A Phase III, Randomized, Observer-Blind, Controlled, Multicenter Clinical Study to Evaluate the Efficacy, Safety and Immunogenicity of an MF59-Adjuvanted Quadrivalent Influenza Vaccine Compared to Non-influenza Vaccine Comparator in Adults ≥ 65 Years of Age
Phase: PHASE3
Conditions: Influenza
Sponsor: Seqirus

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CLINICAL STUDY PROTOCOL V118_18 Version 5
A Phase III, Randomized, Observer-Blind, Controlled, Multicenter Clinical Study to 
Evaluate the Efficacy, Safety and Immunogenicity of an MF59-Adjuvanted 
Quadrivalent Influenza Vaccine Compared to Non-influenza Vaccine Comparator 
in Adults ≥ 65 Years of Age
Phase III Efficacy Study of aQIV in Elderly Adults
EudraCT number 2015-000728-27
Property of Seqirus UK Ltd. (hereafter referred to as Seqirus)
Confidential
May not be used, divulged, published or otherwise disclosed without written
consent of Seqirus.
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TABLE OF CONTENTS
TABLE OF CONTENTS ................................................................................................ 2
PROTOCOL SYNOPSIS V118_18 VERSION 5 ............................................................ 8
LIST OF ABBREVIATIONS........................................................................................ 31
DEFINITIONS.............................................................................................................. 33
1.
BACKGROUND AND RATIONALE ................................................................. 35
1.1
Background ..................................................................................................... 35
1.2
Rationale ......................................................................................................... 37
2.
OBJECTIVES...................................................................................................... 38
2.1
Primary Objective(s)........................................................................................ 38
2.2
Secondary Objective(s).................................................................................... 38
2.3
Exploratory Objective(s).................................................................................. 39
3.
STUDY DESIGN................................................................................................. 40
3.1
Overview of Study Design............................................................................... 40
3.2
Study Period.................................................................................................... 43
3.3
Blinding Procedures......................................................................................... 43
3.4
Data Collection................................................................................................ 43
3.4.1
Data Collected from Subjects.................................................................... 43
3.4.2
Tools Used for Data Collection................................................................. 44
3.5
Collection of Clinical Specimens ..................................................................... 46
3.6
Stopping/Pausing Guidelines ........................................................................... 47
3.7
Data Monitoring Committee ............................................................................ 47
3.8
Premature Withdrawal from Study................................................................... 48
3.9
End of Study.................................................................................................... 51
4.
SELECTION OF STUDY POPULATION........................................................... 52
4.1
Inclusion Criteria ............................................................................................. 52
4.2
Exclusion Criteria............................................................................................ 52
4.3
Criteria for Delay of Vaccination..................................................................... 54
5.
STUDY PROCEDURES...................................................................................... 55
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5.1
Vaccination Clinic Visit - Pre-vaccination Procedures ..................................... 55
5.1.1
Informed Consent ..................................................................................... 55
5.1.2
Screening.................................................................................................. 56
5.1.3
Enrollment................................................................................................ 58
5.1.4
Randomization.......................................................................................... 59
5.2
Vaccination Clinic Visit – Vaccination and Post-vaccination procedures ......... 60
5.2.1
Post-vaccination Procedures...................................................................... 60
5.2.2
Post-vaccination Reminder Calls............................................................... 62
5.3
Post-vaccination Visit(s).................................................................................. 63
5.3.1
Follow-up Clinic Visit(s) .......................................................................... 63
5.3.2
Safety Follow-up Calls.............................................................................. 65
5.3.3
Active Influenza Surveillance Phone Calls/Messages................................ 66
5.4
Unscheduled Visits.......................................................................................... 66
5.4.1
Subjects Meeting the Influenza-Like-Illness Criteria................................. 66
5.5
Study Termination Visit................................................................................... 67
5.5.1
Early Termination Visit ............................................................................ 68
6.
TREATMENT OF SUBJECTS............................................................................ 70
6.1
Study Vaccine(s) ............................................................................................. 70
6.2
Non-Study Vaccines ........................................................................................ 72
6.3
Vaccine Preparation and Administration.......................................................... 72
6.4
Vaccine Administration Error or Overdose of Vaccine..................................... 74
6.5
Prior and Concomitant Medications and Vaccines............................................ 74
6.6
Vaccine Supply, Labeling, Storage and Tracking............................................. 76
7.
ASSESSMENTS.................................................................................................. 78
7.1
Safety Assessment ........................................................................................... 78
7.1.1
Solicited Adverse Events .......................................................................... 78
7.1.2
Unsolicited Adverse Events ...................................................................... 80
7.1.3
Evaluation of Adverse Events ................................................................... 80
7.1.4
Serious Adverse Events ............................................................................ 82
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7.1.4.1 Adverse Events of Special Interest ..................................................... 83
7.1.5
Methods for Recording Adverse Events and Serious Adverse Events........ 84
7.1.5.1 Post-Study Events.............................................................................. 85
7.1.6
Pregnancies............................................................................................... 85
7.1.7
Safety Laboratory Measurements.............................................................. 85
7.2
Efficacy Assessment........................................................................................ 85
7.3
Immunogenicity Assessment............................................................................ 86
8.
STATISTICAL CONSIDERATIONS.................................................................. 87
8.1
Endpoints ........................................................................................................ 87
8.1.1
Primary Endpoint(s).................................................................................. 87
8.1.1.1 Primary Safety Endpoint(s) ................................................................ 87
8.1.1.2 Primary Efficacy Endpoint(s)............................................................. 87
8.1.1.3 Primary Immunogenicity Endpoint(s)................................................. 87
8.1.2
Secondary Endpoint(s).............................................................................. 88
8.1.2.1 Secondary Safety Endpoint(s) ............................................................ 88
8.1.2.2 Secondary Efficacy Endpoint(s)......................................................... 88
8.1.2.3 Secondary Immunogenicity Endpoint(s)............................................. 88
8.1.3
Exploratory Endpoint(s)............................................................................ 89
8.1.3.1 Exploratory Safety Endpoint(s) .......................................................... 89
8.1.3.2 Exploratory Efficacy Endpoint(s)....................................................... 89
8.1.3.3 Exploratory Immunogenicity Endpoint(s)........................................... 89
8.2
Success Criteria ............................................................................................... 89
8.2.1
Success Criteria for Primary Objective(s).................................................. 89
8.2.1.1 Success Criteria for Primary Safety Objective(s)................................ 89
8.2.1.2 Success Criteria for Primary Efficacy Objective(s)............................. 90
8.2.1.3 Success Criteria for Primary Immunogenicity Objective(s) ................ 90
8.2.2
Success Criteria for Secondary Objective(s).............................................. 90
8.2.2.1 Success Criteria for Secondary Safety Objective(s) ............................ 90
8.2.2.2 Success Criteria for Secondary Efficacy Objective(s)......................... 90
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8.2.2.3 Success Criteria for Secondary Immunogenicity Objective................. 90
8.3
Analysis Sets ................................................................................................... 91
8.3.1
All Enrolled Set ........................................................................................ 91
8.3.2
All Exposed Set ........................................................................................ 91
8.3.3
Safety Set.................................................................................................. 91
8.3.4
Full Analysis Set (FAS) Efficacy/Immunogenicity Set.............................. 91
8.3.5
Per Protocol (PP) Set Efficacy/Immunogenicity Set.................................. 92
8.3.6
Subgroups................................................................................................. 93
8.3.7
Protocol Deviations................................................................................... 94
8.4
Statistical Analysis Plan................................................................................... 94
8.4.1
Analysis of Demographic and Baseline Characteristics ............................. 94
8.4.2
Analysis of Primary Objective(s) .............................................................. 94
8.4.2.1 Analysis of Primary Safety Objective(s)............................................. 94
8.4.2.1.1
Analysis of Extent of Exposure ................................................... 94
8.4.2.1.2
Analysis of Solicited Local, Systemic and Other Adverse Events 94
8.4.2.1.3
Analysis of Unsolicited Adverse Events...................................... 95
8.4.2.1.4
Analysis of Safety Laboratory Values.......................................... 96
8.4.2.2 Analysis of Primary Efficacy Objective(s).......................................... 96
8.4.2.2.1
Statistical Hypotheses.................................................................. 96
8.4.2.2.2
Analysis Sets............................................................................... 97
8.4.2.2.3
Statistical Methods...................................................................... 97
8.4.2.3 Analysis Of Primary Immunogenicity Objective(S)............................ 98
8.4.2.3.1
Statistical Hypotheses.................................................................. 98
8.4.2.3.2
Analysis Sets............................................................................... 98
8.4.2.3.3
Statistical Methods...................................................................... 98
8.4.3
Analysis of Secondary Objective(s) .......................................................... 99
8.4.3.1 Analysis of Secondary Safety Objective(s)......................................... 99
8.4.3.1.1
Analysis of Extent of Exposure ................................................... 99
8.4.3.1.2
Analysis of Solicited Local, Systemic and Other Adverse Events 99
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8.4.3.1.3
Analysis of Unsolicited Adverse Events...................................... 99
8.4.3.1.4
Statistical Hypotheses.................................................................. 99
8.4.3.1.5
Analysis Sets............................................................................... 99
8.4.3.1.6
Statistical Methods...................................................................... 99
8.4.3.2 Analysis of Secondary Efficacy Objective(s)...................................... 99
8.4.3.2.1
Statistical Hypotheses.................................................................. 99
8.4.3.2.2
Analysis Sets............................................................................... 99
8.4.3.2.3
Statistical Methods.................................................................... 100
8.4.3.3 Analysis of Secondary Immunogenicity Objective(s) ....................... 100
8.4.3.3.1
Statistical Hypotheses................................................................ 100
8.4.3.3.2
Analysis Sets............................................................................. 100
8.4.3.3.3
Statistical Methods.................................................................... 100
8.4.4
Analysis of Exploratory Objectives......................................................... 101
8.4.4.1 Analysis of Exploratory Safety Objective(s)..................................... 101
8.4.4.2 Analysis of Exploratory Efficacy Objective(s).................................. 101
8.4.4.3 Analysis of Exploratory Immunogenicity Objective(s) ..................... 101
8.5
Sample Size and Power Considerations of Primary and Secondary Objectives102
8.6
Interim Analysis ............................................................................................ 104
9.
SOURCE DOCUMENTATION, STUDY MONITORING AND AUDITING ... 109
9.1
Source Documentation................................................................................... 109
9.2
Study Monitoring, Auditing and Source Data Verification............................. 110
10.
DATA MANAGEMENT ................................................................................... 111
10.1 Data Entry and Management.......................................................................... 111
10.2 Data Clarification .......................................................................................... 111
10.3 Data Protection.............................................................................................. 111
11.
RECORD RETENTION .................................................................................... 112
12.
USE OF INFORMATION AND PUBLICATION.............................................. 113
13.
ETHICAL CONSIDERATIONS........................................................................ 114
13.1 Regulatory and Ethical Compliance ............................................................... 114
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13.2 Informed Consent Procedures ........................................................................ 114
13.3 Responsibilities of the Investigator and IRB/EC ............................................ 115
13.4 Protocol Amendments.................................................................................... 116
14.
REFERENCE LIST............................................................................................ 117
APPENDIX 1: EXAMPLES OF PRE-EXISTING MEDICAL CONDITIONS............ 120
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PROTOCOL SYNOPSIS V118_18 VERSION 5
Name of Sponsor:
Seqirus UK Ltd.
Protocol 
number: 
V118_18
Generic name of study vaccine(s):
MF59-adjuvanted Quadrivalent Subunit 
Inactivated Egg-derived Influenza Vaccine
Tetanus Toxoid, Reduced Diphtheria 
Toxoid and Acellular Pertussis Vaccine, 
Adsorbed
Title of Study:
A Phase III, Randomized, Observer-Blind, Controlled, Multicenter Clinical Study to 
Evaluate the Efficacy, Safety and Immunogenicity of an MF59-Adjuvanted Quadrivalent 
Influenza Vaccine Compared to Non-influenza Vaccine Comparator in Adults ≥ 65 Years 
of Age
Study Period:
The total study period will be 
approximately 12 months following a single 
vaccination.
Clinical Phase:
III
Background and Rationale:
The purpose of this study is to demonstrate the efficacy, safety and immunogenicity of an 
MF59-adjuvanted inactivated egg-derived quadrivalent influenza vaccine (aQIV) in 
preventing seasonal influenza in elderly adults. Seasonal influenza is a significant cause 
of morbidity and mortality, particularly in children and elderly (Neuzil, Mellen et al. 
2000); (Mullooly, Bridges et al. 2007); (MMWR,2010). The efficacy of vaccination in 
preventing influenza in the elderly appears to be lower compared with younger adults 
(Osterholm, Kelley et al. 2012; Beyer, McElhaney et al. 2013). One potential explanation 
for the absolute decrease in vaccine efficacy compared with younger adults may be a less 
robust immune response after influenza vaccination (Goodwin, Viboud et al. 2006;
Sasaki, Sullivan et al. 2011).
Therefore, novel approaches are sought to improve the immunogenicity of influenza 
vaccines in the elderly population. One way to increase immunogenicity of influenza 
vaccines is through the use of adjuvants, such as the squalene and water emulsion, MF59. 
FLUAD®, Seqirus’ trivalent influenza vaccine combined with MF59, has been licensed 
for use in Europe since 1997. The administration of FLUAD® to elderly patients results in 
significantly higher geometric mean Haemagglutination Inhibition (HI) titers and rates of 
seroconversion in comparison to non-adjuvanted trivalent influenza vaccine (TIV) (Frey 
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Name of Sponsor:
Seqirus UK Ltd.
Protocol 
number: 
V118_18
Generic name of study vaccine(s):
MF59-adjuvanted Quadrivalent Subunit 
Inactivated Egg-derived Influenza Vaccine
Tetanus Toxoid, Reduced Diphtheria 
Toxoid and Acellular Pertussis Vaccine, 
Adsorbed
et al. 2014).
Most licensed influenza vaccines contain antigens derived from three strains of virus, 
A/H1N1, A/H3N2 and B. The B strains of virus are genetically classified into two main 
lineages, B/Yamagata and B/Victoria. During a typical influenza season, a single A/H1N1 
and A/H3N2 will predominate. The epidemiology of disease caused by B strains is 
different and during the past decade it is common for both strains to circulate 
simultaneously (Ambrose and Levin et al. 2012). This can result in a clinically significant 
mismatch between the vaccine composition and circulating strains (Lo, Chuang et al. 
2013). Quadrivalent vaccines contain HA and NA antigens from both B strains of 
influenza which may provide additional clinical benefit during seasons where a mismatch 
occurs.
Seqirus has recently begun the clinical study of aQIV in children, manufactured using a 
similar process to that of FLUAD®. The goal of this current randomized, observer-blind, 
controlled study is to demonstrate that aQIV prevents influenza in elderly adults. Direct 
comparison with a non-influenza comparator vaccine, Boostrix®, a tetanus toxoid, 
reduced diphtheria toxoid and acellular pertussis (TdaP) vaccine, licensed for use in 
elderly adults, will enable an estimation of the absolute efficacy of aQIV in preventing 
influenza in elderly adults while simultaneously providing benefit to subjects randomized 
to not receive influenza vaccine. Placebo or non-influenza vaccine comparators have been 
used to show influenza vaccine efficacy in elderly subjects (DeVilliers et al. 2009). This 
approach is consistent with CBER Guidance for the licensure of seasonal influenza 
vaccines and was recently used to demonstrate the benefit of an inactivated non-
adjuvanted quadrivalent vaccine in children (Jain et al. 2013). The data from this study 
will be used to support the licensure of FLUAD® and aQIV for the prevention of seasonal 
influenza in adults ≥ 65 years of age.
Study Objectives:
The primary and secondary efficacy objectives will be measured in all subjects in relation 
to cases of influenza occurring from 21 through 180 days after vaccination or through the 
end of influenza season, whichever is longer. In all cases, efficacy will be determined 
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Name of Sponsor:
Seqirus UK Ltd.
Protocol 
number: 
V118_18
Generic name of study vaccine(s):
MF59-adjuvanted Quadrivalent Subunit 
Inactivated Egg-derived Influenza Vaccine
Tetanus Toxoid, Reduced Diphtheria 
Toxoid and Acellular Pertussis Vaccine, 
Adsorbed
based on influenza cases caused by A (H1N1 and H3N2) and either B lineage.
Primary Efficacy Objective:
1.
To demonstrate absolute vaccine efficacy of aQIV versus non-influenza comparator 
(Boostrix®) when administered as a single dose to prevent first occurrence RT-PCR-
confirmed influenza, due to any strain of influenza regardless of antigenic match to 
the strains selected for the seasonal vaccine, in subjects ≥ 65 years of age.
Primary Safety Objectives:
2.
To evaluate the safety of aQIV through assessment for local and systemic solicited 
adverse events through Day 7 in a subset of subjects.
3.
To evaluate the rates in each vaccine group of medically-attended adverse events 
within 30 days after the first occurrence RT-PCR confirmed ILI.
4.
To evaluate the rates in each vaccine group of unsolicited adverse events for 21 days 
after vaccination and adverse events leading to withdrawal, serious adverse events
(SAEs), adverse events of special interest (AESI), and new onset of chronic diseases 
(NOCD) for 365 days after vaccination.
Key Secondary Efficacy Objective:
1.
To demonstrate absolute vaccine efficacy of aQIV versus non-influenza comparator 
when administered as a single dose to prevent first occurrence culture-confirmed 
influenza, due to strains antigenically matched to the strains selected for the seasonal 
vaccine.
Secondary Efficacy Objectives:
2.
To evaluate absolute vaccine efficacy of aQIV versus non-influenza comparator 
when administered as a single dose to prevent first occurrence culture-confirmed 
influenza, due to any strain of influenza regardless of antigenic match to the strains 
selected for the seasonal vaccine.
3.
To evaluate absolute vaccine efficacy of aQIV versus non-influenza comparator 
when administered as a single dose to prevent first occurrence culture-confirmed 
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Name of Sponsor:
Seqirus UK Ltd.
Protocol 
number: 
V118_18
Generic name of study vaccine(s):
MF59-adjuvanted Quadrivalent Subunit 
Inactivated Egg-derived Influenza Vaccine
Tetanus Toxoid, Reduced Diphtheria 
Toxoid and Acellular Pertussis Vaccine, 
Adsorbed
influenza, due to strains antigenically unmatched to the strains selected for the 
seasonal influenza vaccine.
4.
To evaluate the absolute efficacy of aQIV versus non-influenza comparator when 
administered as a single dose to prevent first occurrence RT-PCR-confirmed 
influenza due to any strain of influenza regardless of antigenic match from 7 days to 
180 days after vaccination or at the end of influenza season, whichever is longer 
(early efficacy).
Secondary Immunogenicity Objectives:
5. To evaluate the immunogenicity of aQIV measured by HI titer 21 days after 
vaccination, against influenza strains homologous to the seasonal vaccine.
Exploratory Immunogenicity Objective:
6. To characterize the immunogenicity of aQIV using other immunological assays (such 
as microneutralization assay).
7. To explore potential immune correlates of protection based on HI and/or other 
immunological assays (such as microneutralization assay).
The results of this exploratory analysis may be presented in an addendum to the 
Clinical Study Report (CSR).
Study Design:
The study is a phase III, stratified, randomized, observer-blind, non-influenza 
comparator-controlled, multicenter study to evaluate the efficacy, safety and 
immunogenicity of an MF59-adjuvanted quadrivalent subunit influenza vaccine 
compared with a non-influenza comparator vaccine in subjects ≥ 65 years of age. 
The study vaccine, aQIV, contains 15 µg of each of the four seasonal influenza strains 
(A/H1N1, A/H3N2, B [Yamagata and Victoria lineage]) and MF59 adjuvant. The non-
influenza comparator (Boostrix®) vaccine will be used to provide a comparative 
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Name of Sponsor:
Seqirus UK Ltd.
Protocol 
number: 
V118_18
Generic name of study vaccine(s):
MF59-adjuvanted Quadrivalent Subunit 
Inactivated Egg-derived Influenza Vaccine
Tetanus Toxoid, Reduced Diphtheria 
Toxoid and Acellular Pertussis Vaccine, 
Adsorbed
assessment for efficacy, immunogenicity and safety.
Stratification according to age (≥ 65 to 74 and ≥ 75), study site and comorbidity status (at 
risk/ not at risk) will be performed (see Section 5.1.4, Randomization and Section 5.1.2, 
Screening). Sample size, among other factors, depends mainly on the number of RT-PCR 
confirmed influenza cases observed during the influenza seasons, so the overall number 
of subjects to be recruited provided here may change and enrolment over multiple seasons
may be required to ensure 238 PCR-confirmed influenza cases have occurred and/or
based on the results of the interim analysis for efficacy and futility. Nasopharyngeal swab 
samples will be analyzed in batches and the number of RT-PCR confirmed influenza
cases will be reviewed on a regular basis. Once the number of RT-PCR confirmed 
influenza cases exceeds 119, an interim analysis for efficacy and futility with an 
appropriate adjustment of the type I error will be performed by an independent Data 
Monitoring Committee (DMC). Another interim analysis might be recommended before 
target 238 RT-PCR confirmed influenza cases are observed. Once the number of RT-PCR 
confirmed influenza cases is ≥ 238 the Sponsor will stop and unblind the trial and 
perform the final analysis. Stopping rules for futility and efficacy and any additional 
details regarding the DMC can be found in the DMC Charter.
Two definitions of ILI will be used. Primary protocol-defined ILI will be used to trigger 
nasopharyngeal swab retrieval and completion of the ILI booklet. The respiratory 
symptoms in both definitions are considered a new onset or exacerbation of a pre-existing 
condition.

Primary protocol-defined ILI: At least one of the following respiratory symptoms: 
sore throat, cough, sputum production, wheezing, or difficulty breathing; concurrently 
with at least one of the following systemic symptoms: temperature of > 37.2°C/ 99°F, 
chills, tiredness, headache, or myalgia. 

Modified Centers for Disease Control and Prevention (CDC) ILI definition: Fever 
(temperature of > 37.2° C/99°F) with cough or sore throat.
The ILI onset day is defined as the first day that the subject meets the primary protocol-
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Name of Sponsor:
Seqirus UK Ltd.
Protocol 
number: 
V118_18
Generic name of study vaccine(s):
MF59-adjuvanted Quadrivalent Subunit 
Inactivated Egg-derived Influenza Vaccine
Tetanus Toxoid, Reduced Diphtheria 
Toxoid and Acellular Pertussis Vaccine, 
Adsorbed
defined ILI.
Each subject will have two stages of study participation: Treatment Period (Day 1 to Day 
22) and Follow-up Period (Day 23 to Day 366). A subset of subjects will be selected to 
participate in an assessment of immunogenicity and solicited adverse events.
The study procedures consist of four (4) clinic visits, and three (3) safety phone calls. 
After enrolment and vaccination on Day 1, all subjects will then return to the clinic for 
three (3) additional clinic visits, on Days 22, 181 and 366. During the study there will 
also be three (3) safety phone calls on Days 15, 91, and 271. Subjects participating in the 
solicited safety subset will receive an additional call on day 3 reminding them to complete 
their diary card. 
Additionally, all subjects will receive weekly phone calls or messages to assess for 
primary protocol-defined ILI symptoms during the active ILI surveillance period, defined 
as from Day 1 through Day 181 or until the end of the influenza season, whichever is 
longer. The purpose of the ILI surveillance phone calls/message is to trigger a clinic or 
home visit to collect a nasopharyngeal swab. Subjects will also be asked for the duration 
of the trial (through day 366) to contact the site at the onset of ILI symptoms to schedule 
a clinic visit for NP swab collection.
After an initial screening, subjects will be vaccinated with a single dose of aQIV or non-
influenza comparator on Day 1. Subjects will be observed for at least 30 minutes post-
vaccination on Day 1 for any immediate reactions. Subjects participating in the solicited
safety subset will receive a Subject Diary along with instructions to ensure proper 
completion and assessment on reactogenicity. These subjects will be instructed to 
complete a Subject Diary to describe solicited local and systemic adverse events that may 
occur post-vaccination from Day 1 through Day 7. For all subjects any adverse event and 
concomitant medication use, after vaccination from Day 1 to Day 22 will be collected at 
the Day 15 safety phone call and during the Day 22 clinic visit. Information collected at 
these visits will be documented in the subject’s source records and captured in the 
Electronic Case Report Form (eCRF). All subjects will also receive an ILI booklet on 
Day 1, and will be instructed to measure their body temperature using the thermometer 
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Name of Sponsor:
Seqirus UK Ltd.
Protocol 
number: 
V118_18
Generic name of study vaccine(s):
MF59-adjuvanted Quadrivalent Subunit 
Inactivated Egg-derived Influenza Vaccine
Tetanus Toxoid, Reduced Diphtheria 
Toxoid and Acellular Pertussis Vaccine, 
Adsorbed
provided starting from onset day of primary protocol defined ILI to the day they come in
to the clinic for the NP swab collection. Subjects will be asked to return the ILI booklet at 
the time of their NP clinic visit. 
During the remaining follow-up phase of the study (up to Day 366), safety data including 
adverse events leading to withdrawal, AESI, NOCD, SAE and concomitant medication 
use related to these events will be captured via safety phone calls or clinic visits.
Subjects experiencing an ILI will have one (1) additional clinic visits and one (1) safety
call: (1) a clinic or home visit to collect a nasopharyngeal (NP) swab as soon as possible
preferably within 3, but up to 6, days after the first day of onset of primary protocol-
defined ILI symptoms, and (2) a safety follow-up call 30 days after ILI onset to determine 
if subsequent medically-attended adverse events occurred and concomitant medication
associated with these events were used. The use of anti-viral medications will be 
permitted after a NP swab has been obtained and will be documented as concomitant 
medications. Nasopharyngeal swabs will be processed for viral culture and RT-PCR 
confirmation. Culture positive samples will undergo antigenic characterization.
One season in which at least 2800 subjects are anticipated to be enrolled will be selected 
for the collection of immunogenicity samples. Samples from approximately 2800 subjects 
participating in the selected season will be collected at Day 1 (baseline) and Day 22 (visit 
3). In order to maintain the study blind equal numbers of subjects from both treatment 
groups will be asked to provide blood specimens (see Section 3.5, Collection of Clinical 
Specimens). After all of the specimens have been obtained a subset of samples from those 
collected will be randomly selected on a 4:1 ratio (1,362 aQIV; 340 Boostrix) for the 
purpose of completing the analysis of the immunogenicity objectives. Anti-HA antibody 
will be measured using a validated haemagglutination inhibition (HI) assay with egg-
derived HA antigens from homologous strains of the virus. Serum samples from subjects 
with RT-PCR confirmed influenza, along with a subset of subjects who did not have RT-
PCR confirmed influenza, may be tested to estimate the correlate of protection. The 
serologic component of the correlate of protection will be measured using either a 
validated haemagglutination inhibition (HI) and/or other immunological assays (such as 
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Name of Sponsor:
Seqirus UK Ltd.
Protocol 
number: 
V118_18
Generic name of study vaccine(s):
MF59-adjuvanted Quadrivalent Subunit 
Inactivated Egg-derived Influenza Vaccine
Tetanus Toxoid, Reduced Diphtheria 
Toxoid and Acellular Pertussis Vaccine, 
Adsorbed
microneutralization).
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Version No. 4 / Version Date: January 29, 2015
Name of Sponsor:
Seqirus UK Ltd.
Protocol 
number: 
V118_18
Generic name of study vaccine(s):
MF59-adjuvanted Quadrivalent Subunit 
Inactivated Egg-derived Influenza Vaccine
Tetanus Toxoid, Reduced Diphtheria 
Toxoid and Acellular Pertussis Vaccine, 
Adsorbed
Number of Subjects Planned:
As described in the study design section this study will employ group sequential design 
and therefore the total study size (and study duration) will depend on the number of RT-
PCR confirmed influenza cases observed during the influenza seasons (see Section 3.7, 
DMC and Section 8.6, Interim Analysis).
The sample size, among other factors, depends mainly on the number of PCR-confirmed 
influenza cases observed during the influenza seasons so the overall number of subjects to 
be recruited may change and enrolment over multiple seasons may be required to ensure 
238 PCR-confirmed influenza cases have occurred and/or based on the results of the 
interim analysis for efficacy and futility. It is anticipated that in order to obtain 238 cases, 
including a drop-out rate of 10%, approximately 10,692 subjects ≥ 65 years, will need to 
be enrolled into the trial. Approximately 5,346 subjects will be enrolled per vaccine group
will be randomized to receive either aQIV or non-influenza comparator (Boostrix®) in a 
1:1 allocation ratio, stratifying by age (≥65 to 74 and ≥ 75) and by comorbidity status (at 
risk/not at risk, see Section 5.1.2, Screening).
Specimens from those collected during the immunogenicity season will be randomly 
selected in a 4:1 ratio for analysis. In total approximately 1,702 of the up to 2800 samples
collected are planned to be included the analysis (1,362 aQIV; 340 Boostrix). The serum 
samples may also be analyzed to facilitate the estimation of immune correlate of 
protection.
With 4,860 evaluable subjects in each treatment group, the probability of detecting a rare 
safety event which occurs at 0.001 (1/1000) rate will be 99%. Approximately 2,100
subjects are planned to be enrolled in the Solicited Safety Subset. With 1,053 subjects in 
each treatment group, the probability of detecting a rare safety event which occurs at 
0.002 (1/500) rate will be ≥86%, assuming a drop-out/missing data rate of up to 5%. The 
number of enrolled subjects should be sufficient to capture such adverse events.
More details on sample size calculation can be found in the respective section on sample 
size and power considerations of this synopsis.
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Name of Sponsor:
Seqirus UK Ltd.
Protocol 
number: 
V118_18
Generic name of study vaccine(s):
MF59-adjuvanted Quadrivalent Subunit 
Inactivated Egg-derived Influenza Vaccine
Tetanus Toxoid, Reduced Diphtheria 
Toxoid and Acellular Pertussis Vaccine, 
Adsorbed
Study Population and Subject Characteristics:
This study will enroll males and females ≥ 65 years old who are healthy or are at risk of 
complications from influenza infection.
The list of inclusion and exclusion criteria is included in protocol Section 4, Selection of 
Study Population.
Study Procedures:
All subjects enroled in this study will receive a single vaccination with either aQIV or 
non-influenza comparator (Boostrix®). For the full course of the trial (Day 1-366)
subjects will be asked to notify study personnel at the onset of ILI symptoms, (preferably 
within 3, but up to 6, days), so that either unscheduled clinic evaluation or home visit to 
retrieve nasopharyngeal (NP) swab samples, can be occur. All subjects will also receive 
an ILI booklet on Day 1, and will be instructed to measure their body temperature using 
the thermometer provided starting from onset day of primary protocol defined ILI to the 
day they come in to the clinic for their NP swab collection. Subjects will be asked to 
return the ILI booklet at the time of their NP clinic visit. 
During the Treatment Period on Day 15, for all subjects a safety phone call will be 
performed to collect information regarding unsolicited adverse events and concomitant 
medication. On Day 22 a symptom directed physical examination will be performed by a 
qualified health care practitioner in addition to evaluating safety data on all subjects.
During the Follow-up Period subjects will be asked to return to the clinic for two (2) 
additional scheduled visits for a symptom directed physical examination and to evaluate 
safety on Day 181 and Day 366. Additionally, all subjects will participate in two (2) 
safety phone calls on Days 91, and 271. Subjects will also receive weekly phone calls or 
messages to assess for ILI symptoms during the active ILI surveillance period, defined as 
Day 1 through Day 181 or until the end of the influenza season whichever is longer. 
Subjects experiencing a primary protocol-defined ILI will have one (1) additional clinic 
visit and one (1) additional safety call which will be scheduled relative to the timing of 
the ILI: (1) a clinic or home visit to collect a nasopharyngeal swab as soon as possible 
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Name of Sponsor:
Seqirus UK Ltd.
Protocol 
number: 
V118_18
Generic name of study vaccine(s):
MF59-adjuvanted Quadrivalent Subunit 
Inactivated Egg-derived Influenza Vaccine
Tetanus Toxoid, Reduced Diphtheria 
Toxoid and Acellular Pertussis Vaccine, 
Adsorbed
following the onset of symptoms (preferably within 3, but up to 6, days after the first day 
of ILI symptoms). Subjects with a NP swab taken for an ILI will be contacted by phone 
for a safety follow-up call 30 days after ILI onset to capture all medically-attended 
adverse events, and concomitant medication use. 
Subjects participating in the immunogenicity subset will have blood samples collected at 
their clinic visits 1 and 3 (Days 1 and 22). Subjects participating in the solicited safety 
subset will be asked to return their completed Subject Diary at their Day 22 clinic visit. 
If a subject withdraws from the study, they will be asked to undergo a final assessment 
for safety.
Study Vaccines:
The study vaccine is an egg-derived quadrivalent inactivated subunit influenza vaccine 
which includes MF59 adjuvant. Haemagglutinin and neuraminidase antigens are derived 
from the four influenza virus strains (A/H1N1, A/H3N2, B/Yamagata and Victoria 
lineage) recommended by the US CDC and WHO (World Health Organization) for 
inclusion in the seasonal vaccine. Fifteen (15) µg of each HA antigen is present in 0.5 ml 
of the vaccine which is formulated in a pre-filled syringe (PFS).
The non-influenza comparator, TdaP, is a non-infectious, sterile, vaccine indicated for 
active booster vaccination against tetanus, diphtheria and acellular pertussis. It contains 
tetanus toxoid, reduced diphtheria toxoid, and pertussis antigens (inactivated pertussis 
toxin [PT] and formaldehyde-treated filamentous haemagglutinin [FHA] and pertactin). 
Efficacy Endpoints: 
The primary efficacy endpoint is the time of first-occurrence of RT-PCR-confirmed 
influenza due to A (H1N1 and H3N2) or either B lineage due to any strain of influenza 
regardless of antigenic match to the strains selected for the seasonal vaccine from 21 
through 180 days after vaccination or end of the influenza season, whichever is longer.
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Name of Sponsor:
Seqirus UK Ltd.
Protocol 
number: 
V118_18
Generic name of study vaccine(s):
MF59-adjuvanted Quadrivalent Subunit 
Inactivated Egg-derived Influenza Vaccine
Tetanus Toxoid, Reduced Diphtheria 
Toxoid and Acellular Pertussis Vaccine, 
Adsorbed
The end of the influenza season will be defined as the end of June for Northern 
Hemisphere (NH) influenza season and end of December for Southern Hemisphere (SH) 
influenza season. For tropical countries, with no typical NH or SH influenza season, the 
season is defined by the use of the strains in the vaccine formulation (i.e. strains as 
recommended for the NH or the SH influenza season) and the timing of vaccination. The 
investigators will be advised of the date enrollment will be closed in their country or 
hemisphere. The actual date selected for the end of each season in each hemisphere will 
be documented in the SAP.
In addition to the primary efficacy endpoint, additional endpoints for the secondary 
efficacy objectives are sought, based on antigenic match of culture isolated influenza to 
the strains of virus contained in the seasonal vaccine.
Vaccine efficacy will be determined based on either:

Antigenically matched strains of influenza virus (Secondary Efficacy Objective 1)

Influenza strains regardless of antigenic match (Secondary Efficacy Objectives 2
and 4)

Antigenically unmatched strains of influenza virus (Secondary Efficacy Objective 3)
An influenza event is defined as RT-PCR or culture-confirmed influenza infection in the 
setting of an influenza-like illness (ILI). Two definitions of ILI will be used in this study. 
Primary protocol-defined ILI requires at least one of the following respiratory symptoms: 
sore throat, cough, sputum production, wheezing, or difficulty breathing; concurrently 
with at least one of the following systemic symptoms: temperature of > 37.2°C/ 99°F, 
chills, tiredness, headache, or myalgia and is based on that used to demonstrate the 
efficacy of Fluzone High Dose (DiazGranados, 2014). The second (modified CDC) 
definition will be fever (temperature of > 37.2°C/ 99°F) with cough or sore throat. The 
respiratory symptoms in both definitions are considered a new onset or exacerbation of a 
pre-existing condition. The primary and key secondary efficacy endpoints will be 
assessed using the primary protocol-defined ILI definition to determine success in the 
study. Primary and secondary efficacy objectives 1-4 will also be analyzed using both 
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Name of Sponsor:
Seqirus UK Ltd.
Protocol 
number: 
V118_18
Generic name of study vaccine(s):
MF59-adjuvanted Quadrivalent Subunit 
Inactivated Egg-derived Influenza Vaccine
Tetanus Toxoid, Reduced Diphtheria 
Toxoid and Acellular Pertussis Vaccine, 
Adsorbed
definitions of the first occurrence of ILI.
Subgroup analyses based on age-related cohorts (≥65-74, ≥75-84, and ≥85 years), 
baseline risk of complications from ILI and other demographic factors including baseline
medical comorbidity and current smoking status will be performed for primary and all 
secondary endpoints.
Safety Endpoint(s):

Safety objective 2 will be assessed by calculating the percentage of subjects in the 
solicited safety subset with solicited local and systemic adverse events from Day 1 
through Day 7. Solicited local and systemic adverse event data from Day1-7 will be 
obtained from data collected on the subject diaries. Only subjects randomly selected 
for participation in the solicited safety subset will be asked to fill out a Subject Diary 
from Day 1-7.
Safety objectives will be assessed by comparing the following between cohorts that 
received aQIV or non-influenza comparator:

Percentage of subjects with medically-attended adverse events within 30 days after 
the first occurrence ILI.

Percentage of subjects with any unsolicited AEs and concomitant medications 
reported from Day 1 through Day 22.

Percentage of subjects reporting SAEs, AEs leading to withdrawal from the study, 
NOCD, AESI and all concomitant medications associated with these events from 
Day 1 to Day 366.
Immunogenicity Endpoint(s):
The measures of immunogenicity used for Objective 5 as determined by the HI assay 
against homologous strains at Days 1 and 22, include the following:

Geometric mean HI titer (GMT).
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Name of Sponsor:
Seqirus UK Ltd.
Protocol 
number: 
V118_18
Generic name of study vaccine(s):
MF59-adjuvanted Quadrivalent Subunit 
Inactivated Egg-derived Influenza Vaccine
Tetanus Toxoid, Reduced Diphtheria 
Toxoid and Acellular Pertussis Vaccine, 
Adsorbed

Geometric mean ratio calculated at Day 22/Day 1.

Percentage of subjects with an HI titer ≥1:40.1

Percentage of subjects achieving seroconversion (defined as: HI titer ≥1:40 for 
subjects sero-negative at baseline [HI titer <1:10]; or a minimum 4-fold increase in HI 
titer for subjects sero-positive at baseline [HI titer ≥1:10]) on Day 22.1

Reverse cumulative distributions of HI titers at Day 22.
Exploratory Endpoint(s):
The exploratory endpoints determined by the microneutralization (MN) assay against 
homologous strains at Days 1 and 22, include the following:

Geometric mean titer (GMT).

Geometric mean ratio calculated at Day 22/Day 1.

Percentage of subjects with a four-fold rise in MN antibody titer at Day 22

Reverse cumulative distributions of MN titers at Day 22.
Additionally, an estimate of the serologic correlate of protection on the basis of HI or 
other immunological responses including MN, measured three weeks after vaccination 
against the respective strain
                                               
1 The endpoints based on percent of subjects achieving seroconversion and HI titer ≥ 1:40 at Day 22 will be 
assessed against the criteria described in CBER Guidance Clinical Data Needed to Support the Licensure of 
Seasonal Inactivated Influenza Vaccines (2007). Specifically, this will be that:

The lower bound of the two-sided 95% CI for the percent of subjects achieving seroconversion for 
HI antibody should meet or exceed 30%

The lower bound of the two-sided 95% CI for the percent of subjects achieving an HI antibody 
titer ≥ 1:40 should meet or exceed 60%
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Name of Sponsor:
Seqirus UK Ltd.
Protocol 
number: 
V118_18
Generic name of study vaccine(s):
MF59-adjuvanted Quadrivalent Subunit 
Inactivated Egg-derived Influenza Vaccine
Tetanus Toxoid, Reduced Diphtheria 
Toxoid and Acellular Pertussis Vaccine, 
Adsorbed
Statistical Analyses:
Criteria for Assessing Primary Efficacy Objective:
Primary Efficacy Objective:
The primary measure of absolute efficacy will be tested in elderly subjects ≥ 65 years of 
age according to the following null (H0) and alternative (H1) hypotheses:
H0: 1- HR = VE ≤ 0.4
versus
H1: VE > 0.4
where HR is defined as hazard ratio of the incidence of protocol defined ILI in aQIV 
versus a non-influenza comparator that will be estimated by the proportional hazards 
model. More details on the analysis methods will be described in the Statistical Analysis 
Plan (SAP).
The study is successful if the lower-limit (LL) of the two-sided 95% confidence interval 
(CI) (to be adjusted for one interim analysis) of absolute vaccine efficacy endpoint > 0.4. 
In case another interim analysis is necessary the type 1 error alpha and hence the CI will 
be adjusted.
Overall Study Success Criteria:
The study is successful if the primary efficacy objective is achieved. 
Sample Size and Power Calculation for Primary Objective:
Sample size and power consideration for the aQIV efficacy objective is based on criteria 
for demonstrating efficacy in placebo controlled studies provided in CBER guidance, 
specifically that the study should be powered to assess the lower bound of the two-sided 
95% CI of vaccine effectiveness, anticipated to be substantially above zero.
This study is planned using a group sequential design. The power of Cox Regression 
which is planned to be used for analysis is dependent on the overall number of RT-PCR 
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Name of Sponsor:
Seqirus UK Ltd.
Protocol 
number: 
V118_18
Generic name of study vaccine(s):
MF59-adjuvanted Quadrivalent Subunit 
Inactivated Egg-derived Influenza Vaccine
Tetanus Toxoid, Reduced Diphtheria 
Toxoid and Acellular Pertussis Vaccine, 
Adsorbed
confirmed influenza cases, so the sample sizes on number of subjects described in the 
sections above is provided more for operational reasons. Additional information is 
described in Section 8.6, Interim Analysis.
For the primary efficacy objective: with 1-sided alpha of 2.5% (adjusted for possible 
interim analysis) and assuming an attack rate of influenza of 3.5% among subjects 
enroled in the non-influenza comparator group and 1.4% among the aQIV group, i.e. 60% 
assumed vaccine efficacy for aQIV, 238 events (i.e. 5,346 subjects per group under the 
assumed event rates (ER)) are needed with 86.5% power to show the absolute efficacy of
aQIV versus non-influenza comparator, in preventing first occurrence RT-PCR confirmed 
influenza A and/or B, due to any strain of influenza regardless of antigenic match to the 
strains in aQIV, in subjects ≥ 65 years of age, using a margin of 40% for lower bound of 
the CI for absolute vaccine efficacy2.
For the first secondary efficacy objective: With group vaccine efficacy of 65% but 
expecting conservatively reduced ERs of RT-PCR confirmed influenza cases due to 
matched strains of 2.5% among subjects in the non-influenza comparator group and 0.9%
among the aQIV group then 144 events are estimated with power approximately 88.5% to 
show the absolute efficacy of aQIV versus non-influenza comparator, using a margin of 
40% for lower bound of the 95% CI. 
Assuming a drop-out rate of 10%, approximately 10,692 subjects ≥ 65 years, 5,346 per 
vaccine group will be randomized to receive either aQIV or non-influenza comparator 
(Boostrix®) in a 1:1 allocation ratio, stratifying by age groups: 
≥ 65 to 74 and ≥ 75 years of age and by the presence or absence of medical co- morbidity
(see Section 5.1.2, Screening for assessment of comorbidity and risk of complications 
                                               
2 The attack rate of 3.5% is estimated based on the attack rate published in placebo controlled studies 
(DeVilliers, 2009; Treanor, 2011; Frey, 2009)
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Name of Sponsor:
Seqirus UK Ltd.
Protocol 
number: 
V118_18
Generic name of study vaccine(s):
MF59-adjuvanted Quadrivalent Subunit 
Inactivated Egg-derived Influenza Vaccine
Tetanus Toxoid, Reduced Diphtheria 
Toxoid and Acellular Pertussis Vaccine, 
Adsorbed
from influenza).
Sample Size for Secondary Immunogenicity Objective (Immunogenicity Subset):
The immunogenicity objective is considered as secondary and so no alpha adjustment for 
multiplicity will be done for the analysis therefore a significance level of 5% (2-sided) or 
2.5% (1-sided) was used for sample size calculation.
Using the following assumptions from the V70_27 study in elderly adult subjects: 
specifically after aTIV vaccination, seroconversion rates, H1N1: 77%, H3N2: 74% and B: 
47%, and percentages of subjects with a HI titer ≥ 40, H1N1: 91%, H3N2: 99%, B: 64%
(Table 1).
With samples analyzed from 1,362 subjects (1,226 evaluable subjects assuming a rate of 
10% for missing data) in the aQIV group there will be at least 80% power to evaluate 
CBER criteria with all four strains contained in aQIV.
Table 1:
CBER criteria for subjects ≥ 65 years of age
Strain
πi
(proportion in 
aQIV, based on 
data of V70_27)
π0
(CBER 
threshold)
Sample size for 
aQIV 
Marginal Power
Proportion of subjects with Seroconversion
H1N1
77%
30%
1226 
99%
H3N2
74%
30%
1226 
99%
B strains
47%
30%
1226
99%
Proportion of subjects with HI titer ≥40
H1N1
91%
60%
1226 
99%
H3N2
99%
60%
1226 
99%
B strains
64%
60%
1226 
82% 
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Name of Sponsor:
Seqirus UK Ltd.
Protocol 
number: 
V118_18
Generic name of study vaccine(s):
MF59-adjuvanted Quadrivalent Subunit 
Inactivated Egg-derived Influenza Vaccine
Tetanus Toxoid, Reduced Diphtheria 
Toxoid and Acellular Pertussis Vaccine, 
Adsorbed
Sample Size for Safety:
With 4,860 evaluable subjects in each treatment group, the probability of detecting a rare 
safety event which occurs at 0.001 (1/1000) rate will be 99%. With 1,053 subject selected 
for Solicited Safety Subset, assuming up to 5% dropout/missing data rate; there will at 
least 1000 evaluable subjects for analysis of solicited adverse events. With 1000
evaluable subjects in each treatment group, the probability of detecting a safety event 
which occurs at a rate of 0.002 will be 86%.
Interim Analysis:
Unblinded interim analyses for efficacy and futility will be performed by an independent 
DMC if the number of RT-PCR confirmed influenza cases observed ranges between 119
and 238. After formally requesting unblinding, the DMC will be provided with the 
unblinded data generated by an unblinded statistician to enable unblinded analysis of the 
interim dataset during a closed session. Another interim analysis might be recommended 
before target 238 cases are observed.
Further details regarding the interim analysis are given in Section 8.6, Interim Analysis. 
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Name of Sponsor:
Seqirus UK Ltd.
Protocol 
number: 
V118_18
Generic name of study vaccine(s):
MF59-adjuvanted Quadrivalent Subunit 
Inactivated Egg-derived Influenza Vaccine
Tetanus Toxoid, Reduced Diphtheria 
Toxoid and Acellular Pertussis Vaccine, 
Adsorbed
Data Monitoring Committee:
An independent DMC will be used for this study. The main purpose of the DMC will be 
to ensure the safety of subjects and scientific integrity of the study on an ongoing basis 
during the trial. The DMC will review blinded, and if requested, semi- or fully -unblinded 
safety and efficacy data during the study. The DMC will perform the interim analysis for 
futility and efficacy and make a recommendation about continuing or stopping the trial. 
Unblinded data will be reviewed in closed sessions of the DMC, without participation of 
the Sponsor. All descriptions of these closed sessions will be unavailable to the Sponsor 
until study unblinding has occurred.
After reviewing safety and efficacy data, the DMC will recommend that enrolment be 
continued, halted temporarily (pending additional information from the Sponsor or 
modification to the study design) or halted permanently as specified in the Charter. 
Stopping rules for futility and efficacy and any additional details regarding the DMC can 
be found in the DMC Charter and in Section 3.7, Data Monitoring Committee of the 
protocol.
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LIST OF ABBREVIATIONS 
ACIP
Advisory Committee on Immunization Practices
AE
Adverse Event
AESI
Adverse Events of Special Interest
BLA
Biologics Licensure Application
B&SR
Biostatistics and Statistical Reporting
BMI
Body Mass Index
CBER
Center for Biologics Evaluation and Research
CDC
Centers for Disease Control and Prevention
CHMP
Committee for Medicinal Products for Human Use
CI
Confidence Interval
CRF
Case Report Form
CRO
Contract Research Organization
CSR
Clinical Study Report 
DCF
Data Clarification Form
DMC
Data Monitoring Committee
EC
Ethics Committee
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EMA
European Medicines Agency
ER
Event Rate
FAS
Full Analysis Set
FDA
United States Food and Drug Administration
GCP
Good Clinical Practices
GMC
Geometric Mean Concentration
GMR
Geometric Mean Ratio
GMT
Geometric Mean Titer
HA
Haemagglutinin
HI
Haemagglutination Inhibition
HIPAA
Health Insurance Portability and Accountability Act 
HIV
Human Immunodeficiency Virus
IB
Investigator’s Brochure
ID
Identification
ICF
Informed Consent Form
ICH
International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use
ILI
Influenza-Like Illness
IM
Intramuscular
IRB
Institutional Review Board
IRT
Interactive Response Technology
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MedDRA
Medical Dictionary for Regulatory Activities
MN
Microneutralization
NA
Neuraminidase
NOCD
New Onset of Chronic Disease
NP
Nasopharyngeal
NH
Northern Hemisphere
PCR
Polymerase Chain Reaction
PFS
Pre-filled Syringes
PP
Per Protocol
PPS
Per Protocol Set
PRO
Patient Reported Outcome
PV
Pharmacovigilance
PT
Pertussis Toxin
aQIV
Adjuvanted Quadrivalent Influenza Vaccine
QIV
Quadrivalent Influenza Vaccine
RT-PCR
Reverse Transcription Polymerase Chain Reaction
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SC 
Seroconversion
SDA
Source Data Agreement
SOC
System Organ Class
SOP
Standard Operating Procedure
TdaP
Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular 
Pertussis
TIV
Trivalent Influenza Vaccine
TNF
Tumor Necrosis Factor
VSAE
Vaccine Serious Adverse Events
WHO
World Health Organization
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DEFINITIONS
Culture confirmed matched strains are defined by as those with a < 8 fold difference in 
titer as compared to the vaccine strain.
Culture confirmed unmatched strains are defined as those with a ≥ 8 fold difference in 
titer as compared to the vaccine strain.
End of influenza season: The end of the influenza season will be defined as the end of 
June for Northern Hemisphere (NH) influenza season and end of December for Southern 
Hemisphere (SH) influenza season. For tropical countries, with no typical NH or SH 
influenza season, the season is defined by the use of the strains in the vaccine formulation 
(i.e. strains as recommended for the NH or the SH influenza season) and the timing of 
vaccination.
Influenza case: An ILI associated with RT-PCR or culture confirmed influenza.
ILI onset: The first day on which a subject fulfils the criteria for protocol-defined ILI.
Medically-attended Adverse Event3: Defined as symptoms or illnesses requiring 
hospitalization, or emergency room visit, or visit to/by a health care provider.
Modified CDC Influenza-like illness (ILI)4: Fever (temperature of > 37.2°C/ 99°F) with 
cough or sore throat.
Protocol-defined ILI: At least one of the following respiratory symptoms: sore throat, 
cough, sputum production, wheezing, or difficulty breathing; concurrently with at least 
one of the following systemic symptoms: temperature of > 37.2°C/ 99°F, chills, tiredness, 
headache, or myalgia.
Qualified healthcare professional: Any licensed health care professional who is 
permitted by institutional policy to perform clinical interventions and assessments such as 
physical examinations and who is identified within the Study Staff Signature Log.
Trained healthcare professional: Any health care professional who is permitted by 
institutional policy and trained to perform delegated tasks and who is identified within the 
Study Staff Signature Log.
                                               
3 Please also refer to the CRF instructions for further guidance.
4 The respiratory symptoms in both definitions are considered a new onset or exacerbation of a pre-existing 
condition.
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1.
BACKGROUND AND RATIONALE
1.1
Background
Seasonal influenza is a major cause of morbidity and mortality in the elderly. On average 
from 1976 through 2007, nearly 90% of all deaths attributed to seasonal influenza in the 
United States occurred in people 65 years of age or older. During this period the number 
of deaths per year in the elderly population ranged from 673 to 5,546 per year (MMWR, 
2010). Much of the mortality attributed to influenza is due to respiratory and
cardiovascular illnesses, such as secondary bacterial pneumonia and exacerbation of 
underlying cardiac and respiratory disease (Mullooly, 2007).
Vaccination is an effective way to prevent influenza and the related complications. In the 
US seasonal influenza vaccination was estimated to prevent 3.2 million medically 
attended illnesses and nearly 80,000 fewer hospitalizations (MMWR, 2013). It is 
estimated that 56% of the prevented hospitalizations were amongst patients 65 year or 
older (MMWR, 2013). In an earlier study of elderly not residing in chronic care facilities, 
vaccination was associated with a 27% reduction in the risk of hospitalization for 
pneumonia or influenza and a 48% reduction in the risk of death (Nichol, 2007). Seasonal 
influenza vaccination also appears to have a salutary effect on the incidence of cardiac 
diseases. In a prospective randomized controlled study of patients with recent myocardial 
infarction, seasonal influenza vaccination reduced the incidence of subsequent 
cardiovascular death and re-hospitalization (Gurfinkel, 2002). Since the majority of 
influenza-related hospitalizations and deaths occur in the elderly, the derived benefit of 
vaccination in this age group is large. However, the effectiveness and efficacy of current 
influenza vaccines is substantially reduced in the elderly relative to younger populations 
(Osterholm, 2012; Beyer, 2013 and MMWR 2013). The reason for the reduced efficacy 
of influenza vaccines in the elderly is not completely known but may be explained by 
qualitative and quantitative differences in the immune response after vaccination 
(Goodwin, 2006; Sasaki 2011). The risk of complications from influenza infection is 
uniform amongst the elderly and chronic medical illness appears to increase the risk of 
hospitalization due to pneumonia and influenza and death. A clinical prediction rule was 
previously developed and validated to determine the risk of complications from influenza 
infection in the elderly (Hak, 2004).
Therefore, vaccines with improved effectiveness in the elderly could further reduce the 
burden of disease resulting from complications of influenza. One way to increase 
immunogenicity of influenza vaccines is through the use of adjuvants, such as the 
squalene and water emulsion, MF59. FLUAD®, Seqirus’ trivalent influenza vaccine 
combined with MF59, has been licensed for use in Europe since 1997. When 
administered to elderly, this vaccine results in significantly higher geometric mean HI 
titers and rates of seroconversion in comparison to a non-adjuvanted trivalent influenza 
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vaccine (TIV) (Scheifele, 2013; Frey et al. 2014). The improved immunogenicity of 
FLUAD is not associated with significant increase in risk compared with non-adjuvanted 
vaccine. Administration of FLUAD to elderly patients results in higher local and systemic 
reactogenicity compared with non-adjuvanted vaccines but the reactions are mild and 
self-limited (Scheifele, 2013; Frey, 2014). In a large prospective, observational study and 
a smaller, retrospective, case-control study, FLUAD appears to be more effective than 
non-adjuvanted comparators (Mannino, 2012; VanBuynder, 2013). Furthermore, there 
does not appear to be an increased risk of rare but potentially serious adverse events 
based on a prospective analysis of subjects enroled in the study referred to above (Villa, 
2013).
Seqirus has received accelerated approval by the United States Food and Drug 
Administration (FDA) to market FLUAD for the prevention of seasonal influenza in
elderly subjects. Final licensure through the accelerated approval pathway is dependent 
on the demonstration of clinical benefit. Seqirus proposes to use a quadrivalent 
inactivated influenza vaccine combined with the adjuvant MF59, in this study and the 
FDA has agreed with this approach. Both aTIV and aQIV subunit vaccines are 
manufactured in a similar way and, in the case of aQIV, the fourth antigen is derived from 
a second B strain of influenza. B strains of influenza viruses are genetically classified into 
two main lineages, B/Yamagata and B/Victoria. During a typical influenza season, a 
single A/H1N1 and A/H3N2 will predominate. The epidemiology of disease caused by B 
strains is different and during the past decade it is common for both strains to circulate 
simultaneously (Ambrose and Levin et al. 2012). This can result in a clinically significant 
mismatch between the vaccine composition and circulating strains (Lo, Chuang et al. 
2013).
The goal of this current randomized, observer-blind, controlled study is to demonstrate 
that aQIV prevents influenza in elderly adults. Direct comparison with a non-influenza 
comparator vaccine (Boostrix®) licensed for use in elderly adults, will enable an 
estimation of the absolute efficacy of aQIV in preventing influenza in elderly adults while 
simultaneously providing benefit to subjects randomized to not receive influenza vaccine. 
Placebos, or non-influenza vaccine comparators, have been used to show influenza 
vaccine efficacy in elderly subjects (DeVilliers et al. 2009). This approach is consistent 
with CBER Guidance for the licensure of seasonal influenza vaccines and was recently 
used to demonstrate the benefit of an inactivated non-adjuvanted quadrivalent vaccine in 
children (Jain et al. 2013). 
The data from this study will be used to support the licensure of FLUAD and aQIV for 
the prevention of seasonal influenza in adults 65 years of age and older.
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1.2
Rationale
The purpose of this study is to demonstrate the clinical efficacy of Seqirus’ adjuvanted 
inactivated quadrivalent vaccine in adults 65 years of age and older. This randomized, 
observer-blind, non-influenza comparator-controlled study is intended to demonstrate that 
aQIV prevents RT-PCR confirmed influenza. This study is intended to fulfil a 
requirement of the accelerated approval pathway in the US. In particular to demonstrate 
the clinical benefit of aQIV, the quadrivalent version of Fluad, which was recently 
licensed for use in the US in adults 65 years and older.
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2.
OBJECTIVES
2.1
Primary Objective(s)
The primary and secondary efficacy objectives will be measured in all subjects in relation 
to cases of influenza occurring from 21 through 180 days after vaccination or through the 
end of influenza season, whichever is longer. In all cases, efficacy will be determined 
based on influenza cases caused by A (H1N1 and H3N2) and either B lineage.
Primary Efficacy Objective:
1. To demonstrate absolute vaccine efficacy of aQIV versus non-influenza comparator 
(Boostrix®) when administered as a single dose to prevent first occurrence RT-PCR-
confirmed influenza, due to any strain of influenza regardless of antigenic match to 
the strains selected for the seasonal vaccine, in subjects ≥ 65 years of age.
Primary Safety Objectives:
2. To evaluate the safety of aQIV through assessment for local and systemic solicited 
adverse events through Day 7 in a subset of subjects.
3. To evaluate the rates in each vaccine group of medically-attended adverse events 
within 30 days after the first occurrence RT-PCR confirmed ILI.
4. To evaluate the rates in each vaccine group of unsolicited adverse events for 21 days 
after vaccination and adverse events leading to withdrawal, serious adverse events
(SAEs), adverse events of special interest (AESI), and new onset of chronic diseases 
(NOCD) for 365 days after vaccination.
2.2
Secondary Objective(s)
Key Secondary Efficacy Objective:
1. To demonstrate absolute vaccine efficacy of aQIV versus non-influenza comparator 
when administered as a single dose to prevent first occurrence culture-confirmed 
influenza, due to strains antigenically matched to the strains selected for the seasonal 
vaccine.
Secondary Efficacy Objectives:
2. To evaluate absolute vaccine efficacy of aQIV versus non-influenza comparator when 
administered as a single dose to prevent first occurrence culture-confirmed influenza, 
due to any strain of influenza regardless of antigenic match to the strains selected for 
the seasonal vaccine. 
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3. To evaluate absolute vaccine efficacy of aQIV versus non-influenza comparator when 
administered as a single dose to prevent first occurrence culture-confirmed influenza, 
due to strains antigenically unmatched to the strains selected for the seasonal 
influenza vaccine.
4. To evaluate the absolute efficacy of aQIV versus non-influenza comparator when 
administered as a single dose to prevent first occurrence RT-PCR-confirmed influenza 
due to any strain of influenza regardless of antigenic match from 7 days to 180 days 
after vaccination or at the end of influenza season, whichever is longer (early 
efficacy).
Secondary Immunogenicity Objective:
5. To evaluate the immunogenicity of aQIV measured by HI titer 21 days after 
vaccination, against influenza strains homologous to the seasonal vaccine. 
2.3
Exploratory Objective(s)
1. To characterize the immunogenicity of aQIV using other immunological assays (such
as microneutralization assay).
2. To explore potential immune correlates of protection based on HI and/or other 
immunological assays (such as microneutralization assay).
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3.
STUDY DESIGN
3.1
Overview of Study Design
The study is a phase III, stratified, randomized, observer-blind, non-influenza 
comparator-controlled, multicenter study to evaluate the efficacy, safety and 
immunogenicity of an MF59-adjuvanted quadrivalent subunit influenza vaccine 
compared with a non-influenza comparator vaccine in subjects ≥ 65 years of age. 
The study vaccine, aQIV, contains 15 µg of each of the four seasonal influenza strains 
(A/H1N1, A/H3N2, B [Yamagata and Victoria lineage]) and MF59 adjuvant. The non-
influenza comparator (Boostrix®) vaccine will be used to provide a comparative 
assessment for efficacy, immunogenicity and safety.
Stratification according to age (≥ 65 to 74 and ≥ 75 years), study site and comorbidity 
status (at risk/not at risk) will be performed (see Section 5.1.4, Randomization and
Section 5.1.2, Screening). Sample size, among other factors, depends mainly on the 
number of RT-PCR confirmed influenza cases observed during the influenza seasons, so 
the overall number of subjects to be recruited provided here may change and enrolment 
over multiple seasons may be required to ensure 238 PCR-confirmed influenza cases have 
occurred and/or based on the results of the interim analysis for efficacy and futility. 
Nasopharyngeal swab samples will be analyzed in batches and the number of RT-PCR 
confirmed influenza cases will be reviewed on a regular basis. Once the number of RT-
PCR confirmed influenza cases exceeds 119, an interim analysis for efficacy and futility 
with an appropriate adjustment of the type I error will be performed by an independent 
Data Monitoring Committee (DMC). Another interim analysis might be recommended 
before target 238 RT-PCR confirmed influenza cases are observed. Once the number of 
RT-PCR confirmed influenza cases is ≥ 238 the Sponsor will stop and unblind the trial
and perform the final analysis. Stopping rules for futility and efficacy and any additional 
details regarding the DMC can be found in the DMC Charter.
Each subject will have two stages of study participation: Treatment Period (Day 1 to Day 
22) and Follow-up Period (Day 23 to Day 366).
The study procedures consist of four (4) clinic visits, and three (3) safety phone calls. 
After enrolment and vaccination on Day 1, all subjects will then return to the clinic for 
three (3) additional clinic visits, on Days 22, 181 and 366. During the study there will 
also be three (3) safety phone calls on Days 15, 91 and 271. Subjects participating in the
solicited safety subset will receive an additional call on day 3 reminding them to complete 
their diary card.
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Additionally, all subjects will receive weekly phone calls or messages to assess for 
primary protocol-defined ILI symptoms during the active ILI surveillance period, defined 
as from Day 1 through Day 181 or until the end of the influenza season, whichever is 
longer. The purpose of the ILI surveillance phone calls/message is to trigger a clinic or 
home visit to collect a nasopharyngeal swab. Subjects will also be asked for the duration 
of the trial (up to Day 366) to contact the site at the onset of ILI symptoms to schedule a 
clinic visit for NP swab collection.
After an initial screening, subjects will be vaccinated with a single dose of aQIV or non-
influenza comparator on Day 1. Subjects will be observed for at least 30 minutes post-
vaccination on Day 1 for any immediate reactions. A subset of randomly selected subjects 
from both treatment groups will be chosen to participate in a solicited safety subset.
Subjects participating in the solicited safety subset will receive a Subject Diary along 
with instructions and training to ensure proper completion and assessment of
reactogenicity. Each subject in the solicited safety subset will be instructed to document 
in their Subject Diary solicited local and systemic adverse events that may occur post-
vaccination from Day 1 through Day 7. Subjects in the solicited safety subset will be 
asked to return their completed Subject Diary at their Day 22 clinic visit. 
For all subjects, any unsolicited adverse event and concomitant mediation use, after 
vaccination from Day 1 to Day 22 will be collected at the Day 15 safety phone call and 
during the Day 22 clinic visit. Information collected at these visits will be documented in 
the subject’s source records and captured in the Electronic Case Report Form (eCRF). All 
subjects will also receive an ILI booklet on Day 1, and will be instructed to measure their 
body temperature using the thermometer provided starting from onset day of primary 
protocol defined ILI to the day they come into the clinic for their NP swab collection.
Subjects will be asked to return the ILI booklet at the time of their NP clinic visit.
During the remaining follow-up phase of the study, safety data including adverse events 
leading to withdrawal, AESI, NOCD and SAE and concomitant medication use related to 
these events will be captured via safety phone calls or clinic visits throughout the 
remainder of the trial (up to Day 366).
Subjects experiencing an ILI will have one (1) additional clinic visit and one (1) 
additional safety call: (1) a clinic or home visit to collect a nasopharyngeal swab as soon 
as possible within 3, but up to 6, days after the first day of onset of primary protocol-
defined ILI symptoms, and (2) a safety follow-up call 30 days after ILI onset to determine 
if subsequent medically-attended adverse events occurred and if any concomitant 
medication associated with these adverse events were used. The use of anti-viral 
medications will be permitted after NP swab has been obtained and will be documented 
as concomitant medications. Nasopharyngeal swabs will be processed for viral culture 
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and RT-PCR confirmation. Culture positive samples will undergo antigenic 
characterization.
One season in which at least 2800 subjects are anticipated to be enrolled will be selected 
for the collection of immunogenicity samples. Samples from approximately 2800 subjects 
participating in the selected season will be collected at Day 1 (baseline) and Day 22 (visit 
3). In order to maintain the study blind equal numbers of subjects from both treatment 
groups will be asked to provide blood specimens (see Section 3.5, Collection of Clinical 
Specimens). After all of the blood specimens have been obtained a subset of samples 
from those collected will be randomly selected on a 4:1 ratio (1,362 aQIV; 340 Boostrix) 
for the purpose of completing the analysis of the immunogenicity objectives. Serum 
samples from subjects with RT-PCR confirmed influenza, along with a subset of subjects 
who did not have RT-PCR confirmed influenza, may be tested to estimate the correlate of 
protection. The serologic component of the correlate of protection will be measured using 
either a validated haemagglutination inhibition (HI) and/or other immunological assays 
(such as microneutralization).
Study Case Definition of Influenza-Like-Illness
Two definitions of ILI will be used. Primary protocol-defined ILI will be used to trigger 
nasopharyngeal swab retrieval (Section 3.5, Collection of Clinical Specimens) and 
completion of the ILI booklet (Section 3.4.2, Tools Used for Data Collection). The
respiratory symptoms in both definitions are considered a new onset or exacerbation of a 
pre-existing condition.

Primary protocol-defined ILI: At least one of the following respiratory symptoms: 
sore throat, cough, sputum production, wheezing, or difficulty breathing; concurrently 
with at least one of the following systemic symptoms: temperature of > 37.2°C/ 99°F, 
chills, tiredness, headache, or myalgia.

Modified CDC ILI definition: Fever (temperature of > 37.2° C/99°F) with cough or 
sore throat.
The ILI onset day is defined as the first day that the subject meets the primary protocol-
defined ILI.
The ILI end date is defined as the date the last symptom resolves. 
A new ILI episode will only be taken into account after resolution of the previous one, as 
judged by the investigator (suggested interval between two ILI episodes is 14 symptom-
free days).
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3.2
Study Period
Each subject should expect to participate in the study for approximately one year, from 
the time of enrolment through the last study visit.
3.3
Blinding Procedures
The trial is designed as an observer-blind study. Designated unblinded nurse(s) or 
physician(s) will be responsible for administrating the study vaccines to the subjects and 
will be instructed not to reveal the identity of the study vaccines either to the subject or 
the investigative site staff (i.e., investigator and study nurse) involved in the monitoring 
of conduct of the trial up until completion of the trial and final data review, except in a 
medical emergency. Vaccines will be selected and administered according to the Pack ID 
assigned to the subjects by IRT. Neither the subject nor any of the investigative staff who 
are involved in the treatments or clinical evaluation of the subject will be aware of the 
vaccine administered. Vaccine administration should be shielded from the subject and 
blinded study personnel. The unblinded personnel should not be involved in data 
collection such as safety assessments and/or physical assessment and should not access 
the blinded data entry fields. In case of an emergency, the Investigator can disclose the 
subject’s assigned vaccine. The information can be retrieved from the IRT system either 
via web or phone (a 24/7 backup service). 
Except in the case of medical necessity, a subject’s treatment should not be unblinded 
without the approval of the Sponsor. In such instance of medical emergency, every effort 
should be made to contact the Sponsor prior to unblinding. If unblinding should occur (by 
either accidental unblinding or emergency unblinding for an SAE) prior to completion of 
the study, the investigator must promptly contact the Sponsor and document the 
circumstances on the appropriate forms. Instructions regarding emergency unblinding will 
be provided to the investigator.
All personnel involved in performing laboratory assays and others who are directly 
involved in the conduct of the trial or in the analysis of the final trial results will remain 
blinded to the treatment codes until at least the database has been locked for final 
analysis.
3.4
Data Collection
3.4.1
Data Collected from Subjects
The following data will be collected from each subject during their study participation:

Medical History
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
Vaccination History

Demographic Information.

Post-vaccination unsolicited AEs (from Day 1-22)

Adverse Events
-
AEs leading to withdrawal
-
AESIs
-
NOCDs
-
SAEs
-
ILI
-
Medically-attended adverse events within 30 days after the ILI onset

Concomitant Medications (as defined in Section 6.5)

Reason for study termination

Body temperature measurements from the onset of ILI until day of clinic visit for NP 
sample collection.
All data collected must only be identified using the Subject ID, as described in Section 
5.1.4, Randomization.
The investigator will request a vaccination card or other documentation of previous 
vaccination history from the subject. If available, the card or other documentation will be 
copied and placed in the subject’s file to serve as source documentation. If documentation 
of vaccination history is not available, the subject’s verbal recall of prior vaccination of 
the subject will be recognized as sufficient medical history; this approach and the 
collected information must be captured in the source documentation.
3.4.2
Tools Used for Data Collection
ILI Booklet
Subject’s experiencing an ILI will be asked to document their daily body temperature in 
an ILI booklet. An ILI booklet will be given to all subjects at their Day 1 visit. The 
booklet will be used to collect information on body temperature measurements which are 
to be completed daily (using the supplied thermometers) until the subject comes in for 
their NP sample collection. At the ILI clinic visit the subject will be asked to turn in their 
ILI booklet. A new booklet will be administered in case the subject experiences another 
ILI.
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No corrections or additions to the information recorded by the subject or legal guardian
within the ILI booklet will be allowed after it is delivered to the site. Any blank or 
illegible fields on the ILI booklet must be described as missing in the eCRF.
Subject Diary
Subjects participating in the solicited safety subset will be given a paper diary at their 
Day 1 clinic visit to complete. The paper diaries (pDiaries) to be completed by subjects 
participating in the solicited safety subset, hereafter referred to as Subject Diaries, will be 
the only source document allowed for solicited local and systemic adverse events 
(including body temperature measurements), starting after the initial 30 minute post-
vaccination period at the clinic through Day 7. 
At the Day 22 clinic visit subjects participating in the solicited safety subset are to return 
their completed diary and the site staff should review the completed diary with them. The 
following additional rules apply to documentation of safety information collected in the 
Subject Diary.
1. No corrections or additions to the information recorded by the subject or legal 
guardian within the Subject Diary will be allowed after it is delivered to the site.
2. Any blank or illegible fields on the Subject Diary must be described as missing in the 
CRF.
Case Report Forms
This study utilizes Electronic Case Report Forms (eCRFs) to collect study-related data 
from each subject. A qualified site staff member(s) is required to enter subject data in the 
eCRFs in English based on the medical information available in each subject’s source 
record.
Data should be entered into the eCRF in a timely fashion following each subject’s clinic 
visit, study procedure, or phone call. Each subject’s eCRF casebook will be compared 
with the subject’s source records by a Seqirus-approved study monitor (or designee) over 
the duration of the study in order to ensure data collection accuracy.
The following additional rules apply to documentation of Subject Diary information 
collected in the CRFs:
1. The site must enter all readable entries in the Subject Diary into the CRF, including 
those values that may be biologically implausible (e.g. body temperature: 400°C).
2. Any illegible or implausible data should be reviewed with the subject or legal 
guardian. If an underlying solicited or unsolicited adverse event is described on 
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review with the subject, this should be described in the source document and reported 
as an unsolicited adverse event in the Adverse Event CRF (e.g., if the subject above 
confirms body temperature of 40°C on the day in which body temperature: 400°C was 
written into his/her Subject Diary, this fever of 40°C should be recorded in the 
Adverse Event CRF).
3. Any newly described safety information (including a solicited adverse event) must not 
be written into the Subject Diary and must be described in the study file as a verbally 
reported adverse event. Any adverse event reported in this fashion must be described 
as an unsolicited adverse event and therefore entered on the Adverse Event CRF.
3.5
Collection of Clinical Specimens
The following clinical specimens are required to be collected from each subject in this 
study:

Nasopharyngeal swabs (as needed from subjects experiencing symptoms that meet 
primary protocol-defined ILI criteria).
The following clinical specimens are required to be collected from subjects participating 
in the immunogenicity subset:

Blood at the Day 1 and 22 clinic visit 
Collection and processing of each specimen should be completed by a qualified site 
member and in accordance with the study-specific Laboratory Manual. Testing of clinical 
specimens will be performed by a Seqirus or designated laboratory. Refer to the study-
specific Laboratory Manual for additional details.
Blood Specimens
Approximately 10 mL sample of blood will be drawn from approximately 2800 subjects 
participating in the immunogenicity season at Days 1 and 22. The blood volume will not 
exceed 10 mL at each time point in order to provide the necessary serum volume 
(approximately half of the blood draw volume) for the serology assays (see Section 7, 
Assessments for additional details).
The total amount of blood collected over the study period per subject will be 
approximately 20 mL.
Nasopharyngeal Swabs
Subjects, who from Visit 1 (Day 1) onwards, experience symptoms meeting the primary 
protocol-defined ILI criteria (i.e. at least one of the following respiratory symptoms (new 
onset or exacerbation of pre-existing condition): sore throat, cough, sputum production, 
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wheezing, or difficulty breathing concurrently with at least one of the following systemic
symptoms: temperature of > 37.2°C/ 99°F, chills, tiredness, headache, or myalgia), will 
have one NP swab collected for evaluation of the presence of influenza virus by RT-PCR. 
The NP swab will be collected as soon as possible within 3 days of ILI onset, but 
collection up to 6 days will be permitted.
All samples will also be cultured for the growth of the strain of influenza obtained from 
the subjects in order to conduct antigenic characterization (to determine whether the 
clinical isolate is antigenically matched or antigenically unmatched to the vaccine strain).
3.6
Stopping/Pausing Guidelines
NP swabs will be analyzed in batches on a rolling basis throughout the study. When the 
number of RT-PCR confirmed influenza cases is between 119 and 238 interim analyses 
for efficacy and futility will be performed by an independent DMC. At least one interim 
analysis will be performed based on the number of RT-PCR confirmed influenza cases 
accrued at the time of the first interim analysis. After periodic review of safety and 
efficacy data, the DMC will make a recommendation as to whether enrolment in the study 
should continue, be stopped or paused (see Section 8.6 Interim Analysis).
Independent of the DMC, the Sponsor can halt the study at any time. If the study is 
halted, the Sponsor will promptly notify the health authorities and investigators, who will 
promptly inform the study subjects and local Ethics Committee/ Institutional Review 
Board (EC/IRB) as per local regulations. Study vaccinations and further enrolment will 
only occur after written authorization is provided by the Sponsor in conjunction with a 
recommendation to proceed by the DMC and in consultation with the health authorities 
and EC/IRB, as appropriate.
3.7
Data Monitoring Committee
An independent DMC will be constituted for this trial. The members of the DMC shall 
have no involvement in the design or conduct of the trial and no financial interest in the 
outcome of the trial. The DMC will comprise solely of non-Seqirus employees, and 
include medical experts and a biostatistician. The main purpose of the DMC will be to 
monitor study progress and ensure the safety of subjects on an ongoing basis during the 
trial. In addition, DMC will provide recommendation on stopping the study for either 
efficacy or futility after unblinded review of efficacy data in a pre-planned interim 
analysis.
Unblinded interim analyses for efficacy and futility will be executed by the DMC, if the 
number of RT-PCR confirmed influenza cases is between 119 and 238. In addition, the 
DMC will also review blinded, and if requested, semi-or fully-unblinded safety data at 
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pre-specified intervals during the study. Another interim analysis might be recommended 
before target 238 cases are observed. Any unblinded data will be reviewed in closed 
sessions of the DMC, without participation of the Sponsor. All descriptions of these 
closed sessions will be unavailable to the Sponsor until study unblinding has occurred. 
All reports, following open sessions of blinded data review will be available to the 
Sponsor as appropriate. DMC recommendations will be expressed clearly to the Sponsor, 
at minimum in written communication. 
After reviewing safety and efficacy data, the DMC will recommend that enrolment be
continued, halted temporarily (pending additional information from the Sponsor or 
modification to the study design) or halted permanently as specified in the DMC charter.
The DMC charter will be written to clearly describe the operational processes and the 
roles and responsibilities, including the timing of meetings, methods of providing 
information to and from the DMC, format and content of data to be reviewed, frequency 
and format of meetings, and membership requirements.
3.8
Premature Withdrawal from Study
Subjects may withdraw at any time, or be dropped from the study at the discretion of the 
investigator should any untoward effects occur and/or for safety reasons. In addition, a 
subject may be withdrawn by the investigator or the Sponsor if he/she violates the study 
plan or for administrative reasons. The investigator or study coordinator must notify the 
Sponsor immediately when a subject has been withdrawn due to an adverse event.
The circumstances above are referred to as premature withdrawal from the study, and the 
reason for premature withdrawal should be clearly documented and detailed in the source 
documentation. The investigator should make every attempt to evaluate the subject’s 
safety, including resolution of ongoing AEs, at the time of premature withdrawal. If a 
subject wants to withdraw from the study prior to the last planned study visit, the subject 
will be asked to be followed for safety for the duration of the study. If an enrolled subject 
withdraws from the study before receiving vaccine they will be considered an early 
withdrawal but no further study procedures will be performed. When a subject withdraws,
or is withdrawn, from the study, the procedures described in Section 5.5.1, Early 
Termination Visit should be completed if possible. Withdrawn subjects will not be 
replaced.
The reasons for premature withdrawal from the study include: Adverse event, death, 
withdrawal of consent, lost to follow-up, administrative reason, and protocol deviation. 
These reasons are described in greater detail below.
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Adverse Event
For any subject withdrawn from study participation prior to the planned Study 
Termination Visit, it is important to determine if an AE was associated with the reason for 
discontinuing the study. This AE must be identified on the AE CRF page by indicating 
“Withdrawn from study due to AE”. Any ongoing AEs at the time of study withdrawal 
must be followed until resolution or stabilization.
If a medically attended adverse event occurred within 30 days following a primary 
protocol definition of ILI, the event should also be reported on the AE eCRF page (see 
Section 7.2, Efficacy Assessment).
Death
For any subject withdrawn from study participation due to death, this should be noted on 
the Study Termination eCRF page and the associated SAE that led to the death must be 
reported (see Section 7.2, Efficacy Assessment).
Withdrawal of consent
A subject or legal guardian can withdraw consent for participation in the study at any 
time without penalty or loss of benefit to which the subject is otherwise entitled. Reason 
for early termination should be deemed as “withdrawal of consent” if the subject 
withdraws from participation due to a non-medical reason (i.e., reason other than AE). If 
the subject or legal guardian intends to withdraw consent from the study, the investigator 
should clarify if the subject will withdraw completely from the study or if the subject will 
continue study participation for safety, or a subset of other study procedures. If the 
subject requests complete withdrawal from the study, no further study interventions will 
be performed with the subject.
In countries where the Health Insurance Portability and Accountability Act (HIPAA) is 
applicable, if a subject or legal guardian withdraws consent but does not revoke the 
HIPAA authorization, the Sponsor will have full access to the subject’s medical records, 
including termination visit information. If a subject or legal guardian revokes only the 
HIPAA authorization, the Sponsor will have full access to all of the subject’s medical 
records prior to the date and time of written revocation.
Lost to Follow-Up
For subjects who fail to show up for final visits (clinic or telephone contacts), or for three 
consecutive visits, study staff are encouraged to make at least three documented attempts 
to contact the subject by telephone and at least one documented written attempt to contact 
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the subject or legal guardian to encourage the completion of study termination 
procedures. These efforts to contact the subject should be recorded in the source 
document. The termination date for the subject to be captured on the Study Termination 
eCRF page is the date of the last successful contact (clinic visit or telephone) with the 
subject.
Administrative Reason
Examples for subjects withdrawn from the study due to administrative reason can include: 
Sponsor decision to terminate the study, subject meeting a pre-specified withdrawal 
criterion, subject discontinuation for insurance issues, moving, no time, etc. This reason 
should be noted in the Study Termination eCRF page and any ongoing AEs at the time of 
study withdrawal must be followed until resolution/stabilization.
If the clinical study is prematurely terminated by the Sponsor, the investigator is to 
promptly inform the study subjects and local EC/IRB and should assure appropriate 
therapy and follow up for the subjects. All procedures and requirements pertaining to the 
archiving of study documents should be followed. All other study materials (study 
medication/vaccines, etc.) must be returned to the Sponsor.
For subjects who are withdrawn from the study due to receipt of an excluded 
medication/vaccination or due to significant protocol non-compliance, this reason should 
be noted in the Study Termination CRF page.
Protocol Deviation
A protocol deviation is any change, divergence, or departure from the study design or 
procedures of a study protocol. In general, subjects associated with protocol deviations 
may remain in the study unless continuation in the study jeopardizes the subject’s health, 
safety, or rights.
Investigators will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Seqirus or its agents, if any, monitoring the 
study to request approval of a protocol deviation, as no authorized deviations are 
permitted. If the investigator feels a change to the protocol would improve the conduct of 
the study this must be considered a protocol amendment, and unless such an amendment 
is agreed upon by Seqirus and approved by the IRB/EC and health authorities it cannot be 
implemented. 
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3.9
End of Study
Evaluation of the primary efficacy objective requires the testing of biological samples 
from the study subjects, which can only be completed after all samples are collected. 
Nasopharyngeal swabs may be collected up to Day 366. For the purpose of this protocol, 
end of study is defined as the completion of the testing of such biological samples, to be 
achieved no later than 8 months after collection of the last biological sample visit 7
(Day 366).
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4.
SELECTION OF STUDY POPULATION
4.1
Inclusion Criteria
In order to participate in this study, all subjects must meet ALL of the inclusion criteria 
described.
1. Males and females ≥ 65 years old who are healthy or have co-morbidities (see Table 
5.1.2-1).
2. Individuals who or whose legal guardian have voluntarily given written consent after 
the nature of the study has been explained according to local regulatory requirements, 
prior to study entry.
3. Ability to attend all scheduled visits and to comply with study procedures including 
follow-up5 (and responding to messages and telephone contact).
4.2
Exclusion Criteria
Each subject must not have:
1. Receipt of diphtheria or tetanus toxoid or pertussis (acellular or whole cell) vaccines 
within the previous 5 years.
2. History of behavioral or cognitive impairment or psychiatric condition that, in the 
opinion of the investigator, may interfere with the subject's ability to participate in the 
study.
3. History of any medical condition considered an adverse event of special interest, see 
Section 7.1.4.1, Adverse Events of Special Interest. 
4. Progressive or severe neurological disorder, seizure disorder, or history of Guillain-
Barré syndrome.
5. Hypersensitivity, including allergy, to any component of vaccines see Table 6.1-1 and 
Table 6.1-2, medicinal products or medical equipment whose use is foreseen in this 
study.
6. Encephalopathy (e.g. coma, decreased level of consciousness, prolonged seizures) 
within 7 days of administration of a previous pertussis antigen-containing vaccine.
                                               
5 A subject or legal guardian is considered to be compliant if the Investigator judges that the subject will
complete the Subject Diary when applicable, return for all the follow-up visits, and be available for 
telephone calls as scheduled in the study.
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7. Clinical conditions representing a contraindication to intramuscular vaccination and 
blood draws, including bleeding diathesis, or any other condition that may be 
associated with prolonged bleeding. 
8. Abnormal function of the immune system resulting from:
a.
Clinical conditions.
b. Systemic administration of corticosteroids (PO/IV/IM) at a dose equivalent to 20 
mg of prednisone for more than 14 consecutive days within 90 days prior to 
informed consent.
c.
Administration of antineoplastic and immunomodulating agents (e.g. TNF α 
antagonists or anti-B cell antibodies) or radiotherapy within 1 year prior to 
informed consent.
9. Receipt of immunoglobulins or any blood products within 180 days prior to informed 
consent.
10. Receipt of an investigational or non-registered medicinal product within 30 days prior 
to informed consent or before completion of the safety follow-up period in another 
study and who are unwilling to refuse participation in another clinical study at any 
time during the conduct of this study (note: concomitant participation in an 
observational study not involving drugs, vaccines, or medical devices, is acceptable).
11. Study personnel or immediate family members (brother, sister, child, parent), the 
spouse of study personnel or individuals who are financially or emotionally dependent 
on study staff
12. Receipt of any influenza vaccine within 6 months prior to enrolment in this study or 
who plan to receive influenza vaccine while participating in the study. 
13. Receipt of any inactivated vaccine 14 days or live-attenuated vaccine 28 days prior to 
enrolment in this study or who are planning to receive any vaccine within 28 days 
from study vaccination. 
14. Fever at the time of screening, defined as oral temperature ≥38.0 degrees Celsius (≥ 
100.4° F). Enrolment could be considered if fever is absent for 72 hours. 
15. Signs or symptoms of acute respiratory tract infection at the time of screening. 
Enrolment could be deferred if signs and symptoms are absent for 72 hours.
16. Residence in a chronic care facility (e.g. nursing home).
17. Participation in this trial in a prior season, if applicable. 
18. Fatal prognosis of an underlying medical condition (<12 months life expectancy).
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19. Any other clinical condition that, in the opinion of the investigator, might interfere 
with the results of the study or pose additional risk to the subject due to participation 
in the study.
4.3
Criteria for Delay of Vaccination
There may be instances when individuals meet all eligibility criteria for vaccination yet 
have a transient clinical circumstance which may warrant delay of vaccination: fever
[≥38.0° C (≥ 100.4° F), signs or symptoms of acute respiratory tract infection or use of 
antipyretics and/or analgesic medications within 24 hours prior to vaccination. Under 
such circumstances, a subject may be considered eligible for study enrolment after the 72 
hours have passed and inclusion/exclusion criteria have been rechecked, and if the subject 
is confirmed to be eligible.
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5.
STUDY PROCEDURES
The sections that follow provide an overview of the procedures that are to be followed in 
enrolling, evaluating, and following subjects who participate in this clinical study. Visits 
can be either clinic visits or safety follow-up telephone calls, as specified in the Table 
below and in the Time and Events Table 2, 3 and 4.
Table 5-1:
Study Procedures
Visit Category
Procedures
Vaccination Clinic Visit – Pre-vaccination
Procedures
Section 5.1. describes procedures to be followed prior to study 
vaccination: informed consent, screening, enrolment, and 
randomization
Vaccination Clinic Visit(s) – Vaccination 
and Post-vaccination Procedures
Section 5.2 describes procedures to be followed during each 
clinic visit involving vaccination: vaccination, post-
vaccination procedures, and post-vaccination reminder calls
Post-vaccination Visit(s) 
Section 5.3 describes follow-up clinic visits, safety follow-up 
calls, and active ILI surveillance calls
Unscheduled Visit(s)
Section 5.4 describes possible procedures to be followed at 
unscheduled clinic visits
Study Termination Visit
Section 5.5 describes procedures to be followed at the last 
study visit for a subject (may include early termination visit)
5.1
Vaccination Clinic Visit - Pre-vaccination Procedures
This section describes the procedures that must be performed for each potential subject 
prior to vaccination, including obtaining informed consent, screening, enrolment and 
randomization. Please refer to Time and Events Table 2.
5.1.1
Informed Consent
"Informed consent" is the voluntary agreement of an individual or his/her legal 
guardian(s) to participate in research. Consent must be given with free will of choice, and 
without undue inducement. The individual must have sufficient knowledge and 
understanding of the nature of the proposed research, the anticipated risks and potential 
benefits, and the requirements of the research to be able to make an informed decision.
Informed consent following local IRB/EC guidance must be obtained before conducting 
any study-specific procedure (i.e., all of the procedures described in the protocol). The 
process of obtaining informed consent should be documented in the subject source 
document in addition to maintaining a copy of the signed and dated informed consent.
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If a subject or legal guardian is unable to read, an impartial witness should be present 
during the entire informed consent discussion. An impartial witness is defined as a person 
who is independent from study conduct, who cannot be unfairly influenced by those 
involved with the study, who attends the informed consent process if the subject or, if 
applicable, the subject's legally acceptable representative cannot read, and who reads the 
informed consent form (ICF) and any other written information supplied to the subject. 
After the written ICF and any other written information to be provided to subjects, is read 
and explained to the subject or legal guardian and after the subject or legal guardian has 
verbally consented to the subject’s participation in the study and, if capable of doing so, 
has signed and personally dated the ICF, the witness should sign and personally date the 
consent form. By signing the consent form, the witness attests that the information in the 
consent form and any other written information was accurately explained to, and 
apparently understood by, the subject or legal guardian and that informed consent was 
freely given by the subject or legal guardian.
The informed consent process may be conducted within 10 days prior to Day 1.
5.1.2
Screening
After an individual has consented to participate in the study and informed consent is 
signed, that individual will be given a unique Screening Number. The subject’s unique 
Screening Number will be documented in the Screening and Enrolment log. The 
eligibility of the subject will be determined based on the inclusion and exclusion criteria 
listed in Section 4, Selection of Study Population and evaluated during this screening 
procedure.
Prior to study enrolment, demographic data will be collected from the subject, including: 
age, sex, race, ethnicity, height and weight, prior influenza vaccination, smoking status 
and, comorbidity and risk of complications from influenza indicated by a calculated 
score. The risk assessment which incorporates medical comorbidity among other baseline 
characteristics is a validated predictor of risk of complications from influenza in subjects 
≥65 years of age (Hak, 2004) (see Table 5.1.2-1, Prediction Rule for Estimating the 
Probability of Hospitalization Due to Pneumonia or Influenza and Death Due to Any 
Cause). Using this model, a score of <50 is considered low risk and a score of ≥ 50 is 
considered high risk.
It is important to note that the determination of pre-existing medical conditions, for the 
purpose of calculating the risk score, should be made by the investigator based on his or 
her clinical judgment. A list of conditions which are associated with increased risk of 
complications from influenza are presented in Appendix 1 as a reference for the 
Investigator (Website CDC and Mullooly et al., 2007).
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understanding of the risk score and of an adverse event that occurs during study 
participation, if it represents an exacerbation of an underlying disease/pre-existing 
problem.
Review of systems is a structured interview that queries the subject or legal guardian as to 
any complaints the subject has experienced across each organ system. This will be 
performed before enrolment and used to guide physical examination.
If applicable, prior and concomitant medications or vaccinations taken prior to start of 
study should be collected (refer to Section 6.5, Prior and Concomitant Medications and 
Vaccines for further details).
Collection of vital signs is to be performed: heart rate, blood pressure, respiratory rate and 
pre-vaccination body temperature (preferably oral). If body temperature is ≥38.0°C (or 
≥100.4°F) at the time of screening, vaccination must be postponed until 3 days after the 
fever has resolved (see Section 4.3, Criteria for Delay of Vaccination).
Measure height and weight. Measurement and recording of vital signs, height, weight and 
body temperature, may be conducted by a trained health care professional.
A general physical examination is to be performed by a qualified health care practitioner. 
“Qualified health care practitioner” refers to any licensed health care professional who is 
permitted by institutional policy to perform physical examinations and who is identified 
within the Study Staff Signature Log.
The data described above will be written in the source document (see Section 9.1, Source 
Documentation). Should the physical assessment reveal any abnormal values or events, 
these must be documented as part of medical history.
Prior to vaccination, approximately10 mL of blood will be drawn from approximately 
2800 subjects participating in the immunogenicity season (see Section 3.5, Collection of 
Clinical Specimens).
In the event that the individual is determined ineligible for study participation, he/she is 
considered a screen failure. The reason for screen failure must be documented in the 
Screening and Enrolment log. If the individual is determined to be eligible for the study, 
he/she will be enroled into the study.
5.1.3
Enrollment
After signing the ICF, if an individual is determined to be eligible for study participation, 
the investigator or delegate will enroll the subject and enter subject information and
stratification information into the Interactive Response Technology (IRT) system.
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5.1.4
Randomization
Enroled subjects will be randomized in the IRT system by a 1:1 ratio to receive either 
aQIV or the non-influenza comparator vaccine Boostrix® and will be automatically 
assigned a unique Subject ID and Pack ID indicating the assigned treatment. The Subject 
ID will be the subject’s unique identification number for all CRFs and associated study 
documentation that will be used for duration of the study. The Subject ID consists of a 7-
digit number resulting from the combination of the site number, and the subject’s order of 
randomization at the site. After randomization, the Screening Number ceases to be used 
and remains in the Screening and Enrolment Log only. The list of randomization 
assignments is produced by the IRT service provider and approved by Seqirus or 
delegate.
Randomization will be stratified by age (cohorts 65 to 74 years and 75 years and above), 
study site and also based on risk for complications from influenza (assessment score < 50 
or ≥50).
If for any reason, after signing the ICF, the subject who is eligible and enroled fails to be 
randomized, this is called a randomization failure. Further guidance is provided in the 
CRF Instructions. The reason for all randomization failures should be recorded in the 
Screening and Enrolment Log and in the source document as specified in the Source Data 
Agreement (SDA). The information on subjects who are randomization failures should be 
kept distinct from subjects who are screen failures, as described in Section 5.1.2, 
Screening.
If for any reason, after randomization the subject fails to undergo treatment, this is an 
Early Termination and the reason should be recorded in source document as specified in 
the SDA. The information on these Early Termination subjects should be kept distinct in 
the source documentation from randomization failures.
Subjects from a single season will have blood samples collected for inclusion in an 
immunogenicity subset. Samples from approximately 2800 subjects participating in the 
selected season will be collected at Day 1 (baseline) and Day 22 (visit 3). In order to 
maintain the study blind equal numbers of subjects from both treatment groups will be 
asked to provide blood specimens (see Section 3.5, Collection of Clinical Specimens). 
The IRT-system will be used to identify subjects from which blood specimens are to be 
collected. After all of the blood specimens have been collected a randomly selected subset
of these samples will be analyzed. Detailed information regarding the randomization 
procedures associated with the selection of the samples to be analyzed can be found in the 
Statistical Analysis Plan (SAP). 
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A subset of approximately 2,100 subjects from multiple seasons and countries 
participating in the trial will be randomly selected for participation in the solicited safety 
subset. Equal numbers of subjects from both treatment arms will be selected for 
participation in this subset. Detailed information regarding the randomization procedures 
associated with the selection of the subjects participating in this subset can be found in 
the Statistical Analysis Plan (SAP). 
5.2
Vaccination Clinic Visit – Vaccination and Post-vaccination procedures
Please refer to Time and Events Table 2. Vaccination will be performed on Day 1 using 
the vaccine identified by the assigned Pack ID.
The Day 1 serology sample collected from selected subjects participating in the 
immunogenicity season must be taken prior to vaccination.
After completing the pre-vaccination procedures as described in Section 5.1, Vaccination 
Clinic Visit - Pre-vaccination Procedures, the vaccine will be administered to the subject 
according to the procedures described in Section 6.3, Vaccine Preparation and 
Administration, observing the blinding procedures described in Section 3.3, Blinding 
Procedures.
Prior to administration of the study vaccination, it needs to be confirmed that the subject 
is eligible for vaccination and does not meet any criteria for exclusion or delaying study 
vaccination as described in Section 4, Selection of Study Population.
5.2.1
Post-vaccination Procedures
The following post-vaccination procedures will be performed on Day 1.
Observation Period
After vaccination, the subject will be observed for at least 30 minutes for unsolicited 
adverse events, solicited adverse events, and a body temperature measurement (preferably 
oral) will be taken. During this observation period, the subject should be trained on how 
to use the thermometer and for subjects participating in the solicited safety subset, the 
ruler provided and how to measure local solicited adverse events (see Section 7.1.1, 
Solicited Adverse Events). All safety data collected during this time should be recorded in 
the subject’s source document.
Subject Diary Training
A Subject Diary will be dispensed to subjects participating in the solicited safety subset to 
document solicited adverse events from Day 1 to Day 7. The Subject Diary is the only 
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source for collection of these data; therefore, it is critical that the subject completes the 
Subject Diary correctly. The subject should be trained on how and when to complete each 
field of the Subject Diary. The Subject Diary should be completed on a daily basis and 
the entries should be written clearly in pen. See additional rules in Section 3.4.2, Tools 
Used for Data Collection.
The subject or legal guardian should be trained on how to self-measure local solicited 
adverse events and body temperature (preferably oral). The measurement of solicited 
local adverse events is to be performed using the ruler provided by the site.
The subject or legal guardian should be instructed how to perform body temperature 
measurement using the thermometer provided by the site. If the subject feels unusually 
hot or cold during the day, the subject or legal guardian should check body temperature. 
If the subject has fever, the highest body temperature observed that day should be 
recorded in the Subject Diary.
Subject Diary completion starts on the day of vaccination. The subject will be instructed 
to check for solicited adverse events approximately 6 hours after the vaccination or prior 
to going to bed. Entries on subsequent days should be performed around the same time, 
preferably in the evening.
Subject Diary training should be directed at the individual(s) who will perform the 
measurements of adverse events and who will enter the information into the Subject 
Diary. In some situations, the Subject Diary may be completed by somebody other than 
the subject or legal guardian (except study site personnel). If a person other than the 
subject or legal guardian enters information into the Subject Diary, the reason that the 
subject cannot complete their own Subject Diary and the person’s identity and 
relationship to the subject must be documented in the Subject Diary. Any individual that 
makes entries into the Subject Diary must receive training on completion of the Subject 
Diary at the time of the visit. This training must be documented in the subject’s source 
record.
The same individual should complete the Subject Diary throughout the course of the 
study.
Plan Next Study Activities
The site should schedule the next study activity with the subject or legal guardian. It is 
recommended for the site to already schedule in advance the remaining upcoming study 
activities. 
Discharge
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The subject or legal guardian should be reminded to contact the site if there are any 
questions, and to contact the site immediately (or as soon as the subject is medically 
stable) if the subject has a medical condition that leads to a hospitalization or an 
emergency room visit or to a visit to/by a doctor or is otherwise of concern.
An ILI instruction sheet will be provided with instructions for reporting possible ILIs. 
The subject or legal guardian will be reminded to contact the site immediately if the 
subject experiences symptoms meeting primary protocol-defined ILI criteria in order to 
have a NP swab collected for evaluation of the presence of influenza virus. If anti-viral 
medications (e.g. neuraminidase inhibitors) are prescribed it is recommended that an NP 
swab be obtained prior to the first dose. 
An ILI booklet will be dispensed to document, in case of a protocol-defined ILI, the 
subject’s daily body temperature. The subject or legal guardian will be instructed to start
recording the subject’s daily body temperature (preferably oral) daily from protocol-
defined ILI onset day until the day the subject comes in to the clinic for their NP sample 
collection. Subjects will be asked to return the ILI booklet at the time of their ILI clinic 
visit. At the ILI visit the subject’s will be given a new ILI booklet in case they experience 
another ILI.
Completion instructions should be directed at the individual(s) who will enter the 
information into the ILI booklet. In some situations, the ILI booklet may be completed by 
somebody other than the subject or legal guardian, except study site personnel. If a person 
other than the subject or legal guardian enters information into the ILI booklet, the reason 
that the subject cannot complete the ILI booklet and the person’s identity and relationship 
to the subject must be documented in the ILI booklet. Any individual that makes entries 
into the ILI booklet must receive completion instructions at the time of the clinic visit. In 
some countries based on local requirements and practices subjects may also be given a 
subject identification card which will contain emergency contact information.
5.2.2
Post-vaccination Reminder Calls
Subject Diary Reminder Calls
Subjects participating in the solicited safety subset will receive a diary reminder call on 
Day 3. The purpose of this call is to remind the subject or legal guardian about 
completion of the Subject Diary. The call follows the Subject Diary Reminder Phone Call 
Script provided to the site. The subject or legal guardian should be reminded to contact 
the site via the telephone number provided in the informed consent to discuss medical 
questions.
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The reminder call is not intended to be an interview for collection of safety data. If the 
subject or legal guardian wishes to describe safety-relevant information, the call should 
be continued by a healthcare professional from the study site, and the safety data should 
be recorded in the subject’s medical chart.
5.3
Post-vaccination Visit(s)
Please refer to Time and Events Table 2 and 3. Post-vaccination visits will be performed 
on Days 15, 22, 91, 181, 271 and 366. In the event that a scheduled or unscheduled visit 
or call/message coincides, procedures may be combined. 
5.3.1
Follow-up Clinic Visit(s)
Safety follow-up clinic visits will be performed on Days 22 and 181.
During the follow-up clinic visit on Day 22, for subjects participating in the solicited 
safety subset, the Subject Diary will be reviewed and collected. No changes to the 
information recorded within the Subject Diary are permissible. For details on the Subject 
Diary see Sections 3.4.2, Tools Used for Data Collection and 5.2.1, Post-vaccination 
Procedures. The subject or legal guardian will be interviewed to determine if any 
unsolicited adverse events (including SAEs, ILIs, NOCDs, AEs leading to withdrawal 
and AESIs) occurred and if any concomitant medications or vaccines were taken/
received during the time since the last clinic visit. This interview will follow a script 
which will facilitate the collection of relevant safety information. The healthcare 
professional reviewing these data will discuss the symptoms (if any) reported by the 
subject and will determine if any additional diagnoses and/or adverse events are present. 
All adverse events reported by the subject or legal guardian at this follow-up clinic visit 
must be recorded in the subject's source document and on an Adverse Events CRF, as 
specified in Section 7.1, Safety Assessment, and not written on the script used for the 
interview.
During the follow-up clinic visit on Day 181, the subject will be interviewed to obtain 
information relating to a subset of unsolicited AEs (all SAEs, ILIs, NOCDs, AEs leading 
to withdrawal and AESIs) and use of medication to treat these. 
During both follow-up clinic visits, the subject will be asked as to whether he or she was 
hospitalized or was evaluated at an emergency room or a physician’s office for any illness 
since the site’s last contact with the subject. If an SAE has been identified by the site staff 
during the interview which has not previously been reported by the subject, this SAE will 
be reported by the site within 24 hours to Seqirus or delegate. Any additional relevant 
medical history will be recorded as needed.
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During both follow-up clinic visits, an ILI assessment will be performed to determine if 
symptoms of ILI are present. Potential ILI symptoms will be documented in the subject’s 
source records. If the onset of the ILI is 6 days or less before the visit, a NP swab should 
be collected from the subject for influenza testing and study staff will document the ILI 
on an Adverse Event and ILI CRF (see procedures described in Section 5.4, Unscheduled 
Visits). 
During both follow-up clinic visits, a brief symptom-directed physical examination will 
be performed by a qualified health care practitioner according to symptoms the subject 
has reported. This physical examination will include an examination of organ systems 
that are considered relevant by the investigator based on review of the subject’s reported 
adverse events, and concomitant medication use. This assessment may include 
measurement of vital signs (respiratory rate, blood pressure and heart rate), body 
temperature (preferably oral) and a check of general appearance. The physical assessment 
must be performed by the investigator or designee of the investigator, who is qualified to 
perform a physical assessment in accordance with their institutional policy. Measurement 
and recording of vital signs and body temperature may be conducted by a trained health 
care professional. Corresponding information is documented in the subject’s source 
document and eCRF(s). 
During the Day 22 follow-up clinic visit, approximately 10 ml of blood will be drawn 
from selected subjects participating in the immunogenicity season (see Section 3.5, 
Collection of Clinical Specimens).
The site should also schedule the next study activity, the safety call, with the subject or 
legal guardian. It is recommended for the site to also schedule in the remaining upcoming 
study activities whenever possible.
The subject or legal guardian will receive a written reminder of the next planned study 
activity. The subject or legal guardian will be reminded to contact the site immediately 
(or as soon as the subject is medically stable) if the subject has a medical condition that 
leads to a hospitalization, an emergency room visit, or a visit to/by a doctor, or is 
otherwise of concern.
The subject or legal guardian will be reminded to contact the site immediately if the 
subject experiences symptoms meeting primary protocol-defined ILI criteria in order to 
have a NP swab collected for evaluation of the presence of influenza virus. If anti-viral 
medications (e.g. neuraminidase inhibitors) are prescribed it is recommended that an NP 
swab be obtained prior to the first dose.
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5.3.2
Safety Follow-up Calls
Safety follow-up calls will be performed on Days 15, 91 and 271.
Safety follow-up calls are calls made to the subject by a healthcare professional 
designated on the site log. These calls will follow a script which will facilitate the 
collection of relevant safety information. The subject or legal guardian will be 
interviewed according to the script. On Day 15, information will be collected regarding 
all unsolicited adverse events and concomitant medications or vaccinations associated 
with those events. Safety follow-up calls performed on Days 91 and 271 will collect
information relating to a subset of unsolicited adverse events including SAEs, adverse 
events of special interest (AESIs), AEs leading to withdrawal, new onset of chronic 
disease (NOCD), ILI and concomitant medications or vaccinations associated with those 
events. All safety information described by the subject must be written down in a 
designated location within the source document and not written on the script used for the 
telephone call.
The subject will be asked as to whether he or she was hospitalized or was evaluated at an 
emergency room for any illness since the site’s last contact with the subject. If an SAE 
has been identified by the site staff during the interview which has not previously been 
reported by the subject, this SAE will be reported by the site within 24 hours to Seqirus or 
delegate. Any additional relevant medical history will be reported to Seqirus or delegate
and recorded as needed.
ILI assessments will be performed to determine if symptoms of ILI are present. If the 
subject reports during phone contact that a medical event has occurred with symptoms 
consistent with an ILI, the subject will be asked to visit the site for further evaluation and 
potential NP swab taking. An NP swab should be collected, for evaluation of the presence 
of influenza virus, preferably within 3, but up to 6, days after the first day of onset of ILI 
symptoms. See procedures described in Section 5.4, Unscheduled Visits.
The subject or legal guardian will receive a reminder of the next planned study activity. 
The subject or legal guardian will be reminded to contact the site immediately (or as soon 
as the subject is medically stable) if the subject has a medical condition that leads to a 
hospitalization or an emergency room visit or to a visit to/by a doctor or is otherwise of 
concern.
The subject or legal guardian will be reminded to contact the site immediately if the 
subject experiences symptoms meeting primary protocol-defined ILI criteria to have a NP 
swab collected for evaluation of the presence of influenza virus. If anti-viral medications 
(e.g. neuraminidase inhibitors) are prescribed it is recommended that an NP swab be 
obtained prior to the first dose.
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5.3.3
Active Influenza Surveillance Phone Calls/Messages
Active surveillance for ILI for each subject will be conducted weekly either via telephone 
contacts or message from Day 1 to Day 181, or until the end of the influenza season, 
whichever is longer. The subject will be asked via phone/message a scripted set of 
questions to determine if symptoms of ILI are present. The purpose of the phone 
call/message is to trigger a clinic (or home) visit and a NP swab sample collection if ILI 
symptoms are present. Should ILI symptoms be present, the subject will also be reminded 
to complete the ILI booklet. Neither phone calls nor message are intended to collect any 
clinical data. Site personnel’s follow up on all cases meeting primary protocol-defined ILI
criteria is to be documented in the subject’s source records and monitored in order to 
ensure that all subjects with ILI symptoms are scheduled for the NP swab sample 
collection visit as soon as possible within 3, but up to 6, days after the first day of onset of 
ILI symptoms. Data collected will be monitored by the study monitors in order to ensure 
adherence to the study protocol.
The subject will also be reminded to contact the site immediately if he or she experiences 
symptoms meeting primary protocol-defined ILI criteria to have a NP swab collected for 
evaluation of the presence of influenza virus. If anti-viral medications (e.g. neuraminidase 
inhibitors) are prescribed it is recommended that an NP swab be obtained prior to the first 
dose.
5.4
Unscheduled Visits
Please refer to Time and Events Table 4. An unscheduled visit describes a non-routine 
study visit triggered by a specific event. These could include anticipated or unanticipated 
adverse events or interventions.
5.4.1
Subjects Meeting the Influenza-Like-Illness Criteria
Clinic Visit or Home Visit – Obtaining NP Swab
Subjects will be asked to come to the site for an unscheduled clinic visit when 
experiencing symptoms meeting the primary protocol-defined ILI criteria. In the 
exceptional case that a clinic visit is not feasible, a home visit may be considered. The 
visit should occur as soon as possible within 3, but up to 6, days after the first day of 
onset of ILI symptoms. During the visit the following procedures should be carried out: 

Assess ILI symptoms and assess associated medication. Document any anti-viral 
medication use from the first day of onset of ILI symptoms.

Collect a NP swab for evaluation of the presence of influenza virus following the 
procedures for collecting, processing and shipping as described in the Lab Manual.
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
Evaluate the subject’s body temperature (preferably oral), heart rate, respiratory rate 
and blood pressure and perform a symptom-directed physical examination.

Record the ILI, related information, medically-attended adverse events from ILI onset 
and associated concomitant medication in the source documents and in the eCRF 
(ILI-report and adverse events section).

Schedule in next study activity
ILI Follow-up Safety Call
An ILI follow-up safety call will be performed at 30 (+7) days after primary protocol-
defined ILI onset, amongst subjects who have had their NP swab obtained
During the visit the following procedures should be carried out:

Assess ILI symptoms and associated medication, if any.

Assess for medically-attended adverse event.

Remind subject of next study activity.
5.5
Study Termination Visit
The study termination visit will occur on Day 366. The termination visit must be a clinic 
visit; unless the subject is early terminated in which case a study termination visit may be 
a telephone call. The date of termination is the date of the last contact (clinic visit or 
telephone call) in which the subject’s health status was assessed or, in cases where the 
subject does not agree to any further safety follow-up; it is the date consent is withdrawn. 
This date should be recorded on the termination eCRF page. For visit procedures to be 
performed for a subject whose planned study participation ends prematurely, please see 
Section 5.5.1, Early Termination Visit.
At the clinic visit, the following procedures will be performed:

Interview the subject to obtain information regarding potential SAEs, ILIs, NOCDs, 
AEs leading to withdrawal and AESIs and the medication to treat these. 

Ask the subject as to whether he or she was hospitalized or was evaluated at an 
emergency room for any illness since the site’s last contact with the subject. If an 
SAE has been identified by the site staff during the interview and has not previously 
been reported by the subject, this SAE must be reported by the site within 24 hours to 
Seqirus or delegate. Record any additional relevant medical history as needed.
An assessment will be performed to determine if symptoms of ILI are present. 
Potential ILI symptoms will be documented in the subject’s source records. If the 
onset of the ILI is 3, or at most 6, days before the visit, an NP swab should be 
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collected from the subject for influenza testing and study staff will document the ILI 
on an Adverse Event and ILI CRF. See procedures described in Section 5.4, 
Unscheduled Visits. Should an ILI be identified, it is recommended to postpone the 
study termination visit, to allow for the ILI follow-up visit to occur.

Should the subject have experienced a protocol defined ILI for which an NP swab was 
obtained, please ensure collection and review of the ILI booklet and collect the 
information of any medically-attended adverse events which have occurred within 30 
days after the onset of the of ILI.

A qualified healthcare professional will perform a brief symptom-directed physical 
examination if necessary according to symptoms the subject has reported. This is a 
physical examination that will include an examination of organ systems that are 
relevant to the investigator based on review of the subject’s reported adverse events, 
concomitant medication use. This assessment may include: measurement of vital 
signs (respiratory rate, blood pressure and heart rate), body temperature (preferably 
oral) and a check of general appearance. The physical assessment must be performed 
by the investigator or designee of the investigator, who is qualified to perform a 
physical assessment in accordance with their institutional policy. Measurement and 
recording of vital signs and body temperature may be conducted by a trained health 
care professional. Corresponding information is documented in the subject’s source 
document and eCRF(s). Measurement and recording of vital signs and body 
temperature may be conducted by a trained health care professional.
The site will review with the subject or legal guardian the plan of when information 
relating to the subject’s participation in the study may be available (e.g., study results, 
treatment assignments). It will also be discussed how information relating to the subject’s 
participation in the study will be shared with the subject’s healthcare provider, if the 
subject or legal guardian chooses to share this information.
The site will complete the termination eCRF page and this will mark the completion of 
the subject’s participation in the study.
5.5.1
Early Termination Visit
When a subject is withdrawn from treatment or withdraws from the study, the investigator 
will notify the Sponsor and, when possible, will perform the procedures listed below. The 
reason(s) for the early termination will be included in the subject’s source documentation. 
If the Early Termination Visit is a telephone call, collect as much information as possible. 
At the clinic visit or during the telephone call, the same procedures will be performed as 
during the study termination visit, see Section 5.5 Study Termination Visit, if possible.
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In addition, the following procedures will be performed:

Collect and review Subject Diary, if applicable.

Review the subject’s safety data (if collection of these was in progress at the time of 
study termination).

Collect and review ILI booklet, if applicable.
The site will review with the subject or legal guardian the plan of when information 
relating to the subject’s participation in the study may be available (e.g., study results, 
treatment assignments). It will also be discussed how information relating to the subject’s 
participation in the study will be shared with the subject’s healthcare provider, if the 
subject or legal guardian chooses to share this information.
The site will complete the termination eCRF page and this will mark the completion of 
the subject’s participation in the study.
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6.
TREATMENT OF SUBJECTS
All vaccines associated with this study are to be stored separately from other vaccines and 
medications in a secure location under appropriate storage conditions with temperature 
monitoring. All vaccines associated with this study must be checked for expiration 
date prior to use. Expired vaccines must not be administered to subjects.
6.1
Study Vaccine(s)
The term ‘study vaccine’ refers to those vaccines provided by the Sponsor, which will be 
evaluated as part of the study objectives. The study vaccines specific to this study are 
described below.
Investigational Vaccine: aQIV
An approximately 0.5 mL dose of aQIV (quadrivalent MF59C.1 adjuvanted influenza 
vaccine) contains nominally 15 µg of haemagglutinin (HA) of each of the 2 influenza 
type A strains and each of the 2 influenza type B strains for a total of 60 µg of HA in the 
vaccine. The strain composition will be that recommended by the WHO for quadrivalent 
influenza vaccines contemporaneous to the timing of the study. The full composition of 
the vaccine is reported in Table 6.1-1.
Table 6.1-1:
aQIV Vaccine Composition
Names of Ingredients
Quantity per dose*
Function
Active Ingredients
Haemagglutinin (HA) and Neuraminidase (NA) 
antigens from the influenza virus strains 
recommended by the WHO / CBER/ CHMP for the 
manufacture of influenza vaccine for season 
A/ (H1N1)
A/ (H3N2)
B/ (Yamagata lineage)
B/ (Victoria lineage)
nominally 15g 
HA/strain 
Active ingredient
Adjuvant
Squalene
9.75mg
oil phase
Polysorbate 80
1.175mg
Surfactant
Sorbitan trioleate
1.175mg
Surfactant
Sodium citrate
0.66mg
Buffer
Citric acid
0.04mg
Buffer
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Names of Ingredients
Quantity per dose*
Function
Other Ingredients
Sodium chloride
4.00mg
Isotonic aid
Potassium chloride
0.10mg
Buffer
Potassium dihydrogen phosphate
0.10mg
Buffer
Disodium phosphate dihydrate
0.67mg
Buffer
Magnesium chloride hexahydrate
0.05mg
Stabiliser
Calcium chloride dihydrate
0.06mg
Stabiliser
Water for injection
up to 0.50mL
Diluent
**
Volume of Formulation
0.5 mL
Appearance
Liquid, milky-white emulsion
Vaccine Presentation
Pre-filled syringe
*
the quantities indicated in this table reflect the amount in a 0.5 mL dose. 
** residues of special relevance: barium sulphate, cetyltrimethylammonium bromide (CTAB), chicken 
proteins, such as ovalbumin, formaldehyde, kanamycin and neomycin sulphate.
Control Vaccine: Boostrix®
Boostrix® is a combined Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular 
Pertussis Vaccine, Adsorbed. An approximately 0.5 mL dose of Boostrix® will be 
administered to the subject. The full composition of the vaccine is reported in Table 6.1-
2. For a comprehensive review of Boostrix® please refer to the Summary of Products 
Characteristics/ Package Insert supplied by Seqirus or delegate; this document should be 
reviewed by the Investigators prior to initiating the study. 
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Table 6.1-2:
Boostrix® Vaccine Composition
Names of Ingredients
Quantity per dose*
Active Ingredients 
Diphtheria toxoid
Not less than 2 International Units 
(IU) (2.5 Lf)
Tetanus toxoid
Not less than 20 International Units 
(IU) (5.0 Lf)
Bordetella pertussis antigens 
Pertussis toxoid
8 micrograms
Filamentous Heamagglutinin
8 micrograms
Pertactin
2.5 micrograms
Adjuvants
Adsorbed on aluminium hydroxide
≤ 0.39 milligrams Al3+
Other Ingredients
Sodium chloride
4.5 milligrams
Water for injection
Volume of Formulation
0.5 mL
Appearance
Liquid, turbid white suspension
Vaccine Presentation
Pre-filled syringe
*
the quantities indicated in this table reflect the amount in a 0.5 mL dose. 
** residues of special relevance: polysorbate 80 (Tween 80) and formaldehyde.
6.2
Non-Study Vaccines
The term ‘non-study vaccine’ refers to those vaccines which will be intentionally given to 
study subjects but not formally included in the analysis of study objectives. Non-study 
vaccines will not be provided by Seqirus. 
6.3
Vaccine Preparation and Administration
The vaccine must be prepared according to the instruction sheet (aQIV) or package insert
(Boostrix®) before use. Expired vaccines must not be administered.
The investigator or designee will be responsible for oversight of the administration of 
vaccine to subjects enrolled in the study according to the procedures stipulated in this 
study protocol. All vaccines will be administered only by unblinded personnel who are 
qualified to perform that function under applicable local laws and regulations for the 
specific study site.
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Both vaccines are to be provided in prefilled syringes (PFS), each with an injectable 
volume of approximately 0.5 mL. The full volume contained in the PFS is to be 
administered.
Vaccination will be performed intramuscularly, preferably in the deltoid muscle of the 
non-dominant arm.
It is recommended that 25 gauge, 25mm (1 inch) of length needle is used for the vaccine 
administration.
Detailed vaccine preparation and administration instructions will be provided to 
investigators in the Protocol Ancillary Document prior to study start.
PRECAUTIONS TO BE OBSERVED IN ADMINISTERING STUDY VACCINE:
Prior to vaccination, subjects must be determined to be eligible for study vaccination and 
it must be clinically appropriate in the judgment of the investigator to vaccinate. 
Eligibility for study vaccine administration is determined by evaluating the entry criteria 
outlined in protocol Sections 4.1, Inclusion Criteria and 4.2, Exclusion Criteria.
Delay of study vaccination is determined by following the criteria outlined in Section 4.3, 
Criteria for Delay of Vaccination.
Study vaccines should not be administered to individuals with known hypersensitivity to 
any component of the vaccines. 
Shake the vaccine well before use to form a homogeneous suspension. The vaccine 
should be visually inspected for particulate matter and discoloration prior to 
administration. In the event of any foreign particulate matter and/or variation of physical 
aspect being observed, do not administer the vaccine and contact the Sponsor and report 
the issue as a Pharmaceutical Technical Complaint. Do not discard the vaccine until 
authorized by Seqirus.
Standard vaccination practices are to be observed and care should be taken to administer 
the injection intramuscularly. Before administering vaccine, the vaccination site is to be 
disinfected with a skin disinfectant (e.g., 70% alcohol). Allow the skin to dry. DO NOT 
inject intravascularly.
As with all injectable vaccines, trained medical personnel and appropriate medical 
treatment should be readily available in case of anaphylactic reactions following vaccine 
administration. For example, epinephrine 1:1000, diphenhydramine, and/or other 
medications for treating anaphylaxis should be available.
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6.4
Vaccine Administration Error or Overdose of Vaccine 
Vaccine administration error is defined as receiving a dose of study vaccine that was not 
reconstituted as instructed or administered by a different route from the intended route of 
administration. An overdose of study vaccine (whether accidental or intentional) is 
defined when a dosage higher than the recommended dosage (as per the aQIV dosing 
regimen referred to in Table 6.1-1 or as per the package insert of Boostrix®) is 
administered.
Any vaccine administration error or overdose of study vaccine detailed in this protocol 
must be reported as an adverse event, and if the vaccine administration error or overdose 
is associated with a SAE, it must be reported as such within 24 hours to the Sponsor.
6.5
Prior and Concomitant Medications and Vaccines
All influenza vaccination history in the 5 years prior to subject enrolment into the study is 
to be obtained from the subject and recorded in the subject’s source records. All influenza 
vaccinations received by the subject in the 12 months prior to enrolment into the study 
should additionally be recorded on the Prior and Concomitant Medications eCRF.
All medications and vaccines taken or received by the subject within 2 months prior to 
the start of the study are to be recorded on the Prior and Concomitant Medications eCRF.
Any blood products received within 3 months prior to enrolment must also be 
documented in the Prior and Concomitant Medications eCRF. Vitamins and minerals are 
excluded from this scope.
In addition, the following are considered prior medications for this protocol and should be 
documented in the Prior and Concomitant Medications CRF: all medication/vaccines 
described in the inclusion and exclusion criteria (see Section 4, Selection of Study 
Population) of this protocol including: 

Any influenza vaccine within 1 year prior to enrolment.

Any diphtheria or tetanus toxoid or pertussis (acellular or whole cell) vaccines within 
the previous 5 years.

Systemic administration of corticosteroids (PO/IV/IM) at a dose equivalent to 20 mg 
of prednisone for more than 14 consecutive days within 90 days prior to informed 
consent.

Administration of antineoplastic and immunomodulating agents (e.g TNFα 
antagonists or anti-B cell monoclonal antibodies) or radiotherapy within 1 year prior 
to informed consent.

Immunoglobulins or any blood products within 180 days prior to informed consent.
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
Any investigational or non-registered medicinal product within 30 days prior to 
informed consent.

Any inactivated vaccines 14 days or live-attenuated vaccine 28 days prior to 
enrolment in this study.
The use of antipyretics and/or analgesic medications within 24 hours prior to vaccination 
must be identified and the reason for their use (prophylaxis versus treatment) must be 
described in the source document and Concomitant Medications eCRF. The use of 
antipyretics/analgesics within 24 hours prior to vaccine administration is a reason to delay 
study vaccination (see Section 4.3, Criteria for Delay of Vaccination.
The use of antipyretics and/or analgesic medications and the reason for their use 
(prophylaxis versus treatment) will be documented along with solicited adverse events on 
the Subject Diary daily until Day 7 for subjects participating in the solicited safety subset
(see Section 7.1.1 Solicited Adverse Events).
Medications taken for prophylaxis are those intended to prevent the onset of symptoms. 
Medications taken for treatment are intended to reduce or eliminate the presence of 
symptoms that are present.
Concomitant medications include all medications (including vaccines) taken 
by/administered to the subject at and after enrolment.
The following concomitant medications will be recorded in the Concomitant Medications 
eCRF:

All concomitant medications (including vaccines) from Day 1 to Day 22.

All medications associated with SAEs, NOCD, AESIs, ILIs and AEs that lead to 
premature withdrawal from the study, from Visit 1 to study termination.

All medications associated with any medically-attended adverse events within 30 days
after the ILI onset
When recording concomitant medications/vaccines, they should be checked against the 
study entry and continuation criteria in Section 4, Selection of Study Population to ensure 
that the subject should be enrolled/continue in the study.
In addition, use of the following concomitant medications after enrolment should be 
documented on the Concomitant Medication eCRF page as they may have an effect on 
the interpretation of the study objectives and therefore if used, may be determined to be a 
reason for exclusion from one of the analysis sets.

Anti-viral medication following ILI, prior to obtaining NP swab
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
Administration of the seasonal influenza vaccines during study participation

Blood, blood products or a parenteral immunoglobulin preparation 

Oral or systemic corticosteroids (topical, inhaled, intranasal corticosteroids are 
permitted)

Other immunosuppressive agents

Any vaccine within 28 days of study vaccination
6.6
Vaccine Supply, Labeling, Storage and Tracking
The Sponsor will ensure the following:

Supply the study vaccine(s).

Appropriate labeling of all study vaccines provided that complies with the legal 
requirements of each country where the study is to be performed.
The investigator must ensure the following:

Acknowledge receipt of the study vaccines by a designated staff member at the site, 
including:
-
Confirmation that the vaccines were received in good condition
-
Confirmation to the Sponsor of the temperature range during shipment from the 
Sponsor to the investigator’s designated storage location
-
Confirmation by the Sponsor that the vaccines are authorized for use.

Proper storage of the study vaccines, including:
-
Storage in a secure, locked, temperature-controlled location.
-
Proper storage according to the instructions specified on the labels.
-
Appropriate record keeping and inventory of the study vaccines, including regular 
documentation of adequate storage temperature.

Appropriate use of the study vaccines, including:
-
Not use of vaccines prior to receipt of authorization for use from the Sponsor.
-
Use only in accordance with the approved protocol.
-
Proper handling, including confirmation that the vaccine has not expired prior to 
administration.
-
Appropriate blinded documentation of administration of vaccines to study subjects 
including:
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▪
Date, dosage, batch/lot numbers, expiration dates, unique identifying numbers 
assigned to subjects and study vaccines, and time of vaccine administration. 
This information will be maintained in an accountability log that will be 
reviewed by the site monitor.
▪
Reconciliation of all vaccines received from the Sponsor. Reconciliation is 
defined as maintaining records of which and how many vaccines were 
received, which vaccines were administered to subjects, which vaccines were 
destroyed at the site, and which vaccines were returned to the Sponsor, as 
applicable.

Proper adherence to the local institutional policy with respect to destruction of study 
vaccines.

Complete record keeping of vaccine use, wastage, return or destruction, including 
documentation of:
-
Copy of the site’s procedure for destruction of hazardous material.
-
Number of doses destroyed, date of destruction, destruction code (if available), 
method of destruction, and name of individual performing destruction.
Vaccines that have been stored differently from the manufacturer’s indications must not
be used unless the Sponsor provides written authorization for use. In the event that the use 
cannot be authorized, the Sponsor will make every effort to replace the vaccine supply. 
All vaccines used in conjunction with this protocol must be stored separately from normal 
hospital/practice stocks to prevent unintentional use of study vaccines outside of the 
clinical study setting.
Monitoring of vaccine accountability will be performed by the study monitor during site 
visits and at the completion of the study.
At the conclusion of the study, and as appropriate during the course of the study, the 
investigator must ensure that all unused study vaccines, packaging and supplementary 
labels are destroyed locally (upon approval from Sponsor) or returned to the Sponsor.
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7.
ASSESSMENTS
7.1
Safety Assessment
The measures of safety used in this study are routine clinical procedures. They include a 
close vigilance for, and stringent reporting of, selected local and systemic adverse events 
routinely monitored in vaccine clinical studies as indicators of reactogenicity.
An adverse event (AE) is defined as any untoward medical occurrence in a subject or 
clinical investigation subject administered a pharmaceutical product at any dose that does 
not necessarily have to have a causal relationship with this treatment. Therefore, an AE 
can be any unfavorable and unintended sign (including an abnormal laboratory finding, 
for example), symptom, or disease temporally associated with the use of an 
investigational product, whether or not considered related to the investigational product. 
This definition includes intercurrent illnesses or injuries and exacerbation of pre-existing 
conditions.
The period of observation for AEs extends from the time the subject signs informed 
consent until he or she completes the specified safety follow-up period Day 366 or 
terminates the study early (whichever comes first). AEs occurring after the ICF is signed 
but prior to receiving study vaccine/product will be documented as an adverse event and 
recorded within source document. However, any AEs occurring prior to receipt of any 
study vaccine will be analyzed separately from “treatment emergent” AEs (AEs occurring 
after administration of the first study vaccine).
Adverse events are collected as either solicited or unsolicited adverse events. Solicited 
events are derived from organized data collection systems, such as Subject Diaries or 
interview.
7.1.1
Solicited Adverse Events
The term “reactogenicity” refers to solicited signs and symptoms (“solicited adverse 
events”) occurring in the hours and days following a vaccination, to be collected by 
subjects participating in the solicited safety subset subject or legal their guardian for 7
consecutive days, using a pre-defined Subject Diary.
The following solicited adverse events are included in the Subject Diary. Each adverse 
event is to be assessed using the scoring system reported below:
Solicited Local Adverse Events
Induration, erythema and ecchymosis will be measured by the subject and recorded 
directly on the Subject Diary.
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Injection site pain will be measured as follows: grade 0= absent, grade 1/mild= present 
but does not interfere with activity, grade 2/moderate = interferes with activity, grade 
3/severe = prevents daily activity.
Solicited Systemic Adverse Events
Loss of appetite will be measured as follows: grade 0 = none, grade 1/mild = eating less 
than usual with no effect on normal activity, grade 2/moderate = eating less than usual / 
interfered with normal activity, grade 3/severe = not eating at all.
Nausea will be measured as follows: grade 0 = none, grade 1/mild = no interference with 
daily activity, grade 2/moderate = interferes with daily activity, grade 3/severe = prevents 
daily activity.
Fatigue, generalized myalgia, generalized arthralgia, headache and chills will be 
measured using the following scoring system: grade 0 = none, grade 1/mild= no 
interference with daily activity, grade 2/moderate = interferes with daily activity, grade 
3/severe = prevents daily activity.
Vomiting will be measured as follows: grade 0 = none, grade 1/mild = 1-2 times per 24 
hours, grade 2/moderate = 3 to 5 times per 24 hours, grade 3/severe = 6 or more times in 
24 hours or requires intravenous hydration.
Diarrhea will be measured as follows: grade 0 = fewer than 2 loose stools per 24 hours, 
grade 1/mild = 2-3 loose stools in 24 hours, grade 2/moderate = 4-5 stools in 24 hours, 
grade 3/severe = 6 or more loose stools in 24 hours or requires intravenous hydration.
Other Solicited Adverse Events

Use of analgesics/antipyretics will be captured as “absent” or “present” and will also 
be summarized by “for treatment” or “for prophylaxis”

Body temperature will be captured. Fever is defined as body temperature ≥38.0 ◦C, as 
measured preferably orally
For subjects participating in the solicited safety subset, the study staff must review the 
data entered into the Subject Diary as described in Section 3.4.2, Tools Used for Data 
Collection and section 5.3.1, Follow-up Clinic Visit(s).
Note: Any solicited adverse event that meets any of the following criteria must be entered 
into subjects’ source document (see Section 9.1, Source Documentation) and also as an 
adverse event on the Adverse Event CRF:
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
Solicited local or systemic adverse event that continues beyond Day 7 after 
vaccination.

Solicited local or systemic adverse event that leads to a visit to a healthcare provider 
(medically attended adverse event, see Section 7.1.3, Evaluation of Adverse Events).

Solicited local or systemic adverse event leading to the subject withdrawing from the 
study or the subject being withdrawn from the study by the investigator (adverse 
event leading to withdrawal, see Section 7.1.3, Evaluation of Adverse Events).

Solicited local or systemic adverse event that otherwise meets the definition of a SAE
(see Section 7.1.4, Serious Adverse Events).
7.1.2
Unsolicited Adverse Events
An unsolicited adverse event is an adverse event that was not solicited using a Subject 
Diary and that was spontaneously communicated by a subject or legal guardian who has 
signed the informed consent.
Potential unsolicited AEs may be medically attended (defined as symptoms or illnesses 
requiring hospitalization, or emergency room visit, or visit to/by a health care provider –
refer to CRF Instructions for further guidance), or were of concern to the subject or legal 
guardian(s). In case of such events, subjects or legal guardian(s) will be instructed to 
contact the site as soon as possible to report the event(s). The detailed information about 
the reported unsolicited AEs will be collected by the qualified site personnel during the 
interview and will be documented in the subject’s records.
Unsolicited AEs that are not medically attended nor perceived as a concern by subjects or 
legal guardian(s) will be collected during interview with the subject or legal guardian(s)
and by review of available medical records at the next visit (see section 5.3, Post-
vaccination Visit(s)).
7.1.3
Evaluation of Adverse Events
Every effort should be made by the investigator to evaluate safety information reported 
by a subject for an underlying diagnosis and to capture this diagnosis as the event in the 
AE page. In other words, the practice of reporting only symptoms (e.g., “cough” or “ear 
pain”) are better reported according to the underlying cause (e.g., “asthma exacerbation” 
or “otitis media”).
The severity of events reported on the Adverse Events CRF will be determined by the 
investigator as:
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Mild:
transient with no limitation in normal daily activity.
Moderate:
some limitation in normal daily activity.
Severe:
unable to perform normal daily activity.
The relationship of the study treatment to an AE will be determined by the investigator 
based on the following definitions:
1. Not Related
The AE is not related to an investigational vaccine if there is evidence that clearly 
indicates an alternative explanation. If the subject has not received the vaccine, the timing 
of the exposure to the vaccine and the onset of the AE are not reasonably related in time, 
or other facts, evidence or arguments exist that reasonably suggest an alternative 
explanation, then the AE is not related.
2. Possibly Related
The administration of the investigational vaccine and AE are considered reasonably 
related in time and the AE could be explained by exposure to the investigational vaccine 
or by other causes.
3. Probably Related
Exposure to the investigational vaccine and AE are reasonably related in time and no 
alternative explanation has been identified.
The relationship of the study treatment to an unsolicited AE will be determined by the 
investigator. 
Note: solicited AEs will not be evaluated for relationship to study treatment. Grading for 
severity of solicited local and systemic AEs is described in Section 7.1.1, Solicited 
Adverse Events.
Adverse events will also be evaluated by the investigator for the co-existence of any of 
the other following conditions:

AESI see Section 7.1.4.1, AESI.

“New onset of chronic disease” (NOCD): an adverse event that represents a new 
diagnosis of a chronic medical condition that was not present or suspected in a subject 
prior to study enrolment.

AEs leading to withdrawal: adverse events leading to study or vaccine withdrawal.
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If solicited or unsolicited adverse events have been reported and the subject or legal 
guardian(s) indicated that the symptoms required medical attendance or were of concern, 
the subject or legal guardian(s) must be contacted for further information.
When the subject or legal guardian(s) is contacted for any of these reasons, the contact 
must be documented in the subject’s source documentation.
All AEs, regardless of severity, will be monitored until resolution or until the investigator 
assesses them as chronic or stable. All subjects experiencing AEs - whether considered 
associated with the use of the study vaccine or not - must be monitored until symptoms 
subside and any abnormal laboratory values have returned to baseline, or until there is a 
satisfactory explanation for the changes observed, or until death, in which case a full 
pathologist’s report should be supplied, if possible. The investigator’s assessment of 
ongoing Adverse Events at the time of each subject’s last visit should be documented in 
the subject’s medical chart.
7.1.4
Serious Adverse Events
A SAE is defined as any untoward medical occurrence that at any dose results in one or 
more of the following:

Death.

Is life-threatening (i.e., the subject was, in the opinion of the investigator, at 
immediate risk of death from the event as it occurred); it does not refer to an event 
which hypothetically might have caused death if it were more severe.

Required or prolonged hospitalization.

Persistent or significant disability/incapacity (i.e., the event causes a substantial 
disruption of a person’s ability to conduct normal life functions).

Congenital anomaly/or birth defect.

An important and significant medical event that may not be immediately life 
threatening or resulting in death or hospitalization but, based upon appropriate 
medical judgment, may jeopardize the subject or may require intervention to prevent 
one of the other outcomes listed above.
Adverse events which do not fall into these categories are defined as non-serious.
It should be noted that a severe adverse event need not be serious in nature and that a 
SAE need not, by definition, be severe.
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Serious adverse events will be captured both on the Vaccines Serious Adverse Event 
(VSAE) form as well as on the AE CRF. All SAEs will be evaluated by the investigator 
for relationship of the event to study vaccine. SAEs that are judged to be possibly or 
probably related to the study vaccine should be reported to the Sponsor as 
related/suspected events.
The relationship of the study treatment to an SAE will be determined by the investigator 
based on the following definitions:
1. Related/suspected
The SAE is judged by the investigator to be possibly or probably related to the study 
vaccine on the AE CRF page (see Section 7.1.3, Evaluation of Adverse Events).
2. Not Related
The SAE is not related if exposure to the study vaccine has not occurred, or the 
occurrence of the SAE is not reasonably related in time, or the SAE is considered 
unlikely to be related to use of the study vaccine, i.e., there are no facts (evidence) or 
arguments to suggest a causal relationship.
The relationship of the study vaccine to an SAE will be determined by the investigator.
In addition, SAEs will be evaluated by the Sponsor or designee for “expectedness.” An 
unexpected AE is one that is not listed in the current Summary of Product Characteristics 
or the Investigator’s Brochure or an event that is by nature more specific or more severe 
than a listed event.
In addition, a pre-existing event or condition that results in hospitalization should be 
recorded on the Medical History CRF. If the onset of an event occurred before the subject 
entered the study (e.g., any pre-planned hospitalization for conditions like cosmetic 
treatments or for non-emergency routine visits for a pre-existing condition), the 
hospitalization would not lead to an AE being classified as serious unless, in the view of 
the investigator, hospitalization was prolonged as a result of participation in the clinical 
study or was necessary due to a worsening of the pre-existing condition.
7.1.4.1
Adverse Events of Special Interest
The investigator will be provided with a list of AESIs prior to FSFV. Receipt of this list 
will be documented and stored, along with the list of AESIs in the Investigator Study File.
During the course of the trial the list of AESI may change. If this occurs the investigators 
will be advised of the change and confirmation of receipt will be documented. The 
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updated list of AESIs and documentation of receipt are also stored in the Investigator 
Study File.
Subjects will be assessed at each visit for any new medical events or signs or symptoms 
that could possibly indicate an AESI. The subject will be asked whether any new 
diagnosis has been given to the subject through a review of recent medical history. 
Should a qualified health care practitioner who is not the investigator suspect a potential 
AESI, she/he should promptly inform the investigator. The AESI diagnosis will be 
recorded in the medical chart/source document as well as in the Adverse Events CRF
along with any medication used to treat the condition.
A diagnosis of an AESI is to be reported in the same manner and time frame as an SAE 
using the VSAE form. The investigator must notify Seqirus within 24hrs. The AESI 
diagnosis as well as any medication taken to treat the condition, will be recorded in the 
subject’s source documents and on the Adverse Events eCRF.
7.1.5
Methods for Recording Adverse Events and Serious Adverse Events
Findings regarding Adverse Events must be reported on an Adverse Events CRF, as 
specified in Section 7.1.1, Solicited Adverse Events, and on the VSAE form, if 
applicable, which is part of the Investigator Site File. All findings in subjects 
experiencing AEs must be reported also in the subject's source document.
All SAEs which occur during the course of the study, whether considered to be associated 
with the study vaccination or not, must be reported within 24 hours of the site becoming 
aware of the event to Seqirus or its designee. Specific instructions and contact details for 
collecting and reporting SAEs to Seqirus or delegate will be provided to the investigator.
All SAEs are also to be documented on the Adverse Events CRF. Any medication or 
other therapeutic measures used to treat the AE will be recorded on the appropriate 
CRF(s) in addition to the outcome of the AE.
After receipt of the initial report, representatives of Seqirus or its designee will contact 
the investigator if it is necessary to obtain further information for assessment of the event.
All SAEs must be reported by the investigator to his/her corresponding EC/IRB or
applicable regulatory authorities in accordance with institutional policy/regulatory 
requirements and adequate documentation of this notification must be provided to the 
Sponsor.
Seqirus or its designee must also comply with the applicable regulatory requirement(s) 
related to the reporting of suspected unexpected serious adverse vaccine reactions (also 
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known as SUSARs) to the regulatory authority (ies) and the IRB/EC. If a SUSAR or other 
safety signal relating to use of one of the study vaccines is reported to Seqirus or its 
designee, the Sponsor will communicate the information to the investigator and the 
investigator will be responsible for submitting this information to the EC/IRB and other 
relevant authorities.
7.1.5.1
Post-Study Events
Any SAE that occurs outside of the protocol-specified follow-up period and considered to 
be caused by the study vaccine must be reported to Seqirus or its designee. These SAEs 
will be processed by Seqirus or its designee as during the course of the study, until 6 
months afterwards. Instructions and contact details for collecting and reporting these 
suspected SAEs will be provided to the investigator.
7.1.6
Pregnancies
Not applicable for this study.
7.1.7
Safety Laboratory Measurements
No scheduled safety laboratory measurements are planned for this study.
7.2
Efficacy Assessment
Confirmation of influenza infection by RT-PCR or culture from a nasopharyngeal swab 
sample is necessary for the efficacy assessment in the study. Nasopharyngeal swab
retrieval will be initiated after primary protocol-defined ILI has been identified. Primary 
protocol-defined ILI can occur at any time during the study and will be evaluated in each 
subject from Visit 1 (Day 1) through Study Termination. ILI symptoms will be captured 
during study visits. The ILI onset day is defined as the first day that the subject meets the 
primary protocol-defined ILI. The end date is defined as the date the last symptom 
resolves. A new ILI episode will only be taken into account after resolution of the 
previous one, as judged by the investigator (suggested interval between two ILI episodes 
is 14 symptom-free days). 
Subjects with primary protocol defined ILI will have a NP swab collected for evaluation
of the presence of influenza virus. NP swabs should be targeted for collection within 3 
days from the ILI onset to ensure optimal viral yield, however samples will be accepted if
collected up to 6 days following the day of ILI onset. NP swabs will not be taken beyond 
a total of 7 days (6 days following onset of ILI) as the level of virus detectable beyond 
this period can be negligible, particularly for influenza A. 
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All NP swabs collected from subjects with ILI will be shipped under pre-specified
conditions in viral transport media to a qualified lab and stored for analysis for influenza.
NP swabs will be analyzed by RT-PCR and placed into culture. The result of the RT-PCR 
assay will be the presence or absence of influenza virus. The viral culture will be used for 
the purpose of viral expansion to enable phenotypic characterization of the influenza virus 
(e.g. antigenic match). Testing will be conducted by a designated laboratory in a blinded 
manner towards the treatment arm. Please see the Protocol Ancillary Document for 
name(s) and details.
7.3
Immunogenicity Assessment
The measures of immunogenicity used in this study are standard, i.e., widely used and 
generally recognized as reliable, accurate, and relevant (able to describe the quality and 
extent of the immune response).
The secondary immunogenicity analysis will evaluate immunogenicity of aQIV measured 
by the HI assay by titrating antibodies against the influenza strains homologous to the 
seasonal vaccine (see Section 2.2, Secondary Objectives). Additional immunologic 
assays, including microneutralization, may be used to measure neutralizing antibodies and 
to facilitate exploration and estimation of an immune correlate of protection.
The time points for the evaluation of antibody responses after vaccination will help to 
inform how a subject responds to the aQIV vaccine compared to the non-influenza 
comparator vaccine at Day 1 (baseline) and 22 for HI Peak antibody responses to the 
strains selected for the seasonal vaccine are typically observed after 3 weeks of 
vaccination. 
Testing will be conducted by a Seqirus or designated laboratory in a blinded manner 
towards the treatment arm and the visit. Please see the Protocol Ancillary Document for 
name(s) and details.
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8.
STATISTICAL CONSIDERATIONS
8.1
Endpoints
8.1.1
Primary Endpoint(s)
8.1.1.1
Primary Safety Endpoint(s)
Safety objective 2 will be assessed by calculating the percentage of subjects in the 
solicited safety subset with solicited local and systemic adverse events from Day 1 
through Day 7. Solicited local and systemic adverse event data from Day1-7 will be 
obtained from data collected on subject diary cards. Only subjects randomly selected for 
participation in the solicited safety subset will be asked to fill out subject diary cards from 
Day 1-7. Safety objectives 3 and 4 will be assessed based on:

Percentage of subjects with medically-attended adverse events within 30 days after of 
first occurrence RT-PCR confirmed ILI.

percentages of subjects with any unsolicited AEs and concomitant medications 
reported from Day 1 through Day 22;

percentages of subjects with SAEs, AEs leading to withdrawal from the study, 
NOCD, AESI reported from Day 1 to Day 366 and all concomitant medications 
associated with these events.
8.1.1.2
Primary Efficacy Endpoint(s)
The primary efficacy endpoint is the time to first-occurrence of RT-PCR-confirmed 
influenza from 21 through 180 days after vaccination or end of the influenza season, 
whichever is longer.
The end of the influenza season will be defined as the end of June for Northern 
Hemisphere (NH) influenza season and end of December for Southern Hemisphere (SH) 
influenza season. For tropical countries, with no typical NH or SH influenza season, the 
season is defined by the use of the strains in the vaccine formulation (i.e. strains as 
recommended for the NH or the SH influenza season) and the timing of vaccination.
An influenza event is defined as RT-PCR- or culture-confirmed influenza infection in the 
setting of an influenza-like illness (ILI). The primary protocol-definition of ILI will be 
used to define success for the primary and key secondary efficacy endpoint.
8.1.1.3
Primary Immunogenicity Endpoint(s)
There are no primary immunogenicity endpoints in this study.
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8.1.2
Secondary Endpoint(s)
8.1.2.1
Secondary Safety Endpoint(s)
There are no secondary safety endpoints in this study.
8.1.2.2
Secondary Efficacy Endpoint(s)
Additional efficacy endpoints are sought based on antigenic match of culture isolated 
influenza to the strains of virus contained in the seasonal vaccine. Both definitions of ILI 
will be used to determine the efficacy endpoints
Vaccine efficacy will be determined based on either:
-
Antigenically matched strains of influenza virus (Secondary Efficacy Objective 
1).
-
Influenza strains regardless of antigenic match (Secondary Efficacy Objective 2
and 4)
-
Antigenically unmatched strains of influenza (Secondary Efficacy Objective 3). 
8.1.2.3
Secondary Immunogenicity Endpoint(s)
The measures of immunogenicity used for Objective 5 as determined by the HI assay 
against homologous strains at Days 1 and 22, include the following:

Geometric mean HI titers (GMT);

GMT ratios (GMRs) at Day 22/Day 1;

Percentages of subjects with an HI titer ≥1:40;6

Percentages of subjects achieving seroconversion (defined as: HI ≥1:40 for subjects 
sero-negative at baseline [HI titer <1:10]; or a minimum 4-fold increase in HI titer for 
subjects sero-positive at baseline [HI titer ≥1:10]) on Day 22;1
                                               
6 The endpoints of percent of subjects achieving seroconversion and HI titer ≥ 1:40 at Day 22 will be 
assessed against the criteria described in CBER Guidance Clinical Data Needed to Support the Licensure of 
Seasonal Inactivated Influenza Vaccines (2007). Specifically, this will be that:

the lower bound of the two-sided 95% CI for the percent of subjects achieving seroconversion for 
HI antibody should meet or exceed 30%

the lower bound of the two-sided 95% CI for the percent of subjects achieving an HI antibody titer 
≥ 1:40 should meet or exceed 60%.
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
Reverse cumulative distributions of HI titers at Day 22.
8.1.3
Exploratory Endpoint(s)
8.1.3.1
Exploratory Safety Endpoint(s)
There are no exploratory safety endpoints in this study.
8.1.3.2
Exploratory Efficacy Endpoint(s)
There are no exploratory efficacy endpoints in this study.
8.1.3.3
Exploratory Immunogenicity Endpoint(s)
The exploratory endpoints determined by the MN assay against homologous strains at 
Days 1 and 22, include the following:

Geometric mean titer (GMT).

Geometric mean ratio calculated at Day 22/Day 1.

Percentage of subjects with a four-fold rise in MN antibody titer at Day 22

Reverse cumulative distributions of MN titers at Day 22.

Additionally, an estimate of the serologic correlate of protection on the basis of HI 
or other immunological responses including MN, measured three weeks after 
vaccination against the respective strain.
Further details regarding the statistical approach to estimate potential immunologic 
correlates of protection are further described in section 8.4.4.3.
8.2
Success Criteria
The study is considered successful if the primary efficacy objective is achieved together 
with an acceptable safety profile for aQIV vaccine.
8.2.1
Success Criteria for Primary Objective(s)
8.2.1.1
Success Criteria for Primary Safety Objective(s)
Not applicable.
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8.2.1.2
Success Criteria for Primary Efficacy Objective(s)
The primary efficacy objective is achieved if the lower-limit (LL) of the two-sided 95% 
CI of absolute vaccine efficacy estimate is > 0.4 using the primary protocol definition of 
ILI. In case more than one interim analysis is necessary the type 1 error (alpha) and hence 
the confidence level of the interval will be adjusted.
8.2.1.3
Success Criteria for Primary Immunogenicity Objective(s)
Not applicable.
8.2.2
Success Criteria for Secondary Objective(s)
8.2.2.1
Success Criteria for Secondary Safety Objective(s)
Not applicable.
8.2.2.2
Success Criteria for Secondary Efficacy Objective(s)
The key secondary objective is achieved if the lower-limit (LL) of the two-sided 95% CI 
of absolute vaccine efficacy estimate is > 0.4. As for the primary efficacy objective, the 
CI confidence level will be adjusted to reflect adjustment of type 1 error (alpha) in case of 
more than one interim analysis.
Other secondary efficacy/effectiveness objectives will not be tested for success.
8.2.2.3
Success Criteria for Secondary Immunogenicity Objective
The endpoints of percent of subjects achieving seroconversion and HI titer ≥ 1:40 at 
Day 22 will be assessed against the criteria described in CBER Guidance Clinical Data 
Needed to Support the Licensure of Seasonal Inactivated Influenza Vaccines (2007):

The lower bound of the two-sided 95% CI for the percentage of subjects achieving 
seroconversion for HI antibody should meet or exceed 30%. 

The lower bound of the two-sided 95% CI for the percentage of subjects achieving an 
HI antibody titer ≥1:40 should meet or exceed 60%.
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8.3
Analysis Sets
8.3.1
All Enrolled Set
All screened subjects who provide informed consent, received subject ID and provided 
demographic and/or baseline screening assessments, regardless of the subject’s 
randomization and treatment status in the study.
8.3.2
All Exposed Set
All subjects in the enrolled set who receive a study vaccination.
8.3.3
Safety Set
Solicited Safety Set (solicited local and systemic adverse events and other solicited 
adverse events)
A randomly selected sample of 1053 subjects from each treatment arm of the Exposed Set 
with any solicited adverse event data, indicating the occurrence or lack of occurrence of 
solicited adverse events (e.g., use of analgesics/antipyretics medication).
Unsolicited Safety Set (unsolicited adverse events)
All subjects in the Exposed Set with unsolicited adverse event data, indicating the 
occurrence or lack of occurrence of an adverse event.
Overall Safety Set
All subjects who are in the Solicited Safety Set and/or Unsolicited Safety Set.
Subjects will be analyzed as “treated” (i.e., according to the vaccine a subject received, 
rather than the vaccine to which the subject may have been randomized).
Subjects with reportable stratification errors will be analyzed “as corrected”, (i.e. analyze 
subject in corrected stratum) in safety. Subjects with non-reportable stratification errors 
will be shifted and analyzed in their correct stratum in safety.
8.3.4
Full Analysis Set (FAS) Efficacy/Immunogenicity Set
Full Analysis Set Efficacy (primary and secondary efficacy objectives)
All subjects in the All Enrolled Set who are randomized and receive a study vaccination, 
are under observation for at least 21 days post-vaccination and provide efficacy data.
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Full Analysis Set Immunogenicity
A randomly selected sample of 1,702 subjects including subjects from both treatment 
arms (1,362 aQIV; 340 Boostrix), in the All Enroled Set who are randomized, receive a
study vaccination and provide blood specimens before and after vaccination. Several 
FASs for all relevant immunogenicity endpoints will be detailed in the SAP.
8.3.5
Per Protocol (PP) Set Efficacy/Immunogenicity Set
All subjects in the FAS Efficacy / Immunogenicity who:

Correctly receive the vaccine (i.e., receive the vaccine to which the subjects is 
randomized and at the scheduled time points).

Have no protocol deviations leading to exclusion (see Section 8.3.7, Protocol 
Deviations) as defined prior to unblinding / analysis.

Are not excluded due to other reasons defined prior to unblinding or analysis (see 
Section 8.3.7, Protocol Deviations).
PPS are subsets of FAS and should be always defined even if the objectives do not 
require it.
Examples for subjects excluded due to other reasons than protocol deviations are subjects 
who withdrew informed consent.
In case of misrandomization with regard to treatment arm, the subject is excluded from 
the PPS. If a subject receives a vaccine, labelled for another subject but the same as the 
one the subject was randomized to, the subject will not be removed from the PPS.
If a subject received the correct study vaccine (dose, batch) but from another ongoing 
study at the site then the subject should be excluded from the PPS.
Subjects with reportable stratification error will be excluded from the PPS. A 
stratification error is considered “reportable” when it has a major impact to the 
vaccination dose and/or to the vaccination schedule of a subject. 
Subjects with non-reportable stratification errors will be analyzed in the correct stratum in 
PPS.
If a subject is unblinded during the study, except for SUSAR, or AESI he/she will be 
excluded from the PPS.
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8.3.6
Subgroups
The primary efficacy analysis will be performed by stratifying for the following 
subgroups:

Age at enrolment (≥65-74, ≥75-84, and ≥85 years);

Comorbidity/risk (yes/no defined as assessment score < 50 or ≥50 based on scale 
described in the Section 5.1.2) (Hak, 2004);

Previous influenza vaccination in the past 5 years (yes/no);

Smoking status (yes/no);

Sex;

Race;

Country;

By season, if applicable.
Immunogenicity analysis at Day 22 will be performed by stratifying for the following 
subgroups:

Age at enrolment (≥65-74, ≥75-84, and ≥85years);

Comorbidity/risk ( yes/no defined as assessment score < 50 or ≥50 based on scale 
described in the Section 5.1.2) (Hak, 2004);

Previous influenza vaccination in the past 5 years (yes/no);

Sex;

Race;
Safety analysis of any unsolicited adverse events and of any local, any systemic, or any 
other solicited adverse events (all adverse events combined for each such category) will 
be performed by stratifying for the following subgroups:

Age at enrolment (≥65-74, ≥75-84, and ≥85years);

Sex;

Race;

Country
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8.3.7
Protocol Deviations
A protocol deviation is any change, divergence, or departure from the study design or 
procedures of a study protocol. A protocol deviation may be a reason to remove data from 
an analysis set at the time of analysis. CSR-reportable protocol deviations as well as 
exclusion actions taken will be specified in the SAP. In some cases exclusion of data may 
be due to a reason other than a protocol deviation, e.g. early termination.
8.4
Statistical Analysis Plan
8.4.1
Analysis of Demographic and Baseline Characteristics
Descriptive statistics (mean, standard deviation, median, minimum and maximum) for 
age, height, weight, BMI and comorbidity score at enrolment will be calculated overall 
and by vaccine group. 
Distributions of subjects by sex, age, ethnic origin (race, ethnicity), previous vaccination 
status, smoking status, comorbidity and risk of complications from influenza will be 
summarized overall, by vaccine group, and by age group and vaccine group.
8.4.2
Analysis of Primary Objective(s)
8.4.2.1
Analysis of Primary Safety Objective(s)
8.4.2.1.1
Analysis of Extent of Exposure
The number of subjects actually receiving the vaccination will be summarized by vaccine 
group.
8.4.2.1.2
Analysis of Solicited Local, Systemic and Other Adverse Events
Solicited local AEs include: injection site erythema, induration, ecchymosis and pain.
Solicited systemic AEs include: loss of appetite, nausea, fatigue, generalized myalgia, 
generalized arthralgia, headache, chills, vomiting, diarrhea.
All solicited adverse events will be summarized according to defined severity grading 
scales. 
Frequencies and percentages of subjects experiencing each adverse event will be 
presented for each symptom severity. Summary tables showing the occurrence of any 
local or systemic adverse event overall and at each time point will also be presented.
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Post-vaccination solicited adverse events reported from day 1 to Day 7 will be 
summarized for the intervals Day 1-3, Day 4-7, Day 1-7 by maximal severity and by 
vaccine group, excluding the 30 minute measurement, which will be summarized 
separately. Injection-site erythema, ecchymosis and induration will be summarized 
according to categories based on linear measurements, please refer to the SAP for 
definition of categories.
Injection site pain and systemic adverse events (except fever) occurring up to 7 days after 
each vaccination will be summarized according to “mild”, “moderate” or “severe” 
categorization. For the definition of severity grades please refer to the Section 7.1.1 of the 
protocol.
Each solicited local and systemic adverse event will also be further summarized as 
“none” versus “any”. “Any” will include reactions with a diameter of at least 1 mm. 
Implausible measurements (for further definition see SAP) will be left out of the analysis.
Use of antipyretics and analgesics will be summarized by frequency and percentage of 
subjects reporting use. Summaries by type of use (prophylactic versus treatment) and by 
treatment arm will be provided.
Body temperature will be summarized by 0.5 °C and 1.0 °C increments from 36.0 °C up 
to ≥40 °C and will be broken down according to route of measurement. In addition, fever 
will be summarized according to “mild”, “moderate” or “severe” categorization. For the 
definition of severity grades please refer to the SAP.
8.4.2.1.3
Analysis of Unsolicited Adverse Events
This analysis applies to all adverse events occurring during the study, judged either as 
probably related, possibly related, or not related to vaccination by the investigator, 
recorded in AE CRF, with a start date on or after the date of first vaccination. AE starting 
prior to the first vaccination will only be listed. The original verbatim terms used by 
investigators to identify adverse events in the CRFs will be mapped to preferred terms 
using the Medical Dictionary for Regulatory Activities (MedDRA) dictionary. The 
adverse events will then be grouped by MedDRA preferred terms into frequency tables 
according to system organ class (SOC).
All reported adverse events, as well as adverse events judged by the investigator as at 
least possibly related to study vaccine, will be summarized according to SOC and 
preferred term within SOC. These summaries will be presented by vaccination group and 
by interval of study observation. When an adverse event occurs more than once for a 
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subject, the maximal severity and strongest relationship to the vaccine group will be 
counted.
Separate summaries will be produced for the following categories:

SAE;

Adverse events that are possibly or probably related to vaccine;

Medically attended adverse events that occur within 30 days following RT-PCR 
confirmed ILI

AESI;

NOCD;

Adverse event leading to withdrawal;

Adverse event resulting in death.
Data listings of all adverse events will be provided by subject. In addition, adverse events 
in the categories above will be provided as listed data.
For handling of missing data the entire study period will be divided into disjoint 
intervals based upon the time and event schedule in the protocol: 
Solicited AEs: 30 min, 6h-Day 3, Day 4-Day 7, and one overall interval: 6h-Day 7.
Unsolicited AEs: [Day 1-22], [Day 23-181], [Day 182-366], and [Day 1-366]. 
No imputation of missing solicited or unsolicited AEs will be used. The percentage of 
subjects with missing solicited AE assessments (e.g. missing Patient Diary) and missing 
Safety Phone Call or safety assessment will be reported for each time period.
8.4.2.1.4
Analysis of Safety Laboratory Values
Not applicable.
8.4.2.2
Analysis of Primary Efficacy Objective(s)
8.4.2.2.1
Statistical Hypotheses
The primary absolute efficacy objective will be evaluated using following null (H0) and 
alternative (H1) hypotheses:
H0: 1- HR = VE ≤ 0.4 
versus
H1: VE > 0.4,
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where HR is a hazard ratio of aQIV versus non-influenza comparator.
8.4.2.2.2
Analysis Sets
Primary vaccine efficacy analyses will be based on the Efficacy FAS, and repeated on the 
Efficacy PPS. 
8.4.2.2.3
Statistical Methods
Cox Proportional Hazards (PH) model will be used to estimate the hazard ratio:
HR = λaQIV(t)/ λComp(t) = exp(βg ( xig-xjg) + βa ( xia-xja) + βc ( xic-xjc)),
where λaQIV(s)(t) and λComp(s)(t) are stratum-specific hazards at time t, for stratum s that 
reflects a combination of age group (<75 vs ≥ 75 years) and low vs high (score <50 vs ≥ 
50) risk of influenza complications, in aQIV and comparator group, respectively; βg
denotes regression coefficient and xig(s), xjg(s) are indicators of treatment group for 
individuals i and j within stratum Subjects that did not experience ILI during observation 
period and subjects that dropped out from the study during observational period will be 
censored (right-censoring). The estimate of the hazard ratio, the respective estimate for 
absolute VE and pertaining 2-sided 95% CIs will be calculated based on this model. If the 
study continues over several seasons, estimates will be also adjusted for the factor season 
(s). Factor site/center or country might be added to the model if appropriate. In case of 
more than one interim analysis confidence level for the estimates at the final stage will be 
adjusted.
Estimates for hazard ratio in the PH model will be calculated using Maximum Partial 
Likelihood (MPL) method. In case of problems with convergence (algorithm does not 
converge or converges to infinite estimates) penalized ML approach will be used (Heinze 
and Schemper, 2001).
In case interim analyses will be performed a k-stages group - sequential test procedure for 
time-to-event data will be implemented. As the K-stage interim analysis for relative 
vaccine efficacy introduces a multiple test problem, alpha will be adjusted using error-
spending function as described in Section 8.6. For this group sequential test procedure 
parameters like information level and/or standard error at each stage will be calculated by 
the above described model and then used to calculate the actual group sequential test that 
compared the test statistic at each stage with the respective boundaries. Repeated CIs for 
each stage and also the final estimator and the respective CI can be retrieved by the group 
sequential test method to maintain simultaneous coverage probability (Jennison, 2000).
Further details of the statistical methods will be provided in the SAP.
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Missing immunogenicity values are considered missing completely at random (MCAR) 
and therefore will not contain information that impact the result of the analysis (i.e., not 
informative). Imputation methods will therefore not be used. The secondary objectives 
will be analyzed using the FAS (immunogenicity). If the percentage of vaccinated subject 
excluded from the FAS (immunogenicity) is greater than 5%, a secondary analysis based 
on the PPS will be performed to complement the FAS.
Efficacy data will be analyzed using both the FAS (Efficacy) and the PPS, irrespective of 
the difference in size between the two analysis sets. 
The following algorithm will be applied:
1. If less than 20% of subjects are without efficacy data (e.g., ILI swabs collected without 
any RT-PCR assessment record), then the analyses will be run on FAS and PPS and no 
further statistical evaluation will be performed.
2. If observations are missing for 20% or more of subjects, the missing mechanism will 
be analyzed with vaccine group as a categorical variable and a newly created variable 
describing the missing information as dependent variable (1=efficacy record present; 
0=efficacy record not present). It will be tested, by chi-square test, if the proportion of 
missing observations/subjects varies significantly between vaccine groups. If the 
difference is significant with P<0.05 then a sensitivity analysis will be performed of the 
primary efficacy analysis imputing randomly x% (from 0% to 100% in 10% increments) 
of missing data as PCR-confirmed cases.
8.4.2.3
Analysis Of Primary Immunogenicity Objective(S)
There are no primary immunogenicity objectives in this study.
8.4.2.3.1
Statistical Hypotheses
Not applicable.
8.4.2.3.2
Analysis Sets
Not applicable.
8.4.2.3.3
Statistical Methods
Not applicable.
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8.4.3
Analysis of Secondary Objective(s)
8.4.3.1
Analysis of Secondary Safety Objective(s)
There are no secondary safety objectives in this study.
8.4.3.1.1
Analysis of Extent of Exposure
Not applicable.
8.4.3.1.2
Analysis of Solicited Local, Systemic and Other Adverse Events
Not applicable.
8.4.3.1.3
Analysis of Unsolicited Adverse Events
Not applicable.
8.4.3.1.4
Statistical Hypotheses
Not applicable.
8.4.3.1.5
Analysis Sets
Not applicable.
8.4.3.1.6
Statistical Methods
Not applicable.
8.4.3.2
Analysis of Secondary Efficacy Objective(s)
8.4.3.2.1
Statistical Hypotheses
Hypotheses for testing key secondary objective are formulated in the similar way as for 
the primary efficacy objective. Other secondary efficacy objectives are not associated 
with any hypothesis testing.
8.4.3.2.2
Analysis Sets
All secondary efficacy objectives will be evaluated based on the Efficacy FAS, and 
analysis for the key secondary objective will be also repeated based on Efficacy PPS.
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8.4.3.2.3
Statistical Methods
Similarly to the primary efficacy objectives, the PH model will be used to estimate 
absolute vaccine efficacy for secondary objectives 1-4. Evaluation of the key secondary 
objective will be done according to the conditional testing procedure. Absolute efficacy 
of aQIV with respect to the culture confirmed matched influenza will be demonstrated 
only providing successful demonstration of the primary objective (absolute efficacy with 
respect to RT-PCR-confirmed influenza regardless of antigenic match). This conditioning 
allows testing of both primary and key secondary efficacy objectives on the same 
significance level alpha.
8.4.3.3
Analysis of Secondary Immunogenicity Objective(s)
8.4.3.3.1
Statistical Hypotheses
No statistical testing will be performed for the comparative secondary immunogenicity 
objectives.
CBER requirements for the aQIV vaccine group translate into following hypothesis:
H0k
(SC): πik - π0 ≤ 0
vs.
H1k
(SC): πik - π0 > 0
H0k
(SP): τik - τ0 ≤ 0
vs.
H1k
(SP): τik - τ0 > 0,
assuming that responses Yij, Zij are independent identically distributed Bernoulli variables 
B(1, πik) and B(1, τik), where i denotes vaccine group; j=1,..,ni denotes subject, k denotes 
strain, πik and τik represent the population proportions of subjects achieving 
seroconversion and post-vaccination HI titer ≥1:40, respectively, π0 and τ0 denote the 
thresholds for seroconversion (π0 = 0.3) and the threshold for proportion of subjects with 
HI titer ≥ 1:40 (τ0 = 0.6).
All hypothesis related to CBER criteria will be tested on unadjusted 5% significance 
level.
8.4.3.3.2
Analysis Sets
Secondary immunogenicity objectives will be evaluated based on the FAS.
8.4.3.3.3
Statistical Methods
All statistical analyses for HI titers will be performed on the logarithmically (base 10) 
transformed values. Individual HI titers below detection limit (<10) will be set to half of 
that limit (5).
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Crude estimates for GMTs, GMRs and pertaining 2-sided 95% CIs will be calculated 
assuming log-normal distribution of the titers and will be completed by providing 
minimum, maximum and median titers for each vaccine group.
Binary data (i.e., percentages of subjects with seroconversion and with titer ≥1:40) will 
be summarized for each group using crude estimates and will be reported together with 2-
sided 95% CIs calculated according to Clopper’s and Pearson’s (1934) method. No 
multiplicity adjustment to the CI levels will be implemented.
For immunogenicity data, it may be reasonable to consider missing immunogenicity 
values as missing completely at random (MCAR), i.e., not informative. Therefore, the key 
secondary analysis will comprise a complete case analysis only, without introducing any 
bias. Imputation methods will not be used.
8.4.4
Analysis of Exploratory Objectives
8.4.4.1
Analysis of Exploratory Safety Objective(s)
There are no exploratory safety objectives in this study.
8.4.4.2
Analysis of Exploratory Efficacy Objective(s)
There are no exploratory efficacy objectives in this study.
8.4.4.3
Analysis of Exploratory Immunogenicity Objective(s)
Exploratory objectives related to the MN-assay will be evaluated using methods for 
lognormal and binomial data as described in the Section 8.4.3.3.3.
Evaluation of a Serological Predictor of Protection Against Influenza
The immunogenicity data of the blood draw 21 days after vaccination from all subjects 
reporting an influenza case and subjects randomized from the population without an 
influenza case serving as the control group will be used to evaluate the relationship 
between antibody levels tested with the HI assay and clinical protection from influenza.
The Prentice criterion will be used to assess, whether an immunologic correlate of
protection can be determined.
To accommodate the criterion a linear logistic regression model will be fitted with 
vaccine group included as independent predictor and incidence of influenza as dependent 
variable to show that the observed vaccine effect be explained in a statistical model using 
immunologic data. 
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A second logistic regression model will be fitted, adjusted for log-transformed antibody 
titer and vaccine group to determine the effect of antibody titer on the incidence of 
influenza. Then, the relationship between the occurrence of influenza and antibody titer 
level will be modeled using the logistic regression model advocated by Dunning that 
accommodates both antibody titers and factors independent of antibody titers. 
In this model, the probability that a subject develops influenza is the probability that the 
subject is susceptible multiplied by the probability that susceptible individuals develop 
disease. Susceptibility is characterized by the probability l, and the probability that a 
subject with titer t is protected is represented by a 2-parameter logit function. Analyses 
will be conducted to determine the level of HI (or other assays that might be performed) 
antibody titer associated with 50%, 60%, 70%, 80% and 90% probability of protection.
The statistical and modelling considerations of estimating correlates of protection will 
further described in the SAP.
8.5
Sample Size and Power Considerations of Primary and Secondary Objectives
Efficacy objectives:
Sample size and power consideration for the aQIV efficacy objective is based on criteria 
for demonstrating efficacy in placebo controlled studies provided in CBER guidance, 
specifically that the study should be powered to assess the lower bound of the two-sided 
95% CI of vaccine effectiveness, anticipated to be substantially above zero. This study is 
planned using a group sequential design. The power of Cox Regression which is planned 
to be used for analysis is dependent on the overall number of influenza cases, so the 
sample sizes on number of subjects described in this section is provided more for 
operational reasons. Additional information on the planning of number of subjects that 
may need to be enroled if it is decided to continue enrolment after interim analyses is 
described in Section 8.6. 
For the primary efficacy objective: with 1-sided alpha of 2.5% and assuming an attack 
rate of influenza of 3.5% among subjects enroled in the non-influenza comparator group 
and 1.4% among the aQIV group, i.e. 60% assumed vaccine efficacy for aQIV, 238
events (i.e. 4,860 subjects per group under the assumed ERs) are needed with 86.5% 
power to show the absolute efficacy of aQIV versus non-influenza comparator, in 
preventing first occurrence RT-PCR-confirmed influenza A and/or B, due to any strain of 
influenza regardless of antigenic match to the strains in aQIV, in subjects ≥ 65 years of 
age, using a margin of 40% for lower bound of the CI for absolute vaccine efficacy.
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For the first secondary efficacy objective: with a group vaccine efficacy of 65% but 
expecting conservatively reduced event rates of influenza cases due to matched strains of 
2.5% among subjects in the non-influenza comparator group and 0.9% among the aQIV 
group then 144 events has estimated power approximately 88.5% to show the absolute 
efficacy of aQIV versus non-influenza comparator, using a margin of 40% for lower 
bound of the CI. 
Assuming a drop-out rate of 10%, approximately 10,692 subjects ≥ 65 years, 5,346 per 
vaccine group will be randomized to receive either aQIV or non-influenza comparator 
(Boostrix®) in a 1:1 allocation ratio, stratifying by age (≥ 65 to 74 and ≥ 75 years of age), 
study site and by low vs high risk of influenza complications (score <50 vs ≥50).
Immunogenicity objective:
Anti-HA antibody will be measured using a validated haemagglutination inhibition (HI) 
assay with egg-derived HA antigens from homologous strains of the virus.
The immunogenicity objective is considered as secondary and so no alpha adjustment for 
multiplicity will be done for the analysis therefore a significance level of 5% (2-sided) or 
2.5% (1-sided) was used for sample size calculation. One season in which at least 2800
subjects are anticipated to be enrolled will be selected for the collection of 
immunogenicity samples. Samples from approximately 2800 subjects participating in the 
immunogenicity season will be obtained. In order to maintain the study blind blood 
samples from an equal number of subjects participating in both treatment groups will be 
collected at Day 1 (baseline) and Day 22 (visit 3). 
After all of the specimens have been obtained a subset of samples from those collected 
will be randomly selected on a 4:1 ratio for analysis. In total approximately 1,702 samples 
are planned to be included the analysis (1,362 aQIV; 340 Boostrix). The details and the 
guidelines regarding the selection process of these samples can be found in the SAP. 
Following assumptions from the V70_27 study in elderly adult subjects were used: 
specifically after aTIV vaccination, seroconversion rates, H1N1: 77%, H3N2: 74% and B: 
47%, and percentages of subjects with a HI titer ≥ 40, H1N1: 91%, H3N2: 99%, B: 64%. 
With samples from at least 1,362 enroled subjects (1,226 evaluable subjects assuming a 
rate of 10% for missing data in the aQIV group) there will be enough power to evaluate 
achievement of CBER criteria with all four strains contained in the vaccine (see Table 
8.5-1).
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Table 8.5-1:
Power to assess CBER criteria for subjects ≥ 65 years of age
Strain
πi
(proportion in 
aQIV, based 
on data of 
V70_27)
π0
(CBER 
threshold)
Sample size for 
aQIV 
Marginal 
Power
Proportion of subjects with Seroconversion
H1N1
77%
30%
1226
99%
H3N2
74%
30%
1226
99%
B strains
47%
30%
1226
99%
Proportion of subjects with HI titer ≥1:40
H1N1
91%
60%
1226 
99%
H3N2
99%
60%
1226 
99%
B strains
64%
60%
1226 
82% 
Safety objectives:
With 4,860 evaluable subjects in each treatment group, the probability of detecting a rare 
safety event which occurs at 0.001 (1/1000) rate will be 99%. With 1,000 evaluable
subjects in each treatment group of the Solicited Safety Set, the probability of detecting 
an event which occurs at a rate of 0.002 will be ≥86%, assuming a drop-out/missing data 
rate of up to 5%.
Sample size calculations were performed using nQuery 7.0 and SAS 9.2.
8.6
Interim Analysis
As the circulation of influenza viruses is seasonal and the rates of influenza are difficult 
to predict, this study is group sequentially designed with maximally 2 interim analyses 
planned over the course of the study. The goal of Interim analyses is, first, to minimize 
the risk of not being able to take a significant test decision after the end of the study, and 
second, to be able to stop the study for early evidence of efficacy or for futility after 
observing at least 50% of planned ILI-cases. 

If the number of RT-PCR confirmed influenza cases is less or equal to 119 overall, no 
interim analysis for efficacy and futility will be done and the study will be continued
because the probability to make a conclusion for futility or efficacy is too low.

If the number of influenza cases ranges equal to 120 but less than 238 unblinded 
interim analyses for efficacy and futility will be performed by an independent Data 
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Monitoring Committee (DMC). To maintain the overall 95% significance level (α = 
2.5%, 1-sided) for primary objective testing, an error-spending-function will be used. 
The benefit of using an error-spending-function is that no maximum number of 
analysis stages and the timing of the analyses need to be pre-specified, what in 
practice means that the duration of the study in terms of number of seasons can be left 
open. Error-spending function is applied to calculate α-boundaries, forming the 
adjusted probabilities for the type 1 error. If the p-value for primary objectives test is 
lower than the respective α-boundary the trial stops early (i.e. without reaching the 
targeted number of cases of 238) for efficacy. Similarly β-boundaries are calculated, 
i.e. the adjusted probabilities for the type 2 error β, and if the p-value is higher than 
the β-boundary, the trial stops early for futility at that stage. In other words the trials 
stops early for futility, when the data provides sufficient evidence that the alternative 
hypotheses is not true, i.e. that the test vaccine is not as good as expected. Otherwise, 
the trial continues enrolment. Decisions to stop or continue the trial will be made on 
the basis of discussions between the DMC and Sponsor’s Senior Management. 

If the number of influenza cases is greater or equal to 238 (targeted number of cases 
to be able to evaluate the primary objective) the trial will be stopped, data will be 
unblinded and the final analysis will be performed by the Sponsor. If the trial
proceeds to the final analysis (upon reaching 238 cases) the boundaries for acceptance 
or rejection are identical to the assumed type 1 and type 2 errors for the overall 
design, and the trial stops to either reject or not reject the null hypothesis of the
primary objective.
In case DMC states that the observed data provides already the full information level 
needed for the final test decision, then the final analysis can be done on full alpha level 
and no further enrolment is needed. However if the decision of the group-sequential test 
is to continue the study then it is on the DMC to determine the number of subjects needed 
to be additionally enroled. The monitoring committee should not be influenced by the 
results of the efficacy testing at the interim analysis when planning further subjects’ 
accrual or the times of future analysis. Only the overall number of cases is allowed to be 
used for further planning. The following formula for determination of sample sizes for 
further enrolment may be used: 
Ntotal = (Cplanned –Cobserved) *200 / (ERaQIV + ERComp),
where Ntotal denotes the total number of subjects needed for further enrolment, Cplanned is 
the overall number of cases needed for the test, i.e. 238 cases, Cobserved is the number of 
cases observed at current stage, and ER are the respective ERs assumed for each 
treatment group, i.e. 1.4 for aQIV and 3.5 for non-influenza comparator. A drop-out rate 
of 10% should be added. 
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For the analysis of early stopping for futility and for efficacy, an error-spending function 
will be applied to provide statistical stopping rules for efficacy (α-boundaries) and futility 
(β-boundaries) for the first interim analysis and second interim analysis, if necessary, 
based on the information accumulated until that specific interim stage, i.e. based on the 
accumulated variance of the parameter of interest. 
These boundaries will be calculated on a p-value scale ( 
https://support.sas.com/documentation/onlinedoc/stat/131/seqdesign.pdf)
At each interim stage, α-boundaries, forming the adjusted probabilities for the type 1 
error, are calculated using error-spending function and if the p-value for the test of 
primary objective is lower than the respective α-boundary the trial stops for efficacy at 
this stage. Using the same error-spending-function applied on the overall type 2 error of
0.1 (Power 90%), β-boundaries are calculated, i.e. the adjusted probabilities for the type 2 
error β, and if the p-value is higher than the β-boundaries, the trial stops early for futility 
at this stage. 
In other words the trial stops early for efficacy if data collected at this stage allows to 
demonstrate primary efficacy objective (reject null-hypothesis); and the trial stops early 
for futility, if the data provides sufficient evidence that the test vaccine is not good as 
expected (the alternative hypotheses of absolute vaccine efficacy over the protocol-
specified margin is not true, i.e VE<0.4). Otherwise, the trial continues to the next stage 
and more subjects will be enrolled.
The cumulative O’Brien-Fleming type error-spending-function (Lan and DeMets, 1983; 
option ERRFUNCOBF in SAS® PROC SEQDESIGN) will be used for both α- and β-
boundaries; the error-spending function is defined as:
where a equals α for α spending function and β for beta spending function, and where t is 
the information fraction. 
With a specified type 1 error, α, and information level t at stage k, the cumulative error is 
αE(t; α) https://support.sas.com/documentation/onlinedoc/stat/131/seqdesign.pdf
If the trial proceeds to the final analysis, the boundary for rejection of null hypothesis is 
identical to the type 1 error (that is as the 0.025 one-sided alpha level) ) with power 
specified for the overall design, and the trial stops to either reject or not reject the null
hypothesis of the primary objective.
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Additional interim analyses may be requested by the DMC, particularly if the first interim 
analysis is conducted soon after 119 cases of influenza have been reported. In this case, 
the DMC may request that a second interim analysis be conducted to allow for greater 
accuracy to determine if the trial should stop or continue.
Table 8.6-1 shows the needed total number of cases at each stage of the two-stage design 
together with boundaries for early stopping for futility or efficacy, calculated on p-value 
scale using the cumulative error spending function. With 1/2 information collected at the 
stage of interim analysis (that is, with exactly 119 confirmed ILIs) the trial would stop
early for futility at this stage in case a p-value higher than 0.35022 is observed, or it 
would stop early for efficacy if the p-value is lower than 0.00625. Otherwise the trial will 
be continued and more subjects will be enrolled. The actual boundaries used for decision 
making would depend on number of confirmed ILIs occurring and reported for Interim 
Analysis.
Table 8.6-1: Example of a Two Stages Group-Sequential Design
Stage 1
First Interim
Stage 2
Final
Number of Events
119
238
Alpha Boundary on p-value scale (equivalent 
to Type 1 error, 1-sided), early stopping for 
efficacy
0.00625
0.02275
Beta Boundary on p-value scale (equivalent 
to Type 2 error, 1-sided), early stopping for 
futility
0.35022
0.02275
The stopping rules given above are statistical and should be completed with clinical and 
strategic stopping rules that allow the DMC to make a decision on a broader picture of the 
data which includes safety endpoints and the other endpoints of the study. Another
interim look at the data with appropriate adjustment of type 1 error might be 
recommended before reaching the targeted 238 cases. 
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Further details of the statistical methods are provided in the SAP and more information
regarding clinical or strategic stopping rules will be provided in the DMC charter.
For the interim analyses, if needed a restricted unblinding will be done, i.e. only 
independent DMC members and unblinded individuals responsible for the analyses will 
receive access to the randomization codes and unblinded data for the purpose of preparing 
the interim analyses (further information on handling of the blinding for the interim 
analyses can be found in Section 3.3). The results of the interim analyses will be used 
only for DMC purposes and will not be reported in a Clinical Study Report (CSR).
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9.
SOURCE DOCUMENTATION, STUDY MONITORING AND AUDITING
In order to ensure consistency across sites, study monitoring and auditing will be 
standardized and performed in accordance with the Sponsor’s or delegated contract 
research organization’s (CRO) SOPs and applicable regulatory requirements (e.g., FDA, 
European Medicines Agency (EMA), and ICH guidelines).
Prior to enrolment of the first study subject, Seqirus or delegate will train investigators 
and/or their study staff on the study protocol, all applicable study procedures, 
documentation practices and all electronic systems. CRFs supplied by the Sponsor must 
be completed for each enroled subject (see Section 8.3.1, All Enroled Set for definition of 
enroled subject). Documentation of screened but not enroled subjects must be maintained 
at the site and made available for review by the site monitor. Data and documents will be 
checked by the Sponsor and/or monitor.
9.1
Source Documentation
Prior to the start of the study, the site staff participating in the study conduct will be 
instructed on what documents will be required for review as source documents. The kinds 
of documents that will serve as source documents will be agreed between Sponsor or 
delegate and investigator and designees and specified in the SDA prior to subject 
enrolment.
In addition, source documentation must include all of the following: subject identification 
(on each page), eligibility and participation, proper informed consent procedures, dates of 
visits, adherence to protocol procedures, adequate reporting and follow-up of adverse 
events, documentation of prior/concomitant medication/vaccines, study vaccine 
receipt/dispensing/return records, study vaccine administration information, any data 
collected by a telephone conversation with the subject and date of completion and reason.
The subject must also allow access to the subject’s medical records. Each subject must be 
informed of this prior to the start of the study and consent for access to medical records 
may be required in accordance with local regulations.
All safety data reported by subjects must be written down in source documents prior to 
entry of the data into eCRFs. If there are multiple sources of information (e.g., Subject 
Diary, verbal report of the subject, telephone contact details, medical chart) supporting 
the diagnosis of an adverse event, these sources must be identified in the source 
documents, discrepancies between sources clarified, the ultimate diagnosis must be 
justified and written in the source documents, and this diagnosis must be captured in the 
Adverse Event eCRF (AE eCRF). The AE eCRF must also capture which source(s) of 
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information were used to determine the adverse event (e.g., subject recall, medical chart, 
Subject Diary).
9.2
Study Monitoring, Auditing and Source Data Verification
Prior to enrolment of the first study subject, Seqirus or its designee (e.g., a CRO) will 
develop a Clinical Monitoring Plan to specify how centralized and/or on-site monitoring, 
including clinical specimens reconciliation, will be performed for the study. Study 
progress will be monitored by Seqirus or its designee as frequently as necessary to ensure:

that the rights and well-being of human subjects are protected,

the reported study data are accurate, complete, and verifiable from the source 
documents and

the conduct of the study is in compliance with the current approved 
protocol/amendment(s), GCP and applicable regulatory requirements.
Contact details for the Seqirus team or its designee involved in study monitoring will be 
provided to the investigator. Study data recorded on eCRFs will be verified by checking 
the eCRF entries against source documents in order to ensure data completeness and 
accuracy as required by study protocol.
Data verification may also be performed through a centralized review of data (e.g., 
checking for outliers or other anomalies). Additional documents such as the investigator 
site file, pharmacy records, and informed consent documentation must also be available 
for review if requested. Arrangements for monitoring visits will be made in advance in 
accordance with the monitoring plan, except in case of emergency.
The investigator and/or site staff must make source documents of subjects enroled in this 
study available for inspection by Seqirus or its representative at the time of each 
monitoring visit and Sponsor audits, when applicable. These documents must also be 
available for inspection, verification and copying, as required by regulations, by officials 
of the regulatory health authorities (e.g., FDA, EMA and others) and/or ECs/IRBs. The 
investigator and study site staff must comply with applicable privacy, data protection and 
medical confidentiality laws for use and disclosure of information related to the study and 
enroled subjects.
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10.
DATA MANAGEMENT
10.1
Data Entry and Management
In this study, all clinical data (including, but not limited to, AE/SAEs, concomitant 
medications, medical history, and physical assessments), safety data, and immunogenicity 
data will be entered onto CRFs in a timely fashion by the investigator and/or the 
investigator’s dedicated site staff. Data entered onto CRFs are stored on a secure website. 
The data collected on this secure website are assimilated into an electronic data capture 
(EDC) system, which is compliant with Title 21 Part 11 policies of the Code of Federal 
Regulations (FDA 1997). The data system includes password protection and internal 
quality checks. The EDC system will be designed and validated by the Sponsor prior to 
activation for data entry by sites. The investigator or designated delegate must review 
data entered and electronically sign the CRFs to verify their accuracy.
Access to the EDC system for data entry or review will require training and distinct 
individual access code assignments to those site staff members who will be entering study 
data and those involved in study oversight who may review study data. Data are collected 
within the EDC system, to which the Sponsor and site monitors have exclusively “read 
only” access.
10.2
Data Clarification
As part of the conduct of the trial, the Sponsor may have questions about the data entered 
by the site, referred to as queries. The monitors and the Sponsor are the only parties that 
can generate a query. All corrections and clarifications will be entered into the EDC 
system and will be identified by the person entering the information, the reason for the 
change, as well as the time of the changes made. If changes are made to a previously and 
electronically signed CRF, the investigator must confirm and endorse the changes.
10.3
Data Protection
Seqirus respects the subjects’ rights to privacy and will ensure the confidentiality of their 
medical information in accordance with all applicable laws and regulations.
The Sponsor as Data Controller according to the European Directive on the protection of 
individuals with regard to the processing of personal data and on the free movement of 
such data (95/46/EC) confirms herewith compliance to Directive 95/46/EC in all stages of 
Data Management.
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11.
RECORD RETENTION
Investigators must retain all study records required by Seqirus and by the applicable 
regulations in a secure and safe facility. The investigator must consult a Seqirus
representative before disposal of any study records, and must notify the Sponsor of any 
change in the location, disposition, or custody of the study files. Essential documents 
must be retained for 15 years. “Essential documents” are defined as documents that 
individually and collectively permit evaluation of the conduct of a study and the quality 
of the data produced. These documents should be retained for a longer period, however, if 
required by the applicable national regulatory or institutional requirements. 
Laboratory samples, provided that the integrity of the stored sample permits testing, will 
be retained up to 15 years.
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12.
USE OF INFORMATION AND PUBLICATION
Seqirus assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov, and in compliance with current regulations.
Seqirus also assures that key results of this clinical study will be posted in a publicly 
accessible database within the required time-frame from the end of study as defined in 
Section 3.9, End of Study.
In accordance with standard editorial, ethical practices and current guidelines of Good 
Publication Practice (Graf 2009), Seqirus will generally support publication of 
multicenter studies only in their entirety and not as individual center data. In this case, a 
coordinating investigator will be designated by mutual agreement prior to the start of the 
study. The coordinating investigator will also sign the clinical study report on behalf of 
the principal investigators. Authorship will be determined by mutual agreement and in 
line with International Committee of Medical Journal Editors authorship requirements. 
Any formal publication of the study in which contribution of Seqirus personnel exceeded 
that of conventional monitoring will be considered as a joint publication by the 
investigator and the appropriate Seqirus personnel.
Seqirus must be notified of any intent to publish data collected from the study and prior 
approval from Seqirus must be obtained prior to submission for publication.
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13.
ETHICAL CONSIDERATIONS
13.1
Regulatory and Ethical Compliance
The study will be conducted in compliance with the protocol, GCP and applicable 
regulatory requirement(s).
This clinical study was designed and shall be implemented and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with 
applicable local regulations: including European Directive 2001/20/EC, US Code of 
Federal Regulations Title 21, and Japanese Ministry of Health, Labor, and Welfare, 
Seqirus codes on protection of human rights, and with the ethical principles laid down in 
the Declaration of Helsinki (European Council 2001, US Code of Federal Regulations, 
ICH 1997).
13.2
Informed Consent Procedures
Eligible subjects may only be included in the study after providing written informed 
consent or assent, as described in Section 5.1.1, Informed Consent/Assent. Before the 
start of the study, the investigator will have the informed consent and any other materials 
that will be provided to the subjects reviewed and approved by the IRB/EC. This review 
and approval will be documented and stored with other study documents. The investigator 
or designee must fully inform the subject or legal guardian of all pertinent aspects of the 
study. A copy of the written informed consent will be given to the subject or the designee. 
The subject/designee must be allowed ample time to ask about the details of the study and 
to make a decision as to whether or not to participate in the study. The subject and/or 
legal guardian(s) must sign the consent form indicating their agreement to participate in 
the study before any study-related procedures are conducted. The informed consent 
process may be conducted up to 10 days prior to vaccination on Day 1. If the subject 
and/or legal guardian(s) is unable to read and write, a witness must be present during the 
informed consent discussion and at the time of informed consent signature.
Prior to the start of the study, Seqirus or delegate will provide to investigators a proposed 
ICF that complies with the ICH GCP guideline and regulatory requirements and is 
considered appropriate for this study. Any changes to the proposed consent form 
suggested by the investigator must be agreed to by Seqirus before submission to the 
IRB/EC and a copy of the approved version must be provided to the Seqirus monitor or 
delegate after IRB/EC approval.
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13.3
Responsibilities of the Investigator and IRB/EC
The protocol and the proposed ICF must be reviewed and approved by a properly 
constituted IRB/EC before study start. Properly constituted IRB/EC is defined in ICH 
Guideline for Good Clinical Practice E6 (R1), Section 3 (ICH 1997). A signed and dated 
statement that the protocol and informed consent have been approved by the IRB/EC 
must be given to Seqirus or delegate before study initiation. Prior to study start and at any 
time the protocol is amended during study conduct, the investigator is required to sign a 
protocol signature page confirming his/her agreement to conduct the study in accordance 
with these documents and all of the instructions and procedures found in this protocol and 
to give access to all relevant data and records to Seqirus monitors, auditors, Seqirus
Clinical Quality Assurance representatives, designated agents of Seqirus, IRBs/ECs, and 
regulatory authorities as required. If an inspection of the clinical site is requested by a 
regulatory authority, the investigator must inform Seqirus immediately that this request 
has been made.
The investigator also responsible for the following:

Maintaining a list of appropriately qualified persons to whom the investigator has 
delegated significant study-related duties.

Demonstrating the capability of recruiting the required number of suitable subjects 
within the recruitment period.

Demonstrating sufficient time and staffing to properly conduct and complete the study 
within the agreed study period.

Ensuring that all persons assisting with the study are adequately informed about the 
protocol, the investigational product(s), and their study-related duties and functions

Ensuring that appropriately trained health care professionals are responsible for all 
study-related medical decisions and for ensuring appropriate medical care of subjects 
experiencing any adverse event related to the study.

If permission to do so is given by the subject or legal guardian, ensuring that the 
subject’s primary healthcare provider is informed of the subject’s participation in the 
study.
The investigator should not implement any deviation from, or changes of the protocol 
without agreement by the Sponsor and prior review and documented approval/favourable 
opinion from the IRB/IEC of an amendment, except where necessary to eliminate an 
immediate hazard(s) to study subjects, or when the change(s) involves only logistical or 
administrative aspects of the study (e.g., change in monitor(s), change of telephone 
number(s)). In addition, the investigator, or person designated by the investigator, should 
document and explain any deviation from the approved protocol.
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The investigator may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to study subjects without prior IRB/IEC 
approval/favourable opinion. As soon as possible, the implemented deviation or change,
the reasons for it, and, if appropriate, the proposed protocol amendment(s) should be 
submitted:
(a) to the IRB/IEC for review and approval/favourable opinion,
(b) to the Sponsor for agreement and, if required,
(c) to the regulatory authority(ies).
13.4
Protocol Amendments
An amendment is a written description of change(s) to or formal clarification of a study 
protocol which may impact on the conduct of the clinical study, potential benefit of the 
clinical study, or may affect subject safety, including changes of study objectives, study 
design, subject population, sample sizes, study procedures, or significant administrative 
aspects. An administrative change of a study protocol is a minor correction or 
clarification that has no significant impact on the way the clinical study is to be conducted 
and no effect on subject safety (e.g., change of telephone number(s), logistical changes). 
Protocol amendments must be approved by Seqirus, health authorities where required, 
and the IRB/EC. In cases when the amendment is required in order to protect the subject 
safety, the amendment can be implemented prior to IRB/EC approval. Notwithstanding, 
the need for formal approval of a protocol amendment, the investigator is expected to take 
any immediate action required for the safety of any subject included in this study, even if 
this action represents a deviation from the protocol. In such cases, Seqirus should be 
notified of this action, the IRB/EC at the study site, and, if required by local regulations, 
the relevant health authority) should be informed within 10 working days.
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14.
REFERENCE LIST
59th World Medical Association General Assembly (October 2008). Declaration of 
Helsinki - Ethical Principles for Medical Research Involving Human Subjects. Seoul, 
Korea.
Ambrose, C. S. and Levin, M. J. (2012). "The rationale for quadrivalent influenza 
vaccines." Hum Vaccin Immunother 8(1): 81-88.
Beyer, W. E., J., McElhaney, et al. (2013). "Cochrane re-arranged: support for policies to 
vaccinate elderly people against influenza." Vaccine 31(50): 6030-6033.
Clopper CJ, Pearson ES. The use of confidential or fiducial limits illustrated in the case of 
the binomial. Biometrika 1934; 26:404-413
Code of Federal Regulations (1997): Food and Drug Administration, U.S. Department of 
Health and Human Services: Title 21, Part 11: Electronic Records Electronic Signatures. 
Federal Register 62: 13464.
De Villiers, P.J., Steele, A.D., et al. (2009) "Efficacy and safety of a live attenuated 
influenza vaccine in adults 60 years of age and older." Vaccine 28(1):228-34.
Dempster, A. L. (1977). Maximum likelihood from incomplete data via the EM 
algorithm. J R Stat Soc Series B Stat Methodol, 1-38.
DiazGranados, et al. (2014) "Efficacy of High-Dose versus Standard-Dose Influenza 
Vaccine in Older Adults" N Engl J Med. 317(7):635-645-91.
European Parliament (1995): Directive 95/46/EC of the European Parliament and of the 
Council of 4 April 2001. Official Journal of the European Communities. L 281/31-39.
European Parliament (2001): Directive 2001/20/EC of the European Parliament and of 
the Council of 4 April 2001. Official Journal of the European Communities. L 121/34-44.
Frey, S., et al. (2009). "Clinical Efficacy of Cell Culture–Derived and Egg-Derived 
Inactivated Subunit Influenza Vaccines in Healthy Adults". Clinical Infectious Diseases;
51(9):997–1004.
Frey, A. K. (2014). "Comparison of the Safety and Immunogenicity of an MF59®-
adjuvanted with a Non-adjuvanted Seasonal Influenza Vaccine in Elderly Subjects." 
Vaccines. Manuscript Reference No.: JVAC-D-14-00218R1.
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6 FEB 17 Version 5
Page 118 of 121
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 4 / Version Date: January 29, 2015
Goodwin, K., C. Viboud, et al. (2006). "Antibody response to influenza vaccination in the 
elderly: a quantitative review." Vaccine 24(8): 1159-1169.
Graf C, Battisti WP, Bridges D (2009). Good publication practice for communicating 
company Sponsored medical research: the GPP2 guidelines. BMJ; 339: b4330.
Gurfinkel, E., R. L. Fuente, et al. (2002). “Influenza Vaccine Pilot Study in Acute 
Coronary Syndromes and Planned Percutaneous Coronary Interventions: The FLU 
Vaccination Acute Coronary Syndromes (FLUVACS) Study.” Circulation, 2143-2147.
Hak, E. F. (2004). Development and Validation of a Clinical Prediction Rule for 
Hospitalization Due to Pneumonia or Influenza or Death during Influenza Epidemics 
among Community-Dwelling Elderly Persons. Journal of Infectious Diseases, 450-458.
Heinze, G. and Schemper M. (2001). “A Solution to the Problem of Monotone Likelihood 
in Cox Regression.” Biometrics, 57(1): 114-119.
ICH (1997). ICH Harmonised Tripartite ICH Guideline for Good Clinical Practices E6 
(R1). Federal Register, 62 (90): 25691-25709.
ICH (1998). ICH Harmonised Tripartite ICH Guideline for Statistical Principles for 
Clinical Trials E9. Federal Register, 63 (179): 49583.
Jain VK, Rivera L, et al. (2013). "Vaccine for prevention of mild and moderate-to-severe 
influenza in children." N Engl J Med. 369(26):2481-91.
Jennison, C. T. (2000). Group sequential methods with applications to clinical trials. New 
York: Chapman and Hall.
Lo, Y. C., J. H. Chuang, et al. (2013). "Surveillance and vaccine effectiveness of an 
influenza epidemic predominated by vaccine-mismatched influenza B/Yamagata-lineage 
viruses in Taiwan, 2011-12 season." PLoS One 8(3): e58222.
Mannino, S., M. Villa, et al. (2012). “Effectiveness of Adjuvanted Influenza Vaccination 
in Elderly Subjects in Northern Italy.” American Journal of Epidemiology, 176(6): 527-
533.
MMWR Morb Mortal Wkly Rep (2010), 59(33): 1057-1062.
MMWR Morb Mortal Wkly Rep (2013), 62(49): 997-1000. 
Mullooly, J. P., C. B. Bridges, et al. (2007). "Influenza- and RSV-associated 
hospitalizations among adults." Vaccine 25(5): 846-855.
Doc ID: 82653103, Version: 1, Approval Date: 10Feb17

 Seqirus
Confidential
Protocol V118_18
6 FEB 17 Version 5
Page 119 of 121
PRO-01 TEMP 06 / Atlas No. 293620
Version No. 4 / Version Date: January 29, 2015
Neuzil, K. M., B. G. Mellen, et al. (2000). "The effect of influenza on hospitalizations, 
outpatient visits, and courses of antibiotics in children." N Engl J Med 342(4): 225-231.
Nichol, K.L., J.D. Nordin, et al. (2007). “Effectiveness of Influenza Vaccine in the 
Community-Dwelling Elderly.” N Engl J Med 357(14): 1373-1381.
Osterholm, M. T., N. S. Kelley, et al. (2012). "Efficacy and effectiveness of influenza 
vaccines: a systematic review and meta-analysis." Lancet Infect Dis 12(1): 36-44.
Rubin, D. (1987). Multiple Imputation for Nonresponse in Surveys. New York: John 
Wiley and Sons.
Sasaki, S., M. Sullivan, et al. (2011). "Limited efficacy of inactivated influenza vaccine in 
elderly individual is associated with decreased production of vaccine-specific antibodies." 
J Clin Invest 121(8): 3109-3119.
Scheifele, D.W, S.A. Mcneil, et al. (2013). “Safety, immunogenicity, and tolerability of 
three influenza vaccines in older adults.” Results of a randomized, controlled comparison. 
Human Vaccines & Immunotherapeutics, 9(11): 1-14.
Treanor, J., et al (2011). "Protective efficacy of a trivalent recombinant hemagglutinin 
protein vaccine (FluBlok®) against influenza in healthy adults: A randomized, placebo-
controlled trial". Vaccine 29: 7733– 7739.
U.S. Department of Health and Human Services, Food and Drug Administration, CBER 
(2009): Guidance for Industry Patient-Reported Outcome Measures: Use in Medical 
Product Development to Support Labeling Claims.
Van Buynder, P. G., S. Konrad, (2013). "The comparative effectiveness of adjuvanted 
and unadjuvanted trivalent inactivated influenza vaccine (TIV) in the elderly.” Vaccine 
31: 6122-6128.
Villa, M., S. Black, et al. (2013). “Safety of MF59-Adjuvanted Influenza Vaccination in 
the Elderly: Results of a Comparative Study of MF59-Adjuvanted Vaccine Versus 
Nonadjuvanted Influenza Vaccine in Northern Italy.” American Journal of Epidemiology, 
1-7.
http://www.cdc.gov/flu/about/disease/high_risk.htm Accessed 25 March 2015.
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APPENDIX 1: EXAMPLES OF PRE-EXISTING MEDICAL CONDITIONS
1.
Pulmonary Disease
a.
Asthma
b. Chronic bronchitis
c.
Chronic obstructive lung disease or emphysema
d. Pneumoconioses
e.
Pulmonary fibrosis
f.
Pulmonary tuberculosis and diseases due to other mycobacteria
g. Sarcoidosis
2.
Heart Disease
h. Coronary artery disease
i.
Valvular heart disease
j.
Congenital heart disease
k. Hypertensive heart disease
l.
Ischemic heart disease
m. Diseases of pulmonary circulation
n. Myocarditis
o. Arrhythmias, including atrial fibrillation
p. Congestive heart failure
3.
Renal Disease
q. Hypertensive renal disease
r.
Dialysis
s.
Renal transplantation
t.
Nephritis, nephrotic syndrome, nephrosis
u. Chronic pyelonephritis
v. Dialysis and transplant
4.
Dementia or stroke
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w. Neurologic and neurodevelopmental conditions [including disorders of the brain, 
spinal cord, peripheral nerve, and muscle such as cerebral palsy, epilepsy (seizure 
disorders), stroke, intellectual disability (mental retardation), moderate to severe 
developmental delay, muscular dystrophy, or spinal cord injury].
x. Cerebrovascular disease
y.
Dementia
z.
Hereditary and degenerative diseases of CNS
5.
Non-hematological and hematological cancer (excluding cancer of the skin other 
than melanoma)
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UserName: 
 
Title:  Seqirus Clinical Medical Lead 
Date: Friday, 10 February 2017, 17:23   GMT 
Meaning: As an approver, I agree with the content and format of this document. / Als Genehmiger bin ich mit dem Inhalt und der Form
des Dokumentes einverstanden. / In qualità di Approvatore, concordo con il contenuto ed il formato di questo documento 
================================================
Doc ID: 82653103, Version: 1, Approval Date: 10Feb17