An Open-label Phase 4 Study to Evaluate the Immunogenicity and Safety of Intramuscular Injections of BLB-750 in Healthy Adult Subjects
Phase: PHASE4
Conditions: Pandemic Influenza Prevention
Sponsor: Takeda

 
 
Title: A Phase 4, Open-label Study to Evaluate the Immunogenicity and Safety of 
Intramuscular Injections of BLB-750 in Healthy Adult Subjects 
 
NCT Number: NCT03370289 
Protocol Approve Date: 21-Nov-2017 
 
Certain information within this protocol has been redacted (ie, specific content is 
masked irreversibly from view with a black/blue bar) to protect either personally 
identifiable information or company confidential information. 
 
This may include, but is not limited to, redaction of the following: 
 
Named persons or organizations associated with the study. 
 
Patient identifiers within the text, tables, or figures or in by-patient data listings. 
 
Proprietary information, such as scales or coding systems, which are considered 
confidential information under prior agreements with license holder. 
 
Other information as needed to protect confidentiality of Takeda or partners, 
personal information, or to otherwise protect the integrity of the clinical study. 
 
If needed, certain appendices that contain a large volume of personally identifiable 
information or company confidential information may be removed in their entirety if it 
is considered that they do not add substantially to the interpretation of the data (eg, 
appendix of investigator’s curriculum vitae). 
 
Note; This document was translated into English as the language on original version 
was Japanese. 

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Post-marketing Study Protocol
<Title>
A Phase 4, Open-label Study to Evaluate
the Immunogenicity and Safety of Intramuscular Injections of BLB-750 in Healthy Adult Subjects
<Short Title>
A Phase 4 Post-marketing Study of Intramuscular Injections of BLB-750 in Healthy Adult Subjects
Name of Sponsor
Takeda Pharmaceutical Company Limited
1-1, Doshomachi 4-chome, Chuo-ku, Osaka
Protocol number
BLB-750/CCT-901 
IND Number
Not applicable
EudraCT Number
Not applicable
Compound
BLB-750 (Cell-Culture Influenza Vaccine H5N1 “Takeda” 1 mL)
Date:
21 Nov 2017
Version Number
Amendment 02
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement by the 
recipient that no information contained herein will be published or disclosed without written authorization from Takeda 
except to the extent necessary to obtain informed consent from those persons to whom the drug may be administered. 
Furthermore, the information is only meant for review and compliance by the recipient, his or her staff, and applicable 
institutional review committee and regulatory agencies to enable conduct of the post-marketing study.

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1.0
ADMINISTRATIVE INFORMATION AND PRINCIPLES OF CLINICAL STUDIES
1.1
Contacts and Responsibilities of Study-Related Activities
See the attachments.
1.2
Principles of Clinical Studies
This study will be conducted with the highest respect for the individual participants in accordance with the 
requirements of this clinical study protocol and also in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated Guideline. 

All applicable laws and regulations, including, without limitation, data privacy laws, clinical trial disclosure 
laws, and regulations.
1.3
Summary of Changes in the Amended Protocol
The changes in the amended version of the protocol are described below. 
The key changes in this amended protocol are summarized below. Details of the changes are described in Appendix
C.
1.
Addition of requirements to avoid possible bleeding at the intramuscular injection site.
Reason for the change: To reflect the revised package insert with additional precautionary text, the exclusion 
criteria and the list of excluded medications and treatments have been updated to include new requirements.

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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
Summary of Changes in the Amended Protocol............................................................................... 2
2.0
STUDY SUMMARY .............................................................................................................................. 8
3.0
LIST OF ABBREVIATIONS................................................................................................................ 13
4.0
INTRODUCTION................................................................................................................................. 14
4.1
Background .................................................................................................................................... 14
4.1.1
Benefit/Risk Profile................................................................................................................. 14
4.2
Rationale for the Proposed Study................................................................................................... 15
5.0
STUDY OBJECTIVES AND ENDPOINTS......................................................................................... 16
5.1
Objectives....................................................................................................................................... 16
5.2
Endpoints........................................................................................................................................ 16
5.2.1
Primary Endpoints................................................................................................................... 16
5.2.2
Secondary Endpoints............................................................................................................... 16
5.2.3
Additional Endpoints............................................................................................................... 16
6.0
STUDY DESIGN AND DESCRIPTION.............................................................................................. 18
6.1
Study Design .................................................................................................................................. 18
6.2
Rationales for the Selection of Study Design, Vaccination Dosage, and Endpoints ...................... 18
6.2.1
Rationales for the Selection of Study Design.......................................................................... 18
6.2.2
Rationales for the Selection of Vaccination Dosage Regimen and Strain ............................... 19
6.2.3
Rationales for the Selection of Endpoints ............................................................................... 19
6.3
Premature Termination or Suspension of Study or Study Site ....................................................... 19
6.3.1
Criteria for Premature Termination or Suspension of the Study.............................................. 19
6.3.2
Criteria for Premature Termination or Suspension of Study Sites........................................... 20
6.3.3
Procedures for Premature Termination or Suspension of the Study or the Participation of 
Study Site(s) ............................................................................................................................ 20
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS .................................... 21
7.1
Inclusion Criteria............................................................................................................................ 21
7.2
Exclusion Criteria........................................................................................................................... 21
7.3
Excluded Medications and Treatments........................................................................................... 23
7.4
Diet, Fluid, Activity Control........................................................................................................... 23
7.5
Criteria for Discontinuation or Withdrawal of a Subject................................................................ 24
7.6
Procedures for Discontinuation or Withdrawal of a Subject .......................................................... 25
8.0
CLINICAL TRIAL MATERIAL MANAGEMENT............................................................................. 26
8.1
Study Drug and Materials............................................................................................................... 26
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling ........................................................ 26
8.1.1.1 Study Drug ...................................................................................................................... 26
8.1.1.2 Ancillary Materials......................................................................................................... 27

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8.1.2
Storage..................................................................................................................................... 27
8.1.3
Dose and Regimen................................................................................................................... 27
8.1.4
Overdose.................................................................................................................................. 28
8.2
Study Drug Dispensing Procedures................................................................................................ 28
8.3
Accountability and Destruction of Sponsor-Supplied Drugs ......................................................... 28
9.0
STUDY PLAN...................................................................................................................................... 29
9.1
Study Procedures............................................................................................................................ 29
9.1.1
Informed Consent Procedure................................................................................................... 29
9.1.2
Demographics, Medical History, and Medication History Procedure ..................................... 29
9.1.3
Physical Examination Procedure............................................................................................. 29
9.1.4
Weight and Height................................................................................................................... 29
9.1.5
Vital Signs Procedure .............................................................................................................. 29
9.1.6
Documentation of Concomitant Medications.......................................................................... 30
9.1.7
History of Present Illness......................................................................................................... 30
9.1.8
Contraception and Pregnancy Avoidance Procedure............................................................... 30
9.1.9
Pregnancy................................................................................................................................ 31
9.1.10
Immunogenicity Evaluation .................................................................................................... 31
9.1.11
Injection Site and Systemic Reactions (Diary-based Assessment).......................................... 31
9.1.12
Documentation of Subjects Failure before Enrollment in the Study ....................................... 34
9.1.13
Documentation of Enrollment in the Study............................................................................. 34
9.2
Vaccination Status in Subjects........................................................................................................ 34
9.3
Schedule of Observations and Procedures ..................................................................................... 34
9.3.1
<Screening Period/Day 1 (Starting before the Initial Vaccination and Ending after the 
Completion of the Initial Vaccination)> .................................................................................. 34
9.3.2
<Treatment Period/Day 1 (after the Initial Vaccination) to Day 22 (before Visiting the Study 
Site)> ....................................................................................................................................... 35
9.3.3
<Treatment Period/Day 22 (Starting before the Second Vaccination and Ending after the 
Completion of the Second Vaccination)>................................................................................ 36
9.3.4
<Treatment Period/Day 22 (after the Second Vaccination) to Day 43 (before Visiting the Study 
Site)> ....................................................................................................................................... 36
9.3.5
<Treatment Period/at the End of Study/Day 43> .................................................................... 36
9.3.6
<Treatment Period/at Discontinuation> .................................................................................. 37
9.4
Biological Sample Retention and Destruction ............................................................................... 37
9.5
Amount and Frequency of Blood Collection.................................................................................. 37
10.0
ADVERSE EVENTS............................................................................................................................ 38
10.1
Definitions...................................................................................................................................... 38
10.1.1
AEs.......................................................................................................................................... 38
10.1.2
Additional Points to Consider for AEs .................................................................................... 38
10.1.3
SAEs........................................................................................................................................ 39
10.1.4
AEs of Special Interest ............................................................................................................ 40
10.1.5
Severity of AEs........................................................................................................................ 40
10.1.6
Causality of AEs...................................................................................................................... 40

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10.1.7
Relationship to Study Procedures............................................................................................ 41
10.1.8
Start Date................................................................................................................................. 41
10.1.9
End Date.................................................................................................................................. 41
10.1.10 Pattern of Adverse Events ....................................................................................................... 41
10.1.11 Action Taken with Study Treatment........................................................................................ 41
10.1.12 Outcome of Event.................................................................................................................... 42
10.2
Procedures ...................................................................................................................................... 42
10.2.1
Collection and Reporting of AEs............................................................................................. 42
10.2.1.1 AE Collection Period...................................................................................................... 42
10.2.1.2 AE Reporting .................................................................................................................. 42
10.2.1.3 AEs of Special Interest Reporting ................................................................................. 43
10.2.2
Collection and Reporting of SAEs .......................................................................................... 43
10.3
Follow-up of SAEs......................................................................................................................... 43
10.3.1
Safety Reporting to Investigators, IRBs, and Regulatory Authorities..................................... 44
11.0
STUDY-SPECIFIC COMMITTEES..................................................................................................... 45
12.0
DATA HANDLING AND RECORDKEEPING................................................................................... 46
12.1
CRFs............................................................................................................................................... 46
12.2
Record Retention............................................................................................................................ 46
13.0
STATISTICAL METHODS.................................................................................................................. 48
13.1
Statistical and Analytical Plans ...................................................................................................... 48
13.1.1
Analysis Sets ........................................................................................................................... 48
13.1.2
Analysis of Demographics and Other Baseline Characteristics .............................................. 48
13.1.3
Immunogenicity Analysis........................................................................................................ 48
13.1.4
Safety Analysis ........................................................................................................................ 49
13.2
Interim Analysis and Criteria for Early Termination...................................................................... 50
13.3
Determination of Sample Size........................................................................................................ 50
14.0
QUALITY CONTROL AND QUALITY ASSURANCE..................................................................... 51
14.1
Study-Site Monitoring Visits.......................................................................................................... 51
14.2
Protocol Deviation.......................................................................................................................... 51
14.3
Quality Assurance Audits and Regulatory Agency Inspections ..................................................... 51
15.0
ETHICAL ASPECTS OF THE STUDY............................................................................................... 52
15.1
IRB Approval ................................................................................................................................. 52
15.2
Subject Information, Informed Consent, and Subject Authorization.............................................. 52
15.3
Subject Confidentiality................................................................................................................... 53
15.4
Publication, Disclosure, and Clinical Trial Registration Policy ..................................................... 53
15.4.1
Publication and Disclosure...................................................................................................... 53
15.4.2
Clinical Trial Registration ....................................................................................................... 53
15.4.3
Clinical Trial Results Disclosure............................................................................................. 54
15.5
Insurance and Compensation for Injury ......................................................................................... 54
16.0
REFERENCES...................................................................................................................................... 55
APPENDIX A
SCHEDULE OF STUDY PROCEDURES ...................................................................... 56

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APPENDIX B
RESPONSIBILITIES OF THE INVESTIGATOR........................................................... 58
APPENDIX C
DETAILS OF AMENDMENTS....................................................................................... 59

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LIST OF IN-TEXT TABLES
Table 7.a
Excluded Medications and Treatments.................................................................................... 23
Table 8.a
Components and Dose Strength of BLB-750 Injection 0.5 mL .............................................. 26
Table 9.a
Amount and Frequency of Blood Collection........................................................................... 37
Table 10.a
Takeda Medically Significant AE List..................................................................................... 40
LIST OF IN-TEXT FIGURES
Figure 6.a
Schematic of Study Design...................................................................................................... 18
Figure 8.a
Labeling Sample of the Outer Box for the Study Drug........................................................... 27
LIST OF APPENDIXES
Appendix A
Schedule of Study Procedures ................................................................................................. 56
Appendix B
Responsibilities of the Investigator ......................................................................................... 58
Appendix C
Details of Amendments ........................................................................................................... 59

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2.0
STUDY SUMMARY
Clinical Study Sponsor(s):
Takeda Pharmaceutical Company Limited
Study Drug
BLB-750 (Cell-Culture Influenza Vaccine H5N1 
“Takeda” 1 mL)
Title of Protocol: A Phase 4, Open-label Study to Evaluate 
the Immunogenicity and Safety of Intramuscular Injections of 
BLB-750 in Healthy Adult Subjects
IIND Number: Not 
applicable
EudraCT Number: Not 
applicable
Study Number: BLB-750/CCT-901
Phase: 4 
Study Design:
This is a phase 4, Open-label study to evaluate the immunogenicity and safety of two intramuscular vaccinations 
with BLB-750 at a 3-week interval in healthy Japanese adults.
Participants considered eligible as subjects for the study during the eligibility assessment at a visit after providing 
informed consent will receive the initial intramuscular vaccination with the study drug BLB-750 (Day 1) and the 
second intramuscular vaccination with BLB-750 during the study visit at 21 days after the initial vaccination (Day 
22).
The study duration will be 43 days, starting on the day of initial vaccination (Day 1). Subjects will return to the 
study site 21 days after the initial vaccination (Day 22) and 21 days after the second vaccination (Day 43).
The total planned number of subjects to receive the study vaccination is 55.
Objectives:
To evaluate the immunogenicity and safety of two intramuscular vaccinations with BLB-750 in healthy Japanese 
adults
Study Population: Healthy Japanese adults (male or female)
Planned Number of Subjects:
BLB-750: 55 subjects
Planned Number of Study Sites:
1 institution
Dose Level(s):
Two doses of BLB-750 at 0.5 mL (HA antigen level of 7.5 µg) 
will be injected into the upper arm muscle (the deltoid muscle) 
at a 3-week interval.
As the manufacturing strain for BLB-750, the following 
attenuated strain (H5N1 influenza virus attenuated using 
reverse genetics technology) will be used:
●
Qinghai RG strain
[A/bar-headed goose/Qinghai/1A/2005(H5N1)
(SJRG-163222)]
Vaccination Route:
Intramuscular injection
Duration of Vaccination:
Two doses at a 3-week interval
Period of Evaluation:
43 days

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Inclusion Criteria
1.
In the opinion of the investigator, the subject is capable of understanding and complying with protocol 
requirements.
2.
The subject signs and dates a written, informed consent form prior to the initiation of any study procedures.
3.
The subject is a healthy Japanese adult man or woman.
4.
The subject is aged 20 to 49 years, inclusive, at the time of informed consent.
5.
A female subject of childbearing potential who is sexually active with a nonsterilized male partner agrees to 
use routinely adequate contraception from signing of informed consent throughout the duration of the study.
Exclusion Criteria
1.
The subject has received vaccination with any other investigational or study products within 4 months prior to 
vaccination with the study vaccine.
2.
The subject has a history of vaccination with an H5N1 influenza vaccine.
3.
The subject has a history of infection with H5N1 virus.
4.
The subject is at high risk of contracting H5N1 influenza infection (e.g., poultry workers).
5.
The subject is an immediate family member, study site employee, or is in a dependent relationship with a study 
site employee who is involved in conduct of this study (e.g., spouse, parent, child, sibling) or may consent
under duress.
6.
The subject has poorly controlled, clinically significant manifestations of neurological, cardiovascular, 
pulmonary, hepatic, renal, metabolic, gastrointestinal, urologic, endocrine, or other disorders, which may 
impact their ability to participate as subjects or may potentially confound the study results.
7.
The subject has a body temperature (oral) ≥37.5°C prior to vaccination with the study vaccine on Day 1.
8.
The subject has any medically diagnosed or suspected immune-deficiency condition.

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9.
The subject has an immunocompromising condition or disease, or is currently undergoing a form of treatment 
or was undergoing a form of treatment that can be expected to influence immune response within 30 days prior 
to vaccination with the study vaccine. 
Such treatments include, but are not limited to, systemic or high dose inhaled corticosteroids (>800 μg/day of 
beclomethasone dipropionate or equivalent; the use of inhaled and nasal steroids that do not exceed this level 
will be permitted), radiation treatment or other immunosuppressive or cytotoxic drugs.
10. The subject has received antipyretics within 4 hours prior to vaccination with the study vaccine.
11. The subject has a history of Guillain-Barré Syndrome, demyelinating disorders (including acute disseminated
encephalomyelitis [ADEM] and multiple sclerosis), or convulsions.
12. The subject has a functional or anatomic asplenia.
13. The subject has a rash, other dermatologic conditions or tattoos that may interfere with the evaluation of local 
reaction.
14. The subject has a past or present history of infection with the Hepatitis B Virus (HBV), Hepatitis C Virus 
(HCV) or Human Immunodeficiency Virus (HIV).
15. The subject has a known hypersensitivity to any component of BLB-750.
16. The subject has a history of severe allergic reactions or anaphylaxis.
17. The subject has a history of drug abuse (defined as any illicit drug use) or a history of alcohol dependence 
within 1 year prior to vaccination with the study vaccine or is unwilling to agree to abstain from excessive 
alcohol and drugs throughout the study.
18. The subject has received any blood product (e.g., blood transfusion or immunoglobulin) within 90 days prior to 
vaccination with the study vaccine.
19. The subject has received any live vaccine within 4 weeks (28 days) prior to vaccination with the study vaccine 
or any inactivated vaccine within 2 weeks (14 days) prior to vaccination with the study vaccine.
20. The subject is a pregnant or lactating woman or wishes to become pregnant before signing informed consent, 
during, or within 12 weeks after the last vaccination with the study vaccine or intends to donate ova during such 
time period
21. For males: The subject has donated whole blood ≥200 mL within 4 weeks (28 days) or ≥400 mL within 12 
weeks (84 days) prior to the first vaccination with the study vaccine.
For females: The subject has donated whole blood ≥200 mL within 4 weeks (28 days) or ≥400 mL within 16 
weeks (112 days) prior to the first vaccination with the study vaccine.
22. For males: The subject has donated whole blood ≥800 mL in total within 52 weeks (364 days) prior to the first 
vaccination with the study vaccine.
For females: The subject has donated whole blood ≥400 mL in total within 52 weeks (364 days) prior to the 
first vaccination with the study vaccine.
23. The subject has donated blood components within 2 weeks (14 days) prior to the first vaccination with the study 
vaccine.
24. In the opinion of the investigator, the subject is unlikely to comply with protocol requirements or is considered 
ineligible for any other reason.
25. The subject has thrombocytopenia or coagulopathy, or is currently receiving anticoagulant therapy or received 
anticoagulant therapy within 30 days prior to the first vaccination with the study vaccine.

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Main Criteria for Evaluation and Analyses:
[Primary Endpoints]
Immunogenicity:
●
Seroprotection rate as measured by SRH antibody titer (defined as the proportion of subjects with SRH antibody 
titer ≥25 mm2) for the vaccine strain at 21 days after the second vaccination
●
Seroconversion rate as measured by SRH antibody titer (defined as the proportion of subjects with a 50% or 
more increase in SRH antibody titer from baseline for those who have a baseline value >4 mm2 or SRH 
antibody titer ≥25 mm2 for those who have a baseline value ≤4 mm2) for the vaccine strain at 21 days after the 
second vaccination
●
Geometric mean fold increase (GMFI) in SRH antibody titer from baseline for the vaccine strain at 21 days after 
the second vaccination
[Secondary Endpoints]
Immunogenicity:
●
Seroprotection rate as measured by SRH antibody titer (defined as the proportion of subjects with SRH antibody 
titer ≥25 mm2) for the vaccine strain at 21 days after the initial vaccination
●
Seroconversion rate as measured by SRH antibody titer (defined as the proportion of subjects with a 50% or 
more increase in SRH antibody titer from baseline for those who have a baseline value >4 mm2 or SRH 
antibody titer ≥25 mm2 for those who have a baseline value ≤4 mm2) for the vaccine strain at 21 days after the 
initial vaccination
●
GMFI in SRH antibody titer from baseline for the vaccine strain at 21 days after the initial vaccination
●
Geometric mean titer (GMT) of SRH antibody titer for the vaccine strain at 21 days after each vaccination
Safety:
●
Solicited local and systemic adverse events (AEs) to be recorded in the subject diary
●
AEs
●
Vital signs
[Additional Endpoints]
Immunogenicity:
●
Seroprotection rate as measured by MN antibody titer (defined as the proportion of subjects with MN antibody 
titer ≥20) for the vaccine strain at 21 days after each vaccination
●
Seroconversion rate as measured by MN antibody titer (defined as the proportion of subjects with 4-fold or more 
increase in MN antibody titer from baseline) for the vaccine strain at 21 days after each vaccination
●
GMFI in MN antibody titer from baseline for the vaccine strain at 21 days after each vaccination
●
GMT of MN antibody titer for the vaccine strain at 21 days after each vaccination

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Statistical Considerations:
[Immunogenicity] Using the full analysis set (FAS), frequency tabulations of the SRH antibody titer and the 
seroprotection and seroconversion rates at 21 days after the second vaccination will be presented, and their point 
estimates and two-sided 95% confidence intervals will be calculated. For the GMFI in the SRH antibody titer at 21 
days after the second vaccination, summary statistics and geometric means with corresponding two-sided 95% 
confidence intervals of the fold increase in the SRH antibody titer from baseline will be calculated.
Two-sided 95% confidence intervals of the geometric means will be calculated by back-transforming the upper and 
lower limits of two-sided 95% confidence intervals of the log transformed mean values.
[Safety] Using the safety analysis set, the following analyses will be performed:
For injection site and systemic AEs to be collected in the diary, frequency tabulations, frequency tabulations by 
severity, and frequency tabulations by vaccination and by timing of onset will be presented.
Treatment-emergent adverse events (TEAEs) are defined as AEs observed after vaccination with the study drug.
For TEAEs, the following analyses will be performed: TEAEs will be coded using the MedDRA and be summarized 
by System Organ Class and Preferred Term.
●
Frequency tabulation of all TEAEs
●
Frequency tabulation of TEAEs considered “related” to the study drug
●
Frequency tabulation of all TEAEs by severity
●
Frequency tabulation of TEAEs considered “related” to the study drug by severity
●
Frequency tabulation of serious TEAEs
●
Frequency tabulation of all TEAEs by vaccination and by timing of onset
Rationales for the Determination of Sample Size:
The objective of this study is to evaluate the immunogenicity and safety of two intramuscular vaccinations with 
BLB-750 in healthy Japanese adults. Therefore, the sample size for this study was determined to be 55 subjects, as 
the number of subjects to be vaccinated, by reference to the “Guidelines for the Development of Prototype Vaccines 
in Preparedness for Pandemic Influenza.” There are no statistical rationales for the determination of this sample size.

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3.0
LIST OF ABBREVIATIONS
ADEM
acute disseminated encephalomyelitis
AE
adverse event
CRO
contract research organization
EDC
electronic data capture
FDA
Food and Drug Administration
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
GMT
geometric mean titer
HA
hemagglutinin
HBV
hepatitis B virus 
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HIV
human immunodeficiency virus 
ICH
International Conference on Harmonisation
MedDRA
Medical Dictionary for Regulatory Activities
MHRA
Medicines and Healthcare products Regulatory Agency
MN
microneutralization
PMDA
Pharmaceuticals and Medical Devices Agency
SAE
serious adverse event
SRH
single radial hemolysis
SUSARs
suspected unexpected serious adverse reactions
TEAE
treatment-emergent adverse event
WHO
World Health Organization

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4.0
INTRODUCTION
4.1
Background
In Japan’s National Action Plan for Pandemic Influenza and New Infectious Diseases [1], pandemic influenza is 
defined as “an influenza infectious disease in humans caused by newly emerging influenza virus as an etiological 
agent that acquires the ability of human-to-human transmission.” Especially, there are concerns that when the 
highly pathogenic avian influenza virus H5N1 newly acquires the ability of human-to-human transmission and 
causes pandemic influenza (H5N1), it can constitute an enormous health hazard due to its high mortality rate. At 
present, therapeutic strategies for the treatment of pandemic influenza (H5N1) may include administration of 
anti-influenza virus drugs, such as oseltamivir phosphate and zanamivir hydrate. However, fatality due to acquired 
drug resistance during the treatment with oseltamivir phosphate has been suggested [2], which warrants the 
consideration of potential emergence of resistant virus strains before the use of anti-influenza virus drugs. In 
August 2004, a report by a subcommittee for the review of measures against pandemic influenza of the Section of 
Infectious Diseases, Health Sciences Council of the Ministry of Health, Labour and Welfare (MHLW) was 
prepared, in which the development, production, and stabilization of the supply of pandemic influenza vaccines are 
listed as primary aspects of measures against pandemic influenza.
Takeda Pharmaceutical Company Limited and 
 co-developed a vaccine indicated for “the prevention 
of pandemic influenza (H5N1)”, and approval for the manufacture and marketing of Cell-Culture Influenza 
Vaccines H5N1 “
” and “Takeda” 5 mL was obtained June 2013 (approval withdrawn in September 2016). In 
March 2014, Takeda Pharmaceutical Company Limited obtained approval for the manufacture and marketing of 
Cell-Culture Influenza Vaccine H5N1 “Takeda” 1 mL. BLB-750 is an influenza vaccine containing inactivated 
whole influenza virions as an active ingredient. It is produced by inactivating influenza (H5N1 subtype) viruses that 
infected and replicated in cultured cells using formaldehyde treatment and ultraviolet irradiation.
4.1.1
Benefit/Risk Profile
Currently there is no established treatment available for pandemic influenza (H5N1), and viral drug resistance 
associated with the use of anti-influenza virus drugs has been reported. Therefore, it is considered extremely 
important to prevent the development or aggravation of influenza infectious diseases through vaccination. BLB-750 
has been shown to be effective for the prevention of the development of influenza infectious diseases in mice and 
ferrets. In addition, clinical study results show that the vaccine is immunogenic. Based on these findings, it is 
expected that vaccination with BLB-750 will be useful for the prevention of the development or aggravation of 
pandemic influenza (H5N1).
BLB-750 may also be suitable as a vaccine prepared for a pandemic possibly caused by the H5N1 subtype for the 
following reasons: cell culture technology is applied for the manufacturing of the vaccine, which requires less time 
for vaccine production than other vaccines manufactured using chicken egg culture method; the manufacturing of 
BLB-750 is not affected by the availability of chicken eggs; and BLB-750 can be used in those who are allergic to 
hen’s egg.
Frequently observed adverse events of BLB-750 in clinical studies of the vaccine include transient pain, bleeding, 
and induration for injection site reactions, and headache, fatigue, malaise, hyperhidrosis, myalgia, chills, 
oropharyngeal pain, pyrexia, and arthralgia for systemic reactions, with no major issues in terms of the tolerability 
or safety. The safety profile of BLB-750 is similar to that of existing seasonal influenza vaccines, and there 
considered to be no specific risk associated with vaccination with BLB-750. Although results from clinical studies 
of BLB-750 indicate the immunogenicity of BLB-750, it may not be effective for the prevention of pandemic 
influenza (H5N1) in all subjects due to various factors, including differences in the immunoreactivity among 
vaccinated individuals and between prevalent virus strains and the vaccine strain.
PPD
CCI

BLB-750
Study No. CCT-901
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4.2
Rationale for the Proposed Study
As required by the MHLW, a strain attenuated using reverse genetics technology must be used as an H5N1 subtype 
virus strain for the production of pre-pandemic vaccine stockpiles as one of measures against pandemic influenza.
Clinical studies in Japanese adults for the purpose of the application for the approval of a cell-culture influenza 
vaccine (H5N1 strain) and clinical studies in the Japanese elderly and in children were conducted using a vaccine 
manufactured using a wild type strain as an H5N1 subtype virus strain, and there is no clinical experience with a 
vaccine manufactured using an attenuated strain.
Therefore, we planned a phase 4, open-label study to evaluate the immunogenicity and safety of two intramuscular 
vaccinations with BLB-750 at a 3-week interval in healthy Japanese adults, in which a cell-culture influenza 
vaccine (H5N1 strain) manufactured using an attenuated strain will be used..

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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
To evaluate the immunogenicity and safety of two intramuscular vaccinations with BLB-750 in healthy Japanese 
adults
5.2
Endpoints
5.2.1
Primary Endpoints
Immunogenicity:

Seroprotection rate as measured by SRH antibody titer (defined as the proportion of subjects with SRH 
antibody titer ≥25 mm2) for the vaccine strain at 21 days after the second vaccination

Seroconversion rate as measured by SRH antibody titer (defined as the proportion of subjects with a 50% or 
more increase in SRH antibody titer from baseline for those who have a baseline value >4 mm2 or SRH 
antibody titer ≥25 mm2 for those who have a baseline value ≤4 mm2) for the vaccine strain at 21 days after the 
second vaccination

Geometric mean fold increase (GMFI) in SRH antibody titer from baseline for the vaccine strain at 21 days 
after the second vaccination
5.2.2
Secondary Endpoints
Immunogenicity:

Seroprotection rate as measured by SRH antibody titer (defined as the proportion of subjects with SRH 
antibody titer ≥25 mm2) for the vaccine strain at 21 days after the initial vaccination

Seroconversion rate as measured by SRH antibody titer (defined as the proportion of subjects with a 50% or 
more increase in SRH antibody titer from baseline for those who have a baseline value >4 mm2 or SRH 
antibody titer ≥25 mm2 for those who have a baseline value ≤4 mm2) for the vaccine strain at 21 days after the 
initial vaccination

GMFI in SRH antibody titer from baseline for the vaccine strain at 21 days after the initial vaccination

Geometric mean titer (GMT) of SRH antibody titer for the vaccine strain at 21 days after each vaccination
Safety:

Solicited local and systemic adverse events (AEs) to be recorded in the subject diary

AEs

Vital signs
5.2.3
Additional Endpoints
Immunogenicity:

Seroprotection rate as measured by MN antibody titer (defined as the proportion of subjects with MN antibody 
titer ≥20) for the vaccine strain at 21 days after each vaccination

Seroconversion rate as measured by MN antibody titer (defined as the proportion of subjects with 4-fold or 
more increase in MN antibody titer from baseline) for the vaccine strain at 21 days after each vaccination

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
GMFI in MN antibody titer from baseline for the vaccine strain at 21 days after each vaccination

GMT of MN antibody titer for the vaccine strain at 21 days after each vaccination

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6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design
This is a phase 4, open-label study to evaluate the immunogenicity and safety of two intramuscular vaccinations 
with BLB-750 at a 3-week interval in healthy Japanese adults.
Subjects considered eligible after providing informed consent will receive the initial intramuscular vaccination with 
the study drug BLB-750 (Day 1) and the second intramuscular vaccination with BLB-750 during the study visit at 
21 days after the initial vaccination (Day 22).
The study duration will be 43 days, starting on the day of initial vaccination (Day 1). Subjects will return to the 
study site 21 days after the initial vaccination (Day 22) and 21 days after the second vaccination (Day 43).
The total planned number of subjects to receive the study vaccination is 55.
A schematic of the study design is shown in Figure 6.a
For the testing, observations, and assessment schedule, see Appendix A
Figure 6.a
Schematic of Study Design
6.2
Rationales for the Selection of Study Design, Vaccination Dosage, and Endpoints
6.2.1
Rationales for the Selection of Study Design
This study has been designed to evaluate the immunogenicity and safety of BLB-750 given intramuscularly in two 
doses at an interval of 3 weeks (open-label, uncontrolled study).
Clinical studies in Japanese adults for the purpose of the application for the approval of a cell-culture influenza 
vaccine (H5N1 strain) and clinical studies in the Japanese elderly and in children were conducted using a vaccine 
manufactured using a wild type strain as an H5N1 subtype virus strain. For this study, healthy adults were selected 
as a study population because the immunogenicity and safety of vaccination with a vaccine manufactured using an 
attenuated strain as an H5N1 subtype virus strain will be evaluated. For an age group for the study, a population 
Screening period
Treatment period
VISIT
Administration of the
study vaccine
Days from initial
vaccination
-28 to 1
Immunogenicity
evaluation
Informed
consent
Start of
vaccination
End of study
Emrollment
▲
▲
1
2
1
43
22
3
BLB-750 group
(6 weeks)

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aged between 20 and 49 years was selected as a 20 years and older age group, which was not considered to have a 
major difference in immunogenicity within the group.
6.2.2
Rationales for the Selection of Vaccination Dosage Regimen and Strain
The package insert [3] specifies the dosage regimen of the cell-culture influenza vaccine (H5N1 strain) as “usually 
two doses of 0.5 mL should be intramuscularly or subcutaneously injected with an at least 3-week interval,” and “as 
a general rule, intramuscular injection should be used as a vaccination route, with an exception in which 
subcutaneous injection may be selected based on the state of the subject”. Thus, in accordance with the approved 
dosage regimen, the dosage regimen of BLB-750 in this study was selected to be two doses of 0.5 mL of BLB-750 
with the HA content of 7.5 μg as an H5N1 subtype virus strain to be intramuscularly injected at a 3-week interval.
As described in Section 8.1.1.1, BLB-750 (Qinghai RG strain) was selected as the H5N1 subtype virus strain for 
BLB-750 to be used in this study.
6.2.3
Rationales for the Selection of Endpoints
Immunogenicity
To evaluate the immunogenicity against H5N1 subtype viruses of two intramuscular vaccinations of BLB-750, 
three endpoints as measured by the SRH antibody titer (seroprotection and seroconversion rates and geometric 
mean fold increase) specified as immunogenicity endpoints in the Guidelines for the Development of Prototype 
Vaccines in Preparedness for Pandemic Influenza [4] were selected as primary endpoints. Secondary endpoints 
included three endpoints as measured by the SRH antibody titer after the initial vaccination with BLB-750 
(seroprotection and seroconversion rates and geometric mean fold increase) and the GMT of the SRH antibody titer 
after each vaccination. Additional endpoints were also selected to perform the exploratory evaluation of the MN 
antibody titer considered sensitive and specific in the detection of functional/protective antibodies against avian 
influenza strains [5][6].
Safety
Based on common side effects of influenza vaccines and results of previously conducted overseas clinical studies 
(with BLB-750 given intramuscularly) and Japanese clinical studies (with BLB-750 given intramuscularly and 
subcutaneously), injection site reactions (injection site pain, erythema, swelling, induration, and bleeding) and 
systemic reactions (pyrexia, malaise, chills, fatigue, headache, sweaty, myalgia, and arthralgia) have been reported 
as expected adverse reactions to BLB-750 vaccination. Data on the occurrence of these events during the study 
period (especially within 7 days after vaccination) will be collected using a subject diary. As in previously 
conducted overseas and Japanese studies, the severity of pyrexia and injection site reactions will be assessed by 
reference to the “FDA Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials” [7] (see Section 9.1.11). As safety endpoints commonly used in 
clinical studies, adverse events and vital signs will also be evaluated.
6.3
Premature Termination or Suspension of Study or Study Site
6.3.1
Criteria for Premature Termination or Suspension of the Study
The study will be completed as planned unless 1 or more of the following criteria are satisfied that require 
temporary suspension or early termination of the study.
New information or other evaluation regarding the safety or efficacy of the study drug that indicates a change in the 
known risk/benefit profile for the product, such that the risk is no longer acceptable for subjects participating in the 
study.
Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve the primary study 
objectives or compromises subject safety.

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6.3.2
Criteria for Premature Termination or Suspension of Study Sites
A study site may be terminated prematurely or suspended if the site (including the investigator) is found in 
significant violation of GCP, protocol, or contractual agreement, is unable to ensure adequate performance of the 
study, or as otherwise permitted by the contractual agreement.
6.3.3
Procedures for Premature Termination or Suspension of the Study or the Participation 
of Study Site(s)
In the event that the sponsor, an institutional review board (IRB) or regulatory authority elects to terminate or 
suspend the study or the participation of a study site, a study-specific procedure for early termination or suspension 
will be provided by the sponsor; the procedure will be followed by applicable study sites during the course of 
termination or study suspension.

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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
All entry criteria, including test results, need to be confirmed prior to enrollment in the study.
7.1
Inclusion Criteria
Subject eligibility is determined according to the following criteria prior to entry into the study:
1.
In the opinion of the investigator, the subject is capable of understanding and complying with protocol 
requirements.
2.
The subject signs and dates a written, informed consent form prior to the initiation of any study procedures.
3.
The subject is a healthy Japanese adult man or woman.
4.
The subject is aged 20 to 49 years, inclusive, at the time of informed consent.
5.
A female subject of childbearing potential* who is sexually active with a nonsterilized* male partner agrees to 
use routinely adequate contraception from signing of informed consent throughout the duration of the study.
*Definitions and acceptable methods of contraception are defined in Section 9.1.8 and reporting 
responsibilities are defined in Section 9.1.9.
Rationale for the selection of inclusion criteria
Criteria 1 to 5 were selected as standard conditions for the selection of subjects participating in a clinical study in 
healthy adults. The upper limit of age was determined to be 49 years, which was not considered to make a major 
difference in immunogenicity within the 20-years-and-older age group.
7.2
Exclusion Criteria
Any subject who meets any of the following criteria will not qualify for entry into the study:
1.
The subject has received vaccination with any other investigational or study products within 4 months prior to 
vaccination with the study vaccine.
2.
The subject has a history of vaccination with an H5N1 influenza vaccine.
3.
The subject has a history of infection with H5N1 virus.
4.
The subject is at high risk of contracting H5N1 influenza infection (e.g., poultry workers).
5.
The subject is an immediate family member, study site employee, or is in a dependent relationship with a 
study site employee who is involved in conduct of this study (e.g., spouse, parent, child, sibling) or may 
consent under duress.
6.
The subject has poorly controlled, clinically significant manifestations of neurological, cardiovascular, 
pulmonary, hepatic, renal, metabolic, gastrointestinal, urologic, endocrine, or other disorders, which may 
impact their ability to participate as subjects or may potentially confound the study results.
7.
The subject has a body temperature (oral) ≥37.5°C prior to vaccination with the study vaccine on Day 1.
8.
The subject has any medically diagnosed or suspected immune-deficiency condition.
9.
The subject has an immunocompromising condition or disease, or is currently undergoing a form of treatment 
or was undergoing a form of treatment that can be expected to influence immune response within 30 days prior 
to vaccination with the study vaccine. 
Such treatments include, but are not limited to, systemic or high dose inhaled corticosteroids (>800 μg/day of 
beclomethasone dipropionate or equivalent; the use of inhaled and nasal steroids that do not exceed this level 
will be permitted), radiation treatment or other immunosuppressive or cytotoxic drugs.

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10. The subject has received antipyretics within 4 hours prior to vaccination with the study vaccine.
11. The subject has a history of Guillain-Barré Syndrome, demyelinating disorders (including acute disseminated 
encephalomyelitis [ADEM] and multiple sclerosis), or convulsions.
12. The subject has a functional or anatomic asplenia.
13. The subject has a rash, other dermatologic conditions or tattoos that may interfere with the evaluation of local 
reaction.
14. The subject has a past or present history of infection with the Hepatitis B Virus (HBV), Hepatitis C Virus 
(HCV) or Human Immunodeficiency Virus (HIV).
15. The subject has a known hypersensitivity to any component of BLB-750.
16. The subject has a history of severe allergic reactions or anaphylaxis.
17. The subject has a history of drug abuse (defined as any illicit drug use) or a history of alcohol dependence 
within 1 year prior to vaccination with the study vaccine or is unwilling to agree to abstain from excessive 
alcohol and drugs throughout the study.
18. The subject has received any blood product (e.g., blood transfusion or immunoglobulin) within 90 days prior 
to vaccination with the study vaccine.
19. The subject has received any live vaccine within 4 weeks (28 days) prior to vaccination with the study vaccine 
or any inactivated vaccine within 2 weeks (14 days) prior to vaccination with the study vaccine.
20. The subject is a pregnant or lactating woman or wishes to become pregnant before signing informed consent, 
during, or within 12 weeks after the last vaccination with the study vaccine or intends to donate ova during 
such time period
21. For males: The subject has donated whole blood ≥200 mL within 4 weeks (28 days) or ≥400 mL within 12 
weeks (84 days) prior to the first vaccination with the study vaccine.
For females: The subject has donated whole blood ≥200 mL within 4 weeks (28 days) or ≥400 mL within 16 
weeks (112 days) prior to the first vaccination with the study vaccine.
22. For males: The subject has donated whole blood ≥800 mL in total within 52 weeks (364 days) prior to the first 
vaccination with the study vaccine.
For females: The subject has donated whole blood ≥400 mL in total within 52 weeks (364 days) prior to the 
first vaccination with the study vaccine.
23. The subject has donated blood components within 2 weeks (14 days) prior to the first vaccination with the 
study vaccine.
24. In the opinion of the investigator, the subject is unlikely to comply with protocol requirements or is considered 
ineligible for any other reason.
25. The subject has thrombocytopenia or coagulopathy, or is currently receiving anticoagulant therapy or received
anticoagulant therapy within 30 days prior to the first vaccination with the study vaccine.
Rationale for the selection of exclusion criteria
Criterion 1 was selected, by reference to the “General Considerations for Clinical Trials” (PFSB/ELD Notification 
No. 380 dated April 21, 1998), to ensure the safety of subjects with the use of the period during which the previous 
study would not affect the present study.

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Criteria 2, 3, 4, 8, 9, 12, 18, and 19 were selected to eliminate the possible impact on influenza vaccine evaluation 
(primarily immunogenicity evaluation).
Criteria 5, 6, 14, 17, 20, and 24 were selected as standard conditions for the selection of subjects participating in a 
clinical study in healthy adults.
Criteria 7 and 13 were selected to eliminate the possible impact on influenza vaccine evaluation (primarily safety 
evaluation).
Criterion 10 was selected to eliminate the possible impact on influenza vaccine evaluation (safety and 
immunogenicity evaluation).
Criteria 11, 15, 16, 21, 22, 23, and 25 were selected to ensure the safety of subjects.
7.3
Excluded Medications and Treatments
The use of medications and therapies shown in Table 7.a will be prohibited from the point specified in the table to 
the end of study.
Table 7.a
Excluded Medications and Treatments
In the past
4 months prior to 
vaccination (Day 
1)
90 days prior to 
vaccination 
(Day 1)
30 days prior to 
vaccination (Day 1)
28 days prior 
to vaccination 
(Day 1)
14 days prior to 
vaccination (Day 
1)
• H5N1 
influenza 
vaccines
• Other study 
medications
• Blood 
products 
(transfusion or 
immunoglobu
lin)
• Systemic or high-dose 
inhaled corticosteroids 
(beclomethasone 
dipropionate >800 
μg/day or equivalent)
• Radiotherapy
•
Immunosuppressives
• Cytotoxic drugs
• Anticoagulant therapy
• Live 
vaccines
• Inactivated 
vaccines
The investigator will instruct subjects not to take any drug (including OTC drugs) other than those prescribed by 
the investigator without consulting with the investigator.
7.4
Diet, Fluid, Activity Control
1.
Diet
Subjects should be abstemious during the study period.
2.
Drinking
Excessive consumption of alcohol-containing beverages should be avoided during the study period.
3.
Smoking
Smoking will be prohibited from 1 hour prior to each assessment to the end of assessment.
4.
Exercise
Excessive exercise will be prohibited during the study period.

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5.
Blood donation after the end of study
Blood donation will be prohibited for at least 12 weeks after the completion of final assessment in this study. 
The investigator will provide subjects with counseling on the prohibition of blood donation.
6.
Others
The investigator will instruct subjects that if they visit another medical institution during the study period, they 
must inform the investigator of the reason for the visit and treatments given and must inform the institution of 
their participation in this study.
The investigator will also instruct subjects to keep the study drug injection site clean and to avoid scratching or 
rubbing the injection site without good reason.
For female subjects of childbearing potential who are sexually active with a nonsterilized male partner, the 
investigator will instruct them to use adequate contraception from the time of signing of informed consent, 
throughout the duration of the study, and for 12 weeks after the last vaccination with the study drug.
7.5
Criteria for Discontinuation or Withdrawal of a Subject
The primary reason for discontinuation or withdrawal of the subject from the study or study drug should be 
recorded in the case report form ([e]CRF) using the following categories. For subjects who discontinue/is 
withdrawn before enrollment in this study, see 9.1.12
1.
Death
The subject dies during the study. 
Note: If the subject dies on study, the event will be considered as a serious adverse event (SAE). See Section 
10.2.2 for the reporting procedures.
2.
Adverse event (AE)
The subject has experienced an AE that requires early termination because continued participation imposes an 
unacceptable risk to the subject’s health or the subject is unwilling to continue because of the AE.
3.
Protocol deviation
The discovery after enrollment that the subject failed to meet protocol entry criteria or did not adhere to 
protocol requirements, and continued participation poses an unacceptable risk to the subject’s health.
4.
Lost to follow-up
The subject did not return to the clinic and attempts to contact the subject were unsuccessful. Attempts to 
contact the subject must be documented in the subject’s source documents.
5.
Withdrawal by the subject
The subject wishes to be withdrawn from the study. The reason for withdrawal, if provided, should be 
recorded in the (e)CRF.
Note: All attempts should be made to determine the underlying reason for the withdrawal and, where possible, 
the primary underlying reason should be recorded. In the case of withdrawal due to an AE, however, 
consideration should be given to classifying it as “AE(s)” rather than as “voluntary withdrawal by the subject.”
6.
Study Terminated by sponsor. 
The sponsor terminates the study.
7.
Pregnancy
The subject is found to be pregnant.
Note: If the subject is found to be pregnant, the subject must be withdrawn from the study immediately. The 
procedure is described in Section 9.1.9.
8.
Other

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Note: The specific reasons should be recorded in the “specify” field of the (e)CRF.
7.6
Procedures for Discontinuation or Withdrawal of a Subject
The investigator may discontinue a subject’s study participation at any time during the study when the subject 
meets the study termination criteria described in Section 7.5 In addition, a subject may discontinue his or her 
participation without giving a reason at any time during the study. Should a subject’s participation be discontinued, 
the primary criterion for termination must be recorded by the investigator. In addition, efforts should be made to 
perform all procedures scheduled for the Early Termination Visit. Subjects who are withdrawn from the study after 
receiving vaccination with the study drug will not be replaced.

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8.0
CLINICAL TRIAL MATERIAL MANAGEMENT
This section contains information regarding all medication and materials provided directly by the sponsor, and/or 
sourced by other means, that are required by the study protocol, including important sections describing the 
management of clinical trial material.
8.1
Study Drug and Materials
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling
The study drug in this protocol is defined below.
8.1.1.1
Study Drug
1.
Dosage form and dose strength
Substance code: BLB-750
Trade name: Cell-Culture Influenza Vaccine H5N1 “Takeda” 1 mL
Manufacturer: Takeda Pharmaceutical Company Limited
Dosage form: A clear to whitish liquid injection (vial)
Components and dose strength: One vaccination dosage of 0.5 mL contains components shown in Table 8.a.
Table 8.a
Components and Dose Strength of BLB-750 Injection 0.5 mL
Component
Dose strength
Function
Active ingredient
(vaccine strain)
BLB-750 Qinghai RG strain
[A/bar-headed goose/Qinghai/1A/2005
(H5N1) (SJRG-163222)]
7.5 µg
-
Inactive 
ingredient
Trometamol
1.2 mg
Buffer
Sodium chloride
4.0 mg
Isotonicifier
Polysorbate 80
0.63 mg
Aggregation 
preventer
2.
Packaging and labeling
Two vials of the study drug will be packaged in a box labeled with the following information.

BLB-750
Study No. CCT-901
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<front side of the box>
Figure 8.a
Labeling Sample of the Outer Box for the Study Drug
8.1.1.2
Ancillary Materials
The syringe and injection needle designated by the sponsor should be used for vaccination with the study drug.
8.1.2
Storage
The study drug should be stored at 2°C to 8°C but not frozen, and be protected from light.
The site designee must keep the study drug in an appropriate, limited-access, secure place until it is used or 
returned to the sponsor or designee (CRO). All drugs supplied by the sponsor must be stored under the conditions 
specified on the label. A daily temperature log of the drug storage area must be maintained every working day.
8.1.3
Dose and Regimen
According to the following procedures, two doses of the study drug 0.5 mL will be injected into the brachial muscle 
(deltoid muscle) on Days 1 and 22.

Let the study drug (vial) warm to room temperature.

Prior to administration, shake the vial for 5-10 seconds to mix the vaccine suspension completely.

Prior to administration, visually inspect for any insoluble particulate matter or discoloration. The study drug 
should not be used if any insoluble particulate matter, discoloration, or leakage is observed.

Using a 1-inch long, 25-gauge needle, inject a dose of 0.5 mL into the arm opposite to the one used for blood 
collection to obtain a sample for immunogenicity testing wherever possible.

The following should be noted to avoid the effect of intramuscular vaccination on the tissues and nerves:

Injecting into a nerve tract should be avoided.

In the case of intense pain and/or backflow of blood associated with needle insertion, withdraw the needle 
immediately and inject into another site.
試験薬
2ﾊﾞｲｱﾙ
：
××××××
：
：
試験薬管理⼿順書に記載
：
2℃-8℃で凍結を避けて遮光保存
BLB-750注射剤
(Protocol No.BLB-750/CCT-901)
被験者識別コード
製　造　番　号
使　⽤　期　限
貯　　     　法
室温に戻した後、使⽤時よく振り混ぜること
武⽥薬品⼯業株式会社
⼤阪市中央区道修町四丁⽬1番1号
1001-

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8.1.4
Overdose
An overdose is defined as a known deliberate or accidental vaccination with the study drug at a dose above that 
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 (e)CRF, 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 overdose will be documented on an AE 
page of the CRF(s) in accordance with 10.0 Adverse Events.
SAEs associated with overdose should be reported in accordance with the procedure outlined in 10.2.2.
In the event of drug overdose, the subject should be treated as appropriate by the investigator.
8.2
Study Drug Dispensing Procedures
Subjects will be vaccinated with the study drug according to the study schedule.
8.3
Accountability and Destruction of Sponsor-Supplied Drugs
The site designee will receive the procedures for handling, storage and management of study drugs 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, and collection 
of unused medications as well as their return to the sponsor or their destruction.
The site designee will immediately return unused supplies of the study drug to the sponsor after the study is closed 
at the site.

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9.0
STUDY PLAN
9.1
Study Procedures
The following sections describe the study procedures and data to be collected. For each procedure, subjects are to 
be assessed by the same investigator or site personnel whenever possible. The study schedule is provided in 
Appendix A.
9.1.1
Informed Consent Procedure
The requirements of the informed consent are described in Section 15.2. Informed consent must be obtained from 
each subject before any protocol-directed procedures are performed. A unique subject identification number 
(subject number) will be assigned to each subject at the time that informed consent is explained; this subject 
number will be used throughout the study; this subject number will be used throughout the study.
9.1.2
Demographics, Medical History, and Medication History Procedure
Demographic information to be obtained will include date of birth and sex.
For medical history, clinically significant diseases or symptoms that have healed or resolved within 1 year prior to 
the first vaccination with study drug will be collected. Ongoing conditions are considered present illnesses (see 
Section 9.1.7). History of influenza infection within 1 year prior to the first vaccination with study drug will be 
collected.
Prior treatments to be collected include all drugs discontinued within 4 weeks prior to informed consent. In addition, 
history of influenza vaccination (including pandemic influenza vaccines and other investigational products) within 
1 year prior to informed consent will be collected.
9.1.3
Physical Examination Procedure
A baseline physical examination at baseline (defined as the assessment prior to the first vaccination with study 
drug), will consist of the following body systems:
(1) eyes; (2) ears, nose; and throat; (3) cardiovascular system; (4) respiratory system; (5) gastrointestinal system; 
(6) dermatologic system; (7) extremities; (8) musculoskeletal system; (9) nervous system; (10) lymph nodes; and 
(11) other.
During physical examination after each vaccination with the study drug, the subject will be assessed for any 
abnormalities considered clinically significant in comparison with pre-vaccination physical findings. During study 
visits at Days 22 and 43 and at discontinuation, the subject will be assessed for any pyrexia, systemic and injection 
site reactions, and other events based on the subject diary (see Section 9.1.11).
9.1.4
Weight and Height
A subject should have weight and height measured while wearing indoor clothing on and shoes off. The Takeda 
standard for collecting height is centimeters without decimal places (rounded to the nearest whole number) and for 
weight it is kilograms (kg) with 1 decimal place (rounded to one decimal place).
Example: Height = 176 cm, weight = 79.2 kg
9.1.5
Vital Signs Procedure
Vital signs will include body temperature (oral), respiratory rate, sitting blood pressure (resting more than 
5-minutes), and pulse (beats per minute). No respiratory rate measurement will be required at Day 43 and at 
discontinuation.

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If blood sampling and vital sign measurement are to be performed at the same point, vital sign measurement should 
be performed first.
The subject must measure his/her temperature and record it in the subject diary every day on Days 1-7 and 22-28 
and as needed on Days 8-22 (before study visit) and 29-43 (before study visit) (see Section 9.1.11). Daily 
measurements on Days 1-7 and 22-28 should be transcribed to the (e)CRF.
9.1.6
Documentation of 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. Concomitant medication is not provided by Takeda. 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 through the end of the study), and all medication including vitamin supplements, over-the-counter 
medications, and oral herbal preparations, must be recorded in the (e)CRF.
9.1.7
History of Present Illness
A present illness refers to any clinically significant disease or symptom existing at the first vaccination with study 
drug. All clinically significant laboratory values and abnormal findings observed during examination prior to 
vaccination with the study drug should be regarded as present illnesses. The details of present illnesses (diagnoses) 
should be recorded.
9.1.8
Contraception and Pregnancy Avoidance Procedure
From signing of informed consent, throughout the duration of the study, and for 12 weeks after last dose of study 
drug, female subjects of childbearing potential* who are sexually active with a nonsterilized male partner** must 
use adequate contraception. In addition they must be advised not to donate ova during this period.
*A woman is considered a woman of childbearing potential (WOCBP), i.e. fertile, following menarche and 
until becoming post-menopausal unless permanently sterile. Permanent sterilization methods include 
hysterectomy, and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months 
without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal 
range (FSH >40 IU/L) may be used to confirm a post-menopausal state in younger women (e.g. those < 45 
year old) or women who are not using hormonal contraception or hormonal replacement therapy. However, in 
the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.
**Sterilized males should be at least 1 year post vasectomy and have confirmed that they have obtained 
documentation of the absence of sperm in the ejaculate or have had bilateral orchidectomy.
Such subjects will be provided with information on acceptable methods of contraception as part of the subject 
informed consent process, and will be asked to sign a consent form stating that they understand the requirements 
for avoidance of pregnancy during the course of the study. 
During the course of the study, regular urine human chorionic gonadotropin (hCG) 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 study procedures Appendix A In addition to a urine hCG pregnancy test 
before vaccination on the day of vaccination with the study drug (Day 1), the result of urine hCG test at the end of 
study (or discontinuation) (Day 43) must be confirmed negative.

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In this study, the only acceptable methods of contraception are:
Barrier methods (each time 
the subject has intercourse):
Intrauterine devices (IUDs):
Hormonal 
contraceptives:
Male condom PLUS 
spermicide.
Copper T PLUS condom.
Progesterone T PLUS condom.
Combined pill. 
9.1.9
Pregnancy
If any subject is found to be pregnant during the study she should be withdrawn and any sponsor-supplied drug 
should be immediately discontinued.
If the pregnancy occurs during administration of active study drug, eg, after Day 1 or within 12 weeks of the last 
dose of active study drug, the pregnancy should be reported immediately, using a pregnancy notification form, to 
the contact listed on the attached sheet.
If the female subject agrees to the primary care physician (obstetrician) being informed, the investigator should 
notify the primary care physician that the subject was participating in a clinical study at the time she became 
pregnant and provide details of treatment the subject received.
All pregnancies in subjects on active study drug including comparator will be followed up to final outcome, using 
the pregnancy form. Pregnancies will remain blinded to the study team. The outcome, including any premature 
termination, must be reported to the sponsor. An evaluation after the birth of the child will also be conducted.
9.1.10 Immunogenicity Evaluation
The SRH and MN antibody titers against influenza virus for immunogenicity evaluation will be measured by the 
laboratory specified in the procedures. As for blood sampling, 20 mL of blood per sampling will be collected from 
the forearm vein. The blood sample collected will be used for study-specific endpoint measurements as well as 
immunogenicity evaluation by a government organization, and also may be used for other exploratory 
immunogenicity evaluations (see Section 9.4). No genetic testing will be performed using the samples collected in 
this study.
For the immunogenicity evaluation by a government organization, the protocol and the result report will be 
prepared by the sponsor or the government organization, separately from the protocol and clinical study report for 
this study. If other exploratory immunogenicity evaluations are performed, their protocols and result reports should 
also be prepared.
Detailed procedures for handling and transporting samples are found in separately prepared documented procedures 
for handling of biological samples for immunogenicity evaluation.
9.1.11 Injection Site and Systemic Reactions (Diary-based Assessment)
As AEs related to reactogenicity of vaccination with the study drug, injection site reactions (injection site pain, 
erythema, swelling, induration, and haemorrhage, hereinafter the same applies) and systemic reactions (pyrexia, 
malaise, chills, fatigue, headache, sweaty, myalgia, and arthralgia, hereinafter the same applies) occurring between 
the initial vaccination with study drug and 42 days after the vaccination (Day 43) will be collected via the subject 
diary.
Injection site and systemic AEs occurring within 21 days after each vaccination (Days 22 and 43) will be collected 
via the subject diary (Diary 1 for Days 1-7, Diary 2 for Days 8-22, Diary 3 for Days 22-28, and Diary 4 for Days 
29-43).

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Diaries 1 and 2 will be provided to each subject together with a digital thermometer for oral temperature 
measurement and a ruler for injection site reaction measurement after vaccination with the study drug on Day 1. 
These diaries will be collected and reviewed by the investigator at Day 22 visit.
Information to be recorded in Diary 1 (Days 1-7)

Body temperatures (oral) measured once daily in the evening during the period after vaccination with the study 
drug (Day 1) until Day 7

Injection site reactions

Systemic reactions

Other AEs
Information to be recorded in Diary 2 (Days 8-22)

Body temperatures (oral) measured when the subject experiences any AE with pyrexia during the period after 
Day 8 until Day 22 before study visit

Other AEs
Diaries 3 and 4 will be provided to each subject at Day 22 visit (or at Day 1 visit) and will be collected and 
reviewed by the investigator at Day 43 visit.
Information to be recorded in Diary 3 (Days 22-28) [same as information to be recorded in Diary 1]

Body temperatures (oral) measured once daily in the evening during the period after vaccination with the study 
drug (Day 22) until Day 28

Injection site reactions

Systemic reactions

Other AEs
Information to be recorded in Diary 4 (Days 29-43) [same as information to be recorded in Diary 2]

Body temperatures (oral) measured when the subject experiences any AE with pyrexia during the period after 
Day 29 until Day 43 before study visit

Other AEs
For recording of body temperatures (oral) and injection site reactions in the diary, each subject will be asked to 
follow the instructions below.
<Body temperature (oral) measurement>

Diary 1 (Days 1-7) and Diary 3 (Days 22-28): Subjects will measure their oral temperatures once daily, in the 
evening wherever possible, using the oral digital thermometer provided for the study. Subjects will be asked to 
keep to the same measurement time every day whenever possible. In the case of pyrexia (defined as oral 
temperature ≥38.0°C), oral temperatures should be measured more than once (approximately every 4-8 hours) 
wherever possible and recorded in Diary 1 or 3 until the pyrexia resolves (defined as oral temperature <38.0°C). 
Subjects will record all measurement information (i.e., measurement results and date and time of measurement) 
obtained on Days 1-7 and Days 22-28 in Diary 1 and 3, respectively.

Diary 2 (Days 8-22 [before study visit]) and Diary 4 (Days 29-43 [before study visit]): Daily measurement will 
not be required. Measurements should be obtained using the oral digital thermometer provided for the study 
only when any symptom suggestive of pyrexia is noted. In the case of pyrexia (defined as oral temperature 
≥38.0°C), the subject should measure his/her oral temperature at least once daily, or more than once 

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(approximately every 4-8 hours) wherever possible, and record it in Diary 2 or 4 until the pyrexia resolves 
(defined as oral temperature <38.0°C) to confirm the end date. Subjects will record measurement information 
(i.e., measurement results and date and time of measurement) obtained on Days 8-22 (before study visit) and 
Days 29-43 (before study visit) in Diary 2 and 4, respectively.
<Injection site reactions>

Diary 1 (Days 1-7) and Diary 3 (Days 22-28): If, among injection site reactions, erythema, swelling, or 
induration is observed after vaccination with the study drug, the subject should measure the longest diameter of 
the injection site reaction using the ruler provided for the study and record it in Diary 1 or 3.

Diary 2 (Days 8-22 [before study visit]) and Diary 4 (Days 29-43 [before study visit]): All newly observed 
injection site reactions and all other injection site reactions observed any time during Days 1-7 or Days 22-28 
but that have not resolved during these periods should be recorded in Diary 2 or 4. The longest diameter should 
also be measured and recorded.
Based on records from each subject’s diary collected at Day 22 and 43 visits, the investigator will capture all AEs 
occurring during Days 1-22 and Days 22-43, and record these AEs on the (e)CRF together with the severity and 
causality assessment for each event.
As for pyrexia, the start date is defined as the date on which the first oral temperature measurement ≥38.0°C is 
obtained, and the end date is defined as the date on which the first oral temperature measurement <38.0°C is 
obtained after the onset. Daily oral temperature measurements on Days 1-7 and Days 22-28 recorded in Diaries 1 
and 3 should be transcribed to the (e)CRF even if they are <38.0°C. If two or more temperature measurements are 
recorded for the same day, the highest temperature of that day should be transcribed to the (e)CRF.
The severity of pyrexia and injection site reactions will be assessed using the criteria shown below, by reference to 
the “FDA Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Clinical Trials”[7] For other AEs (including solicited systemic reactions to be recorded in the 
subject diary), assessment will be performed as specified in Section 10.1.5.
Pyrexia:
Mild: ≥38.0°C and <38.5°C
Moderate: ≥38.5°C and <39.0°C
Severe: ≥39.0°C
Measurable injection site reactions (injection site erythema, swelling, and induration): 
Mild: ≥2.5 cm and <5.1 cm
Moderate: ≥5.1 cm and <10.1 cm
Severe: ≥10.1 cm
*Injection site reactions <2.5 cm will not be regarded as AEs. However, the longest diameter recorded in the diary 
will be transcribed to the (e)CRF separately from AEs, regardless of whether it is ≥2.5 cm or <2.5 cm.
Injection site pain and haemorrhage:
Mild: No interference with upper extremity movement
Moderate: Interference with upper extremity movement present.
Severe: Upper extremity impairment/dysfunction

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9.1.12
Documentation of Subjects Failure before Enrollment in the Study
The investigator accounts for all subjects who sign informed consent.
If the subject is found to be not eligible before the start of vaccination with the study drug, the investigator should 
complete the (e)CRF.
The primary reason for subjects failure before the start of vaccination with the study drug is recorded in the (e)CRF 
using the following categories:

Death

Adverse Event

Screen failure (failed inclusion criteria or did meet exclusion criteria)

Protocol deviation

Lost to follow-up

Withdrawal by subject <specify reason>

Study terminated by sponsor

Pregnancy

Sample size sufficient

Other <specify reason>
Subject numbers assigned to subjects who fail screening should not be reused.
9.1.13 Documentation of Enrollment in the Study
Subjects will be enrolled in the study and receive vaccination with the study drug only if they meet all the inclusion 
criteria and do not meet any of the exclusion criteria.
For subjects who did not receive vaccination with the study drug, the investigator should record the primary reason 
for failure on the applicable (e)CRF.
9.2
Vaccination Status in Subjects
The study vaccine will be administered under observation at the study site. The investigator will observe the 
subjects for any abnormalities for at least 30 minutes after vaccination with the study drug at the study site. The 
date of vaccination will be recorded in the subjects' source documents and (e)CRFs. The inventory of the study 
drugs dispensed will be controlled and recorded in the investigational product accountability log or equivalent 
document by a study site pharmacist or a person designated by the investigator.
9.3
Schedule of Observations and Procedures
The schedule for all testing, observation, and assessments is provided in Appendix A. The following testing, 
observation, and assessments should be completed at the designated time points.
9.3.1
<Screening Period/Day 1 (Starting before the Initial Vaccination and Ending after the 
Completion of the Initial Vaccination)>
Enrollment in the study will be performed on Day 1, and the following testing, observation, and assessments will be 
performed: Subjects will be screened in accordance with predefined inclusion and exclusion criteria as described in 
Section 7.0.

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
Informed consent

Demographics, medical history, and medication history procedure

Physical examination

Vital signs (body temperature [oral], blood pressure, and pulse and respiratory rates)

Weight and height

Documentation of concomitant medications

Present illness

Pregnancy test (only for female subjects of childbearing potential)

Blood sampling for the immunogenicity evaluation
Subjects meeting all the inclusion criteria and not meeting any of the exclusion criteria will be enrolled in the study. 
Subjects will receive vaccination with the study drug under the supervision of the investigator at the study site. For 
the procedures for the recording of subjects withdrawn from the study prior to the start of vaccination with the 
study drug, see Section 9.1.12.
9.3.2
<Treatment Period/Day 1 (after the Initial Vaccination) to Day 22 (before Visiting the 
Study Site)>
During the period from Day 1 (after the initial vaccination) to Day 22 (before visiting the study site), the following 
testing, observation, and assessments will be performed: Day 1 (the day of initial vaccination) will be the day of 
study visit, and subjects will monitor themselves at home during the period after the completion of Day 1 visit until 
before Day 22 visit (see Section 9.1.11).

Physical Examination
Time point: Day 1 (after the initial vaccination)
The investigator will monitor for any acute hypersensitivity reaction, etc., for 30 minutes after vaccination.

Vital signs (blood pressure and pulse and respiratory rates)
Time point: Day 1 (after the initial vaccination)
Vital signs will be measured 30 minutes after vaccination.

Vital signs (body temperature [oral])
From Days 1 to 7, subjects will measure their body temperature (oral) and record it in the subject diary. 
From Days 8 to 22 (before visiting the study site), subjects will measure their body temperature (oral) only 
if they develop pyrexia (or any symptoms suggestive of pyrexia) (see Section 9.1.11).

Supply of the subject diary
Time point: Day 1 (Diaries 1 and 2) (Diaries 3 and 4 may be supplied on Day 1)

Completion of the subject diary (by subjects)
Time points: From Day 1 (after the initial vaccination) to Day 7 (Diary 1) and from Day 8 to Day 22 
(before visiting the study site) (Diary 2)
During the periods from Day 1 (after the completion of study visit) to Day 7 and from Day 8 to Day 22 (before 
visiting the study site), subjects will monitor for and record any systemic reactions, injection site reactions, etc. (see 
Section 9.1.11).

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9.3.3
<Treatment Period/Day 22 (Starting before the Second Vaccination and Ending after 
the Completion of the Second Vaccination)>
The following tests, observations, and assessments will be performed on Day 22 (starting before the second 
vaccination and ending after the completion of the second vaccination).

Physical Examination

Vital signs (body temperature [oral], blood pressure, and pulse and respiratory rates)

Collection of concomitant medications and AEs

Blood sampling for the immunogenicity evaluation

Collection of the subject diary (Diaries 1 and 2)
Subjects will receive vaccination with the study drug under the supervision of the investigator at the study site.
9.3.4
<Treatment Period/Day 22 (after the Second Vaccination) to Day 43 (before Visiting the 
Study Site)>
During the period from Day 22 (after the second vaccination) to Day 43 (before visiting the study site), the 
following testing, observation, and assessments will be performed: Subjects will monitor themselves at home 
during the period after the completion of Day 22 visit until before Day 43 visit (see Section 9.1.11).

Physical Examination
Time point: Day 22 (after vaccination)
The investigator will monitor for any acute hypersensitivity reaction, etc., for 30 minutes after vaccination.

Vital signs (blood pressure and pulse and respiratory rates)
Time point: Day 22 (after vaccination)
Vital signs will be measured 30 minutes after vaccination.

Vital signs (body temperature [oral])
Form Days 22 to 28, subjects will measure their body temperature (oral) and record it in the subject diary. 
Form Days 29 to 43 (before visiting the study site), subjects will measure their body temperature (oral) 
only if they develop pyrexia (or any symptoms suggestive of pyrexia) (see Section 9.1.11).

Supply of the subject diary
Time point: Day 22 (Diaries 3 and 4) (Diaries 3 and 4 may be supplied on Day 1)

Completion of the subject diary (by subjects)
Time point: From Day 22 (after vaccination) to Day 28 (Diary 3) and from Day 29 to Day 43 (before 
visiting the study site) (Diary 4)
During the periods from Day 22 (after the completion of study visit) to Day 28 and from Day 29 to Day 43 (before 
visiting the study site), subjects will monitor for and record any systemic reactions, injection site reactions, etc. (see 
Section 9.1.11).
9.3.5
<Treatment Period/at the End of Study/Day 43>
The following testing, observation, and assessments will be performed at the final study visit (for observation) (Day 
43).

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
Physical Examination

Vital signs (body temperature [oral], blood pressure, and pulse rate)

Pregnancy test (only for female subjects of childbearing potential)

Blood sampling for the immunogenicity evaluation

Collection of the subject diary (Diaries 3 and 4)

Collection of concomitant medications and AEs
For all subjects receiving the study drug, the investigator must complete the Subject Status (e)CRF page.
9.3.6
<Treatment Period/at Discontinuation>
For subjects withdrawn from the study, reasons for study discontinuation must be recorded in the subject’s source 
documents and CRF, and the following testing, observation, and assessments should be performed wherever 
possible.

Physical Examination

Vital signs (body temperature [oral], blood pressure, and pulse rate)

Pregnancy test (only for female subjects of childbearing potential)

Blood sampling for the immunogenicity evaluation

Collection of the subject diary

Collection of concomitant medications and AEs
For all subjects receiving the study drug, the investigator must complete the Subject Status (e)CRF page.
9.4
Biological Sample Retention and Destruction
The remainder of serum samples collected in accordance with Section 9.1.10, “Immunogenicity Evaluation” will be 
stored. Serum samples will be discarded after they will no longer be used. Details on sample retention will be 
provided in separately prepared handling procedures.
9.5
Amount and Frequency of Blood Collection
The total amount of blood to be collected from each subject will be as shown in Table 9.a.
Table 9.a
Amount and Frequency of Blood Collection
Test
Amount to be 
collected per 
collection
Frequency of 
collection
Total amount to be 
collected
Immunogenicity testing
20 mL 
Three times
60 mL
Total amount to be collected
60 mL

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10.0
ADVERSE EVENTS
10.1
Definitions
10.1.1 AEs
An AE is defined as any untoward medical occurrence in a clinical investigation subject who has signed informed 
consent to participate in a study; it does not necessarily have to have a causal relationship with this treatment or 
study participation.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal laboratory 
finding), symptom, or disease temporally associated with the study participation whether or not it is considered 
related to the drug or study procedures.
10.1.2 Additional Points to Consider for AEs
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent events for 
pre-existing conditions or underlying diseases should not be considered AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or dose adjustment of the study drug or a concomitant medication.

Be considered unfavorable by the investigator for any reason.
AEs caused by a study procedure (e.g., a bruise after blood draw) should be recorded as an AE.
Diagnoses vs signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs (including abnormal 
laboratory values or ECG findings) or symptoms should NOT be recorded as additional AEs. However, each 
solicited local or systemic AE to be recorded in the subject diary should be recorded as a single event. If a 
diagnosis is unknown, sign(s) or symptom(s) should be recorded appropriately as an AE(s).
Pre-existing conditions:

Pre-existing conditions (present since before the first vaccination with study drug) are considered present 
illnesses and should NOT be recorded as AEs. However, if the present illness worsens after the first 
vaccination with study drug, it should be appropriately recorded as an AE. The investigator should ensure that 
the AE term to be reported reflects a change from baseline (e.g., “worsening of…”).

If a subject has a pre-existing episodic condition (eg, asthma, epilepsy) any occurrence of an episode should 
only be captured as an AE if the episodes become more frequent, serious or severe in nature, that is, 
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 captured as an AE if occurring to a greater extent to that which would be 
expected. Again, investigators should ensure that the AE term recorded captures the change in the condition 
(eg, “worsening of…”).
Change in severity of AEs:

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
If the subject experiences a change in severity of an AE that is not related to starting the study drug or 
changing in the dose or regimen, the event should be captured once with the maximum severity recorded.
Preplanned surgeries or procedures:

Preplanned procedures (surgeries or therapies) that are scheduled prior to signing of informed consent are not 
considered AEs. However, if a preplanned procedure is performed early (e.g., as an emergency) due to a 
worsening of the pre-existing condition, the worsening of the condition should be captured appropriately as 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.
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:

The occurrence of overdose with no associated events should NOT be considered an AE, but instead will be 
documented on an Overdose page of the (e)CRF. Any event associated with overdose should be considered 
AEs and will be recorded on the AE page of the (e)CRF.
10.1.3 SAEs
An SAE is defined as any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product (including a study drug), which:
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.
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.
●
Includes any event or synonym described in the Takeda Medically Significant AE List (Table 10.a).

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Table 10.a
Takeda Medically Significant AE List
Term
Acute respiratory failure/acute respiratory distress 
syndrome
Torsade de pointes / ventricular fibrillation / ventricular 
tachycardia
Malignant hypertension
Convulsive seizure (including seizure and epilepsy)
Agranulocytosis
Aplastic anemia
Toxic epidermal necrolysis/Stevens-Johnson syndrome
Hepatic necrosis
Acute liver failure
Anaphylactic shock
Acute renal failure 
Pulmonary hypertension
Pulmonary fibrosis (including interstitial lung disease)
Confirmed or suspected endotoxin shock
Confirmed or suspected transmission of infectious agent 
by a medicinal product
Neuroleptic malignant syndrome / malignant 
hyperthermia
Spontaneous abortion / stillbirth and fetal death
Note: The terms listed in this table may be “important medical events” that require the reporting of SAEs and are 
therefore broadly defined medical terms.
7.
The following important medical events associated with the use of an influenza vaccine: neuritis, encephalitis, 
vasculitis, Guillain-Barre syndrome, Bell’s palsy (facial palsy), and demyelinating disorder (including acute 
disseminated encephalomyelitis [ADEM] and multiple sclerosis)
10.1.4 AEs of Special Interest
An AE of Special Interest (regardless of whether it is serious or not) is one of scientific and medical concern 
specific to the compound or program, for which ongoing monitoring and rapid communication by the investigator 
to Takeda may be appropriate. Such events may require further investigation in order to characterize and understand 
them.
10.1.5 Severity of AEs
The different categories of intensity are characterized as follows:
Mild:
The event is transient and easily tolerated by the subject.
Moderate:
The event causes the subject interrupts the subject’s usual activities.
Severe:
The event causes considerable interference with the subject’s usual activities.
However, pyrexia and injection site reactions (injection site pain, erythema, swelling, induration, and haemorrhage) 
should be assessed according to the classification specified in 9.1.11.
10.1.6 Causality of AEs
The relationship of each AE to study drug(s) will be assessed using the following categories:
Related:
An AE that follows a reasonable temporal sequence from administration of a drug (including the 
course after withdrawal of the drug), or for which possible involvement of the drug cannot be ruled 
out, although factors other than the drug, such as underlying diseases, present illness, concomitant 
medications and concurrent treatments, may also be responsible.
Not related:
An AE that does not follow a reasonable temporal sequence from administration of a drug and/or 
that can reasonably be explained by other factors, such as underlying diseases, present illness, 
concomitant medications and concurrent treatments.

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10.1.7 Relationship to Study Procedures
Relationship (causality) to study procedures should be determined for all AEs.
The relationship should be assessed as Related if the investigator considers that there is reasonable possibility that 
an event is due to a study procedure. Otherwise, the relationship should be assessed as Not Related. 
10.1.8 Start Date
The start date of the AE is the date that the first signs/symptoms were noted by the subject and/or investigator.
The start date of AEs will be determined using the following criteria;
AEs
Start Date
Any signs/symptoms/diseases (diagnosis)
The date that the first signs/symptoms 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 of present illnesses
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.
10.1.9 End Date
The end date of the AE is the date at which the subject recovered, the event resolved but with sequelae or the 
subject died.
10.1.10 Pattern of Adverse Events
Episodic AEs (eg, vomiting) or those which occur repeatedly over a period of consecutive days are intermittent. All 
other events are continuous.
10.1.11 Action Taken with Study Treatment
Actions concerning the study drug will be classified and defined as follows:
• Drug withdrawn
A study drug is stopped due to the particular AE.
• Dose not changed
The particular AE did not require stopping a study drug.
• Unknown
Only to be used if it has not been possible to determine what action has been taken.
• Not applicable
A study drug was stopped for a reason other than the particular AE eg, the study has been 
terminated, the subject died, vaccination with study drug was already stopped before the 
onset of the AE.

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10.1.12 Outcome of Event
• Recovered/resolved
Subject returned to first assessment status with respect to the AE.
• Recovering/resolving
The intensity is lowered by one or more stages:
The diagnosis or signs/symptoms has almost disappeared; 
The abnormal laboratory value improved, but has not returned to the normal range or 
to baseline; the subject died from a cause other than the particular AE with the 
condition remaining “recovering/resolving”.
• Not recovered/not 
resolved
There is no change in the diagnosis, signs or symptoms; 
The intensity of the diagnosis, signs/ symptoms or laboratory value on the last day of 
the observed study period has got worse than when it started; is an irreversible 
congenital anomaly; the subject died from another cause with the particular AE state 
remaining “Not recovered/not resolved”.
• Recovered/Resolved with 
sequelae
The subject recovered from an acute AE but was left with permanent/significant 
impairment (e.g, recovered from a cardiovascular accident but with some persisting 
paresis.
• Fatal
The AEs which are considered as the cause of death.
• Unknown
The course of the AE cannot be followed up due to hospital change or residence 
change at the end of the subject’s participation in the study.
10.2
Procedures
10.2.1 Collection and Reporting of AEs
10.2.1.1
AE Collection Period
The collection of AEs will be started at the initial vaccination with the study drug (Day 1) and continued until the 
end of study (Day 43).
10.2.1.2
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.
All subjects experiencing AEs after the first exposure to study drug, whether considered associated with the use of 
the study drug or not, must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to baseline or until there is a satisfactory explanation for the changes observed. All 
AEs will be documented in the AE page of the (e)CRF, whether or not the investigator concludes that the event is 
related to the drug treatment. The following information will be documented for each event:
1.
Event term
2.
Start and end date
3.
Pattern
4.
Severity
5.
Investigator’s opinion of the causality between the event and administration of study drug(s)
6.
Investigator’s opinion of the causality to study procedure(s), including the details of the suspected procedure

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7.
Action taken with study treatment
8.
Outcome of event
9.
Seriousness
10. Treatment emergent (After the first exposure to study drug)
11. For pyrexia, the maximum body temperature and the presence or absence of a 24-hour or longer persistence
12. For injection site erythema, swelling, and induration, the longest diameter
10.2.1.3
AEs of Special Interest Reporting
In this study, AEs of special interest will include the following AEs:
Hypersensitivity and anaphylaxis or any events suggestive of hypersensitivity
If this AE of special interest, which occurs during the treatment period or the follow-up period, is considered to be 
clinically significant, it should be reported to the sponsor (described in the separate contact information list) 
immediately or within 1 business day of first onset or subject’s notification of the event. The study-specific 
Solicited AE Form or SAE Form should be completed, signed and/or sealed by the principal investigator, and 
reported to appropriate personnel in the separate contact information list within 10 business days.
The AE of special interest have to be recorded as AEs in the (e)CRF. An evaluation form (the original copy of 
Solicited AE Form or SAE Form) along with all other required documentation must be submitted to the sponsor.
10.2.2 Collection and Reporting of SAEs
When an SAE occurs through the AE collection period it should be reported according to the following procedure:
An SAE should be reported to the sponsor (described in the separate contact information list) within 1 business day 
of first onset or subject’s notification of the event. The principal investigator should submit the completed SAE 
form 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

Subject identification number

Investigator’s name

Name of the study drug(s)

Causality assessment
Any SAE spontaneously reported to the investigator following the AE collection period should be reported to the 
sponsor if considered related to study participation.
The investigator should report any AEs to the sponsor and submit the form within the appropriate period as 
specified by the sponsor.
10.3
Follow-up of SAEs
If information not available at the time of the first report becomes available at a later date, the investigator should 
complete a follow-up SAE form or provide other written documentation and fax it immediately. Copies of any 
relevant data from the hospital notes (eg, ECGs, laboratory tests, discharge summary, postmortem results) should be 
sent to the addressee, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event.

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10.3.1 Safety Reporting to Investigators, IRBs, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions (SUSARs) and any 
other applicable SAEs to regulatory authorities investigators and IRBs /the head of the study site, as applicable in 
accordance with national regulations in the countries where the study is conducted. Relative to the first awareness 
of the event by/or further provision to the sponsor or sponsor’s designee, SUSARs will be submitted to the 
regulatory authorities as expedited report. The sponsor will also prepare an expedited report for other safety issues 
where these might materially alter the current benefit-risk assessment of a study drug or that would be sufficient to 
consider changes in the study drug administration or in the overall conduct of the trial. The study site also will 
forward a copy of all expedited reports to his or her IRB.

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11.0
STUDY-SPECIFIC COMMITTEES
No steering committee, data safety monitoring committee, or clinical endpoint committee will be used in this study.

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12.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management Plan. AEs and medical 
history including present illness will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
Drugs will be coded using the World Health Organization (WHO) Drug Dictionary.
12.1
CRFs
Completed (e)CRFs are required for each subject who signs an informed consent.
The sponsor or its designee will supply investigative sites with access to eCRFs. The sponsor will make 
arrangements to train appropriate site staff in the use of the eCRF. These forms are used to transmit the information 
collected in the performance of this study to the sponsor and regulatory authorities. (e)CRFs must be completed in 
English. Data are transcribed directly onto eCRFs.
Corrections are recorded in an audit trail that captures the old information, the new information, identification of 
the person making the correction, the date the correction was made, and the reason for change.
The principal investigator must review the (e)CRFs for completeness and accuracy and must sign the appropriate 
(e)CRFs as indicated. Furthermore, the investigator must retain full responsibility for the accuracy and authenticity 
of all data entered on the (e)CRFs.
The following data will be recorded directly into the (e)CRFs. However, this will not apply if the subject’s medical 
records contain the data.

Subject eligibility assessment

AE terms, the start and end dates, ongoing/not ongoing at the end of study, onset pattern, severity, causal 
relationship with the study procedures, causal relationship with the study drug, action taken with the study 
drug, outcome, and seriousness

The status of the subject in terms of vaccination with the study drug and the completion of the study

Reason for the use of concomitant medications and ongoing/not ongoing at the end of study
The following data will not be recorded on the (e)CRFs:

Immunogenicity testing results
After the lock of the clinical study database, any change of, modification of or addition to the data on the (e)CRFs 
should be made by the investigator with use of change and modification records of the Data Clarification Form 
provided by the sponsor. The principal investigator must review the data change for completeness and accuracy, 
and must sign, or sign and seal, and date.
(e)CRFs will be reviewed for completeness and acceptability at the study site during periodic visits by study 
monitors. The sponsor or its designee will be permitted to review the subject’s medical and hospital records 
pertinent to the study to ensure accuracy of the (e)CRFs. The completed (e)CRFs 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 and the head of the institution 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, temporary media such as thermal sensitive paper, source worksheets, all 
original signed and dated informed consent forms, electronic copy of eCRFs, including the audit trail, and detailed 
records of drug disposition to enable evaluations or audits from regulatory authorities, the sponsor or its designees. 

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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, the investigator and the 
head of the institution are required to retain essential relevant documents until the day of completion of BLB-750 
reexamination. However, if the sponsor requests a longer time period for retention, the head of the institution 
should discuss how long and how to retain those documents with the sponsor.

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13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized by the statistician prior to the data lock. The SAP
will provide further details regarding the definition of analysis variables and analysis methodology to address all 
study objectives.
A data review will be conducted prior to the data lock. This data review will assess the accuracy and completeness 
of the study database, subject evaluability, and appropriateness of the planned statistical methods.
13.1.1 Analysis Sets
In this study, two kinds of analysis sets are defined: FAS, and safety analysis set. The FAS used as an 
immunogenicity analysis set and the safety analysis set will be defined as “all subjects who received at least one 
dose of the study drug for the treatment period." The definition of each analysis set will be detailed in the separate 
“SAP.”
13.1.2 Analysis of Demographics and Other Baseline Characteristics
In this study, major subject background data in the FAS will be tabulated.
13.1.3 Immunogenicity Analysis
(1)
Primary Endpoints and Their Analyses
(Primary Endpoints)
Immunogenicity:
Seroprotection rate as measured by SRH antibody titer (defined as the proportion of subjects with SRH antibody 
titer ≥25 mm2) for the vaccine strain at 21 days after the second vaccination
Seroconversion rate as measured by SRH antibody titer (defined as the proportion of subjects with a 50% or more 
increase in SRH antibody titer from baseline for those who have a baseline value >4 mm2 or SRH antibody titer 
≥25 mm2 for those who have a baseline value ≤4 mm2) for the vaccine strain at 21 days after the second vaccination
Geometric mean fold increase (GMFI) in SRH antibody titer from baseline for the vaccine strain at 21 days after 
the second vaccination
[Analysis Methods]
Using the FAS, frequency tabulations of the SRH antibody titer and the seroprotection and seroconversion rates at 21 
days after the second vaccination will be presented, and their point estimates and two-sided 95% confidence intervals 
will be calculated. For the geometric mean fold increase in the SRH antibody titer at 21 days after the second 
vaccination, summary statistics and geometric means with corresponding two-sided 95% confidence intervals of the fold 
increase in the SRH antibody titer from baseline will be calculated. Two-sided 95% confidence intervals of the geometric 
means will be calculated by back-transforming the upper and lower limits of two-sided 95% confidence intervals of the 
log transformed mean values.
(2)
Secondary Endpoints and Their Analyses
(Secondary Endpoints)
Immunogenicity:
Seroprotection rate as measured by SRH antibody titer (defined as the proportion of subjects with SRH antibody 
titer ≥25 mm2) for the vaccine strain at 21 days after the initial vaccination

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Seroconversion rate as measured by SRH antibody titer (defined as the proportion of subjects with a 50% or more 
increase in SRH antibody titer from baseline for those who have a baseline value >4 mm2 or SRH antibody titer 
≥25 mm2 for those who have a baseline value ≤4 mm2) for the vaccine strain at 21 days after the initial vaccination
GMFI in SRH antibody titer from baseline for the vaccine strain at 21 days after the initial vaccination
Geometric mean titer (GMT) of SRH antibody titer for the vaccine strain at 21 days after each vaccination
[Analysis Methods]
Using the FAS, frequency tabulations of the SRH antibody titer and the seroprotection and seroconversion rates at 21 
days after the initial vaccination will be presented, and their point estimates and two-sided 95% confidence intervals will 
be calculated. For the geometric mean fold increase in the SRH antibody titer at 21 days after the initial vaccination, 
summary statistics and geometric means with corresponding two-sided 95% confidence intervals of the fold increase in 
the SRH antibody titer from baseline will be calculated. For GMT of the SRH antibody titer at 21 days after each 
vaccination, summary statistics and geometric means with corresponding two-sided 95% confidence intervals will be 
calculated. Two-sided 95% confidence intervals of geometric means will be calculated using the method specified in 
13.1.3(1).
(3)
Additional Endpoints
See Section 5.2.3.
(4)
Methods of Data Transformation and Handling of Missing Data
The details will be provided in the separate “SAP.”
(5)
Confidence Coefficient
Confidence coefficient: 95% (two-sided estimation)
13.1.4 Safety Analysis
Secondary Endpoints and Their Analyses

Solicited local and systemic adverse events (AEs) to be recorded in the subject diary

AEs

Vital signs
Using the safety analysis set, the following analyses will be performed:
For injection site and systemic AEs to be collected from the diaries, frequency tabulations, frequency tabulations by 
severity, and frequency tabulations by vaccination and by timing of onset will be presented. For vital signs, 
summary statistics of measurement values and the changes in post-vaccination values from baseline at each 
assessment point will be calculated. In addition, the changes in each test item over time will be graphically 
presented.
Treatment-emergent adverse events (TEAEs) are defined as AEs observed after the start of vaccination with the 
study drug.
For TEAEs, the following analyses will be performed: TEAEs will be coded using the MedDRA and summarized 
by System Organ Class and Preferred Term.

Frequency tabulation of all TEAEs

Frequency tabulation of TEAEs considered “related” to the study drug

Frequency tabulation of all TEAEs by severity

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
Frequency tabulation of TEAEs considered “related” to the study drug by severity

Frequency tabulation of serious TEAEs

Frequency tabulation of all TEAEs by vaccination and by timing of onset
13.2
Interim Analysis and Criteria for Early Termination
No interim analysis is planned.
13.3
Determination of Sample Size
The number of subjects to be vaccinated: 55
The objective of this study is to evaluate the immunogenicity and safety of two intramuscular vaccinations with 
BLB-750 in healthy Japanese adults. Therefore, the sample size for this study was determined to be 55 subjects, as 
the number of subjects to be vaccinated, by reference to the Notification issued by the Director of the Evaluation 
and Licensing Division of the Pharmaceutical and Food Safety Bureau on October 31, 2011: “Guidelines for the 
Development of Prototype Vaccines in Preparedness for Pandemic Influenza” [4]. There are no statistical rationales 
for the determination of this sample size.

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14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all aspects of the 
protocol are followed. Source documents will be reviewed for verification of data recorded on the (e)CRFs. Source 
documents are defined as original documents, data, and records. The investigator and head of the study site
guarantee access to source documents by the sponsor or its designee (CRO) and by the IRB.
All aspects of the study and its documentation will be subject to review by the sponsor or designee (as long as 
blinding is not jeopardized), including but not limited to the Investigator’s Binder, study drug, subject medical 
records, informed consent documentation, and review of (e)CRFs and associated source documents. It is important 
that the investigator and other study personnel are available during the monitoring visits and that sufficient time is 
devoted to the process.
14.2
Protocol Deviation
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. Significant deviations from the protocol must be 
recorded on the (e)CRFs and reviewed by the sponsor or designee. Significant deviations include, but are not 
limited to, those that involve fraud or misconduct, increase the health risk to the subject, or confound interpretation 
of primary study assessment.
14.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this circumstance, the 
sponsor-designated auditor will contact the site in advance to arrange an auditing visit. The auditor may ask to visit 
the facilities where the medication is stored and prepared, and any other facility used during the study. In addition, 
there is the possibility that this study may be inspected by regulatory agencies, including those of foreign 
governments (eg, the FDA, the United Kingdom Medicines and Healthcare Products Regulatory Agency, the 
Pharmaceuticals and Medical Devices Agency of Japan). If the study site is contacted for an inspection by a 
regulatory body, the sponsor should be notified immediately. The investigator and head of the study site guarantee 
access for quality assurance auditors to all study documents as described in Section 14.1.

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15.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects) according to the 
protocol, the ethical principles that have their origin in the Declaration of Helsinki, and the ICH Harmonised 
Tripartite Guideline for GCP. Each investigator will conduct the study 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 B. The principles of Helsinki are addressed through the protocol and through appendices 
containing requirements for informed consent and investigator responsibilities.
15.1
IRB Approval
IRBs must be constituted according to the applicable local requirements of each participating region. The sponsor 
or designee will require documentation noting all names and titles of members who make up the respective IRB. If 
any member of the IRB has direct participation in this study, 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 Investigator’s Brochure, a copy of the informed consent form, and, if 
applicable, subject recruitment materials and advertisements and other documents required by all applicable laws 
and regulations, must be submitted to a central or local IRB or IEC for approval. The IRB’s written approval of the 
protocol and subject informed consent must be obtained and submitted to the sponsor or designee before 
commencement of the study. The IRB approval must refer to the study by exact protocol title, number, and version 
date; identify versions of other documents (eg, informed consent form) reviewed; and state the approval date. The 
sponsor will notify site once the sponsor has confirmed the adequacy of site regulatory documentation. Until the 
site receives [notification no protocol activities, including screening may occur.
Sites must adhere to all requirements stipulated by their respective IRB. This may include notification to the IRB 
regarding protocol amendments, updates to the informed consent form, recruitment materials intended for viewing 
by subjects, local safety reporting requirements, reports and updates regarding the ongoing review of the study 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 its designee.
Subject incentives should not exert undue influence 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 applicable laws and regulations. The 
informed consent form describe the planned and permitted uses, transfers, and disclosures of the subject’s personal 
and personal health information for purposes of conducting the study. The informed consent form further explain 
the nature of the study, its objectives, and potential risks and benefits, as well as the date informed consent is given. 
The informed consent form will detail the requirements of the participant and the fact that he or she is free to 
withdraw at any time without giving a reason and without prejudice to his or her further medical care.
The investigator is responsible for the preparation, content, and IRB approval of the informed consent form. The 
informed consent form must be approved by both the IRB and the sponsor prior to use.
The informed consent form must be written in a language fully comprehensible to the prospective subject. It is the 
responsibility of the investigator to explain the detailed elements of the informed consent form 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 study and (2) decide whether or not 
to participate in the study. If the subject determines he or she will participate in the study, then the informed consent 

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form must be signed and dated by the subject at the time of consent and prior to the subject entering into the study. 
The subject should be instructed to sign using their legal names, not nicknames, using blue or black ballpoint ink. 
The investigator will also sign and date the informed consent form before the subject enters into the study.
Once signed, the original informed consent form will be stored in the investigator’s site file. The investigator must 
document the date the subject signs the informed consent in the subject’s medical record. Copies of the signed 
informed consent form shall be given to the subject.
All revised informed consent forms must be reviewed and signed by relevant subjects in the same manner as the 
original informed consent. The date the revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised informed consent form.
15.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection against invasion of 
privacy. Throughout this study, a subject’s source data will only be linked to the sponsor’s clinical study 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 may be used to verify the subject and accuracy of the subject’s 
unique identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor requires the 
investigator to permit its monitor or designee’s monitor, representatives from any regulatory authority (eg, FDA, 
Medicines and Healthcare products Regulatory Agency, Pharmaceuticals and Medical Devices Agency), the 
sponsor’s designated auditors, and the appropriate IRBs to review the subject’s original medical records (source 
data or documents), including, but not limited to, admission and discharge summaries for hospital admissions 
occurring during a subject’s study participation, and autopsy reports. Access to a subject’s original medical records 
requires the specific authorization of the subject as part of the informed consent 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 [e]CRF).
15.4
Publication, Disclosure, and Clinical Trial Registration 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 clinical 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 laws, regulations and guidance, Takeda will, at a minimum register interventional clinical trials it 
sponsors anywhere in the world on ClinicalTrials.gov and other publicly accessible websites before start of study, 
as defined in Takeda Policy/Standard. Takeda contact information, along with the study site’s name, 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 will post the results of clinical trials on ClinicalTrials.gov and other publicly accessible websites, as 
required by Takeda Policy/Standard, applicable laws and regulations.
15.5
Insurance and Compensation for Injury
Each subject in the study 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 study 
insurance against the risk of injury to clinical study subjects. Refer to the Clinical Study 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
[1]
“National Action Plan for Pandemic Influenza and New Infectious Diseases” revised on June 7, 2013, 
http://www.cas.go.jp/jp/seisaku/ful/keikaku.html
[2]
Menno D. de Jong, M.D., Ph.D., Tran Tan Thanh,et al. Oseltamivir Resistance during Treatment of Influenza 
A (H5N1) Infection. N Engl J Med. 2005;353:2667-2672.
[3]
Takeda Pharmaceutical Company Limited. The Package Insert for Cell-Culture Influenza Vaccine (H5N1 
strain) created in June 2017 (version 1)
[4]
“Guidelines for the Development of Prototype Vaccines in Preparedness for Pandemic Influenza” (PFSB 
Notification No. 1031-[1] dated October 31, 2011)
[5]
Thomas R., Robert A., Jean H., et al. Detection of Antibody to Avian Influenza A(H5N1) Virus in Human 
Serum by Using a Combination of Serologic Assays.J Clin Microbiol.April 1999;37(4):937-943.
[6]
Iain S., Karl G.,Anthony C., et al.Boosting immunity to influenza H5N1 with MF59-adjuvanted H5N3 
A/Duck/Singapore/97 vaccine in a primed human population.ELSEVIER.April 2003;21(15):1687-1693
[7]
Food and Drug Administration. Guidance for Industry: Toxicity Grading Scale for Healthy Adult and 
Adolescent volunteers Enrolled in Preventive Vaccine Clinical Trials. U.S.Department of Health and Drug 
administration Center for Biologics Evaluation and Research. September 2007

BLB-750
Study No. CCT-901
Page 56 of 59
Protocol Amendment 02
21 Nov 2017
CONFIDENTIAL
Appendix A
Schedule of Study Procedures
Screening
Treatment
Visit number
Visit 1
Visit 2
Visit 3/at discontinuation12)
Day1)
1
1 to 22
22
22 to 43
43/-
Days after the initial 
vaccination
0
0 to 21
21
21 to 42
42 (Visit 2 + 21)/-
Acceptable time window 
for visit (day)
-
-
+0 to 2
-
Visit 2 + 19 to Visit 2 + 23
/date of discontinuation + 28
Pre-
vaccination
Post-
vaccination
Pre-
vaccination
Post-
vaccination
-
Informed Consent
X2)
Demographics
X
Past history, present 
illness, and prior 
treatments
X3)
Height and weight
X
Vital signs (blood 
pressure and pulse and 
respiratory rates)
X
X4)
X
X4)
X5)
Vital signs (body 
temperature [oral])
X
X6) 7)
X
X6) 7)
X
Pregnancy test9)
X
X
Physical examination
X
X9)
X
X9)
X
Eligibility assessment
X
Enrollment
X
Blood sampling 
(immunogenicity 
evaluation)10)
X
X
X
Vaccination with the 
study drug
X
X
Diaries 1 and 2
To be 
provided
To be 
recorded
To be 
collected
(To be collected, if not yet 
collected)
Diaries 3 and 4
To be 
provided11)
To be 
recorded
To be collected
Adverse events
Concomitant medications
1)
The day before vaccination with the study drug is defined as Day -1, and the day of vaccination with the study drug (Visit 1) is 
defined as Day 1.
2)
Informed consent must be obtained before any study procedure is performed. Informed consent is considered valid if it is 
obtained within 28 days prior to Visit 1 (Day -28).
3)
Prior treatments include those given before signing the informed consent form, and past history and present illness include those 
occurring before the first vaccination of study drug.
4)
On the day of vaccination with study drug, blood pressure, pulse rate, and respiratory rate will be measured before vaccination 
and approximately 30 minutes after vaccination.
5)
No respiratory rate measurement will be required at Day 43 and at discontinuation.
6)
Among vital signs, body temperature will be measured by each subject every day in the evening wherever possible for 7 days 
after vaccination (after vaccination on Day 1 until Day 7 and after vaccination on Day 22 until Day 28) and be recorded in the 
diary provided to each subject.

BLB-750
Study No. CCT-901
Page 57 of 59
Protocol Amendment 02
21 Nov 2017
CONFIDENTIAL
7)
During Days 8-22 (before study visit) and Days 29-43 (before study visit), body temperature will be measured by each subject 
and be recorded in the diary provided to each subject only if any symptom of pyrexia occurs. Measurements should be obtained 
approximately every 4-8 hours until the pyrexia resolves and should be recorded in the diary.
8)
Pregnancy test will be performed in female subjects of childbearing potential.
9)
The investigator will monitor for any acute hypersensitivity reaction, etc., for 30 minutes after vaccination.
10) Blood sampling should be performed after vital sign measurement.
11) Provision of Diaries 3 and 4 may take place at Visit 1.
12) The study discontinuation visit should be performed wherever possible.

BLB-750
Study No. CCT-901
Page 58 of 59
Protocol Amendment 02
21 Nov 2017
CONFIDENTIAL
Appendix B
Responsibilities of the Investigator
1.
Conduct the appropriate study in accordance with the protocol and GCP considering the rights, safety and 
wellbeing of human subjects.
2.
When a part of the important activities related to the study are delegated to the investigator or the study 
collaborator, prepare the lists of activities to be delegated and responsible personnel, submit the lists to the 
director of the site in advance to get them accepted.
3.
Prepare a written informed consent form and other written information, and update as appropriate.
4.
Confirm the contents of the clinical study agreement.
5.
Provide necessary information on the protocol, medications and responsibilities of individual personnel to the 
investigator and study collaborator, and provide guidance and supervision.
6.
Screen subjects who meet the requirements of the protocol, provide the explanation of the study in writing and 
obtain the written consent.
7.
Assume responsibility for all the medical judgement related to the study.
8.
Ensure in collaboration with the director of the site that sufficient information on all clinically significant 
adverse events related to the study are provided to subjects throughout and beyond the period when subjects 
participate in the study.
9.
If a subject consults other medical institution or other department, notify the physician of the medical 
institution or department of the subject’s participation in the study upon obtaining the consent of the subject, as 
well as the end and termination of the study in writing, and document such records.
10. In case of urgent report of a SAE, immediately notify the director of the site and the sponsor in writing.
11. Prepare correct and complete (e)CRFs, and submit them to the sponsor with electronic signature.
12. Check and confirm the contents of (e)CRFs prepared by the investigator or transcribed from the source data by 
the study collaborator, and submit them to the sponsor with electronic signature.
13. Discuss any proposal from the sponsor including update of the protocol.
14. Notify the director of the site of the end of the study in writing.

BLB-750
Study No. CCT-901
Page 59 of 59
Protocol Amendment 02
21 Nov 2017
CONFIDENTIAL
Appendix C
Details of Amendments
Specific changes in the amended protocol are described below.
Section 2.0 (Exclusion Criteria) on Page 9 and Section 7.2 on Page 21
After change
25. The subject has thrombocytopenia or coagulopathy, or is currently receiving anticoagulant therapy or 
received anticoagulant therapy within 30 days prior to the first vaccination with the study vaccine.
Reason for the change
Addition of an exclusion criterion to reflect the revised package insert with additional precautionary text.
Section 7.2 on Page 21
Before change
Criteria 11, 15, 16, 21, 22, and 23 were selected to ensure the safety of subjects.
After change
Criteria 11, 15, 16, 21, 22, 23, and 25 were selected to ensure the safety of subjects.
Reason for the change
Addition of an exclusion criterion to reflect the revised package insert with additional precautionary text.
Section 7.3 (Table 7.a) on Page 23
Before change
•
Systemic or high-dose inhaled corticosteroids (beclomethasone dipropionate >800 μg/day or equivalent)
•
Radiotherapy
•  Immunosuppressives
•
Cytotoxic drugs
After change
•
Systemic or high-dose inhaled corticosteroids (beclomethasone dipropionate >800 μg/day or equivalent)
•
Radiotherapy
•  Immunosuppressives
•
Cytotoxic drugs
•
Anticoagulant therapy
Reason for the change
Addition of anticoagulant therapy to the list of excluded medications and treatments to reflect the revised package 
insert with additional precautionary text.

 
  
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ELECTRONIC SIGNATURES 
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BLB-750
Study No. CCT-901
Page 1 of 72
Protocol Amendment 01
25 Oct 2017
CONFIDENTIAL
Post-marketing Study Protocol
<Title>
A Phase 4, Open-label Study to Evaluate
the Immunogenicity and Safety of Intramuscular Injections of BLB-750 in Healthy Adult Subjects
<Short Title>
A Phase 4 Post-marketing Study of Intramuscular Injections of BLB-750 in Healthy Adult Subjects
Name of Sponsor
Takeda Pharmaceutical Company Limited
1-1, Doshomachi 4-chome, Chuo-ku, Osaka
Protocol number
BLB-750/CCT-901 
IND Number
Not applicable
EudraCT Number
Not applicable
Compound
BLB-750 (Cell-Culture Influenza Vaccine H5N1 “Takeda” 1 mL)
Date:
25 Oct 2017
Version Number
Amendment 01
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement by the 
recipient that no information contained herein will be published or disclosed without written authorization from Takeda 
except to the extent necessary to obtain informed consent from those persons to whom the drug may be administered. 
Furthermore, the information is only meant for review and compliance by the recipient, his or her staff, and applicable 
institutional review committee and regulatory agencies to enable conduct of the post-marketing study.

BLB-750
Study No. CCT-901
Page 2 of 72
Protocol Amendment 01
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CONFIDENTIAL
1.0
ADMINISTRATIVE INFORMATION AND PRINCIPLES OF CLINICAL STUDIES
1.1
Contacts and Responsibilities of Study-Related Activities
See the attachments.
1.2
Principles of Clinical Studies
This study will be conducted with the highest respect for the individual participants in accordance with the 
requirements of this clinical study protocol and also in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated Guideline. 

All applicable laws and regulations, including, without limitation, data privacy laws, clinical trial disclosure 
laws, and regulations.
1.3
Summary of Changes in the Amended Protocol
The changes in the amended version of the protocol are described below. 
The key changes in this amended protocol are summarized below. Details of the changes are described in Appendix
C.
1.
The study is conducted in an open-label manner, not a randomized, double-blind, parallel-group comparative 
manner. 
Reason for the change: Because of changes to the study objectives, the study design was changed from a 
randomized study to an open-label study.
2.
This study uses a single group, not three groups.
Reason for the change: Because of changes to the study objectives, the number of the groups was changed 
from three to one. 
3.
Only BLB-750 (Qinghai RG strain) is used as the study drug.
Reason for the change: Because the number of the groups was changed from three to one due to changes to the 
study objectives.
4.
Deletion of the secondary objectives.
Reason for the change: Because the number of the groups was changed from three to one due to changes to the 
study objectives.

BLB-750
Study No. CCT-901
Page 3 of 72
Protocol Amendment 01
25 Oct 2017
CONFIDENTIAL
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
Summary of Changes in the Amended Protocol............................................................................... 2
2.0
STUDY SUMMARY .............................................................................................................................. 8
3.0
LIST OF ABBREVIATIONS................................................................................................................ 13
4.0
INTRODUCTION................................................................................................................................. 14
4.1
Background .................................................................................................................................... 14
4.1.1
Benefit/Risk Profile................................................................................................................. 14
4.2
Rationale for the Proposed Study................................................................................................... 15
5.0
STUDY OBJECTIVES AND ENDPOINTS......................................................................................... 16
5.1
Objectives....................................................................................................................................... 16
5.2
Endpoints........................................................................................................................................ 16
5.2.1
Primary Endpoints................................................................................................................... 16
5.2.2
Secondary Endpoints............................................................................................................... 16
5.2.3
Additional Endpoints............................................................................................................... 16
6.0
STUDY DESIGN AND DESCRIPTION.............................................................................................. 18
6.1
Study Design .................................................................................................................................. 18
6.2
Rationales for the Selection of Study Design, Vaccination Dosage, and Endpoints ...................... 18
6.2.1
Rationales for the Selection of Study Design.......................................................................... 18
6.2.2
Rationales for the Selection of Vaccination Dosage Regimen and Strain ............................... 19
6.2.3
Rationales for the Selection of Endpoints ............................................................................... 19
6.3
Premature Termination or Suspension of Study or Study Site ....................................................... 19
6.3.1
Criteria for Premature Termination or Suspension of the Study.............................................. 19
6.3.2
Criteria for Premature Termination or Suspension of Study Sites........................................... 20
6.3.3
Procedures for Premature Termination or Suspension of the Study or the Participation of 
Study Site(s) ............................................................................................................................ 20
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS .................................... 21
7.1
Inclusion Criteria............................................................................................................................ 21
7.2
Exclusion Criteria........................................................................................................................... 21
7.3
Excluded Medications and Treatments........................................................................................... 23
7.4
Diet, Fluid, Activity Control........................................................................................................... 23
7.5
Criteria for Discontinuation or Withdrawal of a Subject................................................................ 24
7.6
Procedures for Discontinuation or Withdrawal of a Subject .......................................................... 25
8.0
CLINICAL TRIAL MATERIAL MANAGEMENT............................................................................. 26
8.1
Study Drug and Materials............................................................................................................... 26
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling ........................................................ 26
8.1.1.1 Study Drug ...................................................................................................................... 26
8.1.1.2 Ancillary Materials......................................................................................................... 27

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8.1.2
Storage..................................................................................................................................... 27
8.1.3
Dose and Regimen................................................................................................................... 27
8.1.4
Overdose.................................................................................................................................. 28
8.2
Study Drug Dispensing Procedures................................................................................................ 28
8.3
Accountability and Destruction of Sponsor-Supplied Drugs ......................................................... 28
9.0
STUDY PLAN...................................................................................................................................... 29
9.1
Study Procedures............................................................................................................................ 29
9.1.1
Informed Consent Procedure................................................................................................... 29
9.1.2
Demographics, Medical History, and Medication History Procedure ..................................... 29
9.1.3
Physical Examination Procedure............................................................................................. 29
9.1.4
Weight and Height................................................................................................................... 29
9.1.5
Vital Signs Procedure .............................................................................................................. 29
9.1.6
Documentation of Concomitant Medications.......................................................................... 30
9.1.7
History of Present Illness......................................................................................................... 30
9.1.8
Contraception and Pregnancy Avoidance Procedure............................................................... 30
9.1.9
Pregnancy................................................................................................................................ 31
9.1.10
Immunogenicity Evaluation .................................................................................................... 31
9.1.11
Injection Site and Systemic Reactions (Diary-based Assessment).......................................... 31
9.1.12
Documentation of Subjects Failure before Enrollment in the Study ....................................... 34
9.1.13
Documentation of Enrollment in the Study............................................................................. 34
9.2
Vaccination Status in Subjects........................................................................................................ 34
9.3
Schedule of Observations and Procedures ..................................................................................... 34
9.3.1
<Screening Period/Day 1 (Starting before the Initial Vaccination and Ending after the 
Completion of the Initial Vaccination)> .................................................................................. 34
9.3.2
<Treatment Period/Day 1 (after the Initial Vaccination) to Day 22 (before Visiting the Study 
Site)> ....................................................................................................................................... 35
9.3.3
<Treatment Period/Day 22 (Starting before the Second Vaccination and Ending after the 
Completion of the Second Vaccination)>................................................................................ 36
9.3.4
<Treatment Period/Day 22 (after the Second Vaccination) to Day 43 (before Visiting the Study 
Site)> ....................................................................................................................................... 36
9.3.5
<Treatment Period/at the End of Study/Day 43> .................................................................... 36
9.3.6
<Treatment Period/at Discontinuation> .................................................................................. 37
9.4
Biological Sample Retention and Destruction ............................................................................... 37
9.5
Amount and Frequency of Blood Collection.................................................................................. 37
10.0
ADVERSE EVENTS............................................................................................................................ 38
10.1
Definitions...................................................................................................................................... 38
10.1.1
AEs.......................................................................................................................................... 38
10.1.2
Additional Points to Consider for AEs .................................................................................... 38
10.1.3
SAEs........................................................................................................................................ 39
10.1.4
AEs of Special Interest ............................................................................................................ 40
10.1.5
Severity of AEs........................................................................................................................ 40
10.1.6
Causality of AEs...................................................................................................................... 40

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Study No. CCT-901
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10.1.7
Relationship to Study Procedures............................................................................................ 41
10.1.8
Start Date................................................................................................................................. 41
10.1.9
End Date.................................................................................................................................. 41
10.1.10 Pattern of Adverse Events ....................................................................................................... 41
10.1.11 Action Taken with Study Treatment........................................................................................ 41
10.1.12 Outcome of Event.................................................................................................................... 42
10.2
Procedures ...................................................................................................................................... 42
10.2.1
Collection and Reporting of AEs............................................................................................. 42
10.2.1.1 AE Collection Period...................................................................................................... 42
10.2.1.2 AE Reporting .................................................................................................................. 42
10.2.1.3 AEs of Special Interest Reporting ................................................................................. 43
10.2.2
Collection and Reporting of SAEs .......................................................................................... 43
10.3
Follow-up of SAEs......................................................................................................................... 43
10.3.1
Safety Reporting to Investigators, IRBs, and Regulatory Authorities..................................... 44
11.0
STUDY-SPECIFIC COMMITTEES..................................................................................................... 45
12.0
DATA HANDLING AND RECORDKEEPING................................................................................... 46
12.1
CRFs............................................................................................................................................... 46
12.2
Record Retention............................................................................................................................ 46
13.0
STATISTICAL METHODS.................................................................................................................. 48
13.1
Statistical and Analytical Plans ...................................................................................................... 48
13.1.1
Analysis Sets ........................................................................................................................... 48
13.1.2
Analysis of Demographics and Other Baseline Characteristics .............................................. 48
13.1.3
Immunogenicity Analysis........................................................................................................ 48
13.1.4
Safety Analysis ........................................................................................................................ 49
13.2
Interim Analysis and Criteria for Early Termination...................................................................... 50
13.3
Determination of Sample Size........................................................................................................ 50
14.0
QUALITY CONTROL AND QUALITY ASSURANCE..................................................................... 51
14.1
Study-Site Monitoring Visits.......................................................................................................... 51
14.2
Protocol Deviation.......................................................................................................................... 51
14.3
Quality Assurance Audits and Regulatory Agency Inspections ..................................................... 51
15.0
ETHICAL ASPECTS OF THE STUDY............................................................................................... 52
15.1
IRB Approval ................................................................................................................................. 52
15.2
Subject Information, Informed Consent, and Subject Authorization.............................................. 52
15.3
Subject Confidentiality................................................................................................................... 53
15.4
Publication, Disclosure, and Clinical Trial Registration Policy ..................................................... 53
15.4.1
Publication and Disclosure...................................................................................................... 53
15.4.2
Clinical Trial Registration ....................................................................................................... 53
15.4.3
Clinical Trial Results Disclosure............................................................................................. 54
15.5
Insurance and Compensation for Injury ......................................................................................... 54
16.0
REFERENCES...................................................................................................................................... 55
APPENDIX A
SCHEDULE OF STUDY PROCEDURES ...................................................................... 56

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Study No. CCT-901
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APPENDIX B
RESPONSIBILITIES OF THE INVESTIGATOR........................................................... 58
APPENDIX C
DETAILS OF AMENDMENTS....................................................................................... 59

BLB-750
Study No. CCT-901
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CONFIDENTIAL
LIST OF IN-TEXT TABLES
Table 7.a
Excluded Medications and Treatments.................................................................................... 23
Table 8.a
Components and Dose Strength of BLB-750 Injection 0.5 mL .............................................. 26
Table 9.a
Amount and Frequency of Blood Collection........................................................................... 37
Table 10.a
Takeda Medically Significant AE List..................................................................................... 40
LIST OF IN-TEXT FIGURES
Figure 6.a
Schematic of Study Design...................................................................................................... 18
Figure 8.a
Labeling Sample of the Outer Box for the Study Drug........................................................... 27
LIST OF APPENDIXES
Appendix A
Schedule of Study Procedures ................................................................................................. 56
Appendix B
Responsibilities of the Investigator ......................................................................................... 58
Appendix C
Details of Amendments ........................................................................................................... 59

BLB-750
Study No. CCT-901
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CONFIDENTIAL
2.0
STUDY SUMMARY
Clinical Study Sponsor(s):
Takeda Pharmaceutical Company Limited
Study Drug
BLB-750 (Cell-Culture Influenza Vaccine H5N1 
“Takeda” 1 mL)
Title of Protocol: A Phase 4, Open-label Study to Evaluate 
the Immunogenicity and Safety of Intramuscular Injections of 
BLB-750 in Healthy Adult Subjects
IIND Number: Not 
applicable
EudraCT Number: Not 
applicable
Study Number: BLB-750/CCT-901
Phase: 4 
Study Design:
This is a phase 4, Open-label study to evaluate the immunogenicity and safety of two intramuscular vaccinations 
with BLB-750 at a 3-week interval in healthy Japanese adults.
Participants considered eligible as subjects for the study during the eligibility assessment at a visit after providing 
informed consent will receive the initial intramuscular vaccination with the study drug BLB-750 (Day 1) and the 
second intramuscular vaccination with BLB-750 during the study visit at 21 days after the initial vaccination (Day 
22).
The study duration will be 43 days, starting on the day of initial vaccination (Day 1). Subjects will return to the 
study site 21 days after the initial vaccination (Day 22) and 21 days after the second vaccination (Day 43).
The total planned number of subjects to receive the study vaccination is 55.
Objectives:
To evaluate the immunogenicity and safety of two intramuscular vaccinations with BLB-750 in healthy Japanese 
adults
Study Population: Healthy Japanese adults (male or female)
Planned Number of Subjects:
BLB-750: 55 subjects
Planned Number of Study Sites:
1 institution
Dose Level(s):
Two doses of BLB-750 at 0.5 mL (HA antigen level of 7.5 µg) 
will be injected into the upper arm muscle (the deltoid muscle) 
at a 3-week interval.
As the manufacturing strain for BLB-750, the following 
attenuated strain (H5N1 influenza virus attenuated using 
reverse genetics technology) will be used:
●
Qinghai RG strain
[A/bar-headed goose/Qinghai/1A/2005(H5N1)
(SJRG-163222)]
Vaccination Route:
Intramuscular injection
Duration of Vaccination:
Two doses at a 3-week interval
Period of Evaluation:
43 days

BLB-750
Study No. CCT-901
Page 9 of 72
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CONFIDENTIAL
Inclusion Criteria
1.
In the opinion of the investigator, the subject is capable of understanding and complying with protocol 
requirements.
2.
The subject signs and dates a written, informed consent form prior to the initiation of any study procedures.
3.
The subject is a healthy Japanese adult man or woman.
4.
The subject is aged 20 to 49 years, inclusive, at the time of informed consent.
5.
A female subject of childbearing potential who is sexually active with a nonsterilized male partner agrees to 
use routinely adequate contraception from signing of informed consent throughout the duration of the study.
Exclusion Criteria
1.
The subject has received vaccination with any other investigational or study products within 4 months prior to 
vaccination with the study vaccine.
2.
The subject has a history of vaccination with an H5N1 influenza vaccine.
3.
The subject has a history of infection with H5N1 virus.
4.
The subject is at high risk of contracting H5N1 influenza infection (e.g., poultry workers).
5.
The subject is an immediate family member, study site employee, or is in a dependent relationship with a study 
site employee who is involved in conduct of this study (e.g., spouse, parent, child, sibling) or may consent 
under duress.
6.
The subject has poorly controlled, clinically significant manifestations of neurological, cardiovascular, 
pulmonary, hepatic, renal, metabolic, gastrointestinal, urologic, endocrine, or other disorders, which may 
impact their ability to participate as subjects or may potentially confound the study results.
7.
The subject has a body temperature (oral) ≥37.5°C prior to vaccination with the study vaccine on Day 1.
8.
The subject has any medically diagnosed or suspected immune-deficiency condition.

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Study No. CCT-901
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9.
The subject has an immunocompromising condition or disease, or is currently undergoing a form of treatment 
or was undergoing a form of treatment that can be expected to influence immune response within 30 days prior 
to vaccination with the study vaccine. 
Such treatments include, but are not limited to, systemic or high dose inhaled corticosteroids (>800 μg/day of 
beclomethasone dipropionate or equivalent; the use of inhaled and nasal steroids that do not exceed this level 
will be permitted), radiation treatment or other immunosuppressive or cytotoxic drugs.
10. The subject has received antipyretics within 4 hours prior to vaccination with the study vaccine.
11. The subject has a history of Guillain-Barré Syndrome, demyelinating disorders (including acute disseminated 
encephalomyelitis [ADEM] and multiple sclerosis), or convulsions.
12. The subject has a functional or anatomic asplenia.
13. The subject has a rash, other dermatologic conditions or tattoos that may interfere with the evaluation of local 
reaction.
14. The subject has a past or present history of infection with the Hepatitis B Virus (HBV), Hepatitis C Virus 
(HCV) or Human Immunodeficiency Virus (HIV).
15. The subject has a known hypersensitivity to any component of BLB-750.
16. The subject has a history of severe allergic reactions or anaphylaxis.
17. The subject has a history of drug abuse (defined as any illicit drug use) or a history of alcohol dependence 
within 1 year prior to vaccination with the study vaccine or is unwilling to agree to abstain from excessive 
alcohol and drugs throughout the study.
18. The subject has received any blood product (e.g., blood transfusion or immunoglobulin) within 90 days prior to 
vaccination with the study vaccine.
19. The subject has received any live vaccine within 4 weeks (28 days) prior to vaccination with the study vaccine 
or any inactivated vaccine within 2 weeks (14 days) prior to vaccination with the study vaccine.
20. The subject is a pregnant or lactating woman or wishes to become pregnant before signing informed consent, 
during, or within 12 weeks after the last vaccination with the study vaccine or intends to donate ova during such 
time period
21. For males: The subject has donated whole blood ≥200 mL within 4 weeks (28 days) or ≥400 mL within 12 
weeks (84 days) prior to the first vaccination with the study vaccine.
For females: The subject has donated whole blood ≥200 mL within 4 weeks (28 days) or ≥400 mL within 16 
weeks (112 days) prior to the first vaccination with the study vaccine.
22. For males: The subject has donated whole blood ≥800 mL in total within 52 weeks (364 days) prior to the first 
vaccination with the study vaccine.
For females: The subject has donated whole blood ≥400 mL in total within 52 weeks (364 days) prior to the 
first vaccination with the study vaccine.
23. The subject has donated blood components within 2 weeks (14 days) prior to the first vaccination with the study 
vaccine.
24. In the opinion of the investigator, the subject is unlikely to comply with protocol requirements or is considered 
ineligible for any other reason.

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Study No. CCT-901
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Protocol Amendment 01
25 Oct 2017
CONFIDENTIAL
Main Criteria for Evaluation and Analyses:
[Primary Endpoints]
Immunogenicity:
●
Seroprotection rate as measured by SRH antibody titer (defined as the proportion of subjects with SRH antibody 
titer ≥25 mm2) for the vaccine strain at 21 days after the second vaccination
●
Seroconversion rate as measured by SRH antibody titer (defined as the proportion of subjects with a 50% or 
more increase in SRH antibody titer from baseline for those who have a baseline value >4 mm2 or SRH 
antibody titer ≥25 mm2 for those who have a baseline value ≤4 mm2) for the vaccine strain at 21 days after the 
second vaccination
●
Geometric mean fold increase (GMFI) in SRH antibody titer from baseline for the vaccine strain at 21 days after 
the second vaccination
[Secondary Endpoints]
Immunogenicity:
●
Seroprotection rate as measured by SRH antibody titer (defined as the proportion of subjects with SRH antibody 
titer ≥25 mm2) for the vaccine strain at 21 days after the initial vaccination
●
Seroconversion rate as measured by SRH antibody titer (defined as the proportion of subjects with a 50% or 
more increase in SRH antibody titer from baseline for those who have a baseline value >4 mm2 or SRH 
antibody titer ≥25 mm2 for those who have a baseline value ≤4 mm2) for the vaccine strain at 21 days after the 
initial vaccination
●
GMFI in SRH antibody titer from baseline for the vaccine strain at 21 days after the initial vaccination
●
Geometric mean titer (GMT) of SRH antibody titer for the vaccine strain at 21 days after each vaccination
Safety:
●
Solicited local and systemic adverse events (AEs) to be recorded in the subject diary
●
AEs
●
Vital signs
[Additional Endpoints]
Immunogenicity:
●
Seroprotection rate as measured by MN antibody titer (defined as the proportion of subjects with MN antibody 
titer ≥20) for the vaccine strain at 21 days after each vaccination
●
Seroconversion rate as measured by MN antibody titer (defined as the proportion of subjects with 4-fold or more 
increase in MN antibody titer from baseline) for the vaccine strain at 21 days after each vaccination
●
GMFI in MN antibody titer from baseline for the vaccine strain at 21 days after each vaccination
●
GMT of MN antibody titer for the vaccine strain at 21 days after each vaccination

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Statistical Considerations:
[Immunogenicity] Using the full analysis set (FAS), frequency tabulations of the SRH antibody titer and the 
seroprotection and seroconversion rates at 21 days after the second vaccination will be presented, and their point 
estimates and two-sided 95% confidence intervals will be calculated. For the GMFI in the SRH antibody titer at 21 
days after the second vaccination, summary statistics and geometric means with corresponding two-sided 95% 
confidence intervals of the fold increase in the SRH antibody titer from baseline will be calculated.
Two-sided 95% confidence intervals of the geometric means will be calculated by back-transforming the upper and 
lower limits of two-sided 95% confidence intervals of the log transformed mean values.
[Safety] Using the safety analysis set, the following analyses will be performed:
For injection site and systemic AEs to be collected in the diary, frequency tabulations, frequency tabulations by 
severity, and frequency tabulations by vaccination and by timing of onset will be presented.
Treatment-emergent adverse events (TEAEs) are defined as AEs observed after vaccination with the study drug.
For TEAEs, the following analyses will be performed: TEAEs will be coded using the MedDRA and be summarized 
by System Organ Class and Preferred Term.
●
Frequency tabulation of all TEAEs
●
Frequency tabulation of TEAEs considered “related” to the study drug
●
Frequency tabulation of all TEAEs by severity
●
Frequency tabulation of TEAEs considered “related” to the study drug by severity
●
Frequency tabulation of serious TEAEs
●
Frequency tabulation of all TEAEs by vaccination and by timing of onset
Rationales for the Determination of Sample Size:
The objective of this study is to evaluate the immunogenicity and safety of two intramuscular vaccinations with 
BLB-750 in healthy Japanese adults. Therefore, the sample size for this study was determined to be 55 subjects, as 
the number of subjects to be vaccinated, by reference to the “Guidelines for the Development of Prototype Vaccines 
in Preparedness for Pandemic Influenza.” There are no statistical rationales for the determination of this sample size.

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3.0
LIST OF ABBREVIATIONS
ADEM
acute disseminated encephalomyelitis
AE
adverse event
CRO
contract research organization
EDC
electronic data capture
FDA
Food and Drug Administration
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
GMT
geometric mean titer
HA
hemagglutinin
HBV
hepatitis B virus 
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HIV
human immunodeficiency virus 
ICH
International Conference on Harmonisation
MedDRA
Medical Dictionary for Regulatory Activities
MHRA
Medicines and Healthcare products Regulatory Agency
MN
microneutralization
PMDA
Pharmaceuticals and Medical Devices Agency
SAE
serious adverse event
SRH
single radial hemolysis
SUSARs
suspected unexpected serious adverse reactions
TEAE
treatment-emergent adverse event
WHO
World Health Organization

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4.0
INTRODUCTION
4.1
Background
In Japan’s National Action Plan for Pandemic Influenza and New Infectious Diseases [1], pandemic influenza is 
defined as “an influenza infectious disease in humans caused by newly emerging influenza virus as an etiological 
agent that acquires the ability of human-to-human transmission.” Especially, there are concerns that when the 
highly pathogenic avian influenza virus H5N1 newly acquires the ability of human-to-human transmission and 
causes pandemic influenza (H5N1), it can constitute an enormous health hazard due to its high mortality rate. At 
present, therapeutic strategies for the treatment of pandemic influenza (H5N1) may include administration of 
anti-influenza virus drugs, such as oseltamivir phosphate and zanamivir hydrate. However, fatality due to acquired 
drug resistance during the treatment with oseltamivir phosphate has been suggested [2], which warrants the 
consideration of potential emergence of resistant virus strains before the use of anti-influenza virus drugs. In 
August 2004, a report by a subcommittee for the review of measures against pandemic influenza of the Section of 
Infectious Diseases, Health Sciences Council of the Ministry of Health, Labour and Welfare (MHLW) was 
prepared, in which the development, production, and stabilization of the supply of pandemic influenza vaccines are 
listed as primary aspects of measures against pandemic influenza.
Takeda Pharmaceutical Company Limited and 
 co-developed a vaccine indicated for “the prevention 
of pandemic influenza (H5N1)”, and approval for the manufacture and marketing of Cell-Culture Influenza 
Vaccines H5N1 “
” and “Takeda” 5 mL was obtained June 2013 (approval withdrawn in September 2016). In 
March 2014, Takeda Pharmaceutical Company Limited obtained approval for the manufacture and marketing of 
Cell-Culture Influenza Vaccine H5N1 “Takeda” 1 mL. BLB-750 is an influenza vaccine containing inactivated 
whole influenza virions as an active ingredient. It is produced by inactivating influenza (H5N1 subtype) viruses that 
infected and replicated in cultured cells using formaldehyde treatment and ultraviolet irradiation.
4.1.1
Benefit/Risk Profile
Currently there is no established treatment available for pandemic influenza (H5N1), and viral drug resistance 
associated with the use of anti-influenza virus drugs has been reported. Therefore, it is considered extremely 
important to prevent the development or aggravation of influenza infectious diseases through vaccination. BLB-750 
has been shown to be effective for the prevention of the development of influenza infectious diseases in mice and 
ferrets. In addition, clinical study results show that the vaccine is immunogenic. Based on these findings, it is 
expected that vaccination with BLB-750 will be useful for the prevention of the development or aggravation of 
pandemic influenza (H5N1).
BLB-750 may also be suitable as a vaccine prepared for a pandemic possibly caused by the H5N1 subtype for the 
following reasons: cell culture technology is applied for the manufacturing of the vaccine, which requires less time 
for vaccine production than other vaccines manufactured using chicken egg culture method; the manufacturing of 
BLB-750 is not affected by the availability of chicken eggs; and BLB-750 can be used in those who are allergic to 
hen’s egg.
Frequently observed adverse events of BLB-750 in clinical studies of the vaccine include transient pain, bleeding, 
and induration for injection site reactions, and headache, fatigue, malaise, hyperhidrosis, myalgia, chills, 
oropharyngeal pain, pyrexia, and arthralgia for systemic reactions, with no major issues in terms of the tolerability 
or safety. The safety profile of BLB-750 is similar to that of existing seasonal influenza vaccines, and there 
considered to be no specific risk associated with vaccination with BLB-750. Although results from clinical studies 
of BLB-750 indicate the immunogenicity of BLB-750, it may not be effective for the prevention of pandemic 
influenza (H5N1) in all subjects due to various factors, including differences in the immunoreactivity among 
vaccinated individuals and between prevalent virus strains and the vaccine strain.
PPD
CCI

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4.2
Rationale for the Proposed Study
As required by the MHLW, a strain attenuated using reverse genetics technology must be used as an H5N1 subtype 
virus strain for the production of pre-pandemic vaccine stockpiles as one of measures against pandemic influenza.
Clinical studies in Japanese adults for the purpose of the application for the approval of a cell-culture influenza 
vaccine (H5N1 strain) and clinical studies in the Japanese elderly and in children were conducted using a vaccine 
manufactured using a wild type strain as an H5N1 subtype virus strain, and there is no clinical experience with a 
vaccine manufactured using an attenuated strain.
Therefore, we planned a phase 4, open-label study to evaluate the immunogenicity and safety of two intramuscular 
vaccinations with BLB-750 at a 3-week interval in healthy Japanese adults, in which a cell-culture influenza 
vaccine (H5N1 strain) manufactured using an attenuated strain will be used..

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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
To evaluate the immunogenicity and safety of two intramuscular vaccinations with BLB-750 in healthy Japanese 
adults
5.2
Endpoints
5.2.1
Primary Endpoints
Immunogenicity:

Seroprotection rate as measured by SRH antibody titer (defined as the proportion of subjects with SRH 
antibody titer ≥25 mm2) for the vaccine strain at 21 days after the second vaccination

Seroconversion rate as measured by SRH antibody titer (defined as the proportion of subjects with a 50% or 
more increase in SRH antibody titer from baseline for those who have a baseline value >4 mm2 or SRH 
antibody titer ≥25 mm2 for those who have a baseline value ≤4 mm2) for the vaccine strain at 21 days after the 
second vaccination

Geometric mean fold increase (GMFI) in SRH antibody titer from baseline for the vaccine strain at 21 days 
after the second vaccination
5.2.2
Secondary Endpoints
Immunogenicity:

Seroprotection rate as measured by SRH antibody titer (defined as the proportion of subjects with SRH 
antibody titer ≥25 mm2) for the vaccine strain at 21 days after the initial vaccination

Seroconversion rate as measured by SRH antibody titer (defined as the proportion of subjects with a 50% or 
more increase in SRH antibody titer from baseline for those who have a baseline value >4 mm2 or SRH 
antibody titer ≥25 mm2 for those who have a baseline value ≤4 mm2) for the vaccine strain at 21 days after the 
initial vaccination

GMFI in SRH antibody titer from baseline for the vaccine strain at 21 days after the initial vaccination

Geometric mean titer (GMT) of SRH antibody titer for the vaccine strain at 21 days after each vaccination
Safety:

Solicited local and systemic adverse events (AEs) to be recorded in the subject diary

AEs

Vital signs
5.2.3
Additional Endpoints
Immunogenicity:

Seroprotection rate as measured by MN antibody titer (defined as the proportion of subjects with MN antibody 
titer ≥20) for the vaccine strain at 21 days after each vaccination

Seroconversion rate as measured by MN antibody titer (defined as the proportion of subjects with 4-fold or 
more increase in MN antibody titer from baseline) for the vaccine strain at 21 days after each vaccination

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
GMFI in MN antibody titer from baseline for the vaccine strain at 21 days after each vaccination

GMT of MN antibody titer for the vaccine strain at 21 days after each vaccination

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6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design
This is a phase 4, open-label study to evaluate the immunogenicity and safety of two intramuscular vaccinations 
with BLB-750 at a 3-week interval in healthy Japanese adults.
Subjects considered eligible after providing informed consent will receive the initial intramuscular vaccination with 
the study drug BLB-750 (Day 1) and the second intramuscular vaccination with BLB-750 during the study visit at 
21 days after the initial vaccination (Day 22).
The study duration will be 43 days, starting on the day of initial vaccination (Day 1). Subjects will return to the 
study site 21 days after the initial vaccination (Day 22) and 21 days after the second vaccination (Day 43).
The total planned number of subjects to receive the study vaccination is 55.
A schematic of the study design is shown in Figure 6.a
For the testing, observations, and assessment schedule, see Appendix A
Figure 6.a
Schematic of Study Design
6.2
Rationales for the Selection of Study Design, Vaccination Dosage, and Endpoints
6.2.1
Rationales for the Selection of Study Design
This study has been designed to evaluate the immunogenicity and safety of BLB-750 given intramuscularly in two 
doses at an interval of 3 weeks (open-label, uncontrolled study).
Clinical studies in Japanese adults for the purpose of the application for the approval of a cell-culture influenza 
vaccine (H5N1 strain) and clinical studies in the Japanese elderly and in children were conducted using a vaccine 
manufactured using a wild type strain as an H5N1 subtype virus strain. For this study, healthy adults were selected 
as a study population because the immunogenicity and safety of vaccination with a vaccine manufactured using an 
attenuated strain as an H5N1 subtype virus strain will be evaluated. For an age group for the study, a population 
Screening period
Treatment period
VISIT
Administration of the
study vaccine
Days from initial
vaccination
-28 to 1
Immunogenicity
evaluation
Informed
consent
Start of
vaccination
End of study
Emrollment
▲
▲
1
2
1
43
22
3
BLB-750 group
(6 weeks)

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aged between 20 and 49 years was selected as a 20 years and older age group, which was not considered to have a 
major difference in immunogenicity within the group.
6.2.2
Rationales for the Selection of Vaccination Dosage Regimen and Strain
The package insert [3] specifies the dosage regimen of the cell-culture influenza vaccine (H5N1 strain) as “usually 
two doses of 0.5 mL should be intramuscularly or subcutaneously injected with an at least 3-week interval,” and “as 
a general rule, intramuscular injection should be used as a vaccination route, with an exception in which 
subcutaneous injection may be selected based on the state of the subject”. Thus, in accordance with the approved 
dosage regimen, the dosage regimen of BLB-750 in this study was selected to be two doses of 0.5 mL of BLB-750 
with the HA content of 7.5 μg as an H5N1 subtype virus strain to be intramuscularly injected at a 3-week interval.
As described in Section 8.1.1.1, BLB-750 (Qinghai RG strain) was selected as the H5N1 subtype virus strain for 
BLB-750 to be used in this study.
6.2.3
Rationales for the Selection of Endpoints
Immunogenicity
To evaluate the immunogenicity against H5N1 subtype viruses of two intramuscular vaccinations of BLB-750, 
three endpoints as measured by the SRH antibody titer (seroprotection and seroconversion rates and geometric 
mean fold increase) specified as immunogenicity endpoints in the Guidelines for the Development of Prototype 
Vaccines in Preparedness for Pandemic Influenza [4] were selected as primary endpoints. Secondary endpoints 
included three endpoints as measured by the SRH antibody titer after the initial vaccination with BLB-750 
(seroprotection and seroconversion rates and geometric mean fold increase) and the GMT of the SRH antibody titer 
after each vaccination. Additional endpoints were also selected to perform the exploratory evaluation of the MN 
antibody titer considered sensitive and specific in the detection of functional/protective antibodies against avian 
influenza strains [5][6].
Safety
Based on common side effects of influenza vaccines and results of previously conducted overseas clinical studies 
(with BLB-750 given intramuscularly) and Japanese clinical studies (with BLB-750 given intramuscularly and 
subcutaneously), injection site reactions (injection site pain, erythema, swelling, induration, and bleeding) and 
systemic reactions (pyrexia, malaise, chills, fatigue, headache, sweaty, myalgia, and arthralgia) have been reported 
as expected adverse reactions to BLB-750 vaccination. Data on the occurrence of these events during the study 
period (especially within 7 days after vaccination) will be collected using a subject diary. As in previously 
conducted overseas and Japanese studies, the severity of pyrexia and injection site reactions will be assessed by 
reference to the “FDA Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials” [7] (see Section 9.1.11). As safety endpoints commonly used in 
clinical studies, adverse events and vital signs will also be evaluated.
6.3
Premature Termination or Suspension of Study or Study Site
6.3.1
Criteria for Premature Termination or Suspension of the Study
The study will be completed as planned unless 1 or more of the following criteria are satisfied that require 
temporary suspension or early termination of the study.
New information or other evaluation regarding the safety or efficacy of the study drug that indicates a change in the 
known risk/benefit profile for the product, such that the risk is no longer acceptable for subjects participating in the 
study.
Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve the primary study 
objectives or compromises subject safety.

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6.3.2
Criteria for Premature Termination or Suspension of Study Sites
A study site may be terminated prematurely or suspended if the site (including the investigator) is found in 
significant violation of GCP, protocol, or contractual agreement, is unable to ensure adequate performance of the 
study, or as otherwise permitted by the contractual agreement.
6.3.3
Procedures for Premature Termination or Suspension of the Study or the Participation 
of Study Site(s)
In the event that the sponsor, an institutional review board (IRB) or regulatory authority elects to terminate or 
suspend the study or the participation of a study site, a study-specific procedure for early termination or suspension 
will be provided by the sponsor; the procedure will be followed by applicable study sites during the course of 
termination or study suspension.

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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
All entry criteria, including test results, need to be confirmed prior to enrollment in the study.
7.1
Inclusion Criteria
Subject eligibility is determined according to the following criteria prior to entry into the study:
1.
In the opinion of the investigator, the subject is capable of understanding and complying with protocol 
requirements.
2.
The subject signs and dates a written, informed consent form prior to the initiation of any study procedures.
3.
The subject is a healthy Japanese adult man or woman.
4.
The subject is aged 20 to 49 years, inclusive, at the time of informed consent.
5.
A female subject of childbearing potential* who is sexually active with a nonsterilized* male partner agrees to 
use routinely adequate contraception from signing of informed consent throughout the duration of the study.
*Definitions and acceptable methods of contraception are defined in Section 9.1.8 and reporting 
responsibilities are defined in Section 9.1.9.
Rationale for the selection of inclusion criteria
Criteria 1 to 5 were selected as standard conditions for the selection of subjects participating in a clinical study in 
healthy adults. The upper limit of age was determined to be 49 years, which was not considered to make a major 
difference in immunogenicity within the 20-years-and-older age group.
7.2
Exclusion Criteria
Any subject who meets any of the following criteria will not qualify for entry into the study:
1.
The subject has received vaccination with any other investigational or study products within 4 months prior to 
vaccination with the study vaccine.
2.
The subject has a history of vaccination with an H5N1 influenza vaccine.
3.
The subject has a history of infection with H5N1 virus.
4.
The subject is at high risk of contracting H5N1 influenza infection (e.g., poultry workers).
5.
The subject is an immediate family member, study site employee, or is in a dependent relationship with a 
study site employee who is involved in conduct of this study (e.g., spouse, parent, child, sibling) or may 
consent under duress.
6.
The subject has poorly controlled, clinically significant manifestations of neurological, cardiovascular, 
pulmonary, hepatic, renal, metabolic, gastrointestinal, urologic, endocrine, or other disorders, which may 
impact their ability to participate as subjects or may potentially confound the study results.
7.
The subject has a body temperature (oral) ≥37.5°C prior to vaccination with the study vaccine on Day 1.
8.
The subject has any medically diagnosed or suspected immune-deficiency condition.
9.
The subject has an immunocompromising condition or disease, or is currently undergoing a form of treatment 
or was undergoing a form of treatment that can be expected to influence immune response within 30 days prior 
to vaccination with the study vaccine. 
Such treatments include, but are not limited to, systemic or high dose inhaled corticosteroids (>800 μg/day of 
beclomethasone dipropionate or equivalent; the use of inhaled and nasal steroids that do not exceed this level 
will be permitted), radiation treatment or other immunosuppressive or cytotoxic drugs.

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10. The subject has received antipyretics within 4 hours prior to vaccination with the study vaccine.
11. The subject has a history of Guillain-Barré Syndrome, demyelinating disorders (including acute disseminated 
encephalomyelitis [ADEM] and multiple sclerosis), or convulsions.
12. The subject has a functional or anatomic asplenia.
13. The subject has a rash, other dermatologic conditions or tattoos that may interfere with the evaluation of local 
reaction.
14. The subject has a past or present history of infection with the Hepatitis B Virus (HBV), Hepatitis C Virus 
(HCV) or Human Immunodeficiency Virus (HIV).
15. The subject has a known hypersensitivity to any component of BLB-750.
16. The subject has a history of severe allergic reactions or anaphylaxis.
17. The subject has a history of drug abuse (defined as any illicit drug use) or a history of alcohol dependence 
within 1 year prior to vaccination with the study vaccine or is unwilling to agree to abstain from excessive 
alcohol and drugs throughout the study.
18. The subject has received any blood product (e.g., blood transfusion or immunoglobulin) within 90 days prior 
to vaccination with the study vaccine.
19. The subject has received any live vaccine within 4 weeks (28 days) prior to vaccination with the study vaccine 
or any inactivated vaccine within 2 weeks (14 days) prior to vaccination with the study vaccine.
20. The subject is a pregnant or lactating woman or wishes to become pregnant before signing informed consent, 
during, or within 12 weeks after the last vaccination with the study vaccine or intends to donate ova during 
such time period
21. For males: The subject has donated whole blood ≥200 mL within 4 weeks (28 days) or ≥400 mL within 12 
weeks (84 days) prior to the first vaccination with the study vaccine.
For females: The subject has donated whole blood ≥200 mL within 4 weeks (28 days) or ≥400 mL within 16 
weeks (112 days) prior to the first vaccination with the study vaccine.
22. For males: The subject has donated whole blood ≥800 mL in total within 52 weeks (364 days) prior to the first 
vaccination with the study vaccine.
For females: The subject has donated whole blood ≥400 mL in total within 52 weeks (364 days) prior to the 
first vaccination with the study vaccine.
23. The subject has donated blood components within 2 weeks (14 days) prior to the first vaccination with the 
study vaccine.
24. In the opinion of the investigator, the subject is unlikely to comply with protocol requirements or is considered 
ineligible for any other reason.
Rationale for the selection of exclusion criteria
Criterion 1 was selected, by reference to the “General Considerations for Clinical Trials” (PFSB/ELD Notification 
No. 380 dated April 21, 1998), to ensure the safety of subjects with the use of the period during which the previous 
study would not affect the present study.
Criteria 2, 3, 4, 8, 9, 12, 18, and 19 were selected to eliminate the possible impact on influenza vaccine evaluation 
(primarily immunogenicity evaluation).

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Criteria 5, 6, 14, 17, 20, and 24 were selected as standard conditions for the selection of subjects participating in a 
clinical study in healthy adults.
Criteria 7 and 13 were selected to eliminate the possible impact on influenza vaccine evaluation (primarily safety 
evaluation).
Criterion 10 was selected to eliminate the possible impact on influenza vaccine evaluation (safety and
immunogenicity evaluation).
Criteria 11, 15, 16, 21, 22, and 23 were selected to ensure the safety of subjects.
7.3
Excluded Medications and Treatments
The use of medications and therapies shown in Table 7.a will be prohibited from the point specified in the table to 
the end of study.
Table 7.a
Excluded Medications and Treatments
In the past
4 months prior to 
vaccination (Day 
1)
90 days prior to 
vaccination 
(Day 1)
30 days prior to 
vaccination (Day 1)
28 days prior 
to vaccination 
(Day 1)
14 days prior to 
vaccination (Day 
1)
• H5N1 
influenza 
vaccines
• Other study 
medications
• Blood 
products 
(transfusion or 
immunoglobu
lin)
• Systemic or high-dose 
inhaled corticosteroids 
(beclomethasone 
dipropionate >800 
μg/day or equivalent)
• Radiotherapy
•
Immunosuppressives
• Cytotoxic drugs
• Live 
vaccines
• Inactivated 
vaccines
The investigator will instruct subjects not to take any drug (including OTC drugs) other than those prescribed by 
the investigator without consulting with the investigator.
7.4
Diet, Fluid, Activity Control
1.
Diet
Subjects should be abstemious during the study period.
2.
Drinking
Excessive consumption of alcohol-containing beverages should be avoided during the study period.
3.
Smoking
Smoking will be prohibited from 1 hour prior to each assessment to the end of assessment.
4.
Exercise
Excessive exercise will be prohibited during the study period.
5.
Blood donation after the end of study

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Blood donation will be prohibited for at least 12 weeks after the completion of final assessment in this study. 
The investigator will provide subjects with counseling on the prohibition of blood donation.
6.
Others
The investigator will instruct subjects that if they visit another medical institution during the study period, they 
must inform the investigator of the reason for the visit and treatments given and must inform the institution of 
their participation in this study.
The investigator will also instruct subjects to keep the study drug injection site clean and to avoid scratching or 
rubbing the injection site without good reason.
For female subjects of childbearing potential who are sexually active with a nonsterilized male partner, the 
investigator will instruct them to use adequate contraception from the time of signing of informed consent, 
throughout the duration of the study, and for 12 weeks after the last vaccination with the study drug.
7.5
Criteria for Discontinuation or Withdrawal of a Subject
The primary reason for discontinuation or withdrawal of the subject from the study or study drug should be 
recorded in the case report form ([e]CRF) using the following categories. For subjects who discontinue/is 
withdrawn before enrollment in this study, see 9.1.12
1.
Death
The subject dies during the study. 
Note: If the subject dies on study, the event will be considered as a serious adverse event (SAE). See Section 
10.2.2 for the reporting procedures.
2.
Adverse event (AE)
The subject has experienced an AE that requires early termination because continued participation imposes an 
unacceptable risk to the subject’s health or the subject is unwilling to continue because of the AE.
3.
Protocol deviation
The discovery after enrollment that the subject failed to meet protocol entry criteria or did not adhere to 
protocol requirements, and continued participation poses an unacceptable risk to the subject’s health.
4.
Lost to follow-up
The subject did not return to the clinic and attempts to contact the subject were unsuccessful. Attempts to 
contact the subject must be documented in the subject’s source documents.
5.
Withdrawal by the subject
The subject wishes to be withdrawn from the study. The reason for withdrawal, if provided, should be 
recorded in the (e)CRF.
Note: All attempts should be made to determine the underlying reason for the withdrawal and, where possible, 
the primary underlying reason should be recorded. In the case of withdrawal due to an AE, however, 
consideration should be given to classifying it as “AE(s)” rather than as “voluntary withdrawal by the subject.”
6.
Study Terminated by sponsor. 
The sponsor terminates the study.
7.
Pregnancy
The subject is found to be pregnant.
Note: If the subject is found to be pregnant, the subject must be withdrawn from the study immediately. The 
procedure is described in Section 9.1.9.
8.
Other
Note: The specific reasons should be recorded in the “specify” field of the (e)CRF.

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7.6
Procedures for Discontinuation or Withdrawal of a Subject
The investigator may discontinue a subject’s study participation at any time during the study when the subject 
meets the study termination criteria described in Section 7.5 In addition, a subject may discontinue his or her 
participation without giving a reason at any time during the study. Should a subject’s participation be discontinued, 
the primary criterion for termination must be recorded by the investigator. In addition, efforts should be made to 
perform all procedures scheduled for the Early Termination Visit. Subjects who are withdrawn from the study after 
receiving vaccination with the study drug will not be replaced.

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8.0
CLINICAL TRIAL MATERIAL MANAGEMENT
This section contains information regarding all medication and materials provided directly by the sponsor, and/or 
sourced by other means, that are required by the study protocol, including important sections describing the 
management of clinical trial material.
8.1
Study Drug and Materials
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling
The study drug in this protocol is defined below.
8.1.1.1
Study Drug
1.
Dosage form and dose strength
Substance code: BLB-750
Trade name: Cell-Culture Influenza Vaccine H5N1 “Takeda” 1 mL
Manufacturer: Takeda Pharmaceutical Company Limited
Dosage form: A clear to whitish liquid injection (vial)
Components and dose strength: One vaccination dosage of 0.5 mL contains components shown in Table 8.a.
Table 8.a
Components and Dose Strength of BLB-750 Injection 0.5 mL
Component
Dose strength
Function
Active ingredient
(vaccine strain)
BLB-750 Qinghai RG strain
[A/bar-headed goose/Qinghai/1A/2005
(H5N1) (SJRG-163222)]
7.5 µg
-
Inactive 
ingredient
Trometamol
1.2 mg
Buffer
Sodium chloride
4.0 mg
Isotonicifier
Polysorbate 80
0.63 mg
Aggregation 
preventer
2.
Packaging and labeling
Two vials of the study drug will be packaged in a box labeled with the following information.

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CONFIDENTIAL
<front side of the box>
Figure 8.a
Labeling Sample of the Outer Box for the Study Drug
8.1.1.2
Ancillary Materials
The syringe and injection needle designated by the sponsor should be used for vaccination with the study drug.
8.1.2
Storage
The study drug should be stored at 2°C to 8°C but not frozen, and be protected from light.
The site designee must keep the study drug in an appropriate, limited-access, secure place until it is used or 
returned to the sponsor or designee (CRO) . All drugs supplied by the sponsor must be stored under the conditions 
specified on the label. A daily temperature log of the drug storage area must be maintained every working day.
8.1.3
Dose and Regimen
According to the following procedures, two doses of the study drug 0.5 mL will be injected into the brachial muscle 
(deltoid muscle) on Days 1 and 22.

Let the study drug (vial) warm to room temperature.

Prior to administration, shake the vial for 5-10 seconds to mix the vaccine suspension completely.

Prior to administration, visually inspect for any insoluble particulate matter or discoloration. The study drug 
should not be used if any insoluble particulate matter, discoloration, or leakage is observed.

Using a 1-inch long, 25-gauge needle, inject a dose of 0.5 mL into the arm opposite to the one used for blood 
collection to obtain a sample for immunogenicity testing wherever possible.

The following should be noted to avoid the effect of intramuscular vaccination on the tissues and nerves:

Injecting into a nerve tract should be avoided.

In the case of intense pain and/or backflow of blood associated with needle insertion, withdraw the needle 
immediately and inject into another site.
試験薬
2ﾊﾞｲｱﾙ
：
××××××
：
：
試験薬管理⼿順書に記載
：
2℃-8℃で凍結を避けて遮光保存
BLB-750注射剤
(Protocol No.BLB-750/CCT-901)
被験者識別コード
製　造　番　号
使　⽤　期　限
貯　　     　法
室温に戻した後、使⽤時よく振り混ぜること
武⽥薬品⼯業株式会社
⼤阪市中央区道修町四丁⽬1番1号
1001-

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8.1.4
Overdose
An overdose is defined as a known deliberate or accidental vaccination with the study drug at a dose above that 
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 (e)CRF, 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 overdose will be documented on an AE 
page of the CRF(s) in accordance with 10.0 Adverse Events.
SAEs associated with overdose should be reported in accordance with the procedure outlined in 10.2.2.
In the event of drug overdose, the subject should be treated as appropriate by the investigator.
8.2
Study Drug Dispensing Procedures
Subjects will be vaccinated with the study drug according to the study schedule.
8.3
Accountability and Destruction of Sponsor-Supplied Drugs
The site designee will receive the procedures for handling, storage and management of study drugs 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, and collection 
of unused medications as well as their return to the sponsor or their destruction.
The site designee will immediately return unused supplies of the study drug to the sponsor after the study is closed 
at the site.

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9.0
STUDY PLAN
9.1
Study Procedures
The following sections describe the study procedures and data to be collected. For each procedure, subjects are to 
be assessed by the same investigator or site personnel whenever possible. The study schedule is provided in 
Appendix A.
9.1.1
Informed Consent Procedure
The requirements of the informed consent are described in Section 15.2. Informed consent must be obtained from 
each subject before any protocol-directed procedures are performed. A unique subject identification number 
(subject number) will be assigned to each subject at the time that informed consent is explained; this subject 
number will be used throughout the study; this subject number will be used throughout the study.
9.1.2
Demographics, Medical History, and Medication History Procedure
Demographic information to be obtained will include date of birth and sex.
For medical history, clinically significant diseases or symptoms that have healed or resolved within 1 year prior to 
the first vaccination with study drug will be collected. Ongoing conditions are considered present illnesses (see 
Section 9.1.7). History of influenza infection within 1 year prior to the first vaccination with study drug will be 
collected.
Prior treatments to be collected include all drugs discontinued within 4 weeks prior to informed consent. In addition, 
history of influenza vaccination (including pandemic influenza vaccines and other investigational products) within 
1 year prior to informed consent will be collected.
9.1.3
Physical Examination Procedure
A baseline physical examination at baseline (defined as the assessment prior to the first vaccination with study 
drug), will consist of the following body systems:
(1) eyes; (2) ears, nose; and throat; (3) cardiovascular system; (4) respiratory system; (5) gastrointestinal system; 
(6) dermatologic system; (7) extremities; (8) musculoskeletal system; (9) nervous system; (10) lymph nodes; and 
(11) other.
During physical examination after each vaccination with the study drug, the subject will be assessed for any 
abnormalities considered clinically significant in comparison with pre-vaccination physical findings. During study 
visits at Days 22 and 43 and at discontinuation, the subject will be assessed for any pyrexia, systemic and injection 
site reactions, and other events based on the subject diary (see Section 9.1.11).
9.1.4
Weight and Height
A subject should have weight and height measured while wearing indoor clothing on and shoes off. The Takeda 
standard for collecting height is centimeters without decimal places (rounded to the nearest whole number) and for 
weight it is kilograms (kg) with 1 decimal place (rounded to one decimal place).
Example: Height = 176 cm, weight = 79.2 kg
9.1.5
Vital Signs Procedure
Vital signs will include body temperature (oral), respiratory rate, sitting blood pressure (resting more than 
5-minutes), and pulse (beats per minute). No respiratory rate measurement will be required at Day 43 and at 
discontinuation.

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If blood sampling and vital sign measurement are to be performed at the same point, vital sign measurement should 
be performed first.
The subject must measure his/her temperature and record it in the subject diary every day on Days 1-7 and 22-28 
and as needed on Days 8-22 (before study visit) and 29-43 (before study visit) (see Section 9.1.11). Daily 
measurements on Days 1-7 and 22-28 should be transcribed to the (e)CRF.
9.1.6
Documentation of 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. Concomitant medication is not provided by Takeda. 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 through the end of the study), and all medication including vitamin supplements, over-the-counter 
medications, and oral herbal preparations, must be recorded in the (e)CRF.
9.1.7
History of Present Illness
A present illness refers to any clinically significant disease or symptom existing at the first vaccination with study 
drug. All clinically significant laboratory values and abnormal findings observed during examination prior to 
vaccination with the study drug should be regarded as present illnesses. The details of present illnesses (diagnoses) 
should be recorded.
9.1.8
Contraception and Pregnancy Avoidance Procedure
From signing of informed consent, throughout the duration of the study, and for 12 weeks after last dose of study 
drug, female subjects of childbearing potential* who are sexually active with a nonsterilized male partner** must 
use adequate contraception. In addition they must be advised not to donate ova during this period.
*A woman is considered a woman of childbearing potential (WOCBP), i.e. fertile, following menarche and 
until becoming post-menopausal unless permanently sterile. Permanent sterilization methods include 
hysterectomy, and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months 
without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal 
range (FSH >40 IU/L) may be used to confirm a post-menopausal state in younger women (e.g. those < 45 
year old) or women who are not using hormonal contraception or hormonal replacement therapy. However, in 
the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.
**Sterilized males should be at least 1 year post vasectomy and have confirmed that they have obtained 
documentation of the absence of sperm in the ejaculate or have had bilateral orchidectomy.
Such subjects will be provided with information on acceptable methods of contraception as part of the subject 
informed consent process, and will be asked to sign a consent form stating that they understand the requirements 
for avoidance of pregnancy during the course of the study. 
During the course of the study, regular urine human chorionic gonadotropin (hCG) 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 study procedures Appendix A In addition to a urine hCG pregnancy test 
before vaccination on the day of vaccination with the study drug (Day 1), the result of urine hCG test at the end of 
study (or discontinuation) (Day 43) must be confirmed negative.

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In this study, the only acceptable methods of contraception are:
Barrier methods (each time 
the subject has intercourse):
Intrauterine devices (IUDs):
Hormonal 
contraceptives:
Male condom PLUS 
spermicide.
Copper T PLUS condom.
Progesterone T PLUS condom.
Combined pill. 
9.1.9
Pregnancy
If any subject is found to be pregnant during the study she should be withdrawn and any sponsor-supplied drug 
should be immediately discontinued.
If the pregnancy occurs during administration of active study drug, eg, after Day 1 or within 12 weeks of the last 
dose of active study drug, the pregnancy should be reported immediately, using a pregnancy notification form, to 
the contact listed on the attached sheet.
If the female subject agrees to the primary care physician (obstetrician) being informed, the investigator should 
notify the primary care physician that the subject was participating in a clinical study at the time she became 
pregnant and provide details of treatment the subject received.
All pregnancies in subjects on active study drug including comparator will be followed up to final outcome, using 
the pregnancy form. Pregnancies will remain blinded to the study team. The outcome, including any premature 
termination, must be reported to the sponsor. An evaluation after the birth of the child will also be conducted.
9.1.10 Immunogenicity Evaluation
The SRH and MN antibody titers against influenza virus for immunogenicity evaluation will be measured by the 
laboratory specified in the procedures. As for blood sampling, 20 mL of blood per sampling will be collected from 
the forearm vein. The blood sample collected will be used for study-specific endpoint measurements as well as 
immunogenicity evaluation by a government organization, and also may be used for other exploratory 
immunogenicity evaluations (see Section 9.4). No genetic testing will be performed using the samples collected in 
this study.
For the immunogenicity evaluation by a government organization, the protocol and the result report will be 
prepared by the sponsor or the government organization, separately from the protocol and clinical study report for 
this study. If other exploratory immunogenicity evaluations are performed, their protocols and result reports should 
also be prepared.
Detailed procedures for handling and transporting samples are found in separately prepared documented procedures 
for handling of biological samples for immunogenicity evaluation.
9.1.11 Injection Site and Systemic Reactions (Diary-based Assessment)
As AEs related to reactogenicity of vaccination with the study drug, injection site reactions (injection site pain, 
erythema, swelling, induration, and haemorrhage, hereinafter the same applies) and systemic reactions (pyrexia, 
malaise, chills, fatigue, headache, sweaty, myalgia, and arthralgia, hereinafter the same applies) occurring between 
the initial vaccination with study drug and 42 days after the vaccination (Day 43) will be collected via the subject 
diary.
Injection site and systemic AEs occurring within 21 days after each vaccination (Days 22 and 43) will be collected 
via the subject diary (Diary 1 for Days 1-7, Diary 2 for Days 8-22, Diary 3 for Days 22-28, and Diary 4 for Days 
29-43).

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Diaries 1 and 2 will be provided to each subject together with a digital thermometer for oral temperature 
measurement and a ruler for injection site reaction measurement after vaccination with the study drug on Day 1. 
These diaries will be collected and reviewed by the investigator at Day 22 visit.
Information to be recorded in Diary 1 (Days 1-7)

Body temperatures (oral) measured once daily in the evening during the period after vaccination with the study 
drug (Day 1) until Day 7

Injection site reactions

Systemic reactions

Other AEs
Information to be recorded in Diary 2 (Days 8-22)

Body temperatures (oral) measured when the subject experiences any AE with pyrexia during the period after 
Day 8 until Day 22 before study visit

Other AEs
Diaries 3 and 4 will be provided to each subject at Day 22 visit (or at Day 1 visit) and will be collected and 
reviewed by the investigator at Day 43 visit.
Information to be recorded in Diary 3 (Days 22-28) [same as information to be recorded in Diary 1]

Body temperatures (oral) measured once daily in the evening during the period after vaccination with the study 
drug (Day 22) until Day 28

Injection site reactions

Systemic reactions

Other AEs
Information to be recorded in Diary 4 (Days 29-43) [same as information to be recorded in Diary 2]

Body temperatures (oral) measured when the subject experiences any AE with pyrexia during the period after 
Day 29 until Day 43 before study visit

Other AEs
For recording of body temperatures (oral) and injection site reactions in the diary, each subject will be asked to 
follow the instructions below.
<Body temperature (oral) measurement>

Diary 1 (Days 1-7) and Diary 3 (Days 22-28): Subjects will measure their oral temperatures once daily, in the 
evening wherever possible, using the oral digital thermometer provided for the study. Subjects will be asked to 
keep to the same measurement time every day whenever possible. In the case of pyrexia (defined as oral 
temperature ≥38.0°C), oral temperatures should be measured more than once (approximately every 4-8 hours) 
wherever possible and recorded in Diary 1 or 3 until the pyrexia resolves (defined as oral temperature <38.0°C). 
Subjects will record all measurement information (i.e., measurement results and date and time of measurement) 
obtained on Days 1-7 and Days 22-28 in Diary 1 and 3, respectively.

Diary 2 (Days 8-22 [before study visit]) and Diary 4 (Days 29-43 [before study visit]): Daily measurement will 
not be required. Measurements should be obtained using the oral digital thermometer provided for the study 
only when any symptom suggestive of pyrexia is noted. In the case of pyrexia (defined as oral temperature 
≥38.0°C), the subject should measure his/her oral temperature at least once daily, or more than once 

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(approximately every 4-8 hours) wherever possible, and record it in Diary 2 or 4 until the pyrexia resolves 
(defined as oral temperature <38.0°C) to confirm the end date. Subjects will record measurement information 
(i.e., measurement results and date and time of measurement) obtained on Days 8-22 (before study visit) and 
Days 29-43 (before study visit) in Diary 2 and 4, respectively.
<Injection site reactions>

Diary 1 (Days 1-7) and Diary 3 (Days 22-28): If, among injection site reactions, erythema, swelling, or 
induration is observed after vaccination with the study drug, the subject should measure the longest diameter of 
the injection site reaction using the ruler provided for the study and record it in Diary 1 or 3.

Diary 2 (Days 8-22 [before study visit]) and Diary 4 (Days 29-43 [before study visit]): All newly observed 
injection site reactions and all other injection site reactions observed any time during Days 1-7 or Days 22-28 
but that have not resolved during these periods should be recorded in Diary 2 or 4. The longest diameter should 
also be measured and recorded.
Based on records from each subject’s diary collected at Day 22 and 43 visits, the investigator will capture all AEs 
occurring during Days 1-22 and Days 22-43, and record these AEs on the (e)CRF together with the severity and 
causality assessment for each event.
As for pyrexia, the start date is defined as the date on which the first oral temperature measurement ≥38.0°C is 
obtained, and the end date is defined as the date on which the first oral temperature measurement <38.0°C is 
obtained after the onset. Daily oral temperature measurements on Days 1-7 and Days 22-28 recorded in Diaries 1 
and 3 should be transcribed to the (e)CRF even if they are <38.0°C. If two or more temperature measurements are 
recorded for the same day, the highest temperature of that day should be transcribed to the (e)CRF.
The severity of pyrexia and injection site reactions will be assessed using the criteria shown below, by reference to 
the “FDA Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Clinical Trials”[7] For other AEs (including solicited systemic reactions to be recorded in the 
subject diary), assessment will be performed as specified in Section 10.1.5.
Pyrexia:
Mild: ≥38.0°C and <38.5°C
Moderate: ≥38.5°C and <39.0°C
Severe: ≥39.0°C
Measurable injection site reactions (injection site erythema, swelling, and induration): 
Mild: ≥2.5 cm and <5.1 cm
Moderate: ≥5.1 cm and <10.1 cm
Severe: ≥10.1 cm
*Injection site reactions <2.5 cm will not be regarded as AEs. However, the longest diameter recorded in the diary 
will be transcribed to the (e)CRF separately from AEs, regardless of whether it is ≥2.5 cm or <2.5 cm.
Injection site pain and haemorrhage:
Mild: No interference with upper extremity movement
Moderate: Interference with upper extremity movement present.
Severe: Upper extremity impairment/dysfunction

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9.1.12
Documentation of Subjects Failure before Enrollment in the Study
The investigator accounts for all subjects who sign informed consent.
If the subject is found to be not eligible before the start of vaccination with the study drug, the investigator should 
complete the (e)CRF.
The primary reason for subjects failure before the start of vaccination with the study drug is recorded in the (e)CRF 
using the following categories:

Death

Adverse Event

Screen failure (failed inclusion criteria or did meet exclusion criteria)

Protocol deviation

Lost to follow-up

Withdrawal by subject <specify reason>

Study terminated by sponsor

Pregnancy

Sample size sufficient

Other <specify reason>
Subject numbers assigned to subjects who fail screening should not be reused.
9.1.13 Documentation of Enrollment in the Study
Subjects will be enrolled in the study and receive vaccination with the study drug only if they meet all the inclusion 
criteria and do not meet any of the exclusion criteria.
For subjects who did not receive vaccination with the study drug, the investigator should record the primary reason 
for failure on the applicable (e)CRF.
9.2
Vaccination Status in Subjects
The study vaccine will be administered under observation at the study site. The investigator will observe the 
subjects for any abnormalities for at least 30 minutes after vaccination with the study drug at the study site. The 
date of vaccination will be recorded in the subjects' source documents and (e)CRFs. The inventory of the study 
drugs dispensed will be controlled and recorded in the investigational product accountability log or equivalent 
document by a study site pharmacist or a person designated by the investigator.
9.3
Schedule of Observations and Procedures
The schedule for all testing, observation, and assessments is provided in Appendix A. The following testing, 
observation, and assessments should be completed at the designated time points.
9.3.1
<Screening Period/Day 1 (Starting before the Initial Vaccination and Ending after the 
Completion of the Initial Vaccination)>
Enrollment in the study will be performed on Day 1, and the following testing, observation, and assessments will be 
performed: Subjects will be screened in accordance with predefined inclusion and exclusion criteria as described in 
Section 7.0.

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
Informed consent

Demographics, medical history, and medication history procedure

Physical examination

Vital signs (body temperature [oral], blood pressure, and pulse and respiratory rates)

Weight and height

Documentation of concomitant medications

Present illness

Pregnancy test (only for female subjects of childbearing potential)

Blood sampling for the immunogenicity evaluation
Subjects meeting all the inclusion criteria and not meeting any of the exclusion criteria will be enrolled in the study. 
Subjects will receive vaccination with the study drug under the supervision of the investigator at the study site. For 
the procedures for the recording of subjects withdrawn from the study prior to the start of vaccination with the 
study drug, see Section 9.1.12.
9.3.2
<Treatment Period/Day 1 (after the Initial Vaccination) to Day 22 (before Visiting the 
Study Site)>
During the period from Day 1 (after the initial vaccination) to Day 22 (before visiting the study site), the following 
testing, observation, and assessments will be performed: Day 1 (the day of initial vaccination) will be the day of 
study visit, and subjects will monitor themselves at home during the period after the completion of Day 1 visit until 
before Day 22 visit (see Section 9.1.11).

Physical Examination
Time point: Day 1 (after the initial vaccination)
The investigator will monitor for any acute hypersensitivity reaction, etc., for 30 minutes after vaccination.

Vital signs (blood pressure and pulse and respiratory rates)
Time point: Day 1 (after the initial vaccination)
Vital signs will be measured 30 minutes after vaccination.

Vital signs (body temperature [oral])
From Days 1 to 7, subjects will measure their body temperature (oral) and record it in the subject diary. 
From Days 8 to 22 (before visiting the study site), subjects will measure their body temperature (oral) only 
if they develop pyrexia (or any symptoms suggestive of pyrexia) (see Section 9.1.11).

Supply of the subject diary
Time point: Day 1 (Diaries 1 and 2) (Diaries 3 and 4 may be supplied on Day 1)

Completion of the subject diary (by subjects)
Time points: From Day 1 (after the initial vaccination) to Day 7 (Diary 1) and from Day 8 to Day 22 
(before visiting the study site) (Diary 2)
During the periods from Day 1 (after the completion of study visit) to Day 7 and from Day 8 to Day 22 (before 
visiting the study site), subjects will monitor for and record any systemic reactions, injection site reactions, etc. (see 
Section 9.1.11).

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9.3.3
<Treatment Period/Day 22 (Starting before the Second Vaccination and Ending after 
the Completion of the Second Vaccination)>
The following tests, observations, and assessments will be performed on Day 22 (starting before the second 
vaccination and ending after the completion of the second vaccination).

Physical Examination

Vital signs (body temperature [oral], blood pressure, and pulse and respiratory rates)

Collection of concomitant medications and AEs

Blood sampling for the immunogenicity evaluation

Collection of the subject diary (Diaries 1 and 2)
Subjects will receive vaccination with the study drug under the supervision of the investigator at the study site.
9.3.4
<Treatment Period/Day 22 (after the Second Vaccination) to Day 43 (before Visiting the 
Study Site)>
During the period from Day 22 (after the second vaccination) to Day 43 (before visiting the study site), the 
following testing, observation, and assessments will be performed: Subjects will monitor themselves at home 
during the period after the completion of Day 22 visit until before Day 43 visit (see Section 9.1.11).

Physical Examination
Time point: Day 22 (after vaccination)
The investigator will monitor for any acute hypersensitivity reaction, etc., for 30 minutes after vaccination.

Vital signs (blood pressure and pulse and respiratory rates)
Time point: Day 22 (after vaccination)
Vital signs will be measured 30 minutes after vaccination.

Vital signs (body temperature [oral])
Form Days 22 to 28, subjects will measure their body temperature (oral) and record it in the subject diary. 
Form Days 29 to 43 (before visiting the study site), subjects will measure their body temperature (oral) 
only if they develop pyrexia (or any symptoms suggestive of pyrexia) (see Section 9.1.11).

Supply of the subject diary
Time point: Day 22 (Diaries 3 and 4) (Diaries 3 and 4 may be supplied on Day 1)

Completion of the subject diary (by subjects)
Time point: From Day 22 (after vaccination) to Day 28 (Diary 3) and from Day 29 to Day 43 (before 
visiting the study site) (Diary 4)
During the periods from Day 22 (after the completion of study visit) to Day 28 and from Day 29 to Day 43 (before 
visiting the study site), subjects will monitor for and record any systemic reactions, injection site reactions, etc. (see 
Section 9.1.11).
9.3.5
<Treatment Period/at the End of Study/Day 43>
The following testing, observation, and assessments will be performed at the final study visit (for observation) (Day 
43).

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
Physical Examination

Vital signs (body temperature [oral], blood pressure, and pulse rate)

Pregnancy test (only for female subjects of childbearing potential)

Blood sampling for the immunogenicity evaluation

Collection of the subject diary (Diaries 3 and 4)

Collection of concomitant medications and AEs
For all subjects receiving the study drug, the investigator must complete the Subject Status (e)CRF page.
9.3.6
<Treatment Period/at Discontinuation>
For subjects withdrawn from the study, reasons for study discontinuation must be recorded in the subject’s source 
documents and CRF, and the following testing, observation, and assessments should be performed wherever 
possible.

Physical Examination

Vital signs (body temperature [oral], blood pressure, and pulse rate)

Pregnancy test (only for female subjects of childbearing potential)

Blood sampling for the immunogenicity evaluation

Collection of the subject diary

Collection of concomitant medications and AEs
For all subjects receiving the study drug, the investigator must complete the Subject Status (e)CRF page.
9.4
Biological Sample Retention and Destruction
The remainder of serum samples collected in accordance with Section 9.1.10, “Immunogenicity Evaluation” will be 
stored. Serum samples will be discarded after they will no longer be used. Details on sample retention will be 
provided in separately prepared handling procedures.
9.5
Amount and Frequency of Blood Collection
The total amount of blood to be collected from each subject will be as shown in Table 9.a.
Table 9.a
Amount and Frequency of Blood Collection
Test
Amount to be 
collected per 
collection
Frequency of 
collection
Total amount to be 
collected
Immunogenicity testing
20 mL 
Three times
60 mL
Total amount to be collected
60 mL

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10.0
ADVERSE EVENTS
10.1
Definitions
10.1.1 AEs
An AE is defined as any untoward medical occurrence in a clinical investigation subject who has signed informed 
consent to participate in a study; it does not necessarily have to have a causal relationship with this treatment or 
study participation.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal laboratory 
finding), symptom, or disease temporally associated with the study participation whether or not it is considered 
related to the drug or study procedures.
10.1.2 Additional Points to Consider for AEs
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent events for 
pre-existing conditions or underlying diseases should not be considered AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or dose adjustment of the study drug or a concomitant medication.

Be considered unfavorable by the investigator for any reason.
AEs caused by a study procedure (e.g., a bruise after blood draw) should be recorded as an AE.
Diagnoses vs signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs (including abnormal 
laboratory values or ECG findings) or symptoms should NOT be recorded as additional AEs. However, each
solicited local or systemic AE to be recorded in the subject diary should be recorded as a single event. If a 
diagnosis is unknown, sign(s) or symptom(s) should be recorded appropriately as an AE(s).
Pre-existing conditions:

Pre-existing conditions (present since before the first vaccination with study drug) are considered present 
illnesses and should NOT be recorded as AEs. However, if the present illness worsens after the first 
vaccination with study drug, it should be appropriately recorded as an AE. The investigator should ensure that 
the AE term to be reported reflects a change from baseline (e.g., “worsening of…”).

If a subject has a pre-existing episodic condition (eg, asthma, epilepsy) any occurrence of an episode should 
only be captured as an AE if the episodes become more frequent, serious or severe in nature, that is, 
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 captured as an AE if occurring to a greater extent to that which would be 
expected. Again, investigators should ensure that the AE term recorded captures the change in the condition 
(eg, “worsening of…”).
Change in severity of AEs:

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
If the subject experiences a change in severity of an AE that is not related to starting the study drug or 
changing in the dose or regimen, the event should be captured once with the maximum severity recorded.
Preplanned surgeries or procedures:

Preplanned procedures (surgeries or therapies) that are scheduled prior to signing of informed consent are not 
considered AEs. However, if a preplanned procedure is performed early (e.g., as an emergency) due to a 
worsening of the pre-existing condition, the worsening of the condition should be captured appropriately as 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.
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:

The occurrence of overdose with no associated events should NOT be considered an AE, but instead will be 
documented on an Overdose page of the (e)CRF. Any event associated with overdose should be considered 
AEs and will be recorded on the AE page of the (e)CRF.
10.1.3 SAEs
An SAE is defined as any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product (including a study drug), which:
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.
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.
●
Includes any event or synonym described in the Takeda Medically Significant AE List (Table 10.a).

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Table 10.a
Takeda Medically Significant AE List
Term
Acute respiratory failure/acute respiratory distress 
syndrome
Torsade de pointes / ventricular fibrillation / ventricular 
tachycardia
Malignant hypertension
Convulsive seizure (including seizure and epilepsy)
Agranulocytosis
Aplastic anemia
Toxic epidermal necrolysis/Stevens-Johnson syndrome
Hepatic necrosis
Acute liver failure
Anaphylactic shock
Acute renal failure 
Pulmonary hypertension
Pulmonary fibrosis (including interstitial lung disease)
Confirmed or suspected endotoxin shock
Confirmed or suspected transmission of infectious agent 
by a medicinal product
Neuroleptic malignant syndrome / malignant 
hyperthermia
Spontaneous abortion / stillbirth and fetal death
Note: The terms listed in this table may be “important medical events” that require the reporting of SAEs and are 
therefore broadly defined medical terms.
7.
The following important medical events associated with the use of an influenza vaccine: neuritis, encephalitis, 
vasculitis, Guillain-Barre syndrome, Bell’s palsy (facial palsy), and demyelinating disorder (including acute 
disseminated encephalomyelitis [ADEM] and multiple sclerosis)
10.1.4 AEs of Special Interest
An AE of Special Interest (regardless of whether it is serious or not) is one of scientific and medical concern 
specific to the compound or program, for which ongoing monitoring and rapid communication by the investigator 
to Takeda may be appropriate. Such events may require further investigation in order to characterize and understand 
them.
10.1.5 Severity of AEs
The different categories of intensity are characterized as follows:
Mild:
The event is transient and easily tolerated by the subject.
Moderate:
The event causes the subject interrupts the subject’s usual activities.
Severe:
The event causes considerable interference with the subject’s usual activities.
However, pyrexia and injection site reactions (injection site pain, erythema, swelling, induration, and haemorrhage) 
should be assessed according to the classification specified in 9.1.11.
10.1.6 Causality of AEs
The relationship of each AE to study drug(s) will be assessed using the following categories:
Related:
An AE that follows a reasonable temporal sequence from administration of a drug (including the 
course after withdrawal of the drug), or for which possible involvement of the drug cannot be ruled 
out, although factors other than the drug, such as underlying diseases, present illness, concomitant 
medications and concurrent treatments, may also be responsible.
Not related:
An AE that does not follow a reasonable temporal sequence from administration of a drug and/or 
that can reasonably be explained by other factors, such as underlying diseases, present illness, 
concomitant medications and concurrent treatments.

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10.1.7 Relationship to Study Procedures
Relationship (causality) to study procedures should be determined for all AEs.
The relationship should be assessed as Related if the investigator considers that there is reasonable possibility that 
an event is due to a study procedure. Otherwise, the relationship should be assessed as Not Related. 
10.1.8 Start Date
The start date of the AE is the date that the first signs/symptoms were noted by the subject and/or investigator.
The start date of AEs will be determined using the following criteria;
AEs
Start Date
Any signs/symptoms/diseases (diagnosis)
The date that the first signs/symptoms 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 of present illnesses
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.
10.1.9 End Date
The end date of the AE is the date at which the subject recovered, the event resolved but with sequelae or the 
subject died.
10.1.10 Pattern of Adverse Events
Episodic AEs (eg, vomiting) or those which occur repeatedly over a period of consecutive days are intermittent. All 
other events are continuous.
10.1.11 Action Taken with Study Treatment
Actions concerning the study drug will be classified and defined as follows:
• Drug withdrawn
A study drug is stopped due to the particular AE.
• Dose not changed
The particular AE did not require stopping a study drug.
• Unknown
Only to be used if it has not been possible to determine what action has been taken.
• Not applicable
A study drug was stopped for a reason other than the particular AE eg, the study has been 
terminated, the subject died, vaccination with study drug was already stopped before the 
onset of the AE.

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10.1.12 Outcome of Event
• Recovered/resolved
Subject returned to first assessment status with respect to the AE.
• Recovering/resolving
The intensity is lowered by one or more stages:
The diagnosis or signs/symptoms has almost disappeared; 
The abnormal laboratory value improved, but has not returned to the normal range or 
to baseline; the subject died from a cause other than the particular AE with the 
condition remaining “recovering/resolving”.
• Not recovered/not 
resolved
There is no change in the diagnosis, signs or symptoms; 
The intensity of the diagnosis, signs/ symptoms or laboratory value on the last day of 
the observed study period has got worse than when it started; is an irreversible 
congenital anomaly; the subject died from another cause with the particular AE state 
remaining “Not recovered/not resolved”.
• Recovered/Resolved with 
sequelae
The subject recovered from an acute AE but was left with permanent/significant 
impairment (e.g, recovered from a cardiovascular accident but with some persisting 
paresis.
• Fatal
The AEs which are considered as the cause of death.
• Unknown
The course of the AE cannot be followed up due to hospital change or residence 
change at the end of the subject’s participation in the study.
10.2
Procedures
10.2.1 Collection and Reporting of AEs
10.2.1.1
AE Collection Period
The collection of AEs will be started at the initial vaccination with the study drug (Day 1) and continued until the 
end of study (Day 43).
10.2.1.2
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.
All subjects experiencing AEs after the first exposure to study drug, whether considered associated with the use of 
the study drug or not, must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to baseline or until there is a satisfactory explanation for the changes observed. All 
AEs will be documented in the AE page of the (e)CRF, whether or not the investigator concludes that the event is 
related to the drug treatment. The following information will be documented for each event:
1.
Event term
2.
Start and end date
3.
Pattern
4.
Severity
5.
Investigator’s opinion of the causality between the event and administration of study drug(s)
6.
Investigator’s opinion of the causality to study procedure(s), including the details of the suspected procedure

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7.
Action taken with study treatment
8.
Outcome of event
9.
Seriousness
10. Treatment emergent (After the first exposure to study drug)
11. For pyrexia, the maximum body temperature and the presence or absence of a 24-hour or longer persistence
12. For injection site erythema, swelling, and induration, the longest diameter
10.2.1.3
AEs of Special Interest Reporting
In this study, AEs of special interest will include the following AEs:
Hypersensitivity and anaphylaxis or any events suggestive of hypersensitivity
If this AE of special interest, which occurs during the treatment period or the follow-up period, is considered to be 
clinically significant, it should be reported to the sponsor (described in the separate contact information list) 
immediately or within 1 business day of first onset or subject’s notification of the event. The study-specific 
Solicited AE Form or SAE Form should be completed, signed and/or sealed by the principal investigator, and 
reported to appropriate personnel in the separate contact information list within 10 business days.
The AE of special interest have to be recorded as AEs in the (e)CRF. An evaluation form (the original copy of 
Solicited AE Form or SAE Form) along with all other required documentation must be submitted to the sponsor.
10.2.2 Collection and Reporting of SAEs
When an SAE occurs through the AE collection period it should be reported according to the following procedure:
An SAE should be reported to the sponsor (described in the separate contact information list) within 1 business day 
of first onset or subject’s notification of the event. The principal investigator should submit the completed SAE 
form 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

Subject identification number

Investigator’s name

Name of the study drug(s)

Causality assessment
Any SAE spontaneously reported to the investigator following the AE collection period should be reported to the 
sponsor if considered related to study participation.
The investigator should report any AEs to the sponsor and submit the form within the appropriate period as 
specified by the sponsor.
10.3
Follow-up of SAEs
If information not available at the time of the first report becomes available at a later date, the investigator should 
complete a follow-up SAE form or provide other written documentation and fax it immediately. Copies of any 
relevant data from the hospital notes (eg, ECGs, laboratory tests, discharge summary, postmortem results) should be 
sent to the addressee, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event.

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10.3.1 Safety Reporting to Investigators, IRBs, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions (SUSARs) and any 
other applicable SAEs to regulatory authorities investigators and IRBs /the head of the study site, as applicable in 
accordance with national regulations in the countries where the study is conducted. Relative to the first awareness 
of the event by/or further provision to the sponsor or sponsor’s designee, SUSARs will be submitted to the 
regulatory authorities as expedited report. The sponsor will also prepare an expedited report for other safety issues 
where these might materially alter the current benefit-risk assessment of a study drug or that would be sufficient to 
consider changes in the study drug administration or in the overall conduct of the trial. The study site also will 
forward a copy of all expedited reports to his or her IRB.

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11.0
STUDY-SPECIFIC COMMITTEES
No steering committee, data safety monitoring committee, or clinical endpoint committee will be used in this study.

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12.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management Plan. AEs and medical 
history including present illness will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
Drugs will be coded using the World Health Organization (WHO) Drug Dictionary.
12.1
CRFs
Completed (e)CRFs are required for each subject who signs an informed consent.
The sponsor or its designee will supply investigative sites with access to eCRFs. The sponsor will make 
arrangements to train appropriate site staff in the use of the eCRF. These forms are used to transmit the information 
collected in the performance of this study to the sponsor and regulatory authorities. (e)CRFs must be completed in 
English. Data are transcribed directly onto eCRFs.
Corrections are recorded in an audit trail that captures the old information, the new information, identification of 
the person making the correction, the date the correction was made, and the reason for change.
The principal investigator must review the (e)CRFs for completeness and accuracy and must sign the appropriate 
(e)CRFs as indicated. Furthermore, the investigator must retain full responsibility for the accuracy and authenticity 
of all data entered on the (e)CRFs.
The following data will be recorded directly into the (e)CRFs. However, this will not apply if the subject’s medical 
records contain the data.

Subject eligibility assessment

AE terms, the start and end dates, ongoing/not ongoing at the end of study, onset pattern, severity, causal 
relationship with the study procedures, causal relationship with the study drug, action taken with the study 
drug, outcome, and seriousness

The status of the subject in terms of vaccination with the study drug and the completion of the study

Reason for the use of concomitant medications and ongoing/not ongoing at the end of study
The following data will not be recorded on the (e)CRFs:

Immunogenicity testing results
After the lock of the clinical study database, any change of, modification of or addition to the data on the (e)CRFs 
should be made by the investigator with use of change and modification records of the Data Clarification Form 
provided by the sponsor. The principal investigator must review the data change for completeness and accuracy, 
and must sign, or sign and seal, and date.
(e)CRFs will be reviewed for completeness and acceptability at the study site during periodic visits by study 
monitors. The sponsor or its designee will be permitted to review the subject’s medical and hospital records 
pertinent to the study to ensure accuracy of the (e)CRFs. The completed (e)CRFs 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 and the head of the institution 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, temporary media such as thermal sensitive paper, source worksheets, all 
original signed and dated informed consent forms, electronic copy of eCRFs, including the audit trail, and detailed 
records of drug disposition to enable evaluations or audits from regulatory authorities, the sponsor or its designees. 

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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, the investigator and the 
head of the institution are required to retain essential relevant documents until the day of completion of BLB-750 
reexamination. However, if the sponsor requests a longer time period for retention, the head of the institution 
should discuss how long and how to retain those documents with the sponsor.

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13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized by the statistician prior to the data lock. The SAP
will provide further details regarding the definition of analysis variables and analysis methodology to address all 
study objectives.
A data review will be conducted prior to the data lock. This data review will assess the accuracy and completeness 
of the study database, subject evaluability, and appropriateness of the planned statistical methods.
13.1.1 Analysis Sets
In this study, two kinds of analysis sets are defined: FAS, and safety analysis set. The FAS used as an 
immunogenicity analysis set and the safety analysis set will be defined as “all subjects who received at least one 
dose of the study drug for the treatment period." The definition of each analysis set will be detailed in the separate 
“SAP.”
13.1.2 Analysis of Demographics and Other Baseline Characteristics
In this study, major subject background data in the FAS will be tabulated.
13.1.3 Immunogenicity Analysis
(1)
Primary Endpoints and Their Analyses
(Primary Endpoints)
Immunogenicity:
Seroprotection rate as measured by SRH antibody titer (defined as the proportion of subjects with SRH antibody 
titer ≥25 mm2) for the vaccine strain at 21 days after the second vaccination
Seroconversion rate as measured by SRH antibody titer (defined as the proportion of subjects with a 50% or more 
increase in SRH antibody titer from baseline for those who have a baseline value >4 mm2 or SRH antibody titer 
≥25 mm2 for those who have a baseline value ≤4 mm2) for the vaccine strain at 21 days after the second vaccination
Geometric mean fold increase (GMFI) in SRH antibody titer from baseline for the vaccine strain at 21 days after 
the second vaccination
[Analysis Methods]
Using the FAS, frequency tabulations of the SRH antibody titer and the seroprotection and seroconversion rates at 21 
days after the second vaccination will be presented, and their point estimates and two-sided 95% confidence intervals 
will be calculated. For the geometric mean fold increase in the SRH antibody titer at 21 days after the second 
vaccination, summary statistics and geometric means with corresponding two-sided 95% confidence intervals of the fold 
increase in the SRH antibody titer from baseline will be calculated. Two-sided 95% confidence intervals of the geometric 
means will be calculated by back-transforming the upper and lower limits of two-sided 95% confidence intervals of the 
log transformed mean values.
(2)
Secondary Endpoints and Their Analyses
(Secondary Endpoints)
Immunogenicity:
Seroprotection rate as measured by SRH antibody titer (defined as the proportion of subjects with SRH antibody 
titer ≥25 mm2) for the vaccine strain at 21 days after the initial vaccination

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Seroconversion rate as measured by SRH antibody titer (defined as the proportion of subjects with a 50% or more 
increase in SRH antibody titer from baseline for those who have a baseline value >4 mm2 or SRH antibody titer 
≥25 mm2 for those who have a baseline value ≤4 mm2) for the vaccine strain at 21 days after the initial vaccination
GMFI in SRH antibody titer from baseline for the vaccine strain at 21 days after the initial vaccination
Geometric mean titer (GMT) of SRH antibody titer for the vaccine strain at 21 days after each vaccination
[Analysis Methods]
Using the FAS, frequency tabulations of the SRH antibody titer and the seroprotection and seroconversion rates at 21 
days after the initial vaccination will be presented, and their point estimates and two-sided 95% confidence intervals will 
be calculated. For the geometric mean fold increase in the SRH antibody titer at 21 days after the initial vaccination, 
summary statistics and geometric means with corresponding two-sided 95% confidence intervals of the fold increase in 
the SRH antibody titer from baseline will be calculated. For GMT of the SRH antibody titer at 21 days after each 
vaccination, summary statistics and geometric means with corresponding two-sided 95% confidence intervals will be 
calculated. Two-sided 95% confidence intervals of geometric means will be calculated using the method specified in 
13.1.3(1).
(3)
Additional Endpoints
See Section 5.2.3.
(4)
Methods of Data Transformation and Handling of Missing Data
The details will be provided in the separate “SAP.”
(5)
Confidence Coefficient
Confidence coefficient: 95% (two-sided estimation)
13.1.4 Safety Analysis
Secondary Endpoints and Their Analyses

Solicited local and systemic adverse events (AEs) to be recorded in the subject diary

AEs

Vital signs
Using the safety analysis set, the following analyses will be performed:
For injection site and systemic AEs to be collected from the diaries, frequency tabulations, frequency tabulations by 
severity, and frequency tabulations by vaccination and by timing of onset will be presented. For vital signs, 
summary statistics of measurement values and the changes in post-vaccination values from baseline at each 
assessment point will be calculated. In addition, the changes in each test item over time will be graphically 
presented.
Treatment-emergent adverse events (TEAEs) are defined as AEs observed after the start of vaccination with the 
study drug.
For TEAEs, the following analyses will be performed: TEAEs will be coded using the MedDRA and summarized 
by System Organ Class and Preferred Term.

Frequency tabulation of all TEAEs

Frequency tabulation of TEAEs considered “related” to the study drug

Frequency tabulation of all TEAEs by severity

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
Frequency tabulation of TEAEs considered “related” to the study drug by severity

Frequency tabulation of serious TEAEs

Frequency tabulation of all TEAEs by vaccination and by timing of onset
13.2
Interim Analysis and Criteria for Early Termination
No interim analysis is planned.
13.3
Determination of Sample Size
The number of subjects to be vaccinated: 55
The objective of this study is to evaluate the immunogenicity and safety of two intramuscular vaccinations with 
BLB-750 in healthy Japanese adults. Therefore, the sample size for this study was determined to be 55 subjects, as 
the number of subjects to be vaccinated, by reference to the Notification issued by the Director of the Evaluation 
and Licensing Division of the Pharmaceutical and Food Safety Bureau on October 31, 2011: “Guidelines for the 
Development of Prototype Vaccines in Preparedness for Pandemic Influenza” [4]. There are no statistical rationales 
for the determination of this sample size.

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14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all aspects of the 
protocol are followed. Source documents will be reviewed for verification of data recorded on the (e)CRFs. Source 
documents are defined as original documents, data, and records. The investigator and head of the study site
guarantee access to source documents by the sponsor or its designee (CRO) and by the IRB.
All aspects of the study and its documentation will be subject to review by the sponsor or designee (as long as 
blinding is not jeopardized), including but not limited to the Investigator’s Binder, study drug, subject medical 
records, informed consent documentation, and review of (e)CRFs and associated source documents. It is important 
that the investigator and other study personnel are available during the monitoring visits and that sufficient time is 
devoted to the process.
14.2
Protocol Deviation
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. Significant deviations from the protocol must be 
recorded on the (e)CRFs and reviewed by the sponsor or designee. Significant deviations include, but are not 
limited to, those that involve fraud or misconduct, increase the health risk to the subject, or confound interpretation 
of primary study assessment.
14.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this circumstance, the 
sponsor-designated auditor will contact the site in advance to arrange an auditing visit. The auditor may ask to visit 
the facilities where the medication is stored and prepared, and any other facility used during the study. In addition, 
there is the possibility that this study may be inspected by regulatory agencies, including those of foreign 
governments (eg, the FDA, the United Kingdom Medicines and Healthcare Products Regulatory Agency, the 
Pharmaceuticals and Medical Devices Agency of Japan). If the study site is contacted for an inspection by a 
regulatory body, the sponsor should be notified immediately. The investigator and head of the study site guarantee 
access for quality assurance auditors to all study documents as described in Section 14.1.

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15.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects) according to the 
protocol, the ethical principles that have their origin in the Declaration of Helsinki, and the ICH Harmonised 
Tripartite Guideline for GCP. Each investigator will conduct the study 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 B. The principles of Helsinki are addressed through the protocol and through appendices 
containing requirements for informed consent and investigator responsibilities.
15.1
IRB Approval
IRBs must be constituted according to the applicable local requirements of each participating region. The sponsor 
or designee will require documentation noting all names and titles of members who make up the respective IRB. If 
any member of the IRB has direct participation in this study, 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 Investigator’s Brochure, a copy of the informed consent form, and, if 
applicable, subject recruitment materials and advertisements and other documents required by all applicable laws 
and regulations, must be submitted to a central or local IRB or IEC for approval. The IRB’s written approval of the 
protocol and subject informed consent must be obtained and submitted to the sponsor or designee before 
commencement of the study. The IRB approval must refer to the study by exact protocol title, number, and version 
date; identify versions of other documents (eg, informed consent form) reviewed; and state the approval date. The 
sponsor will notify site once the sponsor has confirmed the adequacy of site regulatory documentation. Until the 
site receives [notification no protocol activities, including screening may occur.
Sites must adhere to all requirements stipulated by their respective IRB. This may include notification to the IRB 
regarding protocol amendments, updates to the informed consent form, recruitment materials intended for viewing 
by subjects, local safety reporting requirements, reports and updates regarding the ongoing review of the study 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 its designee.
Subject incentives should not exert undue influence 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 applicable laws and regulations. The 
informed consent form describe the planned and permitted uses, transfers, and disclosures of the subject’s personal 
and personal health information for purposes of conducting the study. The informed consent form further explain 
the nature of the study, its objectives, and potential risks and benefits, as well as the date informed consent is given. 
The informed consent form will detail the requirements of the participant and the fact that he or she is free to 
withdraw at any time without giving a reason and without prejudice to his or her further medical care.
The investigator is responsible for the preparation, content, and IRB approval of the informed consent form. The 
informed consent form must be approved by both the IRB and the sponsor prior to use.
The informed consent form must be written in a language fully comprehensible to the prospective subject. It is the 
responsibility of the investigator to explain the detailed elements of the informed consent form 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 study and (2) decide whether or not 
to participate in the study. If the subject determines he or she will participate in the study, then the informed consent 

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form must be signed and dated by the subject at the time of consent and prior to the subject entering into the study. 
The subject should be instructed to sign using their legal names, not nicknames, using blue or black ballpoint ink. 
The investigator will also sign and date the informed consent form before the subject enters into the study.
Once signed, the original informed consent form will be stored in the investigator’s site file. The investigator must 
document the date the subject signs the informed consent in the subject’s medical record. Copies of the signed 
informed consent form shall be given to the subject.
All revised informed consent forms must be reviewed and signed by relevant subjects in the same manner as the 
original informed consent. The date the revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised informed consent form.
15.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection against invasion of 
privacy. Throughout this study, a subject’s source data will only be linked to the sponsor’s clinical study 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 may be used to verify the subject and accuracy of the subject’s 
unique identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor requires the 
investigator to permit its monitor or designee’s monitor, representatives from any regulatory authority (eg, FDA, 
Medicines and Healthcare products Regulatory Agency, Pharmaceuticals and Medical Devices Agency), the 
sponsor’s designated auditors, and the appropriate IRBs to review the subject’s original medical records (source 
data or documents), including, but not limited to, admission and discharge summaries for hospital admissions 
occurring during a subject’s study participation, and autopsy reports. Access to a subject’s original medical records 
requires the specific authorization of the subject as part of the informed consent 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 [e]CRF).
15.4
Publication, Disclosure, and Clinical Trial Registration 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 clinical 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 laws, regulations and guidance, Takeda will, at a minimum register interventional clinical trials it 
sponsors anywhere in the world on ClinicalTrials.gov and other publicly accessible websites before start of study, 
as defined in Takeda Policy/Standard. Takeda contact information, along with the study site’s name, 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 will post the results of clinical trials on ClinicalTrials.gov and other publicly accessible websites, as 
required by Takeda Policy/Standard, applicable laws and regulations.
15.5
Insurance and Compensation for Injury
Each subject in the study 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 study 
insurance against the risk of injury to clinical study subjects. Refer to the Clinical Study 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
[1]
“National Action Plan for Pandemic Influenza and New Infectious Diseases” revised on June 7, 2013, 
http://www.cas.go.jp/jp/seisaku/ful/keikaku.html
[2]
Menno D. de Jong, M.D., Ph.D., Tran Tan Thanh,et al. Oseltamivir Resistance during Treatment of Influenza 
A (H5N1) Infection. N Engl J Med. 2005;353:2667-2672.
[3]
Takeda Pharmaceutical Company Limited. The Package Insert for Cell-Culture Influenza Vaccine (H5N1 
strain) created in June 2017 (version 1)
[4]
“Guidelines for the Development of Prototype Vaccines in Preparedness for Pandemic Influenza” (PFSB 
Notification No. 1031-[1] dated October 31, 2011)
[5]
Thomas R., Robert A., Jean H., et al. Detection of Antibody to Avian Influenza A(H5N1) Virus in Human 
Serum by Using a Combination of Serologic Assays.J Clin Microbiol.April 1999;37(4):937-943.
[6]
Iain S., Karl G.,Anthony C., et al.Boosting immunity to influenza H5N1 with MF59-adjuvanted H5N3 
A/Duck/Singapore/97 vaccine in a primed human population.ELSEVIER.April 2003;21(15):1687-1693
[7]
Food and Drug Administration. Guidance for Industry: Toxicity Grading Scale for Healthy Adult and 
Adolescent volunteers Enrolled in Preventive Vaccine Clinical Trials. U.S.Department of Health and Drug 
administration Center for Biologics Evaluation and Research. September 2007

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Appendix A
Schedule of Study Procedures
Screening
Treatment
Visit number
Visit 1
Visit 2
Visit 3/at discontinuation12)
Day1)
1
1 to 22
22
22 to 43
43/-
Days after the initial 
vaccination
0
0 to 21
21
21 to 42
42 (Visit 2 + 21)/-
Acceptable time window 
for visit (day)
-
-
+0 to 2
-
Visit 2 + 19 to Visit 2 + 23
/date of discontinuation + 28
Pre-
vaccination
Post-
vaccination
Pre-
vaccination
Post-
vaccination
-
Informed Consent
X2)
Demographics
X
Past history, present 
illness, and prior 
treatments
X3)
Height and weight
X
Vital signs (blood 
pressure and pulse and 
respiratory rates)
X
X4)
X
X4)
X5)
Vital signs (body 
temperature [oral])
X
X6) 7)
X
X6) 7)
X
Pregnancy test9)
X
X
Physical examination
X
X9)
X
X9)
X
Eligibility assessment
X
Enrollment
X
Blood sampling 
(immunogenicity 
evaluation)10)
X
X
X
Vaccination with the 
study drug
X
X
Diaries 1 and 2
To be 
provided
To be 
recorded
To be 
collected
(To be collected, if not yet 
collected)
Diaries 3 and 4
To be 
provided11)
To be 
recorded
To be collected
Adverse events
Concomitant medications
1)
The day before vaccination with the study drug is defined as Day -1, and the day of vaccination with the study drug (Visit 1) is 
defined as Day 1.
2)
Informed consent must be obtained before any study procedure is performed. Informed consent is considered valid if it is 
obtained within 28 days prior to Visit 1 (Day -28).
3)
Prior treatments include those given before signing the informed consent form, and past history and present illness include those 
occurring before the first vaccination of study drug.
4)
On the day of vaccination with study drug, blood pressure, pulse rate, and respiratory rate will be measured before vaccination 
and approximately 30 minutes after vaccination.
5)
No respiratory rate measurement will be required at Day 43 and at discontinuation.
6)
Among vital signs, body temperature will be measured by each subject every day in the evening wherever possible for 7 days 
after vaccination (after vaccination on Day 1 until Day 7 and after vaccination on Day 22 until Day 28) and be recorded in the 
diary provided to each subject.

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7)
During Days 8-22 (before study visit) and Days 29-43 (before study visit), body temperature will be measured by each subject 
and be recorded in the diary provided to each subject only if any symptom of pyrexia occurs. Measurements should be obtained 
approximately every 4-8 hours until the pyrexia resolves and should be recorded in the diary.
8)
Pregnancy test will be performed in female subjects of childbearing potential.
9)
The investigator will monitor for any acute hypersensitivity reaction, etc., for 30 minutes after vaccination.
10) Blood sampling should be performed after vital sign measurement.
11) Provision of Diaries 3 and 4 may take place at Visit 1.
12) The study discontinuation visit should be performed wherever possible.

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Appendix B
Responsibilities of the Investigator
1.
Conduct the appropriate study in accordance with the protocol and GCP considering the rights, safety and 
wellbeing of human subjects.
2.
When a part of the important activities related to the study are delegated to the investigator or the study 
collaborator, prepare the lists of activities to be delegated and responsible personnel, submit the lists to the 
director of the site in advance to get them accepted.
3.
Prepare a written informed consent form and other written information, and update as appropriate.
4.
Confirm the contents of the clinical study agreement.
5.
Provide necessary information on the protocol, medications and responsibilities of individual personnel to the 
investigator and study collaborator, and provide guidance and supervision.
6.
Screen subjects who meet the requirements of the protocol, provide the explanation of the study in writing and 
obtain the written consent.
7.
Assume responsibility for all the medical judgement related to the study.
8.
Ensure in collaboration with the director of the site that sufficient information on all clinically significant 
adverse events related to the study are provided to subjects throughout and beyond the period when subjects 
participate in the study.
9.
If a subject consults other medical institution or other department, notify the physician of the medical 
institution or department of the subject’s participation in the study upon obtaining the consent of the subject, as 
well as the end and termination of the study in writing, and document such records.
10. In case of urgent report of a SAE, immediately notify the director of the site and the sponsor in writing.
11. Prepare correct and complete (e)CRFs, and submit them to the sponsor with electronic signature.
12. Check and confirm the contents of (e)CRFs prepared by the investigator or transcribed from the source data by 
the study collaborator, and submit them to the sponsor with electronic signature.
13. Discuss any proposal from the sponsor including update of the protocol.
14. Notify the director of the site of the end of the study in writing.

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Appendix C
Details of Amendments
Specific changes in the amended protocol are described below.
Title on Page 1 and Title of Protocol in Section 2.0 on Page 8
Before change
Randomized, Double-Blind, Parallel-Group, Comparative Study
After change
Open-label Study
Reason for the change
Because of changes to the study objectives, the study design was changed from a randomized study to an
open-label study.
Section 2.0 (Study Design) on Page 8, Section 4.2 on Page 15, and Section 6.1 on Page 18
Before change
randomized, double-blind, parallel-group, comparative study
After change
Open-label study
Reason for the change
Because of changes to the study objectives, the study design was changed from a randomized study to an
open-label study.
Section 6.2.1 on Page 19
Before change
To objectively evaluate the immunogenicity and safety….., a randomized, double-blind, parallel-group, 
comparison design will be used in this study.
After change
This study has been designed to evaluate the immunogenicity and safety ….. (open-label, uncontrolled study).
Reason for the change
Because of changes to the study objectives, the study design was changed from a randomized study to an
open-label study.
Section 7.0 on Page 21, Section 7.5 on Page 24, Sections 9.1.12 and 9.1.13 on Page 35, Section 9.3.1 on Page 36,
and Appendix A on Page 57
Before change
randomization

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After change
enrollment in the study
Reason for the change
Because of changes to the study objectives, the study design was changed from a randomized study to an
open-label study.
Section 8.2 on Page 28
Before change
Study Drug Assignment and Dispensing Procedures
The investigator will assign study drugs to subjects confirmed eligible prior to vaccination in ascending order of 
drug number and in the order of subject identification numbers as a general rule. The Medication ID Number will 
be entered onto the (e)CRF.
After change
Study Drug Dispensing Procedures
Subjects will be vaccinated with the study drug according to the study schedule.
Reason for the change
Because of changes to the study objectives, the study design was changed from a randomized study to an
open-label study.
Sections 8.3, 8.4, and 8.5 on Pages 28-29
Before change
8.3 Randomization Code Creation and Storage
Randomization personnel of the sponsor or designee will generate the randomization schedule. All randomization 
information will be stored in a secured area, accessible only by authorized personnel.
8.4 Study Drug Blind Maintenance
The investigator must store the emergency key until the time of emergency blind breaking or the end of study.
Results of SRH and MN antibody titers against the vaccine strain measured for immunogenicity evaluation will be 
reported to the sponsor after taking necessary measures (i.e., no inclusion of information on the vaccine strain and 
measured antigens) to maintain the blindness of the study and to ensure that the laboratory’s representative will not 
be able to identify the subject, if these results are disclosed to the sponsor before unblinding the randomization 
table. Detailed procedures are provided in the separate SOP for the handling of biological samples for 
immunogenicity evaluation.
8.5 Unblinding Procedure
The study drug blind shall not be broken by the investigator unless information concerning the study drug is 
necessary for the medical treatment of the subject. In the event of a medical emergency, if possible, sponsor or 
designee should be contacted before the study drug blind is broken to discuss the need for unblinding.
For unblinding a subject, the study drug blind can be obtained by opening sealed envelope.

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The sponsor must be notified as soon as possible if the study drug blind is broken. The date, time, and reason the 
blind is broken must be recorded in the document called Record of Early Blind-Breaking and the same information 
(except the time) must be recorded on the (e)CRF.
If any site personnel are unblinded, study drug must be stopped immediately and the subject must be withdrawn 
from the study.
The investigator must not change subject assessment after unblinding.
After change
Deleted
Reason for the change
Because of changes to the study objectives, the study design was changed from a randomized study to an
open-label study.
Section 9.1.9 on Page 32
Before change
Should the pregnancy occur during or after administration of blinded drug, the investigator must inform the subject 
of their right to receive treatment information. If the subject chooses to receive unblinded treatment information, 
the individual blind should be broken by the investigator.
After change
Deleted
Reason for the change
Because of changes to the study objectives, the study design was changed from a randomized study to an
open-label study.
Section 9.1.12 on Page 35 and Section 9.3.1 on Page 35
Before change
before/prior to the randomization
After change
before/prior to the start of vaccination with the study drug
Reason for the change
Because of changes to the study objectives, the study design was changed from a randomized study to an
open-label study.
Section 9.1.13 on Page 35
Before change
Subjects will be randomized and receive vaccination with the study drug only if…. 
If the subject is found to be not eligible for randomization, …

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After change
Subjects will be enrolled in the study and receive vaccination with the study drug only if….
For subjects who did not receive vaccination with the study drug, the investigator…..
Reason for the change
Because of changes to the study objectives, the study design was changed from a randomized study to an
open-label study.
Section 9.3.1 on Page 35
Before change
…not meeting any of the exclusion criteria will be randomized in accordance with Section 8.2.
After change
…not meeting any of the exclusion criteria will be enrolled in the study.
Reason for the change
Because of changes to the study objectives, the study design was changed from a randomized study to an
open-label study.
Section 13.1 on Page 50
Before change
prior to unblinding of subject’s treatment assignment
After change
prior to the data lock
Reason for the change
Because of changes to the study objectives, the study design was changed from a randomized study to an
open-label study.
Section 13.1 on Page 49
Before change
A blinded data review will be…
After change
A data review will be…
Reason for the change
Because of changes to the study objectives, the study design was changed from a randomized study to an
open-label study.
Section 13.1.1 on Page 49
Before change

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The FAS used as an immunogenicity analysis set will be defined as “all subjects who were randomized and 
received at least one dose of the study drug for the treatment period.” The safety analysis set will be defined as “all 
subjects who received at least one dose of the study drug for the treatment period.”
After change
The FAS used as an immunogenicity analysis set and the safety analysis set will be defined as “all subjects who 
received at least one dose of the study drug for the treatment period.”
Reason for the change
Because of changes to the study objectives, the study design was changed from a randomized study to an
open-label study.
Section 13.1.2 on Page 49
Before change
…of “all randomized subjects”
After change
…in the FAS
Reason for the change
Because of changes to the study objectives, the study design was changed from a randomized study to an
open-label study.
Appendix B on Page 59
Before change
11. Determine the need of emergency key code blinding of a subject in case of emergency.
After change
Deleted
Reason for the change
Because of changes to the study objectives, the study design was changed from a randomized study to an
open-label study.
Section 2.0 (Study Design) on Page 8 and Section 6.1 on Page 18
Before change
The immunogenicity and safety of BLB-750 (Qinghai reverse genetics [RG] strain) vaccinations will be evaluated. 
In addition, the immunogenicity and safety of BLB-750 (Indonesia RG strain) vaccination will be evaluated in 
comparison with BLB-750 (Indonesia wild type [WT] strain) to be given to a control group.
After change
Deleted
Reason for the change

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Because the number of the groups was changed from three to one due to changes to the study objectives.
Section 2.0 (Study Design) on Page 8
Before change
Participants considered eligible as subjects for the study during the eligibility assessment at a visit after providing 
informed consent will be randomized to either one of the following groups in a 1:1:1 ratio: BLB-750 (Qinghai RG 
strain), BLB-750 (Indonesia RG strain), and BLB-750 (Indonesia WT strain).
Subjects will receive the initial intramuscular vaccination with BLB-750 (Qinghai RG strain), BLB-750 (Indonesia 
RG strain), or BLB-750 (Indonesia WT strain) during the first study visit after providing informed consent (Day 1) 
and the second vaccination with the same BLB-750 during the study visit at 21 days after the initial vaccination 
(Day 22).
After change
Participants considered eligible as subjects for the study during the eligibility assessment at a visit after providing 
informed consent will receive the initial intramuscular vaccination with the study drug BLB-750 (Day 1) and the 
second intramuscular vaccination with BLB-750 during the study visit at 21 days after the initial vaccination (Day 
22).
Reason for the change
Because the number of the groups was changed from three to one due to changes to the study objectives.
Section 2.0 (Study Design) on Page 8 and Section 6.1 on Page 18
Before change
165 (55 per group)
After change
55
Reason for the change
Because the number of the groups was changed from three to one due to changes to the study objectives.
Section 2.0 (Planned Number of Subjects) on Page 8
Before change
BLB-750 Qinghai RG strain group: 55 subjects
BLB-750 Indonesia RG strain group: 55 subjects
BLB-750 Indonesia WT strain group: 55 subjects
The total number of subjects: 165
After change
BLB-750: 55 subjects
Reason for the change
Because the number of the groups was changed from three to one due to changes to the study objectives.

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Section 2.0 on Page 8 (Dose Level(s))
Before change
Two doses of BLB-750 (Qinghai RG strain), BLB-750 (Indonesia RG strain), or BLB-750 (Indonesia WT strain) at a 
vaccination dose of 0.5 mL (HA antigen level of 7.5 µg per strain) will be injected into the upper arm muscle (the deltoid 
muscle) at 3-week intervals.
As manufacturing strains for BLB-750, the following attenuated strains (H5N1 influenza virus attenuated using reverse 
genetics technology) and wild-type strain will be used:
●
Qinghai RG strain
[A/bar-headed goose/Qinghai/1A/2005 (H5N1) (SJRG-163222)]
●
Indonesia RG strain
[A/Indonesia/05/2005(H5N1)-PR8-IBCDC-RG2]
●
Indonesia WT strain
[A/Indonesia/05/2005(H5N1)]
After change
Two doses of BLB-750 at 0.5 mL (HA antigen level of 7.5 µg) will be injected into the upper arm muscle (the deltoid 
muscle) at a 3-week interval.
As the manufacturing strain for BLB-750, the following attenuated strain (H5N1 influenza virus attenuated using reverse 
genetics technology) will be used:
●
Qinghai RG strain
[A/bar-headed goose/Qinghai/1A/2005(H5N1) (SJRG-163222)]
Reason for the change
Because the number of the groups was changed from three to one due to changes to the study objectives.
Section 2.0 (Statistical Considerations) on Page 8, Section 13.1.3 on Page 49 and Section 13.1.4 on Page 50
Before change
by vaccination group
After change
Deleted
Reason for the change
Because the number of the groups was changed from three to one due to changes to the study objectives.
Section 2.0 (Rationales for the Determination of Sample Size) on Page 8, Section 6.2.1 on Page 19, and
Section 13.3 on Page 51
Before change
BLB-750(Qinghai RG strain), BLB-750(Indonesia RG strain) or BLB-750 (Indonesia WT strain)
After change
BLB-750
Reason for the change
Because the number of the groups was changed from three to one due to changes to the study objectives.

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Section 2.0 (Rationales for the Determination of Sample Size) on Page 8 and Section 13.3 on Page 51
Before change
a total of 165 subjects, 55 subjects per group
After change
55 subjects
Reason for the change
Because the number of the groups was changed from three to one due to changes to the study objectives.
Section 4.2 on Page 15
Before change
In this study, the immunogenicity and safety of BLB-750 (Qinghai RG strain) vaccination will be evaluated. In 
addition, the immunogenicity and safety of BLB-750 (Indonesia RG strain) vaccination will be evaluated in 
comparison with BLB-750 (Indonesia WT strain), which was used in previously conducted clinical studies in 
Japanese adults, as a comparator
After change
Deleted
Reason for the change
Because the number of the groups was changed from three to one due to changes to the study objectives.
Section 6.1 on Page 18
Before change
Subjects considered eligible after providing informed consent will be randomized to either one of the following 
groups in a 1:1:1 ratio: BLB-750 (Qinghai RG strain), BLB-750 (Indonesia RG strain), and BLB-750 (Indonesia 
WT strain).
Subjects will receive the initial intramuscular vaccination with either BLB-750 (Qinghai RG strain), BLB-750 
(Indonesia RG strain), or BLB-750 (Indonesia WT strain) (Day 1) and the second vaccination with the same 
BLB-750 during the study visit at 21 days after the initial vaccination (Day 22).
After change
Subjects considered eligible after providing informed consent will receive the initial intramuscular vaccination with 
the study drug BLB-750 (Day 1) and the second intramuscular vaccination with BLB-750 during the study visit at 
21 days after the initial vaccination (Day 22).
Reason for the change
Because the number of the groups was changed from three to one due to changes to the study objectives.
Section 6.1 (Figure 6.a) on Page 18
After change

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Replaced schematic of study design
Reason for the change
Because the number of the groups was changed from three to one due to changes to the study objectives.
Section 13.1.2 on Page 49
Before change
...will be tabulated by vaccination group and for the overall population.
After change
...will be tabulated.
Reason for the change
Because the number of the groups was changed from three to one due to changes to the study objectives.
Section 6.2.2 on Page 19
Before change
As described in Section 4.2, BLB-750 (Qinghai RG strain), BLB-750 (Indonesia RG strain), and BLB-750 
(Indonesia WT strain) were selected as H5N1 subtype virus strains for BLB-750 to be used in this study.
After change
As described in Section 8.1.1.1, BLB-750 (Qinghai RG strain) was selected as the H5N1 subtype virus strain for 
BLB-750 to be used in this study.
Reason for the change
Because the number of the groups was changed from three to one due to changes to the study objectives.
Section 8.1.1.1 on Page 26
Before change
Name of the study drug: BLB-750 DB Injection
Manufacturer: Takeda Pharmaceutical Company Limited
Either one of the following 1), 2), or 3) will be packaged in outer boxes that are indistinguishable in appearance.
1) Code name of the study drug: BLB-750 (Qinghai RG strain) Injection
After change
Substance code: BLB-750
Trade name: Cell-Culture Influenza Vaccine H5N1 “Takeda” 1 mL
Manufacturer: Takeda Pharmaceutical Company Limited
Reason for the change
Because the number of the groups was changed from three to one due to changes to the study objectives.
Section 8.1.1.1 (Table 8.a) on Page 26
Before change

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Components and Dose Strength of BLB-750 (Qinghai RG Strain) Injection 0.5 mL
After change
Components and Dose Strength of BLB-750 Injection 0.5 mL
Reason for the change
Because the number of the groups was changed from three to one due to changes to the study objectives.
Section 8.1.1.1 on Page 26
Before change
Text from “2) Code name of the study drug” to Table 8.c
After change
Deleted
Reason for the change
Because the number of the groups was changed from three to one due to changes to the study objectives.
Section 8.1.1.1 (Figure 8.a) on Page 26
After change
Replaced labeling sample of the outer box for the study drug
Reason for the change
Because the number of the groups was changed from three to one due to changes to the study objectives.
Section 13.3 on Page 51
Before change
The number of subjects to be vaccinated: 165
After change
The number of subjects to be vaccinated: 55
Reason for the change
Because the number of the groups was changed from three to one due to changes to the study objectives.
Section 2.0 (Objectives) on Page 8 and Section 5.1 on Page 16
Before change
Primary Objectives: To evaluate the immunogenicity and safety of two intramuscular vaccinations with BLB-750 
(Qinghai RG strain) in healthy Japanese adults
After change
Objectives: To evaluate the immunogenicity and safety of two intramuscular vaccinations with BLB-750 in healthy 
Japanese adults

BLB-750
Study No. CCT-901
Page 69 of 72
Protocol Amendment 01
25 Oct 2017
CONFIDENTIAL
Reason for the change
Because the number of the groups was changed from three to one due to changes to the study objectives.
Section 2.0 (Secondary Objectives) on Page 8 and Section 5.1.2 on Page 16
Before change
Secondary Objectives: To evaluate the immunogenicity and safety of two intramuscular vaccinations with BLB-750 
(Indonesia RG strain) in comparison with two intramuscular vaccinations with BLB-750 (Indonesia WT strain) in 
healthy Japanese adults
After change
Deleted
Reason for the change
Because the number of the groups was changed from three to one due to changes to the study objectives.
Section 8.1.1.1 on Page 26
Before change
One vial containing the study drug
After change
Two vials of the study drug
Reason for the change
Because the packaging was changed.
Appendix A on Page 57
Before change
Acceptable time window for visit (day) for “Visit 2”: +0 to 7
After change
Acceptable time window for visit (day) for “Visit 2”: +0 to 2
Reason for the change
For consistency with Visit 3.
Section 2.0 (Exclusion Criteria) on Page 8 and Section 7.2 on Page 21
Before change
investigational products
After change
investigational or study products
Reason for the change

BLB-750
Study No. CCT-901
Page 70 of 72
Protocol Amendment 01
25 Oct 2017
CONFIDENTIAL
Editorial improvement.
Section 4.1 on Page 14
Before change
 and Takeda Pharmaceutical Company Limited co-developed a vaccine indicated for “the prevention 
of pandemic influenza (H5N1)” (development code: BLB-750),…
After change
Takeda Pharmaceutical Company Limited and
 co-developed a vaccine indicated for “the 
prevention of pandemic influenza (H5N1)”,…
Reason for the change
Editorial improvement.
Section 6.2.2 on Page 19
Before change
According to the package insert [3], which…
After change
Thus, in accordance with the approved dosage regimen…
Reason for the change
Editorial improvement.
Section 6.2.3 on Page 19
Before change
…, possible adverse events of BLB-750 vaccination include…
After change
…have been reported as expected adverse reactions to BLB-750 vaccination
Reason for the change
Editorial improvement.
Section 9.1.10 on Page 32
Before change
The blood sample collected will be used for study-specific endpoint measurement and then for exploratory 
immunogenicity evaluation (see Section 9.4). Genetic testing will not be included in exploratory immunogenicity
evaluation.
This exploratory evaluation may be performed as a cooperative study with an external organization. Apart from the 
protocol and clinical study report for this study, the sponsor and research collaborators will create a plan for and a 
report on exploratory immunogenicity evaluation.
After change
PPD
PPD

BLB-750
Study No. CCT-901
Page 71 of 72
Protocol Amendment 01
25 Oct 2017
CONFIDENTIAL
The blood sample collected will be used for study-specific endpoint measurements as well as immunogenicity 
evaluation by a government organization, and also may be used for other exploratory immunogenicity 
evaluations (see Section 9.4). No genetic testing will be performed using the samples collected in this study.
For the immunogenicity evaluation by a government organization, the protocol and the result report will be 
prepared by the sponsor or the government organization, separately from the protocol and clinical study report for 
this study. If other exploratory immunogenicity evaluations are performed, their protocols and result reports
should also be prepared.
Reason for the change
Editorial improvement.
Section 9.4 on Page 38
Before change
The remainder of serum samples collected in accordance with Section 9.1.10, “Immunogenicity Evaluation” will be 
stored for the exploratory evaluation of immunogenicity endpoints for this study other than SRH and MN antibody 
titers. Serum samples will be discarded after their use in the exploratory immunogenicity evaluation or after 
confirming that they will no longer be used.
After change
The remainder of serum samples collected in accordance with Section 9.1.10, “Immunogenicity Evaluation” will be 
stored. Serum samples will be discarded after they will no longer be used.
Reason for the change
Editorial improvement.
Section 15.4.2 on Page 54
Before change
In order to ensure that information on clinical trials reaches the public in a timely manner and to comply with 
applicable laws, regulations and guidance, Takeda will, at a minimum register interventional clinical trials it 
sponsors anywhere in the world on ClinicalTrials.gov and other publicly accessible websites before start of study, 
as defined in Takeda Policy/Standard. Takeda contact information, along with investigator’s city, country, and 
recruiting status will be registered and available for public viewing.
After change
In order to ensure that information on clinical trials reaches the public in a timely manner and to comply with 
applicable laws, regulations and guidance, Takeda will, at a minimum register interventional clinical trials it 
sponsors anywhere in the world on ClinicalTrials.gov and other publicly accessible websites before start of study, 
as defined in Takeda Policy/Standard. Takeda contact information, along with the study site’s name, city, country, 
and recruiting status will be registered and available for public viewing.
Reason for the change
Editorial improvement.
Section 16.0 on Page 56
Before change

BLB-750
Study No. CCT-901
Page 72 of 72
Protocol Amendment 01
25 Oct 2017
CONFIDENTIAL
The Package Insert for Cell-Culture Influenza Vaccine (H5N1 strain) created in May 2017
After change
The Package Insert for Cell-Culture Influenza Vaccine (H5N1 strain) created in June 2017
Reason for the change
Editorial improvement.

 
  
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