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/informed assent is given. The informed consent/informed assent 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 or IEC approval of the 
informed consent/informed assent form. The informed consent/informed assent form and subject 
information sheet must be approved by both the IRB or IEC and the sponsor prior to use. 
The informed consent/informed assent form and subject information sheet 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/informed assent form and subject 
information sheet to the subject. Information should be given in both oral and written form 
whenever possible and in the manner deemed appropriate by the IRB or IEC. In the event the 
subject is not capable of rendering adequate written informed consent/informed assent, then the 
subject’s legally acceptable representative may provide such consent for the subject in accordance 
with applicable laws and regulations. 
The subject, or the subject’s legally acceptable representative, 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, or the subject’s legally acceptable representative, determines he or she will participate in 
the trial, then the informed consent/informed assent form must be signed and dated by the subject, 
or the subject’s legally acceptable representative, at the time of consent and prior to the subject 
entering into the trial. The subject or the subject’s legally acceptable representative 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/informed assent form 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/informed assent form and subject information sheet 
will be stored in the investigator’s site file. The investigator must document the date the subject 
signs the informed consent/informed assent in the subject’s medical record. Copies of the signed 
informed consent/informed assent form and subject information sheet shall be given to the subject. 
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All revised informed consent/informed assent forms must be reviewed and signed by relevant 
subjects or the relevant subject’s legally acceptable representative in the same manner as the 
original informed consent/informed assent. The date the revised consent was obtained should be 

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recorded in the subject’s medical record, and the subject should receive a copy of the revised 
informed consent/informed assent form. 
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 (e.g., FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, 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/informed assent process (see 
Section 15.2). 
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (i.e., 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 determined by the PIs and the Sponsor. The data analysis centre 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 
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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 patients 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. 
In line with EC Regulation N° 1901/2006, the sponsor will submit the pediatric studies within six 
months of their completion and irrespective of whether it is part of a PIP (completed or not yet 
completed) or not, or whether it is intended for submission later on as part of a variation, extension 
or new stand-alone marketing-authorization application or not. 
15.5 Insurance and Compensation for Injury 
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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. 

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Appendix A  Responsibilities of the Investigator 
 
 
 
 
 
 
 
 
 
 
 
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Appendix B  Investigator Consent to Use of Personal Information 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix C  Elements of the Subject Informed Consent/Informed Assent 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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