Safety and Immunogenicity of Different Dosages of High-Dose Quadrivalent Influenza Vaccine in Children 6 Months to 17 Years of Age
Phase: PHASE2
Conditions: Influenza
Sponsor: Sanofi Pasteur, a Sanofi Company

Sanofi Pasteur 
522 - High-Dose Quadrivalent Influenza Vaccine 
QHD04 
Protocol Version 3.0 
Safety and Immunogenicity of Different Dosages of High-Dose 
Quadrivalent Influenza Vaccine in Children 6 Months to 
17 Years of Age 
Phase II, randomized, staged, modified double-blind, multi-center study in the United States 
and Canada to evaluate the safety and immunogenicity of 3 dosages ofQIV-HD adm皿stered
inhamusculai·ly in chilch·en 6 months to 17 years of age. 
Clinical Study Protocol Amendment 1 
Health Authority File Number: 
WHO Universal Trial Number 
(UTN): 
Study Code: 
Development Phase: 
Sponsor: 
Investigational Product: 
Form/ Route: 
Indication For This Study: 
Manufacturer: 
Coordinating Investigator 
Sponso1·'s Responsible Medical 
Officer: 
Global Safety Officer: 
BB-IND#: 
17556 
Ul 111-1189-3713 
QHD04 
Phase II 
Sanofi Pasteur Inc. 
Discovery Drive, Swiftwater, PA 18370-0187, USA 
High-Dose Influenza Vaccine Quach·ivalent, (Zonal Purified, Split Virus) 
2018-2019 Strains (QIV-HD) 
Liquid / Inti·amuscular 
One dose or 2 doses for subjects 6 months to 17 years of age 
Same as Sponsor 
This is a multi-center study with multiple investigators. Investigators and 
study sites ai·e listed in the "List of Investigators and Centers Involved in 
the Trial" docwnent. 
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NCT03698279

 
 
 
  
 
 
 
 
 
 
 
  
 
 
History of Protocol Versions 
Version 
Date 
Comments 
1.0 
29 March 2018 
Version submitted to the IEC/IRB 
2.0 
24 July 2018 
Version approved by the IEC/IRB and used in the 
study 
 
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Table of Contents 
History of Protocol Versions........................................................................................................... 3 
List of Tables .................................................................................................................................... 9 
List of Figures ................................................................................................................................ 10 
Synopsis .......................................................................................................................................... 11 
Table of Study Procedures 1 (subjects 9 to 17 years of age) ...................................................... 26 
Table of Study Procedures 2 (previously influenza vaccinated subjects 6 months to 
8 years of age) .................................................................................................................. 28 
Table of Study Procedures 3 (previously influenza unvaccinated subjects 6 months to 
8 years of age) .................................................................................................................. 30 
List of Abbreviations ..................................................................................................................... 32 
1 
Introduction ..................................................................................................................... 35 
1.1 
Background ..................................................................................................................... 35 
1.2 
Background of the Investigational Product ..................................................................... 36 
1.3 
Potential Benefits and Risks ........................................................................................... 37 
1.3.1 
Potential Benefits to Subjects ....................................................................................... 37 
1.3.2 
Potential Risks to Subjects ........................................................................................... 37 
1.4 
Rationale for the Study ................................................................................................... 39 
2 
Study Objectives .............................................................................................................. 39 
3 
Investigators and Study Organization ........................................................................... 40 
4 
Independent Ethics Committee / Institutional Review Board .................................... 40 
5 
Investigational Plan ......................................................................................................... 41 
5.1 
Description of the Overall Study Design and Plan ......................................................... 41 
5.1.1 
Study Design ................................................................................................................ 41 
5.1.2 
Justification of the Study Design .................................................................................. 47 
5.1.3 
Study Plan ..................................................................................................................... 47 
5.1.4 
Visit Procedures ............................................................................................................ 49 
5.1.5 
Planned Study Calendar ............................................................................................... 55 
5.1.6 
Early Safety Data Review............................................................................................. 55 
5.2 
Enrollment and Retention of Study Population .............................................................. 56 
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5.2.1 
Recruitment Procedures ................................................................................................ 56 
5.2.2 
Informed Consent Procedures ...................................................................................... 56 
5.2.3 
Screening Criteria ......................................................................................................... 57 
5.2.4 
Inclusion Criteria .......................................................................................................... 57 
5.2.5 
Exclusion Criteria ......................................................................................................... 57 
5.2.6 
Medical History ............................................................................................................ 59 
5.2.7 
Contraindications for Subsequent Vaccination ............................................................ 60 
5.2.7.1 
Temporary Contraindications ..................................................................................... 60 
5.2.7.2 
Definitive Contraindications ...................................................................................... 60 
5.2.8 
Conditions for Withdrawal ........................................................................................... 61 
5.2.9 
Lost to Follow-up Procedures....................................................................................... 61 
5.2.10 
Classification of Subjects Who Discontinue the Study ................................................ 61 
5.2.11 
Follow-up of Discontinuations ..................................................................................... 62 
5.2.12 
Follow-up and Reporting of Pregnancies ..................................................................... 62 
5.3 
Safety Emergency Call ................................................................................................... 63 
5.4 
Modification of the Study and Protocol .......................................................................... 63 
5.5 
Interruption of the Study ................................................................................................. 64 
6 
Vaccines Administered ................................................................................................... 64 
6.1 
Identity of the Investigational Products .......................................................................... 64 
6.1.1 
Identity of Study Product 1 ........................................................................................... 64 
6.1.1.1 
Composition ............................................................................................................... 64 
6.1.1.2 
Preparation and Administration ................................................................................. 65 
6.1.1.3 
Dose Selection and Timing ........................................................................................ 65 
6.1.2 
Identity of Study Product 2 ........................................................................................... 65 
6.1.2.1 
Composition ............................................................................................................... 66 
6.1.2.2 
Preparation and Administration ................................................................................. 66 
6.1.2.3 
Dose Selection and Timing ........................................................................................ 66 
6.1.3 
Identity of Study Product 3 ........................................................................................... 66 
6.1.3.1 
Composition ............................................................................................................... 66 
6.1.3.2 
Preparation and Administration ................................................................................. 67 
6.1.3.3 
Dose Selection and Timing ........................................................................................ 67 
6.1.4 
Identity of Control Product 1 ........................................................................................ 67 
6.1.4.1 
Composition ............................................................................................................... 67 
6.1.4.2 
Preparation and Administration ................................................................................. 68 
6.1.4.3 
Dose Selection and Timing ........................................................................................ 68 
6.1.5 
Identity of Control Product 2 ........................................................................................ 68 
6.1.5.1 
Composition ............................................................................................................... 68 
6.1.5.2 
Preparation and Administration ................................................................................. 69 
6.1.5.3 
Dose Selection and Timing ........................................................................................ 69 
6.2 
Identity of Other Products ............................................................................................... 69 
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6.3 
Product Logistics ............................................................................................................ 69 
6.3.1 
Labeling and Packaging ............................................................................................... 69 
6.3.2 
Product Shipment, Storage, and Accountability ........................................................... 69 
6.3.2.1 
Product Shipment ....................................................................................................... 69 
6.3.2.2 
Product Storage .......................................................................................................... 70 
6.3.2.3 
Product Accountability ............................................................................................... 70 
6.3.3 
Replacement Doses....................................................................................................... 70 
6.3.4 
Disposal of Unused Products ........................................................................................ 70 
6.3.5 
Recall of Products ......................................................................................................... 70 
6.4 
Blinding and Code-breaking Procedures ........................................................................ 70 
6.5 
Randomization and Allocation Procedures ..................................................................... 72 
6.6 
Treatment Compliance .................................................................................................... 73 
6.7 
Concomitant Medications and Other Therapies ............................................................. 73 
7 
Management of Samples ................................................................................................. 74 
7.1 
Sample Collection ........................................................................................................... 74 
7.2 
Sample Preparation ......................................................................................................... 75 
7.3 
Sample Storage and Shipment ........................................................................................ 75 
7.4 
Future Use of Stored Serum Samples for Research ........................................................ 75 
8 
Clinical Supplies .............................................................................................................. 76 
9 
Endpoints and Assessment Methods ............................................................................. 76 
9.1 
Safety .............................................................................................................................. 76 
9.1.1 
Safety Definitions ......................................................................................................... 76 
9.1.2 
Safety Endpoints ........................................................................................................... 79 
9.1.3 
Safety Assessment Methods ......................................................................................... 79 
9.1.3.1 
Immediate Post-vaccination Observation Period ....................................................... 79 
9.1.3.2 
Reactogenicity (Solicited Reactions From Day 0 to Day 7 After Each 
Vaccination) ............................................................................................................... 80 
9.1.3.3 
Unsolicited Adverse Events ....................................................................................... 89 
9.1.3.4 
Adverse Events of Special Interest ............................................................................ 90 
9.1.3.5 
Assessment of Causality ............................................................................................ 90 
9.2 
Immunogenicity .............................................................................................................. 91 
9.2.1 
Immunogenicity Endpoints .......................................................................................... 91 
9.2.1.1 
Immunogenicity by HAI Method ............................................................................... 91 
9.2.1.2 
Immunogenicity by Virus SN Method ....................................................................... 91 
9.2.2 
Immunogenicity Assessment Methods ......................................................................... 92 
9.3 
Efficacy ........................................................................................................................... 93 
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10 
Reporting of Serious Adverse Events ............................................................................ 93 
10.1 
Initial Reporting by the Investigator ............................................................................... 93 
10.2 
Follow-up Reporting by the Investigator ........................................................................ 94 
10.3 
Reporting of SAEs Occurring After a Subject Has Completed the Study ...................... 94 
10.4 
Assessment of Causality ................................................................................................. 94 
10.5 
Reporting SAEs to Health Authorities and IECs / IRBs................................................. 95 
11 
Data Collection and Management ................................................................................. 95 
11.1 
Data Collection and CRB Completion ............................................................................ 95 
11.2 
Data Management ........................................................................................................... 96 
11.3 
Data Review .................................................................................................................... 97 
12 
Statistical Methods and Determination of Sample Size ............................................... 97 
12.1 
Statistical Methods .......................................................................................................... 97 
12.1.1 
Hypotheses and Statistical Methods for the Objectives ............................................... 97 
12.1.1.1 
Hypotheses ................................................................................................................. 97 
12.1.1.2 
Statistical Methods ..................................................................................................... 97 
12.2 
Analysis Sets ................................................................................................................... 98 
12.2.1 
Immunogenicity Analysis Set ....................................................................................... 98 
12.2.2 
Safety Analysis Set ....................................................................................................... 98 
12.2.3 
Populations Used in Analyses ...................................................................................... 99 
12.3 
Handling of Missing Data and Outliers .......................................................................... 99 
12.3.1 
Safety ............................................................................................................................ 99 
12.3.2 
Immunogenicity ............................................................................................................ 99 
12.4 
Interim / Preliminary Analysis ........................................................................................ 99 
12.5 
Determination of Sample Size and Power Calculation ................................................. 100 
13 
Ethical and Legal Issues and Investigator / Sponsor Responsibilities...................... 100 
13.1 
Ethical Conduct of the Study / Good Clinical Practice ................................................. 100 
13.2 
Source Data and Source Documents ............................................................................. 100 
13.3 
Confidentiality of Data, Data Protection, and Access to Subject Records ................... 101 
13.4 
Monitoring, Auditing, and Archiving ........................................................................... 102 
13.4.1 
Monitoring .................................................................................................................. 102 
13.4.2 
Audits and Inspections ............................................................................................... 102 
13.4.3 
Archiving .................................................................................................................... 103 
13.5 
Financial Contract and Insurance Coverage ................................................................. 103 
13.6 
Stipends for Participation .............................................................................................. 103 
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13.7 
Publication Policy ......................................................................................................... 103 
14 
Reference List ................................................................................................................ 104 
15 
Signature Page ............................................................................................................... 106 
 
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List of Tables 
Table 5.1: Description of study design ............................................................................................43 
Table 9.1: Solicited injection site reactions for infants and toddlers aged < 36 months: 
terminology, definitions, and intensity scales .................................................................................81 
Table 9.2: Solicited injection site reactions for children aged 3 to 11 years: terminology, 
definitions, and intensity scales .......................................................................................................82 
Table 9.3: Solicited injection site reactions for children aged 12 to 17 years: terminology, 
definitions, and intensity scales .......................................................................................................84 
Table 9.4: Solicited systemic reactions for infants and toddlers aged < 36 months: terminology, 
definitions, and intensity scales .......................................................................................................86 
Table 9.5: Solicited systemic reactions for children aged 3 to 17 years: terminology, definitions, 
and intensity scales ..........................................................................................................................87 
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List of Figures 
Figure 5.1: Study design flow chart for subjects 6 months to < 5 years of age ..............................45 
Figure 5.2: Study design flow chart for subjects 5 to 8 years of age ..............................................46 
Figure 5.3: Study design flow chart for subjects 9 to 17 years of age ............................................46 
 
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Table S1: Description of study design 
Stage 
(Country) 
Age Group (Vaccination 
Status*) 
Study 
Group 
N 
Vaccine 
Vaccine Dosage 
(µg HA/strain/dose)† 
1 
(US) 
9 to 17 years 
(previously vaccinated and 
unvaccinated) 
12 
30 
QIV-HD 
30 
30 
QIV-HD 
45 
10 
unadjuvanted QIV-SD 
15 
9 to 17 years 
(previously vaccinated and 
unvaccinated) 
13 
30 
QIV-HD 
60 
30 
unadjuvanted QIV-SD 
15 
5 to 8 years  
(previously vaccinated and 
unvaccinated) 
9 
30 
QIV-HD 
30 
10 
unadjuvanted QIV-SD 
15 
36 months to < 5 years 
(previously vaccinated and 
unvaccinated) 
1 
30 
QIV-HD 
30 
10 
unadjuvanted QIV-SD 
15 
2 
(US) 
5 to 8 years  
(previously vaccinated and 
unvaccinated) 
10 
30 
QIV-HD 
45 
10 
unadjuvanted QIV-SD 
15 
36 months to < 5 years 
(previously vaccinated and 
unvaccinated) 
2 
30 
QIV-HD 
45 
10 
unadjuvanted QIV-SD 
15 
6 to < 36 months 
(previously vaccinated and 
unvaccinated) 
3 
30 
QIV-HD 
30 
10 
unadjuvanted QIV-SD 
15 
3 
(US) 
5 to 8 years  
(previously vaccinated and 
unvaccinated) 
11 
30 
QIV-HD 
60 
30 
unadjuvanted QIV-SD 
15 
36 months to < 5 years 
(previously vaccinated and 
unvaccinated) 
4 
45 
QIV-HD 
60 
45 
unadjuvanted QIV-SD 
15 
6 to < 36 months 
(previously vaccinated and 
unvaccinated) 
5 
30 
QIV-HD 
45 
10 
unadjuvanted QIV-SD 
15 
4 
(US) 
6 to < 36 months 
(previously unvaccinated) 
6 
30 
QIV-HD 
30, 45, or 60† 
30 
unadjuvanted QIV-SD 
15 
6 to < 36 months 
(previously vaccinated) 
7 
30 
QIV-HD 
30, 45, or 60† 
30 
unadjuvanted QIV-SD 
15 
4 
(Canada) 
6 to < 24 months 
(previously unvaccinated) 
8 
30 
QIV-HD 
30, 45, or 60† 
30 
adjuvanted TIV 
7.5 
Abbreviations: HA, hemagglutinin; QIV-SD, standard-dose quadrivalent influenza vaccine; TIV, trivalent influenza vaccine; 
µg, microgram. 
* Vaccination status is determined by information provided by the parent / guardian. 
† Dosage selection will be based on the ESDR of the prior Stages. The highest dosage with an acceptable safety review from 
prior Stages will determine the dose evaluated in Stage 4. 
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Figure S1: Study design flow chart for subjects 6 months to < 5 years of age 
 
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Figure S2: Study design flow chart for subjects 5 to 8 years of age 
 
 
Figure S3: Study design flow chart for subjects 9 to 17 years of age 
 
 
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Vaccination 
All eligible subjects will be randomized to receive 1 or 2 doses of either QIV-HD, 
Fluarix® Quadrivalent (unadjuvanted QIV-SD), or FLUAD Pediatric® (adjuvanted 
TIV). The dosage of QIV-HD that is administered will depend on both the age of the 
subject and the stage at which he / she is enrolled. 
• 
Previously influenza vaccinated or unvaccinated subjects 9 to 17 years of age 
(hereafter will be referred to as subjects 9 to 17 years of age) will receive 1 dose 
of the QIV-HD or the comparator vaccine on D0. 
• 
Previously influenza vaccinated subjects 6 months to 8 years of age will receive 
1 dose of the QIV-HD or the comparator vaccine on D0. 
• 
Previously influenza unvaccinated subjects 6 months to 8 years of age will 
receive 2 doses of the QIV-HD or the comparator vaccine. Each dose will be 
administered 28 days apart (at D0 and D28). 
Of note, the highest dosage with an acceptable safety review in prior stages will 
determine the dose evaluated in Stage 4. 
An unblinded administrator at each site will administer the vaccine. 
Blood sampling 
Subjects will provide 2 or 3 blood samples, regardless of the stage of enrollment:  
Subjects 9 to 17 years of age will provide a pre-vaccination (baseline) blood sample 
at V01 (D0) and a post-vaccination blood sample at V03 (D28 [+7 days]) for 
hemagglutination inhibition (HAI) and seroneutralization (SN) testing. 
Note: Subjects 9 to 17 years of age are scheduled for 2 site visits. However, the 
second visit is designated as V03 to be consistent with the visits nomenclature of the 
6 months to 8 years age groups. 
Previously influenza vaccinated subjects 6 months to 8 years of age will provide a 
pre-vaccination (baseline) blood sample at V01 (D0) and a post-vaccination blood 
sample at V03 (D28 [+7 days]) for HAI and SN testing. 
Previously influenza unvaccinated subjects 6 months to 8 years of age will provide a 
pre-vaccination (baseline) blood sample at V01 (D0) and a post-vaccination blood 
sample at V03 (D28 [+7 days]) and V05 (28 days after V03 [+7 days]) for HAI and 
SN testing. 
Note: The blood sample will be taken prior to vaccination during any visit when a 
subject receives a vaccination.  
 
Collection of safety data 
All subjects will be observed for 30 minutes after vaccination, and any unsolicited 
systemic adverse events (AEs) occurring during that time will be recorded as 
immediate unsolicited systemic AEs in the case report book (CRB). 
Solicited reactions will be collected up to 7 days after each vaccination, and 
unsolicited AEs will be collected up to D28 (V03) for subjects receiving 1 dose and 
up to D56 (V05) for subjects receiving 2 doses. Serious adverse events (SAEs) and 
adverse events of special interest (AESIs) will be collected throughout the study (D0 
through approximately 6 months after the last vaccination). It is to be noted that 
AESIs will be captured as SAEs. These include new onset of Guillain-Barré 
syndrome (GBS), encephalitis / myelitis (including transverse myelitis), Bell’s 
palsy, convulsions, optic neuritis, and brachial neuritis. 
Subjects / parents / guardians will be asked to notify the site immediately about any 
potential SAEs (including AESIs) at any time during the study. 
The study staff will contact subjects 9 to 17 years of age or the subjects’ parents / 
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guardians by phone at D8 (+2 days) post-vaccination to identify whether the subject 
experienced any SAEs not yet reported and will remind the subjects / subjects’ 
parents / guardians to bring the completed diary card with them to V03 (D28 
[+7 days]). The study staff will review the D0 to V03 safety data with the subjects at 
V03. 
Subjects 6 months to 8 years of age will return to the site at D8 (+3 days) after each 
vaccination. Staff will review the recorded solicited reactions and unsolicited AEs, 
and determine whether the subject experienced any SAEs and AESIs not yet 
reported. Staff will review the safety data with subjects / subjects’ parents / 
guardians at each visit. Staff will also remind the subjects / subjects’ parents / 
guardians to bring the completed diary card with them to the subsequent visit. 
The interactive response technology (IRT) system will be used to randomly assign 
subjects to a study product and to assign subject numbers in each of the groups.  
Electronic data capture (EDC) will be used for the collection of data. 
Early Safety Data Review: 
The safety of the investigational product will be continuously monitored by the 
Sponsor. ESDRs will be performed, the goal of which is to allow for a cautious, 
stepwise approach to vaccine administration. A stepwise dosage ascension approach 
will be applied to subjects in age group 5 to 8 years (30 µg, 45 µg, and 60 µg 
HA/strain/dose). A stepwise age de-escalation vaccination approach will be taken 
for subjects in age group 36 months to < 5 years of age, with an ESDR prior to 
vaccinating subjects in the age group 6 to < 36 months of age as well as stepwise 
dosage ascension. The ESDR will be performed following V02 in subjects 6 months 
to 8 years of age (refer to Figure S1 and Figure S2). 
The ESDRs for this study are planned after the 6 months to 8 years age groups in 
each stage have been vaccinated and have provided safety data for Days 0 to 7 post-
vaccination, using the data collection methods described in the protocol. ESDR will 
not be performed for subjects 9 to 17 years of age. 
During each ESDR, enrollment of subjects will be paused. However, already 
enrolled subjects 6 months to 8 years of age who require 2 vaccinations because of 
their previous vaccination status will receive their second dose at D28 as scheduled, 
which may be prior to the ESDR. Following a satisfactory safety review, enrollment 
of subjects will resume for the subsequent or appropriate Stage as described in 
Figure S1 and Figure S2. The study visits according to the Table of Study 
Procedures will continue to be followed for enrolled subjects within each active 
Stage (ie, subjects will complete their scheduled visits). 
 
The safety data collected will be entered into the CRBs and summarized by the 
Sponsor in a blinded manner. A review will be performed by the Sponsor during the 
Safety Management Team (SMT) meetings. It is understood that this review is 
based on preliminary data that have not been subject to validation and database lock. 
(The usual and ongoing process of monitoring safety signals outside of those 
specified in the protocol-defined early interim safety analysis will continue 
unchanged.)  
The following safety parameters will be assessed as part of the early safety review: 
• 
Immediate reactions 
• 
Solicited injection site and systemic reactions 
• 
Unsolicited AEs 
• 
SAEs (including AESIs) 
 
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Enrollment will be paused during the review, and the data will be examined for the 
following occurrences: 
• 
An SAE (including AESIs) considered as related to the vaccination by the 
Investigator and Sponsor 
• 
> 10% of subjects experiencing Grade 3 fever within 7 days after vaccination 
If any of the above criteria are met, a decision will be made as to whether 
enrollment in the study will be allowed to resume. 
Case unblinding may be performed if necessary. 
Interruption of the Study 
The study may be discontinued if new data about the investigational product 
resulting from this study or any other studies become available; or for administrative 
reasons; or on advice of the Sponsor, the Investigators, the Independent Ethics 
Committees (IECs)/ Institutional Review Boards (IRBs), or the governing 
regulatory authorities in the US and Canada where the study is taking place.  
If the study is prematurely terminated or suspended, the Sponsor shall promptly 
inform the Investigators, the IECs/IRBs, the regulatory authorities, and any contract 
research organization(s) used in the study of the reason for termination or 
suspension, as specified by the applicable regulatory requirements. The Investigator 
shall promptly inform the subject or subjects’ parents / guardians and should assure 
appropriate subject therapy and/or follow-up. 
Objectives: 
Safety 
To describe the safety of each dosage of QIV-HD during the 28 days following 
each vaccination, and SAEs (including AESIs) throughout the study. 
Immunogenicity 
• 
To describe the antibody response induced by each dosage of QIV-HD used in 
the study compared with unadjuvanted QIV-SD by HAI measurement method. 
• 
To describe the antibody response induced by each dosage of QIV-HD used in 
the study compared with unadjuvanted QIV-SD by virus seroneutralization 
(SN) measurement method. 
• 
To describe the antibody response induced by the highest acceptable dosage of 
QIV-HD compared with adjuvanted TIV by HAI and virus SN measurement 
methods. 
Endpoints: 
Safety 
Safety will be described for all subjects: 
• 
Occurrence, nature (Medical Dictionary for Regulatory Activities [MedDRA] 
preferred term [PT]), duration, intensity, and relationship to vaccination of any 
unsolicited systemic AEs reported in the 30 minutes after each vaccination. 
• 
Occurrence, time to onset, number of days of occurrence, intensity, action 
taken, and whether the reaction led to early termination from the study, of 
solicited (prelisted in the subject’s diary card and CRB) injection site reactions 
and systemic reactions occurring up to 7 days after each vaccination. 
• 
Occurrence, nature (MedDRA system organ class [SOC] and PT), time to 
onset, duration, intensity, relationship to vaccination (for systemic AEs only), 
and whether the event led to early termination from the study, of unsolicited 
AEs up to 28 days after vaccination. 
• 
Occurrence, nature (MedDRA SOC and PT), time to onset, seriousness 
criteria, relationship to vaccination, outcome, and whether the event led to 
early termination from the study, of SAEs (including AESIs) throughout the 
study. 
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• 
Occurrence, nature (MedDRA PT), time to onset, and relationship to 
vaccination of AESIs throughout the study. 
 
Immunogenicity by HAI Method 
For subjects 9 to 17 years of age and previously influenza vaccinated subjects 
6 months to 8 years of age: 
• 
HAI antibody (Ab) titers obtained on D0 and D28 
• 
Individual HAI titers ratio D28/D0 
• 
Seroconversion (titer < 10 [1/dilution {dil}] at D0 and post-injection  titer ≥ 40 
[1/dil] at D28, or titer ≥ 10 [1/dil] at D0 and a ≥ 4-fold increase in titer [1/dil] 
at D28) 
• 
Percentage of subjects with titers ≥ 40 (1/dil) at D0 and D28 
For previously influenza unvaccinated subjects 6 months to 8 years of age: 
• 
HAI Ab titers obtained on D0, D28, and D56 
• 
Individual HAI titers ratio D28/D0 and D56/D0 
• 
Seroconversion (titer < 10 [1/dil] at D0 and post-injection titer ≥ 40 [1/dil] at 
D28 and D56, or titer ≥ 10 [1/dil] at D0 and a ≥ 4-fold increase in titer [1/dil] 
at D28 and D56) 
• 
Percentage of subjects with titers ≥ 40 (1/dil) at D0, D28, and D56 
 
Immunogenicity by SN Method 
For subjects 9 to 17 years of age and previously influenza vaccinated subjects 
6 months to 8 years of age: 
• 
Individual neutralization test (NT) Ab titer on D0 and D28 
• 
Individual NT Ab titer ratio (fold increase in serum NT post-vaccination 
relative to D0) at D28  
• 
Subjects with NT Ab titers ≥ 20 (1/dil), ≥ 40 (1/dil), ≥ 80 (1/dil) at D28  
• 
Fold-increase in NT Ab titer [post/pre] ≥2 and ≥ 4 at D28 
• 
Detectable NT (NT Ab titer ≥ 10 [1/dil]) at D0 and D28   
For previously influenza unvaccinated subjects 6 months to 8 years of age: 
• 
Individual NT Ab titer on D0, D28, and D56  
• 
Individual NT Ab titer ratio (fold increase in serum NT post-vaccination 
relative to D0) at D28 and D56  
• 
Subjects with NT Ab titers ≥ 20 (1/dil), ≥ 40 (1/dil), ≥ 80 (1/dil) at D28 and 
D56  
• 
Fold-increase in NT Ab titer [post/pre] ≥2 and ≥ 4 at D28 and D56 
• 
Detectable NT (NT Ab titer ≥ 10 [1/dil]) at D0, D28, and D56 
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Planned Sample Size: 
A total of 700 subjects are planned to be enrolled: 
• 
Group 1: 40 subjects; 36 months to < 5 years of age (previously influenza 
vaccinated and unvaccinated subjects) 
• 
n = 30 (QIV-HD: 30 µg HA/strain/dose) 
• 
n = 10 (QIV-SD [unadjuvanted]: 15 µg HA/strain/dose) 
• 
Group 2: 40 subjects; 36 months to < 5 years of age (previously influenza 
vaccinated and unvaccinated subjects) 
• 
n = 30 (QIV-HD: 45 µg HA/strain/dose) 
• 
n = 10 (QIV-SD [unadjuvanted]: 15 µg HA/strain/dose) 
• 
Group 3:40 subjects; 6 to < 36 months of age (previously influenza vaccinated 
and unvaccinated subjects) 
• 
n = 30 (QIV-HD: 30 µg HA/strain/dose) 
• 
n = 10 (QIV-SD [unadjuvanted]: 15 µg HA/strain/dose) 
• 
Group 4: 90 subjects; 36 months to < 5 years of age (previously influenza 
vaccinated and unvaccinated subjects) 
• 
n = 45 (QIV-HD: 60 µg HA/strain/dose) 
• 
n = 45 (QIV-SD [unadjuvanted]: 15 µg HA/strain/dose) 
• 
Group 5: 40 subjects; 6 to < 36 months of age (previously influenza vaccinated 
and unvaccinated subjects) 
• 
n = 30 (QIV-HD: 45 µg HA/strain/dose) 
• 
n = 10 (QIV-SD [unadjuvanted]: 15 µg HA/strain/dose) 
 
• 
Group 6: 60 subjects; 6 to < 36 months of age (previously influenza 
unvaccinated subjects) 
• 
n = 30 (QIV-HD: 60 µg, 45 µg, or 30 µg HA/strain/dose)* 
• 
n = 30 (QIV-SD [unadjuvanted]: 15 µg HA/strain/dose) 
• 
Group 7: 60 subjects; 6 to < 36 months of age (previously influenza vaccinated 
subjects) 
• 
n = 30 (QIV-HD: 60 µg, 45 µg, or 30 µg HA/strain/dose)* 
• 
n = 30 (QIV-SD [unadjuvanted]: 15 µg HA/strain/dose) 
• 
Group 8: 60 subjects; 6 to < 24 months of age (previously influenza 
unvaccinated subjects) 
• 
n = 30 (QIV-HD: 60 µg, 45 µg, or 30 µg HA/strain/dose)* 
• 
n = 30 (adjuvanted TIV: 7.5 µg HA/strain/dose) 
 
• 
Group 9: 40 subjects; 5 to 8 years of age (previously influenza vaccinated and 
unvaccinated subjects) 
• 
n = 30 (QIV-HD: 30 µg HA/strain/dose) 
• 
n = 10 (QIV-SD [unadjuvanted]: 15 µg HA/strain/dose) 
• 
Group 10: 40 subjects; 5 to 8 years of age (previously influenza vaccinated and 
unvaccinated subjects) 
• 
n = 30 (QIV-HD: 45 µg HA/strain/dose) 
• 
n = 10 (QIV-SD [unadjuvanted]: 15 µg HA/strain/dose) 
• 
Group 11: 60 subjects; 5 to 8 years of age (previously influenza vaccinated and 
unvaccinated subjects) 
• 
n = 30 (QIV-HD: 60 µg, 45 µg, or 30 µg HA/strain/dose)* 
• 
n = 30 (QIV-SD [unadjuvanted]: 15 µg HA/strain/dose) 
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• 
Group 12: 70 subjects; 9 to 17 years of age (previously influenza vaccinated 
and unvaccinated subjects) 
• 
n = 30 (QIV-HD: 30 µg HA/strain/dose) 
• 
n = 30 (QIV-HD: 45 µg HA/strain/dose) 
• 
n = 10 (QIV-SD [unadjuvanted]: 15 µg HA/strain/dose) 
• 
Group 13: 60 subjects; 9 to 17 years of age (previously influenza vaccinated 
and unvaccinated subjects) 
• 
n = 30 (QIV-HD: 60 µg HA/strain/dose) 
• 
n = 30 (QIV-SD [unadjuvanted]: 15 µg HA/strain/dose) 
* The dosage selection will be based on the ESDR by the SMT. The highest dosage 
with an acceptable safety profile based on the SMT review will be used in Stage 4. 
Duration of Participation in 
the Study: 
The duration of each subject’s active participation in the study will be 
approximately 28 days for subjects receiving 1 dose of vaccine and approximately 
56 days for subjects receiving 2 doses of vaccine.  
There will be a safety follow-up contact at 6 months after the last vaccination 
(approximately 180 days for subjects receiving 1 dose of vaccine and 208 days for 
subjects receiving 2 doses of vaccine). 
Investigational Product 1: 
High-Dose Quadrivalent Influenza Vaccine, (inactivated, Split Virus) 2018–2019 
Strains (QIV-HD), provided in a pre-filled single-dose syringe 
 Form: 
Suspension 
 Composition: 
Each 0.35 milliliter (mL) dose of QIV-HD will contain: 
Strains are based on World Health Organization (WHO) (Vaccines and Related 
Biological Products Advisory Committee [VRBPAC] in the US) recommendations 
for the 2018-2019 Northern Hemisphere (NH) influenza season. 
Active Substances: 
A/Michigan/45/2015 X-275 (H1N1) 
 
30 microgram (µg) HA 
 
A/Singapore/INFIMH-16-0019/2016 IVR-186 (H3N2) 
30 µg HA 
 
B/Maryland/15/2016 BX-69A  
(B/Colorado/6/2017-like virus, Victoria lineage) 
 
30 µg HA 
 
B/Phuket/3073/2013 (Yamagata lineage) 
 
 
30 µg HA 
 
Excipients: 
Buffered saline solution  
 
quantity sufficient (qs) to 
 
 
 
 
 
appropriate volume 
Octylphenol Ethoxylate (Triton X-100®) 
 not more than 175 µg 
Preservative is not used in the manufacture of QIV-HD. 
 Route: 
IM injection into the anterolateral muscle of the thigh or the deltoid muscle of the 
upper arm, as appropriate 
 Batch Number: 
UD20382 (US sites); UD20523 (Canadian sites) 
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Investigational Product 2: 
High-Dose Quadrivalent Influenza Vaccine, (inactivated, Split Virus) 2018–2019 
Strains (QIV-HD), provided in a pre-filled single-dose syringe 
 Form: 
Suspension 
 Composition: 
Each 0.52 mL dose of QIV-HD will contain: 
Strains are based on WHO (VRBPAC in the US) recommendations for the 2018-
2019 NH influenza season. 
Active Substances: 
A/Michigan/45/2015 X-275 (H1N1) 
 
 
45 µg HA 
 
A/Singapore/INFIMH-16-0019/2016 IVR-186 (H3N2) 
45 µg HA 
 
B/Maryland/15/2016 BX-69A  
(B/Colorado/6/2017-like virus, Victoria lineage) 
 
45 µg HA 
 
B/Phuket/3073/2013 (Yamagata lineage) 
 
 
45 µg HA 
 
Excipients: 
Buffered saline solution  
 
qs to appropriate volume 
Octylphenol Ethoxylate (Triton X-100)  
not more than 260 µg 
Preservative is not used in the manufacture of QIV-HD. 
 Route: 
IM injection into the anterolateral muscle of the thigh or the deltoid muscle of the 
upper arm, as appropriate 
 Batch Number: 
UD20383 (US sites); UD20522 (Canadian sites) 
Investigational Product 3: 
High-Dose Quadrivalent Influenza Vaccine, (Zonal Purified, Split Virus) 2018–
2019 Strains (QIV-HD), provided in a pre-filled single-dose syringe 
 Form: 
Suspension 
 Composition: 
Each 0.7 mL dose of QIV-HD will contain: 
Strains are based on WHO (VRBPAC in the US) recommendations for the 2018-
2019 NH influenza season. 
Active Substances: 
A/Michigan/45/2015 X-275 (H1N1) 
 
 
60 µg HA 
 
A/Singapore/INFIMH-16-0019/2016 IVR-186 (H3N2) 
60 µg HA 
 
B/Maryland/15/2016 BX-69A  
(B/Colorado/6/2017-like virus, Victoria lineage) 
 
60 µg HA 
 
B/Phuket/3073/2013 (Yamagata lineage) 
 
 
60 µg HA 
 
Excipients: 
Buffered saline solution  
 
qs to appropriate volume 
Octylphenol Ethoxylate (Triton X-100)  
 not more than 350 µg 
Preservative is not used in the manufacture of QIV-HD. 
 Route: 
IM injection into the anterolateral muscle of the thigh or the deltoid muscle of the 
upper arm, as appropriate 
 Batch Number: 
UD20384 (US sites); UD20524 (Canadian sites) 
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Control Product 1: 
Fluarix Quadrivalent Influenza vaccine, inactivated, non-adjuvanted, presented in 
a pre-filled syringe (unadjuvanted QIV-SD) (GlaxoSmithKline Biologicals, 
Dresden, Germany) 
 Form: 
Liquid solution 
 Composition: 
Each 0.5 mL dose contains 15 µg of hemagglutinin (HA) for each of the following 
strains: 
Strains are based on WHO (VRBPAC in the US) recommendations for the 2018-
2019 NH influenza season. 
Active Substances: 
A/Singapore/GP1908/2015 IVR-180 (H1N1)  
(A/Michigan/45/2015 [H1N1] pdm09-like virus) 
 
15 µg HA 
 
A/Singapore/INFIMH-16-0019/2016 NIB-104 (H3N2)  
15µg HA 
 
B/Maryland/15/2016 BX-69A  
(B/Colorado/6/2017-like virus, Victoria lineage) 
 
15 µg HA 
 
B/Phuket/3073/2013 (Yamagata lineage) 
 
 
15 µg HA 
 
Excipients: 
Octylphenol-10 (Triton X-100)  
 
≤ 0.115 milligram (mg) 
α-Tocopheryl hydrogen succinate   
≤ 0.135 mg 
Polysorbate 80 (Tween 80)  
 
≤ 0.550 mg  
Fluarix Quadrivalent does not contain a preservative. 
 Route: 
IM injection into the anterolateral muscle of the thigh or the deltoid muscle of the 
upper arm, as appropriate 
 Batch Number: 
Commercial batch: HJ9MN 
Control Product 2: 
FLUAD Pediatric: Influenza vaccine, adjuvanted, presented in a pre-filled syringe 
(Seqirus UK Limited, Maidenhead, UK) (adjuvanted TIV)) 
 Form: 
Liquid solution 
 Composition: 
Each 0.25 mL dose contains 7.5 µg of HA for each of the following strains: 
Strains are based on WHO (National Advisory Committee on Immunization [NACI] 
in Canada) recommendations for the 2018-2019 NH influenza season. 
Active Substances: 
A/Singapore/GP1908/2015 IVR-180 (H1N1) 
(A/Michigan/45/2015 [H1N1] pdm09-like virus) 
 
7.5 µg HA 
 
A/Singapore/INFIMH-16-0019/2016, IVR-186 (H3N2) 
 
7.5 µg HA 
 
B/Maryland/15/2016  
(B/Colorado/06/2017-like virus,Victoria lineage)  
 
7.5 µg HA 
 
Excipients: 
Sodium chloride  
 
 
2.00 mg  
Potassium chloride 
 
 
0.05 mg 
Potassium dihydrogen phosphate  
0.05 mg  
Disodium phosphate dehydrate 
 
0.335 mg 
Magnesium chloride hexahydrate  
0.025 mg 
Calcium chloride dihydrate 
 
0.03 mg 
Water for injection  
 
 
qs to appropriate volume 
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FLUAD Pediatric is formulated with the adjuvant MF59, an oil-in-water emulsion 
of squalene oil. 
FLUAD Pediatric does not contain a preservative. 
 Route: 
IM injection into the anterolateral muscle of the thigh or the deltoid muscle of the 
upper arm, as appropriate 
 Batch Number: 
Commercial batch: 253774 
Inclusion Criteria: 
An individual must fulfill all of the following criteria to be eligible for study 
enrollment: 
1) Aged 6 months to 17 years on the day of inclusion. 
2) Assent form has been signed and dated by the subject (7 to 17 years of age) 
and informed consent form has been signed and dated by the parent(s) or 
guardian(s) and by an independent witness, if required by local regulations. 
3) Subject and parent / guardian are able to attend all scheduled visits and to 
comply with all study procedures. 
4) For subjects aged < 24 months: Born at full term of pregnancy (≥ 37 weeks) 
and/or with a birth weight ≥ 2.5 kg. 
Exclusion Criteria: 
An individual fulfilling any of the following criteria is to be excluded from study 
enrollment: 
1) Subject is pregnant, or lactating, or of childbearing potential and not using an 
effective method of contraception or abstinence from at least 4 weeks prior to 
vaccination until at least 4 weeks after vaccination. To be considered of non-
childbearing potential, a female must be pre-menarche. 
2) Participation at the time of study enrollment (or in the 4 weeks preceding the 
first study vaccination) or planned participation during the present study period 
in another clinical study investigating a vaccine, drug, medical device, or 
medical procedure. 
3) Receipt of any vaccine in the 30 days preceding the first study vaccination, or 
planned receipt of any vaccine before Visit 3 for subjects receiving 1 dose of 
influenza vaccine or Visit 5 for subjects receiving 2 doses of influenza vaccine. 
4) For previously influenza vaccinated subjects: Previous vaccination against 
influenza in the preceding 6 months with either the study vaccine or another 
vaccine. 
5) For previously influenza unvaccinated subjects: Any influenza vaccination 
(from birth to the day of inclusion) with either the study vaccine or another 
influenza vaccine. 
6) For previously influenza unvaccinated subjects: Any previous laboratory 
confirmed influenza infection (from birth to the day of inclusion). 
7) Receipt of immune globulins, blood or blood-derived products in the past 3 
months. 
8) Known or suspected congenital or acquired immunodeficiency; or receipt of 
immunosuppressive therapy, such as anti-cancer chemotherapy or radiation 
therapy, within the preceding 6 months; or long-term systemic corticosteroid 
therapy (prednisone or equivalent for more than 2 consecutive weeks within 
the past 3 months). 
9) Known systemic hypersensitivity to any of the vaccine components, or history 
of a life-threatening reaction to the vaccines used in the study or to a vaccine 
containing any of the same substances. 
10) Thrombocytopenia or bleeding disorder, contraindicating IM vaccination 
based on Investigator’s judgement. 
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11) Deprived of freedom by an administrative or court order, or in emergency 
setting, or hospitalized involuntary. 
12) Current alcohol abuse or drug addiction.  
13) Chronic illness that, in the opinion of the investigator, is at a stage where it 
might interfere with study conduct or completion. 
14) Moderate or severe acute illness/infection (according to investigator judgment) 
on the day of vaccination or febrile illness (temperature ≥ 38.0°C [≥ 100.4°F]). 
A prospective subject should not be included in the study until the condition 
has resolved or the febrile event has subsided. 
15) Identified as an immediate family member (ie, spouse, natural or adopted 
child, grandchild, nephew, or niece) of the Investigator or employee with 
direct involvement in the proposed study. 
16) Personal history of GBS. 
17) Any condition that in the opinion of the Investigator would pose a health risk 
to the subject if enrolled or could interfere with the evaluation of the vaccine. 
18) Personal history of clinically significant development delay (at the discretion 
of the Investigator), neurologic disorder, or seizure disorder. 
19) Known seropositivity for hepatitis B or hepatitis C. 
Statistical Methods: 
No hypotheses for safety and immunogenicity are planned. All analyses are 
descriptive.  
For the cohorts controlled by the non-adjuvanted QIV-SD, results will be described 
per stage, according to vaccine received and per age group. Age groups will also be 
pooled within the same vaccine group for the main endpoints. The descriptive 
results may also be presented by the pooled QIV-HD group (60 µg) in the two 
countries. Subgroup immunogenicity analyses according to previous vaccination 
status and/or baseline serostatus may be presented when appropriate. If any of the 
stages are not completed, analyses for the higher dose or next stage will not be 
performed.  
For the cohort controlled by the adjuvanted TIV, results will be described 
according to vaccine received. 
Safety 
The main parameters will be described by the 95% confidence interval (CI) based 
on the Clopper-Pearson method.  
The safety analysis set (SafAS) will be used for the safety analyses. 
Immunogenicity 
Immunogenicity endpoints will be summarized with 95% CIs. The 95% CIs for the 
GMTs and GMT ratios (GMTRs) will be calculated using normal approximation of 
log-transformed titers. The 95% CIs for the proportions will be based on the 
Clopper-Pearson method. The ratios of GMTs will be obtained between groups 
with the 95% CIs calculated using normal approximation of log-transformed titers. 
The differences in the seroconversion rates between groups will be computed along 
with the 2-sided 95% CIs by the Wilson-Score method without continuity 
correction. Additional parameters may be displayed as appropriate. 
Reverse cumulative distribution curves against each strain will be performed for 
baseline (V01) and post-vaccination immunogenicity (D28 or D56 as appropriate). 
The immunogenicity analysis set (IAS) will be used for the main immunogenicity 
analyses. Details of the above analyses will be described in a Statistical Analysis 
Plan (SAP). 
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Calculation of Sample size 
The sample size is not powered.  
 
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Table of Study Procedures 1 (subjects 9 to 17 years of age) 
Phase II Study, 2 Visits, 2 Telephone Calls, 1 Vaccination, 2 Blood Samples, approximately 
180 Days’ Duration per Subject 
Visit/Contact 
V01 
Telephone Call 
V03 
(Second 
Visit)* 
Telephone Call 
Study timelines (days) 
D0 
D8 
D28 
180 days after 
V01 
Time windows (days) 
 
+2 
+7 
+14 
Informed consent form / assent form 
signed and dated 
X 
 
 
 
Inclusion / exclusion criteria 
X 
 
 
 
Collection of demographic data 
X 
 
 
 
Urine pregnancy test (if applicable)† 
X 
 
 
 
History of seasonal influenza vaccination 
X 
 
 
 
Medical history 
X 
 
 
 
Collection of reportable concomitant 
medications 
D0-D28 
 
Physical examination‡ 
X 
 
 
 
Randomization / allocation of subject 
number and unique dose number§ 
X 
 
 
 
Blood sampling (BL), 5 mL 
BL0001** 
 
BL0002 
 
Vaccination 
X 
 
 
 
Immediate surveillance (30 min) 
X 
 
 
 
DC provided†† 
DC1 
 
 
 
DC reviewed and collected 
 
 
DC1 
 
Reporting of solicited injection site and 
systemic reactions 
D0-D7 
 
 
Collection of unsolicited adverse events 
D0-D28 
 
MA provided‡‡ 
 
 
X 
 
Study active phase termination record 
 
 
X 
 
Follow-up telephone call 
 
X§§ 
 
X*** 
Reporting of SAEs (including AESIs)††† 
To be reported at any time during the study 
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Abbreviations: AESI, adverse event of special interest; BL, blood sampling; D, day; DC, diary card; MA, memory aid; SAE, 
serious adverse event; V, visit.  
* Visit 2 is designated as Visit 3 to be consistent with the visits nomenclature of the 6 months to 8 years age groups. 
† For females of childbearing potential. The urine pregnancy test must be performed before vaccination. The pregnancy test must 
be negative for enrollment. 
‡ Targeted physical examination based on medical history will be performed at V01. Targeted physical examination may also be 
performed at the second visit (designated as V03), if necessary. 
§ Before blood sampling and vaccine injection. 
** Collection of the blood sample before vaccination. 
†† Subjects / parents / guardians will use the diary card to record information about solicited reactions, unsolicited AEs, SAEs, and 
AESIs from D0 to D7 after vaccination and will continue to record information about unsolicited AEs, SAEs, and 
AESIs from D8 to the second visit (designated as V03). 
‡‡ Subjects / parents / guardians will use this MA to collect information on SAEs and AESIs from V03 (D28 [+7 days]) to the end 
of the 6- month safety follow-up period.  
§§ During this telephone call, staff will record relevant information concerning the subject’s health status , will find out whether 
the subject experienced any SAEs and AESIs not yet reported, and will remind the subjects to bring the completed 
diary card to the second visit (designated as V03). 
*** During this telephone call, staff will review the MA to identify the occurrence of any SAEs and AESIs that have not yet been 
reported. 
††† AESIs will be captured as SAEs. These include new onset of Guillain-Barré syndrome, encephalitis / myelitis (including 
transverse myelitis), Bell’s palsy, convulsions, optic neuritis, and brachial neuritis. 
 
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Table of Study Procedures 2 (previously influenza vaccinated subjects 
6 months to 8 years of age) 
Phase II Study, 3 Visits, 1 Telephone Call, 1 Vaccination, 2 Blood Samples, approximately 
180 Days’ Duration per Subject 
Visit/Contact 
V01 
V02 
V03 
Telephone Call 
Study timelines (days) 
D0 
D8 
D28 
180 days after 
V01 
Time windows (days) 
 
+3 
+7 
+14 
Informed consent form / assent form (if 
applicable*) signed and dated 
X 
 
 
 
Inclusion / exclusion criteria 
X 
 
 
 
Collection of demographic data 
X 
 
 
 
History of seasonal influenza vaccination 
X 
 
 
 
Medical history 
X 
 
 
 
Collection of reportable concomitant 
medications 
D0-D28 
 
Physical examination† 
X 
 
 
 
Randomization / allocation of subject 
number and unique dose number‡ 
X 
 
 
 
Blood sampling (BL), 5 mL 
BL0001§ 
 
BL0002 
 
Vaccination 
X 
 
 
 
Immediate surveillance (30 min) 
X 
 
 
 
DC provided** 
DC1 
 
 
 
DC reviewed and recorded†† 
 
DC1 
 
 
DC collected 
 
 
DC1 
 
Reporting of solicited injection site and 
systemic reactions 
D0-D7 
 
 
Collection of unsolicited adverse events 
D0-D28 
 
MA provided‡‡ 
 
 
X 
 
Study active phase termination record 
 
 
X 
 
Follow-up telephone call§§ 
 
 
 
X 
Reporting of SAEs (including AESIs)*** 
To be reported at any time during the study 
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Abbreviations: AESI, adverse event of special interest; BL, blood sampling; D, day; DC, diary card; MA, memory aid; SAE, 
serious adverse event; V, visit.  
* For children 7 to 8 years of age. 
† Targeted physical examination based on medical history will be performed at V01. Targeted physical examination may also be 
performed at V03, if necessary. 
‡ Before blood sampling and vaccine injection. 
§ Collection of the blood sample before vaccination. 
** Subjects / parents / guardians will use the diary card to record information about solicited reactions, unsolicited AEs, SAEs, and 
AESIs from D0 to D7 after vaccination and will continue to record information about unsolicited AEs, SAEs, and 
AESIs from D8 to V03. 
†† During V02, staff will review and record D0 to D7 data in the CRB, will find out whether the subject experienced any SAEs 
and AESIs not yet reported, and will remind the subjects to bring the completed diary card to V03. 
‡‡ Subjects / parents / guardians will use this MA to collect information on SAEs and AESIs from V03 to the end of the 6-month 
safety follow-up period.  
§§ During this telephone call, staff will review the MA to identify the occurrence of any SAEs and AESIs that have not yet been 
reported. 
*** AESIs will be captured as SAEs. These include new onset of Guillain-Barré syndrome, encephalitis / myelitis (including 
transverse myelitis), Bell’s palsy, convulsions, optic neuritis, and brachial neuritis. 
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Table of Study Procedures 3 (previously influenza unvaccinated subjects 
6 months to 8 years of age) 
Phase II Study, 5 Visits, 1 Telephone Call, 2 Vaccinations, 3 Blood Samples, approximately 
208 Days’ Duration per Subject 
Visit/Contact 
V01 
V02 
V03 
V04 
V05 
Telephone 
Call 
Study timelines (days) 
D0 
D8 
D28 
8 days 
after V03 
28 days 
after V03 
180 days 
after V03 
Time windows (days) 
 
+3 
+7 
+3 
+7 
+14 
Informed consent form / assent form (if 
applicable*) signed and dated 
X 
 
 
 
 
 
Inclusion / exclusion criteria 
X 
 
 
 
 
 
Collection of demographic data 
X 
 
 
 
 
 
History of seasonal influenza vaccination 
X 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
Collection of reportable concomitant 
medications 
D0-D56 
 
Physical examination† 
X 
 
X 
 
 
 
Randomization / allocation of subject 
number and unique dose number‡ 
X 
 
 
 
 
 
Allocation of unique dose number  
 
 
X 
 
 
 
Temporary and definitive 
contraindications 
 
 
X 
 
 
 
Blood sampling (BL), 5 mL 
BL0001§ 
 
BL0002§ 
 
BL0003 
 
Vaccination 
X 
 
X 
 
 
 
Immediate surveillance (30 min) 
X 
 
X 
 
 
 
DC provided§** 
DC1 
 
DC2 
 
 
 
DC reviewed and recorded†† 
 
DC1 
 
DC2 
 
 
DC collected 
 
 
DC1 
 
DC2 
 
Recording of solicited injection site and 
systemic reactions 
D0-D7 
D28-D35 
 
 
Collection of unsolicited adverse events 
D0-D28 
D28-D56 
 
MA provided‡‡ 
 
 
 
 
X 
 
Study active phase termination record 
 
 
 
 
X 
 
Follow-up telephone call§§ 
 
 
 
 
 
X 
Reporting of serious adverse events 
(SAEs) (including AESIs)*** 
To be reported at any time during the study 
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Abbreviations: AESI, adverse event of special interest; BL, blood sampling; D, day; DC, diary card; SAE, serious adverse event; 
V, visit.  
* For children 7 to 8 years of age. 
† Targeted physical examination based on medical history will be performed at V01. Targeted physical examination may also be 
performed at V03 or V05, if necessary. 
‡ Before blood sampling and vaccine injection 
§ Collection of the blood sample before vaccination. 
** Subjects / parents / guardians will use the diary cards to record information about solicited reactions, unsolicited AEs, SAEs, 
and AESIs after each vaccination (from D0 to D7 and from D28 to D35) and will continue to record information about 
unsolicited AEs, SAEs, and AESIs from D8 to V03 and D36 to V05. 
†† During V02 and V04, staff will review and record D0 to D7 and D28 to D35 data in the CRB, will find out whether the subject 
experienced any SAEs and AESIs not yet reported, and will remind the subjects to bring the completed diary card to 
their next scheduled visit.  
‡‡ Subjects / parents / guardians will use this MA to collect information on SAEs and AESIs from V05 to the end of the 6-month 
safety follow-up period. 
§§ During this telephone call, staff will review the MA to identify the occurrence of any SAEs and AESIs that have not yet been 
reported. 
*** AESIs will be captured as SAEs. These include new onset of Guillain-Barré syndrome, encephalitis / myelitis (including 
transverse myelitis), Bell’s palsy, convulsions, optic neuritis, and brachial neuritis. 
 
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List of Abbreviations 
µg 
microgram 
Ab 
antibody 
ACIP 
Advisory Committee on Immunization Practices  
AE 
adverse event 
AESI 
adverse event of special interest 
ALRI 
acute lower respiratory infections 
AR 
adverse reaction 
BL 
blood sampling 
CDC 
Centers for Disease Control and Prevention 
CDM 
Clinical Data Management 
CI 
confidence interval 
CQA 
Clinical Quality Assessment 
CRA 
Clinical Research Associate 
CRB 
(electronic) case report book [all the case report forms for a subject] 
CRF 
(electronic) case report form 
CRO 
contract research organization 
CTA 
clinical trial agreement 
CTL 
Clinical Team Leader 
D 
day 
DC 
diary card 
dil 
dilution 
DP 
drug product 
EDC 
electronic data capture 
ELISA 
enzyme-linked immunosorbent assay 
ESDR 
early safety data review 
FVFS 
first visit, first subject 
FVLS 
first visit, last subject 
GMT 
geometric mean titer 
GBS 
Guillain-Barré syndrome 
GCI 
Global Clinical Immunology 
GCP 
Good Clinical Practice 
GPV 
Global Pharmacovigilance  
GSK 
GlaxoSmithKline 
GSO 
Global Safety Officer 
HA 
hemagglutinin 
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HAI 
hemagglutination inhibition 
HAU 
hemagglutination unit 
IAS 
immunogenicity analysis set 
IATA 
International Air Transport Association 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IM 
intramuscular 
IME 
important medical event 
IND 
investigational new drug (application) 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
LCLS 
last contact, last subject 
LLOQ 
lower limit of quantitation 
LLT 
lowest level term 
MedDRA 
Medical Dictionary for Regulatory Activities 
MDCK 
Madin-Darby canine kidney 
MA 
memory aid 
mg 
milligram 
mL 
milliliter 
NACI 
National Advisory Committee on Immunization  
NT 
neutralization test 
NH 
Northern Hemisphere 
NMT 
not more than 
NSAID 
non-steroidal anti-inflammatory drug 
PT 
preferred term 
QIV 
quadrivalent influenza vaccine 
QIV-HD 
high-dose quadrivalent influenza vaccine 
QIV-SD 
standard-dose quadrivalent influenza vaccine 
qs 
quantity sufficient 
RBC 
red blood cell 
RMO 
Responsible Medical Officer 
SAE 
serious adverse event 
SafAS 
safety analysis set 
SAP 
statistical analysis plan 
SN 
seroneutralization 
SMT 
Safety Management Team 
SOC 
system organ class 
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TIV-HD 
high-dose trivalent influenza vaccine 
TIV-SD 
standard-dose trivalent influenza vaccine 
TMF 
trial master file 
ULOQ 
upper limit of quantitation 
US 
United States 
V 
visit 
VRBPAC 
Vaccines and Related Biological Products Advisory Committee 
WHO 
World Health Organization 
 
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1 
Introduction 
1.1 
Background 
This study will evaluate the safety and immunogenicity of 3 different dosages of quadrivalent 
influenza vaccine (QIV) in subjects 6 months to 17 years of age. 
Influenza is a highly contagious, acute viral respiratory disease caused by influenza type A and 
type B viruses. Influenza can be a serious illness impacting millions of people each year. In the 
United States (US), for example, an average of over 200,000 people are hospitalized, and 23,000 
people die from influenza-related respiratory and circulatory complications each year (1). During 
the 2015-2016 influenza season, the Centers for Disease Control and Prevention (CDC) reported 
an estimated 24.5 million Americans had influenza and close to 12,000 Americans died from 
pneumonia- and influenza-related deaths (2). 
Influenza is typically characterized by the rapid onset of fever, myalgia, sore throat, and non-
productive cough, and can also cause severe malaise lasting for several days. Members of high 
risk groups (eg, infants, younger children, adults 65 years of age and older, and children and 
adults with underlying medical conditions) are at increased risk of influenza and its 
complications. Complications in the pediatric population include secondary bacterial pneumonia, 
acute otitis media, bronchitis, febrile seizures, Reye’s syndrome, myositis, neurologic conditions, 
and exacerbations of underlying conditions (3) (4) (5). 
According to the CDC, seasonal flu-related hospitalizations have ranged from 7000 to 26,000 
among children younger than 5 years in the US since 2010 (6). In a meta-analysis which estimated 
the global incidence of influenza associated with acute lower respiratory infections (ALRI) and 
the resultant mortality in children aged less than 5 years, 90 million (95% confidence interval 
[CI]: 49-162 million) new cases of influenza episodes, 20 million (95% CI: 13-32 million) cases 
of influenza-associated ALRI, and 1 million (95% CI: 1-2 million) cases of influenza-associated 
severe ALRI were calculated for this age group, causing 27,800 (95% CI: 7400-48,000) deaths 
worldwide in 2008 (7). In the US, 110 pediatric deaths due to influenza were reported during the 
2016-2017 influenza season (8). In Canada, the Public Health Agency of Canada reported 
6546 influenza-associated hospitalizations and 388 influenza-associated deaths during the 2016-
2017 influenza season (9). 
Vaccination currently represents the most effective medical intervention against influenza and its 
severe complications. Thus, the World Health Organization (WHO) recommends that people who 
are most at risk for severe seasonal influenza, such as children less than 5 years, should receive an 
annual vaccination against influenza because it has been shown to be effective in reducing 
influenza-associated morbidity and mortality (10) (11) (12). 
While influenza affects all age groups, infants and young children remain at increased risk for 
influenza because of their maturing immune system and lack of prior exposure and thus lack of 
immunity. Vaccine coverage rates are high in children 6 months to 17 years of age as seen in the 
most recent data from the 2015-2016 US influenza season (59.3% in children versus 41.7% in 
adults) (13). However, data from the US Flu Vaccine Effectiveness Network during the same 
season showed a lower vaccine effectiveness rate against medically-attended influenza in younger 
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children 6 months to 8 years of age versus children 9 to 17 years of age. Therefore, an increase in 
antigen dose may improve protection against influenza in certain pediatric populations. 
Thus, the goal of this Phase II study is to generate safety and immunogenicity data for 3 different 
dosages of high-dose quadrivalent influenza vaccine (QIV-HD) in order to select the appropriate 
vaccine dosage for advancement into the Phase III clinical development. 
1.2 
Background of the Investigational Product 
Standard-dose trivalent influenza vaccines (TIV-SDs) contain 15 micrograms (µg) hemagglutinin 
(HA) of each of the 3 virus strains recommended by the WHO for use in that hemisphere’s 
upcoming influenza season, for a total of 45 µg of HA antigen per dose. The immune response to 
a TIV-SD (15 µg HA/strain/dose) is lower in adults 65 years of age and older than in younger 
healthy adults (13). Thus, Fluzone® High-Dose influenza vaccine (high-dose trivalent influenza 
vaccine [TIV-HD]), containing 60 µg HA of each of 3 virus strains (4 times more antigen than 
TIV-SD, for a total of 180 µg of HA antigen per dose) was developed by Sanofi Pasteur and 
subsequently licensed in the US, Canada, and Australia to improve immune responses to influenza 
vaccine and vaccine efficacy in adults 65 years of age and older (14).  
Previously, influenza vaccines contained a single influenza B strain. Two distinct genetic lineages 
of influenza B virus (the Victoria and the Yamagata lineages) have been co-circulating 
worldwide; both are responsible for influenza illnesses. However, the B strain included in 
seasonal influenza vaccines has not been the dominant circulating B lineage (mismatched strains) 
in approximately 25% of the seasons between 2000 and 2013 (15). To overcome the problem of 
B-strain selection and improve protection of the population against seasonal influenza virus 
strains, Sanofi Pasteur has been transitioning the Fluzone influenza vaccine portfolio from 
trivalent to quadrivalent formulations. The quadrivalent formulations contain 1 Victoria lineage B 
strain and 1 Yamagata lineage B strain. Thus, the issue of having to choose a strain from only one 
B lineage for the seasonal influenza vaccine and the resulting risk posed by the potential 
widespread circulation of a strain from the alternate B lineage is eliminated (16). 
QIV-HD is produced using the same drug substance and drug product (DP) manufacturing 
processes as TIV-HD, except for the DP formulation and filling, which increases the fill volume 
up to 0.7 milliliter (mL) at a maximum in order to include the second influenza B strain at the 
same HA content as the other 3 strains. Since three different dosages of QIV-HD will be used in 
this dose exploration study (30 μg, 45 μg, and 60 μg of HA/strain/dose) to determine the 
appropriate vaccine dosage for the Phase III study, the volume will be reduced when obtaining 
dosages lower than 60 μg HA/strain/dose. Thus, the decrease in the amount of HA content 
corresponds to a decrease in the fill volume (injection volume) and each of the 3 QIV-HD dosages 
will have a different fill volume (injection volume). 
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1.3 
Potential Benefits and Risks 
1.3.1 
Potential Benefits to Subjects 
All subjects enrolled in Study QHD04 will receive an influenza vaccine which will be either 1 of 
the 3 investigational QIV-HD, which differ by the amount of HA per strain, or one of the 2 
licensed comparator vaccines, QIV-SD or adjuvanted TIV. Therefore, they will be vaccinated 
against the influenza viruses recommended by the WHO (Vaccines and Related Biological 
Products Advisory Committee [VRBPAC] in the US) for the 2018-2019 Northern Hemisphere 
(NH) influenza season. These children may be protected against those strains and may be less 
likely to catch influenza or develop complications during the 2018-2019 influenza season. 
1.3.2 
Potential Risks to Subjects 
As with any vaccine, QIV-HD may not protect all recipients against the disease it is designed to 
prevent (ie, influenza). See below for other potential risks. 
Possible Reactions to Blood Draw 
Venipuncture causes transient discomfort and may cause temporary hypotension from a vasovagal 
response (eg, fainting). If pressure is not applied long enough to the venipuncture site, bruising 
due to bleeding beneath the skin may occur. Infection at the site of needle insertion could 
theoretically occur but is exceedingly rare when the standard sterile technique is utilized. 
Possible Reactions to Vaccination 
The most frequent side effect of influenza vaccination is pain or tenderness at the injection site 
that usually resolves within 3 days. Injection site reactions are generally mild. 
Systemic findings such as crying, irritability, or fever (young children); malaise or myalgia (older 
children); and other systemic symptoms can occur following vaccination and most often affect 
persons who have had no prior exposure to the vaccine antigens (eg, young children) (17). 
These reactions usually begin 6 to 12 hours after vaccination and usually resolve within 3 days. 
Results from a previous study of children 6 to 36 months of age demonstrated the safety of 
influenza vaccination in this age group (18). 
Immediate allergic reactions (eg, hives, angioedema, allergic asthma, and systemic anaphylaxis) 
occur rarely after influenza vaccination. These reactions probably result from hypersensitivity to 
some vaccine component. 
Cases of demyelinating disorders (eg, incident multiple sclerosis in adults, acute disseminated 
encephalomyelitis, transverse myelitis), have been reported following influenza vaccines, 
although the National Academy of Medicine (formerly, Institute of Medicine) concluded that the 
evidence is inadequate to accept or reject a causal relationship (19). 
In a study of the 2010–2011 influenza season, the CDC found that there was a risk of fever-
associated seizure (convulsion) occurring on the day of influenza vaccination and for 1 day after 
vaccination in children 6 months through 4 years of age. The risk was higher among children who 
received concomitant inactivated influenza vaccine and 13-valent pneumococcal conjugate 
vaccine and peaked at approximately age 16 months. The magnitude of the increased risk was less 
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than 1 episode per 1000 immunized children. A similar risk was found during the 2011–2012 
season (in which the formulation of the influenza vaccine used was the same as that used during 
the 2010–2011 season); however, an increased risk for febrile seizures following influenza 
vaccination was not observed during the 2012–2013 influenza season. No increased risk was 
found for children older than 4 years of age. After taking into consideration the benefits and risks 
of vaccination, no policy change was recommended for use of inactivated influenza vaccine or 
13-valent pneumococcal conjugate vaccine (20). 
The potential risks listed here are not exhaustive; refer to the package inserts of the marketed 
vaccines (Fluarix® Quadrivalent and FLUAD Pediatric®) for additional information regarding 
potential risks (21) (22). 
Post-marketing Experience with QIV-SD (Fluzone Quadrivalent), TIV-HD (Fluzone 
High-Dose), and TIV-SD (Fluzone) 
There is no post-marketing experience for QIV-HD as it has not been licensed yet. However, 
QIV-HD has been given to adults 65 years of age and older in 2 clinical studies, and no safety 
risks have been identified. 
Post-marketing experience with QIV-SD and TIV-HD has not identified any events other than 
those described below, which were spontaneously reported during the post-approval use of TIV-
SD, for addition to the QIV-SD package insert (23). 
The following events have been spontaneously reported during the post-approval use of TIV-SD 
and TIV-HD (24). These events are reported voluntarily from a population of uncertain size, 
consequently it is not always possible to reliably estimate the frequency of the events or establish 
a causal relationship to vaccine exposure. Adverse events (AEs) were included based on one or 
more of the following factors: severity, frequency of reporting, or strength of evidence for a 
causal relationship to TIV-SD: 
• Blood and Lymphatic System Disorders: thrombocytopenia, lymphadenopathy 
• Immune System Disorders: anaphylaxis, other allergic/hypersensitivity reactions (including 
urticaria, angioedema) 
Note: This type of reaction is rare and would most likely occur in persons with a severe 
reaction to influenza vaccine in the past. 
• Eye Disorders: ocular hyperemia 
• Nervous System Disorders: Guillain-Barré syndrome (GBS), convulsions, febrile convulsions, 
myelitis (including encephalomyelitis and transverse myelitis), facial palsy (Bell’s palsy), 
optic neuritis/neuropathy, brachial neuritis, syncope (shortly after vaccination), dizziness, 
paresthesia 
• Vascular Disorders: vasculitis, vasodilation/flushing 
• Respiratory, Thoracic and Mediastinal Disorders: dyspnea, pharyngitis, rhinitis, cough, 
wheezing, throat tightness 
• Skin and Subcutaneous Tissue Disorders: Steven-Johnson syndrome 
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• General Disorders and Administration Site Conditions: pruritus, asthenia/fatigue, pain in 
extremities, chest pain 
• Gastrointestinal Disorders: vomiting 
Other events reported during post-approval use of the TIV-HD vaccine include the following: 
• Gastrointestinal Disorders: nausea, diarrhea 
• General Disorder and Administration Site Conditions: chills 
1.4 
Rationale for the Study 
While influenza affects all age groups, infants and young children remain at increased risk for 
influenza because of their maturing immune system and lack of prior exposure and thus lack of 
immunity. Therefore, following a similar rationale that has been applied for adults 65 years of age 
and older, children may benefit from an increased antigen dose. Thus, this Phase II study will 
evaluate if an increased antigen dose in the QIV-HD investigational product is safe and will 
improve immune responses in the pediatric population aged 6 months to 17 years compared to 
currently licensed standard-dose quadrivalent influenza vaccines (QIV-SD) (15 μg HA/strain). 
The goal of QHD04 is to select the appropriate vaccine dosage for advancement to Phase III 
clinical development. 
QHD04 is planned to be conducted during the 2018-2019 NH influenza season in approximately 
700 children 6 months to 17 years of age and will evaluate 3 different dosages of QIV-HD in this 
pediatric population. The comparator vaccine will be Fluarix Quadrivalent which is a 
unadjuvanted QIV-SD and is manufactured by GlaxoSmithKline (GSK). Furthermore, another 
comparator vaccine, FLUAD Pediatric, which is an adjuvanted TIV and manufactured by Seqirus, 
will also be evaluated since FLUAD Pediatric is the only licensed pediatric vaccine which has 
been evaluated in relative efficacy studies. FLUAD Pediatric is only licensed for the pediatric 
indication (6 months to < 2 years of age) in Canada. 
2 
Study Objectives 
Safety 
To describe the safety of each dosage of QIV-HD used in the study during the 28 days following 
each vaccination, and serious adverse events (SAEs) (including adverse events of special interest 
[AESIs]) throughout the study. 
The endpoints for the safety objective are presented in Section 9.1.2 
Immunogenicity 
• To describe the antibody response induced by each dosage of QIV-HD used in the study 
compared with unadjuvanted QIV-SD by hemagglutination inhibition (HAI) measurement 
method. 
• To describe the antibody response induced by each dosage of QIV-HD used in the study 
compared with unadjuvanted QIV-SD by virus seroneutralization (SN) measurement method. 
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• To describe the antibody response induced by the highest acceptable dosage of QIV-HD 
compared with adjuvanted TIV by HAI and virus SN measurement methods. 
The endpoints for the immunogenicity objective are presented in Section 9.2.1 
3 
Investigators and Study Organization 
This study will be conducted in 16 centers in the US and Canada. The Principal Investigators and 
any sub-investigators at the individual sites will be coordinated by 1 Coordinating Investigator. 
Details of the study centers, the Investigators at each center, and the Coordinating Investigator are 
provided in the “List of Investigators and Centers Involved in the Trial” document. 
Safety Management Team 
An internal safety management team (SMT) will perform an analysis of safety data during the 
conduct of the study after the first vaccination (Early Safety Data Review [ESDR]). 
Monitoring, Data Management, and Statistical Analysis 
Biostatistics, data management, monitoring, and medical writing will either be subcontracted to a 
Contract Research Organization (CRO) or performed in-house by the Sponsor. 
Laboratory Analysis 
Testing will be performed at Sanofi Pasteur’s Global Clinical Immunology (GCI) department or at 
an outsourced laboratory under the supervision of GCI. 
The Sponsor’s Responsible Medical Officer (the RMO, the person authorized to sign this protocol 
and any amendments on behalf of the Sponsor) is
 Clinical Team Leader 
(CTL). 
4 
Independent Ethics Committee / Institutional Review Board 
Before the investigational product can be shipped to the investigational site and before the 
inclusion of the first subject, this protocol, the informed consent form (ICF), the assent form, 
subject recruitment procedures, and any other written information to be provided to subjects must 
be approved by, and / or receive favorable opinion from, the appropriate Independent Ethics 
Committees (IECs) or Institutional Review Boards (IRBs). 
In accordance with Good Clinical Practice (GCP) and local regulations, each Investigator and / or 
the Sponsor are responsible for obtaining this approval and / or favorable opinion before the start 
of the study. If the protocol is subsequently amended, approval must be re-obtained for each 
substantial amendment. Copies of these approvals, along with information on the type, version 
number, and date of document, and the date of approval, must be forwarded by the Investigator to 
the Sponsor together with the composition of the IEC / IRB (the names and qualifications of the 
members attending and voting at the meetings). 
The Investigator or Sponsor will submit written summaries of the status of the study to the IEC / 
IRB annually, or more frequently if requested. All SAEs occurring during the study that are 
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related to the product administered will be reported to the IEC / IRB, according to the IEC / IRB 
policy. 
5 
Investigational Plan 
5.1 
Description of the Overall Study Design and Plan 
5.1.1 
Study Design 
QHD04 will be a Phase II, randomized, staged, modified double-blind, active-controlled, multi-
center study to be conducted in 700 children 6 months 17 years of age to evaluate the safety and 
immunogenicity of 3 dosages of QIV-HD administered by IM route versus QIV-SD or adjuvanted 
TIV. 
The study will be divided into 13 groups and will enroll in 4 stages. The study will use a stepwise 
age de-escalation and dose ascension design for children 6 months to < 5 years of age. 
Children 5 to 8 years of age will also undergo a dose ascension design and begin enrollment in 
Stage 1. Children 9 to 17 years of age will be enrolled in Stage 1 and randomized to receive all 
three dose formulations (ie, 30 µg, 45 µg, and 60 µg HA/strain/dose). An ESDR will be 
conducted after Visit (V) 02 (at Day [D] 8 post-vaccination) of Stages 1, 2, and 3 for children 
6 months to < 5 years of age and Stages 1 and 2 for children 5 to 8 years of age. The ESDR for 
children 6 months to < 5 years of age will be independent of the ESDR for children 5 to 8 years of 
age. Enrollment of subjects in the next stage will be initiated if the safety review results are 
satisfactory.   
The 13 study groups are divided according to: 
• Age (9 to 17 yearsa, 5 to 8 yearsb, 36 months to < 5 years, 6 to < 36 months, or 6 to 
< 24 months) 
• Influenza vaccination history (previously influenza vaccinated, previously influenza 
unvaccinated, or both) 
• Administered vaccines (QIV-HD dosages [30 µg, 45 µg, or 60 µg HA/strain/dose], 
unadjuvanted QIV-SD, and adjuvanted TIV). 
The study design and the safety reviews are described in Table 5.1 and Section 5.1.6, respectively. 
The study flow chart is outlined in Figure 5.1, Figure 5.2, and Figure 5.3. The details of the study 
design are described below.  
Stage 1 will include 3 age groups (36 months to < 5 years, 5 to 8 years, and 9 to 17 years) and will 
be conducted in the US: 
                                                 
a  “9 to 17 years” means from the 9th birthday to the day before the 18th birthday. 
b  “5 to 8 years” means from the 5th birthday to the day before the 9th birthday. 
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• Previously influenza vaccinated and unvaccinated subjects 36 months to < 5 years of age 
(Group 1) will be randomized to receive either QIV-HD at 30 µg HA/strain/dose or the 
unadjuvanted QIV-SD. Based on the early safety data review, the study will either stop 
(Group 1 does not pass safety review) or continue into Stage 2 . 
• Previously influenza vaccinated and unvaccinated subjects 5 to 8 years of age (Group 9), will 
be randomized to receive either QIV-HD at 30 µg HA/strain/dose or the unadjuvanted QIV-
SD. Based on the early safety data review, the enrollment of this age group will either stop 
(Group 9 does not pass safety review) or continue into Stage 2.  
• Previously influenza vaccinated and unvaccinated subjects 9 to 17 years of age (hereafter will 
be referred to as subjects 9 to 17 years of age) will be divided into 2 groups (Group 12 and 
Group 13). Group 12 will be enrolled first and will be randomized to receive either QIV-HD 
at 30 µg, or 45 µg HA/strain/dose or the unadjuvanted QIV-SD. Once the enrollment of Group 
12 is complete, subjects in Group 13 will be randomized to receive either QIV-HD at 60 µg or 
the unadjuvanted QIV-SD. Subjects 9 to 17 years of age will not undergo an ESDR. 
Stage 2 will include 3 age groups (6 to < 36 months, 36 months to < 5 years, and 5 to 8 years) and 
will be conducted in the US: 
• Previously influenza vaccinated and unvaccinated subjects 36 months to < 5 years of age 
(Group 2) will receive either QIV-HD at 45 µg HA/strain/dose or the unadjuvanted QIV-SD 
and previously influenza vaccinated and unvaccinated subjects 6 to < 36 months of age 
(Group 3) will receive either QIV-HD at 30 µg HA/strain/dose or the unadjuvanted QIV-SD. 
Based on the early safety data review, the study will either stop (Group 3 does not pass safety 
review), continue and skip to Stage 4 (Group 2 does not pass safety review), or continue to 
Stage 3 (Group 2 and Group 3 both pass the safety review). 
• Previously influenza vaccinated and unvaccinated subjects 5 to 8 years of age (Group 10), will 
be randomized to receive either QIV-HD at 45 µg HA/strain/dose or the unadjuvanted QIV-
SD. Based on the early safety data review, the enrollment of this age group will either stop 
(Group 10 does not pass safety review) or continue into Stage 3.  
Stage 3 will include 3 age groups (6 to < 36 months, 36 months to < 5 years, and 5 to 8 years) and 
will be conducted in the US: 
• Previously influenza vaccinated and unvaccinated subjects 36 months to < 5 years of age 
(Group 4) will receive either QIV-HD at 60 µg HA/strain/dose or the unadjuvanted QIV-SD; 
and previously influenza vaccinated and unvaccinated subjects 6 to < 36 months of age 
(Group 5) will receive either QIV-HD at 45 µg HA/strain/dose or the unadjuvanted QIV-SD. 
Based on the early safety data review, the highest dosage with an acceptable safety review 
will be determined and used in Stage 4. 
• Previously influenza vaccinated and unvaccinated subjects 5 to 8 years of age (Group 11) will 
be randomized to receive either QIV-HD at 60 µg HA/strain/dose or the unadjuvanted QIV-
SD. 
Stage 4 will include 2 age groups (6 to < 36 months and 6 to < 24 months) and will be conducted 
in the US (subjects 6 to < 36 months) and Canada (subjects 6 to < 24 months): 
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• Previously influenza unvaccinated subjects 6 to < 36 months of age (Group 6) and previously 
influenza vaccinated subjects 6 to < 36 months of age (Group 7) will be randomized to receive 
either the highest dosage of QIV-HD with an acceptable safety review or the unadjuvanted 
QIV-SD. 
• Previously influenza unvaccinated subjects 6 to < 24 months of age (Group 8) will receive 
either the highest dosage of QIV-HD with an acceptable safety review or the adjuvanted TIV. 
Table 5.1: Description of study design 
Stage 
(Country) 
Age Group 
(Vaccination Status*) 
Study 
Group 
N 
Vaccine 
Vaccine Dosage 
(µg HA/strain/dose)† 
1 
(US) 
9 to 17 years 
(previously vaccinated 
and unvaccinated) 
12 
30 
QIV-HD 
30 
30 
QIV-HD 
45 
10 
unadjuvanted 
QIV-SD 
15 
9 to 17 years 
(previously vaccinated 
and unvaccinated) 
13 
30 
QIV-HD 
60 
30 
unadjuvanted 
QIV-SD 
15 
5 to 8 years  
(previously vaccinated 
and unvaccinated) 
9 
30 
QIV-HD 
30 
10 
unadjuvanted 
QIV-SD 
15 
36 months to < 5 years 
(previously vaccinated 
and unvaccinated) 
1 
30 
QIV-HD 
30 
10 
unadjuvanted 
QIV-SD 
15 
2 
(US) 
5 to 8 years  
(previously vaccinated 
and unvaccinated) 
10 
30 
QIV-HD 
45 
10 
unadjuvanted 
QIV-SD 
15 
36 months to < 5 years 
(previously vaccinated 
and unvaccinated) 
2 
30 
QIV-HD 
45 
10 
unadjuvanted 
QIV-SD 
15 
6 to < 36 months 
(previously vaccinated 
and unvaccinated) 
3 
30 
QIV-HD 
30 
10 
unadjuvanted 
QIV-SD 
15 
3 
5 to 8 years  
11 
30 
QIV-HD 
60 
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Stage 
(Country) 
Age Group 
(Vaccination Status*) 
Study 
Group 
N 
Vaccine 
Vaccine Dosage 
(µg HA/strain/dose)† 
(US) 
(previously vaccinated 
and unvaccinated) 
30 
unadjuvanted 
QIV-SD 
15 
36 months to < 5 years 
(previously vaccinated 
and unvaccinated) 
4 
45 
QIV-HD 
60 
45 
unadjuvanted 
QIV-SD 
15 
6 to < 36 months 
(previously vaccinated 
and unvaccinated) 
5 
30 
QIV-HD 
45 
10 
unadjuvanted 
QIV-SD 
15 
4 
(US) 
6 to < 36 months 
(previously 
unvaccinated) 
6 
30 
QIV-HD 
30, 45, or 60† 
30 
unadjuvanted 
QIV-SD 
15 
6 to < 36 months 
(previously vaccinated) 
7 
30 
QIV-HD 
30, 45, or 60† 
30 
unadjuvanted 
QIV-SD 
15 
4 
(Canada) 
6 to < 24 months 
(previously 
unvaccinated) 
8 
30 
QIV-HD 
30, 45, or 60† 
30 
adjuvanted 
TIV 
7.5 
Abbreviations: HA, hemagglutinin; QIV-SD, standard-dose quadrivalent influenza vaccine;TIV, trivalent influenza 
vaccine;  µg, microgram. 
* Vaccination status is determined by information provided by the parent / guardian. 
† Dosage selection will be based on the ESDR of the prior Stages. The highest dosage with an acceptable safety 
review from prior Stages will determine the dose evaluated in Stage 4. 
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Figure 5.1: Study design flow chart for subjects 6 months to < 5 years of age 
 
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Figure 5.2: Study design flow chart for subjects 5 to 8 years of age 
 
Figure 5.3: Study design flow chart for subjects 9 to 17 years of age 
 
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5.1.2 
Justification of the Study Design 
QHD04 study will describe the safety of the 3 different dosages of QIV-HD in children 6 months 
to 17 years of age. The study will also describe the immunogenicity of the different dosages of 
QIV-HD compared to a unadjuvanted QIV-SD (Fluarix Quadrivalent, licensed in the US) in all 
stages of the study and compared to an adjuvanted TIV (FLUAD Pediatric, licensed in Canada) 
during Stage 4 after the highest acceptable dosage of QIV-HD is established. Both comparators 
will be obtained commercially and will be used according to the approved indication. 
Given the different volumes in the 3 different dosages of the QIV-HD and the comparator 
vaccines, QHD04 will be a staged, modified double-blind study with an unblinded administrator 
used at each study site. The administrator will not be involved in any of the blinded study 
assessments (eg, safety). 
Since this is the first time that the QIV-HD will be administered to the pediatric population, an 
ESDR will be performed for subjects 6 months to 8 years of age prior to dosage ascension 
(30, 45, and 60 µg HA/strain/dose). 
Given the matured immune system in children 9 to 17 years of age, no ESDR will occur for 
subjects 9 to 17 years of age prior to dosage ascension. Subjects 9 to 17 years of age will be 
randomized to receive the 30 and 45 µg HA/strain/dose vaccines separately from subjects 9 to 17 
years of age who receive the 60 µg HA/strain/dose formulation in order to maintain the 
randomization ratio across all age groups and thus allow for pooling of the 30, 45, and 60 µg 
HA/strain/dose formulations across all age groups as well.  
The comparison of the QIV-HD that will be used in Stage 4 (highest dosage with acceptable 
safety) to the adjuvanted TIV will be an indicator in terms of expected vaccine efficacy since 
FLUAD Pediatric is the only licensed pediatric vaccine with studies evaluating both HAI 
immunogenicity and relative efficacy data. 
5.1.3 
Study Plan 
The study plan is summarized in the Table of Study Procedures. 
Vaccination 
All eligible subjects will be randomized to receive 1 or 2 doses of either QIV-HD, Fluarix® 
Quadrivalent (unadjuvanted QIV-SD), or FLUAD Pediatric® (adjuvanted TIV). The dosage of 
QIV-HD that is administered will depend on both the age of the subject and the stage at which he 
/ she is enrolled. 
• Subjects 9 to 17 years of age will receive 1 dose of the QIV-HD or the comparator vaccine on 
D0. 
• Previously influenza vaccinated subjects 6 months to 8 years of age will receive 1 dose of the 
QIV-HD or the comparator vaccine on D0. 
• Previously influenza unvaccinated subjects 6 months to 8 years of age will receive 2 doses of 
the QIV-HD or the comparator vaccine. Each dose will be administered 28 days apart (at D0 
and D28). 
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Of note, the highest dosage with an acceptable safety review in prior stages will determine the 
dose evaluated in Stage 4. 
An unblinded administrator at each site will administer the vaccine. 
Blood sampling 
Subjects will provide 2 or 3 blood samples, regardless of the stage of enrollment:  
• Subjects 9 to 17 years of age will provide a pre-vaccination (baseline) blood sample at V01 
(D0) and a post-vaccination blood sample at V03 (D28 [+7 days]) for HAI and SN testing. 
Note: Subjects 9 to 17 years of age are scheduled for 2 site visits. However, the second visit is 
designated as V03 to be consistent with the visits nomenclature of the 6 months to 8 years age 
groups. 
• Previously influenza vaccinated subjects 6 months to 8 years of age will provide a pre-
vaccination (baseline) blood sample at V01 (D0) and a post-vaccination blood sample at V03 
(D28 [+7 days]) for HAI and SN testing. 
• Previously influenza unvaccinated subjects 6 months to 8 years of age will provide a pre-
vaccination (baseline) blood sample at V01 (D0) and a post-vaccination blood sample at V03 
(D28 [+7 days]) and V05 (28 days after V03 [+7 days]) for HAI and SN testing. 
Note: The blood sample will be taken prior to vaccination during any visit when a subject receives 
a vaccination. 
Collection of safety data 
All subjects will be observed for 30 minutes after vaccination, and any unsolicited systemic 
adverse events (AEs) occurring during that time will be recorded as immediate unsolicited 
systemic AEs in the case report book (CRB). 
Solicited reactions will be collected up to 7 days after each vaccination, and unsolicited AEs will 
be collected up to D28 (V03) for subjects receiving 1 dose and up to D56 (V05) for subjects 
receiving 2 doses. Serious adverse events (SAEs) and adverse events of special interest (AESIs) 
will be collected throughout the study (D0 through approximately 6 months after the last 
vaccination). It is to be noted that AESIs will be captured as SAEs. These include new onset of 
Guillain-Barré syndrome (GBS), encephalitis / myelitis (including transverse myelitis), Bell’s 
palsy, convulsions, optic neuritis, and brachial neuritis. 
Subjects / parents / guardians will be asked to notify the site immediately about any potential 
SAEs (including AESIs) at any time during the study. 
The study staff will contact subjects 9 to 17 years of age or the subjects’ parents / guardians by 
phone at D8 (+2 days) post-vaccination to identify whether the subject experienced any SAEs not 
yet reported and will remind the subjects / subjects’ parents / guardians to bring the completed 
diary card with them to V03 (D28 [+7 days]). The study staff will review the D0 to V03 safety 
data with subjects at V03. 
Subjects 6 months to 8 years of age will return to the site at D8 (+3 days) after each vaccination. 
Staff will review the recorded solicited reactions and unsolicited AEs, and determine whether the 
subject experienced any SAEs and AESIs not yet reported. Staff will review the safety data with 
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subjects / subjects’ parents / guardians at each visit. Staff will also remind the subjects / subjects’ 
parents / guardians to bring the completed diary card with them to the subsequent visit. 
The interactive response technology (IRT) system will be used to randomly assign subjects to a 
study product and to assign subject numbers in each of the groups.  
Electronic data capture (EDC) will be used for the collection of data. 
Review of safety data 
The study will be divided into 4 stages as described in Section 5.1.1. An ESDR will be conducted 
for subjects 6 months to 8 years of age. The ESDR will occur following the collection of the 
safety data at V02 (approximately 8 days post-vaccination) of Stages 1, 2, and 3 by the SMT. 
Enrollment of subjects in the next stage will be initiated if the safety review results are 
satisfactory. The details of the safety reviews are described in Section 5.1.6.  
5.1.4 
Visit Procedures 
Visit 1 (Day 0): Inclusion, Randomization, Blood sample, and Vaccination – for all subjects 
The Investigator or delegate will: 
1) 
Give the subject and / or subject’s parent / guardian information about the study. 
2) 
Obtain informed consent and assent (for subjects 7 to 17 years of age) and answer any 
questions to ensure that the subjects and/or subject’s parent / guardian have been informed of 
all aspects of the study that are relevant to their decision to participate.  
3) 
Date and sign the ICF (and assent form for subjects 7 to 17 years of age) after it has been 
signed and dated by the subject or subject’s parent / guardian. Retain the original and give a 
signed copy to the subject or subject’s parent / guardian. 
4) 
Check all inclusion and exclusion criteria (see Section 5.2.4 and Section 5.2.5, respectively) 
through physical examination and medical interview of the subject and / or subject’s parent / 
guardian. If the subject is not eligible, only the specific form entitled “Recruitment log” will 
state the subject identification, no CRB will be completed. 
5) 
Collect relevant demographic information (eg, date of birth, sex, ethnicity, and race). 
6) 
For females of childbearing potential, conduct a urine pregnancy test. 
7) 
Obtain verbal information on medical history. 
8) 
Obtain information on seasonal influenza vaccination and any influenza diagnosis as follows: 
• 
For previously influenza unvaccinated subjects, confirm that the subject has not been 
vaccinated with any seasonal influenza vaccine since birth and has never had a known 
influenza diagnosis. 
Note: For the US sites, in following the Advisory Committee on Immunization Practices 
(ACIP) Guidelines, this study will consider subjects 6 months to 8 years of age who have 
never been vaccinated against influenza or who have not received at least 2 doses of 
seasonal influenza vaccine in a prior influenza season as “previously influenza 
unvaccinated subjects” when enrolling and thus these subjects will receive 2 doses of 
study vaccine at least 28 days apart. Subjects whose vaccination history is unknown will 
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also be considered as “previously influenza unvaccinated subjects” when enrolling and 
also receive 2 doses of study vaccine at least 28 days apart. 
For the Canadian sites, in following the National Advisory Committee on Immunization 
(NACI) recommendations, this study will consider subjects 6 months to less than 24 
months of age who have never been vaccinated against influenza in a prior influenza 
season as “previously influenza unvaccinated subjects” when enrolling and thus these 
subjects will receive 2 doses of study vaccine at least 28 days apart. Subjects who have 
received at least one dose of any influenza vaccine in the past will not be considered 
“previously influenza unvaccinated subjects”.  
• 
For previously influenza vaccinated subjects, obtain the date (month and year) when the 
subject was last vaccinated with a seasonal influenza vaccination.  
Note: For the US sites, in following the ACIP Guidelines, this study will consider 
subjects 6 months to 8 years of age who have received at least 2 doses of seasonal 
influenza vaccine in prior influenza seasons as “previously influenza vaccinated 
subjects” when enrolling and thus these subjects will receive only 1 dose of study 
vaccine. 
9) 
For subjects 6 to 12 months of age, obtain information on influenza vaccination during the 
mother’s pregnancy and breastfeeding routines, if any.  
10) Collect any reportable concomitant medications (see Section 6.7). 
11) Perform and document a targeted physical examination per standard site-specific 
immunization practices and record temperaturea in the source documents. 
12) Call the IRT for assignment of the 12-digit subject number, randomization, and allocation of 
a dose number (see Section 6.5).  
13) Draw approximately 5 mL of blood sample (The blood sampling should be performed before 
vaccination). Process the blood sample as specified in the “Management of Samples” section 
(see Section 7). 
Note: If 5 mL of blood sample cannot be drawn, a volume less than 5 mL can be obtained. 
Note: If the subject’s parent / guardian withdraws consent before blood sampling (before any 
invasive procedure has been performed), do not vaccinate the subject. The subject should be 
terminated from the study. 
Note: If the attempt(s) to collect blood is (are) unsuccessful (3 attempts), then the subject is 
still to be included in the study and vaccinated. 
The unblinded qualified study staff member will: 
14) Administer the appropriate vaccine intramuscularly into the anterolateral muscle of the thigh 
or the deltoid muscle of the upper arm, as appropriate (the vaccine must be administered on 
the side opposite to that of the blood sampling). 
15) Record the injection site / side / route / dose number and affix the detachable corresponding 
label in the source documents. 
                                                 
a  Tympanic and temporal artery thermometer should not be used. 
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The Investigator or delegate will: 
16) Keep the subject under medical surveillance for at least 30 minutes after the injection and 
report the occurrence or non-occurrence of any AE in the source documents. 
17) Give the subject or subject’s parent / guardian the diary card (DC) 1 to record any injection 
site reactions and systemic AEs, together with instructions for its completion, including 
explanations on the definition and use of intensity scales for collection of AEs. 
18) Give the subject or subject’s parent / guardian a ruler to measure the size of any injection site 
reaction, a thermometer for temperature measurement, and instructions on how to use them. 
19) Remind the subject or subject’s parent / guardian to bring back the DC1 when they return for 
V02. For subjects 9 to 17 years of age, schedule the D8 telephone call. 
20) Remind the subject or subject’s parent / guardian to promptly notify the site in case of an 
SAE/AESI that may occur at any time during the study. 
21) Complete the relevant CRB forms for this visit. 
Telephone call (8 [+2] days after Visit 1): Collection of Safety Information – for subjects 9 to 
17 years of age 
Note: If the telephone call falls on a weekend or a holiday, the telephone call may be scheduled 
on the next business day. 
The Investigator or delegate will: 
1) Record relevant information concerning the subject’s health status on the telephone contact 
form. If an SAE occurred, follow the instructions in Section 10 for reporting it. 
2) Remind the subject or subject’s parent / guardian to do the following: 
• 
Complete the remaining pages of the DC1 and bring the completed diary to V03 (D28 
[+7 days]). 
• 
Notify the site in case of an SAE. 
Visit 2 (8 [+3] days after Visit 1): Collection of Safety Information – for subjects 6 months to 
8 years of age 
Note: If Visit 2 falls on a weekend or a holiday, the visit may be scheduled on the next business 
day. 
The Investigator or delegate will: 
1) Review (for clarity, content, and completeness) the information in the DC1 with the subject or 
subject’s parent / guardian and clarify with the subject or subject’s parent / guardian, if 
required, any AEs, medications (see Section 6.7), or SAE that occurred since V01. If an SAE 
occurred, follow the instructions in Section 10 for reporting it. 
2) Record the D0 to D7 safety data in the CRB. 
3) Remind the subject or subject’s parent / guardian to do the following: 
• 
Complete the remaining pages of the DC1 and bring the completed diary to V03 
• 
Notify the site in case of an SAE. 
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Visit 3 (28 [+7] days after Visit 1) – for subjects 9 to 17 years of age and for previously 
influenza vaccinated subjects 6 months to 8 years of age 
Note: Subjects 9 to 17 years of age are scheduled for 2 site visits. However, the second visit is 
designated as V03 to be consistent with the visit nomenclature of the 6 months to 8 years age 
groups. 
The Investigator or delegate will: 
1) Review (for clarity, content, and completeness) and collect the DC1 information with the 
parent / guardian and clarify with the parent / guardian if required any AEs, medications (see 
Section 6.7), or SAE that occurred since the telephone call (for subjects 9 to 17 years of age) 
or V02 (for previously vaccinated subjects 6 months to 8 years of age). If an SAE occurred, 
follow the instructions in Section 10 for reporting it. 
2) Draw approximately 5 mL of blood sample. Process the blood sample as specified in the 
“Management of Samples” section (see Section 7). 
Note: If 5 mL of blood sample cannot be drawn, a volume less than 5 mL can be obtained. 
Note: If the attempt(s) to collect blood is (are) unsuccessful (3 attempts), the parent / guardian 
should be given the opportunity to bring his / her child to the study site for another attempt 
within the visit window. If a blood sample cannot be obtained, the reason will be recorded in 
the blood sampling page of the CRB. In this case, the subject will be followed for safety in the 
study. 
3) Provide the subject / parent / guardian with a memory aid (MA) and review the directions for 
its use. 
4) Remind the subject / parent / guardian to promptly notify the site in case of an SAE that may 
occur at any time during the study. 
5) Schedule the 6-month safety follow-up phone call 
6) Record all applicable information obtained into the CRB 
7) Complete the termination record of the CRB. 
Visit 3 (28 [+7] days after Visit 1) – for previously influenza unvaccinated subjects 6 months to 
8 years of age 
The Investigator or delegate will: 
1) Review (for clarity, content, and completeness) and collect the DC1 information with the 
parent / guardian and clarify with the parent / guardian if required any AEs, medications (see 
Section 6.7), or SAE that occurred since V02. If an SAE occurred, follow the instructions in 
Section 10 for reporting it. 
2) Conduct a targeted physical examination, if necessary.  
3) Review temporary and definitive contraindications to vaccination. 
4) Draw approximately 5 mL of blood sample (The blood sampling should be performed before 
vaccination). Process the blood sample as specified in the “Management of Samples” section 
(see Section 7). 
Note: If 5 mL of blood sample cannot be drawn, a volume less than 5 mL can be obtained. 
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Note: If the attempt(s) to collect blood is (are) unsuccessful (3 attempts), the parent / guardian 
should be given the opportunity to bring his / her child to the study site for another attempt 
within the visit window. If a blood sample cannot be obtained, the reason will be recorded in 
the blood sampling page of the CRB. In this case, the subject will remain in the study and 
should be vaccinated after all the attempts to collect blood are complete. 
The unblinded qualified study staff member will: 
5) Call the IRT to obtain a unique dose number 
6) Administer the appropriate vaccine intramuscularly into the anterolateral muscle of the thigh 
or the deltoid muscle of the upper arm, as appropriate (the vaccine must be administered on 
the side opposite to that of the blood sampling). 
7) Record the injection site / side / route / dose number in the source documents and affix the 
detachable corresponding label in the source document. 
The Investigator or delegate will: 
8) Keep the subject under medical surveillance for at least 30 minutes after the injection and 
report the occurrence or non-occurrence of any AE in the source documents. 
9) Give the subject / parent / guardian the DC2 to record any injection site reactions and systemic 
AEs, together with instructions for its completion, including explanations on the definition 
and use of intensity scales for collection of AEs. 
10) Remind the subject / parent / guardian to bring back the DC2 when they return for V04. 
11) Remind the subject / parent / guardian to promptly notify the site in case of an SAE that may 
occur at any time during the study. 
12) Complete the relevant CRB forms for this visit. 
Visit 4 (8 [+3] days after Visit 3) – for previously influenza unvaccinated subjects 6 months to 8 
years of age  
The Investigator or delegate will: 
1) Review (for clarity, content, and completeness) the information in the DC2 with the subject / 
parent / guardian and clarify with the parent / guardian, if required, any AEs, medications (see 
Section 6.7), or SAE that occurred since V03. If an SAE occurred, follow the instructions in 
Section 10 for reporting it. 
2) Record the D28-D35 safety data in the CRB. 
3) Remind the subject / parent / guardian to do the following: 
• 
Complete the remaining pages of the DC2 and bring them to V05 
• 
Notify the site in case of an SAE. 
Visit 5 (28 [+7] days after Visit 3) – for previously influenza unvaccinated subjects 6 months to 
8 years of age  
The Investigator or delegate will: 
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1) Review (for clarity, content, and completeness) and collect the DC2 information with the 
parent / guardian and clarify with the subject / parent / guardian if required any AEs, 
medications (see Section 6.7), or SAE that occurred since V04. If an SAE occurred, follow the 
instructions in Section 10 for reporting it. 
2) Draw approximately 5 mL of blood sample. Process the blood sample as specified in the 
“Management of Samples” section (see Section 7). 
Note: If 5 mL of blood sample cannot be drawn, a volume less than 5 mL can be obtained. 
Note: If the attempt(s) to collect blood is (are) unsuccessful (3 attempts), the parent / guardian 
should be given the opportunity to bring his / her child to the study site for another attempt 
within the visit window. If a blood sample cannot be obtained, the reason will be recorded in 
the blood sampling page of the CRB. In this case, the subject will remain in the study.  
3) Provide the subject / parent / guardian with a MA and review the directions for its use. 
4) Remind the subject / parent / guardian to promptly notify the site in case of an SAE that may 
occur at any time during the study. 
5) Schedule the 6-month safety follow-up phone call 
6) Record all applicable information obtained into the CRB 
7) Complete the termination record of the CRB. 
Safety Follow-up Telephone Call – approximately 6 months after the last vaccination: 
Collection of SAEs 
1) Inquire about new occurrences of SAEs and perform follow-up on SAEs. If an SAE has 
occurred, inquire if the subject has received any vaccinations or other medications since the 
last contact. 
2) Explain that this will be the last contact with the site for this study (except for subjects with 
SAEs that need further follow-up, as stated below). 
If the first contact attempt to complete the last telephone call is unsuccessful, at least 2 separate 
additional attempts, conducted on different days, should be made to contact these subjects. All 
attempts must be documented in the subject’s source notes. If, after at least 3 documented 
attempts, contact cannot be established, the subject should be classified as Lost to Follow-Up (see 
Section 5.2.9 for further details). 
The exceptions for the final phone calls are:  
• Subjects who voluntarily withdrew 
• Subjects who have been previously classified as lost to follow-up 
Follow-up of subjects with Related AEs or with AEs That Led to Study/Vaccination 
Discontinuation: 
A subject who experiences an AE (whether serious or non-serious) during the study must be 
followed until the condition resolves, becomes stable, or becomes chronic (even after the end of 
the subject’s participation in the study) if either of the following is true: 
• The AE is considered by the Investigator to be related to the product administered. 
• The AE caused the discontinuation of the subject from the study or from vaccination. 
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5.1.5 
Planned Study Calendar 
The following dates are approximate. The actual dates may differ as, for example, the study will 
not start until all the appropriate regulatory and ethical approvals have been obtained. 
Planned study period - FVFS (first visit, first subject) to LCLS (last contact, last subject; phone 
call at the end of the 6-months follow up period): 10 October 2018 – 15 October 2019 
Planned inclusion period - FVFS to FVLS (first visit, last subject): 
• Stage 1a: 10 October 2018 – 19 October 2018 
• Stage 2: 05 November 2018 – 09 November 2018 
• Stage 3: 29 November 2018 – 10 December 2018 
• Stage 4: 03 January 2019 – 28 February 2019 
Planned study period (active phase) – FVFS to LVLS (last visit, last subject): 
• Stage 1: 10 October 2018 – 21 November 2018 
• Stage 2: 05 November 2018 – 11 January 2019 
• Stage 3: 29 November 2018 – 11 February 2019 
• Stage 4: 03 January 2019 – 02 May 2019 
Planned end of study (LCLS; phone call at the end of the 6-months follow up period): 15 
October 2019 
Planned date of final clinical study report: 05 March 2020 
5.1.6 
Early Safety Data Review 
The safety of the investigational product will be continuously monitored by the Sponsor. ESDRs 
will be performed, the goal of which is to allow for a cautious, stepwise approach to vaccine 
administration. A stepwise dosage ascension approach will be applied to subjects in age group 5 
to 8 years (30 µg, 45 µg, and 60 µg HA/strain/dose). A stepwise age de-escalation vaccination 
approach will be taken for subjects in age group 36 months to < 5 years of age, with an ESDR 
prior to vaccinating subjects in the age group 6 to < 36 months of age as well as stepwise dosage 
ascension. The ESDR will be performed following V02 in subjects 6 months to 8 years of age 
(refer to Figure 5.1 and Figure 5.2). 
The ESDRs for this study are planned after the 6 months to 8 years age groups in each stage have 
been vaccinated and have provided safety data for Days 0 to 7 post-vaccination, using the data 
collection methods described in the protocol. ESDR will not be performed for subjects 9 to 
17 years of age. 
                                                 
a  Enrollment of subjects 9 to 17 years of age may be extended 
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During each ESDR, enrollment of subjects will be paused. However, already enrolled subjects 
6 months to 8 years of age who require 2 vaccinations because of their previous vaccination status 
will receive their second dose at D28 as scheduled, which may be prior to the ESDR. Following a 
satisfactory safety review, enrollment of subjects will resume for the subsequent or appropriate 
Stage as described in Figure 5.1 and Figure 5.2. The study visits according to the Table of Study 
Procedures will continue to be followed for enrolled subjects within each active Stage (ie, subjects 
will complete their scheduled visits). 
The safety data collected will be entered into the CRBs and summarized by the Sponsor in a 
blinded manner. A review will be performed by the Sponsor during the SMT meetings. It is 
understood that this review is based on preliminary data that have not been subject to validation 
and database lock. (The usual and ongoing process of monitoring safety signals outside of those 
specified in the protocol-defined early interim safety analysis will continue unchanged.)  
The following safety parameters will be assessed as part of the early safety review: 
• Immediate reactions 
• Solicited injection site and systemic reactions 
• Unsolicited AEs 
• SAEs (including AESIs) 
Enrollment will be paused during the review, and the data will be examined for the following 
occurrences: 
• An SAE (including AESIs) considered as related to the vaccination by the Investigator and 
Sponsor 
• > 10% of subjects experiencing Grade 3 fever within 7 days after vaccination 
If any of the above criteria are met, a decision will be made as to whether enrollment in the study 
will be allowed to resume. 
Case unblinding may be performed if necessary. 
5.2 
Enrollment and Retention of Study Population 
5.2.1 
Recruitment Procedures 
Subjects may be recruited from the general population. The sites will ensure that any 
advertisements used to recruit subjects (letters, pamphlets, posters, etc.) are submitted to Sanofi 
Pasteur prior to submission to the IEC / IRB for approval. 
5.2.2 
Informed Consent Procedures 
Informed consent is the process by which a subject’s parent / guardian voluntarily confirms his or 
her willingness to participate in a particular study. Informed consent must be obtained before any 
study procedures are performed. The process is documented by means of a written, signed, and 
dated ICF. 
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In addition to the ICF, subjects that are 7 years of age and older will be asked to review and sign a 
separate assent form. 
In accordance with GCP, prior to signing and dating the consent form, the subject’s parent / 
guardian must be informed by appropriate study personnel about all aspects of the study that are 
relevant to making the decision to participate and must have sufficient time and opportunity to ask 
any questions. A subject whose parent / guardian cannot read will not be included in the study. 
The actual ICF used at each center may differ, depending on local regulations and IEC / IRB 
requirements. However, all versions must contain the standard information found in the sample 
ICF provided by the Sponsor. Any change to the content of the ICF must be approved by the 
Sponsor and the IEC / IRB prior to the form being used. 
If new information becomes available that may be relevant to the subject / subject’s parent’s / 
guardian’s willingness to continue participation in the study, this will be communicated to him / 
her in a timely manner. Such information will be provided via a revised ICF or an addendum to 
the original ICF. 
Informed consent forms will be provided in duplicate, or a photocopy of the signed consent will 
be made. The original will be kept by the Investigator, and the copy will be kept by the subject / 
subject’s parent / guardian. 
Documentation of the consent process should be recorded in the source documents. 
5.2.3 
Screening Criteria 
There are no screening criteria other than the inclusion and exclusion criteria. 
5.2.4 
Inclusion Criteria 
An individual must fulfill all of the following criteria to be eligible for study enrollment: 
1) Aged 6 months to 17 years on the day of inclusiona. 
2) Assent form has been signed and dated by the subject (7 to 17 years of age) and informed 
consent form has been signed and dated by the parent(s) or guardian(s) and by an independent 
witness, if required by local regulations. 
3) Subject and parent / guardian are able to attend all scheduled visits and to comply with all 
study procedures. 
4) For subjects aged < 24 months: Born at full term of pregnancy (≥ 37 weeks) and/or with a 
birth weight ≥ 2.5 kg. 
5.2.5 
Exclusion Criteria 
An individual fulfilling any of the following criteria is to be excluded from study enrollment: 
                                                 
a  “6 months to 17 years” means from the 6th month after birth to the day before the 18th birthday. 
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1) Subject is pregnant, or lactating, or of childbearing potential and not using an effective 
method of contraception or abstinence from at least 4 weeks prior to vaccination until at least 
4 weeks after vaccination. To be considered of non-childbearing potential, a female must be 
pre-menarchea. 
2) Participation at the time of study enrollment (or in the 4 weeks preceding the first study 
vaccination) or planned participation during the present study period in another clinical study 
investigating a vaccine, drug, medical device, or medical procedure. 
3) Receipt of any vaccine in the 30 days preceding the first study vaccination, or planned receipt 
of any vaccine before Visit 3 for subjects receiving 1 dose of influenza vaccine or Visit 5 for 
subjects receiving 2 doses of influenza vaccine. 
4) For previously influenza vaccinated subjects: Previous vaccination against influenza in the 
preceding 6 months with either the study vaccine or another vaccineb. 
5) For previously influenza unvaccinated subjects: Any influenza vaccination (from birth to the 
day of inclusion) with either the study vaccine or another influenza vaccinec. 
6) For previously influenza unvaccinated subjects: Any previous laboratory confirmed influenza 
infection (from birth to the day of inclusion). 
7) Receipt of immune globulins, blood or blood-derived products in the past 3 months. 
8) Known or suspected congenital or acquired immunodeficiency; or receipt of 
immunosuppressive therapy, such as anti-cancer chemotherapy or radiation therapy, within 
the preceding 6 months; or long-term systemic corticosteroid therapy (prednisone or 
equivalent for more than 2 consecutive weeks within the past 3 months). 
9) Known systemic hypersensitivity to any of the vaccine components, or history of a life-
threatening reaction to the vaccines used in the study or to a vaccine containing any of the 
same substancesa. 
                                                 
a  Pre-menarche females will declare by themselves that they have not yet started menstruation. If a young female 
subject reaches menarche during the study, then she is to be considered as a woman of childbearing potential from 
that time forward. 
b  For the US sites, in following the ACIP Guidelines, this study will consider subjects 6 months to 8 years of age 
who have received at least 2 doses of seasonal influenza vaccine in prior influenza seasons as “previously 
influenza vaccinated subjects” when enrolling and thus these subjects will receive only 1 dose of study vaccine. 
c  For the US sites, in following the ACIP Guidelines, this study will consider subjects 6 months to 8 years of age 
who have never been vaccinated against influenza or who have not received at least 2 doses of seasonal influenza 
vaccine in a prior influenza season as “previously influenza unvaccinated subjects” when enrolling and thus these 
subjects will receive 2 doses of study vaccine at least 28 days apart. Subjects whose vaccination history is 
unknown will also be considered as “previously influenza unvaccinated subjects” when enrolling and also receive 
2 doses of study vaccine at least 28 days apart. 
For the Canadian sites, in following the NACI’s recommendations, this study will consider subjects 6 months to 
less than 24 months of age who have never been vaccinated against influenza in a prior influenza season as 
“previously influenza unvaccinated subjects” when enrolling and thus these subjects will receive 2 doses of study 
vaccine at least 28 days apart. Subjects who have received at least 1 dose of any influenza vaccine in the past will 
not be considered “previously influenza unvaccinated subjects”. 
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10) Thrombocytopenia or bleeding disorder, contraindicating IM vaccination based on 
Investigator’s judgement. 
11) Deprived of freedom by an administrative or court order, or in an emergency setting, or 
hospitalized involuntarily. 
12) Current alcohol abuse or drug addiction. 
13) Chronic illness that, in the opinion of the investigator, is at a stage where it might interfere 
with study conduct or completionb. 
14) Moderate or severe acute illness/infection (according to investigator judgment) on the day of 
vaccination or febrile illness (temperature ≥ 38.0°C [≥ 100.4°F]). A prospective subject should 
not be included in the study until the condition has resolved or the febrile event has subsided. 
15) Identified as an immediate family member (ie, spouse, natural or adopted child, grandchild, 
nephew, or niece) of the Investigator or employee with direct involvement in the proposed 
study. 
16) Personal history of GBS. 
17) Any condition that in the opinion of the Investigator would pose a health risk to the subject if 
enrolled or could interfere with the evaluation of the vaccine. 
18) Personal history of clinically significant development delay (at the discretion of the 
Investigator), neurologic disorder, or seizure disorder. 
19) Known seropositivity for hepatitis B or hepatitis C. 
5.2.6 
Medical History 
Prior to enrollment, subjects will be assessed for pre-existing conditions and illnesses, both past 
and ongoing. Any such conditions will be documented in the source document. Significant 
(clinically relevant) medical history (reported as diagnosis) including conditions/illnesses for 
which the subject is or has been followed by a physician or conditions/illnesses that could resume 
during the course of the study or lead to an SAE or to a repetitive outpatient care will be collected 
in the CRB. The significant medical history section of the CRB contains a core list of body 
systems and disorders that could be used to prompt comprehensive reporting, as well as space for 
the reporting of specific conditions and illnesses. 
For each condition, the data collected will be limited to: 
• Diagnosis (this is preferable to reporting signs and symptoms) 
• Presence or absence of the condition at enrollment 
The reporting of signs and symptoms in lieu of a diagnosis is strongly discouraged. 
                                                                                                                                                               
a  The components of QIV-HD are listed in Section 6.1 and in the Investigator’s Brochure and the components of 
the comparator products are listed in Section 6.1 and in the package inserts. 
b  Chronic illness may include, but is not limited to, cardiac disorders, renal disorders, auto-immune disorders, 
diabetes, psychiatric disorders or chronic infection 
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Dates, medications, and body systems are not to be recorded, and the information collected will not 
be coded. Its purpose is to assist in the later interpretation of safety data collected during the 
study. 
5.2.7 
Contraindications for Subsequent Vaccination 
The contraindications apply only to previously influenza unvaccinated subjects who are going to 
receive 2 vaccine doses, 28 (+7) days apart.  
5.2.7.1 
Temporary Contraindications 
Should a subject experience one of the conditions listed below, the Investigator will postpone 
further vaccination until the condition is resolved. Postponement must still be within the 
timeframe for vaccination indicated in the Table of Study Procedures. 
• Febrile illness (temperature ≥ 38.0°C [≥ 100.4°F]) or moderate or severe acute illness / 
infection on the day of vaccination, according to Investigator judgment. 
5.2.7.2 
Definitive Contraindications 
The following criteria are applicable to subjects who had never received any influenza vaccine 
before the start of the study and who will be receiving 2 influenza vaccine injections during the 
study (1 at V01 and 1 at V03). Should a subject experience 1 of the conditions listed below, the 
Investigator will discontinue vaccination. 
• D01: An anaphylactic or other significant allergic reaction to the previous dose of vaccine 
• D02: Receipt of any immune globulins, blood, or blood-derived products between V01 and 
V03. 
• D03: Known or suspected congenital or acquired immunodeficiency; or receipt of 
immunosuppressive therapy, such as anti-cancer chemotherapy or radiation therapy, since the 
preceding visit; or long-term systemic corticosteroid therapy (prednisone or equivalent for 
more than 2 consecutive weeks since the preceding visit). 
• D04: Thrombocytopenia or bleeding disorder, which may be a contraindication for IM 
vaccination, based on Investigator’s judgement. 
• D05: Chronic illness that, in the opinion of the investigator, is at a stage where it might 
interfere with study conduct or completion. 
• D06: Development of any condition that in the opinion of the Investigator would pose a health 
risk to the subject or could interfere with the evaluation of the study vaccine (including GBS, 
clinically significant developmental delay, neurologic disorder, seizure disorder, hepatitis B, 
or hepatitis C). 
• D07: Any SAE related to the study vaccines following the previous study vaccination, based 
on investigator’s judgement. 
Subjects with a definitive contraindication will not be vaccinated at V03, but will continue to be 
followed up for the study-defined safety and immunogenicity assessments, as applicable. 
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In the event of a local or national immunization program with a pandemic influenza vaccine or 
other vaccine, subjects who receive pandemic influenza vaccine or other vaccine at any time 
during the study will not be withdrawn from the study. 
5.2.8 
Conditions for Withdrawal  
Subjects / parents / guardians will be informed that they have the right to withdraw from the study 
at any time. A subject may be withdrawn from the study: 
• At the discretion of the Investigator or Sponsor due to safety concerns or significant non-
compliance with the protocol (based on the Investigator’s judgment), without the subject’s 
permission (withdrawal) 
• At the request of the subject / parent / guardian (dropout) 
The reason for a withdrawal or dropout should be clearly documented in the source documents 
and on the CRB.  
The Investigator must determine whether voluntary withdrawal is due to safety concerns (in 
which case, the reason for discontinuation will be noted as “Adverse Event”) or for another 
reason. 
Withdrawn subjects will not be replaced. 
5.2.9 
Lost to Follow-up Procedures 
In the case of subjects who fail to return for a follow-up examination, documented reasonable 
effort (ie, documented telephone calls and certified mail) should be undertaken to locate or recall 
them, or at least to determine their health status while fully respecting their rights. These efforts 
should be documented in the CRB and in the source documents. 
5.2.10 Classification of Subjects Who Discontinue the Study 
For any subject who discontinues the study prior to completion, the most significant reason for 
early termination will be checked in the CRB. Reasons are listed below from the most significant 
to the least significant (refer to the case report form (CRF) completion instructions for additional 
details and examples): 
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Adverse Event 
To be used when the subject is permanently terminated from the study because of an 
AE (including an SAE), as defined in Section 9.1.1. 
This category also applies if the subject experiences a definitive contraindication 
that is an SAE or AE. 
Lost to Follow-up 
To be used when the subject cannot be found or contacted in spite of efforts to locate 
him/her before the date of his/her planned last visit, as outlined in Section 5.2.9. The 
certified letter was sent by the investigator and returned unsigned, and the subject or 
parent/guardian did not give any other news and did not come to any following visit. 
Protocol Deviation To be used: 
• 
In case of significant noncompliance with the protocol (eg, deviation of the 
Inclusion / Exclusion criteria, non-compliance with time windows, blood 
sampling or vaccination refusal, missed injection/treatment, or error in the 
vaccine/treatment administration). 
• 
If the subject experiences a definitive contraindication that is a protocol 
deviation. 
• 
The subject or the parent/guardian signed the certified letter sent by the 
investigator but did not give any other news and did not come to any following 
visit. 
Withdrawal by 
Subject or Parent 
/ Guardian  
To be used: 
• 
When the subject or parent/guardian indicated unwillingness to continue in the 
study 
• 
When the subject or parent/guardian made the decision to discontinue 
participation in the study for any personal reason other than an SAE/AE (eg, 
subject is relocating, inform consent withdrawal, etc.) 
5.2.11 
Follow-up of Discontinuations 
The site should complete all scheduled safety follow-ups and contact any subject or parent / 
guardian of any subject who has prematurely terminated the study because of an AE, a protocol 
deviation, or loss of eligibility, including definitive contraindications. The follow-up duration in 
the event of discontinuation is 6 months after the last vaccination. 
For subjects where the reason for early termination was lost to follow-up or if the subject / parent 
/ guardian withdrew informed consent and specified that they do not want to be contacted again 
and it is documented in the source document, the site will not attempt to obtain further safety 
information. 
If the subject’s status at the end of the study is “Withdrawal by Subject or Parent / Guardian”, the 
site will attempt to contact them for the 6-month follow-up except if they specified that they do 
not want to be contacted again and it is documented in the source document. 
5.2.12 Follow-up and Reporting of Pregnancies 
Pregnancy is an exclusion criterion for enrollment in this study, but a subject could potentially 
become pregnant during her participation. In case of pregnancy, and if at least 1 dose of the study 
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vaccine(s) has been administered, the subject will not be discontinued from the study. However, 
the subject will be followed for safety assessment (and may be followed for immunogenicity 
assessment, if applicable). 
All pregnancy cases should be reported if they occurred during the study and during the 6 month 
follow up period. To report the pregnancy case, the Investigator must fill out Pregnancy Reporting 
forms in the electronic data capture (EDC) system and inform the Sponsor within 1 month of 
identifying a pregnancy case.  
If the EDC system is not available, the investigator must fill out a paper Pregnancy Reporting 
Form (provided by the Sponsor at the start of the study) and inform the Sponsor within 1 month of 
identifying a pregnancy case. 
Study staff must then maintain contact with the subject to obtain information about the outcome 
(i.e., details about the delivery and the newborn, or about pregnancy termination) and must update 
the Pregnancy Reporting forms even after the end of the study. This information should be 
provided to the Sponsor within 1 month of delivery. 
Pregnancy itself is not considered an AE, but any complications during pregnancy are to be 
considered as AEs, and in some cases could be considered SAEs. Spontaneous abortions, blighted 
ovum, fetal death, stillbirth, and congenital anomalies reported in the baby are always considered 
as SAEs, and the information should be provided to the Global Pharmacovigilance (GPV) 
Department regardless of when the SAE occurs (eg, even after the end of the study). 
5.3 
Safety Emergency Call 
If, as per the Investigator’s judgment, a subject experiences a medical emergency, the Investigator 
may contact the Sponsor’s RMO for advice on study related medical question or problem. If the 
RMO is not available, then the Investigator may contact the Call Center—available 24 hours a 
day, 7 days a week—that will forward all safety emergency calls to the appropriate primary or 
back-up Sanofi Pasteur contact, as needed. The toll-free contact information for the Call Center is 
provided in the Operating Guidelines. 
This process does not replace the need to report an SAE. The investigator is still required to 
follow the protocol-defined process for reporting SAEs to the GPV Department (refer to Section 
10). 
In case of emergency code-breaking, the Investigator is required to follow the code-breaking 
procedures described in Section 6.4. 
5.4 
Modification of the Study and Protocol 
Any amendments to this study plan and protocol must be discussed with and approved by the 
Sponsor. If agreement is reached concerning the need for an amendment, it will be produced in 
writing by the Sponsor, and the amended version of the protocol will replace the earlier version. 
All substantial amendments (eg, those that affect the conduct of the study or the safety of 
subjects) require IEC / IRB approval, and must also be forwarded to regulatory authorities. 
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An administrative amendment to a protocol is one that modifies some administrative, logistical, or 
other aspect of the study but does not affect its scientific quality or have an impact on the 
subjects’ safety. Administrative changes do not require IEC / IRB approval; however, the IEC / IRB 
must be notified whenever one is made. 
The Investigator is responsible for ensuring that changes to an approved study, during the period 
for which IEC / IRB approval has already been given, are not initiated without IEC / IRB review 
and approval, except to eliminate apparent immediate hazards to subjects. 
5.5 
Interruption of the Study 
The study may be discontinued if new data about the investigational product resulting from this or 
any other studies become available; or for administrative reasons; or on advice of the Sponsor, the 
Investigators, the IECs/IRBs, or the governing regulatory authorities in the countries where the 
study is taking place.  
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The Investigator shall promptly inform the subjects / subjects’ parents / 
guardians and should assure appropriate subject therapy and/or follow-up. 
6 
Vaccines Administered 
6.1 
Identity of the Investigational Products  
6.1.1 
Identity of Study Product 1 
The investigational QIV-HD is a split virion quadrivalent influenza vaccine (30 μg HA/strain) 
containing virus strains chosen by the WHO (VRBPAC in the US) for the NH 2018-2019 
influenza season. The vaccine contains 2 antigens of type A (H1N1 and H3N2) and 2 antigens of 
type B (one each from Yamagata and Victoria lineages). Each pre-filled syringe contains a total of 
120 μg HA antigen per 0.35 mL dose provided in sterile suspension for IM injection. 
QIV-HD vaccine is thimerosal-free and prepared from influenza viruses propagated in 
embryonated chicken eggs. 
6.1.1.1 
Composition 
Each 0.35 mL dose of vaccine contains the following components: 
(Strains are based on WHO [VRBPAC in the US] recommendations for the 2018-2019 NH 
influenza season): 
Active substances: 
• 
A/Michigan/45/2015 X-275 (H1N1) 
 
 
 
 
 
30 µg HA 
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• 
A/Singapore/INFIMH-16-0019/2016 IVR-186 (H3N2) 
 
 
 
30 µg HA 
• 
B/Maryland/15/2016 BX-69A (B/Colorado/6/2017-like virus, Victoria lineage) 
30 µg HA 
• 
B/Phuket/3073/2013 (Yamagata lineage) 
 
 
 
 
 
30 µg HA 
Excipients: 
• Buffered saline solution  
 
 
quantity sufficient (qs) to appropriate volume 
• Octylphenol Ethoxylate (Triton X-100®) 
not more than (NMT) 175 µg 
Preservative is not used in the manufacture of QIV-HD. 
Batch number: UD20382 (US sites); UD20523 (Canadian sites) 
6.1.1.2 
Preparation and Administration 
The vaccine is provided in a pre-filled single-dose syringe and should be shaken before use. The 
vaccine is to be administered intramuscularly into the anterolateral muscle of the thigh or the 
deltoid muscle of the upper arm, as appropriate. If the vaccine is injected in the arm, it should be 
on the opposite arm from which blood was drawn before vaccination. 
Prior to administration, all study products must be inspected visually for cracks, broken seals, 
correct label content (see Section 6.3.1), and extraneous particulate matter and / or discoloration, 
whenever solution and container permit. If any of these conditions exists, the vaccine must not be 
administered. A replacement dose is to be used, and the event is to be reported to the Sponsor. 
Subjects must be kept under observation for 30 minutes after each vaccination to ensure their 
safety, and any reactions during this period will be documented in the CRB. Appropriate medical 
equipment and emergency medications, including epinephrine (1:1000), must be available on site 
in the event of an anaphylactic, vasovagal, or other immediate allergic reaction. 
6.1.1.3 
Dose Selection and Timing 
The vaccination schedule is per standard practice for receipt of annual influenza vaccination for 
previously influenza vaccinated and influenza unvaccinated subjects and subjects 9 to 17 years of 
age. 
6.1.2 
Identity of Study Product 2 
The investigational QIV-HD is a split virion quadrivalent influenza vaccine (45 μg HA/strain) 
containing virus strains chosen by the WHO (VRBPAC in the US) for the NH 2018-2019 
influenza season. The vaccine contains 2 antigens of type A (H1N1 and H3N2) and 2 antigens of 
type B (one each from Yamagata and Victoria lineages). Each pre-filled syringe contains a total of 
180 μg HA antigen per 0.52 mL dose provided in sterile suspension for IM injection. 
QIV-HD vaccine is thimerosal-free and prepared from influenza viruses propagated in 
embryonated chicken eggs. 
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6.1.2.1 
Composition 
Each 0.52 mL dose of vaccine contains the following components: 
(Strains are based on WHO [VRBPAC in the US] recommendations for the 2018-2019 NH 
influenza season): 
Active substances: 
• 
A/Michigan/45/2015 X-275 (H1N1) 
 
 
 
 
 
 
45 µg HA 
• 
A/Singapore/INFIMH-16-0019/2016 IVR-186 (H3N2) 
 
 
 
 
45 µg HA 
• 
B/Maryland/15/2016 BX-69A (B/Colorado/6/2017-like virus, Victoria lineage) 
 
45 µg HA 
• 
B/Phuket/3073/2013 (Yamagata lineage) 
 
 
 
 
 
 
45 µg HA 
Excipients: 
• Buffered saline solution  
 
 
qs to appropriate volume 
• Octylphenol Ethoxylate (Triton X-100)  
NMT 260 µg 
Preservative is not used in the manufacture of QIV-HD. 
Batch number: UD20383 (US sites); UD20522 (Canadian sites) 
6.1.2.2 
Preparation and Administration 
The procedures for preparing and administering study product 2 are the same as those described 
for study product 1 in Section 6.1.1.2. 
6.1.2.3 
Dose Selection and Timing 
The dose selection and timing for the investigational product 2 are the same as those described for 
the investigational product 1 in Section 6.1.1.3 
6.1.3 
Identity of Study Product 3 
The investigational QIV-HD is a split virion quadrivalent influenza vaccine (60 μg HA/strain) 
containing virus strains chosen by the WHO (VRBPAC in the US) for the NH 2018-2019 
influenza season. The vaccine contains 2 antigens of type A (H1N1 and H3N2) and 2 antigens of 
type B (one each from Yamagata and Victoria lineages). Each pre-filled syringe contains a total of 
240 μg HA antigen per 0.7 mL dose provided in sterile suspension for IM injection. 
QIV-HD vaccine is thimerosal-free and prepared from influenza viruses propagated in 
embryonated chicken eggs. 
6.1.3.1 
Composition 
Each 0.7 mL dose of vaccine contains the following components: 
(Strains are based on WHO [VRBPAC in the US] recommendations for the 2018-2019 NH 
influenza season): 
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Active substances: 
• 
A/Michigan/45/2015 X-275 (H1N1) 
 
 
 
 
 
60 µg HA 
• 
A/Singapore/INFIMH-16-0019/2016 IVR-186 (H3N2) 
 
 
 
60 µg HA 
• 
B/Maryland/15/2016 BX-69A (B/Colorado/6/2017-like virus, Victoria lineage) 
60 µg HA 
• 
B/Phuket/3073/2013 (Yamagata lineage) 
 
 
 
 
 
60 µg HA 
Excipients: 
• Buffered saline solution  
 
 
qs to appropriate volume 
• Octylphenol Ethoxylate (Triton X-100)  
NMT 350 µg 
Preservative is not used in the manufacture of QIV-HD. 
Batch number: UD20384 (US sites); UD20524 (Canadian sites) 
6.1.3.2 
Preparation and Administration 
The procedures for preparing and administering study product 3 are the same as those described 
for study product 1 in Section 6.1.1.2. 
6.1.3.3 
Dose Selection and Timing 
The dose selection and timing for the investigational product 3 are the same as those described for 
the investigational product 1 in Section 6.1.1.3 
6.1.4 
Identity of Control Product 1 
Fluarix Quadrivalent: Influenza vaccine, Inactivated (GlaxoSmithKline Biologicals, Dresden, 
Germany) 
• Form: Liquid solution 
• Dose: 0.5 mL 
• Route: IM 
• Batch number: HJ9MN (commercial product to be provided to the sites by the Sponsor) 
6.1.4.1 
Composition 
Each 0.5 mL dose contains 15 µg of HA for each of the following strains: 
Strains are based on WHO (VRBPAC in the US) recommendations for the 2018-2019 NH 
influenza season. 
Active Substances: 
• A/Singapore/GP1908/2015 IVR-180 (H1N1) 
(A/Michigan/45/2015 [H1N1] pdm09-like virus)  
 
 
15 µg HA 
• A/Singapore/INFIMH-16-0019/2016 NIB-104 (H3N2)  
 
15µg HA 
• B/Maryland/15/2016 NYMC BX-69A  
(B/Colorado/06/2017-like virus, Victoria lineage)  
 
 
15 µg HA 
• 
B/Phuket/3073/2013 (Yamagata lineage) 
 
 
 
 
15 µg HA 
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Excipients: 
• Octylphenol-10 (Triton X-100)   
 
≤ 0.115 milligram (mg) 
• α-Tocopheryl hydrogen succinate  
 
≤ 0.135 mg 
• Polysorbate 80 (Tween 80)  
 
 
≤ 0.550 mg  
Fluarix Quadrivalent does not contain a preservative. 
6.1.4.2 
Preparation and Administration 
Fluarix Quadrivalent will be prepared and administered according to manufacturer’s package 
insert (21). 
6.1.4.3 
Dose Selection and Timing 
Fluarix Quadrivalent will be administered to a randomized set of subjects in Groups 1 through 7 
and Groups 9 through 13 as a single 0.5 mL dose at V01 for subjects 9 to 17 years of age and 
previously influenza vaccinated subjects 6 months to 8 years of age and at V01 and V03 for 
previously influenza unvaccinated subjects 6 months to 8 years of age. 
6.1.5 
Identity of Control Product 2  
FLUAD Pediatric: Influenza vaccine, Surface Antigen, Inactivated, Adjuvanted with MF59C.1 
(Seqirus UK Limited, Maidenhead, UK) 
• Form: Liquid solution 
• Dose: 0.25 mL 
• Route: IM 
• Batch number: 253774 (commercial product to be provided to the sites by the Sponsor) 
6.1.5.1 
Composition 
Each 0.25 mL dose contains 7.5 µg of HA for each of the following strains: 
Strains are based on WHO (NACI in Canada) recommendations for the 2018-2019 NH influenza 
season. 
Active substances: 
• A/Singapore/GP1908/2015 IVR-180 (H1N1)  
(A/Michigan/45/2015 [H1N1] pdm09-like virus)  
 
 
 
7.5 µg HA 
• A/Singapore/INFIMH-16-0019/2016, IVR-186 (H3N2)  
 
 
7.5 µg HA 
• B/Maryland/15/2016 (B/Colorado/06/2017-like virus, Victoria lineage)   
7.5 µg HA 
Excipients 
• Sodium chloride  
 
 
 
2.00 mg  
• Potassium chloride 
 
 
 
0.05 mg 
• Potassium dihydrogen phosphate  
 
0.05 mg  
• Disodium phosphate dehydrate 
 
 
0.335 mg  
• Magnesium chloride hexahydrate  
 
0.025 mg  
• Calcium chloride dihydrate 
 
 
0.03 mg  
• Water for injection  
 
 
 
qs to appropriate volume 
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FLUAD Pediatric is formulated with the adjuvant MF59, an oil-in-water emulsion of squalene oil. 
FLUAD Pediatric does not contain a preservative. 
6.1.5.2 
Preparation and Administration 
FLUAD Pediatric will be prepared and administered according to manufacturer’s product 
monograph (22). 
6.1.5.3 
Dose Selection and Timing 
FLUAD Pediatric will be administered to a randomized set of subjects in Group 8 as a single 
0.25 mL dose at V01 and V03. 
6.2 
Identity of Other Products 
Not applicable 
6.3 
Product Logistics 
6.3.1 
Labeling and Packaging 
The investigational and control vaccines for this study will be provided by the Sponsor, and will 
be labeled in accordance with national regulations. 
The 3 investigational QIV-HDs will be supplied in single dose syringes with investigational 
labeling and packaging. Each single dose will be identified by a unique medication number on the 
label and on the carton. The comparator vaccines, Fluarix Quadrivalent and FLUAD Pediatric, 
will be supplied in single dose syringes with the manufacturer label on the syringes and an 
investigational label on the carton. The carton label will also have a detachable label for the sites 
to attach to the source documents. See the Operating Guidelines for additional label detail. 
6.3.2 
Product Shipment, Storage, and Accountability 
6.3.2.1 
Product Shipment 
The Clinical Logistics Coordinator or designee will contact the Investigator or a designee to 
determine the dates and times of delivery of products. 
Each vaccine shipment will include a temperature-monitoring device to verify maintenance of the 
cold chain during transit. On delivery of the product to the site, the person in charge of product 
receipt will follow the instructions given in the Operating Guidelines, including checking that the 
cold chain was maintained during shipment (ie, verification of the temperature recorders). If there 
is an indication that the cold chain was broken, this person should immediately quarantine the 
product, alert the Sanofi Pasteur representative, and request authorization from Sanofi Pasteur to 
use the product. 
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6.3.2.2 
Product Storage 
The Investigator will be personally responsible for product management or will designate a staff 
member to assume this responsibility. 
At the site, products must be kept in a secure place with restricted access. Vaccines will be stored 
in a refrigerator at a temperature ranging from +2°C to +8°C. The vaccines must not be frozen. 
The temperature must be monitored and documented (see the Operating Guidelines) for the entire 
time that the vaccine is at the study site. In case of accidental freezing or disruption of the cold 
chain, vaccines must not be administered and must be quarantined, and the Investigator or 
authorized designee should contact the Sanofi Pasteur representative for further instructions. 
6.3.2.3 
Product Accountability 
The person in charge of product management at the site will maintain records of product delivery 
to the study site, product inventory at the site, the dose(s) given to each subject, and the disposal 
of or return to the Sponsor of unused doses.  
The necessary information on the product labels is to be entered into the source document and the 
CRB. If applicable, information may also be entered into the subject’s vaccination card. 
The Sponsor’s monitoring staff will verify the study site’s product accountability records against 
the record of administered doses in the CRBs and the communication from the IRT (if 
applicable). 
In case of any expected or potential shortage of product during the study, the Investigator or an 
authorized designee should alert the Sanofi Pasteur representative as soon as possible, so that a 
shipment of extra doses can be arranged. 
6.3.3 
Replacement Doses 
If a replacement dose is required (eg, because the syringe broke or particulate matter was 
observed in the syringe), the site personnel must either contact the IRT to receive the new dose 
allocation, or follow the instructions given in the Operating Guidelines. 
6.3.4 
Disposal of Unused Products 
Unused or wasted products will be returned to the Sponsor in accordance with the instructions in 
the Operating Guidelines. Product accountability will be verified throughout the study period. 
6.3.5 
Recall of Products 
If the Sponsor makes a decision to launch a retrieval procedure, the Investigators will be informed 
of what needs to be done. 
6.4 
Blinding and Code-breaking Procedures 
The study is designed as a staged, modified double-blind study with the following measures to 
ensure to ensure the integrity of the data: 
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• The unblinded qualified study staff member, independent of the safety evaluation and other 
study evaluations, will administer the vaccine 
• The Investigators (or delegates) in charge of safety assessment, the study staff who collect the 
safety data, and the laboratory personnel who analyze the blood samples will not know which 
product was administered 
• The subject / parent / guardian will not know which product was administered. To maintain 
the blinding of the subject / parent / guardian, the vaccine syringe label will be covered with 
appropriate materials prior to administration. 
The Investigator responsible for safety assessment will not attend the vaccination session but will 
be available in case of emergency (eg, anaphylactic shock). 
Dose numbers will be used to identify each vaccine syringe for the purpose of randomization, 
vaccination, and the recording of vaccine administered. Dose numbers will be randomly assigned 
to QIV-HD and the commercial vaccines syringes. The IRT vendor will be responsible for 
providing the subject identification and dose number to be received by the enrolled subject. The 
subject / parent / guardian, the Investigator, and study staff members who collect the safety data 
and laboratory personnel who analyze the blood samples will all be blinded to the group 
assignment. The individual responsible for preparing / administering vaccine will not be 
authorized to collect any safety / serology data. 
The code may be broken in the event of an AE only when the identification of the vaccine 
received could influence the treatment of the subject. Code-breaking should be limited to the 
subject(s) experiencing the AE. 
The blind can be broken by the Investigator or a delegate through the IRT system, as explained in 
the code-breaking procedures described in the Operating Guidelines. Once the emergency has 
been addressed by the site, the Investigator or a delegate must notify the Sanofi Pasteur RMO if a 
subject’s code was broken. All contact attempts with the Sponsor prior to unblinding are to be 
documented in the source documents, and the code breaking CRF is to be completed. 
A request for the code to be broken may also be made: 
• by the GPV Department through an internal system for reporting to Health authorities in the 
case of an SAE as described in International Council for Harmonisation (ICH) E2A. In this 
case, the code will be broken only for the subject(s) in question. The information resulting 
from code-breaking (ie, the subject’s vaccine or group assignment) will not be communicated 
to either the Investigator or the immediate team working on the study, except for the GPV 
representative.  
The IEC / IRB must be notified of the code-breaking. All documentation pertaining to the event 
must be retained in the site’s study records and in the Sanofi Pasteur files. Any intentional or 
unintentional code-breaking must be reported, documented, and explained, and the name of the 
person who requested it must be provided to the Sponsor. 
In any case, the code will be broken after the first database lock, for the primary statistical 
analysis planned to analyze the data collected within the 28 days (for subjects 9 to 17 years of age 
and previously influenza vaccinated subjects 6 months to 8 years of age) and 56 days (for 
previously influenza unvaccinated subjects 6 months to 8 years of age) following the vaccination, 
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but the randomization list will not be provided to Investigators and will be kept internally until the 
end of the statistical analyses after the final database lock. 
6.5 
Randomization and Allocation Procedures 
For the randomization of dose numbers, the Sponsor or designee will supply a computer generated 
randomization list, which will be used for the labeling and packaging. 
The study will be randomized and modified double-blinded for all study groups. On the day of 
enrollment, subjects who meet the inclusion / exclusion criteria and complete the informed 
consent process will be randomly assigned to receive: 
• either QIV-HD at 30 µg or 45 µg HA/strain/dose or Fluarix Quadrivalent in a 3:3:1 ratio for 
previously influenza vaccinated and unvaccinated subjects 9 to 17 years of age enrolled during 
Stage 1 in the US. 
• either QIV-HD at 60 µg HA/strain/dose or Fluarix Quadrivalent in a 1:1 ratio for previously 
influenza vaccinated and unvaccinated subjects 9 to 17 years of age enrolled during Stage 1 in 
the US. 
• either QIV-HD at 30 µg HA/strain/dose or Fluarix Quadrivalent in a 3:1 ratio for previously 
influenza vaccinated and unvaccinated subjects 36 months to 8 years of age enrolled during 
Stage 1 in the US. 
• either QIV-HD at 45 µg HA/strain/dose or Fluarix Quadrivalent in a 3:1 ratio for previously 
influenza vaccinated and unvaccinated subjects 36 months to 8 years of age enrolled during 
Stage 2 in the US. 
• either QIV-HD at 30 µg HA/strain/dose or Fluarix Quadrivalent in a 3:1 ratio for previously 
influenza vaccinated and unvaccinated subjects 6 to < 36 months of age enrolled during Stage 
2 in the US. 
• either QIV-HD at 60 µg HA/strain/dose (highest dosage of QIV-HD) or Fluarix Quadrivalent 
in a 1:1 ratio for previously influenza vaccinated and unvaccinated subjects 36 months to 8 
years of age enrolled during Stage 3 in the US. 
• either QIV-HD at the highest dosage with acceptable safety review or Fluarix Quadrivalent in 
a 1:1 ratio for previously vaccinated subjects 6 to 36 months of age enrolled in Stage 4 in the 
US. 
• either QIV-HD at the highest dosage with acceptable safety review or Fluarix Quadrivalent in 
a 1:1 ratio for previously unvaccinated subjects 6 to 36 months of age enrolled in Stage 4 in 
the US. 
• either QIV-HD at the highest dosage with acceptable safety review or FLUAD Pediatric in a 
1:1 ratio for previously unvaccinated subjects 6 to < 24 months of age enrolled in Stage 4 in 
Canada. 
Site staff will connect to the IRT, enter the identification and security information, and confirm a 
minimal amount of data in response to IRT prompts. The IRT will then provide the group 
assignment and have the site staff confirm it. Stratified randomization will be applied for all 
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subjects enrolled in each group stratified by previous influenza vaccination status and country. 
Site will not be a strata for randomization due to the small sample size in each group. The 
allocation ratios between investigational HD vaccines to the comparators are: 3:1 ratio in groups 
1, 2, 3, 5, 9, and 10; 3:3:1 ratio in group 12; and 1:1 ratio in groups 4, 6, 7, 8, 11, and 13. The full 
detailed procedures for group allocation are described in the Operating Guidelines. If the subject 
is not eligible to participate in the study, then the information will only be recorded on the subject 
recruitment log. 
Subject numbers that are assigned by the IRT will consist of a 12-digit string (a 3-digit country 
identifier [840 for the US and 124 for Canada], a 4-digit study site identifier, and a 5-digit subject 
identifier). For example, Subject 840000100005 is the fifth subject enrolled in Center Number 1 
in the US. 
Subject numbers should not be reassigned for any reason. 
Dose numbers will be 7 digits long. Dose numbers are not used for packaging but only in the IRT 
system. 
6.6 
Treatment Compliance 
The following measures will ensure that the vaccine doses administered comply with those planned, 
and that any non-compliance is documented so that it can be accounted for in the data analyses: 
• All vaccinations will be administered by qualified study personnel 
• The person in charge of product management at the site will maintain accountability records 
of product delivery to the study site, product inventory at the site, dose(s) given to each 
subject, and the disposal of unused or wasted doses 
6.7 
Concomitant Medications and Other Therapies 
At the time of enrollment, ongoing medications and other therapies (eg, blood products) should be 
recorded in the source document as well as new medications prescribed for new medical 
conditions / AEs during study participation.  
Documentation in the CRB of ongoing concomitant medication(s) will be limited to specific 
categories of medication(s) of interest beginning on the day of first vaccination. This may include 
medications of interest that were started prior to the day of vaccination. 
Reportable medications will be collected in the CRB from the day of first vaccination to the end 
of the solicited and unsolicited follow-up period (from D0 to D28 for subjects 9 to 17 years of age 
and previously influenza vaccinated subjects 6 months to 8 years of age and from D0 to D56 for 
previously influenza unvaccinated subjects 6 months to 8 years of age). 
Reportable medications include medications that impact or may impact the consistency of the safety 
information collected after any vaccination and/or the immune response to vaccination. Three 
standard categories of reportable medications are defined: 
• Category 1: medications impacting or that may have an impact on the evaluation of the safety 
(eg, antipyretics, analgesics, and non-steroidal anti-inflammatory drugs [NSAIDs]). 
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• Category 2: medications impacting or that may have an impact on the immune response (eg, 
other vaccines, blood products, immune-suppressors, immune-modulators with 
immunosuppressive properties, anti-proliferative drugs such as DNA synthesis inhibitors). 
• Category 3: medications impacting or that may have an impact on both the safety and the 
immune response (eg, steroids/corticosteroids) 
The information reported in the CRB for each reported medication will be limited to: 
• Trade name or generic name 
• Origin of prescription: prophylaxis Yes/No. Medication(s) prescribed for AE prophylaxis will 
be recorded in the Action Taken of the AE collection tables. 
• Medication category (1, 2, or 3) 
• Start and stop dates 
Dosage and administration route; homeopathic medication; topical, nasal, ophthalmic, otic, and 
inhaled steroids; as well as other topical, ophthalmic, and ear treatments will not be recorded. 
Medications given in response to an AE will be captured in the “Action Taken” section of the AE 
CRF. Details will be recorded in the concomitant medication CRF only if the medication(s) received 
belongs to one of the prelisted categories. Medications will not be coded. 
7 
Management of Samples 
Blood samples for the assessment of antibody responses will be collected at V01 and V03 (D28 
[+7 days]) for subjects 9 to 17 years of age and previously influenza vaccinated subjects 6 months 
to 8 years of age, and at V01, V03, and V05 for the previously influenza unvaccinated subjects 
6 months to 8 years of age. See the Table of Study Procedures and Section 5.1.3 for details of the 
sampling schedule. 
7.1 
Sample Collection 
At V01 and V03 (D28 [+7 days]) for subject 9 to 17 years of age and previously influenza 
vaccinated subjects 6 months to 8 years of age, and at V01, V03, and V05 for the previously 
influenza unvaccinated subjects 6 months to 8 years of age, 5 mL of blood will be collected in 
tubes provided by or recommended by the Sponsor. Immediately prior to the blood draw, the staff 
member performing the procedure will verify the subject’s identity; will verify the assigned 
subject's number on the pre-printed label that contains that subject’s number and the sampling 
stage; and will attach the label to the tube. Blood is to be taken from the limb opposite to the one 
that will be used for vaccination. 
Note: if 5 mL of blood sample cannot be drawn, a volume less than 5 mL can be obtained. 
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7.2 
Sample Preparation 
Detailed instructions on how to prepare blood samples for assessment of immune response are 
contained in the Operating Guidelines provided to the site. An overview of the procedures is 
provided here. 
Following the blood draw, the tubes are to be left undisturbed, positioned vertically and not 
shaken, for a minimum of 1 hour and a maximum of 24 hours to allow the blood to clot. Samples 
can be stored at room temperature for up to 2 hours; beyond 2 hours, they must be refrigerated at 
a temperature of +2°C to +8°C after the period of clotting at room temperature and must be 
centrifuged within a maximum of 24 hours. 
After centrifugation, the serum is transferred to the appropriate number of aliquoting tubes. These 
tubes are pre-labeled with adhesive labels that identify the study code, the subject’s number and 
the sampling stage or visit number. 
The subject’s number and the date of sampling, the number of aliquots obtained, the date and time 
of preparation, and the parent’s / guardian’s consent for future use of his / her child’s samples are 
to be specified on a sample identification list and recorded in the source document. Space is 
provided on this list for comments on the quality of samples. 
7.3 
Sample Storage and Shipment 
During storage, serum tubes are to be kept in a freezer whose temperature is set and maintained at 
-20°C or below. The temperature will be monitored and documented on the appropriate form 
during the entire study. If it rises above -10°C for any period of time, the Clinical Logistics 
Coordinator must be notified. See the Operating Guidelines for further details. 
Shipments to the laboratories will be made only after appropriate monitoring, and following 
notification of the Clinical Logistics Coordinator. Sera will be shipped frozen, using dry ice to 
maintain them in a frozen state, in the packaging container provided by the carrier. Again, 
temperatures will be monitored. Shipments must be compliant with the United Nations (UN) 
Class 6.2 specifications and the International Air Transport Association (IATA) 602 packaging 
instructions. 
Samples will be shipped to GCI at Sanofi Pasteur. The address is provided in the Operating 
Guidelines. 
7.4 
Future Use of Stored Serum Samples for Research 
Subjects’ parents / guardians will be asked to indicate in the ICF whether they will permit the 
future use of any unused stored serum samples for other tests. If they refuse permission, the 
samples will not be used for any testing other than that directly related to this study. If they agree 
to this use, they will not be paid for giving permission. Anonymity of samples will be ensured. 
The aim of any possible future research is unknown today, and may not be related to this 
particular study. It may be to improve the knowledge of vaccines or infectious diseases, or to 
improve existing tests or develop new tests to assess vaccines. Human genetic tests will never be 
performed on these samples without specific individual informed consent. 
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8 
Clinical Supplies 
Sanofi Pasteur will supply the study sites with protocols, ICFs, CRBs, SAE reporting forms, diary 
cards, memory aids, and other study documents, as well as with the following study materials: all 
study vaccines, pregnancy tests, blood collection tubes, cryotubes, cryotube storage boxes, 
cryotube labels, temperature recorders, shipping containers, rulers, and digital thermometers. 
The means for performing Electronic Data Capture (EDC) will be defined by Sanofi Pasteur. If a 
computer is provided by Sanofi Pasteur, it will be retrieved at the end of the study. 
The Investigator will supply all vaccination supplies, phlebotomy, and centrifugation equipment, 
including biohazard and / or safety supplies. The biohazard and safety supplies include needles 
and syringes, examination gloves, laboratory coats, sharps disposal containers, and absorbent 
countertop paper. The site will ensure that all biohazard wastes are autoclaved and disposed of in 
accordance with local practices. The Investigator will also supply appropriate space in a 
temperature-monitored refrigerator for the storage of the products and for the blood samples, and 
appropriate space in a temperature-monitored freezer for serum aliquots. 
In the event that additional supplies are required, study staff must contact Sanofi Pasteur, 
indicating the quantity required. Contact information is provided in the Operating Guidelines.  
9 
Endpoints and Assessment Methods 
9.1 
Safety 
9.1.1 
Safety Definitions 
The following definitions are taken from the ICH E2A Guideline for Clinical Safety Data 
Management: Definitions and Standards for Expedited Reporting. 
Adverse Event (AE): 
An AE is any untoward medical occurrence in a patient or in a clinical investigation subject 
administered a medicinal product and which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom or disease temporally associated with the use 
of a medicinal product, whether or not considered related to the medicinal product.  
Therefore an AE may be: 
• A new illness 
• The worsening of a pre-existing condition 
• An effect of the vaccination, including the comparator 
• A combination of the above 
All AEs include serious and non-serious AEs. 
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Surgical procedures are not AEs; they are the actions taken to treat a medical condition. It is the 
condition leading to the action taken that is the AE (if it occurs during the study period). 
Pre-existing medical conditions are not to be reported as AEs. However, if a pre-existing medical 
condition worsens following study interventions in frequency or intensity, or if according to the 
Investigator there is a change in its clinical significance, this change should be reported as an AE 
(exacerbation). This applies equally to recurring episodes of pre-existing conditions (eg, asthma) 
if the frequency or intensity increases post-vaccination. 
Serious Adverse Event (SAE): 
Serious and severe are not synonymous. The term severe is often used to describe the intensity of 
a specific event as corresponding to Grade 3. This is not the same as serious which is based on 
subject / event outcome or action criteria usually associated with events that pose a threat to a 
subject’s life or functioning. Seriousness, not severity, serves as a guide for defining regulatory 
reporting obligations. 
An SAE is any untoward medical occurrence that at any dose  
• Results in death 
• Is life-threateninga 
• Requires inpatient hospitalization or prolongation of existing hospitalizationb 
• Results in persistent or significant disability / incapacityc 
• Is a congenital anomaly / birth defect 
• Is an important medical event (IME) 
Medical and scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in other situations, such as IMEs that may not be immediately life-threatening 
or result in death or hospitalization but may jeopardize the health of the subject or may require 
intervention to prevent one of the other outcomes listed in the definition above. These IMEs 
should also usually be considered serious. Examples of such events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse, new-onset diabetes, or autoimmune disease. 
                                                 
a  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 which hypothetically might have caused death if it were more severe. 
b  All medical events leading to hospitalizations will be recorded and reported as SAEs, with the exception of: 
hospitalization planned before inclusion into the study or outpatient treatment with no hospitalization.  
c  “Persistent or significant disability or incapacity” means that there is a substantial disruption of a person’s ability 
to carry out normal life functions. 
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Adverse Reaction: 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered adverse reactions (AR). 
(The phrase “responses to a medicinal product” means that a causal relationship between a 
medicinal product and an AE is at least a reasonable possibility) 
The following additional definitions are used by Sanofi Pasteur: 
Immediate Event/Reaction: 
Immediate events are recorded to capture medically relevant unsolicited systemic AEs (including 
those related to the product administered) that occur within the first 30 minutes after vaccination. 
Solicited Reaction: 
A solicited reaction is an “expected” adverse reaction (sign or symptom) observed and reported 
under the conditions (nature and onset) prelisted in the protocol and CRB (eg, injection site pain 
or headache occurring between D0 and D7 post-vaccination). 
By definition, solicited reactions are to be considered as being related to the product administered. 
For injectable vaccines, solicited reactions can either be solicited injection site reactions or 
solicited systemic reactions. 
Unsolicited AE / AR: 
An unsolicited AE is an observed AE that does not fulfill the conditions prelisted in the CRB in 
terms of diagnosis and/or onset window post-vaccination. For example, if headache between D0 
and D7 is a solicited reaction (ie, prelisted in the protocol and CRB), then a headache starting on 
D7 is a solicited reaction, whereas headache starting on D8 post-vaccination is an unsolicited AE. 
Unsolicited AEs includes both serious (SAEs) and non-serious unsolicited AEs. 
Injection Site Reaction: 
An injection site reaction is an AR at and around the injection site. Injection site reactions are 
commonly inflammatory reactions. They are considered to be related to the product administered. 
Systemic AE: 
Systemic AEs are all AEs that are not injection or administration site reactions. They therefore 
include systemic manifestations such as headache, fever, as well as localized or topical 
manifestations that are not associated with the vaccination or administration site (eg, erythema 
that is localized but that is not occurring at the injection site). 
Adverse Event of Special Interest (AESI): 
An adverse event of special interest is one of scientific and medical concern specific to the 
Sponsor’s product or program, for which ongoing monitoring and rapid communication by the 
investigator to the sponsor can be appropriate. Such an event might warrant further investigation 
in order to characterize and understand it. Depending on the nature of the event, rapid 
communication by the study Sponsor to other parties (eg, regulators) might also be warranted. 
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9.1.2 
Safety Endpoints 
The endpoints for the evaluation of safety are: 
• Occurrence, nature (Medical Dictionary for Regulatory Activities [MedDRA] preferred term 
[PT]), duration, intensity, and relationship to vaccination of any unsolicited systemic AEs 
reported in the 30 minutes after each vaccination. 
• Occurrence, time to onset, number of days of occurrence, intensity, action taken, and whether 
the reaction led to early termination from the study, of solicited (prelisted in the subject’s 
diary card and CRB) injection site reactions and systemic reactions occurring up to 7 days 
after each vaccination. 
• Occurrence, nature (MedDRA system organ class [SOC] and PT), time to onset, duration, 
intensity, relationship to vaccination (for systemic AEs only), and whether the event led to 
early termination from the study, of unsolicited AEs up to 28 days after each vaccination. 
• Occurrence, nature (MedDRA SOC and PT), time to onset, seriousness criteria, relationship to 
vaccination, outcome, and whether the event led to early termination from the study, of SAEs 
(including AESIs) throughout the study. 
• Occurrence, nature (MedDRA PT), time to onset, and relationship to vaccination of AESIs 
throughout the study. 
9.1.3 
Safety Assessment Methods 
At V01, the Investigator or a delegate will perform a clinical or medically-driven physical 
examination.  
At V03 (D28 [+7 days]), and / or V05, as applicable, the Investigator or a delegate may perform a 
targeted clinical or medically-driven physical examination, as necessary, and will ask the subject / 
parent / guardian about any solicited reactions and unsolicited AEs recorded in the diary card, as 
well as about any other AEs that may have occurred since the previous visit.  
All relevant data will be transcribed into the CRB according to the instructions provided by the 
Sponsor. 
9.1.3.1 
Immediate Post-vaccination Observation Period 
Subjects will be kept under observation for 30 minutes after each vaccination to ensure their 
safety. The post-vaccination observation should be documented in the source document. Any AE 
that occurs during this period will be noted on the source document and recorded in the CRB, as 
follows: 
• Unsolicited systemic AEs will be recorded as immediate AEs in the CRB (presence marked as 
“yes” and details collected). 
• Solicited and unsolicited injection site reactions and solicited systemic reactions will be 
recorded in the CRB in the same way as any reactions starting on the day of vaccination.  
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• SAEs will be recorded in the CRB and reported to the Sponsor in the same way as any other 
SAEs, according to the procedures described in Section 10. 
9.1.3.2 
Reactogenicity (Solicited Reactions From Day 0 to Day 7 After Each Vaccination) 
After each vaccination, subjects / parents / guardians will be provided with a diary card, a digital 
thermometer, and a flexible ruler, and will be instructed how to use them. The following items 
will be recorded by the subjects in the diary card on the day of vaccination and for the next 7 days 
(ie, D0 to D7) until resolution: 
• Daily temperature, with the route by which it was taken 
• Daily measurement or intensity grade of all other solicited injection site and systemic 
reactions 
• Action taken for each event (eg, medication) 
The action(s) taken by the subject / parent / guardian to treat and/or manage any solicited 
reactions will be classified in the CRB using the following list (all applicable items should 
be checked): 
• None 
• Medication 
• Health care provider contact 
• Hospitalized 
• Discontinuation of study vaccination 
Table 9.1, Table 9.2, Table 9.3, Table 9.4, and Table 9.5 present, respectively, the injection site 
reactions and systemic reactions that are prelisted in the diary cards and CRB, together with the 
intensity scales. 
 
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Table 9.1: Solicited injection site reactions for infants and toddlers aged < 36 months: terminology, definitions, and intensity scales 
CRB term 
(MedDRA LLT) 
Injection site tenderness 
Injection site 
erythema 
Injection site swelling 
Injection site induration 
Injection site bruising 
MedDRA PT 
Injection site pain 
Injection site 
erythema 
Injection site swelling 
Injection site induration 
Injection site bruising 
Diary card term Tenderness 
Redness 
Swelling 
Hardening 
Bruising 
Definition 
Pain when the injection site is 
touched or injected limb 
mobilized 
Presence of a redness 
including the 
approximate point of 
needle entry 
Swelling at or near the injection site 
Swelling or edema is caused by a 
fluid infiltration in tissue or cavity 
and, depending on the space 
available for the fluid to disperse, 
swelling may be either soft 
(typically) or firm (less typical) to 
touch and thus can be best described 
by looking at the size of the swelling 
Hardening at or near the 
injection site. 
Hardening is caused by a 
slow diffusion of the product 
in the tissue leading to a 
thick or hard area to touch at 
or near the injection site and 
thus can be best described by 
looking at the size of the 
hardening. 
Bruising is the result of 
the diffusion of blood in 
the skin from ruptured 
blood vessels that forms a 
purple or black and blue 
spot on the skin. It can be 
best described by looking 
at its size. 
Intensity scale* 
 
Grade 1: Minor reaction when 
injection site is touched 
Grade 2: Cries or protests when 
injection site is touched 
Grade 3: Cries when injected 
limb is mobilized, or the 
movement of the injected limb 
is reduced 
Grade 1: > 0 to < 25 
mm 
Grade 2: ≥ 25 to < 50 
mm 
Grade 3: ≥ 50 mm 
Grade 1: > 0 to < 25 mm 
Grade 2: ≥ 25 to < 50 mm 
Grade 3: ≥ 50 mm 
Grade 1: > 0 to < 25 mm 
Grade 2: ≥ 25 to < 50 
mm 
Grade 3: ≥ 50 mm 
Grade 1: > 0 to < 25 
mm 
Grade 2: ≥ 25 to < 50 
mm 
Grade 3: ≥ 50 mm 
*  For the subjective reaction of tenderness, parents / guardians will record the intensity level (Grade 1, 2, or 3) in the diary card. For the measurable reactions of redness, swelling, 
hardening, and bruising, they will record just the size of the reaction, and the classification as Grade 1, 2, or 3 will be assigned at the time of the statistical analysis. 
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Table 9.2: Solicited injection site reactions for children aged 3 to 11 years: terminology, definitions, and intensity scales 
CRB term 
(MedDRA 
LLT) 
Injection site pain 
Injection site erythema 
Injection site swelling  
Injection site induration 
Injection site bruising 
MedDRA 
PT 
Injection site pain 
Injection site erythema 
Injection site swelling 
Injection site induration 
Injection site bruising 
Diary card 
term 
Pain 
Redness 
Swelling 
Hardening 
Bruising 
Definition 
Pain either present 
spontaneously or when the 
injection site is touched or 
injected limb is mobilized 
Presence of a redness 
including the approximate 
point of needle entry 
Swelling at or near the 
injection site 
Swelling or edema is 
caused by a fluid 
infiltration in tissue or 
cavity and, depending on 
the space available for the 
fluid to disperse, swelling 
may be either soft 
(typically) or firm (less 
typical) to touch and thus 
can be best described by 
looking at the size of the 
swelling 
Hardening at or near the 
injection site. 
Hardening is caused by a slow 
diffusion of the product in the 
tissue leading to a thick or hard 
area to touch at or near the 
injection site and thus can be 
best described by looking at the 
size of the hardening. 
Bruising is the result of the 
diffusion of blood in the skin 
from ruptured blood vessels 
that forms a purple or black 
and blue spot on the skin. It can 
be best described by looking at 
its size. 
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Intensity 
scale* 
 
Grade 1: Easily tolerated 
Grade 2: Sufficiently 
discomforting to interfere 
with normal behavior or 
activities 
Grade 3: Incapacitating, 
unable to perform usual 
activities 
Grade 1: > 0 to < 25 mm 
Grade 2: ≥ 25 to < 50 mm 
Grade 3: ≥ 50 mm 
Grade 1: > 0 to < 25 mm 
Grade 2: ≥ 25 to < 50 mm 
Grade 3: ≥ 50 mm 
Grade 1: > 0 to < 25 mm 
Grade 2: ≥ 25 to < 50 mm 
Grade 3: ≥ 50 mm 
Grade 1: > 0 to < 25 mm 
Grade 2: ≥ 25 to < 50 mm 
Grade 3: ≥ 50 mm 
*  For the subjective reaction of pain, parents / guardians will record the intensity level (Grade 1, 2, or 3) in the diary card. For the measurable reactions of redness, swelling, 
hardening, and bruising, they will record just the size of the reaction, and the classification as Grade 1, 2, or 3 will be assigned at the time of the statistical analysis. 
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Table 9.3: Solicited injection site reactions for children aged 12 to 17 years: terminology, definitions, and intensity scales 
CRB term 
(MedDRA 
LLT) 
Injection site pain 
Injection site erythema 
Injection site swelling  
Injection site induration 
Injection site bruising 
MedDRA 
PT 
Injection site pain 
Injection site erythema 
Injection site swelling 
Injection site induration 
Injection site bruising 
Diary card 
term 
Pain 
Redness 
Swelling 
Hardening 
Bruising 
Definition 
Pain either present 
spontaneously or when the 
injection site is touched or 
injected limb is mobilized 
Presence of a redness 
including the approximate 
point of needle entry 
Swelling at or near the 
injection site 
Swelling or edema is 
caused by a fluid 
infiltration in tissue or 
cavity and, depending on 
the space available for the 
fluid to disperse, swelling 
may be either soft 
(typically) or firm (less 
typical) to touch and thus 
can be best described by 
looking at the size of the 
swelling 
Hardening at or near the 
injection site. 
Hardening is caused by a slow 
diffusion of the product in the 
tissue leading to a thick or hard 
area to touch at or near the 
injection site and thus can be 
best described by looking at the 
size of the hardening. 
Bruising is the result of the 
diffusion of blood in the skin 
from ruptured blood vessels 
that forms a purple or black 
and blue spot on the skin. It can 
be best described by looking at 
its size. 
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Intensity 
scale* 
 
Grade 1: A type of adverse 
event that is usually 
transient and may require 
only minimal treatment or 
therapeutic intervention. 
The event does not 
generally interfere with 
usual activities of daily 
living. 
Grade 2: A type of adverse 
event that is usually 
alleviated with additional 
therapeutic intervention. 
The event interferes with 
usual activities of daily 
living, causing discomfort 
but poses no significant or 
permanent risk of harm to 
the research participant. 
Grade 3: A type of adverse 
event that interrupts usual 
activities of daily living, or 
significantly affects clinical 
status, or may require 
intensive therapeutic 
intervention. 
Grade 1: ≥ 25 to ≤ 50 mm 
Grade 2: ≥ 51 to ≤ 100 mm 
Grade 3: > 100 mm 
Grade 1: ≥ 25 to ≤ 50 mm 
Grade 2: ≥ 51 to ≤ 100 mm 
Grade 3: > 100 mm 
Grade 1: ≥ 25 to ≤ 50 mm 
Grade 2: ≥ 51 to ≤ 100 mm 
Grade 3: > 100 mm 
Grade 1: ≥ 25 to ≤ 50 mm 
Grade 2: ≥ 51 to ≤ 100 mm 
Grade 3: > 100 mm 
* For the subjective reaction of pain, subjects / parents / guardians will record the intensity level (Grade 1, 2, or 3) in the diary card. For the measurable reactions of redness, swelling, 
hardening, and bruising they will record just the size of the reaction, and the classification as Grade 1, 2, or 3 will be assigned at the time of the statistical analysis 
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Table 9.4: Solicited systemic reactions for infants and toddlers aged < 36 months: terminology, definitions, and intensity scales 
CRB term 
(MedDRA LLT) 
Fever 
Vomiting 
Crying abnormal  
Drowsiness 
Appetite lost 
Irritability 
MedDRA PT 
Pyrexia 
Vomiting  
Crying 
Somnolence 
Decreased appetite 
Irritability 
Diary card term 
Temperature 
Vomiting 
Abnormal crying 
Drowsiness 
Loss of appetite 
Irritability 
Definition 
Elevation of 
temperature to ≥°38.0°C 
(≥ 100.4°F) 
Vomiting does not 
include spitting up 
Inconsolable crying 
without a determined 
reason 
Reduced interest in 
surroundings, or 
increased sleeping 
See intensity scale 
An excessive response 
to stimuli: increased 
fussiness, whining, and 
fretfulness despite 
attempts to comfort the 
infant and despite 
caregiver responses that 
would normally be 
soothing 
Intensity scale* 
Grade 1:  
≥ 38.0°C to ≤ 38.5°C 
or ≥ 100.4°F to ≤ 101.3°F 
Grade 1: 1 episode per 
24 hours 
Grade 1: < 1 hour 
Grade 1: Sleepier than 
usual or less interested 
in surroundings 
Grade 1: Eating less 
than normal 
Grade 1: Easily 
consolable 
 
Grade 2: 
> 38.5°C to ≤ 39.5°C 
or > 101.3°F to ≤ 103.1°F 
Grade 2: 2–5 episodes 
per 24 hours 
Grade 2: 1–3 hours  
Grade 2: Not interested 
in surroundings or did 
not wake up for a feed / 
meal 
Grade 2: Missed 1 or 2 
feeds / meals 
completely 
Grade 2: Requiring 
increased attention 
 
Grade 3: > 39.5°C 
or > 103.1°F 
Grade 3: ≥ 6 episodes 
per 24 hours or 
requiring parenteral 
hydration 
Grade 3: > 3 hours 
Grade 3: Sleeping most 
of the time or difficult 
to wake up 
Grade 3: Refuses ≥ 3 
feeds / meals or refuses 
most feeds / meals 
Grade 3: Inconsolable 
*  For all reactions but fever, parents / guardians will record the intensity level (Grade 1, 2, or 3) in the diary card. For fever, they will record the body temperature, and the 
classification as Grade 1, 2, or 3 will be assigned at the time of the statistical analysis based on the unit used to measure the temperature and the intensity scale. 
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Table 9.5: Solicited systemic reactions for children aged 3 to 17 years: terminology, definitions, and intensity scales 
CRB term 
(MedDRA LLT) 
Fever 
 
Headache 
Malaise 
Myalgia 
Shivering 
MedDRA PT 
Pyrexia 
Headache 
Malaise 
Myalgia 
Chills 
Diary card term 
Temperature 
Headache 
Feeling unwell 
Muscle aches and pains 
Chills 
Definition 
Elevation of 
temperature to 
≥°38.0°C (≥ 100.4°F) 
Pain or discomfort in the 
head or scalp. Does not 
include migraine. 
General ill feeling. 
Malaise is a generalized 
feeling of discomfort, illness, 
or lack of well-being that can 
be associated with a disease 
state. It can be accompanied 
by a sensation of exhaustion 
or inadequate energy to 
accomplish usual activities. 
Muscle aches and pains are 
common and can involve 
more than one muscle at the 
same time. Muscle pain can 
also involve the soft tissues 
that surround muscles. These 
structures, which are often 
referred to as connective 
tissues, include ligaments, 
tendons, and fascia (thick 
bands of tendons). 
Does not apply to muscle 
pain at the injection site 
which should be reported as 
injection site pain. 
Cold feeling. 
Intensity scale* 
Grade 1: ≥ 38.0°C to 
≤ 38.4°C, 
or ≥ 100.4°F to 
≤ 101.1°F 
Grade 1: A type of AE that is 
usually transient and may 
require only minimal 
treatment or therapeutic 
intervention. The event does 
not generally interfere with 
usual activities of daily 
living. 
Grade 1: A type of AE that is 
usually transient and may 
require only minimal 
treatment or therapeutic 
intervention. The event does 
not generally interfere with 
usual activities of daily 
living. 
Grade 1: A type of AE that is 
usually transient and may 
require only minimal 
treatment or therapeutic 
intervention. The event does 
not generally interfere with 
usual activities of daily 
living. 
Grade 1: A type of AE that is 
usually transient and may 
require only minimal 
treatment or therapeutic 
intervention. The event does 
not generally interfere with 
usual activities of daily 
living. 
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Grade 2: ≥ 38.5°C to 
≤ 38.9°C, 
or ≥ 101.2°F to 
≤ 102.0°F 
Grade 2: A type of AE that is 
usually alleviated with 
additional therapeutic 
intervention. The event 
interferes with usual activities 
of daily living, causing 
discomfort but poses no 
significant or permanent risk 
of harm to the research 
participant. 
Grade 2: A type of AE that is 
usually alleviated with 
additional therapeutic 
intervention. The event 
interferes with usual activities 
of daily living, causing 
discomfort but poses no 
significant or permanent risk 
of harm to the research 
participant. 
Grade 2: A type of AE that is 
usually alleviated with 
additional therapeutic 
intervention. The event 
interferes with usual activities 
of daily living, causing 
discomfort but poses no 
significant or permanent risk 
of harm to the research 
participant. 
Grade 2: A type of AE that is 
usually alleviated with 
additional therapeutic 
intervention. The event 
interferes with usual 
activities of daily living, 
causing discomfort but poses 
no significant or permanent 
risk of harm to the research 
participant. 
 
Grade 3: ≥ 39.0°C 
or ≥ 102.1°F 
Grade 3: A type of AE that 
interrupts usual activities of 
daily living, or significantly 
affects clinical status, or may 
require intensive therapeutic 
intervention. 
Grade 3: A type of AE that 
interrupts usual activities of 
daily living, or significantly 
affects clinical status, or may 
require intensive therapeutic 
intervention. 
Grade 3: A type of AE that 
interrupts usual activities of 
daily living, or significantly 
affects clinical status, or may 
require intensive therapeutic 
intervention. 
Grade 3: A type of AE that 
interrupts usual activities of 
daily living, or significantly 
affects clinical status, or may 
require intensive therapeutic 
intervention. 
*  For all reactions but fever, subjects / parents / guardians will record the intensity level (Grade 1, 2, or 3) in the diary card. For fever, they will record the body temperature, and the 
classification as Grade 1, 2, or 3 will be assigned at the time of the statistical analysis based on the unit used to measure the temperature and the intensity scale. 
 
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Important notes for the accurate assessment of temperature: 
Subjects / parents / guardians are to measure body temperature once per day, preferably always at 
the same time. The optimal time for measurement is the evening, when body temperature is the 
highest. Temperature is also to be measured at the time of any apparent fever. The observed daily 
temperature and the route of measurement are to be recorded in the diary card, and the highest 
temperature will be recorded by the site in the CRB. The preferred route for this study is rectal for 
subjects 6 months to < 4 years of age and oral for subjects 4 years of age and older. However, 
axillary is also acceptable for subjects 6 months of age and older if unable to obtain the preferred 
route of measurement. Pre-vaccination temperature is also systematically collected by the 
investigator on the source document. Tympanic thermometers must not be used. 
9.1.3.3 
Unsolicited Adverse Events 
In addition to recording solicited reactions, subjects / parents / guardians will be instructed to 
record any other medical events that may occur during the 28-day period after each vaccination. 
Space will be provided in the diary card for this purpose.  
Information on SAEs will be collected and assessed throughout the study, from inclusion until 
6 months after the last vaccination. Any SAE occurring at any time during the study will be 
reported by the Investigator in the CRB according to the completion instructions provided by the 
Sponsor; this includes checking the “Serious” box on the AE CRF and completing the appropriate 
Death/Safety Complementary Information CRFs. All information concerning the SAE is to be 
reported either as part of the initial reporting or during follow-up reporting if relevant information 
became available later (eg, outcome, medical history, results of investigations, copy of 
hospitalization reports). In case a subject experiences febrile convulsion (neurological event 
associating fever and seizure), the assessment will be performed according to the “Guideline for 
definition and collection of cases of febrile convulsion”, and this event will be considered an 
SAE. See Section 10 for further details on SAE reporting. 
For each unsolicited AE (whether serious or non-serious), the following information is to be 
recorded: 
• Start and stop datesa  
• Intensity of the event: 
For measurable unsolicited AEs that are part of the list of solicited reactions, the size of the 
AE as well as the temperature for fever will be collected and analyzed based on the 
corresponding scale used for solicited reactions (see Table 9.1, Table 9.2, Table 9.3, Table 
9.4, and Table 9.5). 
All other unsolicited AEs will be classified according to the following intensity scale: 
                                                 
a  The stop date of all related AEs will be actively solicited. For other events, the investigator will provide the stop 
date when it becomes available. AEs for which no stop date was obtained during the course of the study will be 
considered as ongoing at the end of the study. 
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• Grade 1: A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of 
daily living. 
• Grade 2: A type of AE that is usually alleviated with additional therapeutic intervention. 
The event interferes with usual activities of daily living, causing discomfort but poses no 
significant or permanent risk of harm to the research participant.  
• Grade 3: A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention. 
• Whether the AE was related to the investigational product (for unsolicited systemic AEs) 
The Investigator will assess the causal relationship between the AE and the investigational 
product as either “Not related” or “Related”, as described in Section 9.1.3.5. 
• Action taken for each AE (eg, medication) 
The action(s) taken by the subject / parent / guardian to treat and/or manage any unsolicited 
AEs will be classified in the CRB using the following list (all applicable items should be 
checked): 
• None 
• Medication 
• Health care provider contact 
• Hospitalized 
• Discontinuation of study vaccination  
• Whether the AE was serious 
For each SAE, the investigator will complete all seriousness criteria that apply (outcome, 
elapsed time, and relationship to study procedures) 
• Whether the AE caused study discontinuation 
9.1.3.4 
Adverse Events of Special Interest 
AESIs will be captured as SAEs and will be collected throughout the study. These include new 
onset of GBS, encephalitis / myelitis (including transverse myelitis), Bell’s palsy, convulsions, 
optic neuritis, and brachial neuritis (25) (26) (27). 
9.1.3.5 
Assessment of Causality 
The Investigator will assess the causal relationship between each unsolicited systemic AE and 
the product administered as either not related or related, based on the following definitions: 
Not related – The AE is clearly / most probably caused by other etiologies such as an 
underlying condition, therapeutic intervention, or concomitant therapy; or the delay 
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between vaccination and the onset of the AE is incompatible with a causal relationship; or 
the AE started before the first vaccination (screening phase, if applicable) 
Related – There is a “reasonable possibility” that the AE was caused by the product 
administered, meaning that there is evidence or arguments to suggest a causal relationship 
Note: By convention, all AEs reported at the injection site (whether solicited or unsolicited) and 
all solicited systemic AEs are considered to be related to the administered product and therefore 
are referred to as reactions and do not require the Investigator’s opinion on relatedness. 
Adverse events likely to be related to the product, whether serious or not, that persist at the end of 
the study will be followed up by the Investigator until their complete disappearance or the 
stabilization of the subject’s condition. The Investigator will inform the Sponsor of the date of 
final disappearance of the event or the date of “chronicity” establishment. 
9.2 
Immunogenicity 
9.2.1 
Immunogenicity Endpoints 
9.2.1.1 
Immunogenicity by HAI Method 
The endpoints for the evaluation of immunogenicity by HAI method are: 
For subjects 9 to 17 years of age and previously influenza vaccinated subjects 6 months to 8 
years of age: 
• HAI antibody (Ab) titers obtained on D0 and D28 
• Individual HAI titers ratio D28/D0 
• Seroconversion (titer < 10 [1/dilution {dil}] at D0 and post-injection  titer ≥ 40 [1/dil] at D28, 
or titer ≥ 10 [1/dil] at D0 and a ≥ 4-fold increase in titer [1/dil] at D28) 
• Percentage of subjects with titers ≥ 40 (1/dil) at D0 and D28 
For previously influenza unvaccinated subjects 6 months to 8 years of age: 
• HAI Ab titers obtained on D0, D28, and D56 
• Individual HAI titers ratio D28/D0 and D56/D0 
• Seroconversion (titer < 10 [1/dil] at D0 and post-injection titer ≥ 40 [1/dil] at D28 and D56, or 
titer ≥ 10 [1/dil] at D0 and a ≥ 4-fold increase in titer [1/dil] at D28 and D56) 
• Percentage of subjects with titers ≥ 40 (1/dil) at D0, D28, and D56 
9.2.1.2 
Immunogenicity by Virus SN Method 
The endpoints for the evaluation of immunogenicity by virus SN method are: 
For subjects 9 to 17 years of age and previously influenza vaccinated subjects 6 months to 8 
years of age: 
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• Individual neutralization test (NT) Ab titer on D0 and D28 
• Individual NT Ab titer ratio (fold increase in serum NT post-vaccination relative to D0) at 
D28  
• Subjects with NT Ab titers ≥ 20 (1/dil), ≥ 40 (1/dil), ≥ 80 (1/dil) at D28  
• Fold-increase in NT Ab titer [post/pre] ≥2 and ≥ 4 at D28  
• Detectable NT (NT Ab titer ≥ 10 [1/dil]) at D0 and D28 
For previously influenza unvaccinated subjects 6 months to 8 years of age: 
• Individual NT Ab titer on D0, D28, and D56  
• Individual NT Ab titer ratio (fold increase in serum NT post-vaccination relative to D0) at 
D28 and D56  
• Subjects with NT Ab titers ≥ 20 (1/dil), ≥ 40 (1/dil), ≥ 80 (1/dil) at D28 and D56  
• Fold-increase in NT Ab titer [post/pre] ≥2 and ≥ 4 at D28 and D56 
• Detectable NT (NT Ab titer ≥ 10 [1/dil]) at D0, D28, and D56 
9.2.2 
Immunogenicity Assessment Methods 
Assays will be performed by the Sponsor’s laboratory (GCI, Swiftwater, PA, USA) or at an 
external testing laboratory under GCI supervision. The address is provided in the Operating 
Guidelines. 
Anti-Influenza Virus Ab Titration by Inhibition of Hemagglutination 
Test serum samples and quality control sera (sheep, ferret, and/or human sera) are incubated with 
Sigma Type III neuraminidase from vibrio cholerae to eliminate non-specific inhibitors. 
Adsorption of spontaneous anti-species agglutinins is then performed by incubating the test serum 
samples and quality control sera with a red blood cell (RBC) suspension. Following this, the 
mixtures are centrifuged and the supernatants containing the treated sera are collected for testing. 
Ten two-fold dilutions (starting at 1:10) of the treated test serum samples and quality control sera 
are incubated with a previously titrated influenza antigen at a concentration of 4 hemagglutination 
unit (HAU)/25 µL. Influenza antigen is not added to the serum control wells containing only 
serum and RBCs. The mixture is then incubated and a RBC suspension is added. Following 
incubation, the results are read. The endpoint of the assay is the highest serum dilution in which 
complete inhibition of hemagglutination occurred. Each serum sample is titrated in two 
independent assay runs, and the 2 values, which cannot differ by more than 1 two-fold dilution, 
are reported. The GMT between the 2 values is calculated at the time of statistical analysis. The 
lower limit of quantitation (LLOQ) is set at the lowest dilution used in the assay, 1:10. Titers 
below this level are reported as < 10 (1/dil). If the lowest / first serum dilution used in the assay 
exhibits complete inhibition of hemagglutination, the serum Ab titer will be reported as < 10 
(1/dil). If the highest / last serum dilution used in the assay exhibits complete inhibition of 
hemagglutination, the serum Ab titer will be reported as ≥ 10240 (1/dil).  
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Influenza Virus Neutralization Test 
Assays will be performed by the Sponsor’s laboratory (GCI, Swiftwater, PA, USA).  
This NT measures Abs directed against the viral neutralization epitopes of the influenza virus, 
which may be different from the hemagglutination epitopes, therefore, the NT titers may be 
different from the HAI titers. 
To measure NT, serially diluted, heat-inactivated human serum samples will be pre-incubated 
with a fixed amount of challenge virus prior to the addition of Madin-Darby canine kidney 
(MDCK) cells. After overnight incubation, the viral nucleoprotein production in infected MDCK 
cells is measured by enzyme-linked immunosorbent assay (ELISA), using monoclonal Ab 
specific to either influenza A nucleoprotein or influenza B nucleoprotein. Since serum 
neutralizing Abs to the influenza virus inhibits the viral infection of MDCK cells, the ELISA 
optical density results are inversely proportional to the titers of neutralizing Ab present in the 
serum. The LLOQ is set at the reciprocal of the lowest dilution used in the assay, ie, 10 (1/dil). 
Titers below this level are reported as < 10 (1/dil). The highest titer that would be reported is 
10239 (1/dil). Anything ≥ 10240 (1/dil) will be pre-diluted, retested, and end point titers will be 
reported.  
9.3 
Efficacy 
No clinical efficacy data will be obtained in the study. 
10 Reporting of Serious Adverse Events  
To comply with current regulations on SAE reporting to health authorities, the Investigator must 
document all SAEs regardless of causal relationship, and notify the Sponsor and the Clinical 
Research Associate (CRA) within the notification timelines stated in the following sections. The 
Investigator will give access and provide the Sponsor and the CRA with all necessary information 
to allow the Sponsor to conduct a detailed analysis of the safety of the investigational products. It 
is the responsibility of the Investigator to request all necessary documentation (eg, medical 
records, discharge summary, autopsy) in order to provide comprehensive safety information. All 
relevant information must then be transcribed onto the AE CRF and the appropriate Death/Safety 
Complementary Information CRFs. 
10.1 Initial Reporting by the Investigator 
Serious adverse events occurring during a subject’s participation in the study or experiment must 
be reported within 24 hours to the Sponsor’s GPV Department and to the CRA. Every SAE must 
be reported, even if the Investigator considers that it is not related to the vaccine. The investigator 
(licensed physician [M.D. or D.O.]) must validate the information entered on the AE CRF by 
completing the investigator validation form. 
The Investigator must indicate on the AE CRF that the event was serious and must complete the 
relevant SAE section of this form as well as the appropriate Death/Safety Complementary 
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Information CRFs. An e-mail alert will automatically be sent by the EDC system to the GPV 
mailbox, the CRA and the CTL with relevant SAE information details. 
If the EDC system is unavailable, the site must notify the Sponsor, using the paper version of the 
CRB, as described in the operating guidelines: 
The Investigator must complete the paper copies of the AE CRF and of the appropriate 
Death/Safety Complementary Information CRFs and send them to the Sponsor by one of the 
following means: 
• By fax, to the following number: +1 570-957-2782 
• In PDF format to the following e-mail address, using a method of transmission that 
includes password protection: SanofiPasteurPharmaco@sanofi.com 
• By express mail, to the following address: 
 
 
Global PharmacoVigilance, Sanofi Pasteur 
 
 
Discovery Drive 
 
 
Swiftwater, PA 18370 
When the EDC system becomes available, the Investigator must transcribe the information from 
the paper forms into the EDC system. 
If there is need for urgent consultation, the Investigator is to contact the RMO. If the RMO cannot 
be reached, the Investigator may contact the Call Center as described in Section 5.2.12.  
10.2 Follow-up Reporting by the Investigator 
The AE CRF completed initially must be updated within 24 hours after the Investigator has 
become aware of any new relevant information concerning the SAE (eg, outcome, precise 
description of medical history, results of the investigation). All relevant information must be 
included directly in the AE CRF and the appropriate Death/Safety Complementary Information 
CRFs. An e-mail alert will be sent automatically to the GPV Department and to the CRA. Copies 
of documents (eg, medical records, discharge summary, autopsy) may be requested by the GPV 
Department. 
The anonymity of the subject must always be respected when forwarding this information. 
10.3 Reporting of SAEs Occurring After a Subject Has Completed the Study 
Any SAE that occurs after a subject has completed the study but that is likely to be related to the 
investigational products, or to the experiment must also be reported as soon as possible. In such a 
case, the reporting procedure to be followed is identical to that described in Section 10.1. 
10.4 Assessment of Causality 
The causal relationship between the SAE and the product administered will be evaluated by the 
Investigator as described in Section 9.1.3.5. 
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Following this, the Sponsor’s Global Safety Officer (GSO) will also assess the causal relationship 
to the product, based on the available information and current medical knowledge. 
The causal relationship to study procedures will be also assessed in the CRB. 
The decision to modify or discontinue the study may be made after mutual agreement between the 
Sponsor and the Investigator(s). 
10.5 Reporting SAEs to Health Authorities and IECs / IRBs 
The Sponsor will inform the relevant health authorities of any reportable SAEs according to the 
local regulatory requirements. Reporting to the health authorities will be according to the 
Sponsor’s standard operating procedures. 
The Sponsor’s RMO (Lee-Jah Chang, MD, CTL) will notify the Investigators in writing of the 
occurrence of any reportable SAEs. The Investigators / Sponsor will be responsible for informing 
the IECs or IRBs that reviewed the study protocol. 
11 Data Collection and Management 
11.1 Data Collection and CRB Completion 
Individual diary cards, specifically designed for this study by the Sponsor and provided to the 
study sites, will be given to study participants for the recording of daily safety information as 
described in Section 9.1.3. These diary cards will include prelisted terms and intensity scales (see 
Table 9.1, Table 9.2, Table 9.3, Table 9.4, and Table 9.5) as well as areas for free text to capture 
additional safety information or other relevant details. Subjects / parents / guardians will also be 
provided with rulers for measuring the size of injection site reactions, and with standard digital 
thermometers for measuring daily temperatures. To ensure consistency of reporting, the study 
sites will instruct subjects / parents / guardians on how to correctly use these tools.  
The 6-month follow-up will be done by interviewing subjects / parents / guardians over the 
telephone using a questionnaire to capture SAEs and AESIs, if applicable. A memory aid will be 
provided to the subjects at the preceding study visit to help them record information on events 
occurring between this visit and the 6-month follow-up. 
Relevant information will be transcribed into the AE CRF. Any SAEs captured during this 6-
month follow-up period will be reported and followed-up as per the normal process for reporting 
SAEs. 
At specified intervals, the Investigator or an authorized designee will interview the subjects / 
parents / guardians to collect the information recorded in the diary card, and will attempt to clarify 
anything that is incomplete or unclear. All clinical study information gathered by the study site 
will be reported electronically by the Investigator or authorized designee using a web-based CRB. 
(Any information that was not documented in the diary card will first be captured in the source 
document and then reported electronically.) The CRB has been designed specifically for this 
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study under the responsibility of the Sponsor, using a validated Electronic Records / Electronic 
Signature-compliant platform (21 CFR Part 11). 
To ensure the correct and consistent completion of the CRBs, the Sponsor or authorized 
representative will provide all necessary tools, instructions, and training to all site staff involved 
in data entry prior to study start. Additional instructional documents such as training manuals and 
completion instructions will be provided to assist with data entry during the course of the study. 
Upon completion of training, each user requiring access to the EDC system will be issued a 
unique username and password. In the event of a change in study personnel, each newly assigned 
individual will receive a unique username and password; the username and password of a 
previous user may not be reissued. If any study personnel leave the study, the Investigator is 
responsible for informing the Sponsor immediately so that their access is deactivated. An audit 
trail will be initiated in the EDC system at the time of the first data entry to track all modifications 
and ensure database integrity. 
The Investigator is responsible for the timeliness, completeness, and accuracy of the information 
in the CRBs; must provide explanations for all missing information; and must sign the CRB using 
an e-signature. 
11.2 Data Management 
Management of SAE and Pregnancy Data 
During the study, SAE data (reported on the AE, Death, and Safety Complementary Information 
CRFs) and pregnancy data (reported by the Investigator on ePregnancy Forms) will be integrated 
into the Sponsor’s centralized GPV database upon receipt of these forms and after a duplicate 
check. Each case will be assigned a case identification number. Each case will be assessed by the 
case management platform or its delegate before being reported to the relevant authorities as 
necessary. The assessment of related cases will be done in collaboration with the GSO and the 
RMO. Follow-up information concerning a completed case will be entered into the GPV database, 
and a new version of the case will be created. 
The information from the GPV database cases will be reconciled with that in the clinical database. 
Management of Clinical and Laboratory Data 
Clinical data, defined as all data reported in the CRB, and laboratory data will be handled by the 
Sponsor’s Clinical Data Management (CDM) platform or authorized representative. 
During the study, clinical data reported in the CRBs will be integrated into the clinical database 
under the responsibility of the Sanofi Pasteur CDM platform. Data monitoring at the sites and 
quality control in the form of computerized logic and / or consistency checks will be 
systematically applied to detect errors or omissions. In addition, data reviews may be performed 
several times by the Sponsor’s staff in the course of the study. Any questions pertaining to the 
reported clinical data will be submitted to the investigator for resolution using the EDC system. 
Each step of this process will be monitored through the implementation of individual passwords 
to maintain appropriate database access and to ensure database integrity. 
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The validation of the immunogenicity data will be performed at the laboratory level following the 
laboratory’s procedures. Information from the laboratory will be checked for consistency before 
integration into the clinical Datawarehouse. 
After integration of all corrections in the complete set of data, and after the SAE information 
available from CDM and the GPV Department has been reconciled, the database will be released for 
statistical analysis. 
11.3 Data Review 
A blind review of the data is anticipated through the data review process led by Data Management 
before database lock.  
12 Statistical Methods and Determination of Sample Size 
12.1 Statistical Methods 
All statistical analyses will be performed under the responsibility of the Sponsor’s Biostatistics 
Platform using the SAS® software, Version 9.4 or above (SAS Institute, Cary, North Carolina, 
USA). 
A statistical analysis plan (SAP) will be written and peer reviewed before any analyses. In 
accordance with the protocol, the SAP will describe all analyses to be performed by the Sponsor 
and all the conventions to be taken. 
12.1.1 Hypotheses and Statistical Methods for the Objectives 
12.1.1.1 Hypotheses 
No hypotheses for safety and immunogenicity are planned. All analyses are descriptive.  
12.1.1.2 Statistical Methods 
For the cohorts controlled by the non-adjuvanted QIV-SD, results will be described per stage, 
according to vaccine received, and per age group. Age groups will also be pooled within the same 
vaccine group for the main endpoints. The descriptive results may also be presented by the pooled 
QIV-HD group (60 µg) in the two countries. Subgroup immunogenicity analyses per previous 
vaccination status and/or baseline serostatus may be presented when appropriate. If any of the 
stages are not completed, analyses for the higher dose or next stage will not be performed.  
For the cohort controlled by the adjuvanted TIV, results will be described according to vaccine 
received. 
Safety 
Safety endpoints will be analyzed descriptively for subjects in SafAS who received the QIV-HD. 
Solicited reactions (solicited injection site and systemic reactions), unsolicited AEs, SAEs, and 
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AESIs will be summarized. The main parameters will be described by single proportions with the 
95% CI (Clopper-Pearson method) (28). 
• Immunogenicity 
Immunogenicity endpoints will be summarized with 95% CIs. The 95% CIs for the GMTs and 
GMT ratios (GMTRs) will be calculated using normal approximation of log-transformed titers. 
The 95% CIs for the proportions will be based on the Clopper-Pearson method. The ratios of 
GMTs will be obtained between groups with the 95% CIs calculated using normal approximation 
of log-transformed titers. The differences in the seroconversion rates between groups will be 
computed along with the 2-sided 95% CIs by the Wilson-Score method without continuity 
correction (29). Additional parameters may be displayed as appropriate. 
Reverse cumulative distribution curves against each strain will be performed for baseline (V01) 
and post-vaccination immunogenicity (D28 or D56 as appropriate). 
The immunogenicity analysis set (IAS) will be used for the main immunogenicity analyses. 
Details of the above analyses will be described in a SAP. 
12.2 Analysis Sets 
Two main analysis sets will be used: the IAS and the Safety Analysis Set (SafAS). 
12.2.1 Immunogenicity Analysis Set 
The IAS is defined as the subset of randomized subjects who received 1 dose of a study vaccine 
(for subjects 9 to 17 years of age and for previously influenza vaccinated subjects 6 months to 
8 years of age) or 2 doses of a same study vaccine (for previously influenza unvaccinated subjects 
6 months to 8 years of age) and had a post-vaccination blood sample. Subjects will be analyzed as 
treated. 
12.2.2 Safety Analysis Set 
The SafAS is defined as those subjects who have received at least one dose of the study vaccinesa.  
All subjects will have their safety analyzed as following: 
• After each dose, according to the vaccine they actually received at the dose considered 
• After any dose, according to the vaccine received at the first dose. In case the second dose 
received is different, safety data recorded at V04 and V05 will be excluded from this analysis 
and listed separately. 
Safety data recorded for a vaccine received out of the protocol design will be excluded from the 
analysis (and listed separately). 
                                                 
a  for which safety data are scheduled to be collected 
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12.2.3 Populations Used in Analyses 
All randomized subjects with data in the CRB will be taken into account in the description of the 
population (eg, the disposition, the demographic, or baseline characteristics).  
The safety analyses will be performed on the SafAS. 
The immunogenicity analyses from HAI assay and SN assay will both be performed on the IAS. 
12.3 Handling of Missing Data and Outliers 
12.3.1 Safety 
No replacement will be done. Nevertheless, missing relationship will be considered as related at 
the time of the statistical analysis. No search for outliers will be performed. In all subject listings, 
partial and missing data will be clearly indicated as missing. 
12.3.2 Immunogenicity 
In order to appropriately manage replicate values for analysis purposes, the individual geometric 
mean of all values will be computed for each blood sample after managing extreme values as 
described. The computed value is then considered the titer for that particular blood sample. 
• If a titer is < LLOQ, then the computed value, LLOQ/2, will be used. 
• If a titer is ≥ LLOQ and < upper limit of quantitation (ULOQ) (or ≤ ULOQ), then the titer 
itself will be used. 
• If a titer is ≥ ULOQ (or ˃ ULOQ), then computed value, ULOQ, will be used. 
Any other replacement to be applied to specific endpoints will be described in the SAP. 
Missing data will not be imputed. No test or search for outliers will be performed. 
12.4 Interim / Preliminary Analysis 
For Stages 1, 2, and 3, there will be an early blinded look at the 7-day safety data for subjects 
6 months to 8 years of age to determine whether the next group will be enrolled. No statistical 
adjustment is necessary because no hypotheses will be tested. 
A limited statistical analysis of the unblinded safety and immunogenicity data obtained up to D28 
or D56 may be conducted once data are available and an interim database lock has been 
conducted. A final analysis will be conducted once the 6-month safety data have been collected 
and the final database lock has occurred.  
No statistical adjustment is necessary because no hypotheses will be tested. 
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12.5 Determination of Sample Size and Power Calculation 
QHD04 is a Phase II study to describe the safety and immunogenicity of 3 different dosages of 
QIV-HD. The sample size is not powered. The study will include a total of approximately 
700 subjects that will be divided into 13 groups as follows: 
• Groups 1, 2, 3, 5, 9, and 10 will each include 40 subjects (previously influenza vaccinated or 
previously influenza unvaccinated) in a 3:1 ratio (QIV-HD: QIV-SD). 
• Group 4 will include 90 subjects (previously influenza vaccinated or previously influenza 
unvaccinated) in a 1:1 ratio (QIV-HD: QIV-SD).  
• Groups 7 will include 60 subjects who are previously influenza vaccinated in a 1:1 ratio (QIV-
HD: QIV-SD). 
• Groups 6 and 8 will each include 60 subjects who are previously influenza unvaccinated in a 
1:1 ratio (QIV-HD: QIV-SD or TIV). 
• Group 11 and 13 will each include 60 subjects (previously influenza vaccinated or previously 
influenza unvaccinated) in a 1:1 ratio (QIV-HD: QIV-SD).  
• Group 12 will include 70 subjects (previously influenza vaccinated or previously influenza 
unvaccinated) in a 3:3:1 ratio (QIV-HD: QIV-HD: QIV-SD). 
13 Ethical and Legal Issues and Investigator / Sponsor Responsibilities 
13.1 Ethical Conduct of the Study / Good Clinical Practice 
The conduct of this study will be consistent with the standards established by the Declaration of 
Helsinki and compliant with the ICH guidelines for GCP as well as with all local and / or national 
regulations and directives. 
13.2 Source Data and Source Documents 
“Source data” are the data contained in source documents. Source documents are original 
documents or certified copies, and include, but are not limited to, diary cards, medical and 
hospital records, screening logs, informed consent / assent forms, telephone contact logs, and 
worksheets. The purpose of study source documents is to document the existence of subjects and 
to substantiate the integrity of the study data collected. Investigators must maintain source 
documents so that they are accurate, complete, legible, and up to date. 
For missing or discrepant data on a diary card, the study coordinator will obtain verbal clarification 
from the subject, enter the response into the “investigator’s comment” page of the diary card, and 
transfer the information to the CRB. 
The subject pre-screening log should list all individuals contacted by the Investigators to 
participate in the study, regardless of the outcome. 
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The Investigator must printa any electronic records on an ongoing basis, sign and date them 
immediately after creation, and keep the printouts on file as source documents that can be verified 
by the Sponsor or an inspector against the electronic records. Any subsequent changes of an 
electronic record require the record to be re-printed, dated (with an indication of the date of 
change), and signed. Such records must also be kept together with the original printed copy. 
Good Documentation Practice should be followed by the Investigator and the site staff managing 
source documents. 
13.3 Confidentiality of Data, Data Protection, and Access to Subject Records 
Prior to initiation of the study, the Investigator will sign a fully executed confidentiality 
agreement with Sanofi Pasteur. In the event a subject’s medical records are not at the 
investigational site, it is the responsibility of the investigator to obtain those records if needed. 
All personal data collected related to subjects, Investigators, or any person involved in the study, 
which may be included in the Sponsor’s databases, shall be treated in compliance with all 
applicable laws and regulations including the General Data Protection Regulation. Data collected 
must be adequate, relevant and not excessive, in relation to the purposes for which they are 
collected. Each category of data must be properly justified and in line with the study objective. 
Subjects’ race and ethnicity will be collected in this study because these data are required by the 
Food and Drug Administration in the US (30). 
Subjects will be assigned a unique identifier by the Sponsor. Any subject records or datasets that 
are transferred to the Sponsor will contain the identifier only; subject names or any information 
which would make the subject identifiable will not be transferred. 
The subject must be informed that his/her personal study-related data will be used by the Sponsor 
in accordance with local data protection law. The level of disclosure must also be explained to the 
subject. 
The subject must be informed that his/her medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the Sponsor, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities. 
When archiving or processing personal data pertaining to the Investigator and/or to the subjects, 
the Sponsor shall take all appropriate measures to safeguard and prevent access to this data by any 
unauthorized third party. 
                                                 
a  Unless the electronic medical records are managed by validated computerized systems that are compliant with US 
21 CFR Part 11, in which case they are acceptable on their own. 
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13.4 Monitoring, Auditing, and Archiving 
13.4.1 Monitoring  
Before the start of the study (ie, before the inclusion of the first subject in the first center), the 
Investigators and the Sponsor’s staff or a representative will meet at the site-initiation visit to 
discuss the study protocol and the detailed study procedures. Emphasis will be placed on inclusion 
and exclusion criteria, visit timing, safety procedures, informed consent procedures, SAE 
reporting procedures, CRB completion, and the handling of samples and products. The Sponsor’s 
staff or a representative will ensure and document that all material to be used during the study has 
been received at the site; and that the study investigator team and local Sponsor/delegate staff 
have been properly informed about the study, GCP and regulatory requirements, and the 
Sponsor’s procedures. Specific training sessions for the study investigator team and the CRAs on 
these topics may be performed as necessary, and should be documented. 
The following instruction manuals will be provided: the CRF Completion Instructions for entering 
data into the CRB, and the Operating Guidelines for detailed study procedures such as the product 
management and sample-handling procedures. 
After the start of the study, the Sponsor’s staff or a representative will be in regular contact with 
the investigational team through telephone calls and regular follow-up visits. The Investigator or 
delegate must be available for these visits, and must allow the Sponsor/delegate staff direct access 
to subject medical files and CRBs. During these visits, the Sponsor/delegate staff will: 
• Evaluate the quality of the study progress (adherence to protocol and any study-specific 
guidelines, quality of data collection and document completion, signature of consent forms, 
occurrence of SAEs, sample and product management, cold-chain monitoring, archiving) 
• Source-verify completed CRBs and any corresponding answered queries 
• Determine the number of complete or ongoing issues identified at monitoring visits (eg, 
protocol deviations, SAEs). Any identified problems will be discussed with the Investigator, 
and corrective or preventive actions will be determined, as appropriate. 
• After all protocol procedures have been completed and the data have been entered into the 
CRB, the Investigator must still be available to answer any queries forwarded by the Sponsor. 
All data-related queries must be completed prior to database lock. 
At the end of the study, a close-out visit will be performed to ensure that: 
• The center has all the documents necessary for archiving 
• All samples have been shipped to the appropriate laboratories 
• All unused materials and products have been either destroyed or returned to the Sponsor 
13.4.2 Audits and Inspections 
A quality assurance audit may be performed at any time by the Sponsor’s Clinical Quality 
Assessment department (CQA) or by independent auditors to verify that the study has been 
conducted according to the protocol, GCP and ICH requirements, and other applicable 
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regulations. An inspection may be conducted by regulatory authorities. The Investigator must 
allow direct access to study documents during these inspections and audits. 
13.4.3 Archiving 
The Investigator must keep all study documents after the completion or discontinuation of the 
study, whatever the nature of the investigational center (private practice, hospital, or institution), 
for as long as required by applicable laws and regulations. In the absence of any applicable laws 
or regulations, study documents will be kept at a minimum for the duration indicated on the 
Clinical Trial Agreement (CTA). In no event, should study personnel destroy or permit the 
destruction of any study documents upon less than 90 days advance written notification to the 
Sponsor. In addition, study documents should continue to be stored, at Sponsor's sole expense, in 
the event that the Sponsor requests in writing that such storage continues for a period of time that 
exceeds that required by any applicable law or regulation or the CTA. The Investigator will 
inform Sanofi Pasteur of any address change or if they will no longer be able to house the study 
documents. 
Archived data may be held on electronic records, provided that a back-up exists and that a hard 
copy can be obtained if required. The protocol, documentation, approvals, and all other 
documents related to the study will be kept by the Sponsor in the Trial Master File (TMF). Data 
on AEs are included in the TMF. All data and documents will be made available if requested by 
relevant authorities. 
13.5 Financial Contract and Insurance Coverage 
A CTA will be signed by all the parties involved in the study’s performance, if relevant. The 
Sponsor has an insurance policy to cover any liabilities that may arise from use of the product and 
/ or the study protocol. 
13.6 Stipends for Participation 
Subjects / subjects’ parent / guardian may be provided with a stipend, according to local practice, 
to compensate for the time and travel required for study visits and procedures. 
13.7 Publication Policy 
Data derived from this study are the exclusive property of Sanofi Pasteur. Any publication or 
presentation related to the study must be submitted to Sanofi Pasteur for review before submission 
of the manuscript. After publication of the results of the study, any participating center may 
publish or otherwise use its own data provided that any publication of data from the study gives 
recognition to the study group. In addition, Sanofi Pasteur shall be offered an association with all 
such publications, it being understood that Sanofi Pasteur is entitled to refuse the association. 
Sanofi Pasteur must have the opportunity to review all proposed abstracts, manuscripts, or 
presentations regarding this study at least 90 days prior to submission for publication / 
presentation. Any information identified by Sanofi Pasteur as confidential must be deleted prior to 
submission, it being understood that the results of this study are not to be considered confidential. 
Sanofi Pasteur’s review can be expedited to meet publication guidelines. 
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14 Reference List 
 
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Mitchell DK, Ruben FL, Gravenstein S. Immunogenicity and safety of inactivated influenza 
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