A Phase 3, Single Arm, Open-Label Trial to Evaluate the Immunogenicity and Safety of a Single Heterologous Booster Vaccination of TAK-019 in Healthy Japanese Male and Female Adults Aged 20 Years and Older (COVID-19)
Phase: PHASE3
Conditions: Coronavirus Disease (COVID-19)
Sponsor: Takeda

 
 
Clinical Study Protocol 
 
NCT Number: NCT05299359 
Title: A Phase 3, Single Arm, Open-Label Trial to Evaluate the Immunogenicity and 
Safety of a Single Heterologous Booster Vaccination of TAK-019 in Healthy Japanese 
Male and Female Adults Aged 20 Years and Older 
Study Number: TAK-019-3001 
Document Version and Date: Amendment 1 / 29-Jul-2022 
 
Certain information within this document has been redacted (ie, specific content is 
masked irreversibly from view) to protect either personally identifiable information or 
company confidential information. 
 

TAK-019 
Trial No. TAK-019-3001 
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Protocol Version 2.0 (amendment 1) 
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PROTOCOL 
(English for reference purpose) 
<Title> 
A Phase 3, Single Arm, Open-Label Trial to Evaluate the Immunogenicity and Safety of a 
Single Heterologous Booster Vaccination of TAK-019 in Healthy Japanese Male and Female 
Adults Aged 20 Years and Older 
<Short Title> 
A Phase 3 Single Heterologous Booster Vaccination Study of TAK-019 
in Healthy Japanese Adults 
Sponsor: 
Takeda Pharmaceutical Company Limited 
1-1, Doshomachi 4-chome, Chuo-ku,
Osaka Japan
Trial Identifier: 
TAK-019-3001
IND Number: 
022430 
EudraCT Number: 
2020-004042-11 
Investigational 
Medicinal Product (s): 
TAK-019 
Takeda Approval Date: 29 July 2022 
Version: 
Version 2.0 (amendment 1) 
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1.0 
ADMINISTRATIVE INFORMATION AND PRINCIPLES OF CLINICAL 
STUDIES 
1.1 
Contacts and Responsibilities of Study-Related Activities 
See the annexes. 
1.2 
Principles of Clinical Studies 
This trial will be conducted with the highest respect for the individual subjects in accordance 
with the requirements of this clinical trial protocol and in accordance with the following: 
•
The ethical principles that have their origin in the Declaration of Helsinki [1].
•
International Council for Harmonisation of Technical Requirements for Pharmaceuticals
for Human Use (ICH) E6 (R2) Good Clinical Practice: Consolidated Guideline [2].
•
All applicable laws and regulations, including, but not limited to those related to data
privacy and clinical trial disclosure.
1.3 
Protocol Version Summary of Changes 
This section describes the changes in the protocol version 2.0. 
The primary purpose of this amendment is to update the protocol to include the Extension Part. 
Minor grammatical and editorial changes are included for clarification purposes only. 
Summary of the changes is given in Section 1.3.2. 
1.3.1 Version History 
Date 
Version 
Change Type 
Region 
21 February 2022 
(English for reference purpose: 02 March 2022) 
1.0 
Not applicable 
All trial sites in Japan 
29 July 2022 
(English for reference purpose: 29 July 2022) 
2.0 (amendment 1) 
Substantial 
All trial sites in Japan 
1.3.2 Summary of Changes 
Section 
Description of Change 
Rationale for Change 
Cover page 
Added “English for reference purpose”. 
To clarify the protocol in English has 
been prepared for reference purpose. 
2.0, 2.1, 5.1.1, 5.1.2, 5.1.3, 5.2.1, 5.2.2, 
5.2.3, 6.1, 6.2, 6.3, 7.1, and 7.2. 
Added the Extension Part and set 
existing part as the Main Part. 
To add study part for the second 
booster vaccination. 
2.1, 9.1.2, 9.1.7, 9.1.12, 9.3, 9.3.1, and 
9.3.4. 
Added description to confirm concomitant 
therapies. 
To clarify procedures. 
3.0 
Added and deleted abbreviations. 
To correspond to modification of 
other sections. 
4.1, 4.1.2, 4.1.2.1, 4.1.2.2, 4.1.3, 4.1.4, 
4.2, 6.2, and 16.0. 
Added justification of the Extension Part. 
To justify the addition of the 
Extension Part. 
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Section 
Description of Change 
Rationale for Change 
7.0, 7.3, 7.4, 7.5, 8.1.3, 8.2, 8.2.1, 9.1.1, 
9.1.2, 9.1.3, 9.1.4, 9.1.5, 9.1.6, 9.1.7, 
9.1.12, 9.1.13, 9.1.14, 9.1.15, 9.1.16, 
9.2, 9.3, 9.3.1, 9.3.2, 9.3.3, 9.3.4, 9.3.5, 
9.3.6, 9.3.7, 9.3.8, 9.3.9, 9.3.10, 10.1.3, 
10.1.4, 10.3, 10.4.1.1, 10.4.2, 10.4.3, 
and 10.4.4. 
Modified procedures according to the 
addition of the Extension Part. 
To correspond to the addition of the 
Extension Part. 
8.1, 8.1.1.1, and 8.1.1.2. 
Added description of the commercial 
product. 
Due to the market approval in Japan. 
13.1, 13.1.1, 13.1.3, 13.1.4, 13.2, and 
13.3. 
Added statistical method for the 
Extension Part. 
To correspond to the addition of the 
Extension Part. 
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TABLE OF CONTENTS 
1.0 
ADMINISTRATIVE INFORMATION AND PRINCIPLES OF CLINICAL 
STUDIES .............................................................................................................................2 
1.1 
Contacts and Responsibilities of Study-Related Activities ...........................................2 
1.2 
Principles of Clinical Studies .........................................................................................2 
1.3 
Protocol Version Summary of Changes .........................................................................2 
1.3.1 
Version History ...................................................................................................2 
1.3.2 
Summary of Changes ..........................................................................................2 
TABLE OF CONTENTS .................................................................................................................4 
List of In-Text Tables ................................................................................................................8 
List of In-Text Figures ...............................................................................................................8 
List of Appendices .....................................................................................................................8 
2.0 
TRIAL SUMMARY ............................................................................................................9 
2.1 
Schedule of Trial Procedures .......................................................................................18 
3.0 
LIST OF ABBREVIATIONS ............................................................................................22 
4.0 
INTRODUCTION .............................................................................................................24 
4.1 
Background ..................................................................................................................24 
4.1.1 
Nonclinical Studies ...........................................................................................25 
4.1.2 
Clinical Studies .................................................................................................26 
4.1.3 
Post-Marketing Data .........................................................................................28 
4.1.4 
Benefit-Risk Assessment ..................................................................................28 
4.2 
Rationale for the Proposed Trial ..................................................................................28 
5.0 
TRIAL OBJECTIVES AND ENDPOINTS ......................................................................30 
5.1 
Objectives ....................................................................................................................30 
5.1.1 
Primary Objectives............................................................................................30 
5.1.2 
Secondary Objectives........................................................................................30 
5.1.3 
 .....................................................................................31 
5.2 
Endpoints .....................................................................................................................32 
5.2.1 
Primary Endpoints ............................................................................................32 
5.2.2 
Secondary Endpoints ........................................................................................33 
5.2.3 
 ......................................................................................34 
6.0 
TRIAL DESIGN AND DESCRIPTION ...........................................................................35 
6.1 
Trial Design .................................................................................................................35 
6.2 
Justification for Trial Design, Dose, and Endpoints ....................................................37 
6.3 
Planned Duration of Subject’s Participation in the Trial .............................................38 
6.4 
Premature Termination or Suspension of Trial or Investigational Site .......................38 
6.4.1 
Criteria for Premature Termination or Suspension of the Trial ........................38 
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6.4.2 
Criteria for Premature Termination or Suspension of Investigational 
Sites ...................................................................................................................39 
6.4.3 
Procedures for Premature Termination or Suspension of the Trial or the 
Participation of Investigational Site(s)..............................................................39 
7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS ...............40 
7.1 
Inclusion Criteria .........................................................................................................40 
7.2 
Exclusion Criteria ........................................................................................................41 
7.3 
Prohibited Medications ................................................................................................45 
7.4 
Criteria for Delay of Investigational Medicinal Product Administration ....................45 
7.5 
Criteria for Early Termination of a Subject’s Trial Participation ................................45 
8.0 
CLINICAL TRIAL MATERIAL MANAGEMENT .........................................................47 
8.1 
Investigational Medicinal Product(s) ...........................................................................47 
8.1.1 
Dosage Form, Manufacturing, Packaging, and Labeling .................................47 
8.1.2 
Inventory and Storage .......................................................................................47 
8.1.3 
Dose and Regimen ............................................................................................48 
8.1.4 
Overdose ...........................................................................................................48 
8.2 
Investigational Medicinal Product Dispensing Procedures .........................................48 
8.2.1 
Precautions to Be Observed When Administering the Investigational 
Medicinal Product .............................................................................................48 
8.3 
Randomization Code Creation and Storage .................................................................49 
8.4 
Investigational Medicinal Product Blind Maintenance................................................49 
8.5 
Unblinding Procedure ..................................................................................................49 
8.6 
Accountability and Destruction of Sponsor-Supplied Investigational Medicinal 
Products, and Other Clinical Trial Materials ...............................................................49 
9.0 
TRIAL PLAN ....................................................................................................................51 
9.1 
Trial Procedures ...........................................................................................................51 
9.1.1 
Informed Consent..............................................................................................51 
9.1.2 
Demographics, Medical History and Prior Medications ...................................51 
9.1.3 
Documentation of Trial Entry ...........................................................................52 
9.1.4 
Physical Examination........................................................................................52 
9.1.5 
Vital Signs .........................................................................................................53 
9.1.6 
Immunogenicity Assessments ...........................................................................54 
9.1.7 
Concomitant Medications .................................................................................54 
9.1.8 
Processing, Labeling and Storage of Biological Samples ................................55 
9.1.9 
Safety Assessments ...........................................................................................55 
9.1.10 
Clinical Safety Laboratory Variables ................................................................55 
9.1.11 
Hematology and Blood Chemistry....................................................................55 
9.1.12 
Nasal Swab Sample...........................................................................................55 
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9.1.13 
 ..........................................................................56 
9.1.14 
Contraception and Pregnancy Avoidance Procedure ........................................56 
9.1.15 
Pregnancy ..........................................................................................................57 
9.1.16 
Documentation of Subjects Who Discontinue Prior to the Trial 
Vaccination .......................................................................................................57 
9.2 
Monitoring Subject Compliance ..................................................................................58 
9.3 
Schedule of Observations and Procedures ...................................................................58 
9.3.1 
Pre Booster Vaccination Procedures (Day 1 in the Main Part) ........................59 
9.3.2 
Booster Vaccination Procedures (Day 1 in the Main Part) ...............................59 
9.3.3 
Post Booster Vaccination Procedures (Day 1 in the Main Part) .......................59 
9.3.4 
Site Visits After Booster Vaccination (Day 8, Day 15, Day 29, Day 91, 
and Day 181 in the Main Part) ..........................................................................60 
9.3.5 
Final (End of Trial) Visit in the Main Part .......................................................60 
9.3.6 
Pre Booster Vaccination Procedures (Extension Part Day 1, Participant 
Decision Visit) ..................................................................................................61 
9.3.7 
Booster Vaccination Procedures (Extension Part Day 1, Participant 
Decision Visit) ..................................................................................................61 
9.3.8 
Post Booster Vaccination Procedures (Extension Part Day 1, Participant 
Decision Visit) ..................................................................................................61 
9.3.9 
Site Visits After Booster Vaccination (Extension Part Day 15, Day 29, 
Day 91, and Day 181) .......................................................................................62 
9.3.10 
Final (End of Trial) Visit in the Extension Part ................................................62 
9.3.11 
Post-Trial Care .................................................................................................62 
9.4 
Biological Sample Retention and Destruction .............................................................62 
10.0 
ADVERSE EVENTS .........................................................................................................64 
10.1 
Definitions....................................................................................................................64 
10.1.1 
Pretreatment Events ..........................................................................................64 
10.1.2 
Adverse Events .................................................................................................64 
10.1.3 
Solicited Adverse Events ..................................................................................64 
10.1.4 
Adverse Events of Special Interest ...................................................................66 
10.1.5 
Medically-Attended Adverse Events ................................................................68 
10.1.6 
Serious Adverse Events ....................................................................................68 
10.2 
Causality of Adverse Events ........................................................................................68 
10.2.1 
Relationship to Trial Procedures .......................................................................68 
10.2.2 
Outcome of Adverse Events .............................................................................69 
10.2.3 
Start Date ..........................................................................................................69 
10.2.4 
Stop Date ...........................................................................................................69 
10.2.5 
Frequency ..........................................................................................................70 
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10.3 
Additional Points to Consider for Adverse Events ......................................................70 
10.4 
Procedures ....................................................................................................................72 
10.4.1 
Collection and Reporting of Adverse Events....................................................72 
10.4.2 
Collection and Reporting of Solicited Adverse Events ....................................73 
10.4.3 
Collection and Reporting of Adverse Events of Special Interest/ 
Medically-Attended Adverse Events ................................................................74 
10.4.4 
Collection and Reporting of Serious Adverse Events.......................................74 
10.5 
Follow-up Procedures ..................................................................................................74 
10.5.1 
Adverse Events .................................................................................................74 
10.5.2 
Serious Adverse Events ....................................................................................75 
10.5.3 
Safety Reporting to Investigators, Investigational Review Boards, and 
Regulatory Authorities ......................................................................................75 
10.5.4 
Post-Trial Events ...............................................................................................75 
11.0 
TRIAL-SPECIFIC REQUIREMENT(S) ...........................................................................76 
11.1 
Trial-Specific Committee .............................................................................................76 
11.2 
Halting Rules ...............................................................................................................76 
12.0 
DATA HANDLING AND RECORD KEEPING .............................................................77 
12.1 
Electronic CRFs ...........................................................................................................77 
12.2 
Record Retention .........................................................................................................77 
13.0 
STATISTICAL METHODS ..............................................................................................79 
13.1 
Statistical and Analytical Plans ....................................................................................79 
13.1.1 
Analysis Sets .....................................................................................................79 
13.1.2 
Analysis of Demographics and Other Baseline Characteristics .......................79 
13.1.3 
Immunogenicity Analysis .................................................................................80 
13.1.4 
Safety Analysis .................................................................................................81 
13.2 
Interim Analysis and Criteria for Early Termination ...................................................84 
13.3 
Determination of Sample Size .....................................................................................84 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................85 
14.1 
Trial-Site Monitoring Visits .........................................................................................85 
14.2 
Protocol Deviations ......................................................................................................85 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections ..................................85 
14.4 
Trial Risk Management................................................................................................86 
15.0 
ETHICAL ASPECTS OF THE TRIAL .............................................................................87 
15.1 
Institutional Review Board Approval ..........................................................................87 
15.2 
Subject Information, Informed Consent, and Subject Authorization ..........................87 
15.3 
Subject Confidentiality ................................................................................................88 
15.4 
Clinical Trial Registration, Publication and Disclosure Policy ...................................89 
15.4.1 
Publication and Disclosure ...............................................................................89 
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15.4.2 
Clinical Trial Registration.................................................................................89 
15.4.3 
Clinical Trial Results Disclosure ......................................................................90 
15.4.4 
Publication of Trial Results ..............................................................................90 
15.5 
Insurance and Compensation for Injury .......................................................................90 
16.0 
REFERENCES ..................................................................................................................91 
List of In-Text Tables 
Table 8.a 
 ..................................47 
Table 9.a 
Volume and Numbers of Sampling........................................................................54 
Table 10.a 
Solicited Local (Injection Site) and Systemic AEs ................................................65 
Table 10.b 
Potential Immune-Mediated Medical Conditions (PIMMC) .................................66 
Table 10.c 
Adverse Events Specific to COVID-19a ................................................................67 
List of In-Text Figures 
Figure 6.a 
Schematic of Phase 3 Trial Design (Main Part) .....................................................36 
Figure 6.b 
Schematic of Trial Design (Extension Part) ..........................................................37 
List of Appendices 
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2.0 
TRIAL SUMMARY 
Name of Sponsor: Takeda Pharmaceutical Company Limited 
Product Name: TAK-019 
Trial Title: A phase 3, single arm, open-label trial to evaluate the immunogenicity and safety of a single 
heterologous booster vaccination of TAK-019 in healthy Japanese male and female adults aged 20 years and older 
IND No.: 022430 
EudraCT No.: 2020-004042-11 
Trial Identifier: TAK-019-3001 
Phase: 3 
Blinding Schema: Open-label 
Indication: Prevention of infectious disease caused by severe acute respiratory syndrome coronavirus-2 
(SARS-CoV-2). 
Trial Design: 
Main Part 
This is a phase 3, single arm, open-label trial to evaluate the immunogenicity and safety of a single heterologous 
booster vaccination of TAK-019 by intramuscular (IM) injection in healthy Japanese male and female adults who 
completed 2 doses primary vaccinations with Comirnaty Intramuscular Injection from 6 to 12 months before the 
trial vaccination. 
The trial is planned to enroll 150 subjects (all in the TAK-019 arm). They will be stratified by age; 100 subjects as 
≥20 years to <65 years, and 50 subjects as ≥65 years of age. 
Once all screening assessments following informed consent are completed and eligibility is confirmed, the subject 
will receive a single booster vaccination of TAK-019, by IM injection. All subjects will be followed up for 
immunogenicity and safety for 12 months after the trial vaccination. 
Each subject will be provided with an electronic diary (eDiary). Oral body temperature and solicited local and 
systemic adverse events (AEs) will be recorded in the eDiary by the subjects for 7 days after booster vaccination 
(including the day of vaccination). All subjects will be followed for unsolicited AEs for 28 days following booster 
vaccination (day of vaccination + 27 subsequent days). 
All subjects will be followed for serious AEs (SAEs), AEs of special interest (AESIs), medically-attended AEs 
(MAAEs), and AEs leading to trial withdrawal during their entire participation in the trial. All subjects will also be 
tested for SARS-CoV-2 infection at prespecified visits (Day 1 and Day 15) or, in case of clinical symptoms 
suspected for coronavirus disease 2019 (COVID-19) throughout the trial. 
The primary analysis will be performed for immunogenicity and safety after all subjects have completed the 
Day 29 visit. 
Schematic of Phase 3 Trial Design (Main Part) 
Abbreviations: COVID-19: coronavirus disease 2019; N/n: number of subjects. 
Extension Part 
Extension Part is designed to offer a second single booster vaccination of TAK-019 to participants who received 
the first single booster vaccination of TAK-019 in the Main Part and remained in study follow-up at least 
5 months. The end of the Main Part is defined as the earlier of the completion of the final visit on Day 366 or the 
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initiation of the Extension Part. Therefore, data of the Main Part will consist data of all subjects in the Main 
Part, data of the Extension Part will consist only data of subjects after the initiation of the Extension Part. The 
end of Extension Part is defined as the completion of the final visit on Extension Part Day 366. All analyses will 
be performed descriptively in the Extension Part. 
All subjects who are willing to proceed to the Extension Part and to receive a second booster vaccination of 
TAK-019 will be asked to schedule a Participant Decision Visit about 5 months after the first single booster 
vaccination.  
All subjects who provide additional informed consent for the Extension Part at the Participant Decision Visit and 
are eligible for enrollment in the Extension Part will receive a second single booster vaccination of TAK-019, by 
IM injection (Extension Part Day 1). All subjects in the Extension Part will be followed up for immunogenicity 
and safety for 12 months after the Extension Part Day 1. 
Each subject will be provided an eDiary. Oral body temperature and solicited local and systemic AEs will be 
recorded in the eDiary by the subjects for 7 days after the second booster vaccination (including the Extension 
Part Day 1). All subjects will be followed-up for unsolicited AEs for 28 days following the second booster 
vaccination (Extension Part Day 1 + 27 subsequent days).  
All subjects will be followed-up for SAEs, AESIs, MAAEs, and AEs leading to trial withdrawal in the Extension 
Part. All subjects will also be tested for SARS-CoV-2 infection in case of clinical symptoms suspected for 
COVID-19 in the Extension Part. 
An interim analysis will be performed for immunogenicity and safety after all subjects have completed the 
Extension Part Day 29 visit. 
Schematic of Trial Design (Extension Part) 
Abbreviations: COVID-19: coronavirus disease 2019; ED: Extension Part Day. 
Primary Objectives: 
Main Part 
To evaluate the immunogenicity and safety of a single heterologous booster vaccination of TAK-019 by IM 
injection in healthy Japanese male and female adults aged ≥20 years. 
Immunogenicity: 
To assess the immunogenicity of TAK-019 in terms of: 
•
Non-inferiority of geometric mean titers (GMTs) of neutralizing antibody titers to wild-type virus 14 days
after a single booster vaccination (Day 15) compared with that observed 14 days after the second vaccination
(Day 36) in Study TAK-019-1501.
Safety: 
To assess the safety of TAK-019 in terms of: 
•
Solicited local and systemic AEs for 7 days following booster vaccination (day of vaccination
+ 6 subsequent days).
•
Unsolicited AEs for 28 days following booster vaccination (day of vaccination + 27 subsequent days).
•
SAEs, AESIs, MAAEs, AEs leading to trial withdrawal, and SARS-CoV-2 infection until Day 29.
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Secondary Objectives: 
Main Part 
Immunogenicity: 
To assess the immunogenicity of TAK-019 in terms of: 
•
Serum immunoglobulin G (IgG) antibody levels to SARS-CoV-2 recombinant spike (rS) protein.
•
Serum neutralizing antibody titers to the ancestral strain (wild-type virus).
Safety:
To assess the safety of TAK-019 in terms of: 
•
SAEs, AESIs, MAAEs, AEs leading to trial withdrawal, and SARS-CoV-2 infection throughout the trial.
Extension Part 
To evaluate the immunogenicity and safety of a second single booster vaccination of TAK-019 by IM injection in 
healthy Japanese male and female adults aged ≥20 years. 
Immunogenicity: 
To assess the immunogenicity of TAK-019 in terms of: 
•
Serum IgG antibody levels to SARS-CoV-2 rS protein.
•
Serum neutralizing antibody titers to the ancestral strain (wild-type virus).
Safety:
To assess the safety of TAK-019 in terms of: 
•
Solicited local and systemic AEs for 7 days following the second single booster vaccination (day of
vaccination + 6 subsequent days).
•
Unsolicited AEs for 28 days following the second single booster vaccination (day of vaccination
+ 27 subsequent days).
•
SAEs, AESIs, MAAEs, AEs leading to trial withdrawal, and SARS-CoV-2 infection until Extension Part
Day 29.
•
SAEs, AESIs, MAAEs, AEs leading to trial withdrawal, and SARS-CoV-2 infection throughout the trial.
Subject Population: 
Main Part 
Healthy Subjects: Yes. 
Age Range: ≥20 years (Two age strata: ≥20 years to <65 years and ≥65 years). 
Planned Number of Subjects: 150 subjects stratified by age as ≥20 years to <65 years (100 subjects), and 
≥65 years (50 subjects). 
Planned Number of Trial Arms: 1 arm 
•
Arm 1: (n=150 subjects), Investigational product (TAK-019).
Planned Number of Trial Sites: 2 sites
Extension Part 
Subjects who received a first single booster vaccination of TAK-019 in the Main Part at least 5 months earlier.
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Key Inclusion Criteria: 
Main Part 
•
Healthy Japanese male and female adult subjects aged ≥20 years of age at the time of signing of informed
consent.
•
Subjects who understand and are willing to comply with the trial procedures and are available for the
duration of follow‑up.
•
Subjects who completed 2 doses primary vaccinations with Comirnaty Intramuscular Injection 6 to
12 months prior to the trial vaccination (with showing their vaccination certificate issued by Japanese
municipality).
•
A male subject or a female subject of childbearing potential who is sexually active with a nonsterilized male
partner agrees to use acceptable contraceptive methods from 28 days prior to the first single booster
vaccination until 3 months after the first single booster vaccination.
Extension Part 
•
Subjects who received the first trial vaccination at least 5 months earlier and are currently enrolled in the
Main Part (ie, not have withdrawn or discontinued early).
•
Subjects who signed an additional informed consent form for the Extension Part, understand and are willing 
to comply with trial procedures and are available for the duration of follow‑up.
•
A male subject or a female subject of childbearing potential who is sexually active with a nonsterilized male
partner agrees to use acceptable contraceptive methods from 28 days prior to the second single booster
vaccination until 3 months after the second single booster vaccination.
Key Exclusion Criteria: 
Main Part 
•
Subjects who received any other SARS-CoV-2 vaccine (except for Comirnaty Intramuscular Injection) or
other experimental novel coronavirus vaccine prior to the trial.
•
Subjects who received a booster vaccination (ie, 3rd dose) with Comirnaty Intramuscular Injection or
Spikevax Intramuscular Injection (previously COVID-19 Vaccine Moderna Intramuscular Injection).
•
Subjects who have close contact of anyone known to have COVID-19 within 14 days prior to the first trial
vaccination.
•
Subjects who were tested positive for SARS-CoV-2 prior to the trial.
•
Subjects who have traveled outside of Japan in the 30 days prior to the trial participation.
•
Subjects with a clinically significant active infection (as assessed by the Investigator) or oral temperature
≥38°C within 3 days of the intended date of the first single booster vaccination.
•
Subjects with known hypersensitivity or allergy to any of the investigational vaccine components and/or
Comirnaty Intramuscular Injection.
•
Subjects with history or any illness that, in the opinion of the Investigator, might interfere with the results of
the trial or pose additional risk to the subjects due to participation in the trial.
•
Subjects with known or suspected impairment/alteration of immune function, including history of any
autoimmune disease or neuro-inflammatory disease.
•
Abnormalities of splenic or thymic function.
•
Subjects with a known bleeding diathesis, or any condition that may be associated with a prolonged bleeding
time.
•
Subjects with any serious chronic or progressive disease (eg, neoplasm, insulin dependent diabetes, cardiac,
renal or hepatic disease).
•
Subjects with body mass index (BMI) greater than or equal to 30 kg/m2 (BMI= weight in kg/ height in
meters2).
•
Subjects participating in any clinical trial with another investigational product within 30 days prior to the
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first trial vaccination or intend to participate in another clinical trial at any time during the conduct of this 
trial. 
•
Subjects who received or plan to receive any other licensed vaccines within 14 days (for inactivated
vaccines) or 28 days (for live vaccines) prior to the first trial dose administration.
•
Subjects with acute or chronic clinically significant disease including pulmonary, cardiovascular, hepatic or
renal abnormality evaluated by physical examination.
•
Subjects involved in the trial conduct or their first-degree relatives.
•
Subjects who have history or infection of hepatitis B, hepatitis C, and HIV.
•
Female subjects who are pregnant or breastfeeding.
Extension Part 
•
Subjects with a clinically significant active infection (as assessed by the Investigator) or oral temperature
≥38°C within 3 days of the intended date of the second single booster vaccination.
•
Subjects with known hypersensitivity or allergy to any of the investigational vaccine components and/or
Comirnaty Intramuscular Injection.
•
Subjects with history or any illness that, in the opinion of the Investigator, might interfere with the results of
the trial or pose additional risk to the subjects due to participation in the trial.
•
Subjects with known or suspected impairment/alteration of immune function, including history of any
autoimmune disease or neuro-inflammatory disease.
•
Abnormalities of splenic or thymic function.
•
Subjects with a known bleeding diathesis, or any condition that may be associated with a prolonged bleeding
time.
•
Subjects with any serious chronic or progressive disease (eg, neoplasm, insulin dependent diabetes, cardiac,
renal or hepatic disease).
•
Subjects participating in any clinical trial with another investigational product within 30 days prior to the
second single booter vaccination or intend to participate in another clinical trial at any time during the
conduct of this trial.
•
Subjects who received or plan to receive any other licensed vaccines within 14 days (for inactivated
vaccines) or 28 days (for live vaccines) prior to the second single booter dose administration.
•
Subjects with acute or chronic clinically significant disease including pulmonary, cardiovascular, hepatic or
renal abnormality evaluated by physical examination.
•
Subjects who have history or infection of hepatitis B, hepatitis C, and HIV.
•
Subjects with a history of myocarditis or pericarditis.
•
Female subjects who are pregnant or breastfeeding.
Trial Vaccine and Placebo: 
Trial Vaccine 
Investigational vaccine: TAK-019 for injection as a 0.5 mL volume will be used. The investigational vaccine 
contains 5 µg of SARS-CoV-2 rS plus 0.05 mg of Matrix-M adjuvant. 
Route of Administration: IM injection in the mid deltoid, preferable in the non-dominant upper arm. 
Placebo 
Placebo is not used in this trial. 
Duration of the Trial and Subject Participation: 
Subjects Participating Only in the Main Part 
The trial participation for each subject is for 12 months following the first single booster vaccination. 
Subjects Entering the Extension Part 
The trial participation for each subject is for at least 17 months in total (at least 5 months following the first single 
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booster vaccination in the Main Part and 12 months following the second single booster vaccination in the 
Extension Part). 
Criteria for Evaluation and Analyses: 
Primary Endpoints: 
Main Part 
Immunogenicity: 
•
GMT ratio of neutralizing antibody titers to the ancestral strain (wild-type virus) on Day 15 after a single
booster vaccination (14 days after the booster vaccination) compared with that observed on Day 36 (14 days
after the second vaccination) in subjects from Study TAK-019-1501.
Safety: 
•
Percentage of subjects with reported solicited local AEs: injection site pain, tenderness, erythema/redness,
induration, and swelling for 7 days following the first single booster vaccination (day of vaccination
+ 6 subsequent days).
•
Percentage of subjects with solicited systemic AEs: fever, fatigue, malaise, myalgia, arthralgia,
nausea/vomiting, and headache for 7 days following the first single booster vaccination (day of vaccination
+ 6 subsequent days).
•
Percentage of subjects with unsolicited AEs for 28 days following the first single booster vaccination (day of
vaccination + 27 subsequent days).
•
Percentage of subjects with SAEs until Day 29.
•
Percentage of subjects with AESIs until Day 29.
•
Percentage of subjects with MAAEs until Day 29.
•
Percentage of subjects with any AEs leading to subject’s withdrawal from the trial until Day 29.
•
Percentage of subjects with SARS-CoV-2 infection until Day 29.
Secondary Endpoints: 
Main Part 
Immunogenicity: 
•
GMT, geometric mean fold rise (GMFR), and seroconversion rate (SCR; defined at proportion of subjects
with ≥4-fold rises from baseline [Day 1]) of serum IgG antibody levels to SARS-CoV-2 rS protein on Day 8,
Day 15, Day 29, Day 91, Day 181, and Day 366.
•
GMT, GMFR, and SCR of serum neutralizing antibody titers to the ancestral strain (wild-type virus) on
Day 8, Day 15, Day 29, Day 91, Day 181, and Day 366.
Safety: 
•
Percentage of subjects with SAEs throughout the trial.
•
Percentage of subjects with AESIs throughout the trial.
•
Percentage of subjects with MAAEs throughout the trial.
•
Percentage of subjects with any AEs leading to subject’s withdrawal from the trial from the day of the first
single booster vaccination throughout the trial.
•
Percentage of subjects with SARS-CoV-2 infection throughout the trial.
Extension Part 
Immunogenicity:
•
GMT, GMFR, and SCR (defined at proportion of subjects with ≥4-fold rises from baseline [Extension Part
Day 1]) of serum IgG antibody levels to SARS-CoV-2 rS protein on Extension Part Day 15, Day 29,
Day 91, Day 181, and Day 366.
•
GMT, GMFR, and SCR of serum neutralizing antibody titers to the ancestral strain (wild-type virus) on
Extension Part Day 15, Day 29, Day 91, Day 181, and Day 366.
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Safety: 
•
Percentage of subjects with reported solicited local AEs: injection site pain, tenderness, erythema/redness,
induration, and swelling for 7 days following the second single booster vaccination (day of vaccination
+ 6 subsequent days).
•
Percentage of subjects with solicited systemic AEs: fever, fatigue, malaise, myalgia, arthralgia,
nausea/vomiting, and headache for 7 days following the second single booster vaccination (day of
vaccination + 6 subsequent days).
•
Percentage of subjects with unsolicited AEs for 28 days following the second single booster vaccination (day 
of vaccination + 27 subsequent days).
•
Percentage of subjects with SAEs until Extension Part Day 29.
•
Percentage of subjects with AESIs until Extension Part Day 29.
•
Percentage of subjects with MAAEs until Extension Part Day 29.
•
Percentage of subjects with any AEs leading to subject’s withdrawal from the trial until Extension Part
Day 29.
•
Percentage of subjects with SARS-CoV-2 infection until Extension Part Day 29.
•
Percentage of subjects with SAEs throughout the trial.
•
Percentage of subjects with AESIs throughout the trial.
•
Percentage of subjects with MAAEs throughout the trial.
•
Percentage of subjects with any AEs leading to subject’s withdrawal from the trial from the day of the second
single booster vaccination throughout the trial.
•
Percentage of subjects with SARS-CoV-2 infection throughout the trial.
Statistical Considerations: 
Main Part 
The primary analysis will be performed for immunogenicity and safety after all subjects have completed the 
Day 29 visit. 
Immunogenicity Analysis: 
For immunogenicity endpoints, analyses will be conducted using the Per-protocol Set (PPS). 
For neutralizing antibody titer values to the ancestral strain (wild-type virus), summary statistics, GMT, and the 
two-sided 95% CIs will be calculated. 
For GMT ratio of serum neutralizing antibody titers to the ancestral strain (wild-type virus) between booster 
vaccination group in the proposed study and the 2 doses primary vaccinations group in Study TAK-019-1501 
(called study group), point estimate and the two-sided 95% CIs will be provided using a 2-way analysis of 
variance (ANOVA) model. The 2-way ANOVA model will include log-transformed (common log) serum 
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neutralizing antibody titers to the ancestral strain (wild-type virus) 14 days after vaccination as dependent 
variable, and categorized age (20<= - <65, 65<=) and study group as independent variable. Each estimate by the 
model will be back transformed to the original scale. The lower limit of two-sided 95% CI of the GMT ratio will 
be compared with non-inferiority margin of 0.67 to assess the non-inferiority of neutralizing antibody titers to the 
ancestral strain (wild-type virus) on Day 15 after a single booster vaccination compared with that observed on 
Day 36 (14 days after 2nd vaccination) in subjects from Study TAK-019-1501. If the lower limit of the 95% CI 
will be ≥0.67, the immune response to a single heterologous booster vaccination of TAK-019 will be considered to 
be non-inferior of that to the primary series of TAK-019. 
SCR of each immunogenicity endpoint at each time point will be calculated along with its 95% CI. For antibody 
titer values and GMFR from baseline, summary statistics, GMT, and the two-sided 95% CIs of each endpoint at 
each time point will be calculated. 
Safety analysis: 
For safety endpoints, analyses will be performed using the Safety Analysis Set (SAS). 
Solicited local and systemic AEs will be summarized for each day post the first single vaccination and the total 
duration (day of vaccination + 6 subsequent days). 
Unsolicited AEs for 28 days following the first single booster vaccination will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA) dictionary and tabulated by the System Organ Class (SOC) and 
the Preferred Term (PT). 
The percentage of subjects with SARS-CoV-2 infection will be summarized. 
For continuous variables of vital signs, the observed values and the changes from baseline will be summarized for 
each scheduled time point using descriptive statistics. For categorical variables, shift tables showing the number 
of subjects in each category at baseline and each post-baseline scheduled time point will be provided. 
Extension Part 
Immunogenicity Analysis: 
For immunogenicity endpoints, analyses will be conducted using the PPS in Extension Part. 
SCR of each immunogenicity endpoint at each time point will be calculated along with its 95% CI. For antibody 
titer values, summary statistics, GMT and GMFR from baseline, and 95% CIs of each endpoint at each time point 
will be calculated. 
Safety analysis: 
For safety endpoints, analyses will be performed using the SAS in Extension Part. 
Solicited local and systemic AEs will be summarized for each day post the second single booster vaccination and 
the total duration (day of vaccination + 6 subsequent days).  
Unsolicited AEs for 28 days following the second single booster vaccination will be coded using the MedDRA 
dictionary and tabulated by the SOC and the PT. 
The percentage of subjects with SARS-CoV-2 infection will be summarized. 
For continuous variables of vital signs, the observed values and the changes from baseline (Extension Part 
Day 1) will be summarized for each scheduled time point using descriptive statistics. For categorical variables, 
shift tables showing the number of subjects in each category at baseline and each post-baseline scheduled time 
point will be provided. 
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Sample Size Justification: 
Main Part 
In Study TAK-019-1501, GMT and geometric SD of serum neutralizing antibody titers to wild-type virus after the 
primary vaccinations on Day 36 (14 days after the 2nd vaccination) were 884.4 and 2.80 respectively in the 
vaccine group. 
There is no immunogenicity data of serum neutralizing antibody titers to the ancestral strain (wild-type virus) after 
a booster vaccination of TAK-019 in Japanese subjects available. However, an estimate has been made on the 
results of the primary vaccination in Study TAK-019-1501 and the homoeologous booster vaccination in Study 
2019nCoV-101 (Part 2). The assumption was made that neutralizing antibody titers on Day 15 in the proposed 
study would be equivalent to titers on Day 36 in Study TAK-019-1501 (ie, assuming GMT ratio to be 1 and 
geometric SD to be 2.80). With the guidance document, Principles for the Evaluation of Vaccines Against the 
Novel Coronavirus SARS-CoV-2 (Appendix 1) Evaluation of Vaccines Against Variants, issued by the 
Pharmaceuticals and Medical Devices Agency of Japan, in mind, the non-inferiority margin of GMT ratio 
between booster vaccination group in the proposed study and the primary vaccination group in Study 
TAK-019-1501 is set as 0.67 fold. This results in 132 subjects be required as the number of evaluable subjects in 
PPS to ensure 90% power with the lower limit of 2-sided 95% CI of the GMT ratio exceeding the non-inferiority 
margin. Considering around 10% non-evaluable subjects, 150 subjects will be required into the proposed study. 
Extension Part 
The number of subjects in this part is not based on statistical power considerations as this is an Extension Part of 
Study TAK-019-3001 following the Main Part. 
Interim Analysis: 
No interim analysis is planned for the Main Part. 
An interim analysis of immunogenicity and safety is planned for the Extension Part after all subjects have 
completed Extension Part Day 29 (immunogenicity data through Extension Part Day 15 and safety data through 
Extension Part Day 29). 
Data Monitoring Committee: 
No independent data monitoring committee will be used for this trial. 
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Abbreviations: AE: adverse event; AESI: adverse event of special interest; BMI: body mass index; COVID-19: coronavirus disease 2019; eDiary: electronic diary; MAAE: medically-attended adverse event;  
PCR: polymerase chain reaction; SAE: serious adverse event; SARS-CoV-2: severe acute respiratory syndrome coronavirus-2. 
a
The day before booster vaccination is designated as “Day -1”, and the day of booster vaccination (visit number 1) is designated as “Day 1”.
b
For the subjects who withdraw from the trial, efforts should be made to retain the subjects in the safety observation period, whenever possible. Blood sample for
immunogenicity data will not be collected at the early termination visit. The observation items of Early Termination / Trial End should be carried out as much as possible.
c
To be obtained from the subject prior to initiation of any trial procedure. Signed informed consent obtained between Day -28 to Day 1 is valid.
d
Assessment of eligibility by review of all inclusion and exclusion criteria or contraindications will be documented before the booster vaccination on Day 1.
e
The data within 14 days before Day 1 (Day -14 to Day 1) can be used for the trial.
f
Medical and medication history will be collected at the time of informed consent.
g
Height and weight will be measured on Day 1 before vaccination only and BMI will be calculated. On the day of vaccinations ie, Day 1 the Investigator will monitor for any
findings such as acute hypersensitivity reactions for 30 minutes after each vaccination. Review of systems will be performed as explained in Section 9.1.4.
h
On the day of vaccination, oral body temperature, blood pressure (systolic and diastolic, resting more than 5 minutes), pulse rate, and respiratory rate should be measured
before the vaccination as well as 30 minutes after the vaccination.
i
Urine pregnancy test will be performed only in women of childbearing potential.
j
For 7 days after booster vaccination (including the day of the vaccination) oral body temperature will be measured and recorded in the eDiary every day by the subjects.
k
Solicited local and systemic AEs will be collected for 7 days after booster vaccination (day of vaccination + 6 subsequent days).
l
Unsolicited AEs will be collected for 28 days following booster vaccination (day of vaccination + 27 subsequent days).
m
All concomitant medications (including concomitant therapies) information will be collected for 28 days following booster vaccination until Day 29. Follow up for
concomitant medications (including concomitant therapies) associated with SAEs, AEs leading to withdrawal from trial, and treatments for COVID-19 will be performed
365 days following booster vaccination.
n
SAEs must be reported to the Sponsor within 24 hours of the Investigator becoming aware of the event.
o
Nasal swabs will be collected at prespecified time points (Day 1 and Day 15). In case of suspected for COVID-19 clinical symptoms, samples for COVID-19 diagnostic test
will be collected throughout the trial. If subjects show a sign of SARS-CoV-2 infection during the trial (from Day 1 to Day 366), a sample will be collected from the subject
by medically qualified staff within 72 hours or as soon as possible, at an ad hoc visit or home visit. If a sample for the trial is unavailable, COVID-19 diagnostic test results
including PCR test performed at a local public health or hospital will be accepted.
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a
The day before the booster vaccination in the Extension Part is designated as “Extension Part Day -1”, and the day of booster vaccination (visit number 1) in the
Extension Part is designated as “Extension Part Day 1”.
b
For the subjects who withdraw from the trial, efforts should be made to retain the subjects in the safety observation period, whenever possible. Blood sample for
immunogenicity data will not be collected at the early termination visit. The observation items of Early Termination/Trial End should be carried out as much as possible.
c
To be obtained from the subject prior to initiation of any trial procedure in the Extension Part. Signed informed consent obtained between Extension Part Day -28 to
Extension Part Day 1 is valid.
d
Assessment of eligibility by review of all inclusion and exclusion criteria or contraindications, including prior medications of the 2nd booster vaccination, will be
documented before the booster vaccination at Extension Part Day 1.
e
On the day of vaccination (ie, Extension Part Day 1), the Investigator will monitor for any findings such as acute hypersensitivity reactions for 30 minutes after vaccination. 
Review of systems will be performed as explained in 
 
f
On the day of vaccination, body temperature, blood pressure (systolic and diastolic, resting more than 5 minutes), pulse rate, and respiratory rate should be measured before
the vaccination as well as 30 minutes after the vaccination.
g
Urine pregnancy test will be performed only in women of childbearing potential.
h
For 7 days after booster vaccination (including the day of the vaccination), oral body temperature will be measured and recorded in the eDiary every day by the subjects.
i
Solicited local and systemic AEs will be collected for 7 days after the booster vaccination in the Extension Part (day of vaccination in the Extension Part + 6 subsequent
days).
j
Unsolicited AEs will be collected for 28 days following the booster vaccination in the Extension Part (day of vaccination in the Extension Part + 27 subsequent days).
k
All concomitant medications (including concomitant therapies) information will be collected for 28 days following the booster vaccination in the Extension Part until
Extension Part Day 29. Follow up for concomitant medications (including concomitant therapies) associated with SAEs, AEs leading to withdrawal from trial, and
treatments for COVID-19 will be performed 365 days following the booster vaccination in the Extension Part.
l
SAEs must be reported to the Sponsor within 24 hours of the Investigator becoming aware of the event.
m
Nasal swabs will be collected in case of suspected for COVID-19 clinical symptoms throughout the trial. If subjects show a sign of SARS-CoV-2 infection during the trial
(from Extension Part Day 1 to Extension Part Day 366), a nasal swab sample will be collected from the subject by medically qualified staff within 72 hours or as soon as
possible, at an ad hoc visit or home visit. If a nasal swab sample for the trial is unavailable, PCR test results performed at a local public health or hospital will be accepted.
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3.0 
LIST OF ABBREVIATIONS 
AE 
adverse event 
AESI 
adverse event of special interest 
ANOVA 
analysis of variance 
BMI 
body mass index 
COVID-19 
coronavirus disease 2019 
CRO 
contract research organization 
CSR 
clinical study report 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eDiary 
electronic diary 
EUA 
emergency use authorization 
FAS 
Full Analysis Set 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GMFR 
geometric mean fold rise 
GMT 
geometric mean titer 
GP 
glycoprotein 
GPSP 
Good Post-Marketing Study Practice 
GVP 
Good Vigilance Practice 
IB 
investigator’s brochure 
ICF 
informed consent form  
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IgG 
immunoglobulin G 
IM 
intramuscular 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
ISF 
Investigator Site File 
jRCT 
Japan Registry of Clinical Trials 
MAAE 
medically-attended adverse event 
MedDRA 
Medical Dictionary for Regulatory Activities 
MERS 
Middle East respiratory syndrome 
MHLW 
Ministry of Health, Labour, and Welfare 
mRNA 
messenger RNA 
NDA 
new drug application 
OTC 
over-the-counter 
PCR 
polymerase chain reaction 
PIMMC 
Potential Immune Mediated Medical Conditions 
PMDA 
Pharmaceuticals and Medical Devices Agency 
PPS 
Per-protocol Set 
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PT 
Preferred Term 
PTE 
pretreatment event 
QTL 
quality tolerance limit 
rS 
recombinant spike 
S 
spike 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SARS 
severe acute respiratory syndrome 
SARS-CoV 
severe acute respiratory syndrome coronavirus 
SARS-CoV-2 severe acute respiratory syndrome coronavirus-2 
SAS 
Safety Analysis Set 
SCR 
seroconversion rate 
Sf9 
Spodoptera frugiperda 
SOC 
System Organ Class 
SUSAR 
suspected unexpected serious adverse reaction 
VE 
vaccine efficacy 
VOC 
variant of concern 
VOI 
variant of interest 
WHO 
World Health Organization 
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4.0 
INTRODUCTION 
4.1 
Background 
Coronaviruses are a large family of viruses that cause illness for human ranging from the common 
cold to more severe diseases, such as Middle East respiratory syndrome (MERS) and severe acute 
respiratory syndrome (SARS). 
Coronaviruses are enveloped, positive-stranded RNA viruses, with a characteristic crown-like 
appearance in electron micrographs due to circumferential studding of the viral envelope with 
projections comprising the spike (S) protein. There are 4 different strains (HCoV-229E, 
HCoV-OC43, HCoV-NL63, and HCoV-HKU1) which are ubiquitous in humans and generally 
result in mild upper respiratory illnesses and other common cold symptoms including malaise, 
headache, nasal discharge, sore throat, fever, and cough [3]. 
In December 2019, a respiratory disease caused by novel coronavirus (2019-nCoV) was confirmed 
in Wuhan Hubei Province, China [4]. The ‘virus’ discerned genetic relationship with the 
2002-2003 severe acute respiratory syndrome coronavirus (SARS-CoV) and resulted in adoption 
of name “SARS-CoV-2” (severe acute respiratory syndrome coronavirus-2) with the disease being 
referred as coronavirus disease 2019/“COVID-19” [5]. 
On 11 March 2020, the World Health Organization (WHO) officially declared COVID-19 a 
pandemic [6]. As of 5 June 2022, the WHO reported over 520 million confirmed cases and over 
6 million deaths globally [7]. In Japan, as of 12 June 2022, the Ministry of Health, Labour, and 
Welfare (MHLW) reported over 9 million confirmed cases with a positive polymerase chain 
reaction (PCR) test result for COVID-19, with over 30,000 deaths in Japan [8]. The MHLW has 
reported that the highest risk of disease burden is in older adults (≥65 years old) and people who 
have serious underlying medical conditions, such as chronic obstructive pulmonary disease, 
chronic renal disease, diabetes, hypertension, cardiovascular disease, and obesity (body mass 
index [BMI] of 30 kg/m2 or higher) [9]. 
Multiple vaccines for SARS-CoV-2 are currently under development including inactivated 
vaccines, recombinant protein vaccines, messenger RNA (mRNA) vaccines, DNA vaccines, and 
viral vector vaccines. When this study was planned, as of 18 January 2022, Comirnaty 
Intramuscular Injection and Spikevax Intramuscular Injection (mRNA vaccines), and Vaxzevria 
Intramuscular Injection (a viral vector vaccine) were available in Japan [10]. Thereafter, 
Nuvaxovid Intramuscular Injection (discussed below for Nuvaxovid) has become also available, 
and Jcovden Intramuscular Injection (a viral vector vaccine) has been approved in Japan by June 
2022. 
Novavax, Inc. is developing Nuvaxovid (development code: NVX-CoV2373) as a novel vaccine 
option for SARS-CoV-2. Nuvaxovid is a SARS-CoV-2 recombinant spike (rS) protein 
nanoparticle vaccine (SARS-CoV-2 rS), constructed from the full-length wild-type SARS-CoV-2 
S glycoprotein (GP) based on nucleotides 21563 to 25384 of GenBank gene sequence MN908947, 
derived from 2019 SARS-CoV-2 genome. The S protein is a Type 1 trimeric GP of 1,273 amino 
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acids that is produced as an inactive S0 precursor. To produce the SARS-CoV-2 rS vaccine 
candidate, the S-gene was codon optimized for expression in Spodoptera frugiperda (Sf9) insect 
cells. Nuvaxovid also contains saponin-based adjuvant, Matrix-M, which has previously shown to 
enhance the immunogenicity of other nanoparticle vaccines in nonclinical and clinical studies. In 
Japan, Nuvaxovid is developed by Takeda Pharmaceutical Company Limited (development code: 
TAK-019). 
Nuvaxovid was firstly approved for emergency use authorization (EUA) in Indonesia in 
November 2021. By 1 May 2022, Nuvaxovid have obtained approval, conditional approval, or 
EUA in more than 40 countries. In Japan, before this study was initiated, new drug application 
(NDA) was submitted on 16 December 2021. And after this study was initiated, on 19 April 2022, 
Nuvaxovid was approved in Japan for adults over 18 years of age. Approved regimen in Japan is 
the following: “Primary immunization: Administer 2 doses of 0.5 mL each typically 3 weeks apart 
intramuscularly. Booster immunization: Administer 0.5 mL per dose intramuscularly.” Also, 
intervals were defined as the following: “Primary immunization: If more than 3 weeks have passed 
since the first dose, administer the second dose as soon as possible. Booster immunization: The 
third dose of this product can typically be given at least 6 months after the second dose.” 
4.1.1 Nonclinical Studies 
As nonclinical pharmacological evaluations, immunogenicity evaluation using animal models of 
mice, hamsters, cynomolgus macaques, and baboons, and protective efficacy evaluation using 
mice, hamsters, cynomolgus macaques, and rhesus macaques were conducted. These nonclinical 
studies showed that NVX-CoV2373 has highly immunogenic to induce neutralizing antibody 
production at safe and tolerated doses, and induce reduction in lung inflammation and viral 
replication with one or two doses. In addition, NVX-CoV2373 also appeared to induce strong Th1 
type CD4+ T-cell responses to SARS-CoV-2 S protein without exacerbation of the inflammatory 
response due to viral attack. 
A Good Laboratory Practice (GLP)-compliant toxicity study in rabbit was performed to evaluate 
50 µg of the SARS-CoV-2 rS with and without 50 µg Matrix-M adjuvant by intramuscular (IM) 
injection. SARS-CoV-2 rS with or without 50 µg Matrix-M adjuvant was well tolerated and had 
no effects on mortality, cageside observations, body weight, food consumption, or physical 
examination findings. Serum chemical markers of acute reaction (including fibrinogen and 
C-reactive protein) were transient and recovered. In autopsy and pathology examination, there was
no vaccine-related change, aside from subacute local injection site reactions.
A GLP-compliant reproductive toxicity study was performed in rat. The administration of 
SARS-CoV-2 rS with Matrix-M adjuvant or Matrix-M adjuvant alone had no effect on fertility, 
pregnancy and lactation, growth and development of the embryos/fetuses, and development of 
pups through post-natal 21 days. And given that GLP in vitro genotoxicity studies with Ames test 
and mammalian cell micronucleus assay in Chinese hamster ovary cells showed that Matrix-M 
adjuvant was non-mutagenic in these assays. 
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4.1.2 Clinical Studies 
Following overseas and Japan clinical studies evaluating NVX-CoV2373/TAK-019 in adult 
subjects are ongoing or completed, with accumulating safety data from approximately 
30,000 subjects exposed to NVX-CoV2373/TAK-019. Refer to the latest investigator’s brochure 
(IB) of NVX-CoV2373/TAK-019 and the latest package insert of Nuvaxovid for further details. 
4.1.2.1 Primary Vaccination 
Efficacy, immunogenicity, and safety of NVX-CoV2373/TAK-019 as 2-dose primary series are 
evaluated in the following clinical studies: 
•
Study 2019nCoV-101 (oversea phase 1/2 study, conducted in Australia and the United
States): in this first-in-human study in healthy adults (18 to 59 years of age), 2-dose regimens
of 5 µg and 25 µg SARS-CoV-2 rS with 50 µg Matrix-M adjuvant generated robust immune
responses (anti-S protein immunoglobulin G [IgG] and neutralizing antibody) including a
relative skew toward CD4+ T-cell responses of the Th1 phenotype, supporting the dose
sparing effect of Matrix-M adjuvant. In the phase 2 part of this study, the 2-dose regimen of
5 µg SARS-CoV-2 rS with 50 µg Matrix-M adjuvant was better tolerated than the 2-dose
regimen of 25 µg SARS-CoV-2 rS with 50 µg Matrix-M adjuvant with generally comparable
immune responses between the 2 antigen doses, and thus the lower dose was selected for use in
later stage efficacy studies (later became the approved dosage as primary series in Japan and
oversea countries).
•
Study 2019nCoV-301 (oversea phase 3 study, conducted in the United States and Mexico
when multiple variant of concern [VOC]/variant of interest [VOI] were predominant): in
this study, primary series of NVX-CoV2373 at the later approved dosage was evaluated in
29,582 healthy or medically stable adult subjects (18 years of age or order). Overall vaccine
efficacy (VE) against symptomatic COVID-19 and VE against severe cases of COVID-19
were 90.40% (95% CI: 82.88, 94.62) and 100%, respectively. NVX-CoV2373 was
well-tolerated and showed acceptable safety profile.
•
Study 2019nCoV-302 (oversea phase 3 study, conducted in the United Kingdom when
alpha variant was predominant): in this study, primary series of NVX-CoV2373 at the later
approved dosage was evaluated in 15,139 healthy or medically stable adult subjects (18 years
of age or order). Overall VE against symptomatic COVID-19 and VE against severe cases of
COVID-19 were 89.7% (95% CI: 80.2, 94.6) and 100%, respectively. NVX-CoV2373 was
well-tolerated and showed acceptable safety profile.
•
Study 2019nCoV-501 (oversea phase 2a/b study, conducted in South Africa when beta
variant was predominant): in this study, primary series of NVX-CoV2373 at the later
approved dosage was evaluated in 4,164 HIV-negative subjects (18 to 84 years of age) and
244 HIV-positive subjects (18 to 64 years of age). Overall VE against symptomatic
COVID-19 were 48.6% (95% CI: 28.4, 63.1) in the whole study population and 55.4% (95%
CI: 35.9, 68.9) in the HIV-negative subgroup. VE against severe cases of COVID-19 was
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100% in the HIV-negative subgroup. NVX-CoV2373 was well-tolerated and showed 
acceptable safety profile. 
•
Study TAK-019-1501 (phase 1/2 study, conducted in Japan): in this study, primary series
of TAK-019 at the later approved dosage was evaluated in 200 healthy adult subjects (20 years
of age or order). TAK-019 was well tolerated, and safety and immunogenicity profile of
TAK-019 were generally comparable to those shown in the oversea studies.
4.1.2.2 Booster Vaccination 
Immunogenicity and safety of NVX-CoV2373/TAK-019 as booster vaccination are evaluated in 
the following clinical studies: 
•
Study 2019nCoV-101 (oversea phase 1/2 study, homologous booster, third and fourth
shot): in this study, safety and immunogenicity of NVX-CoV2373 as the third shot at
approximately 6 months after the primary series (Day 189) at the same dosage (later became
the approved dosage for the booster shot in Japan and oversea countries) were evaluated in the
subjects enrolled in the Part 2 and received primary series at the later approved dosage. Prior to
administration of the third shot at Day 189, geometric mean titers (GMTs) of anti-S protein
IgG and neutralizing antibody to ancestral SARS-CoV-2 were markedly lower than those titers
at 2 weeks after the second shot (Day 35). However, GMT of anti-S protein IgG and
neutralizing antibody showed robust increase at 4 weeks after the third shot (Day 217) and
substantially outweighed those of Day 35. Non-inferiority of Day 217 immunogenic response
compared to Day 35 was demonstrated, and the safety profile of the third shot was acceptable.
In addition, safety and immunogenicity of NVX-CoV2373 as the fourth shot at approximately
12 months after the primary series (Day 357) at the same dosage are being evaluated in the
subjects who received the third shot.
•
Study 2019nCoV-301 (oversea phase 3 study, homologous booster, third shot): in this
study, safety and immunogenicity of NVX-CoV2373 as the third shot at 8 months after the
second shot of primary series at the approved dosage are being evaluated.
•
Study 2019nCoV-501 (oversea phase 2a/b study, homologous booster, third shot): in this
study, Blinded Crossover part that administer the third shot of NVX-CoV2373 and one
placebo shot to the original NVX-CoV2373 arm and two NVX-CoV2373 shots (primary
series) to the original placebo arm was commenced at 6 months after the second shot of the
primary series, and safety and immunogenicity of NVX-CoV2373 as the third shot at the
approved dosage were evaluated in this part. Immune response after the third shot
overweighed those induced by the primary series. Also, the third shot was well-tolerated and
showed acceptable safety profile.
•
Study COV-BOOST (oversea phase 2 study, heterologous booster, third shot): as a part of
this study designed to evaluate multiple combinations of heterologous booster shot using
multiple SARS-CoV-2 vaccines, NVX-CoV2373 as the third shot at the approved dosage was
evaluated in 115 adult subjects who received 2 primary shots of Vaxzevria at least 70 days
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before and 114 adult subjects who received 2 primary shots of Comirnaty at least 84 days 
before. Compared to the meningococcal conjugate vaccine arm (control vaccine arm), 
NVX-CoV2373 as the third shot at the approved dosage induced meaningful response of anti-S 
protein IgG and neutralizing antibody. Also, the third shot was well-tolerated and showed 
acceptable safety profile [11]. 
•
Study 2019nCoV-311 (oversea phase 3 study, heterologous booster, third and fourth
shot): in this study, safety and immunogenicity of 2 booster shots of NVX-CoV2373
(ancestral-type SARS-CoV-2 rS 5 µg + Matrix-M adjuvant 50 µg), BA.1 vaccine (BA.1
SARS-CoV-2 rS 5 µg + Matrix-M adjuvant 50 µg), and a bivalent vaccine of these 2 vaccines
are being evaluated in adult subjects who received 2 shots of mRNA vaccine at least 180 days
before and adult subjects who received 3 shots of mRNA vaccine at least 90 days before
(NCT05372588).
4.1.3 Post-Marketing Data 
Based on the post-marketing surveillance, more than 740,000 doses have been administered 
among Australia, Canada, the European Union, New Zealand, and South Korea by 30 April 2022. 
Based on the cumulative safety data, the benefit-risk balance of Nuvaxovid remains positive. 
4.1.4 Benefit-Risk Assessment 
Refer to the latest IB of NVX-CoV2373/TAK-019 and the latest package insert of Nuvaxovid for 
overall benefit-risk profile of NVX-CoV2373/TAK-019. 
4.2 
Rationale for the Proposed Trial 
While SARS-CoV-2 vaccination is being promoted worldwide, the respread of SARS-CoV-2 
infection has been observed in many parts of the world since the summer of 2021. As factors of 
respread of the infection, the mainstream of the epidemic has become variants with high infectious 
and transmissible power, and some cases of breakthrough infection have been observed in 
previously fully vaccinated people [12], raising concerns that the preventive effect of the 
SARS-CoV-2 vaccine may weaken over time. In light of these circumstances, booster vaccination 
for people after primary vaccinations with the SARS-CoV-2 vaccine has been implemented as a 
public health measure to control the respreading of the infection in each country or region. In Japan 
as of 31 January 2022, about 80% of the population has completed their 2 doses primary 
vaccinations; those were mostly by mRNA vaccines, and Comirnaty Intramuscular Injection was 
predominantly used [13]. 
The primary objective of this trial is to evaluate immunogenicity and safety of a single 
heterologous booster vaccination (third dose) of TAK-019 by IM injection in the Main Part in 
Japanese healthy adults who completed 2 doses primary vaccinations with Comirnaty 
Intramuscular Injection 6 to 12 months prior to the trial booster vaccination. As of February 2022, 
2 overseas clinical trials evaluating NVX-CoV2373 as booster are ongoing (phase 2 part of Study 
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2019nCoV-101 and Study COV-BOOST) with no new safety concern observed, which supports 
initiation of this trial in Japan. 
In addition, there is rising importance of evaluating the safety and immunogenicity of TAK-019 as 
the fourth-dose booster shot based on that Japan government is currently recommending the 
fourth-dose booster of mRNA vaccines to high-risk populations (ie, elderlies and those who have 
high-risk underlying diseases) as of June 2022 [14]. Therefore, protocol amendment 1.0 (version 
2.0) added an Extension Part to evaluate the safety and immunogenicity of TAK-019 as the 
fourth-dose booster shot in subjects who have completed the third-dose booster shot of TAK-019 
in the Main Part at least 5 months earlier. This amendment is also supported by robust 
immunogenicity response and acceptable safety profile shown in preceding overseas clinical trials 
evaluating NVX-CoV2373 as booster shots. 
The trial will be conducted in accordance with the protocol, the ethical principles that have their 
origin in the Declaration of Helsinki [1], International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) and Good Clinical Practice (GCP) 
Guidelines E6 (R2) [2], and applicable regulatory requirements. 
If TAK-019 will be approved in Japan prior to completion of the trial, the trial will be continued as 
a post-marketing clinical trial in accordance with the applicable regulations such as Good 
Vigilance Practice (GVP) and Good Post-Marketing Study Practice (GPSP). 
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5.0 
TRIAL OBJECTIVES AND ENDPOINTS 
5.1 
Objectives 
5.1.1 Primary Objectives 
MAIN PART 
The primary objective is to evaluate the immunogenicity and safety of a single heterologous 
booster vaccination of TAK-019 by IM injection in healthy Japanese male and female adults aged 
≥20 years. 
Immunogenicity: 
To assess the immunogenicity of TAK-019 in terms of: 
•
Non-inferiority of GMTs of neutralizing antibody titers to wild-type virus 14 days after a
single booster vaccination (Day 15) compared with that observed 14 days after the second
vaccination (Day 36) in Study TAK-019-1501.
Safety: 
To assess the safety of TAK-019 in terms of: 
•
Solicited local and systemic adverse events (AEs) for 7 days following booster vaccination
(day of vaccination + 6 subsequent days).
•
Unsolicited AEs for 28 days following booster vaccination (day of vaccination
+ 27 subsequent days).
•
Serious AEs (SAEs), AEs of special interest (AESIs), medically-attended AEs (MAAEs), AEs
leading to trial withdrawal, and SARS-CoV-2 infection until Day 29.
EXTENSION PART 
Not applicable. 
5.1.2 Secondary Objectives 
MAIN PART 
Immunogenicity: 
To assess the immunogenicity of TAK-019 in terms of: 
•
Serum IgG antibody levels to SARS-CoV-2 rS protein.
•
Serum neutralizing antibody titers to the ancestral strain (wild-type virus).
Safety: 
To assess the safety of TAK-019 in terms of: 
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•
SAEs, AESIs, MAAEs, AEs leading to trial withdrawal, and SARS-CoV-2 infection
throughout the trial.
EXTENSION PART 
To evaluate the immunogenicity and safety of a second single booster vaccination of TAK-019 by 
IM injection in healthy Japanese male and female adults aged ≥20 years. 
Immunogenicity: 
To assess the immunogenicity of TAK-019 in terms of: 
•
Serum IgG antibody levels to SARS-CoV-2 rS protein.
•
Serum neutralizing antibody titers to the ancestral strain (wild-type virus).
Safety: 
To assess the safety of TAK-019 in terms of: 
•
Solicited local and systemic AEs for 7 days following the second single booster vaccination
(day of vaccination + 6 subsequent days).
•
Unsolicited AEs for 28 days following the second single booster vaccination (day of
vaccination + 27 subsequent days).
•
SAEs, AESIs, MAAEs, AEs leading to trial withdrawal, and SARS-CoV-2 infection until
Extension Part Day 29.
•
SAEs, AESIs, MAAEs, AEs leading to trial withdrawal, and SARS-CoV-2 infection
throughout the trial.
5.1.3 
 
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5.2 
Endpoints 
5.2.1 Primary Endpoints 
MAIN PART 
Immunogenicity: 
•
GMT ratio of neutralizing antibody titers to the ancestral strain (wild-type virus) on Day 15
after a single booster vaccination (14 days after the booster vaccination) compared with that
observed on Day 36 (14 days after the second vaccination) in subjects from
Study TAK-019-1501.
Safety: 
•
Percentage of subjects with reported solicited local AEs: injection site pain, tenderness,
erythema/redness, induration, and swelling for 7 days following the first single booster
vaccination (day of vaccination + 6 subsequent days).
•
Percentage of subjects with solicited systemic AEs: fever, fatigue, malaise, myalgia, arthralgia,
nausea/vomiting, and headache for 7 days following the first single booster vaccination (day of
vaccination + 6 subsequent days).
•
Percentage of subjects with unsolicited AEs for 28 days following the first single booster
vaccination (day of vaccination + 27 subsequent days).
•
Percentage of subjects with SAEs until Day 29.
•
Percentage of subjects with AESIs until Day 29.
•
Percentage of subjects with MAAEs until Day 29.
•
Percentage of subjects with any AEs leading to subject’s withdrawal from the trial until
Day 29.
•
Percentage of subjects with SARS-CoV-2 infection until Day 29.
EXTENSION PART 
Not applicable. 
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5.2.2 Secondary Endpoints 
MAIN PART 
Immunogenicity:  
•
GMT, geometric mean fold rise (GMFR), and seroconversion rate (SCR; defined at proportion
of subjects with ≥4-fold rises from baseline [Day 1]) of serum IgG antibody levels to
SARS-CoV-2 rS protein on Day 8, Day 15, Day 29, Day 91, Day 181, and Day 366.
•
GMT, GMFR, and SCR of serum neutralizing antibody titers to the ancestral strain (wild-type
virus) on Day 8, Day 15, Day 29, Day 91, Day 181, and Day 366.
Safety: 
•
Percentage of subjects with SAEs throughout the trial.
•
Percentage of subjects with AESIs throughout the trial.
•
Percentage of subjects with MAAEs throughout the trial.
•
Percentage of subjects with any AEs leading to subject’s withdrawal from the trial from the
day of the first single booster vaccination throughout the trial.
•
Percentage of subjects with SARS-CoV-2 infection throughout the trial.
EXTENSION PART 
Immunogenicity:  
•
GMT, GMFR, and SCR (defined at proportion of subjects with ≥4-fold rises from baseline
[Extension Part Day 1]) of serum IgG antibody levels to SARS-CoV-2 rS protein on
Extension Part Day 15, Day 29, Day 91, Day 181, and Day 366.
•
GMT, GMFR, and SCR of serum neutralizing antibody titers to the ancestral strain (wild-type
virus) on Extension Part Day 15, Day 29, Day 91, Day 181, and Day 366.
Safety: 
•
Percentage of subjects with reported solicited local AEs: injection site pain, tenderness,
erythema/redness, induration, and swelling for 7 days following the second single booster
vaccination (day of vaccination + 6 subsequent days).
•
Percentage of subjects with solicited systemic AEs: fever, fatigue, malaise, myalgia, arthralgia,
nausea/vomiting, and headache for 7 days following the second single booster vaccination
(day of vaccination + 6 subsequent days).
•
Percentage of subjects with unsolicited AEs for 28 days following the second single booster
vaccination (day of vaccination + 27 subsequent days).
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•
Percentage of subjects with SAEs until Extension Part Day 29.
•
Percentage of subjects with AESIs until Extension Part Day 29.
•
Percentage of subjects with MAAEs until Extension Part Day 29.
•
Percentage of subjects with any AEs leading to subject’s withdrawal from the trial until
Extension Part Day 29.
•
Percentage of subjects with SARS-CoV-2 infection until Extension Part Day 29.
•
Percentage of subjects with SAEs throughout the trial.
•
Percentage of subjects with AESIs throughout the trial.
•
Percentage of subjects with MAAEs throughout the trial.
•
Percentage of subjects with any AEs leading to subject’s withdrawal from the trial from the
day of the second single booster vaccination throughout the trial.
•
Percentage of subjects with SARS-CoV-2 infection throughout the trial.
MAIN PART 
•
Percentage of subjects who not to perform normal daily activities on the level of leaving
school/work due to solicited AEs for 7 days following the first single booster vaccination (day
of vaccination + 6 subsequent days).
EXTENSION PART 
•
Percentage of subjects who not to perform normal daily activities on the level of leaving
school/work due to solicited AEs for 7 days following the second single booster vaccination
(day of vaccination + 6 subsequent days).
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6.0 
TRIAL DESIGN AND DESCRIPTION 
6.1 
Trial Design 
MAIN PART 
This is a phase 3, single arm, open-label trial to evaluate the immunogenicity and safety of a single 
heterologous booster vaccination of TAK-019 by IM injection in healthy Japanese male and 
female adults who completed 2 doses primary vaccinations with Comirnaty Intramuscular 
Injection from 6 to 12 months before the trial vaccination. 
The trial is planned to enroll 150 subjects (all in the TAK-019 arm). They will be stratified by age; 
100 subjects as ≥20 years to <65 years, and 50 subjects as ≥65 years of age. 
Once all screening assessments following informed consent are completed and eligibility is 
confirmed, the subject will receive a single booster vaccination of TAK-019 by IM injection. All 
subjects will be followed up for immunogenicity and safety for 12 months after the trial 
vaccination. 
Each subject will be provided with an electronic diary (eDiary). Oral body temperature and 
solicited local and systemic AEs will be recorded in the eDiary by the subjects for 7 days after 
booster vaccination (including the day of vaccination). All subjects will be followed for 
unsolicited AEs for 28 days following booster vaccination (day of vaccination + 27 subsequent 
days). 
All subjects will be followed for SAEs, AESIs, MAAEs, and AEs leading to trial withdrawal 
during their entire participation in the trial. All subjects will also be tested for SARS-CoV-2 
infection at prespecified visits (Day 1 and Day 15) or, in case of clinical symptoms suspected for 
COVID-19 throughout the trial. 
The primary analysis will be performed for immunogenicity and safety after all subjects have 
completed the Day 29 visit. 
A schematic of the trial design is included as Figure 6.a. 
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Figure 6.a 
Schematic of Phase 3 Trial Design (Main Part) 
Abbreviations: COVID-19: coronavirus disease 2019; N/n: number of subjects. 
EXTENSION PART 
Extension Part is designed to offer a second single booster vaccination of TAK-019 to 
participants who received the first single booster vaccination of TAK-019 in the Main Part and 
remained in study follow-up at least 5 months. The end of the Main Part is defined as the earlier 
of the completion of the final visit on Day 366 or the initiation of the Extension Part. Therefore, 
data of the Main Part will consist data of all subjects in the Main Part, data of the Extension 
Part will consist only data of subjects after the initiation of the Extension Part. The end of 
Extension Part is defined as the completion of the final visit on Extension Part Day 366. All 
analyses will be performed descriptively in the Extension Part. 
All subjects who are willing to proceed to the Extension Part and to receive a second booster 
vaccination of TAK-019 will be asked to schedule a Participant Decision Visit about 5 months 
after the first single booster vaccination.  
All subjects who provide additional informed consent for the Extension Part at the Participant 
Decision Visit and are eligible for enrollment in the Extension Part will receive a second single 
booster vaccination of TAK-019, by IM injection (Extension Part Day 1). All subjects in the 
Extension Part will be followed up for immunogenicity and safety for 12 months after the 
Extension Part Day 1. 
Each subject will be provided an eDiary. Oral body temperature and solicited local and systemic 
AEs will be recorded in the eDiary by the subjects for 7 days after the second booster vaccination 
(including the Extension Part Day 1). All subjects will be followed-up for unsolicited AEs for 
28 days following the second booster vaccination (Extension Part Day 1 + 27 subsequent days). 
All subjects will be followed-up for SAEs, AESIs, MAAEs, and AEs leading to trial withdrawal in 
the Extension Part. All subjects will also be tested for SARS-CoV-2 infection in case of clinical 
symptoms suspected for COVID-19 in the Extension Part. 
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An interim analysis will be performed for immunogenicity and safety after all subjects have 
completed the Extension Part Day 29 visit. 
A schematic of the trial design for the Extension Part is included as Figure 6.b. 
Figure 6.b 
Schematic of Trial Design (Extension Part) 
Abbreviations: COVID-19: coronavirus disease 2019; ED: Extension Part Day. 
6.2 
Justification for Trial Design, Dose, and Endpoints 
MAIN PART 
The Main Part is to evaluate immunogenicity and safety of a single heterologous booster 
vaccination of TAK-019 by IM injection in the Japanese healthy adults who completed 2 doses 
primary vaccinations with Comirnaty Intramuscular Injection, approved in Japan as a 
SARS-CoV-2 vaccine, 6 to 12 months prior to the trial booster vaccination. The trial design 
(assessment timing and period of immunogenicity and safety endpoints and the trial follow-up 
periods) has been developed according to the guidance document, Principles for the Evaluation of 
Vaccines Against the Novel Coronavirus SARS-CoV-2, issued by the Pharmaceuticals and 
Medical Devices Agency of Japan (PMDA) [15].The booster dose of TAK-019 (5 µg of 
SARS-CoV-2 rS and 50 µg of Matrix-M) and the administration route (IM injection) for the trial 
have been selected based on assessment of available safety data from Studies 2019nCoV-101 and 
COV-BOOST outside Japan. 
As the data for 2 doses primary vaccinations, the immunogenicity and safety data in healthy 
Japanese adults of Study TAK-019-1501 were comparable to overseas pivotal studies that showed 
efficacy against COVID-19. The trial design of evaluate effectiveness of booster vaccination has 
been developed according to the guidance document, Principles for the Evaluation of Vaccines 
Against the Novel Coronavirus SARS-CoV-2 (Appendix 1) Evaluation of Vaccines Against 
Variants, issued by the PMDA [16], to assess non-inferiority of GMTs of neutralizing antibody 
titers to wild-type virus 14 days after a single booster vaccination (Day 15) compared with that 
observed 14 days after the second vaccination (Day 36) in Study TAK-019-1501. In order to 
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improve comparability with the data of neutralizing antibody titers at the time of 2 doses primary 
vaccinations in Study TAK-019-1501, which served as a comparison control, healthy Japanese 
adult males and females (including the elderly) matching the subject population of Study 
TAK-019-1501 will be included, and the measurement facility and assay method used for the 
study of neutralizing antibody titer are the same. 
EXTENSION PART 
Study design, dosage, and endpoints of the Extension Part were defined according to those of the 
Main Part. Of note, safety assessments conducted on Day 8 in the Main Part are to be conducted 
on Extension Part Day 15 because no site visit is not scheduled on Extension Part Day 8. 
Based on the approved intervals of the fourth doses of Comirnaty Intramuscular Injection and 
Spikevax Intramuscular Injection (defined as followings in their package inserts: “the fourth dose 
can be determined at least 5 months later than the third dose in elderlies and other populations; 
the determination should be made on their benefits and risks”), vaccination interval from the third 
shot of the Main Part was defined as at least 5 months. 
Also, based on the primary analysis of the Main Part, an interim analysis for immunogenicity 
(until Extension Part Day 15) and safety (until Extension Part Day 29) is planned in the 
Extension Part when all subjects completed Extension Part Day 29 visit. 
6.3 
Planned Duration of Subject’s Participation in the Trial 
SUBJECTS PARTICIPATING ONLY IN THE MAIN PART 
The trial participation for each subject is for 12 months following the first single booster 
vaccination. 
SUBJECTS ENTERING THE EXTENSION PART 
The trial participation for each subject is for at least 17 months in total (at least 5 months following 
the first single booster vaccination in the Main Part and 12 months following the second single 
booster vaccination in the Extension Part). 
6.4 
Premature Termination or Suspension of Trial or Investigational Site 
6.4.1 Criteria for Premature Termination or Suspension of the Trial 
The trial will be completed as planned unless one or more of the following criteria that require 
temporary suspension or early termination of the trial are satisfied. 
•
New information or other evaluation regarding the safety or efficacy of the investigational
vaccine that indicates a change in the known risk/benefit profile, such that the risk/benefit is no
longer acceptable for subjects participating in the trial.
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•
Significant deviation from GCP that compromises the ability to achieve the primary trial
objectives or compromises subject safety.
•
The Sponsor decides to terminate or suspend the trial.
6.4.2 Criteria for Premature Termination or Suspension of Investigational Sites 
A trial site may be terminated prematurely or suspended if the site (including the Investigator) is 
found in significant deviation from GCP, protocol, or contractual agreement, is unable to ensure 
adequate performance of the trial, or as otherwise permitted by the contractual agreement. 
6.4.3 Procedures for Premature Termination or Suspension of the Trial or the 
Participation of Investigational Site(s) 
In the event that the Sponsor, an Institutional Review Board (IRB) or regulatory authority elects to 
terminate or suspend the trial or the participation of an investigational site, a trial-specific 
procedure for early termination or suspension will be provided by the Sponsor; the procedure will 
be followed by applicable investigational sites during the course of termination or trial suspension. 
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7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS 
Subject eligibility is determined according to all criteria for applicable part including laboratory 
test results before each of the trial vaccination. 
7.1 
Inclusion Criteria 
Subject eligibility is determined according to the following criteria: 
MAIN PART 
1. Subjects aged ≥20 years of age at the time of signing of informed consent.
2. Healthy Japanese male and female subjects.
3. Subjects who are in good health at the time of entry into the trial as determined by medical
history, physical examination (including vital signs), and clinical judgment of the Investigator.
4. Subjects who have signed and dated a written, informed consent form (ICF) and any required
privacy authorization prior to the initiation of any trial procedures, after the nature of the trial
has been explained.
5. Subjects who understand and are willing to comply with the trial procedures and are available
for the duration of follow-up.
6. Subjects who completed 2 doses primary vaccinations with Comirnaty Intramuscular Injection
6 to 12 months prior to the trial vaccination.
•
Subjects who can show their vaccination certificate issued by Japanese municipality of
2 doses primary vaccinations with Comirnaty Intramuscular Injection.
7. A male subject or a female subject of childbearing potential* who is sexually active with a
nonsterilized* male partner agrees to use “Acceptable contraceptive methods” from 28 days
prior to the first single booster vaccination until 3 months after the first single booster
vaccination.
*Definitions of childbearing potential female, nonsterilized male and “Acceptable
contraceptive methods” are defined in Section 7.2 and reporting responsibilities on pregnancy
are defined in Section 9.1.15.
EXTENSION PART 
8. Subjects who received the first trial vaccination at least 5 months earlier and are currently
enrolled in the Main Part (ie, not have withdrawn or discontinued early).
9. Subjects who signed an additional ICF for the Extension Part, understand and are willing to
comply with trial procedures and are available for the duration of follow‑up.
10. A male subject or a female subject of childbearing potential* who is sexually active with a
nonsterilized* male partner agrees to use “Acceptable contraceptive methods” from 28 days
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prior to the second single booster vaccination until 3 months after the second single booster 
vaccination. 
*Definitions of childbearing potential female, nonsterilized male and “Acceptable
contraceptive methods” are defined in Section 7.2 and reporting responsibilities on pregnancy
are defined in Section 9.1.15.
7.2 
Exclusion Criteria 
Any subject who meets any of the following criteria will not qualify for entry into the trial: 
MAIN PART 
1. Subjects who received any other SARS-CoV-2 vaccine (except for Comirnaty Intramuscular
Injection) or other experimental novel coronavirus vaccine prior to the trial.
2. Subjects who received a booster vaccination (ie, 3rd dose) with Comirnaty Intramuscular
Injection or Spikevax Intramuscular Injection (previously COVID-19 Vaccine Moderna
Intramuscular Injection).
3. Subjects who have close contact of anyone known to have COVID-19 within 14 days prior to
the first trial vaccination.
“Subjects who have close contact of anyone known to have COVID-19” are defined as
subjects who have contact of COVID-19 diagnosed patients within possible infectious period
(from 2 days prior to the onset) and who meet any of the following criteria:
•
Subjects who live together or have contact for a long period of time (including contacts in a
car or airplane) with COVID-19 diagnosed patients.
•
Subjects who performed physical examination, nursing or caregiving for COVID-19
diagnosed patients without appropriate protective measurements against infection.
•
Subjects most likely who directly touched the contaminants of respiratory secretions or
body fluids from COVID-19 diagnosed patients.
•
Others: subjects who have contact with COVID-19 diagnosed patients for ≥15 minutes
within a distance that can be touched by hand (roughly, 1 m) without necessary preventive
measurements against infection (the patient's infectiveness will be judged for each
situation by taking consideration with surrounding circumstances or contacting situation).
4. Subjects who were tested positive for SARS-CoV-2 prior to the trial.
5. Subjects who have traveled outside of Japan in the 30 days prior to the trial participation.
6. Subjects with a clinically significant active infection (as assessed by the Investigator) or oral
temperature ≥38°C within 3 days of the intended date of the first single booster vaccination.
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7. Subjects with known hypersensitivity or allergy to any of the investigational vaccine
components and/or Comirnaty Intramuscular Injection (including excipients as summarized in
Section 8.1.1.1).
8. Subjects with behavioral or cognitive impairment or psychiatric disease that, in the opinion of
the Investigator, may interfere with the subject’s ability to participate in the trial.
9. Subjects with any history of progressive or severe neurologic disorder, seizure disorder or
neuro-inflammatory disease (eg, Guillain-Barré syndrome).
10. Subjects with history or any illness that, in the opinion of the Investigator, might interfere with
the results of the trial or pose additional risk to the subjects due to participation in the trial.
11. Subjects with known or suspected impairment/alteration of immune function, including:
a. History of any autoimmune disease or neuro-inflammatory disease.
b. Chronic use of oral steroids (20 mg/day prednisolone ≥12 weeks or ≥2 mg/kg body
weight/day prednisolone ≥2 weeks continuously) within 60 days preceding the booster
administration of investigational medicinal product (IMP) (use of inhaled, intranasal, or
topical corticosteroids is allowed).
c. Receipt of parenteral steroids (20 mg/day prednisolone ≥12 weeks or ≥2 mg/kg body
weight/day prednisolone ≥2 weeks continuously) within 60 days preceding the booster
administration of IMP.
d. Receipt of immunoglobulins and/or any blood products within the 3 months preceding the
booster administration of IMP, or planned administration during the trial
e. Receipt of immunostimulants within 60 days preceding the booster administration of IMP.
f.
Receipt of parenteral, epidural or intra-articular Ig preparation, blood products, and/or
plasma derived products within 3 months preceding the booster administration of IMP or
planned administration during the trial.
g. Known HIV infection or HIV-related disease.
h. Genetic immunodeficiency.
12. Abnormalities of splenic or thymic function.
13. Subjects with a known bleeding diathesis, or any condition that may be associated with a
prolonged bleeding time.
14. Subjects with any serious chronic or progressive disease (eg, neoplasm, insulin dependent
diabetes, cardiac, renal or hepatic disease).
15. Subjects with BMI greater than or equal to 30 kg/m2 (BMI= weight in kg/ height in meters2).
16. Subjects participating in any clinical trial with another investigational product within 30 days
prior to the first trial vaccination or intend to participate in another clinical trial at any time
during the conduct of this trial.
17. Subjects who have received blood, blood products and/or plasma derivatives or any parenteral
Ig preparation in the past 3 months (prior to the first trial dose).
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18. Subjects who have used antipyretics and/or analgesic medications within 24 hours prior to the
first trial vaccination.
19. Subjects who received or plan to receive any other licensed vaccines within 14 days (for
inactivated vaccines) or 28 days (for live vaccines) prior to the first trial dose administration.
20. Subjects with acute or chronic clinically significant disease including pulmonary,
cardiovascular, hepatic or renal abnormality evaluated by physical examination.
21. Subjects involved in the trial conduct or their first-degree relatives.
22. Subjects who have history or infection of hepatitis B and hepatitis C.
23. Subjects with history of substance or alcohol abuse within 2 years prior to the first trial
vaccination.
24. Female subjects who are pregnant or breastfeeding.
25. A male subject who is non-sterilized and sexually active with a female partner of childbearing
potential or a female subject of childbearing potential who is sexually active with men and
those have not used any of the “Acceptable contraceptive methods” for at least 28 days prior to
the first trial vaccination.
a) “Childbearing potential” is defined as status post-onset of menarche and not meeting any
of the following conditions: menopausal for at least 2 years, status after bilateral tubal
ligation for at least 1 year, status after bilateral oophorectomy, or status after hysterectomy.
b) “Acceptable contraceptive methods” are defined as follows:
A male subject who is non-sterilized and sexually active with a female partner of
childbearing potential must use male condom with or without spermicide. A female subject
of childbearing potential who is sexually active with a nonsterilized male partner must use
the method of contraception below:
●
Intrauterine device.
●
Bilateral tubal interruption tubal ligation.
●
A Male partner who is the only partner of the subject and was postvasectomy and
have confirmed that they have obtained documentation of the absence of sperm in the
ejaculate.
●
Progestin/estrogen mixed preparation for inhibition of ovulation.
26. A male subject who is non-sterilized and sexually active with a female partner of childbearing
potential, or a female subject of childbearing potential who is sexually active with men and
those refuse to use an “Acceptable contraceptive method” through to 3 months after the first
booster dose of IMP.
27. Any positive or indeterminate pregnancy test (Section 9.1.15).
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EXTENSION PART 
28. Subjects with a clinically significant active infection (as assessed by the Investigator) or oral
temperature ≥38°C within 3 days of the intended date of the second single booster vaccination.
29. Subjects with known hypersensitivity or allergy to any of the investigational vaccine
components and/or Comirnaty Intramuscular Injection (including excipients as summarized in
Section 8.1.1.1).
30. Subjects with history or any illness that, in the opinion of the Investigator, might interfere with
the results of the trial or pose additional risk to the subjects due to participation in the trial.
31. Subjects with known or suspected impairment/alteration of immune function, including
history of any autoimmune disease or neuro-inflammatory disease. Refer to exclusion criterion
#11 for details.
32. Abnormalities of splenic or thymic function.
33. Subjects with a known bleeding diathesis, or any condition that may be associated with a
prolonged bleeding time.
34. Subjects with any serious chronic or progressive disease (eg, neoplasm, insulin dependent
diabetes, cardiac, renal or hepatic disease).
35. Subjects participating in any clinical trial with another investigational product within 30 days
prior to the second single booter vaccination or intend to participate in another clinical trial at
any time during the conduct of this trial.
36. Subjects who have received blood, blood products and/or plasma derivatives or any parenteral
Ig preparation in the past 3 months (prior to the second trial dose).
37. Subjects who have used antipyretics and/or analgesic medications within 24 hours prior to the
second single booster vaccination.
38. Subjects who received or plan to receive any other licensed vaccines within 14 days (for
inactivated vaccines) or 28 days (for live vaccines) prior to the second trial dose
administration.
39. Subjects with acute or chronic clinically significant disease including pulmonary,
cardiovascular, hepatic or renal abnormality evaluated by physical examination.
40. Subjects who have history or infection of hepatitis B and hepatitis C.
41. Subjects with a history of myocarditis or pericarditis.
42. Female subjects who are pregnant or breastfeeding.
43. A male subject who is non-sterilized and sexually active with a female partner of childbearing
potential or a female subject of childbearing potential who is sexually active with men and
those have not used any of the “Acceptable contraceptive methods” for at least 28 days prior to
the second trial vaccination. Refer to exclusion criterion #25 for details.
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44. A male subject who is non-sterilized and sexually active with a female partner of childbearing
potential, or a female subject of childbearing potential who is sexually active with men and
those refuse to use an “Acceptable contraceptive method” through to 3 months after the second
booster dose of IMP.
45. Any positive or indeterminate pregnancy test (Section 9.1.15).
There may be instances when individuals meet all entry criteria except one that relates to transient 
clinical circumstances (eg, body temperature elevation or recent use of prohibited medication[s] or 
vaccine[s]). Under these circumstances, eligibility for trial enrollment may be considered if the 
appropriate window for delay has passed, inclusion/exclusion criteria have been rechecked, and if 
the subject is confirmed to be eligible (Section 7.4). 
7.3 
Prohibited Medications 
Any other SARS-CoV-2 or other experimental novel coronavirus vaccine are prohibited 
throughout the trial. Other licensed vaccines not for SARS-CoV-2 should be administrated 
before/after 14 days for inactivated vaccines or 28 days for live vaccines prior to each trial dose 
administration. 
7.4 
Criteria for Delay of Investigational Medicinal Product Administration 
After enrollment, subjects may encounter clinical circumstances that warrant a delay in the any 
booster administration of IMP. These situations are listed below. In the event that a subject meets a 
criterion for delay of any IMP administration, the subject may receive the IMP for applicable part 
once the window for delay has passed within 7 days as long as the subject is otherwise eligible for 
trial participation. 
•
Subjects with a clinically significant active infection (as assessed by the Investigator) or body
temperature >37.5°C, within 3 days of planned IMP administration. Consider whether
applicable as a criterion for delay or as an exclusion criterion, see Section 7.2.
•
Subjects who have used antipyretics and/or analgesic medications within 24 hours prior to
vaccination. The reason for their use (prophylaxis versus treatment) must be documented. IMP
administration should be delayed to allow for a full 24 hours to have passed between having
used antipyretics and/or analgesic medications and IMP administration.
7.5 
Criteria for Early Termination of a Subject’s Trial Participation 
Under some circumstances, a subject’s trial participation may be terminated early. Even if the 
subject early terminates trial participation, all efforts should be made to continue the collection of 
safety data according to protocol. The primary reason for early termination of the subject’s trial 
participation should be documented in the electronic case report form (eCRF) using the following 
categories. 
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The subjects who receive approved SARS-CoV-2 vaccine except for TAK-019 in the Extension 
Part during the trial will be terminated from the trial. 
1. Adverse Event: The subject has experienced an AE (irrespective of being related/unrelated to
the IMP or trial-related procedures) that requires early termination because continued
participation imposes an unacceptable risk to the subject’s health and/or the subject is
unwilling to continue participation because of the AE. If the subject is unwilling to continue
because of the AE, the primary reason for early termination of trial participation in this case
will be ‘withdrawal due to AE’ and not ‘withdrawal of consent’, see below.
2. Lost to follow-up: The subject did not return to the site and at least 3 attempts to contact the
subject were unsuccessful.
3. Withdrawal of consent: The subject wishes to withdraw from the trial. The primary reason for
early termination will be ‘withdrawal of consent’ if the subject withdraws from participation
due to a non-medical reason (ie, reason other than AE). While the subject has no obligation to
provide a reason for withdrawing consent, attempts should be made to determine the
underlying reason for the withdrawal and, where possible, the primary underlying reason
should be documented.
4. Premature trial termination by the Sponsor, a regulatory agency, the IRB, or any other
authority.
If the clinical trial is prematurely terminated by the Sponsor, the Investigator is to promptly
inform the trial subjects and local IRB and should assure appropriate follow-up for the subjects.
The primary reason for early termination in this case will be ‘trial termination’.
5. Subject’s death during trial participation.
6. Other.
For screen failure subjects, refer to Section 9.1.16.
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8.0 
CLINICAL TRIAL MATERIAL MANAGEMENT 
8.1 
Investigational Medicinal Product(s) 
TAK-019 will be supplied to the trial sites by the Sponsor or its designee. TAK-019 used for 
Extension Part is a commercial product (Nuvaxovid Intramuscular Injection). 
Details regarding the dosage form description and strengths, or composition for the 
extemporaneous preparation, of the IMP can be found in the pharmacy manual. 
8.1.1 Dosage Form, Manufacturing, Packaging, and Labeling 
8.1.1.1 Dosage Form and Contents 
Code of IMP: TAK-019 
Generic name: Recombinant Coronavirus (SARS-CoV-2) Vaccine 
Dosage form: Colorless and milky white liquid available in glass vial for injection. 
8.1.1.2 Package and Labeling 
TAK-019 for Main Part will be labeled and packaged in each carton with 1 vial which include 
storage conditions of the IMP. TAK-019 for Extension Part will be packaged labeled vials as the 
commercial product. 
Refer to the pharmacy manual for details. 
8.1.2 Inventory and Storage 
TAK-019 investigational vaccine should be refrigerated at 2°C to 8°C and should not be frozen. 
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The investigational product storage manager should store the IMP in a secure, environmentally 
controlled and monitored area until it is used or returned to the Sponsor or designee. All 
sponsor-supplied IMP must be stored under the conditions specified on the label. A daily 
temperature log of the vaccine storage area must be maintained every working day. 
8.1.3 Dose and Regimen 
The IMP TAK-019 will be administered as an IM injection (0.5 mL) in the mid deltoid, preferable 
in the non-dominant upper arm on Day 1 in the Main Part and Extension Part Day 1 as explained 
in the pharmacy manual. 
8.1.4 Overdose 
An overdose is defined as a known deliberate or accidental administration of study drug, to or by a 
study subject, at a dose above that which is assigned to that individual subject according to the 
study protocol. 
All cases of overdose (with or without associated AEs) will be documented on an Overdose page 
of the eCRF, in order to capture this important safety information consistently in the database. 
Cases of overdose without manifested signs or symptoms are not considered AEs. AEs associated 
with an overdose will be documented on AE eCRF(s) according to Section 10.0. 
SAEs associated with overdose should be reported according to the procedure outlined in 
Section 10.4.4. 
In the event of drug overdose, the subject should be treated symptomatically. 
8.2 
Investigational Medicinal Product Dispensing Procedures 
Subjects will receive treatment according to the study schedule. The subject number will be 
entered onto the eCRF. 
Where a subject does not meet all the eligibility criteria for the applicable part but incorrectly 
receives the IMP, the Investigator should inform the Sponsor immediately, and a decision 
regarding whether to continue or discontinue the subject should be taken based on discussion with 
the Sponsor. 
The Investigator will administer the IMP. 
If sponsor-supplied IMP is lost or damaged, the site uses a replacement of IMP. Expired IMP must 
not be administered. 
8.2.1 Precautions to Be Observed When Administering the Investigational Medicinal 
Product 
Prior to each IMP booster administration, a subject must be determined to be eligible to receive 
IMP (Sections 7.1 and 7.2), and it must be clinically appropriate in the judgment of the 
Investigator to administer each of the IMP. 
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Standard immunization practices are to be observed and care should be taken when booster 
administering an IMP intramuscularly. In addition, WHO recommendations to reduce anxiety and 
pain at the time of vaccination should be followed [17]. Before each booster administration of IMP, 
the vaccination site must be disinfected with a skin disinfectant (eg, 70% alcohol) and the skin 
allowed to dry. Refer to the pharmacy manual for details on preparation and administration of 
IMP. 
As with all injectable vaccines, the Investigator 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. 
8.3 
Randomization Code Creation and Storage 
Not applicable. 
8.4 
Investigational Medicinal Product Blind Maintenance 
This is an open-label trial. 
8.5 
Unblinding Procedure 
This is an open-label trial. 
8.6 
Accountability and Destruction of Sponsor-Supplied Investigational Medicinal 
Products, and Other Clinical Trial Materials 
The Investigator or designee must ensure that the sponsor-supplied IMP are used in accordance 
with the approved protocol and are administered only to subjects enrolled in the trial. To document 
appropriate use of sponsor-supplied IMP, the Investigator must maintain records of all 
sponsor-supplied IMP delivery to the site, site inventory, administration and use by each subject, 
and return to the Sponsor or designee. 
Upon receipt of sponsor-supplied IMP, 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 IMP 
is received within the labeled storage conditions (ie, no cold chain break has occurred during 
transit), and is in good condition. If quantity and conditions are acceptable, Investigator or 
designee will acknowledge receipt of the shipment to the Sponsor per instructions provided on the 
form. 
If there are any discrepancies between the packing list versus the actual product received, the 
Sponsor or designee must be contacted to resolve the issue. The packing list should be filed in the 
Investigator Site File (ISF). 
The Investigator must maintain 100% accountability for all sponsor-supplied IMPs, and other 
clinical trial material received and administered during their entire participation in the trial. 
Accountability includes, but is not limited to: 
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•
Verifying that actual inventory matches documented inventory.
•
Verifying that the log is completed for the vaccine lot used to prepare each dose.
•
Verifying that all IMP kits used are documented accurately on the log.
•
Verifying that required fields are completed accurately and legibly.
If any dispensing errors or discrepancies are discovered, the Sponsor must be notified 
immediately. 
The Investigator must record the current inventory of all sponsor-supplied IMP on a 
sponsor-approved IMP accountability log. The following information will be recorded at a 
minimum: protocol number and title, name of the Investigator, site identifier and number, 
description of sponsor-supplied IMPs, expiry date, date and amount. The IMP log should include 
all required information as a separate entry for each subject to whom sponsor-supplied IMP is 
administered. 
The Investigator will be notified of any expiry date or retest date extension of IMP during the trial 
conduct. On expiry date notification from the Sponsor or designee, the site must complete all 
instructions outlined in the notification, including segregation of expired clinical trial material for 
return to the Sponsor or designee for destruction. 
The on-site pharmacist (site designee) will receive the pharmacy manual created by the Sponsor, 
according to which the site designee will appropriately manage the sponsor-supplied drug. The 
Investigator will also receive those procedures from the Sponsor. The procedures include those for 
ensuring appropriate receipt, handling, storage, management, and dispensation of the 
sponsor-supplied drug as well as return of them to the Sponsor or destruction of them. The on-site 
pharmacist (site designee) will immediately return unused study drugs to the Sponsor after the 
study is closed at the study site. 
All clinical trial materials will be provided by the trial site, Sponsor or designee, depending upon 
availability. The list of clinical trial materials and source information can be found in the pharmacy 
manual. Prior to site closure or at appropriate intervals throughout the trial, before any IMP or 
clinical trial materials are returned to the Sponsor or designee for destruction, a representative 
from the Sponsor 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. 
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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. All procedures must be performed by 
qualified and trained staff. 
9.1.1 Informed Consent  
The requirements of the informed consent are described in Section 15.2. 
Informed consent must be obtained before any protocol-directed procedures are performed. Signed 
ICF should be obtained from Day -28 to Day 1 in the Main Part ,the same for the Extension Part. 
A unique subject number will be assigned to each subject by the appropriate coding after informed 
consent is obtained for the Main Part. If all eligibility criteria for the Main Part are fulfilled, this 
subject number will be used throughout the trial. Subject numbers assigned to subjects who do not 
receive vaccination should not be reused (Section 9.1.16). 
The subjects who receive approved SARS-CoV-2 vaccine except for TAK-019 in the Extension 
Part during the trial will be terminated from the trial. 
9.1.2 Demographics, Medical History and Prior Medications 
Demographic information to be obtained will include age/date of birth, sex, and race. 
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 (including concomitant therapies), and previous and ongoing illnesses and/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/pre-existing problem. 
Medical history (including corresponding medication) to be obtained will include any significant 
conditions or diseases that have disappeared or resolved at or prior 5 years to signing of ICF for the 
Main Part. 
Adverse medical occurrences emerging during the time between signing of ICF and the first 
booster administration of IMP will be recorded in the medical history eCRF page. If such an 
adverse medical occurrence is assessed as related to a screening procedure this should be recorded 
as an AE related to trial procedure in the eCRF. 
All medications, vaccines, and blood products taken by the subjects are to be collected as prior (if 
the start and stop dates are before Day 1 in the Main Part, the same for Extension Part) and 
concomitant medications (if the stop date is on or after Day 1 in the Main Part, irrespective of the 
start date). 
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<Periods to collect medical and medications information> 
a) Medications: 2 months prior to Day 1 in the Main Part (day of the first booster
vaccination).
b) Primary SARS-CoV-2 vaccinations: Dates of 2 doses primary vaccinations with
Comirnaty Intramuscular Injection on their certificate issued by Japanese municipality
(prior to the first booster vaccination on Day 1 in the Main Part) .
c) Other vaccines: 2 weeks (for inactivated vaccines) and 4 weeks (for live vaccines) each
prior to Day 1 (day of the first booster vaccination) and Extension Part Day 1 (day of the
second booster vaccination).
d) Blood products: 3 months prior to Day 1 in the Main Part (day of the first booster
vaccination) and Extension Part Day 1 (day of the second booster vaccination).
e) Therapies: 30 days prior to Day 1 in the Main Part (day of the first booster vaccination).
The use of antipyretics and/or analgesic medications within 24 hours prior to each of the booster 
vaccination must be identified and the reason for their use (prophylaxis versus treatment) must be 
documented. Booster administration of the IMP should be delayed if subjects have used 
antipyretics and/or analgesics within 24 hours prior to each booster vaccine administration. 
Assess and record concomitant therapies (prescription medications ONLY) and vaccine history 
from 30 days prior to Day 1 in the Main Part in the subject’s source document. 
Any other SARS-CoV-2 or other experimental novel coronavirus vaccines including TAK-019 out 
of the study are prohibited throughout the trial. Other licensed vaccines not for SARS-CoV-2 
should be administrated before/after 14 days for inactivated vaccines or 28 days for live vaccines 
prior to each trial dose administration. 
These data must be written in the source documents. 
9.1.3 Documentation of Trial Entry 
For each part of the study, only subjects who have a signed ICF, and meet all of the inclusion 
criteria and none of the exclusion criteria are eligible for entry and receiving the booster 
vaccination. 
If the subject is ineligible for receiving any of the booster vaccination, the Investigator should 
record the primary reason for failure on the eCRF. 
9.1.4 Physical Examination 
Physical examinations must be performed by a qualified health professional in accordance with 
local regulations and as listed within the site responsibility delegation log. A complete physical 
examination will be performed according to the schedule of procedures (Section 2.1). The date and 
time of the physical examinations and any findings should be documented in the subject’s source 
document and the eCRF. 
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The physical examination will be performed in accordance with standards at the site. The physical 
examination will include, at a minimum, assessments of the body systems listed below: 
•
General appearance.
•
Ears, nose, and throat.
•
Head and Neck.
•
Ophthalmological.
•
Respiratory.
•
Cardiovascular.
•
Abdomen.
•
Neurological.
•
Extremities.
•
Dermatological.
•
Lymphatic.
In addition, height and weight will be measured at the Day 1 in the Main Part before the first 
booster vaccination visit only in accordance with standards of the site and BMI will be calculated. 
Symptom-directed physical examination may be performed if deemed necessary. 
9.1.5 Vital Signs 
Vital signs will be assessed according to the schedule of procedures (Section 2.1). Vital signs will 
include body temperature (oral body temperature), blood pressure (systolic and diastolic, resting 
more than 5 minutes), pulse rate, and respiratory rate. 
Routine vital sign assessments will be taken with the subject in the sitting or supine position after 
5 minutes at rest. Blood pressure should be determined using the same arm and the same 
equipment, and the same body position for each assessment throughout the trial. Blood pressure 
should not be taken on the trial vaccination arm. The Investigator will make a reasonable effort to 
using the same equipment and not taken on the trial vaccination arm to measure the blood pressure. 
During the trial, additional vital signs measurements will be performed if clinically indicated. 
Every effort should be made to measure and record vital signs prior to any blood sample 
collection. 
The Investigator will assess whether a change from baseline (ie, the booster predose measurement 
on Day 1 in the Main Part or Extension Part Day 1) in vital signs may be deemed clinically 
significant and whether the change should be considered and recorded as an AE. 
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9.1.6 Immunogenicity Assessments 
All subjects will undergo blood sampling for immunogenicity testing at visit time points listed 
below: 
•
Day 1, Day 8, Day 15, Day 29, Day 91, Day 181, and Day 366 in the Main Part.
•
Extension Part Day 1, Day 15, Day 29, Day 91, Day 181, and Day 366.
The handling and transport of the samples will be described in the handling manual of samples for 
immunogenicity assessment, separately prepared. 
The maximum volume of blood taken at any single visit for immunogenicity assessment is 
approximately 20 mL, and the approximate total volume of blood for the trial is maximum 220 mL 
for subjects if they enter the Extension Part between Day 91 and Day 181 in the Main Part 
(Table 9.a). 
Table 9.a 
Volume and Numbers of Sampling 
Laboratory tests 
Volume/sampling Number of sampling 
Total volume 
Subjects participating only in the Main Part 
Immunogenicity 
20 mL 
7 
140 mL 
Subjects entering the Extension Part between Day 91 and Day 181 in the Main Part 
Immunogenicity 
20 mL 
11 
(5 in the Main Part,  
6 in the Extension Part) 
220 mL 
9.1.7 Concomitant Medications 
Concomitant medication is any drug given in addition to the study drug. These may be prescribed 
by a physician or obtained by the subject over-the-counter (OTC). Concomitant medication is not 
provided by the Sponsor. At each study visit, subjects will be asked whether they have taken any 
medication other than the study drug (used from signing of informed consent until Day 29 in the 
Main Part or Extension Part Day 29), and all medication including vitamin supplements, OTC 
medications, and oral herbal preparations must be recorded in the eCRF by the Investigator. 
Medications used for treatment of SAEs, AEs leading to withdrawal from trial, and COVID-19 
must be recorded in the eCRF during the trial. When subjects receive approved SARS-CoV-2 
vaccine except for TAK-019 in the study, it must be recorded in the eCRF as well. Concomitant 
therapies given to subjects will be confirmed and recorded in the eCRF similarly. 
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9.1.8 Processing, Labeling and Storage of Biological Samples 
All biological samples will be processed, labeled, and stored according to the laboratory manual or 
other appropriate guideline provided to the site. 
9.1.9 Safety Assessments 
Safety assessments will include collection and recording of solicited local (injection site) reaction 
and solicited systemic AEs, unsolicited AEs, AEs (serious and non-serious), and pregnancies. For 
timing and details refer to Section 2.1. Refer to Section 10.1 for definitions of AEs. Details on 
collection and reporting of AEs are in Sections 10.4 and 10.5. 
9.1.10 Clinical Safety Laboratory Variables 
Not applicable. 
9.1.11 Hematology and Blood Chemistry 
Not applicable. 
9.1.12 Nasal Swab Sample 
Nasal swab samples will be collected for PCR testing of SARS-CoV-2 infection on Day 1 and 
Day 15 in the Main Part in all subjects. 
Also, subjects will consult with the Investigator about the necessity of a COVID-19 diagnostic test 
including PCR test throughout the trial (Day 1 to Day 366 in the Main Part or the Extension Part 
Day 366), if the subject shows the following symptoms of potential SARS-CoV-2 infection and/or 
have/had exposure to an individual confirmed to be infected with SARS-CoV-2. The Investigator 
judges if a COVID-19 diagnostic test is necessary by the information obtained from the subject 
according to the guidance for COVID-19 medical treatment [9]. When the Investigator judges the 
necessity of a COVID-19 diagnostic test, an ad hoc trial visit or home visit by medically qualified 
staff will be arranged as soon as possible (at least within 72 hours) to collect a sample from the 
subject. In the Extension Part, nasal swab sample will be collected, and PCR test results 
performed at a local laboratory will be accepted. 
Subjects may be asked to submit follow-up samples after consultation with the Investigator. If a 
sample is unavailable in the trial for some reason (eg, emergency admission to the hospital or 
COVID-19 intensive care ward), COVID-19 diagnostic test results performed at a local public 
health or hospital will be taken as a valid result for this trial. 
If COVID-19 is confirmed by the diagnostic test, all clinical findings will be recorded in the eCRF 
including relevant concomitant medications (including concomitant therapies) and details about 
severity, seriousness, and outcome. 
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<Symptoms of COVID-19 suspected> 
If subject shows the following symptoms, consult with the Investigator about the necessity of 
collection of COVID-19 diagnostic test samples: 
•
Fever (temperature ≥37.5°C) or chills.
•
Cough.
•
Shortness of breath or difficulty breathing.
•
Fatigue.
•
Muscle or body aches.
•
Headache.
•
New loss of taste or smell.
•
Sore throat.
•
Congestion or runny nose.
•
Nausea or vomiting.
•
Diarrhea.
<In case where a subject possibly has close contact of COVID-19 patients>
The Investigator confirms if the subject meets the definition of “Subjects who have close contact 
of anyone known to have COVID-19” in exclusion criterion #3 of Section 7.2, by the information 
from the subject. 
9.1.13 
 
9.1.14 Contraception and Pregnancy Avoidance Procedure 
All subjects must use “Acceptable contraceptive methods” through to 3 months after each of the 
trial dose of IMP. 
For female subjects of childbearing potential, pregnancy testing (urine pregnancy test with 
measuring human chorionic gonadotropin) will be performed on Day 1 in the Main Part prior to 
trial vaccination, on Day 29 and Day 91 in the Main Part, Extension Part Day 1 prior to trial 
vaccination, and Extension Part Day 29 and Day 91. Subjects will be provided with information 
on acceptable methods of contraception as part of the subject informed consent process and will be 
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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, regular pregnancy tests will be 
performed only for women of childbearing potential and subjects will receive continued guidance 
with respect to the avoidance of pregnancy as part of the trial procedures (Section 2.1). Subjects 
must have a negative pregnancy test prior to receiving each trial vaccination on Day 1 in the Main 
Part and Extension Part Day 1. In each case of delayed menstrual period (over one month 
between menstruations) confirmation of absence of pregnancy is strongly recommended. 
Refer to Section 7.2 (Exclusion Criteria) for contraception. 
9.1.15 Pregnancy 
To ensure the safety of a female subject and the unborn child or the safety of the unborn child of 
the partner of a male subject, each pregnancy in the female subject having received any booster 
IMP or in the partner of the male subject having received any trial IMP must be reported to the 
Sponsor promptly. The follow-up procedures for her according to the protocol should be 
performed, if possible. The Investigator should report the pregnancy to the Sponsor promptly with 
a pregnancy notification form, by taking her course of pregnancy continuously. The pregnancy 
must be followed to determine outcome, including spontaneous or voluntary termination, details 
of birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. The pregnancy for the partner of the male subject, if the partner 
becomes pregnant, will also be followed as much as possible. This follow-up should occur even if 
the intended duration of safety follow-up for the trial has ended. 
Any pregnancy occurring following any IMP administration should be reported immediately, 
using a pregnancy notification form, to the contact listed in the ISF. 
Any SAE occurred during pregnancy should be reported throughout the trial as per timelines and 
procedures described in Section 10.4.4. 
9.1.16 Documentation of Subjects Who Discontinue Prior to the Trial Vaccination 
Investigators must account for all subjects who sign an informed consent. If the subject is found to 
be not eligible at this visit, the Investigator should still complete the eCRF. 
The primary reason for discontinuation prior to the first trial vaccination would be recorded in the 
eCRF using the following categories: 
•
Screen failure (did not meet one or more inclusion criteria or did meet one or more exclusion
criteria).
•
Withdrawal by subject.
•
Trial terminated by the Sponsor.
•
Others (eg, as decided by the Investigator).
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Subject identifier assigned to subjects who discontinue prior to the first trial vaccination should not 
be reused. 
9.2 
Monitoring Subject Compliance 
The doses of trial vaccination should be administered at the site under direct observation of the 
Investigator. The trained site staff injecting the vaccine will confirm that the subject has received 
the entire dose. The location (right or left arm), date and timing of all doses of the trial vaccine will 
be reported in the eCRF. If a subject is not administered the trial vaccine, the reason for missed 
dose will be recorded. 
9.3 
Schedule of Observations and Procedures 
The schedule for all trial-related procedures for all evaluations is shown in Section 2.1. 
The trial visits should be performed on the planned dates and subject should be asked to adhere to 
the trial visit within the visit window. The results of the evaluation will be recorded on the 
appropriate eCRF pages. 
For a subject who withdraws early from the trial, all assessments planned on Day 366 (Visit 7) in 
the Main Part (for withdrawals from the Main Part) or Extension Part Day 366 (for 
withdrawals from the Extension Part) should be performed as possible. 
The screening procedures (Day 1 in the Main Part before the trial vaccination) will be carried out 
within 14 days prior to the first IMP administration. The subjects will receive information on the 
trial objective(s) and procedures from the Investigator. Prior to all screening assessments, the 
written consent form should be signed and dated. The screening assessments for this trial are 
grouped under the heading of a single visit in this protocol. However, it is possible for the 
screening assessments to be performed over more than 1 site visit if necessary, as long as the 
screening visit window prior to Day 1 (Visit 1) in the Main Part is maintained. The following will 
be checked and recorded by the Investigator or designee: 
•
Assess eligibility by review of inclusion/exclusion criteria.
•
Demographics.
•
Medical history.
•
Prior and concomitant medications (including prior and concomitant therapies).
•
Complete physical examination and other vital signs as listed in Sections 9.1.4 and 9.1.5.
•
Review of systems: Review of systems is a structured interview that queries the subject as to
any complaints the subject has experienced across each organ system.
•
Height, weight, and BMI calculation.
•
Pregnancy testing: women of childbearing age will be tested.
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•
Nasal swab sample collection.
All subjects who are willing to proceed to the Extension Part and to receive the second booster 
vaccination of TAK-019 will be asked to schedule a Participant Decision Visit about 5 months 
after the first single booster vaccination. In case of the subjects entering the Extension Part 
between Day 91 and Day 181 in the Main Part, the Participant Decision Visit will be performed 
after Day 91 in the Main Part, and from then trial visits for the Extension Part will be performed 
for the subjects. 
If a subject is not eligible to enter the Extension Part, the subject will be followed in the Main 
Part. 
9.3.1 Pre Booster Vaccination Procedures (Day 1 in the Main Part) 
The following will be checked and recorded by the Investigator or designee prior to the trial 
vaccination on Day 1 in the Main Part. Please refer to Section 2.1 for further details. 
1. Assess eligibility by review of inclusion/exclusion criteria for the Main Part.
2. Prior and concomitant medications (including prior and concomitant therapies).
3. Complete physical examination and other vital signs as listed in Sections 9.1.4 and 9.1.5.
4. Review of systems: Review of systems is a structured interview that queries the subject as to
any complaints the subject has experienced across each organ system.
5. Pregnancy test in women of childbearing potential.
6. Blood sampling for immunogenicity.
7. Nasal swab sample collection.
9.3.2 Booster Vaccination Procedures (Day 1 in the Main Part) 
After confirming eligibility of the subject, perform IMP administration according to the 
procedures described in Section 8.2.1. 
9.3.3 Post Booster Vaccination Procedures (Day 1 in the Main Part) 
After the trial vaccination, the subject will be observed in the trial site by the Investigator for at 
least 30 minutes including confirmation of acute hypersensitivity reactions, measurement of vital 
sign (oral body temperature, blood pressure, pulse rate, and respiratory rate), and observation for 
solicited local (injection site) reactions. 
The Investigator or delegate should confirm that the subject receives training on how and how 
often to record in the eDiary and can perform the recording appropriately. The following 
procedures will be explained: 
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•
Solicited local and systemic AEs and the severity, and oral body temperature will be recorded
in the eDiary for 7 days following booster vaccine administration (day of vaccination
+ 6 subsequent days).
•
The assessment of solicited AEs and measurement of oral body temperature will preferably be
taken place in the evening or at the same time of day. Oral body temperature is to be measured
using the thermometer provided by the site. If the subject has a fever, the highest body
temperature observed that day should be recorded on the eDiary.
9.3.4 Site Visits After Booster Vaccination (Day 8, Day 15, Day 29, Day 91, and Day 181 in 
the Main Part) 
Site visits that do NOT include a booster vaccination prior to the final visit will be performed on 
Day 8, Day 15, Day 29, Day 91, and Day 181 in the Main Part. At these site visits, the 
Investigator will record unsolicited AEs and concomitant medications (including concomitant 
therapies) by confirming to the subject with review of the eDiary. 
The following will be conducted at each visit. Refer to Section 2.1 in detail. 
•
Physical examination and vital sign: Day 8, Day 15, and Day 91 in the Main Part.
•
Pregnancy test in women of childbearing potential: Day 29 and Day 91 in the Main Part.
•
Confirmation of solicited AEs by the eDiary: Day 8 in the Main Part.
•
Confirmation of unsolicited AEs and concomitant medications (including concomitant
therapies): Day 8, Day 15, and Day 29 in the Main Part.
•
Confirmation of SAEs, AEs leading to withdrawal from trial, AESIs, and MAAEs: Day 8,
Day 15, Day 29, Day 91, and Day 181 in the Main Part.
•
Blood sampling for immunogenicity: Day 8, Day 15, Day 29, Day 91, and Day 181 in the
Main Part.
•
Nasal swab sample collection: Day 15 in the Main Part.
•
9.3.5 Final (End of Trial) Visit in the Main Part 
The final (end of trial) visit for the Main Part will be performed on Day 366 in the Main Part. If 
a subject terminates earlier in the Main Part, the final (end of trial) visit procedures should be 
performed at their last trial visit in the Main Part, if possible. The Investigator must complete the 
End of Trial eCRF page for all subjects who received IMP. 
The following will be conducted at the visit. Refer to Section 2.1 in detail. 
•
Physical examination and vital sign.
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•
Confirmation of SAEs, AEs leading to withdrawal from trial, AESIs, and MAAEs.
•
Blood sampling for immunogenicity (except for the early termination visit).
9.3.6 Pre Booster Vaccination Procedures (Extension Part Day 1, Participant Decision 
Visit) 
The following will be checked and recorded by the Investigator or designee prior to the trial 
vaccination on Extension Part Day 1. Please refer to Section 2.1 for further details. 
1. Assess eligibility by review of inclusion/exclusion criteria for the Extension Part.
2. Prior and concomitant medications (including concomitant therapies).
3. Complete physical examination and other vital signs as listed in Sections 9.1.4 and 9.1.5.
4. Review of systems: Review of systems is a structured interview that queries the subject as to
any complaints the subject has experienced across each organ system.
5. Pregnancy test in women of childbearing potential.
6. Blood sampling for immunogenicity.
9.3.7 Booster Vaccination Procedures (Extension Part Day 1, Participant Decision Visit) 
After confirming eligibility of the subject for the Extension Part, perform the second single IMP 
administration according to the procedures described in Section 8.2.1. 
9.3.8 Post Booster Vaccination Procedures (Extension Part Day 1, Participant Decision 
Visit) 
After the second single booster vaccination, the subject will be observed in the trial site by the 
Investigator for at least 30 minutes including confirmation of acute hypersensitivity reactions, 
measurement of vital sign (oral body temperature, blood pressure, pulse rate, and respiratory rate), 
and observation for solicited local (injection site) reactions. 
The Investigator or delegate should confirm that the subject receives training on how and how 
often to record in the eDiary and can perform the recording appropriately. The following 
procedures will be explained: 
•
Solicited local and systemic AEs and the severity, and oral body temperature will be recorded
in the eDiary for 7 days following the second single booster vaccine administration (day of
vaccination + 6 subsequent days).
•
The assessment of solicited AEs and measurement of oral body temperature will preferably be
taken place in the evening or at the same time of day. Oral body temperature is to be measured
using the thermometer provided by the site. If the subject has a fever, the highest body
temperature observed that day should be recorded on the eDiary.
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9.3.9 Site Visits After Booster Vaccination (Extension Part Day 15, Day 29, Day 91, and 
Day 181) 
Site visits that do NOT include a booster vaccination prior to the final visit in the Extension Part 
will be performed on Extension Part Day 15, Day 29, Day 91, and Day 181. At these site visits, 
the Investigator will record unsolicited AEs and concomitant medications (including concomitant 
therapies) by confirming to the subject with review of the eDiary. 
The following will be conducted at each visit. Refer to Section 2.1 in detail. 
•
Physical examination and vital sign: Extension Part Day 15 and Day 91.
•
Pregnancy test in women of childbearing potential: Extension Part Day 29 and Day 91.
•
Confirmation of solicited AEs by the eDiary: Extension Part Day 15.
•
Confirmation of unsolicited AEs and concomitant medications (including concomitant
therapies): Extension Part Day 15 and Day 29.
•
Confirmation of SAEs, AEs leading to withdrawal from trial, AESIs, and MAAEs: Extension
Part Day 15, Day 29, Day 91, and Day 181.
•
Blood sampling for immunogenicity: Extension Part Day 15, Day 29, Day 91, and Day 181.
•
Nasal swab sample collection: throughout the Extension Part for suspected COVID-19 case.
•
9.3.10 Final (End of Trial) Visit in the Extension Part 
The final (end of trial) visit for the Extension Part will be performed on Extension Part Day 366. 
If a subject terminates earlier in the Extension Part, the final (end of trial) visit procedures should 
be performed at their last trial visit in the Extension Part, if possible. The Investigator must 
complete the End of Trial eCRF page for all subjects who received IMP. 
The following will be conducted at the visit. Refer to Section 2.1 in detail. 
•
Physical examination and vital sign.
•
Confirmation of SAEs, AEs leading to withdrawal from trial, AESIs, and MAAEs.
•
Blood sampling for immunogenicity (except for the early termination visit).
9.3.11 Post-Trial Care 
No post-trial care will be provided. 
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. 
After blood draw and serum processing, the serum samples will be preserved and retained at a 
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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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10.0 
ADVERSE EVENTS 
10.1 
Definitions 
10.1.1 Pretreatment Events 
A pretreatment event (PTE) is defined as any untoward medical occurrence in a clinical 
investigation subject who has signed informed consent to participate in a study but prior to 
administration of any study drug; it does not necessarily have to have a causal relationship with 
study participation. 
10.1.2 Adverse Events 
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered an IMP; it does not necessarily have to have a causal relationship with IMP 
administration. 
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the administration of an IMP 
whether or not it is considered related to the IMP. 
AEs will be graded by the Investigator in the following manner. Solicited AEs (Section 10.1.3) 
will be graded by the criteria in Table 10.a. 
Mild 
Grade 1 
Awareness of symptoms that are easily tolerated, causing minimal discomfort 
and not interfering with everyday activities. Relieved with or without 
symptomatic treatment. 
Moderate 
Grade 2 
Sufficient discomfort is present to cause interference with normal activity. Only 
partially relieved with symptomatic treatment. 
Severe 
Grade 3 
Extreme distress, causing significant impairment of functioning or 
incapacitation. Prevents normal everyday activities. Not relieved with 
symptomatic treatment. 
Potentially 
Life-threatening 
Grade 4 
Only used for grading of solicited AEs. Refer to Table 10.a for the criteria of 
each event. 
10.1.3 Solicited Adverse Events 
Subjects will record solicited local and systemic AEs (Table 10.a), and oral body temperature, for 
7 days following each booster vaccination (day of vaccination + 6 subsequent days) in the eDiary. 
Severity grading of solicited AEs will occur automatically based on subject’s entry into the eDiary 
according to the grading scales presented in Table 10.a modified from the Food and Drug 
Administration guidance (Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventative Vaccine Clinical Trials) [18]. 
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If a solicited local or systemic AE continues beyond 7 days after the first or second booster dosing 
(including the day of administration), the solicited AEs should be reviewed by the Investigator 
either via phone call or at the following trial visit. 
Table 10.a 
Solicited Local (Injection Site) and Systemic AEs 
Local Reaction to Injectable Product 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially 
Life-threatening 
(Grade 4) 
Injection site pain 
Does not interfere 
with activity 
Repeated use of 
nonnarcotic pain 
reliever > 24 hours or 
interferes with activity 
Any use of narcotic 
pain reliever or 
prevents daily activity 
Emergency room visit 
or hospitalization 
Tenderness 
Mild discomfort to 
touch 
Discomfort with 
movement 
Significant 
discomfort at rest 
Emergency room visit 
or hospitalization 
Erythema/ 
redness a 
2.5 – 5 cm 
5.1 – 10 cm 
>10 cm
Necrosis or 
exfoliative dermatitis 
Induration a 
2.5 – 5 cm 
5.1 – 10 cm 
>10 cm
Necrosis 
Swelling a 
2.5 – 5 cm 
5.1 – 10 cm 
>10 cm
Necrosis 
Systemic (General) 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially 
Life-threatening 
(Grade 4) 
Fever b 
38.0°C – 38.4°C 
38.5°C – 38.9°C 
39.0°C – 40.0°C 
>40.0°C
Fatigue 
No interference with 
activity 
Some interference with 
activity 
Prevents daily 
activity 
Emergency room visit 
or hospitalization 
Malaise 
No interference with 
activity 
Some interference with 
activity 
Prevents daily 
activity 
Emergency room visit 
or hospitalization 
Myalgia 
No interference with 
activity 
Some interference with 
activity 
Prevents daily 
activity 
Emergency room visit 
or hospitalization 
Arthralgia 
No interference with 
activity 
Some interference with 
activity 
Prevents daily 
activity 
Emergency room visit 
or hospitalization 
Nausea/ 
vomiting 
No interference with 
activity or 1–2 
episodes/24 hours 
Some interference with 
activity or >2 
episodes/24 hours 
Prevents daily 
activity, or requires 
outpatient 
intravenous hydration 
Emergency room visit 
or hospitalization for 
hypotensive shock 
Headache 
No interference with 
activity 
Repeated use of OTC 
pain reliever >24 hours 
or some interference 
with activity 
Any use of 
prescription pain 
reliever or prevents 
daily activity 
Emergency room visit 
or hospitalization 
Abbreviations: AE: adverse event; OTC: over-the-counter. 
a
In addition to grading the measured local reaction at the greatest single diameter, the measurement should be
recorded as a continuous variable.
b
Oral temperature; no recent hot or cold beverages.
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Any solicited AE that meets any of the following criteria must also be recorded in the eCRF: 
•
Medically-attended solicited AE (MAAE).
•
Solicited AE leading to the subject withdrawing from the trial (AE leading to withdrawal).
•
Solicited AE lasting beyond 7 days post any booster injection.
•
Solicited AE that otherwise meets the definition of an SAE.
10.1.4 Adverse Events of Special Interest 
AESIs are defined as AEs that will be specifically highlighted to the Investigator. 
AESIs for the study include the Potential Immune Mediated Medical Conditions (PIMMC) listed 
below and AEs specific to COVID-19 including myocarditis and/or pericarditis [19,20]. The 
Investigators have to be especially vigilant to AESIs. Any AEs considered AESIs will be recorded 
on the AE page of the eCRF. 
PIMMC is included as Table 10.b, and AEs specific to COVID-19 is included as Table 10.c. 
Table 10.b 
Potential Immune-Mediated Medical Conditions (PIMMC) 
Categories 
Diagnoses (as MedDRA PT) 
Neuroinflammatory 
Disorders 
Acute disseminated encephalomyelitis (including site specific variants: eg, 
non-infectious encephalitis, encephalomyelitis, myelitis, myeloradiculomyelitis), 
cranial nerve disorders including paralysis/paresis (eg, Bell’s palsy), generalized 
convulsion, Guillain-Barre syndrome (including Miller Fischer and other variants), 
immune-mediated peripheral neuropathies and plexopathies (including chronic 
inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, and 
polyneuropathies associated with monoclonal gammopathy), myasthenia gravis, 
multiple sclerosis, narcolepsy, optic neuritis, transverse myelitis, and uveitis. 
Musculoskeletal and 
Connective Tissue 
Disorders: 
Antisynthetase syndrome, dermatomyositis, juvenile chronic arthritis (including Still’s 
disease), mixed connective tissue disorder, polymyalgia rheumatic, polymyositis, 
psoriatic arthropathy, relapsing polychondritis, rheumatoid arthritis, scleroderma 
(including diffuse systemic form and CREST syndrome), spondyloarthritis (including 
ankylosing spondylitis, reactive arthritis [Reiter’s Syndrome], and undifferentiated 
spondyloarthritis), systemic lupus erythematosus, systemic sclerosis, and Sjogren’s 
syndrome. 
Vasculitides 
Large vessels vasculitis (including giant cell arteritis such as Takayasu’s arteritis and 
temporal arteritis), medium sized and/or small vessels vasculitis (including polyarteritis 
nodosa, Kawasaki’s disease, microscopic polyangiitis, Wegener’s granulomatosis, 
Churg-Strauss syndrome [allergic granulomatous angiitis], Buerger’s disease 
[thromboangiitis obliterans], necrotizing vasculitis and ANCA-positive vasculitis [type 
unspecified], Henoch-Schonlein purpura, Behcet’s syndrome, leukocytoclastic 
vasculitis). 
Gastrointestinal Disorders 
Crohn’s disease, celiac disease, ulcerative colitis, and ulcerative proctitis. 
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Categories 
Diagnoses (as MedDRA PT) 
Hepatic Disorders 
Autoimmune hepatitis, autoimmune cholangitis, primary sclerosing cholangitis, and 
primary biliary cirrhosis. 
Renal Disorders 
Autoimmune glomerulonephritis (including IgA neuropathy, glomerulonephritis 
rapidly progressive, membranous glomerulonephritis, membranoproliferative 
glomerulonephritis, and mesangioproliferative glomerulonephritis). 
Cardiac Disorders 
Autoimmune myocarditis/cardiomyopathy. 
Myocarditis and/or pericarditis. 
Skin Disorder 
Alopecia areata, psoriasis, vitiligo, Raynaud’s phenomenon, erythema nodosum, 
autoimmune bullous skin diseases (including pemphigus, pemphigoid, and dermatitis 
herpetiformis), cutaneous lupus erythematosus, morphoea, lichen planus, 
Stevens-Johnson syndrome, and Sweet’s syndrome. 
Hematologic Disorders 
Autoimmune hemolytic anemia, autoimmune thrombocytopenia, antiphospholipid 
syndrome, and thrombocytopenia. 
Metabolic Disorders 
Autoimmune thyroiditis, Grave’s or Basedow’s disease, Hashimoto’s thyroiditisa, 
diabetes mellitus type I, and Addison’s disease. 
Other Disorders 
Goodpasture syndrome, idiopathic pulmonary fibrosis, pernicious anemia, and 
sarcoidosis. 
Abbreviations: ANCA: anti-neutrophil cytoplasmic antibody; CREST: calcinosis, Raynaud's phenomenon, 
esophageal dysmotility, sclerodactyly, and telangiectasia; IgA: immunoglobulin A; MedDRA: Medical Dictionary for 
Regulatory Activities; PT: Preferred Term. 
a
For Hashimoto thyroiditis: new onset only
Table 10.c 
Adverse Events Specific to COVID-19a 
Categories 
Diagnoses (as MedDRA SOC/PT) 
Respiratory/Infectious Disorders 
ARDS, pneumonitis, and septic shock-like syndrome 
Cardiac Disorders 
Acute cardiac injury, arrhythmia, and myocarditis and/or pericarditis. 
Coagulopathy 
Deep vein thrombosis, myocardial infarction, and stroke 
Renal Disorder 
Acute kidney injury 
Hematologic Disorders 
Thrombocytopenia, and septic shock-like syndrome. 
Inflammatory Disorders 
Cytokine Release Syndrome related to COVID-19 infectionb and multisystem 
inflammatory syndrome in children. 
Neurologic Disorder 
Generalized convulsions. 
Abbreviations: ARDS: acute respiratory distress syndrome; CEPI: Coalition for Epidemic Preparedness Innovations; 
COVID-19: coronavirus disease 2019; DAIDS: Division of AIDS; MedDRA: Medical Dictionary for Regulatory 
Activities; PT: Preferred Term; SOC: System Organ Class. 
a
COVID-19 manifestations associated with more severe presentation and decompensation with consideration of
enhanced disease potential. The current listing is based on CEPI/Brighton Collaborations Consensus Meeting
(12/13 March 2020) and expected to evolve as evidence accumulates.
b
Cytokines release syndrome related to COVID-19 infection is a disorder characterized by nausea, headache,
tachycardia, hypotension, rash, and/or shortness of breath [21].
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10.1.5 Medically-Attended Adverse Events 
MAAEs are defined as AEs leading to an unscheduled visit to or by a healthcare professional 
including visits to an emergency department, but not fulfilling seriousness criteria. 
10.1.6 Serious Adverse Events 
An SAE is defined as any untoward medical occurrence that: 
1. Results in DEATH.
2. Is LIFE THREATENING.
•
The term “life threatening” refers to an event in which the subject was at risk of death at the
time of the event; it does not refer to an event that hypothetically might have caused death
if it were more severe.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Leads to a CONGENITAL ANOMALY/BIRTH DEFECT in the offspring of a subject.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:
•
May require intervention to prevent items 1 through 5 above.
•
May expose the subject to danger, even though the event is not immediately life
threatening or fatal or does not result in hospitalization.
PTEs that fulfill 1 or more of the serious criteria above are also to be considered SAEs and should 
be reported and followed up in the same manner (see Sections 10.4.4 and 10.5). 
10.2 
Causality of Adverse Events 
Relationship (causality) to the IMP will also be assessed by the Investigator. The relationship of 
each AE to the IMP, including solicited systemic AEs (solicited local AEs are considered as 
related by default) will be assessed using the following categories: 
Related: 
There is suspicion that there is a relationship between the IMP and the AE 
(without determining the extent of probability); there is a reasonable possibility 
that the IMP contributed to the AE. 
Not Related: 
There is no suspicion that there is a relationship between the IMP and the AE; 
there are other more likely causes and administration of the IMP is not suspected 
to have contributed to the AE. 
10.2.1 Relationship to Trial Procedures 
Relationship (causality) to trial procedures should be determined for all AEs. 
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The relationship should be assessed as “Yes” if the Investigator considers that there is a reasonable 
possibility that an event is due to a trial procedure. Otherwise, the relationship should be assessed 
as “No”. 
10.2.2 Outcome of Adverse Events 
Resolved: 
The subject has fully recovered from the event or the condition has returned to the 
level observed at baseline. 
Resolving: 
The event is improving but the subject is still not fully recovered. 
Not resolved: 
The event is ongoing at the time of reporting and the subject has still not recovered. 
Resolved with sequelae: 
As a result of the AE, the subject suffered persistent and significant 
disability/incapacity (eg, became blind, deaf or paralysed). 
Fatal: 
The subject died due to the event. If the subject died due to other circumstances than 
the event, the outcome of the event per se should be stated otherwise (eg, not 
resolved or resolving). 
Unknown: 
If outcome is not known or not reported. 
10.2.3 Start Date 
The start date of the AE/PTE is the date that the first signs/symptoms were noted by the subject 
and/or investigator. 
The start date of PTEs/AEs will be determined using the following criteria; 
PTEs/AEs 
Start Date 
Any signs/symptoms/diseases (diagnosis) 
The date that the first signs/symptoms/diseases were noted by the 
subject and/or the investigator should be recorded. 
Asymptomatic diseases 
The date when examination was performed for diagnosis and 
diagnosis was confirmed should be recorded. 
The date when diagnosis was confirmed should also be recorded 
even when values or findings showed previous values or findings or 
the onset time can be estimated. 
Worsening or complication of concurrent 
medical conditions or any 
signs/symptoms/diseases before treatment 
The date that a worsening or complication of the condition was noted 
first by the subject and/or the investigator should be recorded. 
The examination after start of the study drug 
showed abnormal values/findings. 
The date of examination when an abnormal value or findings that 
was judged to be clinically significant was noted should be recorded. 
The examination at the start of the study drug 
showed abnormal values/findings and the 
subsequent examinations showed worsening 
of the symptoms. 
The date of examination when apparent elevation, reduction, 
increase or decrease was confirmed in judgment according to the 
trends in those values or findings should be recorded. 
10.2.4 Stop Date 
The stop date of the AE/PTE is the date at which the subject recovered, the event resolved but with 
sequelae or the subject died. 
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10.2.5 Frequency 
Episodic AEs/PTE (eg, vomiting) or those which occur repeatedly over a period of consecutive 
days are intermittent. All other events are continuous. 
10.3 
Additional Points to Consider for Adverse Events 
An untoward occurrence generally may: 
•
Indicate a new diagnosis or unexpected worsening of a pre-existing condition. Intermittent
events for pre-existing conditions or underlying disease should not be considered as PTEs or
AEs.
•
Necessitate therapeutic intervention.
•
Require an invasive diagnostic procedure.
•
Require a change in concomitant medication.
•
Be considered unfavorable by the Investigator for any reason.
PTEs/AEs caused by a study procedure (eg, a bruise after blood draw) should be recorded as a 
PTE/AE. 
Diagnoses versus signs and symptoms: 
•
Each event should be recorded to represent a single diagnosis. Accompanying signs (including
abnormal laboratory values) or symptoms should NOT be recorded as additional AEs. If a
diagnosis is unknown, signs or symptoms should be recorded appropriately as an AE(s).
Laboratory values and electrocardiogram (ECG) findings: 
•
Changes in laboratory values or ECG findings are only considered to be PTEs or AEs if they
are judged to be clinically significant (ie, if some action or intervention is required or if the
investigator judges the change to be beyond the range of normal physiologic fluctuation). A
laboratory or ECG retest and/or continued monitoring of an abnormal value or finding are not
considered an intervention. In addition, repeated or additional noninvasive testing for
verification, evaluation or monitoring of an abnormality is not considered an intervention.
•
If abnormal laboratory values or ECG findings are the result of pathology for which there is an
overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be
reported appropriately as a PTE or as an AE.
Pre-existing conditions: 
•
Pre-existing conditions (present at the time of signing of informed consent) are considered
concurrent medical conditions and should NOT be recorded as PTEs or AEs. Baseline
evaluations (eg, laboratory tests, ECG, X-rays etc.) should NOT be recorded as PTEs unless
related to study procedures. However, if the subject experiences a worsening or complication
of such a concurrent medical condition, the worsening or complication should be recorded
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appropriately as a PTE (worsening or complication occurs before start of study drug) or an AE 
(worsening or complication occurs after start of study drug). Investigators should ensure that 
the event term recorded captures the change in the condition (eg, “worsening of ...”). 
•
If a subject has a pre-existing episodic concurrent medical condition (eg, asthma, epilepsy) any
occurrence of an episode should only be captured as a PTE/AE if the condition becomes more
frequent, serious or severe in nature. Investigators should ensure that the AE term recorded
captures the change in the condition from Baseline (eg “worsening of ...”).
•
If a subject has a degenerative concurrent medical condition (eg, cataracts, rheumatoid
arthritis), worsening of the condition should only be recorded as a PTE/AE if occurring to a
greater extent to that which would be expected. Investigators should ensure that the AE term
recorded captures the change in the condition (eg, “worsening of ...”).
Worsening of AEs: 
•
If the subject experiences a worsening or complication of an AE after any booster
administration of the IMP, the worsening or complication should be recorded as a new AE.
Investigators should ensure that the AE term recorded captures the change in the condition (eg,
“worsening of …”).
•
If the subject experiences a worsening or complication of an AE, the worsening or
complication should be recorded as a new AE. Investigators should ensure that the AE term
recorded captures the change in the condition (eg, “worsening of ...”).
Changes in severity of AEs: 
•
If the subject experiences changes in severity of an AE, the event should be captured once with
the maximum severity recorded.
Preplanned surgeries or procedures: 
•
Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of ICF are
not considered as AEs. However, if a preplanned procedure is performed early (eg, as an
emergency) due to a worsening of the pre-existing condition, the worsening of the condition
should be recorded as a PTE or an AE. Complications resulting from any planned surgery
should be reported as AEs.
Elective surgeries or procedures: 
•
Elective procedures performed where there is no change in the subject’s medical condition
should not be recorded as AEs but should be documented in the subject’s source documents.
Complications resulting from an elective surgery should be reported as AEs.
Trial procedures: 
•
Adverse occurrences related to trial procedures after signing of ICF are considered as AEs and
should be reported as AEs.
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Insufficient clinical response (lack of efficacy): 
•
Insufficient clinical response, efficacy, or pharmacologic action, should NOT be recorded as
an AE. The investigator must make the distinction between exacerbation of pre-existing illness
and lack of therapeutic efficacy.
Overdose: 
•
Cases of overdose with any medication without manifested side effects are NOT considered
PTEs or AEs, but instead will be documented on an Overdose page of the eCRF. Any
manifested side effects will be considered PTEs or AEs and will be recorded on the AE page of
the eCRF.
10.4 
Procedures 
10.4.1 Collection and Reporting of Adverse Events 
10.4.1.1 PTE and AE Collection Period 
Collection of PTEs will commence from the time the subject signs the informed consent to 
participate in the study and continue until the subject is booster administered study drug (Visit 1 in 
the Main Part) or until discontinuation prior to the first study drug booster administration. For 
subjects who discontinue prior to the first study drug booster administration, PTEs are collected 
until the subject discontinues study participation. 
Collection of AEs will commence from the time that the subject is booster administered study drug 
(Visit 1 in the Main Part). Routine collection of AEs will continue until Day 366 (Visit 7) in the 
Main Part or Extension Part Day 366. The collection schedule of each AE is located in 
Section 2.1. 
10.4.1.2 PTE and AE Reporting 
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. Subjects experiencing a 
serious PTE must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to baseline or there is a satisfactory explanation for the change. 
Non-serious PTEs, related or unrelated to the study procedure, need not to be followed up for the 
purposes of the protocol. 
All AEs, whether considered related to the use of the IMP or not, must be monitored until 
symptoms subside and any abnormal laboratory values have returned to baseline, or until there is a 
satisfactory explanation for the changes observed, or until death, in which case a full autopsy 
report should be supplied, if possible. All findings must be reported on an AE eCRF and on the 
SAE form (see Section 10.4.4). All findings in subjects experiencing AEs must also be 
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documented in the subject’s source documents. AEs leading to discontinuation from the trial are 
collected throughout the trial. 
The following information will be documented for each event: 
•
Reported term for the AE.
•
Start and end date, duration.
•
Serious (Y/N).
•
Severity.
•
Investigator’s opinion of the causality (relationship) between the event and administration of
IMP (“related” or “not related”).
•
Investigator’s opinion of the causality (relationship) to trial procedure(s), including the details
of the suspected procedure.
•
Action taken with the IMP.
•
Treatment for the AE.
•
Outcome of event.
10.4.2 Collection and Reporting of Solicited Adverse Events 
The occurrence of selected indicators of safety will be collected on eDiary by the subjects for 
7 days following each administration of booster IMP dose (including the day of each 
administration). These will be summarized in the final report under the category “solicited AEs” to 
differentiate them from unsolicited AEs. Any solicited local (injection site) or systemic AE 
observed as continuing beyond 7 days after the first or second booster trial vaccination will be 
additionally recorded as an AE on the AE eCRF for follow-up. For these persistent/prolonged 
solicited AEs, the end date will be captured on the AE eCRF to permit a separate analysis from the 
unsolicited AEs. 
Any solicited AE that meets any of the following criteria must be entered as an AE on the AE 
eCRF page. 
•
Solicited local (injection site) or systemic AEs that lead the subject to withdraw from the trial.
•
Solicited local (injection site) or systemic AEs that lead to the subject being withdrawn from
the trial by the Investigator.
•
Solicited local (injection site) and systemic AEs that otherwise meet the definition of an SAE
(see Section 10.1.3).
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10.4.3 Collection and Reporting of Adverse Events of Special Interest/ Medically-Attended 
Adverse Events 
AESIs/MAAEs will be collected by close monitoring from Day 1 in the Main Part up to Day 366 
in the Main Part or Extension Part Day 366. AESIs /MAAEs need to be reported to the Sponsor 
as soon as possible after the Investigator becoming aware of the event. 
AESIs/MAAEs must be recorded as an AE on the AE eCRF page. AESIs/MAAEs will be 
summarized separately at the end of the trial. 
10.4.4 Collection and Reporting of Serious Adverse Events 
Collection of SAEs will commence from the time that the subject is administered the IMP (Day 1 
in the Main Part). Routine collection of SAEs will continue until the end of the trial (Day 366 in 
the Main Part or Extension Part Day 366). 
SAEs should be reported according to the following procedure: 
An SAE should be reported by the Investigator to the Sponsor within 24 hours of the SAE 
occurrence, along with any relevant information. The Investigator should submit the detailed SAE 
form to the Sponsor within 10 calendar days. The information should be completed as fully as 
possible but contain, at a minimum: 
•
A short description of the event and the reason why the event is categorized as serious.
•
Causality assessment.
•
Protocol number.
•
Subject identification number.
•
Investigator’s name.
The SAE form should be transmitted within 24 hours to for the attention of the contact(s) in the list 
provided to each site. 
The Investigator should submit the original copy of the SAE form to the Sponsor. 
Any SAE spontaneously reported to the Investigator following the AE collection period should be 
reported to the Sponsor if considered related to study participation. 
Reporting of Serious PTEs will follow the procedure described for SAEs. 
10.5 
Follow-up Procedures 
10.5.1 Adverse Events 
All AEs will be monitored until resolution or a stable status is reached or until the satisfactory 
explanation for the changes observed can be found or until the end of the trial, whichever occurs 
first. 
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10.5.2 Serious Adverse Events 
If information not available at the time of the first report becomes available later, the Investigator 
should complete a follow-up SAE form or provide other written documentation immediately. 
Copies of any relevant data from the hospital notes (eg, laboratory tests, discharge summary, 
postmortem results) should be sent to the Sponsor after redaction for privacy. 
All SAEs should be followed up until resolution, permanent outcome of the event, or is otherwise 
explained. The timelines and procedure for follow-up reports are the same as those for the initial 
report. 
10.5.3 Safety Reporting to Investigators, Investigational Review Boards, and Regulatory 
Authorities 
The Sponsor or designee will be responsible for the reporting of all suspected unexpected serious 
adverse reactions (SUSARs) and any other SAEs to regulatory authorities, Investigators and IRB, 
as applicable, in accordance with national regulations in the countries where the trial is conducted. 
Relative to the first awareness of the event by/or further provision to the Sponsor or designee, 
SUSARs will be submitted within 7 days for fatal and life-threatening events and 15 days for other 
SUSARs, unless otherwise required by national regulations. The Sponsor will also prepare an 
expedited report for other safety issues where these might materially alter the current benefit-risk 
assessment of an investigational vaccine or that would be sufficient to consider changes in the IMP 
administration or in the overall conduct of the trial. The investigational site also will also forward a 
copy of all expedited reports to their IRB in accordance with national regulations. 
10.5.4 Post-Trial Events 
Any SAE that occurs outside of the protocol-specified observation period or after the end of the 
trial but is considered to be caused by the IMP must be reported to the Sponsor. Instructions for 
how to submit these SAEs will be provided in a handout in the ISF. 
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11.0 
TRIAL-SPECIFIC REQUIREMENT(S) 
11.1 
Trial-Specific Committee 
No independent data monitoring committee will be used for this trial. 
11.2 
Halting Rules 
Although the Sponsor has every intention of completing this trial, they reserve the right to 
discontinue it at any time for clinical or administrative reasons (see Section 6.4.1). 
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12.0 
DATA HANDLING AND RECORD KEEPING 
The full details of procedures for data handling will be documented in the data management plan. 
AEs, medical history, and concurrent medical conditions will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the WHO Drug 
Dictionary. 
12.1 
Electronic CRFs  
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. These forms are used to 
transmit the information collected in the performance of this trial to the Sponsor and regulatory 
authorities. The 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 designee and will be answered by the site. 
All corrections must be initialed and dated. Corrections to the 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. Reasons for significant 
corrections should additionally be included. 
The Investigator 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. 
All data will have separate source documentation; no data will be recorded directly onto the eCRF. 
After the lock of the trial database, any change of, modification of or addition to the data on the 
eCRFs should be followed by the procedure of the Sponsor or designee (contract research 
organization [CRO]) on the change and modification of the eCRF. The Investigator must confirm 
and ensure the data change for completeness and accuracy. 
The 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 Appendix A and those documents that 
include (but are not limited to) the trial-specific documents, the identification log of all 
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participating subjects, medical records, source worksheets, all original signed and dated ICFs, 
subject authorization forms regarding the use of personal health information (if separate from the 
ICF), electronic copy of eCRFs, including all query responses, and detailed records of vaccine 
disposition to enable evaluations or audits from regulatory authorities, the Sponsor or designee. 
Any source documentation printed on degradable thermal sensitive paper should be photocopied 
by the site and filed with the original in the subject’s chart to ensure long term legibility. 
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 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. 
The Investigator and the head of the study site agree to keep the records stipulated in Section 12.1 
and those documents that include (but are not limited to) the study-specific documents, the 
identification log of all participating subjects, medical records, source worksheets, all original 
signed and dated ICFs, electronic copy of eCRFs, including all query responses, and detailed 
records of drug disposition to enable evaluations or audits from regulatory authorities, the Sponsor 
or its designees. The Investigator and the head of the study site are required to retain essential 
relevant documents until the day specified as 1) or 2) below, whichever comes later. However, if 
the Sponsor requests a longer time period for retention, the head of the study site should discuss 
how long and how to retain those documents with the Sponsor. 
1) The day on which marketing approval of the study drug is obtained (or the day 3 years after the
date of notification in the case that the investigation is discontinued.)
2) The day 3 years after the date of early termination or completion of the study.
In addition, the Investigator and the head of the study site should retain the essential relevant 
documents until the receipt of a sponsor-issued notification to state the retention is no longer 
required. 
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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. This 
document will provide further details regarding the definition of analysis variables and analysis 
methodology to address all trial objectives. 
A data review will be conducted prior to the database lock. This review will assess the accuracy 
and completeness of the trial database, subject evaluability, and appropriateness of the planned 
statistical methods. 
The primary analysis of the Main Part will be performed for immunogenicity and safety after all 
subjects have completed the Day 29 visit in the Main Part. 
An interim analysis will be performed for immunogenicity and safety after all subjects have 
completed the Extension Part Day 29 visit. 
13.1.1 Analysis Sets 
Subject evaluability criteria for each Analysis Set will be specified in the SAP, and be fixed before 
the database lock. 
MAIN PART 
The Full Analysis Set (FAS), Per-protocol Set (PPS), and Safety Analysis Set (SAS) are defined 
for this trial. The FAS is defined as all enrolled subjects who receive at least 1 dose of the trial 
vaccination. Immunogenicity analysis will be conducted using the PPS defined to include subjects 
in the FAS and who have evaluable immunogenicity data and do not have significant protocol 
deviations which influence the immunogenicity assessment. Safety analysis will be conducted 
using the SAS defined as all subjects who receive at least 1 dose of the trial vaccination. The detail 
of the definitions for the analysis sets will be documented in the SAP. 
EXTENSION PART 
The FAS, PPS, and SAS in Extension Part are defined for this trial. The FAS in Extension Part is 
defined as all subjects enrolled in Extension Part who receive at least 1 dose of the trial 
vaccination in Extension Part. Immunogenicity analysis will be conducted using the PPS in 
Extension Part defined to include subjects in the FAS in Extension Part and who have evaluable 
immunogenicity data and do not have significant protocol deviations which influence the 
immunogenicity assessment. Safety analysis will be conducted using the SAS in Extension Part 
defined as all subjects who receive at least 1 dose of the trial vaccination in Extension Part. The 
detail of the definitions for the analysis sets will be documented in the SAP. 
13.1.2 Analysis of Demographics and Other Baseline Characteristics 
Baseline and demographic information will be analyzed by using the SAS. 
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13.1.3 Immunogenicity Analysis 
MAIN PART 
(1) Primary Endpoints
•
GMT ratio of neutralizing antibody titers to the ancestral strain (wild-type virus) on Day 15
after a single booster vaccination (14 days after the booster vaccination) compared with that
observed on Day 36 (14 days after the second vaccination) in subjects from Study
TAK-019-1501.
(2) Analysis for Primary Endpoints
For immunogenicity endpoints, analyses will be conducted using the PPS.
For neutralizing antibody titer values to the ancestral strain (wild-type virus), summary statistics, 
GMT, and the two-sided 95% CIs will be calculated. 
For GMT ratio of serum neutralizing antibody titers to the ancestral strain (wild-type virus) 
between booster vaccination group in the proposed study and the 2 doses primary vaccinations 
group in Study TAK-019-1501 (called study group), point estimate and the two-sided 95% CIs 
will be provided using a 2-way analysis of variance (ANOVA) model. The 2-way ANOVA model 
will include log-transformed (common log) serum neutralizing antibody titers to the ancestral 
strain (wild-type virus) 14 days after vaccination as dependent variable, and categorized age 
(20<= - <65, 65<=) and study group as independent variable. Each estimate by the model will be 
back transformed to the original scale. The lower limit of two-sided 95% CI of the GMT ratio will 
be compared with non-inferiority margin of 0.67 to assess the non-inferiority of neutralizing 
antibody titers to the ancestral strain (wild-type virus) on Day 15 after a single booster vaccination 
compared with that observed on Day 36 (14 days after 2nd vaccination) in subjects from Study 
TAK-019-1501. If the lower limit of the 95% CI will be ≥0.67, the immune response to a single 
heterologous booster vaccination of TAK-019 will be considered to be non-inferior of that to the 
primary series of TAK-019. 
As a sensitivity analysis, statistical results will be demonstrated appropriately based on the 
different model with the primary analysis (eg, add other subject characteristics to the model as 
factors). 
A detailed analysis method will be specified in the SAP. 
(3) Secondary Endpoints
•
GMT, GMFR, and SCR (defined at proportion of subjects with ≥4-fold rises from baseline
[Day 1]) of serum IgG antibody levels to SARS-CoV-2 rS protein on Day 8, Day 15, Day 29,
Day 91, Day 181, and Day 366.
•
GMT, GMFR, and SCR of serum neutralizing antibody titers to the ancestral strain (wild-type
virus) on Day 8, Day 15, Day 29, Day 91, Day 181, and Day 366.
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(4) Analysis for Secondary Endpoints
Analyses will be conducted using the PPS. SCR of each immunogenicity endpoint at each time 
point will be calculated along with its 95% CI. For antibody titer values and GMFR from baseline, 
summary statistics, GMT, and the two-sided 95% CIs of each endpoint at each time point will be 
calculated. 
EXTENSION PART 
(5) Secondary Endpoints
•
GMT, GMFR, and SCR (defined at proportion of subjects with ≥4-fold rises from baseline
[Extension Part Day 1]) of serum IgG antibody levels to SARS-CoV-2 rS protein on
Extension Part Day 15, Day 29, Day 91, Day 181, and Day 366.
•
GMT, GMFR, and SCR of serum neutralizing antibody titers to the ancestral strain (wild-type
virus) on Extension Part Day 15, Day 29, Day 91, Day 181, and Day 366.
(6) Analysis for Secondary Endpoints
Analyses will be conducted using the PPS in Extension Part. SCR of each immunogenicity 
endpoint at each time point will be calculated along with its 95% CI. For antibody titer values, 
summary statistics, GMT and GMFR from baseline (Extension Part Day 1), and 95% CIs of each 
endpoint at each time point will be calculated. 
A detailed analysis method will be specified in the SAP. 
13.1.4 Safety Analysis 
MAIN PART 
(1) Primary Endpoints
•
Percentage of subjects with reported solicited local AEs: injection site pain, tenderness,
erythema/redness, induration, and swelling for 7 days following the first single booster
vaccination (day of vaccination + 6 subsequent days).
•
Percentage of subjects with solicited systemic AEs: fever, fatigue, malaise, myalgia, arthralgia,
nausea/vomiting, and headache for 7 days following the first single booster vaccination (day of
vaccination + 6 subsequent days).
•
Percentage of subjects with unsolicited AEs for 28 days following the first single booster
vaccination (day of vaccination + 27 subsequent days).
•
Percentage of subjects with SAEs until Day 29.
•
Percentage of subjects with AESIs until Day 29.
•
Percentage of subjects with MAAEs until Day 29.
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•
Percentage of subjects with any AEs leading to subject’s withdrawal from the trial until
Day 29.
•
Percentage of subjects with SARS-CoV-2 infection until Day 29.
(2) Secondary Endpoints
•
Percentage of subjects with SAEs throughout the trial.
•
Percentage of subjects with AESIs throughout the trial.
•
Percentage of subjects with MAAEs throughout the trial.
•
Percentage of subjects with any AEs leading to subject’s withdrawal from the trial from the
day of the first single booster vaccination throughout the trial.
•
Percentage of subjects with SARS-CoV-2 infection throughout the trial.
(4) Analysis for Safety Endpoints
Analyses will be performed using the SAS.
Solicited local and systemic AEs will be summarized for each day post the first single booster 
vaccination and the total duration (day of vaccination + 6 subsequent days). 
Unsolicited AEs for 28 days following the first single booster vaccination will be coded using the 
MedDRA dictionary and tabulated by the System Organ Class (SOC) and the Preferred Term (PT). 
The percentage of subjects with SARS-CoV-2 infection will be summarized. 
For continuous variables of vital signs, the observed values and the changes from baseline (Day 1 
in the Main Part) will be summarized for each scheduled time point using descriptive statistics. 
For categorical variables, shift tables showing the number of subjects in each category at baseline 
and each post-baseline scheduled time point will be provided. 
A detailed analysis method will be specified in the SAP. 
EXTENSION PART 
(5) Secondary Endpoints
•
Percentage of subjects with reported solicited local AEs: injection site pain, tenderness,
erythema/redness, induration, and swelling for 7 days following the second single booster
vaccination (day of vaccination + 6 subsequent days).
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•
Percentage of subjects with solicited systemic AEs: fever, fatigue, malaise, myalgia, arthralgia,
nausea/vomiting, and headache for 7 days following the second single booster vaccination
(day of vaccination + 6 subsequent days).
•
Percentage of subjects with unsolicited AEs for 28 days following the second single booster
vaccination (day of vaccination + 27 subsequent days).
•
Percentage of subjects with SAEs until Extension Part Day 29.
•
Percentage of subjects with AESIs until Extension Part Day 29.
•
Percentage of subjects with MAAEs until Extension Part Day 29.
•
Percentage of subjects with any AEs leading to subject’s withdrawal from the trial until
Extension Part Day 29.
•
Percentage of subjects with SARS-CoV-2 infection until Extension Part Day 29.
•
Percentage of subjects with SAEs throughout the trial.
•
Percentage of subjects with AESIs throughout the trial.
•
Percentage of subjects with MAAEs throughout the trial.
•
Percentage of subjects with any AEs leading to subject’s withdrawal from the trial from the
day of the second single booster vaccination throughout the trial.
•
Percentage of subjects with SARS-CoV-2 infection throughout the trial.
(7) Analysis for Safety Endpoints
Analyses will be performed using the SAS in Extension Part.
Solicited local and systemic AEs will be summarized for each day post the second single booster 
vaccination and the total duration (day of vaccination + 6 subsequent days).  
Unsolicited AEs for 28 days following the second single booster vaccination will be coded using 
the MedDRA dictionary and tabulated by the SOC and the PT. 
The percentage of subjects with SARS-CoV-2 infection will be summarized. 
For continuous variables of vital signs, the observed values and the changes from baseline 
(Extension Part Day 1) will be summarized for each scheduled time point using descriptive 
statistics. For categorical variables, shift tables showing the number of subjects in each category at 
baseline and each post-baseline scheduled time point will be provided. 
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A detailed analysis method will be specified in the SAP. 
13.2 
Interim Analysis and Criteria for Early Termination 
No interim analysis is planned for the Main Part. 
An interim analysis of immunogenicity and safety is planned for the Extension Part after all 
subjects have completed Extension Part Day 29 (immunogenicity data through Extension Part 
Day 15 and safety data through Extension Part Day 29). 
13.3 
Determination of Sample Size 
MAIN PART 
In Study TAK-019-1501, GMT and geometric SD of serum neutralizing antibody titers to 
wild-type virus after the primary vaccinations on Day 36 (14 days after the 2nd vaccination) were 
884.4 and 2.80 respectively in the vaccine group. 
There is no immunogenicity data of serum neutralizing antibody titers to the ancestral strain 
(wild-type virus) after a booster vaccination of TAK-019 in Japanese subjects available. However, 
an estimate has been made on the results of the primary vaccination in Study TAK-019-1501 and 
the homoeologous booster vaccination in Study 2019nCoV-101 (Part 2). The assumption was 
made that neutralizing antibody titers on Day 15 in the proposed study would be equivalent to 
titers on Day 36 in Study TAK-019-1501 (ie, assuming GMT ratio to be 1 and geometric SD to be 
2.80). With the guidance document, Principles for the Evaluation of Vaccines Against the Novel 
Coronavirus SARS-CoV-2 (Appendix 1) Evaluation of Vaccines Against Variants, issued by the 
PMDA [16], in mind, the non-inferiority margin of GMT ratio between booster vaccination group 
in the proposed study and the primary vaccination group in Study TAK-019-1501 is set as 0.67 
fold. This results in 132 subjects be required as the number of evaluable subjects in PPS to ensure 
90% power with the lower limit of 2-sided 95% CI of the GMT ratio exceeding the non-inferiority 
margin. Considering around 10% non-evaluable subjects, 150 subjects will be required into the 
proposed study. 
EXTENSION PART 
The number of subjects in this part is not based on statistical power considerations as this is an 
Extension Part of Study TAK-019-3001 following the Main Part. 
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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 
(CRO) 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 ISF, IMP records, subject 
medical records, ICF documentation, documentation of subject authorization to use personal 
health information (if separate from the ICFs), and review of CRFs 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 Sponsor 
(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. 
The Investigator can deviate and change from the protocol for any medically unavoidable reason, 
for example, to eliminate an immediate hazard to study subjects, without a prior written agreement 
with the Sponsor or a prior approval from IRB. In the event of a deviation or change, the principal 
investigator should notify the Sponsor and the head of the study site of the deviation or change as 
well as its reason in a written form, and then retain a copy of the written form. When necessary, the 
principal investigator may consult and agree with the Sponsor on a protocol amendment. If the 
protocol amendment is appropriate, the amendment proposal should be submitted to the head of 
the study site as soon as possible and an approval from IRB should be obtained. 
The Investigator should document all protocol deviations. 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections 
The trial site also may be subject to quality assurance audits by the Sponsor or designee. 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. If the trial site is contacted for an inspection by a regulatory body, the 
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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. 
14.4 
Trial Risk Management 
The ICH E6 addendum (R2) guidance encourages a risk-based approach to the management of 
clinical trials and includes requirements for risk control and risk reporting. Before initiation of the 
trial, Takeda or designee will establish quality tolerance limits (QTLs) taking into consideration 
the medical and statistical characteristics of the variables and the statistical design of the trial. 
At the end of the trial, the quality management approach implemented will be described in the 
clinical study report (CSR). If applicable, the CSR will summarize important deviations from the 
predefined QTL and the remedial actions taken. 
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15.0 
ETHICAL ASPECTS OF THE TRIAL 
This trial will be conducted with the highest respect for the trial subjects according to the protocol, 
the ethical principles that have their origin in the Declaration of Helsinki [1], and the ICH 
Harmonised Tripartite Guideline for GCP E6 (R2) [2]. 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 Approval 
IRBs must be constituted according to the applicable state and federal 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. 
The Sponsor or designee will supply relevant documents for submission to the respective IRB for 
the protocol’s review and approval. This protocol, the IB, a copy of the ICF, 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 ICF must be obtained and submitted to the 
Sponsor or designee before commencement of the trial (ie, before shipment of the IMP 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, ICF) 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/approval 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 ICF, 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. 
Incentives should not be used to exert undue influence on subjects for participation. Payments to 
subjects must be approved by the IRB and Sponsor. 
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 
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applicable laws and regulations. The ICF, subject authorization form (if applicable), and subject 
information sheet describe the planned and permitted uses, transfers, and disclosures of the 
subject’s personal and personal health information for the purpose of conducting the trial. The ICF 
and the subject information sheet further explain the nature of the trial, its objectives, and potential 
risks and benefits, as well as the date informed consent is given. The ICF will detail the 
requirements of the subject and the fact that the subject is free to withdraw at any time without 
giving a reason and without prejudice to the subject’s further medical care. 
Re-consent, re-affirmation of consent: The Investigator should assess the need to re-consent / 
re-affirmation of consent in situations wherein there has been substantial changes to the subject’s 
status of condition since the original consent. The process should comply with relevant local 
regulations. 
The Investigator is responsible for the preparation, content, and IRB approval of the ICF and if 
applicable, the subject authorization form. The ICF, subject authorization form (if applicable), and 
subject information sheet must be approved by both the IRB and the Sponsor prior to use. 
The ICF, subject authorization form (if applicable), 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 ICF, 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 that they will participate in the 
trial, then the ICF 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 ICF and subject authorization (if applicable) at the time of 
consent and prior to the 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 ICF, subject authorization form (if applicable), and subject information 
sheet will be stored in the ISF. The Investigator must document the date the subject signs the ICF 
in the subject’s medical record and CRF. Copies of the signed ICF, the signed subject 
authorization form (if applicable), and subject information sheet (if applicable) shall be given to 
the subject. 
All revised ICFs must be reviewed and signed by the subject in the same manner as the original 
ICF. The date the revised consent was obtained should be recorded in the subject’s medical record 
and CRF, and the subject should receive a copy of the revised ICF. 
15.3 
Subject Confidentiality 
The Sponsor and designee 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 
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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, representatives from any regulatory 
authority, 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, 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 ICF 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 CRF). 
15.4 
Clinical Trial Registration, Publication and Disclosure Policy 
15.4.1 Publication and Disclosure 
The Investigator is obliged to provide the Sponsor with complete test results and all data derived 
by the Investigator from the study. During and after the study, only the Sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the study site agreement, any public disclosure 
(including publicly accessible websites) related to the protocol or study results is the sole 
responsibility of the Sponsor. 
The Sponsor may publish any data and information from the study (including data and information 
generated by the Investigator) without the consent of the Investigator. 
The Investigator needs to obtain a prior written approval from the Sponsor to publish any 
information from the study externally such as to a professional association. 
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, as a minimum register all 
clinical trials conducted in subjects that it sponsors anywhere in the world, on publicly accessible 
websites such as Japan Registry of Clinical Trials (jRCT), ClinicalTrials.gov and/or others 
according to local requirements, before trial initiation. The Sponsor contact information, along 
with the 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 
Takeda clinical trial disclosure policy aims to comply with the clinical trial data disclosure 
requirements of all relevant regions. The Sponsor will post the results of this clinical trial 
regardless of outcome, on publicly accessible websites such as ClinicalTrials.gov and/or others, as 
required by applicable laws and/or regulations. 
Completion of trial corresponds to the date on which the final subject will be examined or receive 
an intervention for the purpose of final collection of data (usually corresponds to last subject last 
visit). 
If the deadline for results disclosure cannot be met, an application for extension with scientific 
justification will be provided. 
15.4.4 Publication of Trial Results 
The results of this trial are expected to be published in a peer-reviewed scientific journal 
publication of trial results will follow Takeda publication policies, applicable international 
standards and guidelines for good publication practice, applicable laws, and/or regulations. 
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. 
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16.0 
REFERENCES 
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20 January 2022]. Available from: 
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