Immunogenicity, Reactogenicity and Safety of Two Formulations of GSK Biologicals' Meningococcal ACWY Conjugate Vaccine (GSK3536820A and Menveo) in Healthy Adults 18 to 40 Years of Age
Phase: PHASE2
Conditions: Infections, Meningococcal
Sponsor: GlaxoSmithKline

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Clinical Study Protocol
Sponsor:
GlaxoSmithKline Biologicals SA
Rue de l’Institut, 89
1330 Rixensart, Belgium
Primary Study vaccine and 
number
!
GlaxoSmithKline (GSK) Biologicals’ 
Meningococcal (serogroups A, C, W and Y) 
oligosaccharide diphtheria CRM197 conjugate 
vaccine, liquid formulation (GSK3536820A).
Other Study vaccine
!
GSK Biologicals’ Meningococcal serogroups A, 
C, W and Y oligosaccharide diphtheria CRM197
conjugate vaccine (Menveo).
eTrack study number and 
Abbreviated Title
205343 (MENACWY CONJ-032 [V59_71])
Investigational New Drug 
(IND) number
11278
EudraCT number
2017-003692-61
Date of protocol
Final version 1: 25 September 2017
Date of protocol amendment
Amendment 1 Final: 17 January 2018
Amendment 2 Final: 15 March 2018
Amendment 3 Final: 08 February 2019
Title
Immunogenicity, reactogenicity and safety of two 
formulations of GSK Biologicals’ Meningococcal 
ACWY conjugate vaccine (GSK3536820A and 
Menveo) in healthy adults 18 to 40 years of age.
Detailed Title
A phase 2b, randomized, controlled, observer-blind, 
multi-center, non-inferiority immunogenicity and 
safety study of two formulations of GSK Biologicals’ 
Meningococcal ACWY conjugate vaccine 
(GSK3536820A and Menveo) administered to healthy 
adults 18 to 40 years of age.
Co-ordinating authors
!
 (XPE Pharma & Science for 
GSK Biologicals)
Contributing authors
!
 (Senior Clinical Research and 
Development Lead)
!
 (Clinical Research and 
Development Lead)
!
(Director Clinical Statistics)
!
 (Study Statistician) 

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PPD
PPD
PPD
PPD
PPD

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eTrack study number and 
Abbreviated Title
205343 (MENACWY CONJ-032 [V59_71])
Investigational New Drug 
(IND) number
11278
EudraCT number
2017-003692-61
Detailed Title
A phase 2b, randomized, controlled, observer-blind, 
multi-center, non-inferiority immunogenicity and 
safety study of two formulations of GSK Biologicals’ 
Meningococcal ACWY conjugate vaccine 
(GSK3536820A and Menveo) administered to healthy 
adults 18 to 40 years of age.
Contributing authors 
(continued)
(Amended 08 February 2019)
!
(Study Statistician)
!
 (Lead Statistician)
!
and 
(Study 
Delivery Lead)
!
 (Clinical Trial Supply Manager)
!
 (Clinical Laboratory 
Sciences Read-out Team Leader)
!
 (Clinical Safety representative)
!
 and 
 (Clinical 
Laboratory Sciences Study Managers)
!
(Oversight Data Manager)
!
(Study Data Manager)
!
 (Lead Scientific Writer)
!
 (Scientific Writer)
!
 (Regulatory Affairs 
representative)
!
 (Global Patents representative)
!
 (Clinical and Epidemiology 
Research & Development Project Lead)
GSK Biologicals’ Protocol DS for Legacy Novartis programs v 1.0
©2017-2019 the GSK group of companies or its licensor. 

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PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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Protocol Amendment 3 Sponsor Signatory Approval
eTrack study number and 
Abbreviated Title
205343 (MENACWY CONJ-032 [V59_71])
IND number
11278
EudraCT number
2017-003692-61
Date of protocol amendment
Amendment 3 Final: 08 February 2019
Detailed Title 
A phase 2b, randomized, controlled, observer-blind, 
multi-center, non-inferiority immunogenicity and 
safety study of two formulations of GSK Biologicals’ 
Meningococcal ACWY conjugate vaccine 
(GSK3536820A and Menveo) administered to healthy 
adults 18 to 40 years of age.
Sponsor signatory
Michele Pellegrini 
Clinical and Epidemiology Research & Development 
Project Lead
Signature
Date
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Protocol Amendment 3 Rationale
Amendment number:
Amendment 3
Rationale/background for changes: 

An update in the list of contributing authors has been included on the protocol
cover page.

Wording of Section 5.3 Method of blinding and Section 5.7.3 Laboratory assays
has been updated to align with the current Company Standards related to blinding
for sample testing.
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Protocol Amendment 3 Investigator Agreement
I agree:

To conduct the study in compliance with this protocol, any future protocol
amendments or protocol administrative changes, with the terms of the clinical trial
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) and all
applicable regulatory requirements.

To ensure that all persons assisting me with the study are adequately informed about
the GSK Biologicals’ study vaccines and other study-related duties and functions as
described in the protocol.

To acquire the reference ranges for laboratory tests performed locally and, if required
by local regulations, obtain the laboratory’s current certification or Quality
Assurance procedure manual.

To ensure that no clinical samples (including serum samples) are retained onsite or
elsewhere without the approval of GSK Biologicals and the express written informed
consent of the subject and/or the subject’s legally acceptable representative.

To perform no other biological assays on the clinical samples except those described
in the protocol or its amendment(s).

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 or the investigational vaccine, 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
205343 (MENACWY CONJ-032 [V59_71])
IND number
11278
EudraCT number
2017-003692-61
Date of protocol amendment
Amendment 3 Final: 08 February 2019
Detailed Title
A phase 2b, randomized, controlled, observer-blind, 
multi-center, non-inferiority immunogenicity and 
safety study of two formulations of GSK Biologicals’ 
Meningococcal ACWY conjugate vaccine 
(GSK3536820A and Menveo) administered to 
healthy adults 18 to 40 years of age.
Investigator name
Signature
Date
Leiter der klinischen 
Prüfung name, function and 
title
Signature
Date
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Sponsor Information
1.
Sponsor
GlaxoSmithKline Biologicals
Rue de l’Institut 89, 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.
4.
Sponsor Study Contact for Reporting of a Serious Adverse Event
GSK Biologicals Central Back-up Study Contact for Reporting SAEs: refer to protocol 
Section 8.4.2.
5.
GSK Biologicals’ Central Safety Physician On-Call Contact information for 
Emergency Unblinding
GSK Biologicals Central Safety Physician and Back-up Phone contact: refer to 
protocol Section 8.8. 
 
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SYNOPSIS
Detailed Title
A phase 2b, randomized, controlled, observer-blind, multi-
center, non-inferiority immunogenicity and safety study of
two formulations of GSK Biologicals’ Meningococcal ACWY 
conjugate vaccine (GSK3536820A and Menveo) administered 
to healthy adults 18 to 40 years of age.
Indication
Active immunization to prevent invasive meningococcal 
disease caused by Neisseria meningitidis serogroups A, C, W 
and Y.
Rationale for the 
study and study 
design

Rationale for the study
GSK Biologicals’ Menveo (Meningococcal serogroups A, C, 
W and Y oligosaccharide diphtheria CRM197 conjugate 
vaccine; MenACWY) is licensed for use in infants through 
adults in more than 60 countries. Menveo vaccine is delivered 
as a vial including the liquid MenCWY conjugate components 
and a vial containing the lyophilized MenA conjugate 
component. The lyophilized component has to be 
reconstituted with a liquid component immediately prior to 
vaccination, which adds to complexity of vaccine 
administration. Furthermore, vaccine components come in 
separate vials which make it bulky and consume cold storage 
space. To simplify the vaccine administration, prevent 
occurrence of administration errors and to optimize vaccine 
shipment and storage, a fully liquid formulation of 
MenACWY vaccine has been developed.
Results of development stability studies indicate that the 
percentage of free saccharides (FS) for serogroup A will 
increase over time when stored at a temperature of 2-8 ̊C.
Additionally, the O-acetylation level of the MenA component 
of the MenACWY liquid vaccine is expected to decrease over 
time during the storage of the vaccine.
Hence, the rationale of this study is to assess the impact of 
serogroup A oligosaccharide degradation as well as of 
acetylation levels on immunogenicity and safety of 
investigational MenACWY liquid vaccine. GSK plans 
therefore to compare the immunogenicity and to assess the 
reactogenicity/safety of the currently licensed MenACWY 
vaccine (Menveo) with the investigational MenACWY liquid 
vaccine formulation tailored to include approximately 30% 
free serogroup A saccharides. A 30% MenA FS level was 
selected as the upper limit of the expected FS range at release 
for the Menveo liquid formulation.
 
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For this study, the formulation with approximately 30% of 
free MenA oligosaccharides will be obtained by storing a 
fresh manufacturing MenA lot at approximately 22.5°C 
(72.5°F) for the time needed to accelerate the formation of the 
free saccharides following the Arrhenius model. Since a 
certain degree of loss of the O-acetyl groups on the 
conjugated MenA component may occur when stored at 
temperature higher than 2 to 8°C, the O-acetylation level of N. 
meningitidis serogroup A capsular polysaccharide of the fully 
liquid vaccine formulation will also be monitored. 
The purpose of the study is to assess the non-inferiority of the 
immune response against serogroup A between the currently 
licensed MenACWY vaccine and the investigational 
MenACWY liquid vaccine with approximately 30% Men A 
FS. The immune response against serogroups C, W and Y and 
the reactogenicity and safety profiles of the study vaccines 
will also be evaluated. However, as the CWY components of 
the investigational vaccine formulation is identical to that of 
the licensed formulation, non-inferiority will not be assessed 
for these serogroups. Safety will be evaluated for 6 months 
after a single dose vaccination.

Rationale for the study design
−
Study population: healthy adults ≥18 to ≤40 years of 
age (YoA) will be enrolled in this study as agreed 
with regulatory authorities for the investigational 
MenACWY liquid vaccine. 
−
Vaccination dose and route of administration: subjects 
will receive a single dose of licensed MenACWY 
vaccine or investigational MenACWY liquid vaccine 
(i.e. dosing scheme currently indicated for Menveo in 
adults).
−
Study blinding: given the different appearance of the 
investigational liquid vaccine and currently licensed 
MenACWY vaccine, double blinding is not possible. 
The study will therefore be conducted in an observer-
blind manner.
Objectives
Primary

To demonstrate non-inferiority of the investigational 
MenACWY liquid vaccine with approximately 30% Men 
A FS to that of currently licensed MenACWY vaccine, as 
measured by the human serum bactericidal assay (hSBA) 
Geometric Mean Titers (GMTs) directed against N. 
meningitidis serogroup A at Day 29 after a single dose 
vaccination.
 
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Criterion to demonstrate non-inferiority: 
Non-inferiority will be concluded if the lower limit of the 
two-sided 95% confidence interval (CI) for the ratio of 
hSBA GMTs against serogroup A between the liquid 
formulation and the licensed formulation is greater than 
0.5.
Secondary

To compare the immunogenicity of the investigational 
MenACWY liquid vaccine with approximately 30% Men 
A FS and the currently licensed MenACWY vaccine, as 
measured by hSBA GMTs directed against N. 
meningitidis serogroups C, W and Y at Day 29.

To compare the immunogenicity of the investigational 
MenACWY liquid vaccine with approximately 30% Men 
A FS to the currently licensed MenACWY vaccine, as 
measured by the percentage of subjects with a ≥ 4-fold 
rise in post-vaccination hSBA titer for N. meningitidis 
serogroups A, C, W and Y at Day 29 compared to Day 1.
Note: The following definition will be used for 4-fold 
rise: a) for individuals whose pre-vaccination titers are < 
the limit of detection (LOD), the post-vaccination titers 
must be ≥ 4-fold the LOD or ≥ the lower limit of 
quantitation (LLOQ) whichever is greater; b) for 
individuals whose pre-vaccination titers are ≥ the LOD 
and ≤ the LLOQ, the post-vaccination titers must be at 
least four times the LLOQ; c) for individuals whose pre-
vaccination titers are > the LLOQ, the post vaccination 
titers must be at least four times the pre-vaccination titer.

To compare the immunogenicity of the investigational 
MenACWY liquid vaccine with approximately 30% Men 
A FS to the currently licensed MenACWY vaccine, as 
measured by the percentage of subjects with hSBA titer 
≥8 and ≥LLOQ* against N. meningitidis serogroups A, C, 
W and Y at Day 29.
* Note: To be assessed for each serogroup if the pre-
defined LLOQ value for that serogroup is >8.

To assess the safety/reactogenicity of the investigational 
MenACWY liquid vaccine with approximately 30% Men 
A FS and the currently licensed MenACWY vaccine.
 
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Study design

Experimental design: Phase IIB, observer-blind, 
randomized, controlled, multi-centric study with two 
parallel groups.

Duration of the study: for each subject enrolled, the 
duration will be approximately 6 months.
−
Epoch 001: starting at Visit 1 (Day 1) and ending at 
last Safety contact (Day 181). 

Primary completion Date (PCD): Visit 2 (Day 29).
Refer to glossary of terms for the definition of PCD.

End of Study (EoS): Last subject last visit (Phone call 3) 
or last testing results released of samples collected at 
Visit 2 (Day 29)* if it occurs after LSLV. 
* In this case EoS must be achieved no later than 8 
months after LSLV.
Refer to glossary of terms for the definition of EoS.

Study groups:
−
Group ACWY_Liq: ~486 healthy adults receiving a 
single dose of investigational MenACWY liquid 
(GSK3536820A) with approximately 30% Men A FS.
−
Group ACWY: ~486 healthy adults receiving a 
single dose of currently licensed GSK’ MenACWY 
vaccine (Menveo).
Synopsis Table 1
Study groups and epochs foreseen in the study
Study groups
Number of 
subjects
Age (Min/Max)
Epochs
Epoch 001
ACWY_Liq
~486
18 – 40 years
x
ACWY
~486
18 – 40 years
x
Synopsis Table 2
Study groups and treatment foreseen in the study
Treatment name
Vaccine/product 
name
Study Groups
ACWY_Liq
ACWY
MenACWY liquid 
with approximately 
30% MenA FS
MenACWY liquid
x
Licensed 
MenACWY
(Menveo*)
MenA lyo
x
MenCWY liquid
* Menveo commercial formulation consisting of a MenA lyophilized component and a MenCWY liquid component to be 
reconstituted together before administration (0.5mL).
 
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
Control: active control

Vaccination schedule: All subjects will receive a single 
dose of one of the study vaccines at Visit 1 (Day 1).

Treatment allocation: Subjects will be randomized using 
a centralized randomization system on internet (SBIR) at 
Visit 1 (Day 1).

Blinding: observer-blind.
Synopsis Table 3
Blinding of study epochs
Study Epochs
Blinding
Epoch 001
observer-blind

Sampling schedule: Blood samples of approximately 20 
mL will be taken at Visit 1 (Day 1; pre-vaccination) and at 
Visit 2 (Day 29).

Type of study: self-contained.

Data collection: Standardised Electronic Case Report 
Form (eCRF). Solicited adverse events (AEs) assessed on 
site during the 30 minutes post-vaccination assessment are 
to be recorded on the source documents and entered in the 
eCRF. Solicited AEs occurring after the 30 minutes post-
vaccination assessment will be collected only using a 
subject Diary (electronic Diary [eDiary]). 
Number of subjects
Approximately 972 subjects (≥18 to ≤ 40 YoA) are planned for 
enrollment into this study, approximately 486 subjects per 
group.
Endpoint(s)
Primary
The following measures will be summarized:

hSBA GMTs against N. meningitidis serogroup A at Day 
29, for each vaccine group and between-group ratios.
Secondary
The following measures will be summarized:

hSBA GMTs against N. meningitidis serogroups A (except 
Day 29), C, W and Y at Day 1 and at Day 29, for each 
vaccine group and between-group ratios.

Within-group ratios of hSBA GMTs against N. 
meningitidis serogroups A, C, W and Y at Day 29 
compared to Day 1.
 
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
Percentages of subjects with a ≥ 4-fold rise in post-
vaccination hSBA titer for N. meningitidis serogroups A, 
C, W and Y at Day 29 compared to Day 1, for each 
vaccine group and between-group differences.
Note: A 4-fold rise is defined as:  a) for individuals whose 
pre-vaccination titers are < the LOD, the post-vaccination 
titers must be ≥ 4-fold the LOD or ≥ the LLOQ whichever 
is greater; b) for individuals whose pre-vaccination titers 
are ≥ the LOD and ≤ the LLOQ, the post-vaccination titers 
must be at least four times the LLOQ; c) for individuals 
whose pre-vaccination titers are > the LLOQ, the post-
vaccination titers must be at least four times the pre-
vaccination titer.

Percentages of subjects with hSBA titer ≥8 and ≥LLOQ* 
against N. meningitidis serogroups A, C, W and Y at Day 
1 and at Day 29, for each vaccine group and between-
group differences.
* Note: To be assessed for each serogroup if the pre-
defined LLOQ value for that serogroup is >8.
Safety of the study vaccine formulations will be evaluated for 
all vaccine groups in terms of the frequency (percentage) of 
reported adverse events including: 

Any unsolicited AEs reported within 30 minutes after 
vaccination;

Solicited local and systemic AEs reported from Day 1 (6 
hours) through Day 7 after vaccination;

Other indicators of reactogenicity (e.g. use of analgesics / 
antipyretics) within 7 days after vaccination;

All unsolicited AEs reported from Day 1 through Day 29 
after vaccination; 
Medically-attended AEs, AEs leading to withdrawal and SAEs 
reported from Day 1 through Day 181 (during the entire study 
period).
 
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TABLE OF CONTENTS
PAGE
SPONSOR INFORMATION ............................................................................................7
SYNOPSIS......................................................................................................................8
LIST OF ABBREVIATIONS...........................................................................................21
GLOSSARY OF TERMS ...............................................................................................24
TRADEMARKS .............................................................................................................28
1.
INTRODUCTION....................................................................................................29
1.1.
Background ................................................................................................29
1.2.
Rationale for the study and study design ....................................................30
1.2.1.
Rationale for the study.................................................................30
1.2.2.
Rationale for the study design......................................................31
1.3.
Benefit: Risk Assessment ...........................................................................31
1.3.1.
Risk Assessment .........................................................................31
1.3.2.
Benefit Assessment.....................................................................33
1.3.3.
Overall Benefit: Risk Conclusion..................................................33
2.
OBJECTIVES.........................................................................................................33
2.1.
Primary objective ........................................................................................33
2.2.
Secondary objectives..................................................................................33
3.
STUDY DESIGN OVERVIEW ................................................................................34
4.
STUDY COHORT...................................................................................................36
4.1.
Number of subjects.....................................................................................36
4.2.
Inclusion criteria for enrollment ...................................................................36
4.3.
Exclusion criteria for enrollment..................................................................37
5.
CONDUCT OF THE STUDY ..................................................................................39
5.1.
Regulatory and ethical considerations, including the informed 
consent process..........................................................................................39
5.2.
Subject identification and randomization.....................................................40
5.2.1.
Subject identification....................................................................40
5.2.2.
Randomization of treatment.........................................................40
5.2.2.1.
Randomization of supplies..........................................40
5.2.2.2.
Treatment allocation to the subject.............................40
5.2.2.2.1.
Study group and treatment 
number allocation ...................................40
5.3.
Method of blinding (Amended 08 February 2019) .......................................41
5.4.
General study aspects ................................................................................41
5.5.
Outline of study procedures ........................................................................42
5.6.
Detailed description of study procedures ....................................................43
5.6.1.
Informed consent.........................................................................43
5.6.2.
Check inclusion and exclusion criteria .........................................43
5.6.3.
Collect demographic data ............................................................43
5.6.4.
Medical history.............................................................................44
 
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5.6.5.
Physical examination ...................................................................44
5.6.6.
Urine pregnancy test....................................................................44
5.6.7.
Check contraindications, warnings and precautions to 
vaccination...................................................................................44
5.6.8.
Assess pre-vaccination body temperature ...................................45
5.6.9.
Measure/record height and weight...............................................45
5.6.10.
Study group and treatment number allocation..............................45
5.6.11.
Sampling......................................................................................45
5.6.11.1.
Blood sampling for immune response 
assessments ..............................................................45
5.6.12.
Study Vaccine administration.......................................................45
5.6.13.
Distribution of Subject Card .........................................................46
5.6.14.
Subject Diary ...............................................................................46
5.6.14.1.
Post-vaccination reminders ........................................47
5.6.14.1.1.
Subject Diary Reminder Alerts................47
5.6.14.2.
Safety Follow-up calls.................................................48
5.6.15.
Check and record concomitant medication/vaccination and 
intercurrent medical conditions ....................................................48
5.6.16.
Recording of AEs, SAEs and pregnancies...................................48
5.6.17.
Study conclusion..........................................................................49
5.7.
Biological sample handling and analysis.....................................................49
5.7.1.
Use of specified study materials ..................................................50
5.7.2.
Biological samples.......................................................................50
5.7.3.
Laboratory assays  (Amended 08 February 2019) .......................50
5.7.4.
Biological samples evaluation......................................................51
5.7.4.1.
Immunological read-outs ............................................51
5.7.5.
Immunological correlates of protection.........................................52
6.
STUDY VACCINES AND ADMINISTRATION ........................................................52
6.1.
Description of study vaccines......................................................................52
6.2.
Storage and handling of study vaccines......................................................53
6.3.
Dosage and administration of study vaccines .............................................54
6.4.
Replacement of unusable vaccine doses....................................................54
6.5.
Contraindications to vaccination .................................................................54
6.6.
Warnings and precautions ..........................................................................54
6.7.
Concomitant medications/products and concomitant vaccinations..............55
6.7.1.
Recording of concomitant medications/products and 
concomitant vaccinations.............................................................55
6.7.2.
Concomitant medications/products/vaccines that may lead 
to the elimination of a subject from per-protocol analyses............55
6.8.
Intercurrent medical conditions that may lead to elimination of a 
subject from per-protocol analyses .............................................................56
7.
HEALTH ECONOMICS ..........................................................................................56
8.
SAFETY.................................................................................................................56
8.1.
Safety definitions ........................................................................................57
8.1.1.
Definition of an adverse event......................................................57
8.1.2.
Definition of a serious adverse event ...........................................58
8.1.3.
Solicited adverse events..............................................................58
8.1.3.1.
Solicited Local Adverse Events...................................59
8.1.3.2.
Solicited Systemic Adverse Events.............................59
 
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8.1.3.3.
Other Solicited Adverse Events ..................................59
8.1.4.
Unsolicited Adverse Events .........................................................60
8.1.5.
Clinical laboratory parameters and other abnormal 
assessments qualifying as adverse events or serious 
adverse events ............................................................................60
8.2.
Events or outcomes not qualifying as adverse events or serious 
adverse events ...........................................................................................61
8.2.1.
Pregnancy ...................................................................................61
8.3.
Detecting and recording adverse events, serious adverse events 
and pregnancies .........................................................................................62
8.3.1.
Time period for detecting and recording adverse events, 
serious adverse events and pregnancies.....................................62
8.3.2.
Post-Study adverse events and serious adverse events..............63
8.3.3.
Evaluation of adverse events and serious adverse events...........64
8.3.3.1.
Active questioning to detect adverse events 
and serious adverse events........................................64
8.3.3.2.
Assessment of adverse events...................................65
8.3.3.2.1.
Assessment of intensity..........................65
8.3.3.2.2.
Assessment of causality .........................66
8.3.3.3.
Assessment of outcomes............................................67
8.3.3.4.
Medically attended visits.............................................67
8.4.
Reporting of serious adverse events, pregnancies, and other events .........68
8.4.1.
Prompt reporting of serious adverse events, pregnancies, 
and other events to GSK Biologicals............................................68
8.4.2.
Contact information for reporting serious adverse events 
and pregnancies ..........................................................................68
8.4.3.
Completion and transmission of SAE reports to GSK 
Biologicals ...................................................................................69
8.4.3.1.
Back-up system in case the electronic 
reporting system does not work..................................69
8.4.4.
Completion and transmission of pregnancy reports to GSK 
Biologicals ...................................................................................69
8.4.5.
Updating of SAE and pregnancy information after removal 
of write access to the subject’s eCRF ..........................................70
8.4.6.
Regulatory reporting requirements for serious adverse 
events..........................................................................................70
8.5.
Follow-up of adverse events, serious adverse events, and 
pregnancies................................................................................................70
8.5.1.
Follow-up of adverse events and serious adverse events............70
8.5.1.1.
Follow-up during the study..........................................70
8.5.1.2.
Follow-up after the subject is discharged from 
the study.....................................................................71
8.5.2.
Follow-up of pregnancies.............................................................71
8.6.
Treatment of adverse events ......................................................................71
8.7.
Unblinding...................................................................................................71
8.8.
Emergency unblinding ................................................................................72
8.9.
Subject card................................................................................................73
9.
SUBJECT COMPLETION AND WITHDRAWAL.....................................................73
9.1.
Subject completion .....................................................................................73
9.2.
Subject withdrawal......................................................................................73
9.2.1.
Subject withdrawal from the study ...............................................73
 
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10. STATISTICAL METHODS......................................................................................74
10.1.
Primary endpoint.........................................................................................74
10.2.
Secondary endpoints ..................................................................................74
10.3.
Determination of sample size......................................................................75
10.4.
Analysis Sets..............................................................................................75
10.4.1.
All Enrolled Set ............................................................................75
10.4.2.
All Exposed Set ...........................................................................75
10.4.3.
Safety Set....................................................................................76
10.4.3.1.
Solicited Safety Set (solicited local and 
systemic adverse events and other solicited 
adverse events)..........................................................76
10.4.3.2.
Unsolicited Safety Set (unsolicited adverse 
events) .......................................................................76
10.4.3.3.
Overall Safety Set ......................................................76
10.4.4.
Full Analysis Set (FAS) Immunogenicity Set................................76
10.4.5.
Per Protocol (PP) Set for Immunogenicity Set .............................76
10.4.6.
Other Analysis Sets .....................................................................77
10.4.7.
Subgroups ...................................................................................77
10.5.
Derived and transformed data.....................................................................77
10.6.
Analysis of demographics...........................................................................78
10.7.
Analysis of immunogenicity.........................................................................78
10.8.
Analysis of safety........................................................................................79
10.8.1.
Analysis of Solicited Local, Systemic and Other Adverse 
Events .........................................................................................79
10.8.2.
Analysis of Unsolicited Adverse Events .......................................80
10.9.
Interpretation of analyses............................................................................80
10.9.1.
Primary immunogenicity objective................................................80
10.9.2.
Secondary Immunogenicity Objectives ........................................81
10.10. Conduct of analyses ...................................................................................81
10.10.1. Sequence of analyses..................................................................81
10.10.2. Statistical considerations for interim analyses..............................81
11. ADMINISTRATIVE MATTERS ...............................................................................82
11.1.
Electronic Case Report Form instructions...................................................82
11.2.
Subject Diary ..............................................................................................82
11.3.
Study Monitoring by GSK Biologicals..........................................................83
11.4.
Record retention .........................................................................................84
11.5.
Quality assurance.......................................................................................84
11.6.
Posting of information on publicly available clinical trial registers and 
publication policy ........................................................................................84
11.7.
Provision of study results to investigators ...................................................85
11.8.
Data Sharing...............................................................................................85
12. COUNTRY SPECIFIC REQUIREMENTS...............................................................86
12.1.
Requirements for Germany.........................................................................86
13. REFERENCES.......................................................................................................87
 
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LIST OF TABLES
PAGE
Table 1
Study groups and epochs foreseen in the study.....................................35
Table 2
Study groups and treatment foreseen in the study .................................35
Table 3
Blinding of study epochs ........................................................................35
Table 4
List of study procedures .........................................................................42
Table 5
Intervals between study visits.................................................................43
Table 6
Biological samples .................................................................................50
Table 7
Humoral Immunity (Antibody determination)...........................................51
Table 8
Immunological read-outs........................................................................51
Table 9
Study vaccines.......................................................................................53
Table 10
Dosage and administration.....................................................................54
Table 11
Reporting periods for collecting safety information .................................63
Table 12
Intensity scales for solicited AEs ............................................................65
Table 13
Timeframes for submitting serious adverse event, pregnancy and 
other events reports to GSK Biologicals .................................................68
Table 14
GSK Biologicals’ laboratories .................................................................89
 
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LIST OF FIGURES
PAGE
Figure 1
Study design overview ...........................................................................34
 
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LIST OF APPENDICES
PAGE
APPENDIX A LABORATORY ASSAYS .......................................................................88
APPENDIX B CLINICAL LABORATORIES ..................................................................89
APPENDIX C AMENDMENTS TO THE PROTOCOL...................................................90
 
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LIST OF ABBREVIATIONS
ADEM:
Acute disseminated encephalomyelitis
AE:
Adverse Event
ATEAM:
Advanced Temperature Excursion Analysis and 
Management 
CBER:
Center for Biologicals Evaluation and Research
CDC:
Centers for Disease Control
CI:
Confidence Interval
CLS:
Clinical Laboratory Sciences
CRM197:
Corynebacterium diphtheriae Cross Reacting 
Material 197
eCRF:
electronic Case Report Form
EoS:
End of Study
EU:
European Union
EudraCT:
European Clinical Trials Database
FAS:
Full Analysis Set
FDA:
Food and Drug Administration, United States 
of America
FS:
Free Saccharides
GBS:
Guillain-Barré syndrome
GCP:
Good Clinical Practice
GMR:
Geometric Mean Ratio
GMT:
Geometric Mean Titer
GSK:
GlaxoSmithKline
HIV:
Human Immunodeficiency Virus
hSBA:
Human Serum Bactericidal Assay
IAF:
Informed Assent Form
 
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IB:
Investigator Brochure
ICF:
Informed Consent Form
ICH:
International Conference on Harmonization
ID:
Identification
IEC:
Independent Ethics Committee
IM:
Intramuscular
IMP:
Investigational Medicinal Product
IND:
Investigational New Drug
IRB:
Institutional Review Board
iSRC:
Internal Safety Review Committee
IV:
Intravenous
KD:
Kawasaki Disease
LAR:
Legally Acceptable Representative
LOD:
Limit of Detection
LLOQ:
Lower Limit of Quantitation
LSLV:
Last Subject Last Visit
MACDP:
Metropolitan Atlanta Congenital Defects 
Program
MedDRA:
Medical Dictionary for Regulatory Activities
MenACWY:
Meningococcal serogroups A, C, W and Y 
oligosaccharide diphtheria CRM197 conjugate 
vaccine; Menveo
N. meningitidis:
Neisseria meningitidis
PCD:
Primary Completion Date
PO:
Per os
PPS:
Per protocol Set
SAE:
Serious Adverse Event
 
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SBIR:
Source DataBase for Internet Randomization
SD:
Standard deviation
SDV:
Source Document Verification
SmPC:
Summary of Product Characteristics
SPM:
Study Procedures Manual
TBD:
To be determined
YoA:
Years of age
 
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GLOSSARY OF TERMS
Adequate contraception:
Adequate contraception is defined as a contraceptive 
method with failure rate of less than 1% per year when 
used consistently and correctly and when applicable, in 
accordance with the product label for example: 

abstinence from penile-vaginal intercourse, when this 
is their preferred and usual lifestyle,

Combined oestrogen and progesterone oral 
contraceptives,

injectable progestogen,

implants of etenogestrel or levonorgestrel,

Contraceptive vaginal ring,

percutaneous contraceptive patches,

intrauterine device or intrauterine system,

male partner sterilization prior to the female subject’s 
entry into the study, and this male is the sole partner 
for that subject,
The information on the male sterility can come from 
the site personnel’s review of the subject’s medical 
records; or interview with the subject on her medical 
history.

male condom combined with a vaginal spermicide 
(foam, gel, film, cream or suppository), and/or 
progesterone alone oral contraceptive.
Adequate contraception does not apply to subjects of
child bearing potential with same sex partners, or for 
subjects who are and will continue to be abstinent from 
penile-vaginal intercourse on a long term and persistent 
basis, when this is their preferred and usual lifestyle.
Adverse event:
Any untoward medical occurrence in a patient or clinical 
investigation subject, temporally associated with the use 
of a medicinal product, whether or not considered related 
to the medicinal product. 
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.
 
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Blinding:
A procedure in which one or more parties to the trial are 
kept unaware of the treatment assignment in order to 
reduce the risk of biased study outcomes. The level of 
blinding is maintained throughout the conduct of the trial, 
and only when the data are cleaned to an acceptable level 
of quality will appropriate personnel be unblinded or 
when required in case of a serious adverse event. In an 
observer-blind study, the subject and the site and sponsor 
personnel involved in the clinical evaluation of the 
subjects are blinded while other study personnel may be 
aware of the treatment assignment (see Section 5.3 for 
details on observer-blinded studies). 
Child in care:
A child who has been placed under the control or 
protection of an agency, organization, 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.
Eligible:
Qualified for enrollment into the study based upon strict 
adherence to inclusion/exclusion criteria.
End of Study 
(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, EoS is defined either as last subject last visit of 
the study (LSLV) or as the date of the last 
testing/reading* released of the Human Biological 
Samples or imaging data related to primary and 
secondary endpoints if occurred after LSLV. 
* In this case, EoS must be achieved no later than 8 
months after LSLV.
Epoch:
An epoch is a set of consecutive timepoints or a single 
timepoint from a single protocol. Epochs are defined to 
support a main purpose which is 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 timepoints included in an epoch must be sufficient 
to fulfil the purpose of the epoch.
 
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Typical examples of epochs are screening, primary 
vaccinations, boosters, yearly immunogenicity follow-
ups, and surveillance periods for efficacy or safety.
eTrack:
GSK’s tracking tool for clinical trials.
Immunological correlate 
of protection:
The defined immune response above which there is a high 
likelihood of protection in the absence of any host factors 
that might increase susceptibility to the infectious agent.
Investigational vaccine:
(Synonym of 
Investigational Medicinal 
Product)
A pharmaceutical form of an active ingredient being 
tested in a clinical trial, including a product with a 
marketing authorization when used in a way different 
from the approved form, or when used for an unapproved 
indication, or when used to gain further information about 
an approved use. 
Menarche:
Menarche is the onset of menses for the first time in a 
young female and is preceded by several changes 
associated with puberty including breast development and 
pubic hair growth. Menarche usually occurs within 1-2 
years of breast development, thelarche. However, a young 
female can become pregnant before her first menses. 
Thus, a conservative definition of non-childbearing 
potential in a pre-menarcheal female is a young female 
who has not yet entered puberty as evidenced by lack of 
breast development (palpable glandular breast tissue).
Menopause:
Menopause is the age associated with complete cessation 
of menstrual cycles, menses, and implies the loss of 
reproductive potential by ovarian failure. A practical 
definition accepts menopause after 1 year without menses 
with an appropriate clinical profile at the appropriate age 
e.g. > 45 years.
Primary completion 
date:
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 was 
concluded according to the pre-specified protocol or was 
terminated.
Randomization:
Process of random attribution of treatment/schedule to 
subjects in order to reduce bias of selection.
Self-contained study:
Study with objectives not linked to the data of another 
study.
 
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Site Monitor:
An individual assigned by the sponsor who is responsible 
for assuring proper conduct of clinical studies at one or 
more investigational sites.
Solicited adverse event:
AEs to be recorded as endpoints in the clinical study. The 
presence/occurrence/intensity of these events is actively 
solicited from the subject or an observer during a 
specified post-vaccination follow-up period.
Study vaccine/product:
Any investigational vaccine/product being tested and/or 
any authorized use of a vaccine/ product /placebo as a 
reference or administered concomitantly, in a clinical trial 
that evaluates the use of an investigational 
vaccine/product.
Sub-cohort:
A group of subjects for whom specific study procedures 
are planned as compared to other subjects or a group of 
subjects who share a common characteristic (e.g. ages, 
vaccination schedule,…) at the time of enrollment.
Subject:
Term used throughout the protocol to denote an 
individual who has been contacted in order to participate 
or participates in the clinical study, either as a recipient of 
the vaccines or as a control.
Subject number:
A unique number identifying a subject, assigned to each 
subject consenting to participate in the study.
Treatment:
Term used throughout the clinical study to denote a set of 
investigational product(s) or marketed product(s) or 
placebo intended to be administered to a subject.
Treatment number:
A unique number identifying a treatment to a subject, 
according to treatment allocation.
Unsolicited adverse 
event:
Any AE reported in addition to those solicited during the 
clinical study. Also any ‘solicited’ symptom with onset 
outside the specified period of follow-up for solicited 
symptoms will be reported as an unsolicited adverse 
event.
 
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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 will 
be written in italics.
Trademarks of the GSK group of 
companies
Generic description
Menveo
Meningococcal (Serogroups A, C, Y, and 
W-135) oligosaccharide diphtheria CRM197 
conjugate vaccine
Trademarks not owned by the GSK 
group of companies
Generic description
Nimenrix (Pfizer, Inc.)
Meningococcal (Serogroups A, C, Y, and 
W-135) oligosaccharide tetanus toxoid 
conjugate vaccine
 
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1.
INTRODUCTION
1.1.
Background
Neisseria (N.) meningitidis is a leading cause of bacterial meningitis and sepsis 
worldwide, capable of causing outbreaks and epidemics of invasive disease. 
Meningococcal disease is associated with high morbidity and mortality even among 
patients who receive early antibiotic treatment.
Based on antigenic differences in their capsular polysaccharide, 13 serogroups of N. 
meningitidis have been identified. Virtually all disease-associated isolates are 
encapsulated, with serogroups A, B, C, W and Y responsible for the majority of invasive 
meningococcal infections worldwide [Granoff, 2003; Rosenstein, 2001]. 
The conjugate vaccines containing capsular oligosaccharides conjugated to a protein 
carrier have been developed and successfully licensed worldwide. These vaccines induce 
T cell-dependent immune responses, and are immunogenic also in infants and young 
children, conferring long lasting protection in all age groups, and priming for 
immunological memory [Pollard, 2009]. 
GlaxoSmithKline (GSK) Biologicals’ Menveo (Meningococcal serogroups A, C, W and 
Y oligosaccharide diphtheria CRM197 conjugate vaccine; MenACWY) is licensed for use 
in infants through adults in more than 60 countries. In the United States, MenACWY is 
approved for active immunization of individuals from 2 months through 55 years of age. 
In the European Union, Menveo is licensed for the active immunization of children (from 
2 years of age), adolescents and adults. As of March 2017, more than 30,000 subjects 
were exposed to MenACWY vaccine in the GSK  sponsored completed clinical studies 
and more than 28 million doses of the vaccine were distributed globally. 
Menveo vaccine is delivered as a vial including the liquid MenCWY conjugate 
components and a vial including the lyophilized MenA conjugate component. The 
lyophilized component has to be reconstituted with a liquid component immediately prior 
to vaccination, which adds to complexity of vaccine administration. Furthermore, vaccine 
components come in separate vials which make it bulky and consume cold storage space. 
To simplify the vaccine administration, prevent occurrence of administration errors and
to optimize vaccine shipment and storage, a fully liquid formulation of MenACWY 
vaccine has been developed.
The investigational liquid formulation of the MenACWY vaccine contains the same 
meningococcal serogroups A, C, W and Y oligosaccharides conjugated to CRM197
protein as the ones included in currently licensed MenACWY (Menveo) vaccine. The 
amount of oligosaccharides (10 µg for serogroup A and 5 µg for each serogroup C, W 
and Y) and the injection volume (0.5 mL) are the same for both vaccine formulations. 
The key difference between Menveo and the investigational MenACWY liquid vaccine is 
that serogroup A component is not lyophilized in the vaccine candidate, and therefore, 
sucrose and potassium dihydrogen phosphate are not included as excipients.
 
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During the manufacturing process, the conjugated oligosaccharides are produced by a 
covalent attachment of the oligosaccharides to the carrier protein (CRM197). The results 
of development stability studies indicate that the percentage of free saccharides (FS) for
serogroup A will increase over time when stored at temperature of 2-8 ̊C. 
Oligosaccharides for serogroups C, W and Y, however remain substantially unchanged 
and no degradation has been observed during stability studies. This is not unexpected, 
given that the manufacturing and storage processes for the C, W and Y components have 
not changed from those used for the currently licensed formulation.  
Additionally, the O-acetylation level of the MenA component of the MenACWY liquid 
vaccine is expected to decrease over time during the storage of the vaccine. One clinical 
trial with Nimenrix showed no impact of different degrees of O-acetylation of a 
MenACWY conjugated vaccine on immunogenicity [Lupisan, 2013].  Moreover, a non-
clinical study [Berry, 2002] has shown that completely non-O-acetylated polysaccharide 
vaccines were not immunogenic and failed to elicit bactericidal antibodies against MenA 
meningococci.
Please refer to the current Menveo Investigator Brochure for information regarding the 
pre-clinical and clinical studies and the epidemiological information of the investigational 
liquid formulation of the MenACWY vaccine. 
1.2.
Rationale for the study and study design
1.2.1.
Rationale for the study
The purpose of the study is to assess the non-inferiority of the immune response against 
serogroup A between the currently licensed GSK Biologicals’ MenACWY vaccine 
(Menveo) and the investigational MenACWY liquid vaccine with approximately 30% 
Men A FS (MenACWY liquid). Immune response against serogroups C, W and Y and the 
reactogenicity and safety profile of the study vaccines will be also evaluated. However, 
as the CWY component of the investigational vaccine formulation is identical to that of 
the licensed formulation, non-inferiority will not be assessed for these serogroups. 
Reactogenicity will be evaluated for 7 days, and safety for 6 months after a single-dose 
vaccination.
For this study, the formulation with approximately 30% of free MenA oligosaccharides 
will be obtained by storing a fresh manufacturing MenA lot at approximately 22.5°C 
(72.5°F) for the time needed to accelerate the formation of the free saccharides following 
the Arrhenius model. Since a certain degree of loss of the O-acetyl groups on the 
conjugated MenA component may occur when stored at temperature higher than 2 to 
8°C, the O-acetylation level of N. meningitidis serogroup A capsular polysaccharide of 
the fully liquid vaccine formulation will also be monitored. 
The results of this study will provide immunogenicity and safety data to support the 
MenACWY liquid specifications at release. 
 
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1.2.2.
Rationale for the study design

Study population: healthy adults ≥18 to ≤40 years of age (YoA) will be enrolled in 
this study as agreed with regulatory authorities for the investigational MenACWY 
liquid vaccine. 

Vaccination dose and route of administration: subjects will receive a single dose of 
licensed MenACWY vaccine or investigational MenACWY liquid vaccine (i.e.  
dosing scheme currently indicated for Menveo in adults). 

Study blinding: given the different appearance of the investigational liquid and 
currently licensed MenACWY vaccines, double blinding is not possible. The study 
will therefore be conducted in an observer-blind manner.
1.3.
Benefit: Risk Assessment
Please refer to the Prescribing Information for information regarding the summary 
potential risks and benefits of the licensed Menveo vaccine. The risks are anticipated to 
be the same for the investigational liquid formulation of the MenACWY vaccine.
The following section outlines the risk assessment and mitigation strategy for this study 
protocol: 
1.3.1.
Risk Assessment
Important Potential/Identified 
Risk
Data/Rationale for Risk
Mitigation Strategy
Menveo and investigational MenACWY liquid vaccine
Important Identified risk:
Reconstitution errors
Cases describing medication errors 
due to administration of the 
MenCWY conjugate liquid 
component only, without 
reconstitution with the MenA
conjugate lyophilized component, or 
due to administration of the MenA 
conjugate lyophilized component 
only after reconstitution with a 
different solvent, have been reported 
during the MenACWY clinical 
development program.
In several sections of the 
protocol (e.g. Section 6.1
“Description of study vaccines”) it 
is clarified that the 2 vaccine 
components have to be 
reconstituted before vaccine 
injection.
Important potential risk:
Guillain-Barré syndrome (GBS)
GBS has been observed with other 
vaccines. No cases have been 
reported during the MenACWY 
clinical development program.
GBS will be monitored through 
SAE collection. 
Important potential risk:
Acute disseminated 
encephalomyelitis (ADEM)
ADEM has been observed with other 
vaccines. Two cases from clinical 
trials were retrieved from the GSK’s 
global safety database for 
MenACWY. None of them has 
provided sufficient evidence of a 
causal association between ADEM 
and MenACWY.
ADEM will be monitored through 
SAE collection.
 
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Important Potential/Identified 
Risk
Data/Rationale for Risk
Mitigation Strategy
Important potential risk:
Thrombocytopenia
Immune thrombocytopenic purpura 
has been reported in association with 
several licensed vaccines. Two 
cases related to MenACWY were 
reported during the clinical 
development program, but none of 
them has provided a clear 
association between 
thrombocytopenia and the vaccine.
Immune thrombocytopenic 
purpura will be monitored 
through SAE collection.
Important potential risk:
Facial paresis
Facial paresis was recognized as an 
important potential risk following the 
results of a sponsored observational 
study (V59_34OB) which found an 
imbalance of cases of facial paresis 
following vaccination with 
MenACWY, mainly when 
administered concomitantly with 
other vaccines. No cases of facial 
paresis were reported from 
interventional clinical trials.
Paralysis of the face is 
mentioned in the list of side 
effects in the ICF. Facial paresis 
will be monitored through SAE 
collection.
Important potential risk:
Vasculitis including Kawasaki 
disease (KD)
There were 7 cases of suspected KD 
reported in three clinical studies of 
Menveo. The occurrence of the 
cases in Menveo studies is 
consistent with the known 
epidemiology of KD in terms of 
geographic and temporal clustering, 
and seasonal variation. Therefore 
there is no evidence of a causal 
association between KD and 
MenACWY vaccine. As the exposure
in clinical trial of subject was limited 
considering the incidence of the 
disease, KD is considered as a 
potential risk.
Vasculitis including Kawasaki 
disease will be monitored 
through SAE collection.
Study Procedures
Risk of blood sampling
Blood sampling associated risk of 
syncope, dizziness, infection at the 
site after or during venepuncture.
Blood samples will be obtained 
by a trained professional and 
medical assistance will be 
available.
The potential risk of feeling faint, 
or experiencing mild local pain, 
bruising, irritation or redness at 
the site where blood was taken, 
is mentioned in the Informed 
Consent Form (ICF). The 
amount of blood to be taken for 
sampling will not be harmful to 
the subject’s health.
 
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1.3.2.
Benefit Assessment
Benefits considerations include:

Medical evaluations/assessments associated with this study (i.e. physical 
examination).

Potential benefit of receiving GSK’s investigational or licensed meningococcal 
vaccine during study duration that may have clinical utility.
1.3.3.
Overall Benefit: Risk Conclusion
Considering the measures taken to minimize risk to subjects participating in this study, 
the potential or identified risks in association with the licensed and investigational 
MenACWY vaccine are justified by the potential benefits (prevention) that may be 
afforded to subject(s) receiving the MenACWY vaccines.
2.
OBJECTIVES
2.1.
Primary objective

To demonstrate non-inferiority of the investigational MenACWY liquid vaccine with 
approximately 30% Men A FS to that of currently licensed MenACWY vaccine, as 
measured by the human serum bactericidal assay (hSBA) Geometric Mean Titers 
(GMTs) directed against N. meningitidis serogroup A at Day 29 after a single dose 
vaccination.
Criterion to demonstrate non-inferiority: 
Non-inferiority will be concluded if the lower limit of the two-sided 95% confidence 
interval (CI) for the ratio of hSBA GMTs against serogroup A between the liquid 
formulation and the licensed formulation is greater than 0.5.
Refer to Section 10.1 for the definition of the primary endpoint.
2.2.
Secondary objectives

To compare the immunogenicity of the investigational MenACWY liquid vaccine 
with approximately 30% Men A FS and the currently licensed MenACWY vaccine, 
as measured by hSBA GMTs directed against N. meningitidis serogroups C, W and 
Y at Day 29.

To compare the immunogenicity of the investigational MenACWY liquid vaccine 
with approximately 30% Men A FS to the currently licensed MenACWY vaccine, as 
measured by the percentage of subjects with a ≥ 4-fold rise in post-vaccination hSBA 
titer for N. meningitidis serogroups A, C, W and Y at Day 29 compared to Day 1.
Note: The following definition will be used for 4-fold rise: a) for individuals whose 
pre-vaccination titers are < the limit of detection (LOD), the post-vaccination titers 
must be ≥ 4-fold the LOD or ≥ the lower limit of quantitation (LLOQ) whichever is 
greater; b) for individuals whose pre-vaccination titers are ≥ the LOD and ≤ the 
 
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LLOQ, the post-vaccination titers must be at least four times the LLOQ; c) for 
individuals whose pre-vaccination titers are > the LLOQ, the post vaccination titers 
must be at least four times the pre-vaccination titer.

To compare the immunogenicity of the investigational MenACWY liquid vaccine 
with approximately 30% Men A FS to the currently licensed MenACWY vaccine, as 
measured by the percentage of subjects with hSBA titer ≥8 and ≥LLOQ* against N. 
meningitidis serogroups A, C, W and Y at Day 29.
*Note: To be assessed for each serogroup if the pre-defined LLOQ value for that 
serogroup is >8.

To assess the safety/reactogenicity of the investigational MenACWY liquid vaccine 
with approximately 30% Men A FS and the currently licensed MenACWY vaccine.
Refer to Section 10.2 for the definition of the secondary endpoints.
3.
STUDY DESIGN OVERVIEW
Figure 1
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 5.5), are essential 
and required for study conduct. 

Experimental design: Phase IIB, observer-blind, randomized, controlled, multi-
centric study with two parallel groups.

Duration of the study: for each subject enrolled, the duration will be approximately 6 
months.

Epoch 001: starting at Visit 1 (Day 1) and ending at last Safety contact (Day 
181). 
 
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
Primary completion Date (PCD): Visit 2 (Day 29).
Refer to glossary of terms for the definition of PCD.

End of Study (EoS): Last subject last visit (Phone call 3) or last testing results 
released of samples collected at Visit 2 (Day 29)* if it occurs after LSLV. 
* In this case EoS must be achieved no later than 8 months after LSLV.
Refer to glossary of terms for the definition of EoS.

Study groups:

Group ACWY_Liq: ~486 healthy adults receiving a single dose of 
investigational MenACWY liquid (GSK3536820A) with approximately 30% 
Men A FS.

Group ACWY: ~486 healthy adults receiving a single dose of currently licensed 
GSK’ MenACWY vaccine (Menveo).
Table 1
Study groups and epochs foreseen in the study
Study 
groups
Number of 
subjects
Age (Min/Max)
Epochs
Epoch 001
ACWY_Liq
~486
18 – 40 years
x
ACWY
~486
18 – 40  years
x
Table 2
Study groups and treatment foreseen in the study
Treatment name
Vaccine/product 
name
Study Groups
ACWY_Liq
ACWY
MenACWYliquid  with
approximately 30% 
MenA FS
MenACWY liquid
x
Licensed MenACWY
(Menveo)*
MenA lyo
x
MenCWY liquid
* Menveo commercial formulation consisting of a MenA lyophilized component and a MenCWY liquid component to be 
reconstituted together before administration (0.5mL).

Control: active control

Vaccination schedule: All subjects will receive a single dose of one of the study 
vaccines at Visit 1 (Day 1).

Treatment allocation: Subjects will be randomized using a centralized randomization 
system on internet (SBIR) at Visit 1 (Day 1). 
Refer to Section 5.2 for a detailed description of the randomization method.

Blinding: observer-blind.
Refer to Section 5.3 for details of blinding procedure.
Table 3
Blinding of study epochs
Study Epochs
Blinding
Epoch 001
observer-blind
 
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
Sampling schedule: Blood samples of approximately 20 mL will be taken at Visit 1 
(Day 1; pre-vaccination) and Visit 2 (Day 29).

Type of study: self-contained.

Data collection: Standardised Electronic Case Report Form (eCRF). Solicited 
adverse events (AEs) assessed on site during the 30 minutes post-vaccination 
assessment are to be recorded on the source documents and entered in the eCRF. 
Solicited AEs occurring after the 30 minutes post-vaccination assessment will be 
collected only using a subject Diary (electronic Diary [eDiary]).
4.
STUDY COHORT
4.1.
Number of subjects
Approximately 972 subjects are planned for enrollment into this study (approximately 
486 subjects per group). Assuming a 10% drop-out rate, there should be approximately 
874 evaluable subjects (approximately 437 evaluable subjects per group).
Refer to Section 10.3 for a detailed description of the criteria used in the determination of 
sample size.
4.2.
Inclusion criteria for enrollment
Deviations from inclusion criteria are not allowed because they can potentially jeopardize 
the scientific integrity, regulatory acceptability of the study or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential.
All subjects must satisfy ALL the following criteria at study entry:
1. Subjects who, in the opinion of the investigator, can and will comply with the 
requirements of the protocol (e.g. completion of the eDiary) or subjects’ 
parent(s)/Legally Acceptable Respresentative(s) [LAR(s)] who, in the opinion of the 
investigator, can and will comply, with the requirements of the protocol (e.g. 
completion of the eDiary).
2. Written informed consent obtained from the subject/from the parent(s)/LAR(s) of the 
subject prior to performance of any study specific procedure.
3. Written informed assent obtained for subjects below legal age of consent, if required 
by local regulations, at the time of enrollment.
4. A male or female between, and including, ≥18 to ≤40 YoA at the time of the first 
vaccination.
5. Healthy subjects as established by medical history and clinical examination before 
entering into the study.
6. Female subjects of non-childbearing potential may be enrolled in the study.

Non-childbearing potential is defined as pre-menarche, current bilateral tubal 
ligation or occlusion, hysterectomy, bilateral ovariectomy or post-menopause.
 
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Please refer to the glossary of terms for the definition of menarche and menopause.
7. Female subjects of childbearing potential may be enrolled in the study, if the subject:

has practiced adequate contraception for 30 days prior to vaccination, and 

has a negative pregnancy test on the day of vaccination, and 

has agreed to continue adequate contraception during the entire treatment period 
(approximately 1 month after vaccination).
Please refer to the glossary of terms for the definition of adequate contraception.
4.3.
Exclusion criteria for enrollment
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity, regulatory acceptability of the study or subject safety. 
Therefore, adherence to the criteria as specified in the protocol is essential.
The following criteria should be checked at the time of study entry. If ANY exclusion 
criterion applies, the subject must not be included in the study:
Each subject must not have:
1. Anaphylaxis following the administration of vaccine
2. Any (clinical) condition that in the judgment of the investigator would make 
intramuscular injection unsafe and/or represents a contraindication to intramuscular 
vaccination and blood draws.
3. Any confirmed or suspected immunosuppressive or immunodeficient condition, 
including HIV infection.
4. Progressive, unstable or uncontrolled clinical conditions.
5. Hypersensitivity, including allergy, to any component of vaccines, medicinal products 
or medical equipment whose use is foreseen in this study.
6. Hypersensitivity to the active substances or to any of the excipients of the vaccine, 
including diphtheria toxoid (CRM197), or a life-threatening reaction after previous 
administration of a vaccine containing similar components.
7. Abnormal function of the immune system resulting from:
−
Clinical conditions.
−
Systemic administration of corticosteroids (Per os [PO]/ Intravenous [IV]/ 
Intramuscular [IM]) for more than 14 consecutive days within 90 days prior to 
informed consent, and until the Day 29 blood draw.
−
Administration of antineoplastic and immuno-modulating agents or radiotherapy 
within 90 days prior to informed consent, and until the Day 29 blood draw.
8.
Received immunoglobulins or any blood products within 180 days prior to informed 
consent.
9.
Received an investigational or non-registered medicinal product within 30 days prior 
to informed consent.
 
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10. Any other clinical condition that, in the opinion of the investigator, might interfere 
with the results of the study or pose additional risk to the subject due to participation 
in the study.
11. History of any meningococcal vaccination.
12. Individuals who received any other vaccines within 7 days (for inactivated vaccines) 
or 14 days (for live vaccines) prior to enrollment in this study or who are planning to 
receive any vaccine within 28 days from the study vaccines*.
* In case an emergency mass vaccination for an unforeseen public health threat (e.g.: 
a pandemic) is organised by the public health authorities, outside the routine 
immunization program, the time period described above can be reduced if necessary 
for that vaccine provided it is licensed and used according to its Summary of Product 
Characteristics (SmPC) or Prescribing Information and according to the local 
governmental recommendations and provided a written approval of the Sponsor is 
obtained.
13. Administration of long-acting immune-modifying drugs at any time during the study 
period (e.g. infliximab).
14. Concurrently participating in another clinical study, at any time during the study 
period, in which the subject has been or will be exposed to an investigational or a 
non-investigational vaccine/product (pharmaceutical product or device).
15. Current or previous, confirmed or suspected disease caused by N. meningitidis.
16. Household contact with and/or intimate exposure to an individual with any 
laboratory confirmed N. meningitidis infection within 60 days prior to study 
vaccination.
17. Acute disease and/or fever within 3 days prior to study vaccination.
Note: enrollment may be postponed/delayed until such transient circumstances have 
ended. 
−
Fever is defined as body temperature 38.0°C / 100.4°F. The preferred location 
for measuring temperature in this study will be the oral cavity.
−
Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory 
infection) without fever may be enrolled at the discretion of the investigator.
18. Received systemic antibiotic treatment within 3 days prior to study vaccination or 
blood draw.
19. Study personnel as an immediate family or household member.
20. Pregnant or lactating women (see Section 8.2.1 for pregnancy).
 
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5.
CONDUCT OF THE STUDY
5.1.
Regulatory and ethical considerations, including the 
informed consent process
The study will be conducted in accordance with all applicable regulatory requirements.
The study will be conducted in accordance with the ICH Guideline for GCP, all 
applicable subject privacy requirements and the guiding principles of the Declaration of 
Helsinki. 
GSK will obtain favourable opinion/approval to conduct the study from the appropriate 
regulatory agency, in accordance with applicable regulatory requirements, prior to a site 
initiating the study in that country.
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 informed consent. 

Investigator reporting requirements as stated in the protocol.
GSK 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) and subject informed assent, as 
appropriate, prior to participation in the study. 
GSK Biologicals will prepare a model Informed Consent Form (ICF) which will embody 
the ICH GCP and GSK Biologicals required elements. While it is strongly recommended 
that this model ICF is to 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 Harmonized Tripartite Guidelines for Good Clinical Practice, 
those subjects who can only be enrolled in the study with the consent of the subject’s 
legally acceptable representative (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 legal representative. It should be assessed whether an assent is 
required depending of the age of the study population and the local requirements.
 
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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.
5.2.
Subject identification and randomization
5.2.1.
Subject identification
Subject identification numbers will be assigned sequentially to the subjects who have 
consented to participate in the study, according to the range of subject identification 
numbers allocated to each study center.
5.2.2.
Randomization of treatment
5.2.2.1.
Randomization of supplies
The randomization of supplies within blocks will be performed at GSK Biologicals, using 
MATerial EXcellence (MATEX), a program developed for use in Statistical Analysis 
System (SAS) (Cary, NC, USA) by GSK Biologicals. Entire blocks will be shipped to the 
study centers /warehouse(s).
To allow GSK Biologicals to take advantage of greater rates of recruitment than 
anticipated at individual centers in this multi-center study and to thus reduce the overall 
study recruitment period, an over-randomization of supplies will be prepared. 
5.2.2.2.
Treatment allocation to the subject
The treatment numbers will be allocated by dose. 
5.2.2.2.1.
Study group and treatment number allocation
The target will be to enrol approximately 972 eligible subjects who will be randomly 
assigned to two study groups in a (1: 1) ratio (approximately 486 subjects in each group).
Allocation of the subject to a study group at the investigator site will be performed using 
the Source DataBase for Internet Randomization system (SBIR). The randomization 
algorithm will use a minimization procedure accounting for center.
 
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After obtaining the signed and dated ICF from the subject and having checked the 
eligibility of the subject, the site staff in charge of the vaccine administration will access 
SBIR. Upon providing the subject identification number, the randomization system will 
determine the study group and will provide the treatment number to be used for the dose.
The number of each administered treatment must be recorded in the eCRF on the Vaccine 
Administration screen.
When SBIR is not available, please refer to the SBIR user guide or the Study Procedures 
Manual (SPM) for specific instructions.
5.3.
Method of blinding (Amended 08 February 2019)
Data will be collected in an observer-blind manner. By observer-blind, it is meant that 
during the course of the study, the vaccine recipient and those responsible for the 
evaluation of any study endpoint (e.g. safety, reactogenicity) will all be unaware of which 
vaccine was administered. To do so, vaccine preparation and administration will be done 
by authorised medical personnel who will not participate in any of the study clinical 
evaluation assays.
The laboratory in charge of the laboratory testing will be blinded to the treatment as well 
as to the subject number. In addition, a randomly selected subject code will be used for 
each timepoint tested. This subject coding will prevent the laboratory from linking the 
consecutive visits to a specific subject.
5.4.
General study aspects
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying 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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5.5.
Outline of study procedures
Table 4
List of study procedures
Age
≥18 to ≤40 YOA
Epoch
Epoch 001
Type of contact
Visit 1
Phone call 1
Visit 2
Phone call 2 Phone call 3
Timepoint (s)
Day 1
Day 15
Day 29
Day 91
Day 181
Sampling timepoint(s)
Pre-Vacc
Post-Vacc
Informed consent
●a
Informed  assent (if applicable as per local 
regulations)
●a
Check inclusion/exclusion criteria
●a
Collect demographic data
●a
Medical history
●a
Physical examination (including vital signs)
●
●b
Urine pregnancy test c
●
Check contraindications and warnings and 
precautions to vaccination
O
Pre-vaccination body temperature
●
Measure/record height and weight
●a
Study group and treatment number allocation
●
Recording of administered treatment number
●
Blood sampling (~20 mL) d
●e
●
Vaccine administration
●
30 Minutes Post Injection Assessment
●
Distribution of Subject Card
Oa
Distribution of eDiary
O
Training on use of eDiary
O
Return of eDiary
O
Record any concomitant medications/vaccinations
●
●
●
Concomitant medication/vaccinations related to 
AEs leading to study discontinuation, SAEs and 
medically attended visits
●
●
●
●
●
Record any intercurrent medical conditions 
●
●
●
●
●
Recording of solicited adverse events (Days 1–7 
post-vaccination in eDiary)
●
Recording of unsolicited adverse events within 28 
days post-vaccination
●
●
●
Recording of medically-attended AEs
●
●
●
●f
●f
Recording of AEs/SAEs leading to withdrawal
●a
●
●
●
●
Recording of SAEs
●
●
●
●
●
Recording of pregnancies
●
●
●
●
●
Study Conclusion
●
Note: The double-line border following Day 29 indicates the interim analysis which will be performed on all data ) 
obtained up to Day 29.
AE = adverse event; GSK = GlaxoSmithKline; SAE = serious adverse event; Vacc: vaccination; YOA = years of age
● 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, but should be 
confirmed in the patient’s source record.
a  The following activities can be performed at a separate visit (maximum 5 days before Visit 1): Informed Consent,
Informed Assent, check of inclusion/exclusion criteria, collection of demographic data, recording of Medical History and 
of height and weight, distribution of subject card.  AEs/SAEs leading to withdrawal and SAEs related to study 
participation or to a concurrent GSK medication/vaccine should also be recorded from the separate visit. 
Inclusion/exclusion criteria should be rechecked prior to vaccination.
 
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bPhysical examination will be performed only if deemed necessary by the Investigator or delegate.
cOnly for women of childbearing potential.
d Before blood sample collection, check if there is no contraindication to blood draw.
e Blood sample collection from Visit 1 will be performed before vaccine administration.
fNon-medically attended AEs after 28 days post-vaccination are not required to be reported in the eCRF.
Whenever possible, the investigator should arrange study visits within the interval 
described in Table 5.
Table 5
Intervals between study visits
Interval
Optimal length of interval
Allowed interval 
Visit 1 Phone call 1
14  days
11 - 17  days
Visit 1 Visit 2
28  days
21 - 42  days
Visit 1 Phone call 2
90  days
76 - 104  days
Visit 1  Phone call 3
180  days
166  - 194 days
5.6.
Detailed description of study procedures
5.6.1.
Informed consent
The signed/witnessed/thumb printed informed consent of the subject/subjects’ 
parent(s)/LAR(s) must be obtained before study participation. The signed informed 
assent of the 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 the local rules 
and regulations. Refer to Section 5.1 for the requirements on how to obtain informed 
consent and assent, as appropriate.
5.6.2.
Check inclusion and exclusion criteria
Check all inclusion and exclusion criteria as described in Sections 4.2 and 4.3 before 
enrollment. 
5.6.3.
Collect demographic data
Record demographic data such as year of birth, sex, race and ethnicity in the subject’s 
eCRF.
Differences in the safety and efficacy of certain medical products, including vaccines 
[Haralambieva, 2013; Kollmann, 2013; Pérez-Losada, 2009], have been observed in 
racially and ethnically distinct subgroups. These differences may be attributable to 
intrinsic factors (e.g. genetics, metabolism, elimination), extrinsic factors (e.g. diet, 
environmental exposure, sociocultural issues), or interactions between these factors. 
Therefore, both race and ethnicity will be collected for all subjects participating in the 
MENACWY CONJ-032 [V59_71] study. Subgroup analysis by race will be performed.
 
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5.6.4.
Medical history
Obtain the subject’s medical history by interview and/or review of the subject’s medical 
records and record any pre-existing conditions or signs and/or symptoms present in a 
subject prior to the study vaccination in the eCRF.
5.6.5.
Physical examination
Review of systems is a structured interview that queries the subject as to any complaints 
the subject has experienced across each organ system. This will be performed before 
enrollment and used to guide physical examination. Collect vital signs (heart rate, blood 
pressure), and temperature (preferably taken orally). Measure height and weight. A 
general physical examination is to be performed by a qualified health care practitioner. 
“Qualified health care practitioner” refers to any licensed health care professional who is 
permitted by institutional policy to perform physical examinations and who is identified 
within the Study Staff Signature Log (or alternatively called Delegation of 
Responsibilities Log). The data collected through study assessments listed above will be 
written in the source document. Should the physical assessment reveal any abnormal 
values or events, these must be documented in the CRF Adverse Events Form. Collected 
information needs to be recorded in the eCRF.
Physical examination at each study visit subsequent to the vaccination visit, will be 
performed only if the subject indicates during questioning that there might be some 
underlying pathology(ies) or if deemed necessary by the Investigator or delegate.
If the investigator determines that the subject’s health on the day of vaccination 
temporarily precludes vaccination, the visit will be rescheduled.
Treatment of any abnormality observed during physical examination has to be performed 
according to local medical practice outside this study or by referral to an appropriate 
health care provider. 
5.6.6.
Urine pregnancy test
Female subjects of childbearing potential are to have a urine pregnancy test prior to any 
study vaccine administration. The study vaccine may only be administered if the 
pregnancy test is negative. 
Note: Pregnancy test must be performed even if the subject is menstruating at the time of 
the study visit.
5.6.7.
Check contraindications, warnings and precautions to 
vaccination
Contraindications, warnings and precautions to vaccination must be checked at the 
beginning of the vaccination visit. Refer to Sections 6.5 and 6.6 for more details. 
 
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5.6.8.
Assess pre-vaccination body temperature
The oral body temperature of each subject needs to be measured prior to any study 
vaccine administration. If the subject has fever (fever is defined as body temperature 
38.0°C/100.4°F regardless the location of measurement) on the day of vaccination, the 
vaccination visit will be rescheduled within the allowed interval for this visit (see Table 
5).
5.6.9.
Measure/record height and weight
Measure height and weight of the subject and record the data in the ‘Physical 
examination’ section of the eCRF.
5.6.10.
Study group and treatment number allocation
Study group and treatment number allocation will be performed as described in Section 
5.2.2. The number of each administered treatment must be recorded in the eCRF.
5.6.11.
Sampling
Refer to the Module on biospecimen management in the SPM and the Central Laboratory 
Manual for detailed instructions for the collection, handling and processing of the 
samples.
5.6.11.1.
Blood sampling for immune response assessments
Blood samples will be taken during certain study visits as specified in Table 4 (List of 
Study Procedures).

A volume of approximately 20 mL of whole blood should be drawn from all subjects 
for each analysis of humoral immune response at each pre-defined timepoint (Visit 1 
and Visit 2). After centrifugation, serum samples should be kept at –20°C/–4°F or 
below until shipment. Refer to the SPM or Central Laboratory Manual for more 
details on sample storage conditions.

An overall volume of approximately 40 mL will be collected during the entire study 
period. 
5.6.12.
Study Vaccine administration

After completing all prerequisite procedures prior to vaccination, one dose of study 
vaccine will be administered intramuscularly (IM) in the deltoid of the non-dominant 
arm (refer to Section 6.3 for detailed description of the vaccine administration 
procedure). If the investigator or delegate determines that the subject’s health on the 
day of administration temporarily precludes vaccine administration, the visit will be 
rescheduled within the allowed interval for this visit (refer to Table 5).
 
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
The subjects will be observed closely for at least 30 minutes following the 
administration of the vaccine, with appropriate medical treatment readily available in 
case of anaphylaxis.
5.6.13.
Distribution of Subject Card
For information regarding the Subject Card, please refer to Section 8.9.
5.6.14.
Subject Diary
An Electronic Diary (eDiary), hereafter referred to as Subject Diary will be used in this 
study to capture solicited adverse events. The subject should be trained on how and when 
to complete each field of the Subject Diary.
Subject Diary training should be directed at the individual(s) who will perform the 
measurements of adverse events and who will enter the information into the Subject 
Diary. This individual may not be the subject/subject’s parent(s)/LAR(s), but if a person 
other than the subject/subjects’ parent(s)/LAR(s) enters information into the Subject 
Diary, this person’s identity must be documented in the subject’s source record. Any 
individual that makes entries into the Subject Diary must receive training on completion 
of the Subject Diary at the time of the visit when Subject Diary is dispensed. This 
training must be documented in the subject’s source record.
The same individual should complete the Subject Diary throughout the course of the 
study.
The subject/subjects’ parent(s)/LAR(s) should be trained on how to self-measure local 
solicited adverse events and body temperature. 
The measurement of solicited local adverse events is to be performed using the ruler 
provided by the site.
Subjects/parents/LARs will be instructed to measure and record the oral body 
temperature in the evening. Should additional temperature measurements be performed at 
other times of day, subjects/parents/LARs will be instructed to record the highest 
temperature in the Subject Diary.
Subject Diary assignment and use:

Each subject/subjects’ parent(s)/LAR(s) will be assigned a Subject Diary and shown 
how to use the device – this will include how to access the diary, performing test 
data entry on sample questions, and how to charge and store the device.

The subject/subjects’ parent(s)/LAR(s) will self-select a numeric access code secret 
to themselves. The same individual should make the assessments and complete the 
Subject Diary throughout the course of the study. 

The subject/subjects’ parent(s)/LAR(s) will select an alarm time that suits their daily 
routines whilst ensuring compliance with protocol requirements.
 
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Subject Diary instructions must ensure that the subject/subjects’ parent(s)/LAR(s)
understands the following:

Timely completion of the Subject Diary on a daily basis is a critical component to 
study participation.

The Subject Diary will allow certain time windows for completion of each day’s 
observations.

The Subject Diary employs the use of audio-visual alarms to ensure timely 
completion of data entry.

The trained and assigned user of the Subject Diary must not share access codes with 
anyone.

A helpdesk will be provisioned for users of subject diary in case of technical issues, 
though it must be stressed that the Helpdesk is not a replacement for normal medical 
care and no medical issues can be discussed with the agents.

The Subject Diary itself must never be considered a substitute for direct medical care 
and any concerns must be communicated to site staff as soon as possible.
5.6.14.1.
Post-vaccination reminders
Reminder calls or alerts are not intended to be an interview for collection of safety data. 
If the subject/subjects’ parent(s)/LAR(s) wishes to describe safety information, this 
information should only be collected by a healthcare professional at the site, and the 
safety data described must be written down in the subject’s medical chart.
5.6.14.1.1. Subject Diary Reminder Alerts
The subject/subjects’ parent(s)/LAR(s) will receive daily reminders via the Subject Diary 
device’s in-built audio-visual alarms to alert the user to complete the diary during the 
post vaccination period. From Day 1 through Day 7, the users will receive daily alerts 
through the Subject Diary to record solicited adverse events, and the incidence of any 
potential unsolicited AEs, and whether these AEs were medically attended (defined as 
symptoms or illnesses requiring hospitalization, or emergency room visit, or visit to/by a 
health care provider), or were of concern. In case of such events, subject/subjects’ 
parent(s)/LAR(s) will be instructed to contact the site as soon as possible to report the 
event(s).
The Subject Diary system will also allow for regular alerts to be issued via email to site 
staff indicating where subjects may need to be contacted due to:

Non-compliance (i.e. failing to enter or transmit diary data),

Reporting of any severe solicited reactions,

Subject experienced an unsolicited adverse event that was medically attended or was 
of concern.
 
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Sites must assess these alerts when received and contact subjects as necessary. Please 
refer to Section 9.2 on the premature withdrawals from the study and Section 8.3.3 on the 
evaluation of Adverse Events for guidance on necessary action in the event of one of 
these alerts.
5.6.14.2.
Safety Follow-up calls
Safety follow-up calls will be performed on Day 15, Day 91, and Day 181 (or within the 
allowed interval specified in Table 5).
Safety follow-up calls are calls made to the subject by a healthcare professional 
designated on the site log. These calls will follow a script which will facilitate the 
collection of relevant safety information. The subject/subjects’ parent(s)/LAR(s) will be 
interviewed according to the script, and information relating to unsolicited adverse events 
(including unsolicited adverse events (AEs) within 28 days post-vaccination, serious 
adverse events (SAEs), medically attended adverse events, AEs or SAEs leading to 
withdrawal, and/or intercurrent medical conditions) and concomitant medications or 
vaccinations associated with those events will be collected, as well as information on 
pregnancy for females of childbearing potential. All safety information described by the 
subject must be written down in a designated location within the source document and 
not written on the script used for the telephone call.
The site should schedule the next study activity (clinic visit/ safety call) with the 
subject/subjects’ parent(s)/LAR(s).
The subject/subjects’ parent(s)/LAR(s) will be reminded to contact the site if there are 
any questions and to contact the site immediately (or as soon as the subject is medically 
stable) if the subject has a medical condition that leads to a hospitalization or an 
emergency room visit.
5.6.15.
Check and record concomitant medication/vaccination and 
intercurrent medical conditions
Concomitant medication/vaccination must be checked and recorded in the eCRF as 
described in Section 6.7.
Intercurrent medical conditions must be checked and recorded in the eCRF as described 
in Section 6.8.
5.6.16.
Recording of AEs, SAEs and pregnancies

Refer to Section 8.3 for procedures for the investigator to record AEs, SAEs and 
pregnancies. Refer to Section 8.4 for guidelines and how to report SAE and 
pregnancy reports to GSK Biologicals.

The subjects/subjects’ parent(s)/LAR(s) will be instructed to contact the investigator 
immediately should they manifest any signs or symptoms they perceive as serious. 
 
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5.6.17.
Study conclusion
The investigator will:

review data collected to ensure accuracy and completeness

complete the Study Conclusion screen in the eCRF.
5.7.
Biological sample handling and analysis
Please refer to the SPM and to the Central Laboratory manual for details on biospecimen 
management (handling, storage and shipment).
Samples will not be labelled with information that directly identifies the subject but will 
be coded with a unique sample identifier.

Collected samples will be used for protocol mandated research and purposes related 
to the improvement, development and quality assurance of the laboratory tests 
described in this protocol. This may include the management of the quality of these 
tests, the maintenance or improvement of these tests, the development of new test 
methods, as well as making sure that new tests are comparable to previous methods 
and work reliably.

It is also possible that future findings may make it desirable to use the samples 
acquired in this study for future research, not described in this protocol. Therefore, 
all subjects in countries where this is allowed will be asked to give a specific consent 
to allow GSK or a contracted partner to use the samples for future research. Future 
research will be subject to the laws and regulations in the respective countries and 
will only be performed once an independent Ethics Committee or Review Board has 
approved this research.
Information on further investigations and their rationale can be obtained from GSK 
Biologicals. 
Any sample testing will be done in line with the consent of the individual 
subject/subjects’ parent(s)/LAR(s). 
Refer also to the Investigator Agreement, where it is noted that the investigator cannot 
perform any other biological assays except those described in the protocol or its 
amendment(s). 
Collected samples will be stored for a maximum of 20 years (counting from when the last 
subject performed the last study visit), unless local rules, regulations or guidelines require 
different timeframes or different procedures, which will then be in line with the subject 
consent. These extra requirements need to be communicated formally to and discussed 
and agreed with GSK Biologicals.
 
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5.7.1.
Use of specified study materials
When materials are provided by GSK Biologicals or designated vendor, it is 
MANDATORY that all clinical samples (including serum samples) be collected and 
stored exclusively using those materials in the appropriate manner. The use of other 
materials could result in the exclusion of the subject from the per-protocol analysis (see 
Section 10.4 for the definition of analysis sets to be analysed). The investigator must 
ensure that his/her personnel and the laboratory(ies) under his/her supervision comply 
with this requirement. However, when GSK Biologicals or designated vendor does not 
provide material for collecting and storing clinical samples, appropriate materials from
the investigator’s site must be used. Refer to the Module on Clinical Trial Supplies in the 
SPM or Central Laboratory manual.
5.7.2.
Biological samples
Table 6
Biological samples
Sample type
Quantity
Unit
Timepoint
Blood
Approximately 20
ml

Visit 1 (Day 1)

Visit 2 (Day 29)
5.7.3.
Laboratory assays (Amended 08 February 2019)
Please refer to APPENDIX A for a detailed description of the assays performed in the 
study. Please refer to APPENDIX B for the address of the clinical laboratories used for 
sample analysis.
The measure of immunogenicity used in this study is standard, i.e., widely used and 
generally recognized as reliable, accurate, and relevant (able to describe the quality and 
extent of the immune response). Testing will be conducted by a GSK or designated 
laboratory in a blinded manner towards the subject number and the treatment arm (please 
refer to Section 5.3 Method of blinding).
The functional measure of immunogenicity used in this study, Serum Bactericidal Assay 
(SBA), is a measure of the ability of antibodies, mediated with human complement, to 
kill meningococci, and is widely used and generally recognized as the serological 
correlate of protection.
 
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The following laboratory assays are planned:
Table 7
Humoral Immunity (Antibody determination)
System
Component
Method
Kit / Manufacturer
Unit*
Cut-off*
Laboratory
Humoral
Neisseria 
meningitidis
serogroup A
Serum 
Bactericidal 
Assay, using 
human 
complement
In house
1/Dilution
TBD
GSK Biologicals** 
or a laboratory 
designated by 
GSK Biologicals
Neisseria 
meningitidis
serogroup C
Neisseria 
meningitidis
serogroup W
Neisseria 
meningitidis
serogroup Y
TBD = to be determined
* For each of the indicator strains to be used in hSBA assays, assay cut-offs and unit will be determined following 
validation of the selected MenACWY hSBA format. This will be documented in the clinical report.
** GSK Biologicals laboratory refers to the Clinical Laboratory Sciences (CLS) in Rixensart, Belgium; Wavre, Belgium; 
or Marburg, Germany.
Additional exploratory testing on the vaccine and/or on the disease under study may be 
performed within the framework of the study if deemed necessary for accurate 
interpretation of the data or should such assay(s) become available at GSK. These assays 
may not be represented in the objectives/endpoints of the study protocol.
The GSK Biologicals’ clinical laboratories have established a Quality System supported 
by procedures. The activities of GSK Biologicals’ clinical laboratories are audited 
regularly for quality assessment by an internal (sponsor-dependent) but laboratory-
independent Quality Department.
5.7.4.
Biological samples evaluation
5.7.4.1.
Immunological read-outs
Table 8
Immunological read-outs
Blood sampling timepoint
No. subjects 
(planned)
Component
Components priority rank
Type of contact and 
timepoint
Sampling 
timepoint
Visit 1 (Day 1)
Pre-Vacc
~972
hSBA
MenA > MenC = MenY > 
MenW
Visit 2 (Day 29)
Post-Vacc
~972
hSBA
MenA > MenC = MenY > 
MenW
hSBA = human Serum Bactericidal Assay
 
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5.7.5.
Immunological correlates of protection
Although an hSBA titer ≥4 is an accepted correlate of protection against invasive 
meningococcal disease caused by N. meningitidis serogroup C, GSK Biologicals has 
historically used a more stringent immunological correlate (hSBA titer ≥8) for the 
definition of seroprotection against N. meningitidis.
Seropositivity cut-off or other hSBA titer values used to support ≥ 4-fold rise definitions 
may change following the generation of additional qualification/validation data as 
expected by Center for Biologicals Evaluation and Research (CBER) to support the 
intended use of the MenACWY hSBAs. The values of LLOQ and LOD for each 
serogroup will be defined at the time of the  generation of qualification and/or validation 
data.
The clinical endpoints used in this study are standard measures used routinely to estimate 
protection against meningococcal disease and have been previously agreed with CBER in 
the frame of Menveo licensure. The anticipated margin of the GMT ratio (lower limit of 
0.5 for the 95% CI of the GMT ratios between groups) for study success has previously 
been used in the demonstration of lot-to-lot consistency in pivotal Menveo trials in 
adolescents. 
The investigator is encouraged to share the immunological assay results for non-
responders with the study subjects/subjects’ parent(s)/LAR(s) at the end of the study, as 
soon as the results are available.
For the subjects identified as non-responders, it remains the responsibility of the 
investigator in charge of the subject’s clinical management to determine the medical need 
for re-vaccination and to re-vaccinate the subjects as per local/regional practices. Subjects 
who do not achieve a ≥ 4-fold rise in hSBA titers (according to the definition in the 
objectives) against any of the 4 serogroups at 1 month post-vaccination with the 
investigational MenACWY liquid vaccine will be offered one dose of a licensed 
quadrivalent MenACWY vaccine (preferably Menveo) after the end of the study and 
outside study procedures.
6.
STUDY VACCINES AND ADMINISTRATION
6.1.
Description of study vaccines
All candidate vaccines to be used have been developed and manufactured by GSK 
Biologicals.
The Quality Control Standards and Requirements for the candidate vaccine are described 
in separate Quality Assurance documents (e.g. release protocols, certificate of analysis) 
and the required approvals have been obtained. 
The vaccines are labelled and packed according to applicable regulatory requirements.
Commercial vaccine is assumed to comply with the specifications given in the 
manufacturer’s Summary of Product Characteristics.
 
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Table 9
Study vaccines
Treatment 
name
Vaccine/product 
name
Formulation
Presentation
Volume to be 
administered
Number 
of doses
MenACWY 
liquid with 
approximately 
30% MenA FS
MenACWY liquid
MenA=10µg CRM197; 
MenC=5µg CRM197; 
MenW=5µg CRM197; 
MenY=5µg CRM197; 
CRM197=25.4-65.8µg
Liquid in a 
monodose vial
0.5 ML
1
Licensed 
MenACWY
(Menveo)*
MenA lyo
MenA=10µg CRM197; 
CRM197=16.7-33.3µg
Lyophilized 
component in a 
vial
0.5 ml
1
MenCWY liquid
MenC=5µg CRM197; 
MenW=5µg CRM197; 
MenY=5µg CRM197; 
CRM197=16-30.8µg
Liquid 
component in a 
vial
* Menveo commercial formulation consisting of a MenA lyphophilized component and of a MenCWY liquid component 
to be reconstituted together before administration (0.5 mL)
6.2.
Storage and handling of study vaccines
The study vaccines must be stored at the respective label storage temperature conditions 
in a safe and locked place. Access to the storage space should be limited to authorized 
study personnel. The storage conditions will be assessed during pre-study activities under 
the responsibility of the sponsor study contact. The storage temperature should be 
continuously monitored with calibrated (if not validated) temperature monitoring 
device(s) and recorded. Refer to the Module on Clinical Trial Supplies in the SPM for 
more details on storage of the study vaccines.
Temperature excursions must be reported in degree Celsius.
Any temperature excursion outside the range of 2.0 to +8.0C (for +2 to +8°C/+36 to 
+46°F label storage condition) impacting investigational medicinal products (IMPs) must 
be reported in the appropriate (electronic) temperature excursion decision form 
(Advanced Temperature Excursion Analysis and Management [ATEAM]). The impacted 
IMPs must not be used and must be stored in quarantine at label temperature conditions 
until usage approval has been obtained from the sponsor.
Non-IMPs that are impacted by a temperature excursion may not be used and must be 
quarantined at label storage conditions until usage approval has been obtained from/via 
the local study contact (e.g. Site Monitor). There is no need for reporting via the (e)TDF.
Refer to the Module on Clinical Trial Supplies in the SPM for details and instructions on 
the temperature excursion reporting and usage decision process, packaging and 
accountability of the study vaccines.
 
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6.3.
Dosage and administration of study vaccines
Table 10
Dosage and administration
Type of contact 
and timepoint
Study group
Treatment 
name
Volume to be 
administered
Route1
Site
Location
Laterality2
Visit 1 (Day 1)
ACWY_Liq
MenACWY liquid 
with 
approximately 
30% MenA FS
0.5 ml
IM
Deltoid
Non-dominant
ACWY
Licensed 
MenACWY
(Menveo)*
1 Intramuscular (IM).
2 The non-dominant arm is the preferred arm of injection. In case it is not possible to administer the vaccine in the non-
dominant arm, an injection in the dominant arm may be performed.
* Menveo commercial formulation consisting of a MenA lyophilized component and of a MenCWY liquid component to 
be reconstituted together before administration (0.5mL). Please refer to the SPM for the preparation methods.
6.4.
Replacement of unusable vaccine doses
In addition to the vaccine doses provided for the planned number of subjects (including 
over-randomization when applicable), at least 30% additional vaccine doses will be 
supplied to replace those that are unusable. 
The investigator will use SBIR to obtain the replacement vial number. The replacement 
numbers will be allocated by dose. The system will ensure, in a blinded manner, that the 
replacement vial matches the formulation the subject was assigned to by randomization.
6.5.
Contraindications to vaccination
The following events constitute contraindications to administration of the investigational 
MenACWY liquid vaccine and the licensed MenACWY vaccine at that point in time; if 
any of these events occur at the time scheduled for vaccination, the subject may be 
vaccinated at a later date, within the time window specified in the protocol (see Section 
5.5), or the subject may be withdrawn at the discretion of the investigator (see Section 
8.5). 

Acute disease and/or fever within 3 days prior to study vaccination. 
−
Fever is defined as body temperature 38.0°C/100.4°F. The preferred location 
for measuring temperature in this study will be the oral cavity.
−
Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory 
infection) without fever can be administered all vaccines.
6.6.
Warnings and precautions
Refer to the approved product label/package insert for Menveo.
 
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6.7.
Concomitant medications/products and concomitant 
vaccinations
At each study visit and at Phone call 1, the investigator or delegate should question the 
subject/subjects’ parent(s)/LAR(s) about any medications/products taken and 
vaccinations received by the subject.
6.7.1.
Recording of concomitant medications/products and 
concomitant vaccinations
The following concomitant medication(s)/product(s)/vaccine(s) must be recorded in 
the eCRF.

All concomitant medications/products, except vitamins and dietary supplements, 
administered during the period of 28 days following the dose of study vaccine (Day 
1 to Day 29).

Any concomitant vaccination administered in the period starting 14 days before the 
dose of study vaccine and ending at Day 29.

Prophylactic medication (i.e. medication administered in the absence of ANY 
symptom and in anticipation of a reaction to the vaccination).
E.g. an anti-pyretic is considered to be prophylactic when it is given in the absence 
of fever and any other symptom, to prevent fever from occurring (fever is defined as 
body temperature 38.0°C/100.4°F regardless the location of measurement). The 
preferred location for measuring temperature in this study will be the oral cavity.

Any concomitant medications/products/vaccines listed in Section 6.7.2.

During the follow-up period, after Day 29 until the last safety phone call, any 
concomitant medications/products/vaccines relevant to a SAE, an AE/SAE leading 
to withdrawal or to an AE requiring a medically attended visit to be reported as per 
protocol. In addition, concomitant medications relevant to SAEs need to be recorded 
on the expedited Adverse Event report.
6.7.2.
Concomitant medications/products/vaccines that may lead to the 
elimination of a subject from per-protocol analyses
The use of the following concomitant medications/products/vaccines will not require 
withdrawal of the subject from the study but may determine a subject’s evaluability in the 
per-protocol analysis. See Section 10.4 for analyses sets to be analysed.

Any investigational or non-registered product (drug or vaccine) other than the study 
vaccines used during the study period. 

Immunosuppressants or other immune-modifying drugs defined as follows:
−
Systemic administration of corticosteroids (PO/IV/IM) within 90 days prior to 
informed consent, and until the Day 29 blood draw.

Administration of antineoplastic and immunomodulating agents or radiotherapy 
within 90 days prior to informed consent, and until the Day 29 blood draw.
 
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
Long-acting immune-modifying drugs administered at any time during the study 
period (e.g. infliximab).

Other vaccines within 7 days (for inactivated vaccines) or 14 days (for live vaccines) 
prior to enrollment in this study or any planned vaccination within 28 days from the 
study vaccines*.  
* In case an emergency mass vaccination for an unforeseen public health threat (e.g.: 
a pandemic) is organized by the public health authorities, outside the routine 
immunization program, the time period described above can be reduced if necessary 
for that vaccine provided it is licensed and used according to its Summary of Product 
Characteristics (SmPC) or Prescribing Information and according to the local 
governmental recommendations and provided a written approval of the Sponsor is 
obtained.

Immunoglobulins and/or any blood products administered during the study period.

Systemic antibiotics within 3 days prior to any blood draw.
6.8.
Intercurrent medical conditions that may lead to elimination 
of a subject from per-protocol analyses
At each study visit/phone call subsequent to the vaccination visit, it must be verified if 
the subject has experienced or is experiencing any intercurrent medical condition. If it is 
the case, the condition(s) must be recorded in the eCRF.
Subjects may be eliminated from the per-protocol set for immunogenicity if, during the 
study period up to Day 29, they incur a condition that has the capability of altering their 
immune response (i.e. confirmed immunosuppressive or immunodeficient condition, 
including HIV) or are confirmed to have an alteration of their initial immune status.
7.
HEALTH ECONOMICS
Not applicable.
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 adverse event (AE) or serious 
adverse event (SAE) as provided in this protocol. 
Each subject/subjects’ parent(s)/LAR(s) will be instructed to contact the investigator 
immediately should they manifest any signs or symptoms they perceive as serious.
 
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8.1.
Safety definitions
8.1.1.
Definition of an adverse event
An AE is any untoward medical occurrence in a clinical investigation subject, temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.
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. 
Examples of an AE include:

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study vaccines administration even 
though they may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
vaccines or a concurrent medication (overdose per se should not be reported as an 
AE/SAE).

Signs, symptoms temporally associated with study vaccines.

Significant failure of expected pharmacological or biological action. 

Pre- or post-treatment events that occur as a result of protocol-mandated procedures 
(i.e. invasive procedures, modification of subject’s previous therapeutic regimen).
AEs to be recorded as endpoints (solicited AEs) are described in Section 8.1.3. All other 
AEs will be recorded as UNSOLICITED AEs.
Examples of an AE DO NOT include:

Medical or surgical procedures (e.g. endoscopy, appendectomy); the condition that 
leads to the procedure is an AE/SAE.

Situations where an untoward medical occurrence did not occur (e.g. social and/or 
convenience admission to a hospital, admission for routine examination).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 

Pre-existing conditions or signs and/or symptoms present in a subject prior to the 
study vaccination. These events will be recorded in the medical history section of the 
eCRF.
 
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8.1.2.
Definition of a serious adverse event 
A 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 hospitalization or prolongation of existing hospitalization,
Note: In general, hospitalization 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 hospitalization are also considered AEs. If a complication prolongs 
hospitalization or fulfils any other serious criteria, the event will also be considered 
serious. When in doubt as to whether ‘hospitalization’ occurred or was necessary, the 
AE should be considered serious.
Hospitalization 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 AE.
d.
Results in disability/incapacity, OR
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.
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 hospitalization but may jeopardize 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 hospitalization.
8.1.3.
Solicited adverse events
The term “reactogenicity” refers to solicited signs and symptoms (“solicited adverse 
events”) occurring in the hours and days following a vaccination, to be collected by the 
subjects/parents/LARs for 7 consecutive days (6 hours  - Day 7), using a pre-defined 
Subject Diary. Solicited adverse events continuing beyond Day 7 should continue to be 
recorded in the eDiary until resolution or next visit.
 
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The following solicited adverse events are included in the Subject Diary. Each adverse 
event is to be assessed using the scoring system reported in parentheses below: 
8.1.3.1.
Solicited Local Adverse Events

Induration at injection site 

Erythema at injection site 

Pain at injection site 
8.1.3.2.
Solicited Systemic Adverse Events

Fever (body temperature ≥38.0°C/100.4°F)

Chills

Nausea 

Myalgia 

Arthralgia 

Headache

Fatigue 

Loss of appetite 
Body temperature will be collected daily (Day 1 - Day 7). The preferred location for 
measuring temperature in this study will be the oral cavity.
8.1.3.3.
Other Solicited Adverse Events
Other indicators of reactogenicity:

Use of analgesics / antipyretics for treatment;

Use of analgesics / antipyretics for prophylaxis; 
The study staff must review the data entered into the Subject Diary as described in 
Section 11.2.
Note: Any solicited adverse event that meets any of the following criteria must be entered 
into subjects’ source document (see Section 11.2) and also as an adverse event on the 
Adverse Event CRF:

Solicited local or systemic adverse event that leads to a visit to a healthcare provider 
(medically attended adverse event, see Section 8.3.3.4).

Solicited local or systemic adverse event leading to the subject withdrawing from the 
study or the subject being withdrawn from the study by the investigator (adverse 
event leading to withdrawal).

Solicited local or systemic adverse event that otherwise meets the definition of a 
serious adverse event (see Section 8.1.2).
 
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8.1.4.
Unsolicited Adverse Events
An unsolicited adverse event is an adverse event that was not solicited using a Subject 
Diary and that was spontaneously communicated by a subject/parent(s)/LAR(s) who has 
signed the informed consent.
Potential unsolicited AEs may be medically attended (defined as symptoms or illnesses 
requiring hospitalization, or emergency room visit, or visit to/by a health care provider), 
or were of concern to the subjects/parents/LARs. In case of such events, 
subjects/parents/LARs will be instructed to contact the site as soon as possible to report 
the event(s). The detailed information about the reported unsolicited AEs will be 
collected by the qualified site personnel during the interview and will be documented in 
the subject’s records.
Unsolicited AEs that are not medically attended nor perceived as a concern by 
subjects/parents/LARs will be collected during interview with the subjects/parents/LARs
and by review of available medical records at the next visit.
8.1.5.
Clinical laboratory parameters and other abnormal assessments 
qualifying as adverse events or serious adverse events 
In absence of diagnosis, abnormal laboratory findings (e.g. clinical chemistry, 
haematology, urinalysis) or other abnormal assessments (e.g. clinical signs, ECG, 
radiological or diagnostic assessments) that are judged by the investigator to be clinically 
significant will be recorded as AE or SAE if they meet the definition of an AE or SAE 
(refer to Sections 8.1.1 and 8.1.2). Clinically significant abnormal laboratory findings or 
other abnormal assessments that are present at baseline and significantly worsen 
following the start of the study will also be reported as AEs or SAEs. However, clinically 
significant abnormal laboratory findings or other abnormal assessments that are present 
or detected at the start of the study and do not worsen, will not be reported as AEs or 
SAEs.
The investigator will exercise his or her medical and scientific judgement in deciding 
whether an abnormal laboratory finding or other abnormal assessment is clinically 
significant.
 
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8.2.
Events or outcomes not qualifying as adverse events or 
serious adverse events 
8.2.1.
Pregnancy
Female subjects who become pregnant after the vaccination may continue the study at the 
discretion of the investigator.
While pregnancy itself is not considered an AE or SAE, any adverse pregnancy outcome 
or complication or elective termination of a pregnancy for medical reasons will be 
recorded and reported as an AE or a SAE.
Note: The pregnancy itself should always be recorded on an electronic pregnancy report.
The following should always be considered as SAE and will be reported as described in 
Sections 8.4.1 and 8.4.3:

Spontaneous pregnancy loss, including:
−
spontaneous abortion, (spontaneous pregnancy loss before/at 22 weeks of 
gestation)
−
ectopic and molar pregnancy
−
stillbirth (intrauterine death of foetus after 22 weeks of gestation).
Note: the 22 weeks cut-off in gestational age is based on WHO-ICD 10 noted in the 
EMA Guideline on pregnancy exposure [EMA, 2006]. It is recognized that national 
regulations might be different.

Any early neonatal death (i.e. death of a live born infant occurring within the first 7 
days of life). 

Any congenital anomaly or birth defect (as per [CDC MACDP] guidelines) 
identified in the offspring of a study subject (either during pregnancy, at birth or 
later) regardless of whether the foetus is delivered dead or alive. This includes 
anomalies identified by prenatal ultrasound, amniocentesis or examination of the 
products of conception after elective or spontaneous abortion.
Furthermore, any SAE occurring as a result of a post-study pregnancy AND considered 
by the investigator to be reasonably related to the study vaccines will be reported to GSK 
Biologicals as described in Section 8.4.3. While the investigator is not obligated to 
actively seek this information from former study participants, he/she may learn of a 
pregnancy through spontaneous reporting.
 
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8.3.
Detecting and recording adverse events, serious adverse 
events and pregnancies
8.3.1.
Time period for detecting and recording adverse events, serious 
adverse events and pregnancies
All AEs starting within 28 days following administration of the dose of study vaccine 
(Day 1 to Day 29) must be recorded into the appropriate section of the eCRF, irrespective 
of intensity or whether or not they are considered vaccination-related.
The time period for collecting and recording SAEs, AEs/SAEs leading to withdrawal 
from the study, and medically-attended AEs and SAEs will begin at the receipt of study 
vaccine and will end 180 days following administration of the dose of study vaccine for 
each subject (at the contact at Day 181). See Section 8.4 for instructions on reporting of 
SAEs.
All AEs/SAEs leading to withdrawal from the study will be collected and recorded from 
the time of the receipt of study vaccine(s)/ product(s).
In addition to the above-mentioned reporting requirements and in order to fulfil 
international reporting obligations, SAEs that are related to study participation (i.e. 
protocol-mandated procedures, invasive tests, a change from existing therapy) or are 
related to a concurrent GSK medication/vaccine will be collected and recorded from the 
time the subject consents to participate in the study until she/he is discharged from the 
study.
The time period for collecting and recording pregnancies will begin at the receipt of study 
vaccine and will end 181 days following administration of the dose of study vaccine. See 
section 8.4 for instructions on reporting of pregnancies.
An overview of the protocol-required reporting periods for AEs, SAEs, and pregnancies  
is given in Table 11.
 
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Table 11
Reporting periods for collecting safety information
V1
Phone 
call 1
V2
Phone 
call 2
Phone call 
3 Study 
Conclusion
D1
D7
D15
D29
D91
D181
Solicited local 
and systemic 
AEs
Unsolicited AEs
AEs/SAEs 
leading to 
withdrawal from 
the study
Medically-
attended AEs, 
SAEs 
SAEs related to 
the study vaccine
SAEs related to 
study participation 
or concurrent GSK 
medication/vaccine 
Pregnancies 
V = visit; D = Day; AE = adverse event; SAE = serious adverse event. 
8.3.2.
Post-Study adverse events and serious adverse events
A post-study AE/SAE is defined as any event that occurs outside of the AE/SAE 
reporting period defined in Table 11. Investigators are not obligated to actively seek AEs 
or SAEs in former study participants. However, if the investigator learns of any SAE at 
any time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the study vaccines, the investigator will promptly notify the 
Study Contact for Reporting SAEs.
 
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8.3.3.
Evaluation of adverse events and serious adverse events
8.3.3.1.
Active questioning to detect adverse events and serious adverse 
events
As a consistent method of collecting AEs, the subject or the subjects’ parent(s)/LAR(s)
be asked a non-leading question such as:
‘Have you felt different in any way since receiving the vaccines or since the previous 
visit?’
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g. hospital progress notes, laboratory and diagnostics reports) relative 
to the event. The investigator will then record all relevant information regarding an 
AE/SAE on the in the eCRF. The investigator is not allowed to send photocopies of the 
subject’s medical records to GSK Biologicals instead of appropriately completing the
eCRF. However, there may be instances when copies of medical records for certain cases 
are requested by GSK Biologicals. In this instance, all subject identifiers will be blinded 
on the copies of the medical records prior to submission to GSK Biologicals.
 
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8.3.3.2.
Assessment of adverse events
8.3.3.2.1.
Assessment of intensity
The intensity of the following solicited AEs will be assessed as described:
Table 12
Intensity scales for solicited AEs 
Adverse Event
Intensity grade
Parameter
Fever*
Record temperature in °C/°F
Induration at injection site
Record greatest surface diameter in mm
Erythema at injection site
Record greatest surface diameter in mm
Pain at injection site
Absent
None
Mild
No interference with daily activity
Moderate
Interferes with daily activity
Severe
Prevents daily activity
Chills
Absent
Normal
Mild
No interference with daily activity
Moderate
Interferes with daily activity
Severe
Prevents daily activity
Nausea
Absent
Normal
Mild
No interference with daily activity
Moderate
Interferes with daily activity
Severe
Prevents daily activity
Myalgia
Absent
Normal
Mild
No interference with daily activity
Moderate
Interferes with daily activity
Severe
Prevents daily activity
Arthralgia
Absent
Normal
Mild
No interference with daily activity
Moderate
Interferes with daily activity
Severe
Prevents daily activity
Headache
Absent
Normal
Mild
No interference with daily activity
Moderate
Interferes with daily activity
Severe
Prevents daily activity
Fatigue
Absent
Normal
Mild
No interference with daily activity
Moderate
Interferes with daily activity
Severe
Prevents daily activity
Loss of appetite
Absent
Normal
Mild
Eating less than usual with no effect on normal activity
Moderate
Eating less than usual / interfered with normal activity
Severe
Not eating at all
* Fever is defined as temperature 38.0°C/100.4°F. preferred location for measuring temperature in this study will be 
the oral cavity.
The maximum intensity of local injection site erythema/induration will be scored at GSK 
Biologicals as follows:
Absent: < 25 mm diameter
Mild: 25 mm to 50 mm diameter
Moderate: > 50 mm to 100 mm diameter
Severe: > 100 mm diameter
 
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Body temperature will be summarized separately according to the 3 schemes described
below and will be broken down according to route of measurement: 

by 0.5 °C increments from 36.0°C up to ≥40°C;

by 1°C increments: <36.0, 36.0-36.9, 37.0-37.9, 38.0-38.9, 39.0-39.9, ≥40°C;

According to different cut-offs (< versus ≥): 38.0, 38.5, 39.0, 39.5, 40.0°C.
The investigator will assess the maximum intensity that occurred over the duration of the 
event for all unsolicited AEs (including SAEs) recorded during the study. The assessment 
will be based on the investigator’s clinical judgement.
Adverse events, reported at a clinic visit or at a scheduled safety call, should be recorded 
in the eCRF verbatim, as reported by the subject. 
The severity of unsolicited adverse events reported on the Adverse Events eCRF will be 
determined by the investigator as:
Mild: transient with no limitation in normal daily activity.
Moderate: some limitation in normal daily activity.
Severe: unable to perform normal daily activity.
8.3.3.2.2.
Assessment of causality
The investigator is obligated to assess the relationship between study vaccines and the 
occurrence of each AE/SAE using clinical judgement. In case of concomitant 
administration of multiple vaccines/products, if possible, the investigator should specify 
if the AE could be causally related to a specific vaccine/product administered (i.e. 
investigational, control/placebo or co-administered vaccine). When causal relationship to 
a specific vaccine(s)/product(s) cannot be determined the investigator should indicate the 
AE to be related to all products.
Alternative plausible causes, such as natural history of the underlying diseases, 
concomitant therapy, other risk factors, and the temporal relationship of the event to the 
study vaccines will be considered and investigated. The investigator will also consult the 
IB and/or SmPC and/or Prescribing Information for marketed products to determine 
his/her assessment.
There may be situations when a SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK Biologicals. However, it is very 
important that the investigator always makes an assessment of causality for every event 
prior to submission of the Expedited Adverse Events Report to GSK Biologicals. The 
investigator may change his/her opinion of causality in light of follow-up information and 
update the SAE information accordingly. The causality assessment is one of the criteria 
used when determining regulatory reporting requirements.
 
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All solicited reactions will be considered causally related to vaccination. Causality of all 
other AEs should be assessed by the investigator using the following question:
Is there a reasonable possibility that the AE may have been caused by the study vaccine?
YES
:
There is a reasonable possibility that the study vaccine contributed 
to the AE. 
NO
:
There is no reasonable possibility that the AE is causally related to 
the administration of the study vaccine. There are other, more 
likely causes and administration of the study vaccine is not 
suspected to have contributed to the AE.
If an event meets the criteria to be determined as ‘serious’ (see Section 8.1.2), additional 
examinations/tests will be performed by the investigator in order to determine ALL 
possible contributing factors for each SAE.
Possible contributing factors include:

Medical history.

Other medication.

Protocol required procedure.

Other procedure not required by the protocol.

Lack of efficacy of the vaccine, if applicable.

Erroneous administration.

Other cause (specify).
8.3.3.3.
Assessment of outcomes
The investigator will assess the outcome of all unsolicited AEs (including SAEs) 
recorded during the study as:

Recovered/resolved.

Recovering/resolving.

Not recovered/not resolved.

Recovered with sequelae/resolved with sequelae.

Fatal (SAEs only).
8.3.3.4.
Medically attended visits
For each solicited and unsolicited symptom the subject experiences, the subject/subjects’ 
parent(s)/LAR(s) will be asked if he/she received medical attention defined as 
hospitalization, or an otherwise unscheduled visit to or from medical personnel for any 
reason, including emergency room visits. This information will be recorded in the eCRF.
 
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8.4.
Reporting of serious adverse events, pregnancies, and 
other events
8.4.1.
Prompt reporting of serious adverse events, pregnancies, and 
other events to GSK Biologicals
SAEs that occur in the time period defined in Section 8.3 will be reported promptly to 
GSK within the timeframes described in Table 13, once the investigator determines that 
the event meets the protocol definition of a SAE.
Pregnancies that occur in the time period defined in Section 8.3 will be reported promptly 
to GSK within the timeframes described in Table 13, once the investigator becomes 
aware of the pregnancy. 
Table 13
Timeframes for submitting serious adverse event, pregnancy and 
other events reports to GSK Biologicals
Type of Event
Initial Reports
Follow-up of Relevant Information on a 
Previous Report
Timeframe
Documents
Timeframe
Documents
SAEs
24 hours* ‡
electronic Expedited 
Adverse Events Report
24 hours*
electronic Expedited Adverse 
Events Report
Pregnancies 
2 weeks*
electronic pregnancy report 
2 weeks*
electronic pregnancy report
* Timeframe allowed after receipt or awareness of the information.
‡ The investigator will be required to confirm review of the SAE causality by ticking the ‘reviewed’ box in the electronic 
Expedited Adverse Events Report within 72 hours of submission of the SAE.
8.4.2.
Contact information for reporting serious adverse events and 
pregnancies
Study Contact for Reporting SAEs and pregnancies
Refer to the local study contact information document.
Back-up Study Contact for Reporting SAEs and pregnancies 
24/24 hour and 7/7 day availability:
GSK Biologicals Clinical Safety & Pharmacovigilance
Outside US & Canada sites:
Fax: 
 or 
Email address: 
US sites only:
Fax: 
Canadian sites only:
Fax: 
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PPD
PPD
PPD
PPD

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8.4.3.
Completion and transmission of SAE reports to GSK Biologicals
Once an investigator becomes aware that a SAE has occurred in a study subject, the 
investigator (or designate) must complete the information in the electronic Expedited 
Adverse Events Report WITHIN 24 HOURS. The report will always be completed as 
thoroughly as possible with all available details of the event. Even if the investigator does 
not have all information regarding a SAE, the report should still be completed within 24
hours. Once additional relevant information is received, the report should be updated 
WITHIN 24 HOURS.
The investigator will always provide an assessment of causality at the time of the initial 
report. The investigator will be required to confirm the review of the SAE causality by 
ticking the ‘reviewed’ box in the electronic Expedited Adverse Events Report within 72 
hours of submission of the SAE.
8.4.3.1.
Back-up system in case the electronic reporting system does not work
If the electronic reporting system does not work, the investigator (or designate) must 
complete, then date and sign a paper Expedited Adverse Events Report and fax it to the 
Study Contact for Reporting SAEs (refer to the Sponsor Information) or to GSK 
Biologicals Clinical Safety and Pharmacovigilance department within 24 hours. 
This back-up system should only be used if the electronic reporting system is not working 
and NOT if the system is slow. As soon as the electronic reporting system is working 
again, the investigator (or designate) must complete the electronic Expedited Adverse 
Events Report within 24 hours. The final valid information for regulatory reporting will 
be the information reported through the electronic SAE reporting system. 
8.4.4.
Completion and transmission of pregnancy reports to GSK 
Biologicals
Once the investigator becomes aware that a subject is pregnant, the investigator (or 
designate) must complete the required information onto the electronic pregnancy report 
WITHIN 2 WEEKS.
Note: Conventionally, the estimated gestational age (EGA) of a pregnancy is dated from 
the first day of the last menstrual period (LMP) of the cycle in which a woman conceives. 
If the LMP is uncertain or unknown, dating of EGA and the estimated date of delivery 
(EDD) should be estimated by ultrasound examination and recorded in the pregnancy 
report.
 
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8.4.5.
Updating of SAE and pregnancy information after removal of 
write access to the subject’s eCRF
When additional SAE or pregnancy information is received after removal of the write 
access to the subject’s eCRF, new or updated information should be recorded on the 
appropriate paper report, with all changes signed and dated by the investigator. The 
updated report should be faxed to the Study Contact for Reporting SAEs (refer to the 
Sponsor Information) or to GSK Biologicals Clinical Safety and Pharmacovigilance 
department within the designated reporting time frames specified in Table 13.
8.4.6.
Regulatory reporting requirements for serious adverse events
The investigator will promptly report all SAEs to GSK in accordance with the procedures 
detailed in Section 8.4.1. GSK Biologicals has a legal responsibility to promptly notify, 
as appropriate, both the local regulatory authority and other regulatory agencies about the 
safety of a product under clinical investigation. Prompt notification of SAEs by the 
investigator to the Study Contact for Reporting SAEs is essential so that legal obligations 
and ethical responsibilities towards the safety of other subjects are met.
Investigator safety reports are prepared according to the current GSK policy and are 
forwarded to investigators as necessary. An investigator safety report is prepared for a 
SAE(s) that is both attributable to the study vaccines and unexpected. The purpose of the 
report is to fulfil specific regulatory and GCP requirements, regarding the product under 
investigation.
8.5.
Follow-up of adverse events, serious adverse events, and 
pregnancies
8.5.1.
Follow-up of adverse events and serious adverse events 
8.5.1.1.
Follow-up during the study
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject and provide additional relevant information on the subject’s condition to GSK 
Biologicals (within 24 hours for SAEs; refer to Table 13).
All SAEs documented at a previous visit/contact and designated as not recovered/not 
resolved or recovering/resolving will be reviewed at subsequent visits/contacts until the 
last visit of the subject.
All AEs documented at a previous visit/contact and designated as not recovered/not 
resolved or recovering/resolving will be reviewed at subsequent visits/contacts until 30 
days after the last vaccination.
 
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8.5.1.2.
Follow-up after the subject is discharged from the study
The investigator will follow subjects:

with SAEs, or subjects withdrawn from the study as a result of an AE, until the event 
has resolved, subsided, stabilised, disappeared, or until the event is otherwise 
explained, or the subject is lost to follow-up. 
If the investigator receives additional relevant information on a previously reported SAE, 
he/she will provide this information to GSK Biologicals using a paper/ electronic 
Expedited Adverse Events Report and/or pregnancy report as applicable.
GSK Biologicals may request that the investigator performs or arranges the conduct of 
additional clinical examinations/tests and/or evaluations to elucidate as fully as possible 
the nature and/or causality of the AE or SAE. The investigator is obliged to assist. If a 
subject dies during participation in the study or during a recognized follow-up period, 
GSK Biologicals will be provided with any available post-mortem findings, including 
histopathology.
8.5.2.
Follow-up of pregnancies
Pregnant subjects will be followed to determine the outcome of the pregnancy. At the end 
of the pregnancy, whether full-term or premature, information on the status of the mother 
and child will be forwarded to GSK Biologicals using the electronic pregnancy report and 
the Expedited Adverse Events Report if applicable. Generally, the follow-up period 
doesn’t need to be longer than six to eight weeks after the estimated date of delivery.
Regardless of the reporting period for SAEs for this study, if the pregnancy outcome is a 
SAE, it should always be reported as SAE.
8.6.
Treatment of adverse events
Treatment of any AE is at the sole discretion of the investigator and according to current 
good medical practice. Any medication administered for the treatment of a SAE should 
be recorded in Expedited Adverse Event Report of the subject’s eCRF (refer to Section 
6.7).
8.7.
Unblinding
GSK Biologicals’ policy (which incorporates ICH E2A guidance, EU Clinical Trial 
Directive and US Federal Regulations) is to unblind the report of any SAE which is 
unexpected and attributable/suspected to be attributable to the study vaccines, prior to 
regulatory reporting. The GSK Biologicals’ Central Safety Physician is responsible for 
unblinding the treatment assignment in accordance with the specified timeframes for 
expedited reporting of SAEs (refer to Section 8.4.1).
 
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8.8.
Emergency unblinding
Unblinding of a subject’s individual treatment code should occur only in the case of a 
medical emergency, or in the event of a serious medical condition, when knowledge of 
the treatment is essential for the clinical management or welfare of the subject, as judged 
by the investigator.
The emergency unblinding process consists of the automated system SBIR that allows the 
investigator to have unrestricted, immediate and direct access to the subject’s individual 
study treatment.
The investigator has the option of contacting a GSK Biologicals’ On-call Central Safety 
Physician (or Backup) if he/she needs medical advice or needs the support of GSK to 
perform the unblinding (i.e. he/she cannot access the automated Internet-based system).
Any emergency unblinding must be fully documented by using the Emergency 
Unblinding Documentation Form, which must be appropriately completed by the 
investigator and sent within 24 hours to GSK Biologicals.
GSK Biologicals’ Contact information for Emergency Unblinding
24/24 hour and 7/7 day availability
GSK Biologicals’ Central Safety Physician:
Outside US/Canada:
 (GSK Biologicals Central Safety Physician on-call)
For US/Canada only:
 (GSK Biologicals Central Safety Physician on-call)
GSK Biologicals’ Central Safety Physician Back-up:
Outside US/Canada:
US/Canada only:
Emergency Unblinding Documentation Form transmission:
Outside US & Canada:
Fax: 
 or 
US/Canada only:
Fax: 
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PPD
PPD
PPD
PPD
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PPD

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8.9.
Subject card
Study subjects/subjects’ parent(s)/LAR(s) must be provided with the address and 
telephone number of the main contact for information about the clinical study.
The investigator (or designate) must therefore provide a “subject card” to each 
subject/subjects’ parent(s)/LAR(s). In an emergency situation this card serves to inform 
the responsible attending physician that the subject is in a clinical study and that relevant 
information may be obtained by contacting the investigator.
Subjects/subjects’ parent(s)/LAR(s) must be instructed to keep subject cards in their 
possession at all times during the study duration.
9.
SUBJECT COMPLETION AND WITHDRAWAL
9.1.
Subject completion
A subject who is available for the concluding contact foreseen in the protocol is 
considered to have completed the study.
9.2.
Subject withdrawal
Withdrawals will not be replaced.
9.2.1.
Subject withdrawal from the study
From an analysis perspective, a ‘withdrawal’ from the study refers to any subject who 
was not available for the concluding contact foreseen in the protocol. 
All data collected until the date of withdrawal/last contact of the subject will be used for 
the analysis.
A subject is considered a ‘withdrawal’ from the study when no study procedure has 
occurred, no follow-up has been performed and no further information has been collected 
for this subject from the date of withdrawal/last contact.
Investigators will make an attempt (3 telephone calls on different days and different times 
of day, and a certified letter to the last known address) to contact those subjects who do 
not return for scheduled visits or follow-up. 
Information relative to the withdrawal will be documented in the eCRF. The investigator 
will document whether the decision to withdraw a subject from the study was made by 
the subject himself/herself, by the subjects’ parent(s)/LAR(s), or by the investigator, as 
well as which of the following possible reasons was responsible for withdrawal:

Serious adverse event.

Unsolicited non-serious adverse event.
 
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
Solicited adverse event

Protocol violation (specify).

Consent withdrawal, not due to an adverse event*.

Moved from the study area.

Lost to follow-up.

Other (specify).
*In case a subject is withdrawn from the study because he/she/the subjects’ 
parent(s)/LAR(s) has withdrawn consent, the investigator will document the reason for 
withdrawal of consent, if specified by the subject/subjects’ parent(s)/LAR(s), in the 
eCRF.
Subjects who are withdrawn from the study because of SAEs/AEs must be clearly 
distinguished from subjects who are withdrawn for other reasons. Investigators will 
follow subjects who are withdrawn from the study as result of a SAE/AE until resolution 
of the event (see Section 8.5.1.2).
10.
STATISTICAL METHODS
10.1.
Primary endpoint
The following measures will be summarized:

hSBA GMTs against N. meningitidis serogroup A at Day 29, for each vaccine group 
and between-group ratios.
10.2.
Secondary endpoints
The following measures will be summarized:

hSBA GMTs against N. meningitidis serogroups A (except Day 29), C, W and Y at 
Day 1 and at Day 29, for each vaccine group and between-group ratios.

Within-group ratios of hSBA GMTs against N. meningitidis serogroups A, C, W and 
Y at Day 29 compared to Day 1.

Percentages of subjects with a ≥ 4-fold rise in post-vaccination hSBA titer for N. 
meningitidis serogroups A, C, W and Y at Day 29 compared to Day 1, for each 
vaccine group and between-group differences.
Note: A 4-fold rise is defined as:  a) for individuals whose pre-vaccination titers are 
< the LOD, the post-vaccination titers must be ≥ 4-fold the LOD or ≥ the LLOQ 
whichever is greater; b) for individuals whose pre-vaccination titers are ≥ the LOD 
and ≤ the LLOQ, the post-vaccination titers must be at least four times the LLOQ; c) 
for individuals whose pre-vaccination titers are > the LLOQ, the post-vaccination 
titers must be at least four times the pre-vaccination titer.
 
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
Percentages of subjects with hSBA titer ≥8 and ≥LLOQ* against N. meningitidis
serogroups A, C, W and Y at Day 1 and at Day 29, for each vaccine group and 
between-group differences.
* Note: To be assessed for each serogroup if the pre-defined LLOQ value for that 
serogroup is >8.
Safety of the study vaccine formulations will be evaluated for all vaccine groups in terms 
of the frequency (percentage) of reported adverse events including: 

Any unsolicited AEs reported within 30 minutes after vaccination;

Solicited local and systemic AEs reported from Day 1 (6 hours) through Day 7 after 
vaccination;

Other indicators of reactogenicity (e.g. use of analgesics / antipyretics, body 
temperature) within 7 days after vaccination;

All unsolicited AEs reported from Day 1 through Day 29 after vaccination; 

Medically-attended AEs, AEs leading to withdrawal and SAEs reported from Day 1 
through Day 181 (during the entire study period).
10.3.
Determination of sample size
With an evaluable sample size of 437 subjects in each group, there will be approximately 
90% power to reject the null hypothesis that the ratio of the hSBA GMT of the 
ACWY_Liq to the ACWY group is equal to or less than 0.5 (given an underlying ratio of 
0.8), assuming a common standard deviation (on log scale) of 0.929 (upper limit of the 
80% confidence interval of the SD observed in study V59P13 for serogroup A in the age 
group 19–55 years), using a two group t-test with a 0.025 one-sided significance level.
Assuming a 10% dropout rate, a total of approximately 972 subjects will need to be 
enrolled in the study, with approximately 486 subjects randomized to each group 
(ACWY and ACWY_Liq). Calculations have been performed using “Two-Sample T-Test 
Assuming Equal Variance (Enter Difference)” procedure in PASS 2012 (Power Analysis 
and Sample Size Version 12.0.2).
10.4.
Analysis Sets
10.4.1.
All Enrolled Set
All screened subjects who provide informed consent and provide demographic and/or 
baseline screening assessments, regardless of the subject’s randomization and treatment 
status in the study and received a Subject ID.
10.4.2.
All Exposed Set
All subjects in the enrolled set who receive a study vaccination.
 
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10.4.3.
Safety Set
10.4.3.1.
Solicited Safety Set (solicited local and systemic adverse events and 
other solicited adverse events)
All subjects in the Exposed Set with any solicited adverse event data.
10.4.3.2.
Unsolicited Safety Set (unsolicited adverse events)
All subjects in the Exposed Set with unsolicited adverse event data.
10.4.3.3.
Overall Safety Set
All subjects who are in the Solicited Safety Set and/or Unsolicited Safety Set.
Subjects will be analyzed as “treated” (i.e., according to the vaccine a subject received, 
rather than the vaccine to which the subject may have been randomized).
10.4.4.
Full Analysis Set (FAS) Immunogenicity Set
FAS (Day 29)
All subjects in the All Enrolled Set who:

are randomized;

receive the study vaccination;

provide an evaluable serum sample at Day 29 that has an available result for 
serogroup A (primary objective)/ for at least one serogroup (secondary objectives). 
For percentages of subjects with a ≥ 4-fold rise, a baseline (Day 1) and a Day 29 
result for at least one serogroup will be needed.
In case of vaccination error, subjects in the FAS sets will be analyzed “as randomized” 
(i.e., according to the vaccine a subject was designated to receive, which may be different 
from the vaccine the subject actually received).
10.4.5.
Per Protocol (PP) Set for Immunogenicity Set
PPS (Day 29): All subjects in the FAS (Day 29) who:

correctly receive the vaccine (i.e., receive the vaccine to which the subjects is 
randomized and at the scheduled time point).

have no protocol deviations leading to exclusion as defined prior to unblinding.

are not excluded due to other reasons defined prior to unblinding.
PPS are subsets of FAS and should be always defined even if the objectives do not 
require it.
 
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Examples for subjects excluded due to other reasons than protocol deviations are:

Subjects who withdrew informed consent.
10.4.6.
Other Analysis Sets
There are no additional analysis sets.
10.4.7.
Subgroups
A subgroup analysis for GMTs, percentage of subjects with hSBA titer ≥8 and ≥LLOQ* 
against N. meningitidis serogroups A, C, W and Y at Day 29, will be performed for 
subjects who were seronegative at baseline. 
In addition, subgroup analyses will be performed for GMTs, 4-fold rise, percentage of 
subjects with hSBA titer ≥8 and ≥LLOQ* by sex, by race, and by country.
* Note: To be assessed for each serogroup if the pre-defined LLOQ value for that 
serogroup is > 8.
10.5.
Derived and transformed data

Immunogenicity
−
Assay cut-off and unit will be determined following validation of the 
MenACWY hSBAs. This will be documented in the clinical report.
−
A seronegative subject is a subject whose titer is below the LOD.
−
A seropositive subject is a subject whose titer is greater than or equal to the 
LOD.
−
The Geometric Mean Titers (GMTs) calculations are performed by taking the 
anti-log of the mean of the log concentration/titer transformations. Values to be 
used for the antibody concentrations/titers below the assay cut-off will be 
described in the Statistical Analysis Plan (SAP). 
−
Handling of missing data: for a given subject and a given immunogenicity 
measurement, missing or non-evaluable measurements will not be replaced.

Reactogenicity and Safety
−
Handling of missing data: Subjects will be analysed to the extent that they are 
exposed to study vaccines and according to the available safety data for the 
subject during any study period. Subjects who withdraw early or who are lost to 
follow-up will be removed from the  denominator for the time period in which 
they have no available safety data collected. 
 
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10.6.
Analysis of demographics
Descriptive statistics (mean, standard deviation, median, minimum and maximum) for 
age, height and weight at enrollment will be calculated overall and by study group. 
Distributions of subjects by sex, race and ethnic origin will be summarized overall and by 
study group.
10.7.
Analysis of immunogenicity
The primary analysis will be based on the per-protocol set for analysis of 
immunogenicity. If, in any study group and timepoint, the percentage of vaccinated 
subjects with serological results excluded from the per-protocol set for analysis of 
immunogenicity is 5% or more, a second analysis based on the FAS will be performed to 
complement the per-protocol analysis.
GMTs, between-group ratios of GMTs and within-group Geometric Mean Ratios 
(GMRs) 
The hSBA titers at each visit will be logarithmically transformed (base10) to obtain 
approximately normally distributed data. For each N. meningitidis serogroup A, C, W and 
Y, GMTs will be calculated, with their associated two-sided 95% CIs, by exponentiating 
the corresponding log-transformed means and their 95% CIs. 
The between-group ratio of hSBA GMTs and corresponding 95% CI, at each of Day 1 
and Day 29 against N. meningitidis serogroups A, C, W and Y will be obtained by 
exponentiating the mean between-group differences in log-transformed titers and the 
corresponding 95% CIs at each of the specified timepoints.
Within each study group and for each serogroup, GMRs will be calculated at Day 29 
versus Day 1. The GMRs and 95% CIs will be constructed by exponentiating the mean
within-group differences in log-transformed titers and the corresponding 95% CIs.
The mean differences will be obtained from an Analysis of Covariance (ANCOVA) 
including pre-vaccination titer (Day 1) as a covariate and with vaccine group and center 
(if applicable) as factors in the model.
Percentages of subjects with a ≥ 4-fold rise in post-vaccination hSBA (Day 29) 
The percentage of subjects with a ≥ 4-fold rise in post-vaccination hSBA (at Day 29 
compared to Day 1) and associated two-sided 95% Clopper-Pearson CIs will be 
computed by group and N. meningitidis serogroups A, C, W and Y. Differences in 
percentages and associated 95% CIs between study groups will be calculated using the 
Miettinen and Nurminen score method. 
Percentage of Subjects With hSBA titer ≥8 and ≥LLOQ* (Day 1 and Day 29)
For each study group the percentage of subjects with hSBA titer ≥8 and ≥LLOQ* and 
associated two-sided 95% Clopper-Pearson CIs will be computed by the N. meningitidis
serogroups A, C, W and Y on Day 1 and Day 29. Differences in percentages and 
 
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associated 95% CIs between study groups will be calculated using the Miettinen and 
Nurminen score method.
* Note: To be assessed for each serogroup if the pre-defined LLOQ value for that 
serogroup is >8.
10.8.
Analysis of safety
Analysis will be performed on the solicited safety set for solicited reactions and on 
unsolicited safety set for unsolicited adverse events. 
10.8.1.
Analysis of Solicited Local, Systemic and Other Adverse Events
All solicited adverse events will be summarized according to defined severity grading 
scales.
Frequencies and percentages of subjects experiencing each adverse event will be 
presented for each symptom severity. Summary tables showing the occurrence of any 
local or systemic adverse event overall and at each time point will also be presented.
Post-vaccination solicited adverse events reported from Day 1 to Day 7 will be 
summarized for the intervals Day 1 (6 hours) – Day 3, Days 4-7, Day 1 (6 hours) – Day 7 
by maximal severity and by study group. Separate analyses will be performed for 
solicited AEs reported 30 minutes after vaccination. The severity of solicited local 
adverse events, including injection-site erythema and induration, will be categorized 
based on linear measurement:  Absent (0-24 mm), Mild (25-50 mm), Moderate (51-100 
mm) or Severe (> 100mm).
Injection site pain and systemic reactions, including fatigue, headache, myalgia, 
arthralgia, chills, nausea, loss of appetite, occurring up to 7 days after each vaccination 
will be summarized according to “mild”, “moderate” or “severe”. 
Each solicited local and systemic adverse event will also be further summarized as 
“absent” versus “any”.
Use of antipyretics and analgesics will be summarized by frequency, by type of use 
(prophylactic versus treatment) and percentage of subjects reporting use.
Body temperature will be summarized separately according to the 3 schemes described
below and will be broken down according to route of measurement: 

by 0.5 °C increments from 36.0°C up to ≥40°C;

by 1°C increments: <36.0, 36.0-36.9, 37.0-37.9, 38.0-38.9, 39.0-39.9, ≥40°C;

According to different cut-offs (< versus ≥): 38.0, 38.5, 39.0, 39.5, 40.0°C.
 
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10.8.2.
Analysis of Unsolicited Adverse Events
This analysis applies to all adverse events occurring during the study, judged either as 
probably related, possibly related, or not related to vaccination by the investigator, 
recorded in AE CRF, with a start date on or after the date of first vaccination. AE starting 
prior to the first vaccination will only be listed. The original verbatim terms used by 
investigators to identify adverse events in the CRFs will be mapped to preferred terms 
using the MedDRA dictionary. The adverse events will then be grouped by MedDRA 
preferred terms into frequency tables according to system organ class (SOC).
All reported adverse events, as well as adverse events judged by the investigator as at 
least possibly related to study vaccine, will be summarized according to SOC and 
preferred term within SOC. These summaries will be presented by study group and by 
interval of study observation. When an adverse event occurs more than once for a subject, 
the maximal severity and strongest relationship to the vaccine will be counted.
Separate summaries will be produced for the following categories:

Adverse events that are possibly or probably related to vaccine

Unsolicited AEs reported within 30 minutes after vaccination

Unsolicited AEs reported within 28 days after vaccination

Adverse events leading to withdrawal

Adverse events leading to a medically attended visit

Serious adverse events.
Data listings of all adverse events will be provided by subject. In addition, adverse events 
in the categories above will be provided as listed data.
10.9.
Interpretation of analyses
10.9.1.
Primary immunogenicity objective
The analysis population for the non-inferiority analysis is the Per Protocol Set (PPS).
To demonstrate non-inferiority of the investigational MenACWY liquid vaccine to the 
currently licensed MenACWY vaccine (Menveo), the lower limit of the two-sided 95% 
confidence interval (CI) for the hSBA GMT ratios for serogroup A at Day 29, must be 
greater than 0.5. Hypothesis testing will be performed at an overall significance level (α) 
of 2.5% (one-sided) using a non-inferiority margin of 0.5 for GMT ratios:
Null hypothesis (inferiority):
versus
Alternative hypothesis (non-inferiority): 
)
5.0
(
log10
ACWY
ACWY_Liq30



)
5.0
(
log10
ACWY
ACWY_Liq30


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Where: 0.5 is the non-inferiority margin for the ratio of GMTs between Group 
ACWY_Liq and Group  ACWY; 
and 
are the population means of the 
logarithmically (base of 10) transformed titers for serogroup A in Group ACWY_Liq and 
Group  ACWY, respectively.
If the lower limit of the two-sided 95% CI for the hSBA GMT ratio is greater than 0.5, 
then we conclude non-inferiority. 
10.9.2.
Secondary Immunogenicity Objectives
Analysis of secondary objectives 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
The analysis will be performed in the following steps:

An interim analysis will be performed after the availability of the Visit 2 (day 29) 
immunogenicity and safety data. The analysis on immunogenicity and safety data 
collected up to day 29 (Visit 2) might be reported in an interim clinical study report 
(CSR) for regulatory purposes.  

The analysis on safety data received after Visit 2 until study end (Day 181) will be 
performed after study end, once all data are available and cleaned. A final integrated 
CSR including the interim and the final analyses will be written at this point in time.
An integrated clinical study report containing all data will be written and made available 
to the investigators.
10.10.2.
Statistical considerations for interim analyses

The interim and final analyses will be performed sequentially. An interim analysis 
will include the analyses of the primary and secondary endpoints and safety data. 
The analysis will be performed after the availability of the Visit 2 immunogenicity 
and safety data. 

The results of the interim analysis will provide information to plan the study design 
for a Phase 3 study. 

The interim analysis will be performed by the BioStatistics and Statistical 
Programming department. Details on how the interim analysis will be performed will 
be added to the Statistical Analysis Plan. 
ACWY_Liq30

ACWY
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11.
ADMINISTRATIVE MATTERS
To comply with ICH GCP administrative obligations relating to data collection, 
monitoring, archiving data, audits, confidentiality, public disclosure requirements and 
publications must be fulfilled. 
11.1.
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.
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 by the investigator or appropriately qualified designee. In all 
cases, the investigator remains accountable for the study data. 
The investigator will be provided with an electronic format in read only mode of the final 
version of the data generated at the investigational site once the database is archived and 
the study report is complete and approved by all parties.
11.2.
Subject Diary
Electronic Diaries (eDiaries), hereafter referred to as Subject Diaries will be the only 
source document allowed for solicited local and systemic adverse events (including body 
temperature measurements), starting after the initial 30 minute post-vaccination period at 
the clinic. The following additional rules apply to documentation of safety information 
collected in the Subject Diary.
The Investigator or delegated staff should monitor the Subject’s Diary status throughout 
the study for compliance and any solicited local and systemic adverse events that were of 
concern to the subject.

No corrections or additions of data recorded by the subjects/parents/LARs will be 
allowed once diary completion for that day has been performed.

The Subject Diary will be designed in such a way as to prevent any blank, 
incomplete or biologically implausible entries. Subjects/parents/LARs will be 
instructed to fully complete the Subject Diary each day, as per the instructions 
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
At or just in advance of each subject visit, site staff must review the Subject Diary 
data via the provider’s web portal. It is necessary for site staff to acknowledge in the 
source documents that review of Subject Diary data for the preceding post-
vaccination period has been performed. At the end of the study it is necessary for the 
investigator to acknowledge in the eCRF that the review of Subject Diary data has 
been performed for each subject.

For vaccination visits, site staff must ensure that each subject’s Diary is prepared for 
data capture in the ensuing post-vaccination period by confirming the visit within the 
eDiary/eDiary system.

Any new safety information reported during the site visit (including a solicited 
adverse event) cannot be entered into the Subject Diary. Such information must be 
described in the source notes as a verbally-reported event. Any adverse event 
reported in this fashion must be described as an unsolicited adverse event and 
therefore entered on the adverse event page of the eCRF.
11.3.
Study Monitoring by GSK Biologicals
GSK will monitor the study to verify that, amongst other items, 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 a eCRF review and a Source Document 
Verification (SDV). 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 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. 
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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11.4.
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. The minimum retention time will 
meet the strictest standard applicable to a particular site, as dictated by ICH GCP, any 
institutional requirements, applicable laws or regulations, or GSK standards/procedures, 
otherwise, the minimum retention period will default to 25 years after completion of the 
study report.
The investigator/institution must notify GSK of any changes in the archival 
arrangements, including, but not limited to archival at an off-site facility, transfer of 
ownership of the records in the event the investigator leaves the site. 
11.5.
Quality assurance
To ensure compliance with GCP 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.
11.6.
Posting of information on publicly available clinical trial 
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. The minimal requirement is to have primary endpoint 
summary results disclosed at latest 12 months post primary completion date (PCD) and to 
have secondary endpoint disclosed at latest 12 months after the last subject last visit 
(LSLV) as described in the protocol.
 
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As per EU regulation, summaries of the results of GSK interventional studies (phase I-
IV) in adult population conducted in at least one EU member state will be posted on 
publicly available EMA registers within 12 months of EoS (as defined in the protocol) in 
the concerned EU member state. However, where, for scientific reasons detailed in the 
protocol, it is not possible to submit a summary of the results within one year in the 
concerned EU member state, the summary of results shall be submitted as soon as it is 
available. In this case, the protocol shall specify when the results are going to be 
submitted, together with a justification. 
GSK also aims to publish the results of these studies in searchable, peer reviewed 
scientific literature and follows the guidance from the International Committee of 
Medical Journal Editors.
11.7.
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 site or other mutually-
agreeable 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.
11.8.
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.
 
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12.
COUNTRY SPECIFIC REQUIREMENTS
12.1.
Requirements for Germany
Explanatory statement concerning Gender Distribution (Article 7, paragraph 2 (12) 
of the German GCP ORDER)
Recruitment for this MENACWY CONJ-032 [V59_71] study will include males and 
females. A subgroup analysis by sex will be performed for the primary and secondary 
objectives. To not expose pregnant women and their foetuses/children to the new liquid 
formulation of the MENACWY vaccine, females enrolled in this trial will either be of 
non-childbearing potential (i.e., have a current tubal ligation or occlusion, hysterectomy, 
bilateral ovariectomy or be premenarchal or postmenopausal), or if she is of childbearing 
potential, she must practice adequate contraception for 30 days prior to the beginning of 
the administration of study treatment, have a negative pregnancy test and continue such 
precautions during the entire treatment period (1 month after vaccination) (Refer to the 
study protocol, Section 4.2 “Inclusion criteria” and Section 4.3 “Exclusion criteria”). The 
recruitment will be closed to females who are pregnant or lactating. 
The indication of the vaccine under investigation is active immunization to prevent 
invasive meningococcal disease caused by N. meningitidis serogroups A, C, W and Y. 
Meningococcal disease affects both men and women. Based on surveillance by the 
European Center for Disease Prevention and Control, the annual notification rate of 
invasive meningococcal disease per 100,000 population is 0.94 in males and 0.83 in 
females of all age groups [Whittaker , 2017]. There are no reports of gender differences 
in the efficacy or safety outcomes for persons having received the licensed Menveo
vaccine.
 
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13.
REFERENCES
Berry D, Lynn F, Lee C, Frasch C, et al. Effect of O acetylation of Neisseria meningitidis 
serogroup A capsular polysaccharide on development of functional immune responses. 
Infection and immunity. 2002; 70(7): 3707-13.
Centers for Disease Control and  Prevention Metropolitan Atlanta Congenital Defects 
Program (CDC MACDP) guidelines. Birth defects and genetic diseases branch 6-digit 
code for reportable congenital anomalies; 
http://www.cdc.gov/ncbddd/birthdefects/documents/MACDPcode0807.pdf
EMA Guideline on the exposure to medicinal products during pregnancy: need for post-
authorization data (Doc. Ref. EMEA/CHMP/313666/2005 ) ‘adopted at Community level 
in May 2006);
http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_g
uideline/2009/11/WC500011303.pdf
Granoff DM, Feavers IM, Borrow R. Chapter 34. Meningococcal vaccines. In: Plotkin S, 
Orenstein WA, editors. Vaccines, 4th ed.: W. B. Saunders; 2003 (in press).
Haralambieva IA, Ovsyannikova IG, Kennedy RB, et al. Race and Sex-Based 
Differences in Cytokine Immune Responses to Smallpox Vaccine in Healthy Individuals. 
Hum Immunol. 2013; 74(10): 1263–1266.
Kollmann TR. Variation between Populations in the Innate Immune Response to Vaccine 
Adjuvants. Front Immunol. 2013; 4: 81.
Lupisan S, Limkittikul K, Sosa N, et al. Meningococcal polysaccharide A O-acetylation 
levels do not impact the immunogenicity of the quadrivalent meningococcal tetanus 
toxoid conjugate vaccine: results from a randomized, controlled phase III study of 
healthy adults aged 18 to 25 years. Clin Vaccine Immunol. 2013; 20(10): 1499-507.
Pérez-Losada M, Posada D, Arenas M, et al. Ethnic differences in the adaptation rate of 
HIV gp120 from a vaccine trial. Retrovirology. 2009; 6: 67.
Pollard AJ, Perrett KP, Beverley PC.  Maintaining protection against invasive bacteria 
with protein-polysaccharide conjugate vaccines. Nat Rev Immunol. 2009; 9(3): 213-20.
Rosenstein NE, Fischer M, Tappero JW. Meningococcal vaccines. Infect Dis Clin North 
Am 2001; 15(1): 155-69.
Whittaker R, Dias JG, Ramliden M, et al. The epidemiology of invasive meningococcal 
disease in EU/EEA countries, 2004–2014. Vaccine. 2017; 35(16): 2034-41.
 
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APPENDIX A
LABORATORY ASSAYS
The following tests will be performed using the aliquots of serum:

The induction of functional anti-meningococcal activity by bactericidal antibodies 
directed against N. meningitidis serogroups A, C, W and Y will be determined by a 
Serum Bactericidal Assay using human complement (hSBA) as exogenous 
complement source.

The testing will be performed at the GSK Biologicals’ laboratories or a laboratory 
designated by GSK Biologicals. Upon validation of the hSBA format, assay cut-offs 
and unit for each of the MenACWY serogroups will be determined and will be 
documented in the clinical report. Titres will be expressed as the reciprocal of the 
dilution resulting in 50% inhibition.
 
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APPENDIX B
CLINICAL LABORATORIES
Table 14
GSK Biologicals’ laboratories
Laboratory
Address
GSK Biological’s Clinical 
Laboratory Sciences, Rixensart 
Biospecimen Reception - B7/44
Rue de l'Institut, 89 - B-1330 Rixensart – Belgium 
GSK Biological’s Clinical 
Laboratory Sciences, Wavre-Nord 
Noir Epine
Avenue Fleming, 20 - B-1300 Wavre – Belgium
GSK Vaccines GmbH
Clinical Laboratory Sciences, 
Marburg, Germany
Emil-von-Behring-Str. 76
35041 Marburg
Germany
 
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APPENDIX C
AMENDMENTS TO THE PROTOCOL
GlaxoSmithKline Biologicals SA
Vaccines R&D
Protocol Amendment 1
eTrack study number 
and Abbreviated Title
205343 (MENACWY CONJ-032 [V59_71])
IND number
11278
EudraCT number
2017-003692-61
Amendment number:
Amendment 1
Amendment date:
17 January 2018
Co-ordinating author:
 (Lead Scientific Writer)
Rationale/background for changes:
!
As per local rules, in some cases the legal age for consent is above 18 years. For 
those subject below the legal age of consent, informed consent will need to be 
collected from their parent(s)/legally acceptable representatives (LAR[s]), and 
informed assent from the subjects themselves.
!
Two of the exclusion criteria were very similar and have therefore been combined 
into one exclusion criterion.
!
The product specifications related to the Corynebacterium diphtheriae Cross 
Reacting Material 197 (CRM197) content of the investigational MenACWY liquid 
vaccine formulation have been updated.
!
Clarification of the immunogenicity endpoints that will be included in the 
subgroups analysis. 
!
A change in the study personnel has been included on the protocol cover page.
!
Some editorial changes have been made throughout the document, including a 
simplification of the names of the study vaccines.
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections:
On the protocol cover page, the following change has been made:
Co-ordinating author
!
 (Lead Scientific Writer)

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PPD

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In the Glossary of Terms, the following changes have been made:
IAF
Informed Assent Form
LAR
Legally Acceptable Representative
In Section 3 Study Design Overivew, the following change was made:
Table 3
Blinding of study epochs
Study Epochs
Blinding
Epoch 001
observer-blind
Refer to Section 10.10.1 for details on when unblinding will be done.
In Section 4.2 Inclusion criteria for enrollment, the following changes have been 
made:
1. Subjects who, in the opinion of the investigator, can and will comply with the 
requirements of the protocol (e.g. completion of the eDiary) or subjects’ 
parent(s)/Legally Acceptable Representative(s) [LAR(s)] who, in the opinion of the 
investigator, can and will comply, with the requirements of the protocol (e.g. 
completion of the eDiary).
2. Written informed consent obtained from the subject/from the parent(s)/LAR(s) of the 
subject prior to performance of any study specific procedure.
3. Written informed assent obtained for subjects below legal age of consent, if 
required by local regulations at the time of enrollment.
In Section 4.3 Exclusion criteria for enrollment, the following changes have been 
made:
2.
Any (clinical) condition that in the judgment of the investigator would make 
intramuscular injection unsafe and/or represents a contraindication to 
intramuscular vaccination and blood draws.
7.
Clinical conditions representing a contraindication to intramuscular vaccination and 
blood draws.
In Section 5.1 Regulatory and ethical considerations, including the informed consent 
process, the following changes have been made:
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) and subject informed assent, 
as appropriate, prior to participation in the study. 
GSK Biologicals will prepare a model Informed Consent Form (ICF) which will embody 
the ICH GCP and GSK Biologicals required elements. While it is strongly recommended 
that this model ICF is to be followed as closely as possible, the informed consent 
requirements given in this document are not intended to pre-empt any local regulations 
 
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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 Harmonized Tripartite Guidelines for Good Clinical 
Practice, those subjects who can only be enrolled in the study with the consent of the 
subject’s legally acceptable representative (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 legal representative. It should be 
assessed whether an assent is required depending of 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.
In Section 5.5 Outline of study procedure, the following changes were made:
 
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Table 4
List of study procedures
Age
≥18 to ≤40 YOA
Epoch
Epoch 001
Type of contact
Visit 1
Phone call 
1 
Visit 2 
Phone call 
2 
Phone call 
3 
Timepoint (s)
Day 1
Day 15
Day 29
Day 91
Day 181
Sampling timepoint(s)
Pre-Vacc 
Post-Vacc 
Informed consent 
●a
Informed  assent (if applicable as per local 
regulations) 
●a
Check inclusion/exclusion criteria 
●a
Collect demographic data 
●a
Medical history 
●a
Physical examination (including vital signs) 
●
●b
Urine pregnancy test c
●
Check contraindications and warnings and 
precautions to vaccination 
O
Pre-vaccination body temperature 
●
Measure/record height and weight 
●a
Study group and treatment number allocation 
●
Recording of administered treatment number 
●
Blood sampling (~20 mL) d
●e
●
Vaccine administration 
●
30 Minutes Post Injection Assessment 
●
Distribution of Subject Card 
Oa
Distribution of eDiary
O
Training on use of eDiary 
O
Return of eDiary 
O
Record any concomitant medications/vaccinations 
●
●
●
Concomitant medication/vaccinations related to 
AEs leading to study discontinuation, SAEs and 
medically attended visits 
●
●
●
●
●
Record any intercurrent medical conditions  
●
●
●
●
●
Recording of solicited adverse events (Days 1–7 
post-vaccination in eDiary) 
●
Recording of unsolicited adverse events within 28 
days post-vaccination 
●
●
●
Recording of medically-attended AEs
●
●
●
●f
●f
Recording of AEs/SAEs leading to withdrawal 
●a
●
●
●
●
Recording of SAEs 
●
●
●
●
●
Recording of pregnancies 
●
●
●
●
●
Study Conclusion 
●
Note: The double-line border following Day 29 indicates the interim analysis which will be performed on all data ) 
obtained up to Day 29.
AE = adverse event; GSK = GlaxoSmithKline; SAE = serious adverse event; Vacc: vaccination; YOA = years of age
● 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, but should be 
confirmed in the patient’s source record.
a  The following activities can be performed at a separate visit (maximum 5 days before Visit 1): Informed Consent, 
Informed Assent, check of inclusion/exclusion criteria, collection of demographic data, recording of Medical History 
and of height and weight, distribution of subject card.  AEs/SAEs leading to withdrawal and SAEs related to study 
participation or to a concurrent GSK medication/vaccine should also be recorded from the separate visit. 
Inclusion/exclusion criteria should be rechecked prior to vaccination. 
bPhysical examination will be performed only if deemed necessary by the Investigator or delegate.
 
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cOnly for women of childbearing potential.
d Before blood sample collection, check if there is no contraindication to blood draw.
e Blood sample collection from Visit 1 will be performed before vaccine administration. 
fNon-medically attended AEs after 28 days post-vaccination are not required to be reported in the eCRF.
In Section 5.6.1 Informed consent, the following changes were made:
The signed/witnessed/thumb printed informed consent of the subject/subjects’ 
parent(s)/LAR(s) must be obtained before study participation. The signed informed 
assent of the 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 the 
local rules and regulations. Refer to Section 5.1 for the requirements on how to obtain 
informed consent and assent, as appropriate.
In Section 5.6.14 Subject Diary, the following changes were made:
Subject Diary training should be directed at the individual(s) who will perform the 
measurements of adverse events and who will enter the information into the Subject 
Diary. This individual may not be the subject/subject’s parent(s)/LAR(s), but if a person 
other than the subject/subjects’ parent(s)/LAR(s) enters information into the Subject 
Diary, this person’s identity must be documented in the subject’s source record. Any 
individual that makes entries into the Subject Diary must receive training on completion 
of the Subject Diary at the time of the visit when Subject Diary is dispensed. This 
training must be documented in the subject’s source record.
The same individual should complete the Subject Diary throughout the course of the 
study.
The subject/subjects’ parent(s)/LAR(s) should be trained on how to self-measure local 
solicited adverse events and body temperature. 
The measurement of solicited local adverse events is to be performed using the ruler 
provided by the site.
Subjects/parents/LARs will be instructed to measure and record the oral body 
temperature in the evening. Should additional temperature measurements be performed at 
other times of day, subjects/parents/LARs will be instructed to record the highest 
temperature in the Subject Diary.
Subject Diary assignment and use:

Each subject/subjects’ parent(s)/LAR(s) will be assigned a Subject Diary and shown 
how to use the device – this will include how to access the diary, performing test 
data entry on sample questions, and how to charge and store the device.

The subject/subjects’ parent(s)/LAR(s) will self-select a numeric access code secret 
to themselves. The same individual should make the assessments and complete the 
Subject Diary throughout the course of the study. 

The subject/subjects’ parent(s)/LAR(s) will select an alarm time that suits their daily 
routines whilst ensuring compliance with protocol requirements.
 
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Subject Diary instructions must ensure that the subject/subjects’ parent(s)/LAR(s)
understands the following:
In Section 5.6.14.1 Post-vaccination reminders, the following change was made:
Reminder calls or alerts are not intended to be an interview for collection of safety data. 
If the subject/subjects’ parent(s)/LAR(s) wishes to describe safety information, this 
information should only be collected by a healthcare professional at the site, and the 
safety data described must be written down in the subject’s medical chart.
In Section 5.6.14.1.1 Subject Diary Reminder Alers, the following changes were made:
The subject/subjects’ parent(s)/LAR(s) will receive daily reminders via the Subject Diary 
device’s in-built audio-visual alarms to alert the user to complete the diary during the 
post vaccination period. From Day 1 through Day 7, the users will receive daily alerts 
through the Subject Diary to record solicited adverse events, and the incidence of any 
potential unsolicited AEs, and whether these AEs were medically attended (defined as 
symptoms or illnesses requiring hospitalization, or emergency room visit, or visit to/by a 
health care provider), or were of concern. In case of such events, subject/subjects’ 
parent(s)/LAR(s) will be instructed to contact the site as soon as possible to report the 
event(s).
In Section 5.6.14.2 Safety Follow-up calls, the following changes were made:
Safety follow-up calls are calls made to the subject by a healthcare professional 
designated on the site log. These calls will follow a script which will facilitate the 
collection of relevant safety information. The subject/subjects’ parent(s)/LAR(s) will be 
interviewed according to the script, and information relating to unsolicited adverse events 
(including unsolicited adverse events (AEs) within 28 days post-vaccination, serious 
adverse events (SAEs), medically attended adverse events, AEs or SAEs leading to 
withdrawal, and/or intercurrent medical conditions) and concomitant medications or 
vaccinations associated with those events will be collected, as well as information on 
pregnancy for females of childbearing potential. All safety information described by the 
subject must be written down in a designated location within the source document and 
not written on the script used for the telephone call.
The site should schedule the next study activity (clinic visit/ safety call) with the 
subject/subjects’ parent(s)/LAR(s).
The subject/subjects’ parent(s)/LAR(s) will be reminded to contact the site if there are 
any questions and to contact the site immediately (or as soon as the subject is medically 
stable) if the subject has a medical condition that leads to a hospitalization or an 
emergency room visit.
In Section 5.6.16 Recording of AEs, SAEs and pregnancies, the following change was 
made:

The subjects/subjects’ parent(s)/LAR(s) will be instructed to contact the investigator 
immediately should they manifest any signs or symptoms they perceive as serious. 
 
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In Section 5.7 Biological sample handling and analysis, the following change was 
made:
Any sample testing will be done in line with the consent of the individual 
subject/subjects’ parent(s)/LAR(s).
In Section 5.7.5 Immunological correlates of protection, the following change was 
made:
The investigator is encouraged to share the immunological assay results for non-
responders with the study subjects/subjects’ parent(s)/LAR(s) at the end of the study, as 
soon as the results are available.
In Section 6.1 Description of study vaccines, the following changes have been made:
Table 9
Study vaccines
Treatment 
name
Vaccine/product 
name
Formulation
Presentation
Volume to be 
administered
Number 
of doses
MenACWY 
liquid with 
approximately 
30% MenA 
FS
Menveo 
MenACWY liquid
MenA=10µg CRM197; 
MenC=5µg CRM197; 
MenW=5µg CRM197; 
MenY=5µg CRM197; 
CRM197=25.4-
65.832.7-64.1µg 
Liquid in a 
monodose vial
0.5 ML 
1
Licensed 
MenACWY
(Menveo*) 
MenA lyo 
MenA=10µg CRM197; 
CRM197=16.7-33.3µg 
Lyophilized 
component in a 
vial
0.5 ML 
1
MenCWY liquid 
MenC=5µg CRM197; 
MenW=5µg CRM197; 
MenY=5µg CRM197; 
CRM197=16-30.8µg 
Liquid component 
in a vial
* Menveo commercial formulation consisting of a MenA lyphophilized component and of a MenCWY liquid component 
to be reconstituted together before administration (0.5 mL)
In Section 6.7 Concomitant medications/products and concomitant vaccinations, the 
following change was made:
At each study visit and at Phone call 1, the investigator or delegate should question the 
subject/subjects’ parent(s)/LAR(s) about any medications/products taken and 
vaccinations received by the subject.
In Section 8 Safety, the following change was made:
Each subject/subjects’ parent(s)/LAR(s) will be instructed to contact the investigator 
immediately should they manifest any signs or symptoms they perceive as serious.
In Section 8.1.3 Solicited adverse events, the following change was made:
The term “reactogenicity” refers to solicited signs and symptoms (“solicited adverse 
events”) occurring in the hours and days following a vaccination, to be collected by the 
subjects/parents/LARs for 7 consecutive days (6 hours  - Day 7), using a pre-defined 
 
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Subject Diary. Solicited adverse events continuing beyond Day 7 should continue to be 
recorded in the eDiary until resolution or next visit.
In Section 8.1.4 Unsolicited Adverse Events, the following changes were made:
An unsolicited adverse event is an adverse event that was not solicited using a Subject 
Diary and that was spontaneously communicated by a subject/parent(s)/LAR(s) who has 
signed the informed consent.
Potential unsolicited AEs may be medically attended (defined as symptoms or illnesses 
requiring hospitalization, or emergency room visit, or visit to/by a health care provider), 
or were of concern to the subjects/parents/LARs. In case of such events, 
subjects/parents/LARs will be instructed to contact the site as soon as possible to report 
the event(s). The detailed information about the reported unsolicited AEs will be 
collected by the qualified site personnel during the interview and will be documented in 
the subject’s records.
Unsolicited AEs that are not medically attended nor perceived as a concern by 
subjects/parents/LARs will be collected during interview with the subjects/parents/LARs
and by review of available medical records at the next visit.
In Section 8.3.3.1 Active questioning to detect adverse events and serious adverse 
events, the following change was made:
As a consistent method of collecting AEs, the subject or the subjects’ parent(s)/LAR(s)
be asked a non-leading question such as:
In Section 8.3.3.4 Medically attended visits, the following change was made:
For each solicited and unsolicited symptom the subject experiences, the subject/subjects’ 
parent(s)/LAR(s) will be asked if he/she received medical attention defined as 
hospitalization, or an otherwise unscheduled visit to or from medical personnel for any 
reason, including emergency room visits. This information will be recorded in the eCRF.
In Section 8.9 Subject card, the following changes were made:
Study subjects/subjects’ parent(s)/LAR(s) must be provided with the address and 
telephone number of the main contact for information about the clinical study.
The investigator (or designate) must therefore provide a “subject card” to each 
subject/subjects’ parent(s)/LAR(s). In an emergency situation this card serves to inform 
the responsible attending physician that the subject is in a clinical study and that relevant 
information may be obtained by contacting the investigator.
Subjects/subjects’ parent(s)/LAR(s) must be instructed to keep subject cards in their 
possession at all times during the study duration.
 
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In Section 9.2.1 Subject withdrawal from the study, the following changes were made:
Information relative to the withdrawal will be documented in the eCRF. The investigator 
will document whether the decision to withdraw a subject from the study was made by 
the subject himself/herself, by the subjects’ parent(s)/LAR(s), or by the investigator, as 
well as which of the following possible reasons was responsible for withdrawal:
*In case a subject is withdrawn from the study because he/she/the subjects’ 
parent(s)/LAR(s) has withdrawn consent, the investigator will document the reason for 
withdrawal of consent, if specified by the subject/subjects’ parent(s)/LAR(s), in the 
eCRF.
In Section 10.4.7 Subgroups, the following changes have been made:
A subgroup analysis for GMTs, percentages of subjects with hSBA titer ≥8 and 
≥LLOQ* against N. meningitidis serogroups A, C, W and Y at Day 29, will be 
performed for subjects who were seronegative at baseline. 
In addition, subgroup analyses will be performed for GMTs, and four4-fold rise, 
percentages of subjects with hSBA titer ≥8 and ≥LLOQ* by sex, by race, and by 
country.
*Note: To be assessed for each serogroup if the pre-defined LLOQ value for that 
serogroup is > 8.
In Section 11.2 Subject Diary, the following changes were made

No corrections or additions of data recorded by the subjects/parents/LARs will be 
allowed once diary completion for that day has been performed.

The Subject Diary will be designed in such a way as to prevent any blank, 
incomplete or biologically implausible entries. Subjects/parents/LARs will be 
instructed to fully complete the Subject Diary each day, as per the instructions 
provided.
 
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GlaxoSmithKline Biologicals SA
Vaccines R &D
Protocol Amendment 2
eTrack study number 
and Abbreviated Title
205343 (MENACWY CONJ-032 [V59_71])
IND number
11278
EudraCT number
2017-003692-61
Amendment number:
Amendment 2
Amendment date:
15 March 2018
Co-ordinating author:
 (Expert Scientific Writer)
Rationale/background for changes:
!
Table 1.3.1 has been updated to reflect the potential and identified risks for 
MenACWY vaccine in alignment with the current version of the EU-RMP.
!
Table 12 “Intensity scales for solicited AEs” has been updated to correct the 
intensity scores of some of the AEs solicited.
!
The text below Table 12 has been updated to change “redness/swelling” to 
“erythema/induration”, in line with the local AEs solicited.
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections:
On the protocol cover page, the second coordinating author’s name was deleted and 
only original protocol author’s name was retained as per the template guidance.
In Section 1.2, Rationale for the study and study design, the following statement was 
updated to correct a typographical error:
For this study, the formulation with approximately 30% of free MenA oligosaccharides 
will be obtained by storing a fresh manufacturing MenA lot at approximately 22.5°C 
(7772.5°F) for the time needed to accelerate the formation of the free saccharides 
following the Arrhenius model.
In Section 1.3, Benefit: Risk Assessment, the risk table was updated to reflect the 
potential and identified risks for MenACWY vaccine in alignment with the current 
version of the EU-RMP and as follows:
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Important Potential/Identified 
Risk
Data/Rationale for Risk
Mitigation Strategy
Menveo and investigational MenACWY liquid vaccine

Guillain-Barré syndrome

Acute disseminated 
encephalomyelitis 

Thrombocytopenia

Vasculitis including Kawasaki 
disease

Brachial neuritis 

Facial Paresis

Severe injection site reactions

Systemic reactions (severe), 
including febrile convulsion
Vaccination failure (lack of efficacy)
Potential risks as included in the 
Menveo EU Risk Management 
Plan.
Accept as Menveo is a licensed 
product and the incidence of the 
potential risks is low to very low.
Important Identified risk:
Reconstitution errors
Cases describing medication 
errors due to administration of 
the MenCWY conjugate liquid 
component only without 
reconstitution with the MenA
conjugate lyophilized 
component, or due to 
administration of the MenA 
conjugate lyophilized 
component only after 
reconstitution with a different 
solvent, have been reported 
during the MenACWY clinical 
development program.
In several sections of the protocol 
(e.g. Section 6.1. “Description of 
study vaccines”) it is clarified that 
the 2 vaccine components have to 
be reconstituted before vaccine 
injection.
Important potential risk:
Guillain-Barré syndrome (GBS)
GBS has been observed with 
other vaccines. No cases have 
been reported during the 
MenACWY clinical 
development program.
GBS will be monitored through 
SAE collection. 
Important potential risk:
Acute disseminated 
encephalomyelitis (ADEM)
ADEM has been observed with 
other vaccines. Two cases 
from clinical trials were 
retrieved from the GSK’s 
global safety database for 
MenACWY. None of them has 
provided sufficient evidence of 
a causal association between 
ADEM and MenACWY.
ADEM will be monitored through 
SAE collection.
Important potential risk:
Thrombocytopenia
Immune thrombocytopenic 
purpura has been reported in 
association with several 
licensed vaccines. Two cases 
related to MenACWY were 
reported during the clinical 
development program, but 
none of them has provided a 
clear association between 
thrombocytopenia and the 
vaccine.
Immune thrombocytopenic 
purpura will be monitored through 
SAE collection.
 
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Important Potential/Identified 
Risk
Data/Rationale for Risk
Mitigation Strategy
Important potential risk:
Facial paresis
Facial paresis was recognized 
as an important potential risk 
following the results of a 
sponsored observational study 
(V59_34OB) which found an 
imbalance of cases of facial 
paresis following vaccination 
with MenACWY, mainly when 
administered concomitantly 
with other vaccines. No cases 
of facial paresis were reported 
from interventional clinical 
trials.
Paralysis of the face is mentioned 
in the list of side effects in the 
ICF. Facial paresis will be 
monitored through SAE 
collection.
Important potential risk:
Vasculitis including Kawasaki 
disease (KD)
There were 7 cases of 
suspected KD reported in three 
clinical studies of Menveo. The 
occurrence of the cases in 
Menveo studies is consistent 
with the known epidemiology 
of KD in terms of geographic 
and temporal clustering, and 
seasonal variation. Therefore 
there is no evidence of a 
causal association between KD 
and MenACWY vaccine. As the 
exposure in clinical trial of 
subject was limited 
considering the incidence of 
the disease, KD is considered 
as a potential risk.
Vasculitis including Kawasaki 
disease will be monitored through 
SAE collection.
Study Procedures
Risk of blood sampling
Blood sampling associated risk of 
syncope, dizziness, infection at 
the site after or during 
venepuncture.
Blood samples will be obtained by a 
trained professional and medical 
assistance will be available.
The potential risk of feeling faint, or 
experiencing mild local pain, 
bruising, irritation or redness at the 
site where blood was taken, is 
mentioned in the Informed Consent 
Form (ICF). The amount of blood to 
be taken for sampling will not be 
harmful to the subject’s health.
For consistency throughout the protocol, the phrase “solicited symptoms” was changed to 
“solicited adverse events”.
Section 8.3.3.2.1, Assessment of intensity, has been updated to correct the intensity 
scores of some of the AEs solicited.
 
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Table 12
Intensity scales for solicited AEs (Amended 15 March 2018)
Adverse Event
Intensity grade
Parameter
Fever*
Record temperature in °C/°F
Induration at injection site
Record greatest surface diameter in mm
Erythema at injection site
Record greatest surface diameter in mm
Pain at injection site
Absent
None
Mild
Any pain neither interfering with nor preventing normal 
every day activities. No interference with daily activity
Moderate
Painful when limb is moved and interferes with every day 
activities. Interferes with daily activity
Severe
Significant pain at rest. Prevents normal every day 
activities. Prevents daily activity
Chills
Absent
Normal
Mild
No interference with daily activity
Moderate
Interferes with daily activity
Severe
Prevents daily activity
Nausea
Absent
Normal
Mild
No interference with daily activity
Moderate
Interferes with daily activity
Severe
Prevents daily activity
Myalgia
Absent
Normal
Mild
No interference with daily activity
Moderate
Interferes with daily activity
Severe
Prevents daily activity
Arthralgia
Absent
Normal
Mild
No interference with daily activity
Moderate
Interferes with daily activity
Severe
Prevents daily activity
Headache
Absent
Normal
Mild
Headache that is easily tolerated. No interference with 
daily activity
Moderate
Headache that interferes with normal activity. Interferes 
with daily activity
Severe
Headache that prevents normal activity. Prevents daily 
activity
Fatigue
Absent
Normal
Mild
Fatigue that is easily tolerated. No interference with 
daily activity
Moderate
Fatigue that interferes with normal activity. Interferes 
with daily activity
Severe
Fatigue that prevents normal activity. Prevents daily 
activity
Loss of appetite
Absent
Normal
Mild
Eating less than usual with no effect on normal activity
Moderate
Eating less than usual / interfered with normal activity
Severe
Not eating at all
* Fever is defined as temperature 38.0°C/100.4°F. preferred location for measuring temperature in this study will be 
the oral cavity.
The maximum intensity of local injection site redness erythema/induration swelling will 
be scored at GSK Biologicals as follows:
Absent: < 25 mm diameter
Mild: 25 mm to 50 mm diameter
 
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Moderate: > 50 mm to 100 mm diameter
Severe: > 100 mm diameter
Body temperature will be summarized separately according to the 3 schemes described
below and will be broken down according to route of measurement: 

by 0.5 °C increments from 36.0°C up to ≥40°C;

by 1°C increments: <36.0, 36.0-36.9, 37.0-37.9, 38.0-38.9, 39.0-39.9, ≥40°C;

According to different cut-offs (< versus ≥): 38.0, 38.5, 39.0, 39.5, 40.0°C.
The investigator will assess the maximum intensity that occurred over the duration of the 
event for all unsolicited AEs (including SAEs) recorded during the study. The assessment 
will be based on the investigator’s clinical judgement.
Adverse events, reported at a clinic visit or at a scheduled safety call, should be recorded 
in the eCRF verbatim, as reported by the subject. 
The severity of unsolicited adverse events reported on the Adverse Events eCRF will be 
determined by the investigator as:
Mild: transient with no limitation in normal daily activity.
Moderate: some limitation in normal daily activity.
Severe: unable to perform normal daily activity.
 
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08-FEB-2019

CONFIDENTIAL
205343 (MENACWY CONJ-032 [V59_71])
Protocol Amendment 3 Final
08-FEB-2019
104
GlaxoSmithKline Biologicals SA
Vaccines R &D
Protocol Amendment 3
eTrack study number 
and Abbreviated Title
205343 (MENACWY CONJ-032 [V59_71])
IND number
11278
EudraCT number
2017-003692-61
Amendment number:
Amendment 3
Amendment date:
08 February 2019
Co-ordinating author:
 (Scientific Writer)
Rationale/background for changes:
!
An update in the list of contributing authors has been included on the protocol 
cover page.
!
Wording of Section 5.3 Method of blinding and Section 5.7.3 Laboratory assays
has been updated to align with the current Company Standards related to blinding 
for sample testing.
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections:
On the protocol cover page, the contributing authors list has been updated, without  
deleting previous authors as per template guidance.
Contributing authors 
(continued)
!
 (Study Statistician; Rosemind 
Consulting for GSK biologicals)
!
 (Lead Statistician)
!
 and 
(Study 
Delivery Lead)
!
 (Clinical Trial Supply Manager)
!
 (Clinical Laboratory 
Sciences Read-out Team Leader)
!
 (Clinical Safety representative)
!
 and 
 (Clinical 
Laboratory Sciences Study Managers)
!
 (Oversight Data Manager)
!
(Study Data Manager)
!
 (Lead Scientific Writer)

CONFIDENTIAL
205343 (MENACWY CONJ-032 [V59_71])
Protocol Amendment 3 Final
bf711450ca6cee6dfc304efa3b016790bceb4241
104
08-FEB-2019
PPD
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CONFIDENTIAL
205343 (MENACWY CONJ-032 [V59_71])
Protocol Amendment 3 Final
08-FEB-2019
105
!
 (Scientific Writer)
!
 (Regulatory Affairs 
representative)
!
 (Global Patents representative)
!
 (Clinical and Epidemiology 
Research & Development Project Lead)
In Section 5.3 Method of blinding, the following changes have been made:
The laboratory in charge of the laboratory testing will be blinded to the treatment as well 
as to the, subject and visit number, and codes will be used to link the subject, visit and 
study (without any link to the treatment attributed to the subject) to each sample. In 
addition, a randomly selected subject code will be used for each timepoint tested. This 
subject coding will prevent the laboratory from linking the consecutive visits to a 
specific subject.
In Section 5.7.3 Laboratory assays, the following changes have been made:
The measure of immunogenicity used in this study is standard, i.e., widely used and
generally recognized as reliable, accurate, and relevant (able to describe the quality and 
extent of the immune response). Testing will be conducted by a GSK or designated 
laboratory in a blinded manner towards the subject number and, the treatment arm 
(please refer to Section 5.3 Method of blinding). and to the visit.

CONFIDENTIAL
205343 (MENACWY CONJ-032 [V59_71])
Protocol Amendment 3 Final
bf711450ca6cee6dfc304efa3b016790bceb4241
105
08-FEB-2019
PPD
PPD
PPD
PPD