Enhanced Safety Surveillance of GSK's Quadrivalent Seasonal Influenza Vaccines
Phase: PHASE4
Conditions: Influenza, Human
Sponsor: GlaxoSmithKline

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Study Protocol
Sponsor:
GlaxoSmithKline Biologicals SA
Rue de l’Institut, 89
B-1330 Rixensart - Belgium
eTrack study number and 
Abbreviated Title
207737 (EPI-FLU-056 VS EU)
Date of protocol
Final Version 1: 24 May 2018
Date of protocol 
amendment
Amendment 1 Final: 11 September 2018
Title
Enhanced safety surveillance of GSK's quadrivalent 
seasonal influenza vaccines
Detailed Title
Passive enhanced safety surveillance of GSK's 
quadrivalent seasonal influenza vaccines: a pilot study 
in Belgium, Germany and Spain during the 2018/19 
influenza season
Co-ordinating author
 4Clinics Belgium for GSK Biologicals’
Contributing authors
!
 Epidemiologist
!
 Clinical Epidemiology Project 
Lead
!
 VP Head of Clinical R&D
!
 Project Statistician
!
 Lead Statistician
!
 Study Delivery Lead
!
, Clinical Safety representative
!
 Clinical Safety representative
!
 Regulatory Affairs representative
!
 Oversight Data Manager
!
 Study Data Manager
GSK Biologicals’ protocol template for observational studies and interventional studies 
without administration of medicinal products as described in a research protocol based 
on the Protocol Document Standard version 15.0
© 2018 GSK group of companies or its licensor.

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PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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Protocol Sponsor Signatory Approval
eTrack study number and 
Abbreviated Title
207737 (EPI-FLU-056 VS EU)
Date of protocol
Final Version 1: 24 May 2018
Date of protocol amendment
Amendment 1 Final: 11 September 2018
Detailed Title
Passive enhanced safety surveillance of GSK's 
quadrivalent seasonal influenza vaccines: a pilot 
study in Belgium, Germany and Spain during the 
2018/19 influenza season
Sponsor signatory
Jacqueline Miller, VP Head of Clinical R&D
Signature
Date
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Protocol Amendment 1 Investigator Agreement
I agree:

To conduct the study in compliance with this protocol, any mutually agreed future 
protocol amendments or protocol administrative changes, with the terms of the study 
agreement and with any other study conduct procedures and/or study conduct 
documents provided by GlaxoSmithKline (GSK) Biologicals.

To assume responsibility for the proper conduct of the study at this site.

That I am aware of, and will comply with ‘Good Clinical Practice’ (GCP) or other 
applicable guidelines (such as Good Epidemiology Practice [GEP] and Good 
Pharmacovigilance Practice [GVP]) and all applicable regulatory requirements.

To ensure that all persons assisting me with the study are adequately informed about 
study-related duties and functions as described in the protocol.

To co-operate with a representative of GSK Biologicals in the monitoring process of 
the study and in resolution of queries about the data.

That I have been informed that certain regulatory authorities require the sponsor to 
obtain and supply, as necessary, details about the investigator’s ownership interest in 
the sponsor, and more generally about his/her financial ties with the sponsor. GSK 
Biologicals will use and disclose the information solely for the purpose of complying 
with regulatory requirements.
Hence I:

Agree to supply GSK Biologicals with any necessary information regarding 
ownership interest and financial ties (including those of my spouse and dependent 
children).

Agree to promptly update this information if any relevant changes occur during the 
course of the study and for one year following completion of the study. 

Agree that GSK Biologicals may disclose any information it has about such 
ownership interests and financial ties to regulatory authorities.

Agree to provide GSK Biologicals with an updated Curriculum Vitae and other 
documents required by regulatory agencies for this study.
 
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eTrack study number and 
Abbreviated Title
207737 (EPI-FLU-056 VS EU)
Date of protocol
Final Version 1: 24 May 2018
Date of protocol amendment
Amendment 1 Final: 11 September 2018
Detailed Title
Passive enhanced safety surveillance of GSK's 
quadrivalent seasonal influenza vaccines: a pilot 
study in Belgium, Germany and Spain during the 
2018/19 influenza season
Investigator name
Signature
Date
Name, function and title of 
the Studienleiter
Signature
Date
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Sponsor Information
1.
Sponsor
GlaxoSmithKline Biologicals
Rue de l’Institut, 89
B-1330 Rixensart - Belgium
2.
Sponsor Medical Expert for the Study
Refer to the local study contact information document.
3.
Sponsor Study Monitor
Refer to the local study contact information document.
 
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Protocol Amendment 1 Rationale
Amendment number:
1
Rationale/background for changes:
The protocol has been amended to respond to comments from the concerned Ethical 
Review Boards. 
In addition, the interim analysis section has been updated to remove the analysis 
planned for end October 2018, due to the expectation that the majority of subject 
recruitment may commence from mid-October 2018, rather than initially planned 
(01-OCT-2018).
The list of abbreviations and the reference list have been revised in alignment with the 
other changes. Grammatical and typographical errors have been corrected.
 
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SYNOPSIS
Detailed Title
Passive enhanced safety surveillance of GSK's quadrivalent 
seasonal influenza vaccines: a pilot study in Belgium, 
Germany and Spain during the 2018/19 influenza season
Objectives
Primary

To estimate, in each country and overall, the cumulative 
percentages of subjects reporting AEIs and/or other AEs 
within 7 days following vaccination with GSK’s 
quadrivalent seasonal influenza vaccine using adverse 
drug reaction (ADR) cards.
Secondary

To estimate, in each country and overall, the weekly 
percentages of subjects reporting AEIs and/or other AEs 
within 7 days following vaccination with GSK’s 
quadrivalent seasonal influenza vaccine using ADR 
cards, overall, by age strata (6 months to 17 years; 18 to 
65 years; >65 years), and risk status (at risk/not at risk).

To estimate, in each country and overall, the cumulative 
percentages of subjects reporting AEIs and/or other AEs 
within 7 days following vaccination with GSK’s 
quadrivalent seasonal influenza vaccine using ADR 
cards, by age strata (6 months to 17 years; 18 to 65 years; 
>65 years), and risk status (at risk/not at risk).
Rationale for the 
study
The European Medicines Agency (EMA) has released 
guidance on enhanced safety surveillance for seasonal 
influenza vaccines in the European Union (EU), replacing the 
annual evaluation of safety and immunogenicity of seasonal 
influenza vaccines in small scale clinical trials since 2015. 
This guidance sets out new standards for surveillance that all 
Marketing Authorisation Holders (MAHs) of vaccines in the 
EU must address. The key objective of the EMA enhanced 
safety surveillance is to rapidly detect a significant increase in 
the frequency and/or severity of expected reactions (local, 
systemic or allergic reactions) that may indicate a potential 
risk.
This study is designed to comply with the EMA guidance and 
aims to assess adverse events of interest (AEIs) experienced 
within 7 days post vaccination with GSK’s quadrivalent 
seasonal influenza vaccine (AlphaRix Tetra in Belgium; 
Influsplit Tetra in Germany, Fluarix Tetra in Spain; referred 
to as GSK’s quadrivalent seasonal influenza vaccine later in 
the text). This study may help to inform decisions regarding 
future influenza vaccine safety surveillance for influenza 
vaccines in Europe.
 
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Study design

Type of design: multi-country, multicentre, prospective, 
passive enhanced safety surveillance (ESS) study 

This is a Targeted Safety Study (TSS)

Study population: subjects aged 6 months or above in 
Spain and aged 18 years or above in Belgium and 
Germany, and receiving GSK’s quadrivalent seasonal 
influenza vaccine according to the local prescribing 
information

Type of study: self-contained

Data collection: Electronic Case Report Form (eCRF)

Sampling schedule: Not applicable

Primary completion Date (PCD): PCD is defined as the 
date of final collection of data for all primary outcomes 

End of Study (EoS): Last Subject Last Visit 

Duration of the study: The study is anticipated to run 
from 01 October 2018 to 15 January 2019. The 
recruitment period is anticipated to run for 3 months from 
01 October 2018 to 31 December 2018, except for 
subjects aged <9 years who have not been previously 
vaccinated against influenza in preceding seasons, for 
whom the recruitment period will end on 
01 December 2018 to allow sufficient time to collect 
information on the second dose that is expected to occur 
at least 4 weeks after the first dose. The target sample size 
is approximately 1,000 vaccinated subjects to be reached 
before 31 December 2018. The intended duration of the 
study per subject will be approximately 8 days for all 
subjects who have previously been vaccinated against 
influenza in preceding seasons or aged ≥9 years at the 
time of vaccination, and approximately 36 days for 
children aged <9 years who have not previously been 
vaccinated against influenza in preceding seasons.

Epoch 001: Prospective data collection starting at 
Visit 1 (Day 1) and ending at Visit 2 (Day 8 or when 
the ADR card is returned by mail) for all subjects 
who have previously been vaccinated against 
influenza in preceding seasons or aged ≥9 years at 
the time of vaccination, or ending at Visit 4 (Day 36 
or when the last ADR card is returned by mail) for 
children aged <9 years who have not previously been 
vaccinated against influenza in preceding seasons).
Subjects will have up to 14 days post vaccination to 
return their ADR card (at the next study visit or by 
mail).
 
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Synopsis Table 1
Study groups and epochs foreseen in the study
Study Groups
Number of subjects
Age (Min/Max)
Epochs
Prospective
Approximately 1000
6 months and above
Epoch 001
Discussion of study 
design
The study is a passive enhanced safety surveillance aiming to 
collect prospectively AEIs and/or other AEs experienced 
within 7 days post vaccination with GSK’s quadrivalent 
seasonal influenza vaccine, using customized Adverse Drug 
Reaction cards. Data will be collected via the healthcare 
professionals (HCP) who administer the seasonal influenza 
vaccination. 
After written informed consent/informed assent is obtained 
from the subject/subject’s parent(s)/Legally Acceptable 
Representative (LAR), an ADR card will be distributed to the 
enrolled subjects/subjects’ parent(s)/LAR who will be asked 
to complete the card and return this to the HCP (or a member 
of his/her team) either in person at the next scheduled visit or 
by mail. Upon return, the card information will be entered into 
a database using eCRF.
The cards will contain pre-defined AEIs to be reported as well 
as a free text field to report other relevant AEs. Subjects will 
also have the possibility to indicate that no AE occurred 
within the 7 days’ time window. 
Number of subjects
Approximately 1000 vaccinees receiving GSK’s quadrivalent 
seasonal influenza vaccine will be enrolled in this study in 
Belgium, Germany and Spain. 
Endpoints
Primary

Occurrence of AEIs and/or other AEs within 7 days post 
each GSK’s quadrivalent seasonal influenza vaccination 
(i.e., the day of vaccination and the following 6 days) 
reported using ADR cards, according to MedDRA 
classification, by cumulative weeks (expected ISO 
weeks 40 to 52).
Secondary

Occurrence of AEIs and/or other AEs within 7 days post 
each GSK’s quadrivalent seasonal influenza vaccination 
(i.e., the day of vaccination and the following 6 days) 
reported using ADR cards, according to MedDRA 
classification, each week (expected ISO weeks 40 to 52).

Occurrence of AEIs and/or other AEs within 7 days post 
each GSK’s quadrivalent seasonal influenza vaccination 
(i.e., the day of vaccination and the following 6 days) 
reported using ADR cards, according to MedDRA 
classification, by cumulative weeks (expected ISO 
weeks 40 to 52).
 
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TABLE OF CONTENTS
PAGE
SYNOPSIS......................................................................................................................7
LIST OF ABBREVIATIONS...........................................................................................14
GLOSSARY OF TERMS ...............................................................................................15
TRADEMARKS .............................................................................................................18
1.
INTRODUCTION....................................................................................................19
2.
BENEFIT : RISK ASSESSMENT............................................................................20
2.1.
Risk Assessment ........................................................................................20
2.2.
Benefit Assessment....................................................................................22
2.3.
Overall Benefit:Risk Assessment ................................................................22
3.
OBJECTIVES.........................................................................................................22
3.1.
Primary Objective .......................................................................................22
3.2.
Secondary Objectives.................................................................................23
4.
STUDY DESIGN OVERVIEW ................................................................................23
4.1.
Discussion of Study Design ........................................................................24
5.
STUDY POPULATION...........................................................................................25
5.1.
Number of Subjects/Centres.......................................................................25
5.2.
Inclusion Criteria for Enrolment...................................................................25
5.3.
Exclusion Criteria for Enrolment..................................................................26
6.
CONDUCT OF THE STUDY ..................................................................................26
6.1.
Regulatory and Ethical Considerations, including the Informed 
Consent Process ........................................................................................26
7.
DETAILED STUDY PROCEDURES.......................................................................27
7.1.
Subject Identification...................................................................................27
7.2.
General Study Aspects ...............................................................................27
7.3.
Outline of the Study Procedures .................................................................28
7.4.
Detailed Description of Study Procedures...................................................29
7.4.1.
Informed consent.........................................................................29
7.4.2.
Check inclusion and exclusion criteria .........................................29
7.4.3.
Collect demographic data ............................................................29
7.4.4.
Collect “at risk status” ..................................................................29
7.4.5.
Record vaccination data for GSK’s quadrivalent seasonal 
influenza vaccine .........................................................................30
7.4.6.
Check and record co-administered vaccination............................30
7.4.7.
ADR cards ...................................................................................30
7.4.8.
Study conclusion..........................................................................30
7.5.
Biological Sample Handling and Analysis ...................................................30
8.
SAFETY.................................................................................................................31
8.1.
Safety Definitions........................................................................................31
 
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8.1.1.
Definition of an adverse event......................................................31
8.1.2.
Definition of a serious adverse event ...........................................31
8.1.3.
Adverse events of specific interest...............................................32
8.2.
Reporting of SAEs and Other Events..........................................................32
9.
SUBJECT COMPLETION AND WITHDRAWAL.....................................................33
9.1.
Subject Completion.....................................................................................33
9.2.
Subject Withdrawal.....................................................................................33
10. STATISTICAL METHODS......................................................................................33
10.1.
Endpoints....................................................................................................33
10.1.1.
Primary endpoint..........................................................................33
10.1.2.
Secondary endpoints ...................................................................34
10.2.
Determination of Sample Size.....................................................................34
10.3.
Sets for Analyses........................................................................................37
10.3.1.
Enrolled Set.................................................................................37
10.3.2.
Exposed Set ................................................................................37
10.3.3.
Safety Set....................................................................................37
10.3.4.
Solicited Safety Set......................................................................37
10.4.
Derived and Transformed Data...................................................................37
10.5.
Analysis of Demographics ..........................................................................37
10.6.
Analysis of Primary Objective .....................................................................38
10.7.
Analysis of Secondary Objectives...............................................................38
10.8.
Other Analyses ...........................................................................................39
10.9.
Interpretation of Analyses ...........................................................................39
10.10. Conduct of Analyses...................................................................................39
10.10.1. Sequence of analyses..................................................................39
10.10.2. Statistical considerations for interim analyses..............................40
11. ADMINISTRATIVE MATTERS ...............................................................................40
11.1.
Case Report Form/Electronic Case Report Form Instructions.....................40
11.2.
Study Monitoring by GSK Biologicals..........................................................41
11.3.
Record Retention........................................................................................42
11.4.
Quality Assurance.......................................................................................42
11.5.
Posting of Information on Publicly Available Registers and 
Publication Policy........................................................................................42
11.6.
Provision of Study Results to Investigators .................................................43
11.7.
Data Sharing...............................................................................................43
12. COUNTRY SPECIFIC REQUIREMENTS...............................................................43
13. REFERENCES.......................................................................................................44
 
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LIST OF TABLES
PAGE
Table 1
Study groups and epochs foreseen in the study.....................................24
Table 2
List of study procedures .........................................................................28
Table 3
Intervals between study visits.................................................................29
Table 4
Probability to observe at least one AE, exact 95% Confidence 
Intervals and Relative Standard Error according to number of 
vaccinated subjects and true percentage of vaccinated subjects 
with the AE.............................................................................................35
Table 5
Cumulative probability to observe at least one AE, exact 95% 
Confidence Intervals and Relative Standard Error by week for a 
true percentage of subjects with the AE of 1% .......................................36
 
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LIST OF APPENDICES
PAGE
APPENDIX A ADR Card...............................................................................................46
APPENDIX B Code list of pre-specified AEIs ...............................................................48
APPENDIX C AMENDMENTS AND ADMINISTRATIVE CHANGES TO THE 
PROTOCOL...........................................................................................49
 
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LIST OF ABBREVIATIONS
ADR
Adverse Drug Reaction
AE
Adverse Event
AEI
Adverse Event of Interest
CDC
Centers for Disease Control and Prevention
CI
Confidence Interval
CIOMS
Council for International Organizations of Medical Sciences
eCRF
electronic Case Report Form
EMA
European Medicines Agency
EoS
End of Study
ESS
Enhanced Safety Surveillance
EU
European Union
GCP
Good Clinical Practice
GEP
Good Epidemiological Practice
GSK
GlaxoSmithKline
GVP
Good Pharmacovigilance Practice
HCP
Healthcare Professional
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ISO
International Organization for Standardization
LAR
Legally Acceptable Representative
MAH
Marketing Authorisation Holder
MedDRA
Medical Dictionary for Regulatory Activities
PCD
Primary Completion Date
RSE
Relative Standard Error
SAE
Serious Adverse Event
SDR
Source Document Review
SDV
Source Document Verification
SPM
Study Procedures Manual
TSS
Targeted Safety Study
WHO
World Health Organization
 
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GLOSSARY OF TERMS
Adverse event (AE):
Any untoward medical occurrence in a subject, temporally 
associated with the use of a medicinal product, whether or 
not considered related to the medicinal product, or 
temporally associated with a study procedure.
An adverse event (AE) can therefore be any unfavourable 
and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a medicinal product. 
For marketed medicinal products, this also includes failure 
to produce expected benefits (i.e., lack of efficacy), abuse or 
misuse.
Child in care:
A child who has been placed under the control or protection 
of an agency, organisation, institution or entity by the 
courts, the government or a government body, acting in 
accordance with powers conferred on them by law or 
regulation. The definition of a child in care can include a 
child cared for by foster parents or living in a care home or 
institution, provided that the arrangement falls within the 
definition above. The definition of a child in care does not 
include a child who is adopted or has an appointed legal 
guardian.
Commitment:
Agreement made with Regulatory Authorities as specific 
condition of regulatory approval and authorisation, either 
made at the time of product approval or during the lifecycle 
of the approved product.
Eligible:
Qualified for enrolment into the study based upon strict 
adherence to inclusion/exclusion criteria.
Epidemiological study:
An observational or interventional study without 
administration of medicinal product(s) as described in a 
research protocol.
End of Study (EoS):
(Synonym of End of 
Trial)
For studies without collection of human biologicals samples 
or imaging data EoS is the Last Subject Last Visit (LSLV). 
For studies with collection of Human Biologicals Samples 
or imaging data, EoS is defined as the date of the last 
testing/reading released of the Human Biological Samples 
or imaging data, related to primary and secondary 
endpoints. EoS must be achieved no later than 8 months 
after LSLV
 
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Enhanced safety 
surveillance (ESS) for 
influenza vaccination:
The main objective of enhanced safety surveillance (ESS) is 
for influenza vaccination to detect a potential increase in 
reactogenicity and allergic events that is intrinsic to the 
product (i.e., not due to a specific batch deviation or local 
programmatic issue) in near real-time in the earliest 
vaccinated cohorts. 
Three options are envisaged for enhanced surveillance as 
per EMA guidance: 
1. Active surveillance; 
2. Passive surveillance; 
3. Data mining or other use of electronic health record data.
Epoch:
An epoch is a set of consecutive time points or a single time
point from a single protocol. Epochs are defined to support 
a main purpose which either to draw conclusions on subject 
participation or to draw a complete conclusion to define or 
precise the targeted label of the product. Supporting means 
that data collected at the time points included in an epoch 
must be sufficient to fulfil the purpose of the epoch.
Typical examples of epochs are screening, immunogenicity 
follow-up, safety follow-up, ESFU, follow-up. 
eTrack:
GSK Biologicals’ tracking tool for clinical/ epidemiological 
trials.
Evaluable:
Meeting all eligibility criteria, complying with the 
procedures defined in the protocol, and, therefore, included 
in the per-protocol analysis (see Section 10.3 for details on 
criteria for evaluability).
Interventional Human 
Subject Research:
Studies in which participants are administered medical care, 
medicinal products and/or medical/scientific procedures as 
described in a research protocol.
International 
Organization for 
Standardization (ISO)
week:
The ISO week date system is a system that is part of the ISO 
8601 date and time standard issued by the International 
Organization for Standardization week which specifies 
numeric representations of date and time. This standard 
notation helps to avoid confusion in international 
communication caused by the many different national 
notations and increases the portability of computer user 
interfaces.
Legally acceptable 
representative (LAR):
(The terms legal 
representative or legally 
authorized representative 
are used in some settings)
An individual or juridical or other body authorized under 
applicable law to consent, on behalf of a prospective 
subject, to the subject's participation in the trial.
 
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Primary completion date
(PCD):
The date that the final subject was examined or received an 
intervention for the purpose of final collection of data for all
primary outcomes, whether the clinical trial/ pharmaco-
epidemiological study was concluded according to the pre-
specified protocol or was terminated.
Prospective study:
A study in which the subjects/cases are identified and then 
followed forward in time in order to address one or more 
study objectives.
Research protocol:
A document that describes the objective(s), design, 
methodology, statistical considerations, and organisation of 
a study. The protocol usually also gives the background and 
rationale for the study, but these could be provided in other 
protocol referenced documents.
Self-contained study:
Study with objectives not linked to the data of another 
study.
Site Monitor:
An individual assigned by the sponsor who is responsible 
for assuring the proper conduct of epidemiological studies at 
one or more investigational sites.
Study population:
Sample of population of interest.
Subject:
Term used throughout the protocol to denote an individual 
who has been contacted in order to participate or 
participates in the epidemiological study or a person about 
whom some medical information has been recorded in a 
database.
Subject number:
A unique number identifying a subject, assigned to each 
subject consenting to participate in the study.
Surveillance:
The ongoing systematic collection, collation, analysis, and 
interpretation of descriptive epidemiological health data on 
a specific disease. Surveillance can monitor incidence 
and/or prevalence, and/or inform about when and where 
health problems are occurring and who is affected.
Targeted Safety Study
(TSS):
Studies specifically planned or conducted to examine an 
actual or hypothetical safety concern in a product marketed 
anywhere in the world. This includes any GSK sponsored 
pharmaco-epidemiological study or clinical trial conducted 
anywhere in the world with the aim of identifying or 
quantifying a safety hazard. Although all clinical trials 
collect safety information as a matter of routine, only those 
initiated to examine a specific safety concern are considered 
a targeted safety study.
 
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TRADEMARKS
The following trademarks are used in the present protocol.
Note: In the body of the protocol (including the synopsis), the names of the 
vaccines/products will be written without the superscript symbol ™ or ® and in 
italics.
Trademarks of the GlaxoSmithKline 
group of companies
Generic description
AlphaRix Tetra™ (Belgium) 
Influsplit Tetra™ (Germany) 
Fluarix Tetra™ (Spain) 
Quadrivalent Seasonal Influenza vaccine
 
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1.
INTRODUCTION
Influenza is an acute, highly contagious, respiratory disease caused by influenza 
viruses, mainly spread through respiratory droplets. The illness is accompanied by 
fever and variable degrees of other systemic symptoms, ranging from mild fatigue to 
respiratory failure and even death. 
Influenza is a major public health burden. It is responsible for 50 million disease 
episodes and 15,000 to 70,000 deaths in the EU/EEA each year, although with 
considerable variation from season to season Uhart, 2016and by methodology used
Nicoll, 2012. Influenza occurs in annual epidemics that are associated with 
significant morbidity and mortality and have substantial public health impact, in 
particular in the elderly and in children younger than one year of age Zhou, 2012. In 
the US, approximately 9.2 to 60.8 million people contract influenza annually, resulting 
in an average of 140,000 to 710,000 hospitalisations and 12,000 to 56,000 deaths
CDC, 2016a. 
Annual influenza vaccination is the most effective measure to reduce the risk of 
influenza infection and its complications Foppa, 2015. During the 2015-2016 
influenza season, CDC estimated that the overall influenza vaccination coverage 
among all people ≥6 months of age was 45.6%. It prevented almost 5 million influenza 
illnesses, 2.5 million medical visits to health providers, 71,000 hospitalizations, and 
3,000 deaths CDC, 2016b. However, due to frequent genetic and antigenic changes in 
influenza viruses, seasonal vaccines are frequently reformulated with updated viral 
strains based on annual World Health Organization (WHO) recommendations WHO, 
2018. Therefore, there is a need for constant benefit-risk monitoring of these vaccines.
The European Medicines Agency (EMA) has released guidance on enhanced safety 
surveillance for seasonal influenza vaccines in the European Union (EU) [EMA, 2014; 
EMA, 2016], replacing the annual evaluation of safety and immunogenicity of seasonal
influenza vaccines in small scale clinical trials since 2015. This guidance sets out new 
standards for surveillance that all Marketing Authorisation Holders (MAHs) of vaccines 
in the EU must address. The key objective of the EMA enhanced safety surveillance is to 
rapidly detect a significant increase in the frequency and/or severity of expected reactions 
(local, systemic or allergic reactions) that may indicate a potential risk.
This study is designed to comply with the EMA guidance and aims to assess adverse 
events of interest (AEIs) experienced within 7 days post vaccination with GSK’s 
quadrivalent seasonal influenza vaccine (AlphaRix Tetra in Belgium; Influsplit Tetra in 
Germany, Fluarix Tetra in Spain; referred to as GSK’s quadrivalent seasonal influenza 
vaccine later in the text). 
Of note GSK’s quadrivalent seasonal influenza vaccine is indicated for active 
immunisation of adults and children from 6 months of age for the prevention of 
influenza disease caused by the two influenza A virus subtypes and the two influenza B 
virus types contained in the vaccine. The use of GSK’s quadrivalent seasonal vaccines 
should be based on official recommendations. Immunisation should be carried out by 
intramuscular injection. Annual revaccination with the current vaccine is 
 
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recommended because immunity declines during the year after vaccination, and 
because circulating strains of influenza virus might change from year to year. The 
vaccine is recommended for a single dose except for children aged <9 years, who have 
not previously been vaccinated against influenza, for whom a second dose should be 
given after an interval of at least 4 weeks.
This study may help to inform decisions regarding future influenza vaccine safety 
surveillance for influenza vaccines in Europe.
2.
BENEFIT : RISK ASSESSMENT
The EPI-FLU-056 study does not involve administration of an investigational product
and does not imply random allocation of vaccination to enrolled subjects. Subjects will 
be receiving their vaccination as per routine care prior to enrolment in the study, which is 
a passive enhanced safety surveillance aiming to collect prospectively AEIs and/or other 
AEs (see APPENDIX C) experienced within 7 days post vaccination with GSK’s 
quadrivalent seasonal influenza vaccine, using customized Adverse Drug Reaction cards 
(see APPENDIX A). 
Please refer to the current reference safety information and/or prescribing information for 
the summary of potential risks and benefits of GSK’s quadrivalent seasonal influenza 
vaccine.
Although vaccination itself is not part of the protocol, for general information, the 
following section outlines the risk assessment and mitigation strategy per the EU risk 
management plan:
2.1.
Risk Assessment
Important Potential 
Risks
Data/Rationale for Risk 
Mitigation Strategy
Anaphylaxis
Anaphylaxis can occur at any age, 
with the highest age-specific rates 
observed in the 0-19 year group 
(70 cases per 100,000 person-years). 
Anaphylaxis following immunisation is 
serious but rare; the estimated 
incidences are in the range of 1-10 
per 1 million doses distributed 
depending on the vaccine distributed 
[Ruggeberg, 2007].
The investigator/prescribers are 
advised of possible anaphylaxis 
following GSK’s quadrivalent 
seasonal influenza vaccine
administration by information 
included in product labels.
 
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Important Potential 
Risks
Data/Rationale for Risk 
Mitigation Strategy
Febrile seizure
In April 2010, there was a reported 
increase in febrile convulsion following 
influenza vaccination in young 
children in Western Australia. 
Following extensive investigations into 
this safety issue, epidemiological 
analyses determined that 
administration of the 2010 seasonal 
influenza vaccines, Fluvax® and 
Fluvax Junior® (manufactured by Bio 
CSL), was associated with an 
increased risk of febrile convulsions, 
however, the risk has not been 
confirmed for other influenza 
vaccines, including GSK’s 
quadrivalent seasonal influenza 
vaccine.
As with other vaccines, vaccination 
with GSK’s quadrivalent seasonal 
influenza vaccine should be 
postponed in subjects suffering from 
an acute febrile illness; fever is also 
listed as an adverse reaction.
Guillain-Barré 
syndrome (GBS)
A few cases of GBS have been 
reported to GSK. Most published 
studies investigating GBS suggest 
incidence estimates between 0.84 and 
1.91 per 100,000 persons per year. 
To date, a total of 29 published 
studies investigating GBS have been 
carried out in ten European countries. 
The majority of studies (21/29) 
provided an incidence estimate that 
fell between 1.0 and 2.0 per 100,000 
persons per year. [McGrogan, 2009].
None: GBS is listed as rare adverse 
reaction in the label. There is no 
known prevention for GBS.
Bell’s palsy
The annual incidence of Bell's palsy is 
15 to 30 per 100,000 people. The 
peak incidence occurs between the 
second and fourth decades (15 to 45 
years). 10% of patients experience 
one or more recurrences [Greco, 
2012]. Bell’s palsy has been reported 
in people who had intranasal influenza 
vaccine. A link between Bell’s palsy 
and seasonal influenza vaccine that 
are given by intramuscular injection 
has not been established.
None
 
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Important Potential 
Risks
Data/Rationale for Risk 
Mitigation Strategy
Narcolepsy
Several epidemiological studies have 
reported an increased risk of 
narcolepsy in subjects who received 
GSK’s pandemic vaccine, 
Pandemrix™ H1N1. Although 
H1N1pdm09 strain has been included 
in Flu D-QIV, there is no clinical 
evidence of increased risk of 
narcolepsy for GSK seasonal 
vaccines, including Flu D-QIV. 
None
Injection site 
haemorrhage in 
individuals with 
thrombocytopenia or 
any other coagulation 
disorder 
Injection site haemorrhage may occur 
at the injection site in populations at 
increased risk of haemorrhage, such 
as those with thrombocytopenia or 
acquired/hereditary coagulation 
disorders.
The investigator/prescribers are 
advised of possible injection site 
haemorrhage in individuals with 
thrombocytopenia or any 
coagulation disorder following 
GSK’s quadrivalent seasonal 
influenza vaccine administration by 
information included in product 
labels
There are no inherent risks noted for subjects as a direct result of participating in this 
study.
2.2.
Benefit Assessment
By receiving GSK’s quadrivalent seasonal influenza vaccine as part of their standard 
medical care, the subject may have the benefit of being protected against seasonal 
influenza. 
2.3.
Overall Benefit:Risk Assessment
The decision to receive GSK quadrivalent seasonal influenza vaccine is made between 
the healthcare professional (HCP) and the subject, weighing the potential benefits and 
risks as part of standard medical care.
3.
OBJECTIVES
3.1.
Primary Objective

To estimate, in each country and overall, the cumulative percentages of subjects 
reporting AEIs and/or other AEs within 7 days following vaccination with GSK’s 
quadrivalent seasonal influenza vaccine using adverse drug reaction (ADR) cards.
Refer to Section 10.1.1 for the definition of the primary endpoints.
 
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3.2.
Secondary Objectives

To estimate, in each country and overall, the weekly percentages of subjects 
reporting AEIs and/or other AEs within 7 days following vaccination with GSK’s 
quadrivalent seasonal influenza vaccine using ADR cards, overall, by age strata 
(6 months to 17 years; 18 to 65 years; >65 years), and risk status (at risk/not at risk).

To estimate, in each country and overall, the cumulative percentages of subjects 
reporting AEIs and/or other AEs within 7 days following vaccination with GSK’s 
quadrivalent seasonal influenza vaccine using ADR cards, by age strata (6 months to 
17 years; 18 to 65 years; >65 years), and risk status (at risk/not at risk).
Refer to Section 10.1.2 for the definition of the secondary endpoints.
4.
STUDY DESIGN OVERVIEW
Protocol waivers or exemptions are not allowed unless necessary for the management of 
immediate safety concerns. Therefore, adherence to the study design requirements, 
including those specified in the outline of study procedures (Section 7), are essential and 
required for study conduct. 

Type of design: multi-country, multicentre, prospective, passive enhanced safety 
surveillance (ESS) study

This is a Targeted Safety Study (TSS)

Study population: subjects aged 6 months or above in Spain and aged 18 years or 
above in Belgium and Germany, and receiving GSK’s quadrivalent seasonal 
influenza vaccine according to the local prescribing information 

Biological samples: Not applicable

Sampling schedule: Not applicable

Type of study: self-contained

Data collection: Electronic Case Report Form (eCRF)

Primary completion Date (PCD): PCD is defined as the date of final collection of 
data for all primary outcomes 
Refer to glossary of terms for the definition of PCD.

End of Study (EoS): Last Subject Last Visit
Refer to glossary of terms for the definition of EoS.

Duration of the study: The study is anticipated to run from 01 October 2018 to 
15 January 2019. The recruitment period is anticipated to run for 3 months from 
01 October 2018 to 31 December 2018, except for subjects aged <9 years who have 
not been previously vaccinated against influenza in preceding seasons, for whom the 
recruitment period will end on 01 December 2018 to allow sufficient time to collect 
information on the second dose that is expected to occur at least 4 weeks after the 
first dose. The target sample size is approximately 1,000 vaccinated subjects to be 
reached before 31 December 2018. The intended duration of the study per subject 
 
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will be approximately 8 days for all subjects who have previously been vaccinated 
against influenza in preceding seasons or aged ≥9 years at the time of vaccination, 
and approximately 36 days for children aged <9 years who have not previously been 
vaccinated against influenza in preceding seasons.

Epoch 001: Prospective data collection starting at Visit 1 (Day 1) and ending at 
Visit 2 (Day 8 or when the ADR card is returned by mail) for all subjects who 
have previously been vaccinated against influenza in preceding seasons or aged 
≥9 years at the time of vaccination, or ending at Visit 4 (Day 36 or when the last 
ADR card is returned by mail) for children aged <9 years who have not 
previously been vaccinated against influenza in preceding seasons). Subjects 
will have up to 14 days post vaccination to return their ADR card (at the next 
study visit or by mail).
Table 1
Study groups and epochs foreseen in the study
Study Groups
Number of subjects
Age (Min/Max)
Epochs
Prospective
Approximately 1000
6 months and above
Epoch 001
4.1.
Discussion of Study Design
The study is a passive enhanced safety surveillance aiming to collect prospectively AEIs 
and/or other AEs (see APPENDIX C) experienced within 7 days post vaccination with 
GSK’s quadrivalent seasonal influenza vaccine, using customized Adverse Drug 
Reaction cards (see APPENDIX A). Data will be collected via the HCP or study medical 
staff who administer the seasonal influenza vaccination or who provide the informed
consent form and the ADR cards. 
After written informed consent/informed assent is obtained from the subject/subject’s 
parent(s)/Legally Acceptable Representative (LAR), an ADR card will be distributed to 
the enrolled subjects/subjects’ parent(s)/LAR who will be asked to complete the card and 
return this to the HCP (or a member of his/her team) either in person at the next 
scheduled visit or by mail. Upon return, the card information will be entered into a 
database using eCRF.
The cards will contain pre-defined AEIs to be reported as well as a free text field to 
report other relevant AEs experienced by the subjects. Subjects will also have the 
possibility to indicate that no AE occurred within the 7 days’ time window. 
 
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5.
STUDY POPULATION
5.1.
Number of Subjects/Centres
Approximately 1000 vaccinees receiving GSK’s quadrivalent seasonal influenza vaccine 
will be enrolled in this study in Belgium, Germany and Spain. 
The number of study subjects (n = 1000) is expected to enable detection of very common 
(≥1/10), common (≥1/100 to <1/10) and uncommon (≥1/1,000 to <1/100) AEIs and/or 
other AEs.
Refer to Section 10.2 for the additional details of the criteria used in the estimation of 
sample size. 
5.2.
Inclusion Criteria for Enrolment
Deviations from inclusion criteria are not allowed because they can potentially jeopardise 
the scientific integrity and regulatory acceptability of the study or subject safety. 
Therefore, adherence to the criteria as specified in the protocol is essential.
The objective of the study is to cover all age ranges as per GSK’s quadrivalent vaccine 
indication. However, due to feasibility constraints, Belgium and Germany will only 
recruit subjects 18 years of age and above (German participating sites will target 
essentially older adults subjects aged from 50 years onwards). Spain will target 
subjects between 6 months and 65 years of age at the time of the vaccination.
All subjects must satisfy ALL the following criteria at study entry:

Subjects who, in the opinion of the investigator, can and will comply with the 
requirements of the protocol (e.g., complete the ADR card, return for the next 
scheduled visit or return the ADR card by mail within a timely manner).

A male or female subject vaccinated with GSK’s quadrivalent seasonal influenza 
vaccine (one or two dose schedule) according to the routine medical practices 
between 01 October 2018 and 31 December 2018.

Subjects aged 6 months or above at the time of the vaccination according to the 
countries’ specificities.

Written informed consent/informed assent obtained from the subjects/subjects’
parent(s)/Legally Acceptable Representative(s) (LARs).
 
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5.3.
Exclusion Criteria for Enrolment
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardise the scientific integrity and regulatory acceptability of the study. Therefore, 
adherence to the criteria as specified in the protocol is essential.
The following criterion should be checked at the time of study entry. If ANY exclusion 
criterion applies, the subject must not be included in the study:

Child in care
Please refer to the glossary of terms for the definition of child in care.
6.
CONDUCT OF THE STUDY
6.1.
Regulatory and Ethical Considerations, including the 
Informed Consent Process
The study will be conducted in accordance with the International Conference on 
Harmonisation (ICH) Guideline for Good Clinical Practice (GCP), Good Epidemiology 
Practice (GEP), Good Pharmacovigilance Practice (GVP), or other applicable guidelines, 
all applicable subject privacy requirements and the guiding principles of the Declaration 
of Helsinki. 
The study has been designed and will be conducted in accordance with the ICH 
Harmonised Tripartite Guideline for clinical investigation of medicinal products in the 
paediatric population (ICH E11) and all other applicable ethical guidelines.
GSK will obtain favourable opinion/approval to conduct the study prior to a site initiating 
the study in that country or will document that neither a favourable opinion nor an 
approval to conduct the study is needed.
Conduct of the study includes, but is not limited to, the following:

Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and 
favourable opinion/approval of study protocol and any subsequent amendments.

Subject/ subject’s parent(s)/LAR(s) informed consent and subject informed assent, as 
appropriate.

Investigator reporting requirements as stated in the protocol. 
GSK Biologicals will provide full details of the above procedures to the investigator, 
either verbally, in writing, or both.
Freely given and written or witnessed/thumb printed informed consent must be obtained 
from each subject and/or each subject’s parent(s)/LAR(s) or the impartial witness and 
subject informed assent, as appropriate, prior to participation in the study.
 
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GSK Biologicals will prepare a model Informed Consent Form (ICF) which will embody 
the applicable ICH GCP or other applicable guidelines and GSK Biologicals required 
elements. While it is strongly recommended that this model ICF be followed as closely as 
possible, the informed consent requirements given in this document are not intended to 
pre-empt any local regulations which require additional information to be disclosed for 
informed consent to be legally effective. Clinical judgement, local regulations and 
requirements should guide the final structure and content of the local version of the ICF.
In accordance with the ICH Harmonised Tripartite Guidelines for Good Clinical Practice, 
a subject who can only be enrolled in the study with the consent of his/her parent(s) or 
LAR (e.g., minors), should be informed about the study to the extent compatible with the 
subject’s understanding and, if capable, the subject should sign and personally date a 
written informed assent form (IAF). It is required that the assent be signed by each 
subject, if capable, in addition to the informed consent that is to be signed by his/her 
parent or LAR. It should be assessed whether an assent is required depending on the age 
of the study population and the local requirements.
GSK Biologicals strongly recommends that if the subject reaches the age of consent 
during the study they will be asked to provide consent at the next study visit (if 
applicable). This procedure should be applied according to local laws and regulations.
The investigator has the final responsibility for the final presentation of the ICF and IAF, 
respecting the mandatory requirements of local regulations. The ICF and IAF generated 
by the investigator with the assistance of the sponsor’s representative must be acceptable 
to GSK Biologicals and be approved (along with the protocol, and any other necessary 
documentation) by the IRB/IEC.
7.
DETAILED STUDY PROCEDURES
7.1.
Subject Identification
Subject numbers will be assigned sequentially to subjects consenting to participate in the 
study, according to the range of subject numbers allocated to each study centre.
7.2.
General Study Aspects
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Procedures Manual (SPM). The SPM provides the 
investigator and the site personnel with administrative and detailed technical information 
that does not impact the safety of the subjects.
 
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7.3.
Outline of the Study Procedures
Table 2
List of study procedures
Epoch 
Prospective data collection
Visit number
Visit 1
Visit 2
Visit 3 #
Visit 4 #
Time points
Day 1
Day 8
Day 29
Day 36
Type of contact
Study visit
Study visit or 
mailing*
Study visit Study visit or 
mailing*
Country
Belgium, 
Germany, and 
Spain
Belgium, 
Germany, and 
Spain
Spain
Spain
Informed consent
●
Check inclusion criteria
●
Check exclusion criteria
●
Collect demographic data
●
Collect "at risk" status as per HCP assessment
●
Record the vaccination data for GSK’s quadrivalent 
seasonal influenza vaccine
●
●
Check and record co-administered vaccination
●
●
Distribute ADR cards
O
O
Train subject/subject’s parent (or LAR) to complete 
ADR cards
O
O
Subject/subject’s parent (or LAR) records post-
vaccination AEIs and/or other AEs occurring within 7 
days post vaccination
●
●
●
●
Subject/subject’s parent (or LAR) returns ADR cards *
O
O
Investigator or delegate transcribes data from ADR 
cards into the eCRF
●
●
Record of vaccine-related SAEs occurring within 7 
days post vaccination
●
●
●
●
Study conclusion
●##
●
ADR card: adverse drug reaction card; AE: adverse event; AEI: adverse event of interest; eCRF: electronic case report 
form; HCP: healthcare professional; LAR: legally acceptable representative; SAE: serious adverse event
● is used to indicate a study procedure that requires documentation in the individual eCRF 
○ is used to indicate a study procedure that does not require documentation in the individual eCRF
# Only applicable for children aged <9 years who have not previously been vaccinated against influenza in preceding 
seasons and to whom a second dose should be given after an interval of at least 4 weeks and within the study period 
(see Table 3), and if the second dose of influenza vaccine is GSK’s quadrivalent seasonal influenza vaccine.
## Not applicable for children aged <9 years if they follow the recommendations of a 2-dose schedule with 4 weeks 
interval.
* Subject/subject’s parent (or LAR) returns ADR cards either in person during a study visit or by mail, to the HCP (or a 
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Whenever possible, the investigator should arrange study visits within the optimal 
intervals and no later than the allowed intervals (Table 3).
Table 3
Intervals between study visits
Interval
Optimal length of interval
Allowed interval
Visit 1 (Day 1) Visit 2 (Day 8)
7 days
7 days – 14 days
Visit 1 (Day 1) Visit 3 # (Day 29)
28 days
28 days – 42 days
Visit 3 # (Day 29) Visit 4 # (Day 36)
7 days
7 days – 14 days
# Only applicable for children aged <9 years who have not previously been vaccinated against influenza in preceding 
seasons and to whom a second dose should be given after an interval of at least 4 weeks and within the study period, 
and if the second dose of influenza vaccine is GSK’s quadrivalent seasonal influenza vaccine.
7.4.
Detailed Description of Study Procedures
7.4.1.
Informed consent
The signed/witnessed/thumb printed informed consent of the subject/subject’s 
parent(s)/LAR(s) must be obtained before study participation. The signed informed 
assent of a subject below the age of consent (i.e., minor) should be obtained in addition to 
the signed informed consent by his/her parent(s)/LAR(s) according to local rules and 
regulations. Refer to Section 6.1 for the requirements on how to obtain informed consent 
and assent, as appropriate.
7.4.2.
Check inclusion and exclusion criteria
Check all applicable inclusion and exclusion criteria as described in Sections 5.2 and 5.3
before enrolment.
7.4.3.
Collect demographic data
Record demographic data (including month and year of birth, gender and race) in the 
subject’s eCRF.
7.4.4.
Collect “at risk status”
Record the “risk status” (i.e., at risk/not at risk) for influenza-associated morbidity and 
mortality as per HCP assessment in the subject’s eCRF.
The risk status should be defined by the HCP based on his/her judgment and experience. 
Risk groups usually recommended for seasonal influenza vaccination in the EU include 
but are not limited to:

pregnant women 

individuals >6 months with chronic heart or lung diseases, metabolic or renal 
disease, chronic liver disease, chronic neurological conditions or 
immunodeficiencies 

residents of long-term care facilities for older persons and the disabled 
 
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
children aged 6–59 months

healthcare workers including those who work in facilities that care for the elderly or 
persons with disabilities
7.4.5.
Record vaccination data for GSK’s quadrivalent seasonal 
influenza vaccine
Record in the subject’s eCRF information on seasonal influenza vaccine, such as the date 
of administration and the batch number.
7.4.6.
Check and record co-administered vaccination 
Co-administered vaccination administered on the same day as the subject’s GSK’s 
quadrivalent seasonal influenza vaccine must be recorded in the eCRF.
7.4.7.
ADR cards
Customized ADR cards will be used to collect the AEIs and/or other AEs within 7 days 
post each vaccination (i.e., the day of vaccination and the following 6 days). After written 
informed consent/informed assent is obtained from the subject/the subject’ 
parent(s)/LAR, the ADR cards will be provided to the subjects/subjects’ parent’(s)/LAR 
on the day of vaccination. The subjects/subjects’ parent’(s)/LAR will be asked to 
complete the ADR cards with any AEIs and/or other AEs occurring within 7 days post 
vaccination and to return the cards to the HCP at the next study visit or by mail. The 
investigator or delegate will transcribe the collected information into the eCRF database.
Note: ADR cards can be filled in by a minor subject under the supervision of the 
subject’s parent(s)/LAR(s) provided that the minor has the competence to assess and 
report the information to be provided on the ADR cards. The ultimate accountability for 
the completion of the ADR cards remains with the subject’s parent(s)/LAR(s). The 
investigator should discuss this accountability with the subject’s parent(s)/LAR(s).
7.4.8.
Study conclusion
The investigator will:

Review all the data collected to ensure accuracy and completeness.

Complete the Study Conclusion screen in the eCRF.
7.5.
Biological Sample Handling and Analysis
Not applicable.
 
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8.
SAFETY
The investigator or site staff is/are responsible for the detection, documentation and 
reporting of events meeting the criteria and definition of an AE of specific interest or an 
SAE as provided in this protocol. 
Each subject/subject’s parent(s)/ LAR(s) will be instructed to contact the investigator 
immediately should they/the subject manifest any signs or symptoms they perceive as 
serious/of concern or indicating a change in their health status.
8.1.
Safety Definitions
8.1.1.
Definition of an adverse event
An AE is any untoward medical occurrence in a subject, temporally associated with the 
use of a medicinal product, whether or not considered related to the medicinal product, or 
temporally associated with a study procedure.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with 
the use of a medicinal product. For marketed medicinal products, this also includes 
failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse. 
8.1.2.
Definition of a serious adverse event
An SAE is any untoward medical occurrence that:
a.
Results in death,
b.
Is life-threatening,
Note: The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in 
which the subject was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, had it been more severe.
c.
Requires hospitalisation or prolongation of an existing hospitalisation,
Note: In general, hospitalisation signifies that the subject has been admitted at the 
hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician’s office or in an out-patient setting. 
Complications that occur during hospitalisation are also considered AEs. If a 
complication prolongs hospitalisation or fulfils any other serious criteria, the event 
will also be considered serious. When in doubt as to whether ‘hospitalisation’ 
occurred or was necessary, the AE should be considered serious.
Hospitalisation for elective treatment of a pre-existing condition (known or 
diagnosed prior to informed consent signature) that did not worsen from baseline is 
NOT considered an SAE.
 
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d.
Results in disability/incapacity, 
Note: The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhoea, influenza like illness, and accidental trauma (e.g., sprained 
ankle) which may interfere or prevent everyday life functions but do not constitute a 
substantial disruption.
or
e.
Is a congenital anomaly/birth defect in the offspring of a study subject.
Medical or scientific judgement should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalisation but may jeopardise 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition. These should also be considered 
serious. Examples of such events are invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalisation.
8.1.3.
Adverse events of specific interest
AEs that comprise the primary interest of the study are designated as AEIs. Please refer 
to APPENDIX C for the pre-defined list of AEIs.
8.2.
Reporting of SAEs and Other Events
It will be clearly communicated to participating HCPs that the study does not replace 
reporting of AEs/SAEs that should occur as part of routine practice as specified by local 
regulations. It is not the intention of the surveillance to influence or change the usual 
local reporting processes. HCPs should continue to report any AEs/SAEs they would 
typically report using the mechanisms routinely used in their healthcare practice. 
Therefore, although the data collected for this study is primarily safety-related data, 
reporting mechanisms of AEs to regulatory authorities should not be altered and are to 
continue according to local standards. 
If the participating HCP becomes aware of an SAE experienced by a study participant 
occurring within 7 days post vaccination that is deemed to be related to GSK’s 
quadrivalent seasonal influenza vaccine according to the judgement of the HCP, the SAE 
should be reported to GSK within 24 hours of becoming of aware using the eCRF. This 
will be linked to the central safety database (Argus) with a study ID link mechanism 
therefore it is not necessary to report separately to central safety (GSK Biologicals 
Clinical Safety & Pharmacovigilance, e-mail: 
 using the 
GSK reporting forms) unless there are issues with access to the eCRF preventing the
electronic reporting of the SAE within the required timeframe. If GSK deems additional 
information is necessary, request for additional information will be sent to the HCP.

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9.
SUBJECT COMPLETION AND WITHDRAWAL
9.1.
Subject Completion
A subject who returns for the concluding visit foreseen in the protocol or has returned the 
completed ADR card is considered to have completed the study.
9.2.
Subject Withdrawal
A subject who does not return for the concluding visit foreseen in the protocol or has 
not returned the completed ADR card will be considered a withdrawal from the study. 
If the subject informs the Investigator of the reason for withdrawal from the study, the 
reason for this will be entered into the electronic Case Report Form as detailed below:

Seasonal influenza vaccine-related Serious Adverse Event

Protocol Violation (to be specified)

Consent withdrawal, not due to an adverse event (to be specified if the information 
is available)

Not willing/not able to participate in the visit

Migrated/moved from the study area

Lost to follow-up

Sponsor study termination

Other (please specify)
10.
STATISTICAL METHODS
10.1.
Endpoints
10.1.1.
Primary endpoint

Occurrence of AEIs and/or other AEs within 7 days post each GSK’s quadrivalent 
seasonal influenza vaccination (i.e., the day of vaccination and the following 6 days) 
reported using ADR cards, according to MedDRA classification, by cumulative 
weeks (expected ISO weeks 40 to 52).
 
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10.1.2.
Secondary endpoints

Occurrence of AEIs and/or other AEs within 7 days post each GSK’s quadrivalent 
seasonal influenza vaccination (i.e., the day of vaccination and the following 6 days) 
reported using ADR cards, according to MedDRA classification, each week 
(expected ISO weeks 40 to 52).

Occurrence of AEIs and/or other AEs within 7 days post each GSK’s quadrivalent 
seasonal influenza vaccination (i.e., the day of vaccination and the following 6 days) 
reported using ADR cards, according to MedDRA classification, by cumulative 
weeks (expected ISO weeks 40 to 52).
10.2.
Determination of Sample Size
Approximately 1000 subjects will be enrolled in this study. 
Table 4 shows the probability to observe at least one AE, the exact 95% Confidence 
Intervals (CIs) for the percentage of vaccinated subjects with the AE and Relative 
Standard Error (RSE) for a range of scenarios in term of number of vaccinated subjects 
and true percentage of vaccinated subjects with the AE: 

With an overall sample size of 1000 vaccinated subjects (whole study period, all 
countries) and a true percentage of vaccinated subjects with the AE ranging from 1% 
to 10%, the corresponding probability to observe at least one vaccinated subject with 
the AE is >99% and the RSE ranges from 9.5% to 31.5%. 

With an overall sample size of 75 vaccinated subjects (by week, all countries) and a 
true percentage of vaccinated subjects with the AE ranging from 1% to 10%, the 
corresponding probability to observe at least one vaccinated subject with the AE 
ranges from 52.9% to >99% and the RSE ranges from 34.6% to 114.9%.
Table 5 shows the evolution by week of the cumulative probability to observe at least one 
AE, the exact 95% CI for the cumulative percentage of vaccinated subjects with the AE 
and RSE in the course of the study for an overall sample size of 1000 (all countries) and 
333 (by country) vaccinated subjects and a true percentage of vaccinated subjects with 
the AE of 1%.
 
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Table 4
Probability to observe at least one AE, exact 95% Confidence 
Intervals and Relative Standard Error according to number of 
vaccinated subjects and true percentage of vaccinated subjects with 
the AE 
Number of vaccinated subjects
True 
percentage 
of vaccinated 
subjects with 
the AE
(%)
Probability§ to 
observe ≥1 
vaccinated 
subject with 
the AE
(%)
Number of 
vaccinated 
subjects 
with the AE
Exact 95% CI* 
on the 
percentage of 
vaccinated 
subjects with 
the AE
Associated 
relative 
standard 
error
(%)
Lower 
Limit
Upper 
limit
1500 (whole study period, all countries) 10
>99
150
8.53
11.63
7.7
8
>99
120
6.68
9.49
8.8
6
>99
90
4.85
7.32
10.2
4
>99
60
3.07
5.12
12.6
2
>99
30
1.35
2.84
18.1
1
>99
15
0.56
1.64
25.7
0.5
>99
7.5
0.21
1.00
36.4
0.1
77.7
1.5
0.01
0.43
81.6
1000 (whole study period, all countries) 10
>99
100
8.21
12.03
9.5
8
>99
80
6.39
9.86
10.7
6
>99
60
4.61
7.66
12.5
4
>99
40
2.87
5.41
15.5
2
>99
20
1.23
3.07
22.1
1
>99
10
0.48
1.83
31.5
0.5
>99
5
0.16
1.16
44.6
0.1
63.2
1
0.00
0.56
99.9
75 (per week, all countries)
10
>99
7.5
4.27
19.12
34.6
8
>99
6
2.99
16.60
39.2
6
99.0
4.5
1.83
13.99
45.7
4
95.3
3
0.83
11.25
56.6
2
78.0
1.5
0.14
8.28
80.8
1
52.9
0.75
0.01
6.65
114.9
500 (whole study period, by country)
10
>99
50
7.51
12.97
13.4
8
>99
40
5.78
10.73
15.2
6
>99
30
4.08
8.45
17.7
4
>99
20
2.46
6.11
21.9
2
>99
10
0.96
3.65
31.3
1
>99
5
0.33
2.32
44.5
0.5
91.8
2.5
0.08
1.59
63.1
0.1
39.4
0.5
0.00
0.93
141.4
333 (whole study period, by country)
10
>99
33.3
7.00
13.74
16.4
8
>99
26.6
5.32
11.45
18.6
6
>99
20
3.70
9.12
21.7
4
>99
13.3
2.17
6.70
26.8
2
>99
6.7
0.79
4.15
38.4
1
96.5
3.3
0.23
2.76
54.5
0.5
81.2
1.7
0.04
1.99
77.3
0.1
28.3
0.3
0.00
1.30
173.2
25 (per week, by country)
10
92.8
2.5
1.70
28.67
60.0
8
87.6
2
0.98
26.03
67.8
6
78.7
1.5
0.44
23.27
79.2
4
64.0
1
0.10
20.35
98.0
 
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Number of vaccinated subjects
True 
percentage 
of vaccinated 
subjects with 
the AE
(%)
Probability§ to 
observe ≥1 
vaccinated 
subject with 
the AE
(%)
Number of 
vaccinated 
subjects 
with the AE
Exact 95% CI* 
on the 
percentage of 
vaccinated 
subjects with 
the AE
Associated 
relative 
standard 
error
(%)
Lower 
Limit
Upper 
limit
2
39.7
0.5
0.00
17.21
140.0
1
22.2
0.25
0.00
15.52
199.0
§ Binomial distribution
* [Clopper, 1934]
Table 5
Cumulative probability to observe at least one AE, exact 95% 
Confidence Intervals and Relative Standard Error by week for a true 
percentage of subjects with the AE of 1%
Number of 
vaccinated 
subjects
ISO 
weeks
Cumulative 
number of 
vaccinated 
subjects
Cumulative 
probability§ to 
observe ≥1 
vaccinated 
subject with 
the AE
(%)
Cumulative 
number of 
vaccinated 
subjects with 
the AE
Average
percentage 
of vaccinated 
subjects with 
the AE
(%)
Exact 95% CI* on 
the cumulative 
percentage of 
vaccinated 
subjects with the 
AE
Associated 
relative 
standard 
error
(%)
Lower 
Limit
Upper 
limit
1000 (whole 
study period, 
all countries)
40-40 75
52.9
0
1.00
0.00
4.80
114.9
40-41 150
77.9
1
1.00
0.02
3.66
81.2
40-42 225
89.6
2
1.00
0.11
3.17
66.3
40-43 300
95.1
3
1.00
0.21
2.89
57.4
40-44 375
97.7
3
1.00
0.17
2.32
51.4
40-45 450
98.9
4
1.00
0.24
2.26
46.9
40-46 525
>99
5
1.00
0.31
2.21
43.4
40-47 600
>99
6
1.00
0.37
2.16
40.6
40-48 675
>99
6
1.00
0.33
1.92
38.3
40-49 750
>99
7
1.00
0.38
1.91
36.3
40-50 825
>99
8
1.00
0.42
1.90
34.6
40-51 900
>99
9
1.00
0.46
1.89
33.2
40-52 1000
>99
10
1.00
0.48
1.83
31.5
333 (whole 
study period, 
by country)
40-40 25
22.2
0
1.00
0.00
13.72
199.0
40-41 50
39.5
0
1.00
0.00
7.11
140.7
40-42 75
52.9
0
1.00
0.00
4.80
114.9
40-43 100
63.4
1
1.00
0.03
5.45
99.5
40-44 125
71.5
1
1.00
0.02
4.38
89.0
40-45 150
77.9
1
1.00
0.02
3.66
81.2
40-46 175
82.8
1
1.00
0.01
3.14
75.2
40-47 200
86.6
2
1.00
0.12
3.57
70.4
40-48 225
89.6
2
1.00
0.11
3.18
66.3
40-49 250
91.9
2
1.00
0.10
2.86
62.9
40-50 275
93.7
2
1.00
0.09
2.61
60.0
40-51 300
95.1
3
1.00
0.21
2.89
57.4
40-52 333
96.5
3
1.00
0.19
2.61
54.5
§ Binomial distribution
* [Clopper, 1934]
 
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10.3.
Sets for Analyses
10.3.1.
Enrolled Set
The Enrolled Set will include all subjects with informed consent signed.
10.3.2.
Exposed Set
The Exposed Set will include all enrolled subjects who are vaccinated with GSK’s 
quadrivalent seasonal influenza vaccine.
10.3.3.
Safety Set
The Safety Set will include all subjects from the Exposed Set who received the ADR 
card.
10.3.4.
Solicited Safety Set
The Solicited Safety Set will include all subjects from the Safety Set who returned the 
ADR card.
10.4.
Derived and Transformed Data
Demography:

For a given subject and a given demographic variable, missing measurements will 
not be imputed.

Age at the vaccination will be computed as the difference between the vaccination 
date and the date of birth. The age will be expressed in years.
Safety:

Subjects who did not report an adverse event will be considered as subjects who did 
not experience adverse event.
10.5.
Analysis of Demographics
The number of subjects included in each analysis set will be tabulated by ISO week 
(expected ISO weeks 40 to 52), overall and by country.
Demographic characteristics (age at study vaccination in years, gender, race) and risk 
status will be summarised overall and by country using descriptive statistics for each 
analysis set:

Frequency tables will be generated for categorical variables such as gender.

Mean, standard deviation, median, minimum and maximum will be provided for 
continuous data such as age.
 
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10.6.
Analysis of Primary Objective
The primary analysis of AEIs and/or other AEs reported using ADR cards will be 
descriptive and will be performed on the Safety Set.
For each vaccine dose*, the cumulative percentage of subjects reporting AEIs and/or
other AEs within 7 days post-vaccination period (i.e., the day of vaccination and the 
following 6 days) using ADR cards from study start up to each study week (ISO weeks 
40 to 52) will be estimated by MedDRA Preferred Term, overall and by country, as 
follows:

The denominator will be the number of subjects from the Safety Set vaccinated with 
GSK’s quadrivalent seasonal influenza vaccine at any point from study start (i.e., 
01 October 2018) up to the end of the week of interest, in a given country or for all
countries.

The numerator will be the number of subjects from the denominator who reported 
the AE on the ADR card within 7 days following vaccination.
* Note that a second dose of GSK’s quadrivalent seasonal influenza vaccine is planned to 
be administered only to children aged <9 years who have not previously been vaccinated 
against influenza in preceding seasons. 
95% CI will be computed on all estimated percentages. The method for estimating the 
CIs will be described in the statistical analysis plan.
10.7.
Analysis of Secondary Objectives
The primary analysis of AEIs and/or other AEs reported using ADR cards will be 
descriptive and will be performed on the Safety Set.
For each vaccine dose*, the weekly percentage of subjects reporting AEIs and/or other 
AEs within 7 days post-vaccination period (i.e., the day of vaccination and the following 
6 days) using ADR cards will be estimated by MedDRA Preferred Term, overall and by 
country, as follows:

The denominator will be the number of subjects from the Safety Set vaccinated with 
GSK’s quadrivalent seasonal influenza vaccine during the week of interest (ISO 
weeks 40 to 52), in a given country or for all countries.

The numerator will be the number of subjects from the denominator who reported 
the AE on the ADR card within 7 days following vaccination.
In addition, for each vaccine dose*, the weekly and cumulative percentages of subjects 
reporting AEIs and/or other AEs within 7 days post-vaccination period using ADR cards, 
according to MedDRA Primary System Organ Class classification, will be estimated in 
each country and overall, by age strata (6 months to 17 years; 18 to 65 years; >65 years) 
and risk status (at risk/not at risk).
 
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* Note that a second dose of GSK’s quadrivalent seasonal influenza vaccine is planned to 
be administered only to children aged <9 years who have not previously been vaccinated 
against influenza in preceding seasons. 
95% CI will be computed on all estimated percentages. The method for estimating the 
CIs will be described in the statistical analysis plan.
10.8.
Other Analyses
The GSK’s quadrivalent seasonal influenza vaccine batch numbers administered during 
the study vaccination period will be tabulated by ISO week, overall and by country, on 
the Exposed Set.
The percentage of subjects who returned the ADR card will be tabulated by centre, 
country and overall on the Safety Set.
As a sensitivity analysis, the analysis of AEIs and/or other AEs reported using ADR 
cards will also be performed on the Solicited Safety Set.
SAEs occurring within 7 days post vaccination (i.e., the day of vaccination and the 
following 6 days) and assessed as related to GSK’s quadrivalent seasonal influenza 
vaccine will be described in detail.
The percentage of subjects who received co-administered vaccination on the same day as 
their GSK’s quadrivalent seasonal influenza vaccine will be tabulated by GSK’s 
quadrivalent seasonal influenza vaccine dose, overall and by country.
10.9.
Interpretation of Analyses
All analyses will be descriptive.
10.10.
Conduct of Analyses
Any deviation(s) or change(s) from the original statistical plan outlined in this 
protocol will be described and justified in the final study report.
10.10.1.
Sequence of analyses
Three interim analyses and a final analysis will be performed.

The first interim analysis will be performed by mid-November 2018

The second interim analysis will be performed by end-November 2018

The third interim analysis will be performed by mid-December 2018

The final analysis will be performed when all data up to the end of the study will be 
available and cleaned
 
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10.10.2.
Statistical considerations for interim analyses
The interim analyses will be generated to evaluate the trend of reporting of AEs (i.e. 
safety monitoring) and will be performed on data which are cleaned as much as possible. 
The following analyses will be performed for each interim analysis, overall and by 
country: 

The number of subjects vaccinated with GSK’s quadrivalent seasonal influenza 
vaccine during each ISO week will be tabulated overall, by age strata and risk status.

Demographic characteristics (age at study vaccination in years, gender, race) will be 
summarised using descriptive statistics.

The weekly percentage of subjects reporting AEIs and/or other AEs within 7 days 
post-vaccination period (i.e., the day of vaccination and the following 6 days) using 
ADR cards will be estimated by MedDRA Preferred Term, with 95% CI.
Since there is no hypothesis testing, no adjustment of type I error will be needed.
No study report will be written for the interim analyses. 
11.
ADMINISTRATIVE MATTERS
To comply with ICH Guideline for GCP or other applicable guidelines (such as GEP and 
GVP) administrative obligations relating to data collection, monitoring, archiving data, 
audits, confidentiality, ownership and publications must be met.
Anticipated study milestones are presented below. Any changes to those initial 
milestones will be reported in the study report:
Milestone
Planned date
Actual date*
Comments
Approval by Ethics 
Committees
28 September 2018
24 August 2018
Approval of the protocol
First subject enrolled  
01 October 2018
N/A
First visit anticipated
Last subject enrolled  
15 January 2019
N/A
Last visit anticipated 
Database Freeze
22 March 2019
N/A
None
Completion of Statistical 
Analysis 
19 April 2019
N/A
None
Final Report of Main 
Study Results 
06 June 2019
N/A
None
*to be completed at the date of the final study report
11.1.
Case Report Form/Electronic Case Report Form Instructions
A validated GSK defined electronic data collection tool will be used as the method for 
data collection.
In all cases, subject initials will not be collected nor transmitted to GSK. Subject data 
necessary for analysis and reporting will be entered/transmitted into a validated database 
or data system. Clinical data management will be performed in accordance with 
applicable GSK standards and data cleaning procedures.
 
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While completed eCRFs are reviewed by a GSK Biologicals’ Site Monitor at the study 
site, omissions or inconsistencies detected by subsequent eCRF review may necessitate 
clarification or correction of omissions or inconsistencies with documentation and 
approval by the investigator or appropriately qualified designee. In all cases, the 
investigator remains accountable for the study data. 
Once the database is archived and the clinical study report is complete and approved by 
all parties, each participating investigator will be provided with a CD-ROM of the final 
version of the data generated at his/her investigational site.
11.2.
Study Monitoring by GSK Biologicals
GSK will monitor the study to verify that, amongst others, the: 

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol, any other 
study agreements, GCP and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents.
The investigator must ensure provision of reasonable time, space and qualified personnel 
for monitoring visits.
Direct access to all study-site related and source data is mandatory for the purpose of 
monitoring review. The monitor will perform an eCRF review and a Source Document 
Verification (SDV)/Source Document Review (SDR) per Risk Based Monitoring Plan. 
By SDV we understand verifying eCRF entries by comparing them with the source data 
that will be made available by the investigator for this purpose. 
The Source Documentation Agreement Form describes the source data for the different 
data in the eCRF. This document should be completed and signed by the site monitor and 
investigator and should be filed in the monitor’s and investigator’s study file. Any data 
item for which the eCRF will serve as the source must be identified, agreed and 
documented in the source documentation agreement form.
For eCRF, the monitor will mark completed and approved screens at each visit. 
Upon completion or premature discontinuation of the study, the monitor will conduct site 
closure activities with the investigator or site staff, as appropriate, in accordance with 
applicable regulations, GCP, and GSK procedures.
 
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11.3.
Record Retention
Following closure of the study, the investigator must maintain all site study records 
(except for those required by local regulations to be maintained elsewhere) in a safe and 
secure location. The records must be easily accessible, when needed (e.g., audit or 
inspection), and must be available for review in conjunction with assessment of the 
facility, supporting systems, and staff. Where permitted by applicable laws/regulations or 
institutional policy, some or all of these records can be maintained in a validated format 
other than hard copy (e.g., microfiche, scanned, electronic); however, caution needs to be 
exercised before such action is taken. The investigator must ensure that all reproductions 
are legible and are a true and accurate copy of the original and meet accessibility and 
retrieval standards, including re-generating a hard copy, if required. Furthermore, the 
investigator must ensure that an acceptable back-up of the reproductions exists and that 
there is an acceptable quality control procedure in place for making these reproductions.
GSK will inform the investigator/institution of the time period for retaining these records 
to comply with all applicable regulatory requirements. However, the 
investigator/institution should seek the written approval of the sponsor before proceeding 
with the disposal of these records. The minimum retention time will meet the strictest 
standard applicable to a particular site, as dictated by ICH GCP or other applicable 
guidelines, any institutional requirements or applicable laws or regulations, or GSK 
standards/procedures; otherwise, the minimum retention period will default to 30 years. 
The investigator/institution must notify GSK of any changes in the archival 
arrangements, including, but not limited to, archival at an off-site facility and transfer of 
ownership of the records in the event the investigator leaves the site.
11.4.
Quality Assurance
To ensure compliance with GCP, GEP, GVP, or other applicable guidelines and all 
applicable regulatory requirements, GSK may conduct a quality assurance audit. 
Regulatory agencies may also conduct a regulatory inspection of this study. Such 
audits/inspections can occur at any time during or after completion of the study. If an 
audit or inspection occurs, the investigator and institution agree to allow the 
auditor/inspector direct access to all relevant documents and to allocate his/her time and 
the time of his/her staff to the auditor/inspector to discuss findings and any relevant 
issues.
11.5.
Posting of Information on Publicly Available Registers and 
Publication Policy
GSK assures that the key design elements of this protocol will be posted on the GSK 
website and in publicly accessible database(s) such as clinicaltrials.gov, in compliance 
with the current regulations.
GSK also assures that results of this study will be posted on the GSK website and in 
publicly accessible regulatory registry(ies) within the required time-frame, in compliance 
with the current regulations.
 
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11.6.
Provision of Study Results to Investigators
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK Biologicals site or other 
mutually-agreed location.
GSK Biologicals will also provide the investigator with the full summary of the study 
results. The investigator is encouraged to share the summary results with the study 
subjects, as appropriate.
11.7.
Data Sharing
Under the framework of the SHARE initiative, results of GSK studies may be combined 
with non- GSK studies, to investigate further about the study product(s) and other 
product(s), and /or the disease/condition under investigation and related diseases and 
conditions.
12.
COUNTRY SPECIFIC REQUIREMENTS
There are no country-specific requirements for Belgium or Spain and one for Germany 
related to gender distribution.
Explanatory statement concerning Gender Distribution (Article 7, paragraph 2 (12) 
of the German GCP ORDER)
The EPI-FLU-056 study does not involve administration of an investigational product. 
GSK’s quadrivalent seasonal influenza vaccine is approved for active immunization of 
persons aged 6 months and older for the prevention of disease caused by influenza A 
subtype viruses and type B viruses contained in the vaccine and will be administered 
according to routine medical practice prior to subject’s enrolment in the study. As per 
inclusion criteria, both females and males are eligible to be part of the study with no 
specific restrictions associated with gender. The objective of the study is to assess AEIs 
or other AEs experienced within 7 days post vaccination regardless of gender.
There is no intent to analyse the safety of GSK’s quadrivalent seasonal influenza vaccine 
by gender which implies that the potential relationship between the gender distribution 
and the safety outcomes will not be under scrutiny in this enhanced safety surveillance. 
 
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13.
REFERENCES
Centers for Disease Control and Prevention (CDC). Estimated influenza illnesses, 
medical visits, hospitalizations, and deaths averted by influenza vaccination in the 
United States. 2016a. Available at: https://wwwcdcgov/flu/about/disease/2015-16htm.
Centers for Disease Control and Prevention (CDC). Laboratory-Confirmed Influenza 
Hospitalizations. 2016b. Available at: gis.cdc.gov/GRASP/Fluview/FluHospRates.html.
Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of 
the binomial. Biometrika. 1934;26:404-13.
EMA. Interim guidance on enhanced safety surveillance for seasonal influenza vaccines 
in the EU. EMA/PRAC/222346/2014. 2014. Last accessed 12 March 2018. URL: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/04/
WC500165492.pdf
EMA. Guideline on Influenza Vaccines. Non-clinical and Clinical Module. 
EMA/CHMP/VWP/457259/2014. 2016. Last accessed 12 March 2018. URL: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2016/07/
WC500211324.pdf
Greco A, Gallo A, Fusconi M, Marinelli C, Macri GF, deVincentis M. Bell’s Palsy and 
autoimmunity. Autoimmunity Reviews. 2012;12:323-8.
McGrogan A, Madle GC, Seaman HE, et al. The Epidemiology of Guillain-Barré 
syndrome worldwide. Neuroepidemiology. 2009;32:150-63.
Nicoll A, Ciancio BC, Lopez Chavarrias V, et al. Influenza-related deaths--available 
methods for estimating numbers and detecting patterns for seasonal and pandemic 
influenza in Europe. Euro Surveill. 2012 May 3;17(18). 
Foppa B, Po-Yung C, Reynolds S. et al. Deaths averted by influenza vaccination in the 
U.S. during the seasons2005/06 through 2013/14. Vaccine. 2015; 33(26): 3003-9.
Ruggeberg JU, Gold MS, Bayas JM, et al. Anaphylaxis: case definition and guidelines 
for data collection, analysis, and presentation of immunization safety data. Vaccine. 
2007;25:5675-84.
Uhart M, Bricout H, Clay E, et al. Public health and economic impact of seasonal 
influenza vaccination with quadrivalent influenza vaccines compared to trivalent 
influenza vaccines in Europe. Hum Vaccin Immunother. 2016; 12:2259–68. 
World Health Organization (WHO). Influenza. WHO recommendations on the 
composition of influenza virus vaccines. 2018. Available from: 
http://wwwwhoint/influenza/vaccines/virus/recommendations/en/.
 
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Zhou H, Thompson WW, Viboud CG, et al. Hospitalizations Associated With Influenza 
and Respiratory Syncytial Virus in the United States, 1993–2008. Clin Infect Dis. 2012; 
54: 1427–36.
 
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APPENDIX A
ADR Card
CONFIDENTIAL
Subject Number:
Enhanced safety surveillance of GSK's quadrivalent seasonal 
influenza vaccine
This surveillance is designed to capture adverse events following immunisation. 
Please report if you get any adverse event experienced following your influenza (flu) vaccination.  
2. When/where the flu vaccine was administered?  
What date were you vaccinated / was the vaccine given?   ___ /____ /2018
Who administered the vaccine? a Healthcare Professional:
Yes
No  
If no,  please say who administered the vaccine :  _______________________________
3. Please report any symptoms/conditions in the 7 days after the flu vaccine
(i.e., the day of vaccination and the following 6 days)
Please look at the list of possible adverse events following vaccination on the next page. 
Please tick the box and indicate the start date for any adverse event you/the person vaccinated 
experienced.  
Please return the card in the envelope provided to your healthcare professional or study medical staff.
Please  return by post or in person.  
Thank you for your help
4. If there were no symptoms experienced in the 7 days after vaccination 
(i.e., the day of vaccination and the following 6 days), tick and return 
I have NOT/the person vaccinated has NOT experienced any adverse event following 
vaccination:
Please return the card in the envelope provided to your healthcare professional or study medical staff.
Please  return by post or in person.  
Thank you for your help
Formal study name:
Passive enhanced safety surveillance of GSK's quadrivalent seasonal influenza vaccines: a pilot 
study in Belgium, Germany and Spain during the 2018/19 influenza season
GSK study abbreviation:
EPI-FLU 056 VS EU
Contact:
XXXXX
Version 6 – 24 May 2018
1. About you / About the person vaccinated
Date of Birth  __ / ____ (mm/yyyy)
Male            Female
-
 
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Symptoms or reactions you experienced
in the 7 days (i.e., the day of vaccination and the 
following 6 days) after your influenza vaccination
Please tick if you 
experienced the symptom
Start date of the symptom
dd/mm/yyyy
Irritated or red eyes
__/___/___
Runny nose
__/___/___
Blocked nose 
__/___/___
Nose bleed
__/___/___
Common cold 
__/___/___
Cough
__/___/___
Sore throat
__/___/___
Hoarse voice
__/___/___
Wheezing
__/___/___
Loss of appetite 
__/___/___
Nausea – feeling sick to your stomach
__/___/___
Vomiting – being sick to your stomach
__/___/___
Diarrhoea
__/___/___
Fever (temperature >38°C)
__/___/___
Allergic reaction (rash, itchy skin and/or eyes, 
runny nose)
__/___/___
Severe allergic reaction (Rash, difficulty breathing, 
dizziness, fast heart rate, swelling of lips/tongue)
__/___/___
Swelling of the face
__/___/___
Rash in a restricted part of the body
__/___/___
Rash all over body
__/___/___
Feeling irritable
__/___/___
Feeling tired
__/___/___
Headache
__/___/___
Shivering or feeling shaky
__/___/___
Seizure / fits
__/___/___
Muscle aches
__/___/___
Joint pain
__/___/___
Redness around injection site
__/___/___
Swelling around injection site
__/___/___
Pain at the injection site
__/___/___
Other
1. ____________________
2.  ____________________
3.  ____________________
__/___/___
__/___/___
__/___/___
Enhanced safety surveillance of GSK's quadrivalent seasonal influenza vaccine
CONFIDENTIAL
Subject Number:
-
 
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APPENDIX B
Code list of pre-specified AEIs
 
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APPENDIX C
AMENDMENTS AND ADMINISTRATIVE 
CHANGES TO THE PROTOCOL 
GlaxoSmithKline Biologicals SA
Vaccines R & D
Protocol Amendment 1
eTrack study number 
and Abbreviated Title
207737 (EPI-FLU-056 VS EU)
Amendment number:
Amendment 1
Amendment date:
11 September 2018
Co-ordinating author:
 4Clinics Belgium for GSK Biologicals’
Rationale/background for changes: 
The protocol has been amended to respond to comments from the concerned Ethical 
Review Boards. 
In addition, the interim analysis section has been updated to remove the analysis 
planned for end October 2018, due to the expectation that the majority of subject 
recruitment may commence from mid-October 2018, rather than initially planned 
(01-OCT-2018).
The list of abbreviations and the reference list have been revised in alignment with the 
other changes. Grammatical and typographical errors have been corrected.
Amended text has been included in bold italics in the body of the protocol. The 
amended text (in bold italics) and the deleted text (in strikethrough) are provided 
below:
Contributing authors
!
 Epidemiologist
!
 Clinical Epidemiology Project Lead
!
 VP Head of Clinical R&D
!
 Project Statistician
!
 Lead Statistician
!
h, Study Delivery Lead
!
 Clinical Safety representative
!
 Clinical Safety representative
!
 Regulatory Affairs representative
!
 Oversight Data Manager
!
 Study Data Manager
!
 Study Data Manager

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PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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LIST OF ABBREVIATIONS
CDC
Centers for Disease Control and Prevention
WHO
World Health Organization
1. 
INTRODUCTION
Influenza is an acute, highly contagious, respiratory disease caused by influenza 
viruses, mainly spread through respiratory droplets. The illness is accompanied by 
fever and variable degrees of other systemic symptoms, ranging from mild fatigue to 
respiratory failure and even death. 
Influenza is a major public health burden. It is responsible for 50 million disease 
episodes and 15,000 to 70,000 deaths in the EU/EEA each year, although with 
considerable variation from season to season Uhart, 2016and by methodology used 
Nicoll, 2012. Influenza occurs in annual epidemics that are associated with 
significant morbidity and mortality and have substantial public health impact, in 
particular in the elderly and in children younger than one year of age Zhou, 2012. In 
the US, approximately 9.2 to 60.8 million people contract influenza annually, resulting 
in an average of 140,000 to 710,000 hospitalisations and 12,000 to 56,000 deaths 
CDC, 2016a. 
Annual influenza vaccination is the most effective measure to reduce the risk of 
influenza infection and its complications Foppa, 2015. During the 2015-2016 
influenza season, CDC estimated that the overall influenza vaccination coverage 
among all people ≥6 months of age was 45.6%. It prevented almost 5 million influenza 
illnesses, 2.5 million medical visits to health providers, 71,000 hospitalizations, and 
3,000 deaths CDC, 2016b. However, due to frequent genetic and antigenic changes in 
influenza viruses, seasonal vaccines are frequently reformulated with updated viral 
strains based on annual World Health Organization (WHO) recommendations WHO, 
2018. Therefore, there is a need for constant benefit-risk monitoring of these vaccines.
…
Of note GSK’s quadrivalent seasonal influenza vaccine is indicated for active 
immunisation of adults and children from 6 months of age for the prevention of 
influenza disease caused by the two influenza A virus subtypes and the two influenza B 
virus types contained in the vaccine. The use of GSK’s quadrivalent seasonal vaccines 
should be based on official recommendations. Immunisation should be carried out by 
intramuscular injection. Annual revaccination with the current vaccine is 
recommended because immunity declines during the year after vaccination, and 
because circulating strains of influenza virus might change from year to year. The 
vaccine is recommended for a single dose except for children aged <9 years, who have 
not previously been vaccinated against influenza, for whom a second dose should be 
given after an interval of at least 4 weeks.
 
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2.
Benefit : Risk Assessment
The EPI-FLU-056 study does not involve administration of an investigational product 
and does not imply random allocation of vaccination to enrolled subjects. 
4.1 
Discussion of Study Design
Data will be collected via the HCP or study medical staff who administer the seasonal 
influenza vaccination or who provide the inform informed consent form and the ADR 
cards.
5.2 
Inclusion Critera for Enrolment
The objective of the study is to cover all age ranges as per GSK’s quadrivalent vaccine 
indication. However, due to feasibility constraints, Belgium and Germany will only 
recruit subjects 18 years of age and above (German participating sites will target 
essentially older adults subjects aged from 50 years onwards). Spain will target 
subjects between 6 months and 65 years of age at the time of the vaccination.
All subjects must satisfy ALL the following criteria at study entry:
…

Subjects aged 6 months or above at the time of the vaccination according to the 
countries’ specificities
8.2 
Reporting of SAEs and Other Events
If GSK deems additional information is necessary, request of for additional information 
will be sent to the HCP.
9.2
Subject Withdrawal
A subject who does not return for the concluding visit foreseen in the protocol or has 
not returned the completed ADR card will be considered a withdrawal from the study. 
If the subject informs the Investigator of the reason for withdrawal from the study, the 
reason for this will be entered into the electronic Case Report Form as detailed below:

Seasonal influenza vaccine-related Serious Adverse Event

Protocol Violation (to be specified)

Consent withdrawal, not due to an adverse event (to be specified if the information 
is available)

Not willing/not able to participate in the visit

Migrated/moved from the study area

Lost to follow-up

Sponsor study termination

Other (please specify)
 
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10.6
Analysis of Primary Objective
For each vaccine dose*, the cumulative percentage of subjects reporting AEIs and/or 
other AEs within 7 days post-vaccination period (i.e., the day of vaccination and the 
following 6 days) using ADR cards from study start up to each study week (ISO weeks 
40 to 52) will be estimated by MedDRA Preferred Term, overall and by country, as 
follows:

The denominator will be the number of subjects from the Safety Set vaccinated with 
GSK’s quadrivalent seasonal influenza vaccine at any point from study start (i.e., 
01 October 2018) up to the end of the week of interest, in a given country or for all 
countries.
10.7
Analysis of Secondary Objectives
For each vaccine dose*, the weekly percentage of subjects reporting AEIs and/or other 
AEs within 7 days post-vaccination period (i.e., the day of vaccination and the following 
6 days) using ADR cards will be estimated by MedDRA Preferred Term, overall and by 
country, as follows:

The denominator will be the number of subjects from the Safety Set vaccinated with 
GSK’s quadrivalent seasonal influenza vaccine during the week of interest (ISO 
weeks 40 to 52), in a given country or for all countries.
10.10.1
Sequence of analyses
Four Three interim analyses and a final analysis will be performed.

The first interim analysis will be performed by end-October 2018.

The second first interim analysis will be performed by mid-November 2018

The third second interim analysis will be performed by end-November 2018

The fourth third interim analysis will be performed by mid-December 2018

The final analysis will be performed when all data up to the end of the study will be 
available and cleaned
11.
ADMINISTRATIVE MATTERS
Anticipated study milestones are presented below. Any changes to those initial 
milestones will be reported in the study report:
Milestone
Planned date
Actual date*
Comments
Approval by Ethics Committees
28 September 2018
24 August 2018
Approval of the protocol
First subject enrolled  
01 October 2018
N/A
First visit anticipated
Last subject enrolled  
15 January 2019
N/A
Last visit anticipated 
Database Freeze
22 March 2019
N/A
None
Completion of Statistical Analysis 
19 April 2019
N/A
None
Final Report of Main Study Results 
06 June 2019
N/A
None
*to be completed at the date of the final study report
 
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11.3. Record Retention
GSK will inform the investigator/institution of the time period for retaining these records 
to comply with all applicable regulatory requirements. However, the 
investigator/institution should seek the written approval of the sponsor before proceeding 
with the disposal of these records. The minimum retention time will meet the strictest 
standard applicable to a particular site, as dictated by ICH GCP or other applicable 
guidelines, any institutional requirements or applicable laws or regulations, or GSK 
standards/procedures; otherwise, the minimum retention period will default to 15 30 
years. 
13.
REFERENCES
Centers for Disease Control and Prevention (CDC). Estimated influenza illnesses, 
medical visits, hospitalizations, and deaths averted by influenza vaccination in the 
United States. 2016a. Available at: https://wwwcdcgov/flu/about/disease/2015-16htm.
Centers for Disease Control and Prevention (CDC). Laboratory-Confirmed Influenza 
Hospitalizations. 2016b. Available at: gis.cdc.gov/GRASP/Fluview/FluHospRates.html.
Nicoll A, Ciancio BC, Lopez Chavarrias V, et al. Influenza-related deaths--available 
methods for estimating numbers and detecting patterns for seasonal and pandemic 
influenza in Europe. Euro Surveill. 2012 May 3;17(18). 
Foppa B, Po-Yung C, Reynolds S. et al. Deaths averted by influenza vaccination in the 
U.S. during the seasons2005/06 through 2013/14. Vaccine. 2015; 33(26): 3003-9.
Uhart M, Bricout H, Clay E, et al. Public health and economic impact of seasonal 
influenza vaccination with quadrivalent influenza vaccines compared to trivalent 
influenza vaccines in Europe. Hum Vaccin Immunother. 2016; 12:2259–68. 
World Health Organization (WHO). Influenza. WHO recommendations on the 
composition of influenza virus vaccines. 2018. Available from: 
http://wwwwhoint/influenza/vaccines/virus/recommendations/en/.
Zhou H, Thompson WW, Viboud CG, et al. Hospitalizations Associated With Influenza 
and Respiratory Syncytial Virus in the United States, 1993–2008. Clin Infect Dis. 2012; 
54: 1427–36.
 
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207737 (EPI-FLU-056 VS EU)
Protocol Amendment 1 Final
8863e9a762c1803169074ae9515a8d212ac74ffb
53
11-SEP-2018

PPD