Immunogenicity and Safety of Meningococcal MenABCWY Vaccine, and of rMenB+OMV NZ and MenACWY Administered Concomitantly in the Same Arm or in 2 Different Arms, or Alone
Phase: PHASE2
Conditions: Meningitis, 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 MenABCWY vaccine 
(GSK3536819A)
Other study vaccines
!
GSK Biologicals’ meningococcal rMenB+OMV 
NZ vaccine (Bexsero; GSK3536829A)
!
GSK Biologicals’ meningococcal MenACWY 
vaccine (Menveo; GSK3536820A)
eTrack study number and 
abbreviated title
208205 MENABCWY-016 (V102_19)
EudraCT number
2017-005128-12
Date of protocol
Final: 09 February 2018
Date of protocol 
amendment
Amendment 1 Final: 15 May 2018
Amendment 2 Final: 29 August 2018
Title
Immunogenicity and Safety of Meningococcal 
MenABCWY Vaccine, and of rMenB+OMV NZ and 
MenACWY Administered Concomitantly in the Same 
Arm or in 2 Different Arms, or Alone
Detailed title
A Phase II, Randomized, Open-label, Multicenter
Study to Assess the Immunogenicity and Safety of 
GSK Meningococcal MenABCWY Vaccine, and of 
GSK Meningococcal Group B and MenACWY 
Conjugate Vaccines Administered Concomitantly in 
the Same Arm or in 2 Different Arms, or Alone in 
Healthy Subjects 10 to 25 Years of Age
Co-ordinating author
, Principal Medical Writer, PPD, for 
GSK Biologicals
Contributing authors
(Amended 29 Aug 2018)
!
, Clinical Research Development 
Lead
!
, Project Statistician
!
, Lead Statistician
!
/
, Study Delivery Lead
!
, Study Delivery Associate
!
, Clinical Trial Supply Manager
!
, Scientific Writer

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PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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eTrack study number and 
abbreviated title
208205 MENABCWY-016 (V102_19)
EudraCT number
2017-005128-12
Detailed title
A Phase II, Randomized, Open-label, Multicenter
Study to Assess the Immunogenicity and Safety of 
GSK Meningococcal MenABCWY Vaccine, and of 
GSK Meningococcal Group B and MenACWY 
Conjugate Vaccines Administered Concomitantly in 
the Same Arm or in 2 Different Arms, or Alone in 
Healthy Subjects 10 to 25 Years of Age
Contributing authors 
(continued)
!
, Clinical and Epidemiology R&D 
Project Lead
!
, Clinical Laboratory Sciences 
Study Manager
!
, Clinical Laboratory Sciences Study 
Manager
!
, Clinical Laboratory 
Sciences Read-out Team Leader
!
/
, SERM Safety Scientist,
for GSK Biologicals
!
, Oversight Data Management
!
, Regulatory Affairs 
Representative
!
, Global Patents Representative
GSK Biologicals’ Protocol Document Standard for Legacy Novartis programs v 1.0
©2018 GSK group of companies or its licensor.

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PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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Protocol Amendment 2 Sponsor Signatory Approval
eTrack study number and 
abbreviated title
208205 MENABCWY-016 (V102_19)
EudraCT number
2017-005128-12
Date of protocol amendment
Amendment 2 Final: 29 August 2018
Detailed title 
A Phase II, Randomized, Open-label, Multicenter
Study to Assess the Immunogenicity and Safety of 
GSK Meningococcal MenABCWY Vaccine, and of 
GSK Meningococcal Group B and MenACWY 
Conjugate Vaccines Administered Concomitantly in 
the Same Arm or in 2 Different Arms, or Alone in 
Healthy Subjects 10 to 25 Years of Age
Sponsor signatory
Daniela Toneatto, MD
Clinical and Epidemiology R&D Project Lead
Signature
Date
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For internal use only
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Protocol Amendment 2 Rationale
Amendment number:
Amendment 2, substantial
Rationale/background for changes:

A tertiary objective was added to allow potential exploratory evaluation of
immune responses induced by the study vaccine(s) against a panel of strains
of Neisseria species in a subset of subjects.

Protocol Clarification Letter 1 was incorporated, which removed reference to
a pregnancy electronic case report form.

The window for Subject Diary reminder calls was clarified.

Other minor changes were made to correct typos, and improve clarity and
alignment within the document.
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Protocol Amendment 2 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/PPD.

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/PPD 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 vaccines, and more generally about his/her financial
ties with the sponsor. GSK Biologicals/PPD will use and disclose the information
solely for the purpose of complying with regulatory requirements.
Hence I:

Agree to supply GSK Biologicals/PPD 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 1 year following completion of the study.

Agree that GSK Biologicals/PPD may disclose any information it has about such
ownership interests and financial ties to regulatory authorities.

Agree to provide GSK Biologicals/PPD 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
208205 MENABCWY-016 (V102_19)
EudraCT number
2017-005128-12
Date of protocol amendment
Amendment 2 Final: 29 August 2018
Detailed title
A Phase II, Randomized, Open-label, Multicenter
Study to Assess the Immunogenicity and Safety of 
GSK Meningococcal MenABCWY Vaccine, and of 
GSK Meningococcal Group B and MenACWY 
Conjugate Vaccines Administered Concomitantly in 
the Same Arm or in 2 Different Arms, or Alone in 
Healthy Subjects 10 to 25 Years of Age
Investigator name
Signature
Date
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29-AUG-2018
For internal use only
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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
Central Back-up Study Contact for Reporting SAEs: refer to protocol Section 8.4.2.
 
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SYNOPSIS
Study title
A Phase II, Randomized, Open-label, Multicenter Study to 
Assess the Immunogenicity and Safety of GSK Meningococcal 
MenABCWY Vaccine, and of GSK Meningococcal Group B 
and MenACWY Conjugate Vaccines Administered 
Concomitantly in the Same Arm or in 2 Different Arms, or 
Alone in Healthy Subjects 10 to 25 Years of Age
EudraCT number
2017-005128-12
Study protocol 
number
208205 MENABCWY-016 (V102_19)
Final: 09 February 2018
Amendment 1 Final: 15 May 2018
Amendment 2 Final: 29 August 2018
Investigational 
product (primary 
study vaccine and 
number)
GlaxoSmithKline (GSK) Biologicals’ meningococcal 
MenABCWY vaccine (GSK3536819A)
Phase
II
Rationale for the 
study
In previous clinical studies of MenABCWY versus 
rMenB+OMV NZ, immune responses against serogroup B 
antigens were lower than immune responses assessed when 
rMenB+OMV NZ was administered alone. One possible reason 
that has been theorized is biological immune interference, 
possibly due to immunological stress to the lymph nodes in the 
arm where the combination vaccine is administered. The 
purpose of the current study is to evaluate whether there is 
immune interference when MenABCWY is administered to 
healthy adolescents and adults.
Risk/Benefit 
assessment
No significant safety signals have been identified for 
MenABCWY. Cumulative safety data have not identified new 
important safety risks. The balance of anticipated benefits and 
apparent risks associated with MenABCWY continues to be 
acceptable following the ongoing systematic review of safety 
data.
Taking into account the measures taken to minimize risk to 
subjects participating in this study, the potential or identified 
risks identified in association with rMenB+OMV NZ, 
MenACWY, and MenABCWY are justified by the potential 
benefits (prevention/treatment) that may be afforded to subjects.
 
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Used medicinal 
products
Primary study vaccine

GSK Biologicals’ meningococcal MenABCWY vaccine 
(GSK3536819A)
Other study vaccines

GSK Biologicals’ meningococcal rMenB+OMV NZ 
vaccine (Bexsero; GSK3536829A)

GSK Biologicals’ meningococcal MenACWY vaccine 
(Menveo; GSK3536820A)
Number of subjects
Target enrollment will be approximately 500 subjects 
(approximately 100 subjects per group). The sample size is for 
exploratory statistical analysis purposes only.
Purpose of this 
clinical study
This Phase II, randomized, open-label clinical study is designed 
to evaluate the potential immune interference when 
MenABCWY is administered to healthy subjects as 
2 injections, 2 months apart.
Indication
Primary immunization against Neisseria meningitidis
serogroups A, B, C, W-135, and Y.
Objectives
Primary

To assess the immune response to 2 doses of MenABCWY, 
rMenB+OMV NZ, or rMenB+OMV NZ and MenACWY 
administered concomitantly in the same arm or in 
2 different arms, and to a single dose of MenACWY at 
1 month after the last vaccination.
Secondary
Immunogenicity Objective

To assess the immune response to 2 doses of MenABCWY, 
rMenB+OMV NZ, or rMenB+OMV NZ and MenACWY 
administered concomitantly in the same arm or in 
2 different arms at 1 month after the first vaccination.
Safety Objective

To assess the safety and tolerability of 2 doses of 
MenABCWY, rMenB+OMV NZ, or rMenB+OMV NZ and 
MenACWY administered concomitantly in the same arm or 
in 2 different arms, and to a single dose of MenACWY.
 
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Tertiary

To further characterize the immune response induced by 
the study vaccine(s) against an additional panel of strains 
of Neisseria species in a subset of subjects.
Note: This tertiary objective is exploratory and suitable 
assays may or may not be developed. The tertiary objective 
will be assessed in a subset of subjects using remaining 
serum after the primary and secondary analyses have been 
completed; no additional blood samples will be collected 
from subjects. Any outcome of exploratory testing that 
would be of scientific/medical relevance will be reported in 
an annex/addendum to the final study report.
(Amended 29 Aug 2018)
Method of 
evaluation
Primary

Immune responses against N. meningitidis serogroup B* test 
strains and N. meningitidis serogroups A, C, W-135, and Y, 
as measured by a serum bactericidal assay using human 
complement (hSBA), 1 month after the last vaccination in 
all study groups

hSBA geometric mean titers (GMTs) against each of 
the N. meningitidis serogroup B test strains and against 
N. meningitidis serogroups A, C, W-135, and Y

hSBA GMTs against all of N. meningitidis serogroup 
B test strains (pooled) 

Percentage of subjects with hSBA titers ≥ the lower 
limit of quantitation (LLOQ) against each 
N. meningitidis serogroup B test strains and against 
N. meningitidis serogroups A, C, W-135, and Y 

Percentage of subjects with a 4-fold increase in hSBA 
titers against N. meningitidis serogroups B test strains 
and against N. meningitidis serogroups A, C, W-135, 
and Y 

hSBA geometric mean ratios (GMRs) against each of 
the N. meningitidis serogroup B test strains and against 
N. meningitidis serogroups A, C, W-135, and Y at 
1 month after the last vaccination against baseline 
(Day 1)
*Serogroup B strains that will be tested are M14459 (factor H 
binding protein; fHbp), 96217 (Neisserial adhesin A; NadA), 
NZ98/254 (PorA), and M07-0241084 (Neisseria heparin 
 
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binding antigen; NHBA) and will be pooled to estimate the 
effect of immune interference due to stress to lymph nodes.
Note: A 4-fold rise is defined as: 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 
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 4 times the LLOQ; and 
c) for individuals whose pre-vaccination titers are ≥the LLOQ, 
the post-vaccination titers must be at least 4 times the 
pre-vaccination titer.
Secondary
Immunogenicity Endpoints

Immune responses against N. meningitidis serogroup B test 
strains and N. meningitidis serogroups A, C, W-135, and Y, 
as measured by hSBA, 1 month after the first vaccination 
in all groups (except for subjects in the MenACWY group)
The statistical analyses and comparisons for the secondary 
immunogenicity endpoints will be the same as described for the 
primary endpoint.
Safety Endpoints

Solicited local and systemic adverse events (AEs) in all 
study groups

Occurrence of solicited local and systemic AEs during 
the 7 days (including the day of vaccination) after each 
vaccination (Day 1 to Day 7 and Day 61 to Day 67 
[Day 1 to Day 7 only for subjects in the MenACWY 
group])

Unsolicited AEs in all study groups

Occurrence of unsolicited AEs during the 30 days 
(including the day of vaccination) after each 
vaccination (Day 1 to Day 31 and Day 61 to Day 91 
[Day 1 to Day 31 only for subjects in the MenACWY 
group])

Serious AEs (SAEs), medically attended AEs, AEs leading 
to withdrawal, and AEs of special interest, in all study 
groups from informed consent signature to Visit 4 (Day 91)
Note: Arthritis is the only AE of special interest in this 
study.
 
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Tertiary
Endpoints related to the tertiary objective will be described in 
a separate statistical analysis plan. (Amended 29 Aug 2018)
Study population
Inclusion criteria
All subjects must satisfy ALL the following criteria at study 
entry:
1. Subjects and/or subjects’ parent(s)/Legally Acceptable 
Representative(s) (LARs) who, in the opinion of the 
investigator, can and will comply, with the requirements of 
the protocol (e.g. completion of the paper diary [pDiary], 
return for follow-up visits, availability for all visits 
scheduled in the study).
2. Written informed consent obtained from the subject and/or 
from the parent(s)/LAR(s) of the subject prior to performing 
any study specific procedure.
3. Written informed assent obtained from subjects below the 
legal age of consent prior to performing any study specific 
procedure.
4.
A male or female between, and including, 10 to 25 years of 
age 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, or bilateral ovariectomy. 
7.
Female subjects of childbearing potential may be enrolled 
in the study, if the subject:

has practiced highly effective contraception for 
30 days prior to vaccination, and

has a negative pregnancy test on the day of 
vaccination, and

has agreed to continue highly effective contraception 
during the entire treatment period and for 2 months 
after completion of the vaccination series. 
 
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Exclusion criteria
If ANY exclusion criterion applies, the subject must not be 
included in the study:
1. Female planning to become pregnant or planning to 
discontinue contraceptive precautions.
2. Pregnant or lactating female.
3. Child in care.
Each subject must not have:
4. Current or previous, confirmed or suspected disease caused 
by N. meningitidis.
5. Known contact to an individual with any 
laboratory-confirmed N. meningitidis infection within 
60 days prior to enrollment.
6. Previous vaccination against N. meningitidis at any time 
prior to informed consent.
7. Progressive, unstable or uncontrolled clinical conditions.
8. Hypersensitivity, including allergy, to any component of 
vaccines, medicinal products or medical equipment whose 
use is foreseen in this study.
9. Clinical conditions representing a contraindication to 
intramuscular (IM) vaccination and blood draws.
10. Abnormal function of the immune system resulting from:

Clinical conditions.

Systemic administration of corticosteroids 
(oral/intravenous/IM) for more than 14 consecutive 
days within 90 days prior to informed consent.

Administration of antineoplastic and 
immune-modulating agents or radiotherapy within 
90 days prior to informed consent.
11. Received immunoglobulins or any blood products within 
180 days prior to informed consent.
12. Received an investigational or non-registered medicinal 
product within 30 days prior to informed consent.
13. 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.
14. Concurrently participating in another clinical study, at any 
time during the study period, in which the subject has been 
 
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or will be exposed to an investigational or a 
non-investigational vaccine/product (pharmaceutical 
product or device).
15. Acute or chronic, clinically significant pulmonary, 
cardiovascular, hepatic, or renal functional abnormality, as 
determined by physical examination.
16. Any confirmed or suspected immunosuppressive or 
immunodeficient condition, based on medical history and 
physical examination (no laboratory testing required).
17. Are obese at screening (e.g. with a body mass index [BMI] 
30 kg/m2, where BMI reflects obesity and not high muscle 
mass).
18. Family history of congenital or hereditary 
immunodeficiency. 
19. History of neuroinflammatory or autoimmune condition.
20. History of significant neurological disorder or seizure 
(history of febrile convulsion should not lead to exclusion).
21. Serious chronic illness.
22. History of chronic alcohol consumption and/or drug abuse 
(including current consumption/abuse).
23. Any study personnel as an immediate family or household 
member.
24. Administration of a vaccine not foreseen by the study 
protocol in the period starting 14 days (for inactivated 
vaccines), 28 days (for live vaccines), or 7 days (for 
influenza vaccines) before each dose and ending 14 days 
(for inactivated vaccines), 28 days (for live vaccines), or 
7 days (for influenza vaccines) after each dose of study 
vaccine(s) administration.
25. Thrombocytopenia, bleeding disorders, or be receiving 
anticoagulant therapy.
Criteria for 
withdrawal from 
the study
From an analysis perspective, a “withdrawal” from the study 
refers to when a subject does not come back for the concluding 
visit foreseen in the protocol. A subject is considered 
“withdrawn” 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. Information relative to the withdrawal 
will be documented in the electronic case report form (eCRF). 
The investigator will document whether the decision to 
withdraw a subject from the study was made by the subject 
 
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himself/herself, by the subject’s parent(s)/LAR(s), or by the 
investigator.
A “withdrawal” from the study vaccine(s) refers to when a 
subject any subject who does not receive the complete 
treatment, i.e. when no further planned dose is administered 
from the date of withdrawal. A subject withdrawn from the 
study vaccine(s) may not necessarily be withdrawn from the 
study as further study procedures or follow-up may be 
performed (safety or immunogenicity) if planned in the study 
protocol. Information relative to premature discontinuation of 
the study vaccine(s) will be documented in the eCRF.
Reasons was responsible for withdrawal:

Serious AE

Unsolicited non-serious AE

Solicited AE

Protocol violation (specify)

Consent withdrawal, not due to an AE

Moved from the study area

Lost to follow-up

Other (specify)
Treatment, Dose 
level(s)
See Dosage and Administration Table.
 
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Synopsis Table 1
Dosage and administration
Type of 
contact 
and time 
point
Study group
Treatment 
name
Volume to be 
administered Route1
Site
Location
Directionality2
Laterality3
Visit 1 
(Day 1)
MenABCWY
MenABCW
Y4
0.5 mL
IM
Deltoid
Upper or lower
Non-
dominant 
rMenBOMV+A
CWY_S5
rMenB+O
MV NZ
0.5 mL
Upper Deltoid 
(approximately 
2.5 cm above 
MenACWY 
injection)
Upper
Non-
dominant
MenACWY
6
0.5 mL
Lower Deltoid 
(approximately 
2.5 cm below 
rMenB+OMV NZ 
injection)
Lower
Non-
dominant
rMenBOMV+A
CWY_D7
rMenB+O
MV NZ 
0.5 mL
Deltoid
Upper or lower
Non-
dominant
MenACWY
6
0.5 mL
Deltoid
Upper or lower
Dominant
rMenBOMV
rMenB+O
MV NZ 
0.5 mL
Deltoid
Upper or lower
Non-
dominant
MenACWY
MenACWY
6
0.5 mL
Deltoid
Upper or lower
Non-
dominant
Visit 3 
(Day 61)
MenABCWY
MenABCW
Y4
0.5 mL
IM
Deltoid
Upper or lower
Non-
dominant
rMenBOMV+A
CWY_S5
rMenB+O
MV NZ 
0.5 mL
Upper Deltoid 
(approximately 
2.5 cm above 
MenACWY 
injection)
Upper
Non-
dominant
MenACWY
6
0.5 mL
Lower Deltoid 
(approximately 
2.5 cm below 
rMenB+OMV NZ 
injection)
Lower
Non-
dominant
rMenBOMV+A
CWY_D7
rMenB+O
MV NZ 
0.5 mL
Deltoid
Upper or lower
Non-
dominant
MenACWY
6
0.5 mL
Deltoid
Upper or lower
Dominant
rMenBOMV
rMenB+O
MV NZ 
0.5 mL
Deltoid
Upper or lower
Non-
dominant
1Intramuscular (IM)
2Directionality is a qualifier for further detailing the location of the vaccine(s) administration (e.g. Upper, Lower)
3The non-dominant arm is the preferred arm of injection. In case it is not possible to administer the vaccine(s) in the 
non-dominant arm, an injection in the dominant arm may be performed.
4MenABCWY is to be reconstituted as a 0.5 mL solution between MenACWY lyo (lyophilized component) and 
rMenB+OMV NZ (liquid component) by trained staff.
5S refers to administration in the same arm (approximately 2.5 cm apart).
6MenACWY is to be reconstituted as a 0.5 mL solution between Men A lyo (lyophilized component) and Men CWY 
liquid (liquid component) by trained staff.
7D refers to administration in 2 different arms.
 
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Route of 
administration
IM
Excluded 
concomitant 
medications
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.

Any investigational or non-registered product (drug or 
vaccine) other than the study vaccine(s) used during the 
study period. 

Immunosuppressants or other immune-modifying drugs 
administered chronically (i.e. more than 14 consecutive days 
in total) during the study period. Inhaled and topical steroids 
are allowed.

Long-acting immune-modifying drugs administered at any 
time during the study period (e.g. infliximab).

A vaccine not foreseen by the study protocol administered 
during the period of 14 days (for in activated vaccines), 
28 days (for live vaccines), or 7 days (for influenza 
vaccines) before or after administration of the study 
vaccine(s) at Visit 1 and Visit 3.

Drug and/or alcohol abuse that, in the opinion of the 
investigator, will interfere with the results of the study or 
pose additional risk to the subject.
Overview of the 
study design
This Phase II, randomized, open-label clinical study is designed 
to evaluate the potential immune interference when 
MenABCWY is administered to healthy subjects as 2 injections, 
2 months apart. To accomplish this aim, immune responses to 
MenABCWY will be assessed and compared with responses to 
MenACWY (Menveo) and rMenB+OMV (Bexsero) when 
administered concomitantly (in the same arm or in 2 different 
arms) or either vaccine alone. Immune responses will be 
measured by hSBA using a standard panel consisting of 
N. meningitidis serogroup A, C, W-135, and Y and serogroup B 
test strains directed against each of the major corresponding 
meningococcal antigens included in the vaccines (Men B test 
strains for rMenB+OMV NZ and Men A, C, W-135, and Y test 
strains for MenACWY). Concomitant administration of 
MenACWY and rMenB+OMV NZ vaccines in the same arm 
(approximately 2.5 cm apart) or in 2 different arms will allow 
evaluation of a potential immune interference due to 
immunological stress to lymph nodes in the arm where the 
combination vaccine is administered.
 
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Study design

Experimental design: Phase II, open-label, randomized, 
controlled, multi-centric, study with 5 parallel study groups

Duration of the study: Up to 91 days (4 visits, 30 days apart)

Epoch 001: Starting at Visit 1 (Day 1) and ending at 
Visit 4 (Day 91) 

Primary Completion Date: Visit 4 (Day 91)

End of Study: Date of the last testing results released for the
samples collected at Visit 4 (Day 91), to be achieved no later 
than 8 months after the Last Subject Last Visit

Study groups: 
Approximately 500 subjects will be randomly assigned at a 
1:1:1:1:1 ratio to receive one of the following:

MenABCWY: Approximately 100 subjects (50 subjects 
aged 10 to 17 years and 50 subjects aged 18 to 
25 years) will receive 1 IM dose of MenABCWY twice, 
2 months apart.

rMenBOMV+ACWY_S: Approximately 100 subjects 
(50 subjects aged 10 to 17 years and 50 subjects aged 
18 to 25 years) will concomitantly receive 1 IM dose of 
rMenB+OMV NZ and 1 IM dose of MenACWY in the 
same arm (approximately 2.5 cm apart) twice, 2 months 
apart.

rMenBOMV+ACWY_D: Approximately 100 subjects 
(50 subjects aged 10 to 17 years and 50 subjects aged 
18 to 25 years) will concomitantly receive 1 IM dose of 
rMenB+OMV NZ and 1 IM dose of MenACWY in 
2 different arms twice, 2 months apart.

rMenBOMV: Approximately 100 subjects (50 subjects 
aged 10 to 17 years and 50 subjects aged 18 to 
25 years) will receive 1 IM dose of rMenB+OMV NZ
twice, 2 months apart.

MenACWY: Approximately 100 subjects (50 subjects 
aged 10 to 17 years and 50 subjects aged 18 to 
25 years) will receive 1 IM dose of MenACWY once.
 
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Synopsis Table 2
Study groups and epochs foreseen in the study
Study groups
Number of subjects1
Age (Min – Max)
Epochs
Epoch 001
MenABCWY 
100
10 years – 25 years
x
rMenBOMV+ACWY_S2
100
10 years – 25 years
x
rMenBOMV+ACWY_D3
100
10 years – 25 years
x
rMenBOMV
100
10 years – 25 years
x
MenACWY 
100
10 years – 25 years
x
1Approximate number of subjects.
2S refers to administration in the same arm (approximately 2.5 cm apart).
3D refers to administration in 2 different arms.
Synopsis Table 3
Study groups and treatment foreseen in the study
Treatment 
name
Vaccine name
Study groups
MenABCWY
rMenBOMV
+ACWY_S1
rMenBOMV
+ACWY_D2
rMenBOMV
MenACWY
MenABCWY
MenACWY lyo
x
rMenB+OMV NZ
rMenB+OMV NZ
rMenB+OMV NZ
x
x
x
MenACWY
MenA lyo
x
x
x
MenCWY liquid
1S refers to administration in the same arm (approximately 2.5 cm apart).
2D refers to administration in 2 different arms.

Control: active control

Vaccination schedules: First vaccination at Visit 1 (Day 1) 
and second vaccination at Visit 3 (Day 61), with the 
exception of the MenACWY study group, which will have 
only 1 vaccination at Visit 1 (Day 1)

Treatment allocation: Randomization will be performed 
prior to or at Visit 1 (Day 1). The randomization list will be 
generated using MATerial EXcellence (MATEX). Central 
randomization will be performed using the Source DataBase 
for Internet Randomization (SBIR) system.
Note: Within each age stratum (10 to 17 years and 18 to 
25 years) the randomization algorithm will use a 
minimization procedure accounting for center.

Blinding: Open-label
Synopsis Table 4
Blinding of study epochs
Study Epochs
Blinding
Epoch 001
Open
 
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
Sampling schedule: Blood samples of approximately 20 mL 
will be taken at Visit 1, Visit 2, and Visit 4, with the 
exception of the MenACWY study group, which will have 
blood samples collected only at Visit 1 and Visit 2

Type of study: Self-contained

Data collection: Standardized eCRF; solicited symptoms 
will be collected using a subject pDiary
Statistical 
methodology
For more information about statistical methodology, see 
protocol Section 10.
 
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Synopsis Table 5
List of study procedures
Epoch
Epoch 001
Type of contact
Visit 1
Safety call 1 
Visit 2
Visit 3
Safety call 2
Visit 4
Time points
Day 1
Day 15
Day 31
Day 61
Day 75
Day 91
Sampling time points
Pre-Vacc 1 
Post-Vacc 
1 
Post-Vacc 2 
Informed consent
●1 
Check inclusion/exclusion 
criteria
●1 
○
Collect demographic data
●1 
Medical history
●1 
History directed physical 
examination
○
Physical examination
○
○
Urine pregnancy test
●2, 3 
●2,3 
Check contraindications and 
warnings and precautions to 
vaccination
●
●4 
Pre-vaccination body 
temperature
●
●4 
Measure/record height and 
weight
●1 
Study group and treatment 
number allocation
●
Recording of administered 
treatment number
●
●4 
Blood sampling (~20 mL)
●5 
●
●4
Vaccine(s) administration
●
●4
Record any concomitant 
medications/vaccinations
●
●
●
●4 
●4 
●4 
Record any intercurrent medical 
conditions
●
●
●
●4 
●4 
●4 
Distribution of pDiary
○
○4,6
Review of pDiary
○
○4 
○4 
Return of pDiary
○6
○4,6
○4,6
Recording of AEs within 
30 minutes post-vaccination
●
●4
Recording of solicited AEs 
(days 1 to 7 post-vaccination)
●
●4
Recording of unsolicited AEs 
(days 1 to 30 post-vaccination) 
●
●
●
●4 
●4 
●4 
Recording of AEs, SAEs, 
medically attended AEs, AESI, 
and AEs leading to withdrawal 
●1
●
●
●
●
●
Recording of AEs/SAEs related 
to study participation or to a 
concurrent GSK 
medication/vaccine
●1 
●
●
●
●
●
Recording of SAEs related to 
study vaccine(s) 
●1
●
●
●
●
●
Study conclusion
●
 
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1Activities that can be performed at a separate visit before Visit 1 (maximum 5 days before the Visit 1). All AEs/SAEs, 
including those related to study participation or to a concurrent GSK medication/vaccine should be recorded starting 
from informed consent signature. Inclusion/exclusion criteria should be re-checked prior to vaccination at Visit 1.
2For women of childbearing age. The pregnancy test is to be performed locally onsite.
3A pregnancy test is mandatory even if performed during a prior separate visit.
4This study procedure will not be performed at this time point for the MenACWY group, administered only 1 dose of 
vaccine at Visit 1 (no Visit 3 performed) 
5Blood sample collection will be performed before vaccine(s) administration. 
6Subjects who receive a single dose of MenACWY only will return their pDiary at Visit 2 (Day 31). All subjects in the 
other treatment groups will return their first pDiary at Visit 3 (Day 61) and will receive a second pDiary for the 
remainder of the study.
● 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.
AE = adverse event; AESI = adverse event of special interest; eCRF = electronic case report form; 
GSK = GlaxoSmithKline; Pre-Vacc: pre-vaccination; Post-Vacc: post-vaccination; SAE = serious adverse event
 
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TABLE OF CONTENTS
PAGE
SPONSOR INFORMATION ............................................................................................7
SYNOPSIS......................................................................................................................8
LIST OF ABBREVIATIONS...........................................................................................31
GLOSSARY OF TERMS ...............................................................................................33
TRADEMARKS .............................................................................................................38
1.
INTRODUCTION....................................................................................................39
1.1.
Background ................................................................................................39
1.2.
Rationale for the study and study design ....................................................39
1.2.1.
Rationale for the study.................................................................39
1.2.2.
Rationale for the study design......................................................40
1.3.
Benefit:Risk assessment.............................................................................40
1.3.1.
Risk assessment..........................................................................41
1.3.2.
Benefit assessment .....................................................................45
1.3.3.
Overall benefit : risk conclusion ...................................................45
2.
OBJECTIVES.........................................................................................................45
2.1.
Primary objective ........................................................................................45
2.2.
Secondary objectives..................................................................................46
2.3.
Tertiary objective ........................................................................................46
3.
STUDY DESIGN OVERVIEW ................................................................................46
4.
STUDY COHORT...................................................................................................49
4.1.
Number of subjects/centers ........................................................................49
4.2.
Inclusion criteria for enrollment ...................................................................49
4.3.
Exclusion criteria for enrollment..................................................................50
5.
CONDUCT OF THE STUDY ..................................................................................52
5.1.
Regulatory and ethical considerations, including the informed 
consent process..........................................................................................52
5.2.
Subject identification and randomization.....................................................53
5.2.1.
Subject identification....................................................................53
5.2.2.
Randomization of treatment.........................................................53
5.2.2.1.
Treatment allocation to the subject.............................53
5.2.2.1.1.
Study group and treatment 
number allocation ...................................53
5.2.2.1.2.
Treatment number allocation for 
subsequent doses ..................................54
5.3.
Method of blinding ......................................................................................54
5.4.
General study aspects ................................................................................54
5.5.
Outline of study procedures ........................................................................54
5.6.
Detailed description of study procedures ....................................................56
5.6.1.
Informed consent.........................................................................56
5.6.2.
Check inclusion and exclusion criteria .........................................56
 
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5.6.3.
Collect demographic data ............................................................56
5.6.4.
Medical history.............................................................................57
5.6.5.
Physical examination ...................................................................57
5.6.6.
Pregnancy test.............................................................................57
5.6.7.
Check contraindications, warnings, and precautions to 
vaccination...................................................................................57
5.6.8.
Assess pre-vaccination body temperature ...................................57
5.6.9.
Study group and treatment number allocation..............................57
5.6.10.
Sampling......................................................................................58
5.6.10.1.
Blood sampling for immune response 
assessments ..............................................................58
5.6.11.
Study vaccines administration......................................................58
5.6.12.
Check and record concomitant medication/vaccination and 
intercurrent medical conditions ....................................................58
5.6.13.
Recording of adverse events, serious adverse events, 
pregnancies, and adverse events of special interest....................58
5.6.13.1.
Subject diary...............................................................59
5.6.13.2.
Post-vaccination reminders ........................................59
5.6.13.2.1.
Subject diary reminder calls....................59
5.6.13.3.
Safety follow-up calls..................................................60
5.6.14.
Study conclusion..........................................................................60
5.7.
Biological sample handling and analysis.....................................................60
5.7.1.
Use of specified study materials ..................................................61
5.7.2.
Biological samples.......................................................................61
5.7.3.
Laboratory assays .......................................................................62
5.7.4.
Biological samples evaluation......................................................64
5.7.4.1.
Immunological read-outs ............................................64
5.7.5.
Immunological correlates of protection.........................................64
6.
STUDY VACCINES ADMINISTRATION.................................................................65
6.1.
Description of study vaccines......................................................................65
6.2.
Storage and handling of study vaccines......................................................67
6.3.
Dosage and administration of study vaccines .............................................67
6.4.
Replacement of unusable vaccine doses....................................................69
6.5.
Contraindications to subsequent vaccination ..............................................69
6.6.
Warnings and precautions ..........................................................................70
6.7.
Concomitant medications/products and concomitant vaccinations..............70
6.7.1.
Recording of concomitant medications/products and 
concomitant vaccinations.............................................................70
6.7.2.
Concomitant medications/products/vaccines that may lead 
to the elimination of a subject from per-protocol analyses............70
6.8.
Intercurrent medical conditions that may lead to elimination of a 
subject from per-protocol analyses .............................................................71
7.
HEALTH ECONOMICS ..........................................................................................71
8.
SAFETY.................................................................................................................71
8.1.
Safety definitions ........................................................................................72
8.1.1.
Definition of an adverse event......................................................72
8.1.2.
Definition of a serious adverse event ...........................................73
8.1.3.
Solicited adverse events..............................................................73
8.1.3.1.
Solicited local adverse events ....................................74
 
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8.1.3.2.
Solicited systemic adverse events..............................74
8.1.3.3.
Other solicited adverse events ...................................74
8.1.4.
Unsolicited adverse events ..........................................................74
8.1.5.
Clinical laboratory parameters and other abnormal 
assessments qualifying as adverse events or serious 
adverse events ............................................................................75
8.1.6.
Adverse events of special interest................................................75
8.1.6.1.
Arthritis.......................................................................75
8.2.
Events or outcomes not qualifying as adverse events or serious 
adverse events ...........................................................................................76
8.2.1.
Pregnancy ...................................................................................76
8.3.
Detecting and recording adverse events, serious adverse events, 
and pregnancies .........................................................................................77
8.3.1.
Time period for detecting and recording adverse events, 
serious adverse events, and pregnancies....................................77
8.3.2.
Post-study adverse events and serious adverse events...............79
8.3.3.
Evaluation of adverse events and serious adverse events...........80
8.3.3.1.
Active questioning to detect adverse events 
and serious adverse events........................................80
8.3.3.2.
Assessment of adverse events...................................80
8.3.3.2.1.
Assessment of intensity..........................80
8.3.3.2.2.
Assessment of causality .........................82
8.3.3.3.
Assessment of outcomes............................................83
8.3.3.4.
Medically attended visits.............................................83
8.4.
Reporting of serious adverse events, pregnancies, and other events .........83
8.4.1.
Prompt reporting of serious adverse events, pregnancies, 
and other events..........................................................................83
8.4.2.
Contact information for reporting serious adverse events, 
pregnancies, and adverse events of special interest....................84
8.4.3.
Completion and transmission of SAE reports...............................84
8.4.3.1.
Back-up system in case the electronic 
reporting system does not work..................................85
8.4.4.
Completion and transmission of pregnancy reports .....................85
8.4.5.
Reporting of adverse events of special interest............................85
8.4.6.
Updating of serious adverse event, pregnancy, and 
adverse events of special interest information after 
removal of write access to the subject’s electronic case 
report form...................................................................................86
8.4.7.
Regulatory reporting requirements for serious adverse 
events..........................................................................................86
8.5.
Follow-up of adverse events, serious adverse events, and 
pregnancies................................................................................................86
8.5.1.
Follow-up of adverse events and serious adverse events............86
8.5.1.1.
Follow-up during the study..........................................86
8.5.1.2.
Follow-up after the subject is discharged from 
the study.....................................................................86
8.5.2.
Follow-up of pregnancies.............................................................87
8.6.
Treatment of adverse events ......................................................................87
8.7.
Subject card................................................................................................87
9.
SUBJECT COMPLETION AND WITHDRAWAL.....................................................88
9.1.
Subject completion .....................................................................................88
 
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9.2.
Subject withdrawal......................................................................................88
9.2.1.
Subject withdrawal from the study ...............................................88
9.2.2.
Subject withdrawal from study vaccines.......................................89
9.3.
Screen failures............................................................................................89
10. STATISTICAL METHODS......................................................................................90
10.1.
Primary endpoint.........................................................................................90
10.2.
Secondary endpoints ..................................................................................91
10.3.
Tertiary endpoint.........................................................................................92
10.4.
Determination of sample size......................................................................92
10.5.
Analysis sets...............................................................................................93
10.5.1.
All Enrolled Set ............................................................................93
10.5.2.
All Exposed Set ...........................................................................94
10.5.3.
Safety Set....................................................................................94
10.5.3.1.
Solicited Safety Set (solicited local and 
systemic adverse events and other solicited 
adverse events)..........................................................94
10.5.3.2.
Unsolicited Safety Set (unsolicited adverse 
events) .......................................................................94
10.5.3.3.
Overall Safety Set ......................................................94
10.5.4.
Full Analysis Set, Immunogenicity ...............................................94
10.5.4.1.
Full Analysis Set 1......................................................94
10.5.4.2.
Full Analysis Set 2......................................................94
10.5.4.3.
Full Analysis Set 3......................................................94
10.5.4.4.
Full Analysis Set 4......................................................95
10.5.5.
Per-Protocol Set, Immunogenicity................................................95
10.5.6.
Other analysis sets ......................................................................95
10.5.7.
Subgroups ...................................................................................95
10.6.
Derived and transformed data.....................................................................95
10.7.
Analysis of demographics...........................................................................96
10.8.
Analysis of immunogenicity.........................................................................96
10.9.
Analysis of safety........................................................................................98
10.9.1.
Analysis of extent of exposure .....................................................98
10.9.2.
Analysis of local and systemic adverse events ............................98
10.9.3.
Analysis of other adverse events .................................................99
10.10. Interpretation of analyses............................................................................99
10.11. Conduct of analyses .................................................................................100
10.11.1. Sequence of analyses................................................................100
10.11.2. Statistical considerations for interim analyses............................100
11. ADMINISTRATIVE MATTERS .............................................................................100
11.1.
Electronic case report form instructions ....................................................100
11.2.
Subject diary.............................................................................................100
11.3.
Study monitoring.......................................................................................101
11.4.
Record retention .......................................................................................102
11.5.
Quality assurance.....................................................................................102
11.6.
Posting of information on publicly available clinical trial registers and 
publication policy ......................................................................................103
11.7.
Provision of study results to investigators .................................................103
11.8.
Data sharing .............................................................................................103
12. COUNTRY SPECIFIC REQUIREMENTS.............................................................103
 
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13. REFERENCES.....................................................................................................104
 
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LIST OF TABLES
PAGE
Table 1
Study groups and epochs foreseen in the study.....................................48
Table 2
Study groups and treatment foreseen in the study .................................48
Table 3
Blinding of study epochs ........................................................................49
Table 4
List of study procedures .........................................................................55
Table 5
Intervals between study visits.................................................................56
Table 6
Biological samples .................................................................................62
Table 7
Humoral immunity (antibody determination) ...........................................63
Table 8
Immunological read-outs........................................................................64
Table 9
Study vaccines.......................................................................................66
Table 10
Dosage and administration.....................................................................68
Table 11
Reporting periods for collecting safety information .................................79
Table 12
Intensity scales for solicited symptoms...................................................81
Table 13
Timeframes for submitting serious adverse event, pregnancy, 
and other events reports ........................................................................84
Table 14
Sample size calculation results ..............................................................93
Table 15
GSK Biologicals’ laboratories ...............................................................106
 
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LIST OF FIGURES
PAGE
Figure 1
Study design diagram ............................................................................47
 
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LIST OF APPENDICES
PAGE
Appendix A
LABORATORY ASSAYS .....................................................................105
Appendix B
CLINICAL LABORATORIES ................................................................106
Appendix C
AMENDMENTS AND ADMINISTRATIVE CHANGES TO THE 
PROTOCOL.........................................................................................107
 
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LIST OF ABBREVIATIONS
ADEM
Acute disseminated encephalomyelitis
AE
Adverse event
AESI
Adverse events of special interest
ANCOVA
Analysis of covariance
ATEAM
Advanced Temperature Excursion Analysis and 
Management
BMI
Body mass index
CFS
Chronic fatigue syndrome
CI
Confidence interval
eCRF
Electronic case report form 
EoS
End of Study
EU
European Union
FAS
Full Analysis Set
fHbp
Factor H binding protein
GBS
Guillain-Barré Syndrome
GCP
Good Clinical Practice
GMR
Geometric mean ratio
GMT
Geometric mean titer
GSK
GlaxoSmithKline
hSBA
Serum bactericidal assay using human complement
IAF
Informed assent form
ICF
Informed consent form
ICH
International Council for Harmonisation
IM
Intramuscular(ly)
IMD
Invasive meningococcal disease
 
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LAR
Legally Acceptable Representative
LLOQ
Lower limit of quantitation
LOD
Limit of detection
LSLV
Last Subject Last Visit
MATEX
MATerial EXcellence
MedDRA
Medical Dictionary for Regulatory Activities
NadA
Neisserial adhesin A
NHBA
Neisseria heparin binding antigen
OMV
Outer membrane vesicles
PCD
Primary Completion Date
pDiary
Paper diary
PPS
Per-Protocol Set
SD
Standard deviation
SAE
Serious adverse event
SBIR
Source DataBase for Internet Randomization
SmPC
Summary of Product Characteristics
SPM
Study Procedures Manual
US
United States
 
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GLOSSARY OF TERMS
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 unfavorable
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.
Adverse events of special 
interest:
Adverse events of special interest (AESIs): are predefined 
(serious or non-serious) adverse events of scientific and 
medical concern specific to the product or program, for 
which ongoing monitoring and rapid communication by 
the investigator to the sponsor can be appropriate, 
because such an event might warrant further investigation 
in order to characterize and understand it.
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 
open-label study, no blind is used. Both the investigator 
and the subject know the identity of the treatment 
assigned.
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.
 
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End of Study:
(Synonym of End of Trial)
For studies with collection of Human Biologicals 
Samples or imaging data, End of Study (EoS) is defined 
as the date of the last testing/reading released of the 
Human Biological Samples or imaging data, related to 
primary and secondary endpoints. EoS must be achieved 
no later than 8 months after the Last Subject Last Visit 
(LSLV).
Epoch:
An epoch is a set of consecutive time points or a single 
time point from a single protocol. Epochs are defined to 
support a main purpose which 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 time points included in an epoch must be sufficient 
to fulfil the purpose of the epoch.
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.
Highly effective
contraception:
Highly effective contraceptive methods, defined as 
contraceptive methods with a failure rate of less than 1% 
per year according to the Pearl Index, when used 
consistently and correctly and in accordance with the 
product label, when applicable. These methods include:

combined (estrogen and progestogen containing) 
hormonal contraception associated with inhibition of 
ovulation:

oral

intravaginal (i.e. contraceptive vaginal ring)

percutaneous delivery system (i.e. transdermal 
patch)

progestogen-only hormonal contraception associated 
with inhibition of ovulation:

injectable

implantable

intrauterine device

intrauterine hormone-releasing system

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
vasectomized partner (provided that partner is the sole 
sexual partner of the female subject and that the 
vasectomized partner has received medical 
assessment of the surgical success, i.e. documented 
sterility). The documentation on male sterility can 
come from the site personnel’s: review of subject’s 
medical records, medical examination of the subject 
and/or semen analysis, or medical history interview 
provided by her or her partner.

sexual abstinence (defined as refraining from penile-
vaginal intercourse during the entire period of risk 
associated with the study treatments). Periodic 
abstinence (e.g. calendar, ovulation, symptothermal, 
post-ovulation methods) and withdrawal are not 
acceptable methods of contraception.
Highly effective 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.
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. 
Legally acceptable 
representative:
(The terms legal 
representative or legally 
authorized representative 
are used in some settings)
An individual or juridical or other body authorized under 
applicable law to consent, on behalf of a prospective 
subject, to the subject’s participation in the clinical trial.
Medically-attended 
adverse event:
Symptoms or illnesses requiring hospitalization, or 
emergency room visit, or visit to/by a health care 
provider.
 
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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 to 
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).
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.
Protocol amendment:
The International Council for Harmonisation (ICH) 
defines a protocol amendment as: “A written description 
of a change(s) to or formal clarification of a protocol.”
GSK Biologicals further details this to include a change 
to an approved protocol that affects the safety of subjects, 
scope of the investigation, study design, or scientific 
integrity of the study.
Protocol administrative 
change:
A protocol administrative change addresses changes to 
only logistical or administrative aspects of the study.
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.
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:
Adverse events 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.
 
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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.
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.
Subset:
(Synonym of 
Immunosubset)
Selection of blood samples among all blood samples
collected at given time point(s) for testing by specific 
assay.
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 without the superscript symbol ™ or ® and in italics.
Trademarks of the GSK group of 
companies
Generic description
Bexsero
Neisseria meningitidis serogroup B vaccine
Menveo
Neisseria meningitidis serogroups ACWY 
conjugate vaccine
 
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1.
INTRODUCTION
1.1.
Background
GlaxoSmithKline (GSK) Biologicals is developing a combination vaccine intended for 
primary immunization against Neisseria meningitidis serogroups A, B, C, W-135, and Y
(MenABCWY vaccine). The availability of a meningococcal vaccine based on the 
combination of antigens in 2 separate vaccines against serogroups ACWY (Menveo) and 
B (Bexsero) in a single vaccine/administration would reduce the number of injections and 
allow greater flexibility in dose administration schedules, and could increase coverage for 
meningococcal disease caused by N. meningitidis serogroups A, B, C, W-135, and Y 
worldwide.
Please refer to the current Investigator Brochure for information regarding the 
pre-clinical and clinical studies for MenABCWY.
1.2.
Rationale for the study and study design
1.2.1.
Rationale for the study
Invasive meningococcal disease (IMD) occurs when, following an average incubation 
period of 4 days (range: 2 to 10 days), the normally asymptomatically carried 
encapsulated gram-negative bacterium N. meningitidis enters the bloodstream and 
multiplies, potentially causing sepsis. If the bacteria cross the blood-brain barrier, 
meningitis occurs. Sepsis and meningitis caused by N. meningitidis are serious diseases 
that can be fatal or leave permanent sequelae. In European Union (EU)/European 
Economic Area countries, despite the availability of advanced medical treatment and 
effective antibiotics, case-fatality rates are high at approximately 7% to 15%, with most 
cases caused by serogroup B [ECDC, 2016]. Up to one fifth of survivors suffer long-term 
sequelae, including mental retardation, hearing loss, and loss of limb use [Rosenstein, 
2001].
MenACWY is a meningococcal oligosaccharide conjugate vaccine licensed for active 
immunization to prevent IMD caused by N. meningitidis serogroups A, C, W-135, and Y. 
It is approved for adolescents and adults in more than 60 countries; many of these 
countries have also approved its use in children. In the EU, the vaccine is indicated for 
use in individuals 2 years of age and older, and in the United States (US), in individuals 
2 months to 55 years of age. Through 14-MAR-2017, more than 31,500 subjects across 
all age groups were exposed to MenACWY in clinical trials, and more than 28 million 
individuals were estimated to have been exposed to the vaccine within the post-marketing 
setting.
The rMenB+OMV NZ vaccine is approved for use in the EU, US, and several other 
countries for active immunization to prevent IMD caused by N. meningitidis serogroup B. 
In the EU, the vaccine is indicated for use in individuals 2 months of age and older; in the 
US, in individuals 10 to 25 years of age. Through 13-JAN-2017, more than 
13,500 subjects across all age groups were exposed to all formulations of meningococcal 
group B vaccine in clinical trials. The vaccination course with meningococcal group B 
 
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vaccine can vary between 2 and 4 doses per subject depending on age. Thus, 
post-marketing cumulative subject exposure since the first launch up to 13-JAN-2017 
was estimated as being between a minimum of 3,569,743 and a maximum of 7,139,487.
The investigational MenABCWY combination vaccine is based upon the 
2 aforementioned and well established GSK Biologicals’ vaccines, MenACWY and 
rMenB+OMV NZ. Both of these vaccines have been extensively tested in clinical trials in 
order to support marketing authorizations in several jurisdictions.
The clinical development program of the investigational MenABCWY combination 
vaccine has included 1 Phase I trial, 7 Phase II trials, and 2 Phase IIb trials. In the recent 
Phase IIb study MenABCWY-011 (V102_15), non-inferiority in terms of geometric 
mean titers (GMTs) could not be shown for 2 doses of MenABCWY versus 2 doses of 
rMenB+OMV NZ, given 2 months apart. Across several other studies of the 
MenABCWY program, immune responses against serogroup B antigens were also lower 
than immune responses assessed when rMenB+OMV NZ was administered alone. One 
possible reason that has been theorized is biological immune interference, possibly due to 
immunological stress to the lymph nodes in the arm where the combination vaccine is 
administered. The purpose of the current study is to evaluate whether there is immune 
interference when MenABCWY (consisting of MenACWY lyophilized component and 
rMenB+OMV NZ liquid component) is administered to healthy adolescents and adults 
following a 2-dose vaccination schedule with MenABCWY administered 2 months apart.
1.2.2.
Rationale for the study design
This Phase II, randomized, open-label clinical study is designed to evaluate the potential 
immune interference when MenABCWY is administered to healthy subjects as 
2 injections, 2 months apart. To accomplish this aim, immune responses to MenABCWY 
will be assessed and compared with responses to MenACWY and rMenB+OMV when 
administered concomitantly (in the same arm or in 2 different arms) or either vaccine 
alone. Immune responses will be measured by a serum bactericidal assay using human 
complement (hSBA) using a standard panel consisting of N. meningitidis serogroup A, C, 
W-135, and Y and serogroup B test strains directed against each of the major 
corresponding meningococcal antigens included in the vaccines (Men B test strains for 
rMenB+OMV NZ and Men A, C, W-135, and Y test strains for MenACWY). 
Concomitant administration of MenACWY and rMenB+OMV NZ vaccines in the same 
arm (approximately 2.5 cm apart) or in 2 different arms will allow evaluation of a 
potential immune interference due to immunological stress to lymph nodes in the arm 
where the combination vaccine is administered.
1.3.
Benefit:Risk assessment
Please refer to the current Investigator Brochure for the summary of potential risks and 
benefits of MenABCWY. Please refer to the Summary of Product Characteristics (SmPC) 
for information regarding the summary of potential risks and benefits of MenACWY and 
rMenB+OMV NZ.
The following section outlines the risk assessment and mitigation strategy for this study 
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1.3.1.
Risk assessment
Important 
potential/identified 
risk
Data/Rationale for risk
Mitigation strategy
Investigational vaccine: MenABCWY
Important potential risk:
Anaphylaxis, 
anaphylactic shock
Anaphylaxis and anaphylactic 
shock have been observed with 
other vaccines. No cases of 
anaphylaxis related to 
MenABCWY have been 
reported in the MenABCWY 
clinical development program. 
Allergic reaction (including 
anaphylactic reaction) is listed 
in the MenABCWY Investigator 
Brochure.
Anaphylaxis following the 
administration of MenABCWY 
constitutes an absolute 
contraindication to subsequent 
vaccination (see Section 6.5).
The subjects will be observed 
closely for at least 30 minutes 
following the administration of the 
vaccines, with appropriate 
medical treatment readily 
available in case of anaphylaxis 
(see Section 5.6.11).
Investigational vaccine: rMenB+OMV NZ
Important identified 
risk:
Fever
Fever may occur following 
vaccination. Fever is listed in 
the rMenB+OMV NZ SmPC. 
Any febrile illness constitutes a 
contraindication to administration 
of the vaccine at the time 
scheduled for vaccination (see 
Section 6.5). Prophylactic use of 
analgesic/antipyretic medications 
(preferably paracetamol) during 
the first 7 days after vaccination 
is allowed on a voluntary basis, 
but must be recorded in the 
source document and 
Concomitant Medications 
electronic case report form 
(eCRF) field (see Section 6.7.1).
Important potential risk:
Guillain-Barré 
Syndrome (GBS)
GBS has been observed with 
other vaccines. No cases 
related to this important 
potential risk have been 
identified in the rMenB+OMV 
NZ clinical development 
program. 
GBS will be monitored through 
serious adverse event (SAE) 
collection.
Important potential risk: 
Acute disseminated 
encephalomyelitis 
(ADEM)
ADEM has been observed with 
other vaccines. No cases have 
been identified in the 
rMenB+OMV NZ clinical 
development program.
ADEM will be monitored through 
SAE collection.
 
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Important 
potential/identified 
risk
Data/Rationale for risk
Mitigation strategy
Important potential risk:
Chronic fatigue 
syndrome (CFS)
No cases of CFS have been 
reported from clinical trials nor 
from post-marketing 
experience with rMenB+OMV 
NZ. A potential concern was 
raised with CFS following the 
vaccination with MenBvac 
(another outer membrane 
vesicles [OMV] vaccine) in 
Norway. The results of a 
case-control study showed no 
increased risk [Magnus, 2009].
No specific mitigation in this 
study. SAE collection is part of 
the study protocol.
Important potential risk:
Anaphylaxis and 
anaphylactic shock
No cases of anaphylaxis 
related to rMenB+OMV NZ 
have been reported in the 
rMenB+OMV NZ clinical 
development program. 
However, 1 related case of 
anaphylaxis within 30 minutes 
post-vaccination was reported 
in a third party expanded 
access program (V72_70TP). 
Allergic reactions (including 
anaphylactic reactions) are 
listed (see SmPC).
Anaphylaxis following the 
administration of rMenB+OMV 
NZ constitutes an absolute 
contraindication to subsequent 
vaccination (see Section 6.5). 
The subjects will be observed 
closely for at least 30 minutes 
following the administration of the 
vaccines, with appropriate 
medical treatment readily 
available in case of anaphylaxis 
(see Section 5.6.11).
Important potential risk:
Decrease of 
immunogenicity 
secondary to 
prophylactic use of 
paracetamol
Prophylactic use of 
paracetamol reduces the 
incidence and severity of fever 
without affecting the 
immunogenicity of either 
rMenB+OMV NZ or routine 
vaccines [Prymula, 2014]. The 
effect of antipyretics other than 
paracetamol on the immune 
response has not been studied. 
Prophylactic use of
analgesic/antipyretic medications 
(preferably paracetamol) to 
reduce febrile reactions during 
the first 7 days after vaccination 
is allowed on a voluntary basis, 
but must be recorded in the 
source document and 
Concomitant Medications eCRF 
field (see Section 6.7.1).
 
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Important 
potential/identified 
risk
Data/Rationale for risk
Mitigation strategy
Important potential risk:
Arthritis
This risk is based on a signal 
observed for rMenB+OMV NZ. 
Attenuated live virus vaccines 
(rubella) have been reported to 
be associated with joint-related 
diseases [Tingle, 1986]. Among 
inactivated vaccines, different 
manifestations of arthritis 
following hepatitis B 
vaccination (psoriatic arthritis, 
reactive arthritis, etc.) have 
been described [IOM, 2011]. 
However, there has been no 
association of arthritis with 
meningococcal vaccines 
reported in the literature. One 
clinical case of juvenile 
idiopathic arthritis possibly 
related to rMenB+OMV NZ and 
6 spontaneous reports 
considered to have a possible 
causal relationship have been 
observed.
Arthritis will be monitored through 
Adverse Events of Special 
Interest (AESI) collection (see 
Section 8.1.6.1).
Investigational vaccine: MenACWY
Important potential risk: 
Reconstitution errors
Cases describing medication 
errors due to administration of 
the serogroup CWY vaccine 
component only without 
addition of the lyophilized 
serogroup have been reported 
during the MenACWY clinical 
development program.
See Section 6.1.
Important potential risk:
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. 
 
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Important 
potential/identified 
risk
Data/Rationale for risk
Mitigation strategy
Important potential risk:
ADEM
ADEM has been observed with 
other vaccines. Two cases 
from clinical trials and 5 cases 
from spontaneous reporting 
were retrieved from the GSK’s 
global safety database. None 
have 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 have 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. No cases of 
facial paresis were reported 
from interventional clinical 
trials.
No specific risk mitigation in 
place in this study.
Important potential risk:
Vaccination failure 
(lack of efficacy)
It is known that a protective 
immune response may not be 
generated in every recipient. 
The number of reports 
suggestive of vaccination 
failure reported cumulatively 
does not suggest a significantly 
or unexpectedly high rate of 
vaccine failure. 
No specific risk mitigation in 
place in this study.
 
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Important 
potential/identified 
risk
Data/Rationale for risk
Mitigation strategy
Study Procedures 
Risk of blood 
sampling
Blood sampling is associated 
with a risk of syncope, 
dizziness, and infection after or 
during venipuncture.
Blood samples will be obtained 
by a trained professional and 
medical assistance will be 
available. The amount of blood to 
be taken for sampling will not be 
harmful to the health of the 
subject.
1.3.2.
Benefit assessment
Benefit considerations include:

Medical evaluations/assessments associated with this study (e.g. physical 
examinations).

Contributing to the process of developing new therapies in an area of unmet need.

Potential benefit of receiving the licensed rMenB+OMV NZ and MenACWY 
vaccines.
1.3.3.
Overall benefit : risk conclusion
No significant safety signals have been identified for MenABCWY. Cumulative safety 
data have not identified new important safety risks. The balance of anticipated benefits 
and apparent risks associated with MenABCWY continues to be acceptable following the 
ongoing systematic review of safety data.
Taking into account the measures taken to minimize risk to subjects participating in this 
study, the potential or identified risks identified in association with rMenB+OMV NZ, 
MenACWY, and MenABCWY are justified by the potential benefits 
(prevention/treatment) that may be afforded to subjects.
2.
OBJECTIVES
2.1.
Primary objective

To assess the immune response to 2 doses of MenABCWY, rMenB+OMV NZ, or 
rMenB+OMV NZ and MenACWY administered concomitantly in the same arm or in 
2 different arms, and to a single dose of MenACWY at 1 month after the last 
vaccination.
Refer to Section 10.1 for the definition of the primary endpoint.
 
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2.2.
Secondary objectives
Immunogenicity Objective

To assess the immune response to 2 doses of MenABCWY, rMenB+OMV NZ, or 
rMenB+OMV NZ and MenACWY administered concomitantly in the same arm or in 
2 different arms at 1 month after the first vaccination.
Safety Objective

To assess the safety and tolerability of 2 doses of MenABCWY, rMenB+OMV NZ, 
or rMenB+OMV NZ and MenACWY administered concomitantly in the same arm or 
in 2 different arms, and to a single dose of MenACWY.
Refer to Section 10.2 for the definition of the secondary endpoints.
2.3.
Tertiary objective

To further characterize the immune response induced by the study vaccine(s)
against an additional panel of strains of Neisseria species in a subset of subjects. 
Note: This tertiary objective is exploratory and suitable assays may or may not be 
developed. The tertiary objective will be assessed in a subset of subjects using 
remaining serum after the primary and secondary analyses have been completed; no 
additional blood samples will be collected from subjects. Any outcome of exploratory 
testing that would be of scientific/medical relevance will be reported in an 
annex/addendum to the final study report.
Refer to Section 10.3 for the definition of the tertiary endpoint and to Section 10.11.1
for the reporting of tertiary endpoint results.
(Amended 29 Aug 2018)
3.
STUDY DESIGN OVERVIEW
The study design diagram is provided in Figure 1.
 
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Figure 1
Study design diagram
A list of procedures that may be performed before Visit 1 is detailed in Table 4.
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 II, open-label, randomized, controlled, multi-centric, 
study with 5 parallel study groups

Duration of the study: Up to 91 days (4 visits, 30 days apart)

Epoch 001: Starting at Visit 1 (Day 1) and ending at Visit 4 (Day 91) 

Primary Completion Date (PCD): Visit 4 (Day 91)
Refer to glossary of terms for the definition of PCD.

End of Study (EoS): Date of the last testing results released for the samples collected 
at Visit 4 (Day 91), to be achieved no later than 8 months after the Last Subject Last 
Visit (LSLV)
Refer to glossary of terms for the definition of EoS.
 
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
Study groups:
Approximately 500 subjects will be randomly assigned at a 1:1:1:1:1 ratio to receive 
one of the following:

MenABCWY: Approximately 100 subjects (50 subjects aged 10 to 17 years and 
50 subjects aged 18 to 25 years) will receive 1 intramuscular (IM) dose of 
MenABCWY twice, 2 months apart.

rMenBOMV+ACWY_S: Approximately 100 subjects (50 subjects aged 10 to 
17 years and 50 subjects aged 18 to 25 years) will concomitantly receive 1 IM 
dose of rMenB+OMV NZ and 1 IM dose of MenACWY in the same arm 
(approximately 2.5 cm apart) twice, 2 months apart.

rMenBOMV+ACWY_D: Approximately 100 subjects (50 subjects aged 10 to 
17 years and 50 subjects aged 18 to 25 years) will concomitantly receive 1 IM 
dose of rMenB+OMV NZ and 1 IM dose of MenACWY in 2 different arms
twice, 2 months apart.

rMenBOMV: Approximately 100 subjects (50 subjects aged 10 to 17 years and 
50 subjects aged 18 to 25 years) will receive 1 IM dose of rMenB+OMV NZ
twice, 2 months apart.

MenACWY: Approximately 100 subjects (50 subjects aged 10 to 17 years and 
50 subjects aged 18 to 25 years) will receive 1 IM dose of MenACWY once.
Table 1
Study groups and epochs foreseen in the study
Study groups
Number of subjects1
Age (Min – Max)
Epochs
Epoch 001
MenABCWY 
100
10 years – 25 years
x
rMenBOMV+ACWY_S2
100
10 years – 25 years
x
rMenBOMV+ACWY_D3
100
10 years – 25 years
x
rMenBOMV
100
10 years – 25 years
x
MenACWY 
100
10 years – 25 years
x
1Approximate number of subjects.
2S refers to administration in the same arm (approximately 2.5 cm apart).
3D refers to administration in 2 different arms.
Table 2
Study groups and treatment foreseen in the study
Treatment 
name
Vaccine name
Study groups
MenABCWY
rMenBOMV
+ACWY_S1
rMenBOMV
+ACWY_D2
rMenBOMV
MenACWY
MenABCWY
MenACWY lyo
x
rMenB+OMV NZ
rMenB+OMV NZ
rMenB+OMV NZ
x
x
x
MenACWY
MenA lyo
x
x
x
MenCWY liquid
1S refers to administration in the same arm (approximately 2.5 cm apart).
2D refers to administration in 2 different arms.
 
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
Control: active control

Vaccination schedules: First vaccination at Visit 1 (Day 1) and second vaccination at 
Visit 3 (Day 61), with the exception of the MenACWY study group, which will have 
only 1 vaccination at Visit 1 (Day 1)

Treatment allocation: Randomization will be performed prior to or at Visit 1 (Day 1). 
The randomization list will be generated using MATerial EXcellence (MATEX). 
Central randomization will be performed using the Source DataBase for Internet 
Randomization (SBIR) system.

Blinding: Open-label
Table 3
Blinding of study epochs
Study Epochs
Blinding
Epoch 001
Open

Sampling schedule: Blood samples of approximately 20 mL will be taken at Visit 1, 
Visit 2, and Visit 4, with the exception of the MenACWY study group, which will 
have blood samples collected only at Visit 1 and Visit 2

Type of study: Self-contained

Data collection: Standardized eCRF; solicited symptoms will be collected using a 
subject paper diary (pDiary)
4.
STUDY COHORT
4.1.
Number of subjects/centers
The target enrollment will be approximately 500 subjects (approximately 100 subjects 
per study group). Refer to Section 10.3 for a detailed description of the criteria used in 
the determination of sample size.
Overview of the recruitment plan:

This is a multicenter study.

Enrollment will be terminated when approximately 500 subjects have been enrolled.

The recruitment and randomization will be monitored by SBIR.
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:
 
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1. Subjects and/or subjects’ parent(s)/Legally Acceptable Representative(s) (LARs) 
who, in the opinion of the investigator, can and will comply, with the requirements of 
the protocol (e.g. completion of the pDiary, return for follow-up visits, availability for 
all visits scheduled in the study).
2. Written informed consent obtained from the subject and/or from the parent(s)/LAR(s) 
of the subject prior to performing any study specific procedure.
3. Written informed assent obtained from subjects below the legal age of consent prior 
to performing any study specific procedure.
4. A male or female between, and including, 10 to 25 years of age 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, or bilateral ovariectomy.
Please refer to the glossary of terms for the definition of menarche.
7. Female subjects of childbearing potential may be enrolled in the study, if the subject:

has practiced highly effective for 30 days prior to vaccination, and

has a negative pregnancy test on the day of vaccination, and

has agreed to continue highly effective contraception during the entire treatment 
period and for 2 months after completion of the vaccination series. 
Please refer to the glossary of terms for the definition of highly effective 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:
1. Female planning to become pregnant or planning to discontinue contraceptive 
precautions.
2. Pregnant or lactating female.
3. Child in care.
Please refer to the glossary of terms for the definition of child in care.
Each subject must not have:
4. Current or previous, confirmed or suspected disease caused by N. meningitidis.
 
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5. Known contact to an individual with any laboratory-confirmed N. meningitidis
infection within 60 days prior to enrollment.
6. Previous vaccination against N. meningitidis at any time prior to informed consent.
7. Progressive, unstable or uncontrolled clinical conditions.
8. Hypersensitivity, including allergy, to any component of vaccines, medicinal products 
or medical equipment whose use is foreseen in this study.
9. Clinical conditions representing a contraindication to IM vaccination and blood 
draws.
10. Abnormal function of the immune system resulting from:

Clinical conditions.

Systemic administration of corticosteroids (oral/intravenous/IM) for more than 
14 consecutive days within 90 days prior to informed consent.

Administration of antineoplastic and immune-modulating agents or radiotherapy 
within 90 days prior to informed consent.
11. Received immunoglobulins or any blood products within 180 days prior to informed 
consent.
12. Received an investigational or non-registered medicinal product within 30 days prior 
to informed consent.
13. 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.
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. Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic, or renal 
functional abnormality, as determined by physical examination.
16. Any confirmed or suspected immunosuppressive or immunodeficient condition, 
based on medical history and physical examination (no laboratory testing required).
17. Are obese at screening (e.g. with a body mass index [BMI] 30 kg/m2, where BMI 
reflects obesity and not high muscle mass).
18. Family history of congenital or hereditary immunodeficiency. 
19. History of neuroinflammatory or autoimmune condition.
20. History of significant neurological disorder or seizure (history of febrile convulsion 
should not lead to exclusion).
21. Serious chronic illness.
22. History of chronic alcohol consumption and/or drug abuse (including current 
consumption/abuse).
23. Any study personnel as an immediate family or household member.
 
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24. Administration of a vaccine not foreseen by the study protocol in the period starting 
14 days (for inactivated vaccines), 28 days (for live vaccines), or 7 days (for influenza 
vaccines) before each dose and ending 14 days (for inactivated vaccines), 28 days (for 
live vaccines), or 7 days (for influenza vaccines) after each dose of study vaccine(s) 
administration.
25. Thrombocytopenia, bleeding disorders, or be receiving anticoagulant therapy.
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 International Council for
Harmonisation (ICH) Guideline for Good Clinical Practice (GCP), all applicable subject 
privacy requirements and the guiding principles of the Declaration of Helsinki. 
The study has been designed and will be conducted in accordance with the ICH 
Harmonised Tripartite Guideline for clinical investigation of medicinal products in the 
pediatric population (ICH E11) and all other applicable ethical guidelines.
PPD, the contract research organization for this study, will obtain favorable
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/Independent Ethics Committee review and favorable
opinion/approval of study protocol and any subsequent amendments.

Subject/subject’s parent(s)/LAR(s) informed consent and subject informed assent, as 
appropriate.

Investigator reporting requirements as stated in the protocol.
PPD 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. 
PPD 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. 
 
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Clinical judgement, local regulations and requirements should guide the final structure 
and content of the local version of the ICF.
In accordance with the ICH Harmonised Tripartite Guidelines for GCP, those subjects 
who can only be enrolled in the study with the consent of the subject’s parent(s)/LAR(s)
(e.g. minors), should be informed about the study to the extent compatible with the 
subject’s understanding and the subject should sign and personally date a written 
informed assent form (IAF). It is required that the assent be signed by each subject in 
addition to the informed consent that is to be signed by his/her parent(s)/LAR(s).
PPD 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 PPD and be approved (along with the protocol, and any other necessary 
documentation) by the Institutional Review Board/Independent Ethics Committee and 
other regulatory bodies as applicable.
5.2.
Subject identification and randomization
5.2.1.
Subject identification
Subject identification numbers will be assigned sequentially to the subjects who have 
consented or provided assent with consent from each subject’s parent(s)/LAR(s) 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.
Treatment allocation to the subject
The treatment numbers will be allocated by dose.
5.2.2.1.1.
Study group and treatment number allocation
The target will be to enroll approximately 500 eligible subjects who will be randomly 
assigned to 5 study groups in a (1:1:1:1:1) ratio (approximately 100 subjects in each 
study group).
The enrollment will be performed to ensure equal distribution of the population across 
the 2 age strata of 10 to 17 years and 18 to 25 years in each study group (i.e., of the 
approximately 100 subjects in each study group, approximately 50 subjects will be aged 
10 to 17 years and approximately 50 subjects will be aged 18 to 25 years).
The randomization list will be generated using MATEX, a program developed by GSK 
for use in SAS. Central randomization will be performed using SBIR.
 
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Allocation of the subject to a study group at the investigator site will be performed using 
the SBIR system. Within each age stratum (10 to 17 years and 18 to 25 years), the 
randomization algorithm will use a minimization procedure accounting for center. 
Minimization factors will have equal weight in the minimization algorithm.
After obtaining the signed and dated ICF/IAF from the subject/subject’s parent(s)/LAR(s)
and having checked the eligibility of the subject, the study staff in charge of the 
vaccine(s) administration will access SBIR. Upon providing the age (10 to 17 years and
18 to 25 years) and the subject identification number, the randomization system will 
determine the study group and will provide the treatment number to be used for each 
dose.
The number of each administered treatment must be recorded in the eCRF on the Vaccine 
Administration form/screen.
When SBIR is not available, please refer to the SBIR user guide or the Study Procedures 
Manual (SPM) for specific instructions.
After the target of 50 subjects per age group stratification (10 to 17 years or 18 to 
25 years) has been reached in any of the 5 study groups, the enrollment will be frozen for 
that age and study group.
5.2.2.1.2.
Treatment number allocation for subsequent doses
For each dose subsequent to the first dose, the study staff in charge of the vaccine(s)
administration will access SBIR, provide the subject identification number, and the 
system will provide a treatment number consistent with the allocated study group.
The number of each administered treatment must be recorded in the eCRF on the Vaccine 
Administration form/screen.
5.3.
Method of blinding 
This will be an open-label study.
The laboratory in charge of the laboratory testing will be blinded to the treatment, 
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.
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.
5.5.
Outline of study procedures
Refer to the list of study procedures in Table 4.
 
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Table 4
List of study procedures
Epoch
Epoch 001
Type of contact
Visit 1
Safety call 1 
Visit 2
Visit 3
Safety call 2
Visit 4
Time points
Day 1
Day 15
Day 31
Day 61
Day 75
Day 91
Sampling time points
Pre-Vacc 1 
Post-Vacc 
1 
Post-Vacc 2 
Informed consent
●1 
Check inclusion/exclusion 
criteria
●1 
○
Collect demographic data
●1 
Medical history
●1 
History directed physical 
examination
○
Physical examination
○
○
Urine pregnancy test
●2, 3 
●2,3 
Check contraindications and 
warnings and precautions to 
vaccination
●
●4 
Pre-vaccination body 
temperature
●
●4 
Measure/record height and 
weight
●1 
Study group and treatment 
number allocation
●
Recording of administered 
treatment number
●
●4 
Blood sampling (~20 mL)
●5 
●
●4
Vaccine(s) administration
●
●4
Record any concomitant 
medications/vaccinations
●
●
●
●4 
●4 
●4 
Record any intercurrent medical 
conditions
●
●
●
●4 
●4 
●4 
Distribution of pDiary
○
○4,6
Review of pDiary
○
○4 
○4 
Return of pDiary
○6
○4,6
○4,6
Recording of AEs within 
30 minutes post-vaccination
●
●4
Recording of solicited AEs
(days 1 to 7 post-vaccination)
●
●4
Recording of unsolicited AEs 
(days 1 to 30 post-vaccination) 
●
●
●
●4 
●4 
●4 
Recording of AEs, SAEs, 
medically attended AEs, AESI, 
and AEs leading to withdrawal 
●1
●
●
●
●
●
Recording of AEs/SAEs related 
to study participation or to a 
concurrent GSK 
medication/vaccine
●1 
●
●
●
●
●
Recording of SAEs related to 
study vaccine(s)
●1
●
●
●
●
●
Study conclusion
●
 
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1Activities that can be performed at a separate visit before Visit 1 (maximum 5 days before the Visit 1). All AEs/SAEs, 
including those related to study participation or to a concurrent GSK medication/vaccine should be recorded starting 
from informed consent signature. Inclusion/exclusion criteria should be re-checked prior to vaccination at Visit 1.
2For women of childbearing age. The pregnancy test is to be performed locally onsite.
3A pregnancy test is mandatory even if performed during a prior separate visit.
4This study procedure will not be performed at this time point for the MenACWY group, administered only 1 dose of 
vaccine at Visit 1 (no Visit 3 performed) 
5Blood sample collection will be performed before vaccine(s) administration. 
6Subjects who receive a single dose of MenACWY only will return their pDiary at Visit 2 (Day 31). All subjects in the 
other treatment groups will return their first pDiary at Visit 3 (Day 61) and will receive a second pDiary for the 
remainder of the study.
● 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.
AE = adverse event; AESI = adverse event of special interest; eCRF = electronic case report form; GSK = 
GlaxoSmithKline; Pre-Vacc: pre-vaccination; Post-Vacc: post-vaccination; SAE = serious adverse event
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 (Min – Max)1
Visit 1 (Day 1) Safety call 1 (Day 15)
14 days
11 days – 17 days (Days 12 – 18)
Visit 1 (Day 1) Visit 2 (Day 31)
30 days
23 days – 40 days (Days 24 – 41)
Visit 1 (Day 1) Visit 3 (Day 61)
60 days
53 days – 70 days (Days 54 – 71)
Visit 3 (Day 61) Safety call 2 (Day 75)
14 days
11 days – 17 days (Days 72 – 78)
Visit 3 (Day 61) Visit 4 (Day 91)
30 days
23 days – 40 days (Days 84 – 101)
1Safety call time intervals will not be used for the assessment of protocol deviations. The Study Day ranges shown in 
the table are based on optimal intervals; the actual Study Day ranges for Safety Call 2 and Visit 4 will be based on 
when Visit 3 occurs.
5.6.
Detailed description of study procedures
5.6.1.
Informed consent
The signed/witnessed/thumb printed informed consent of the subject/subject’s 
parent(s)/LAR(s) must be obtained before study participation. The signed informed 
assent of 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 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 date of birth (year only), gender, and ethnic origin in 
the subject’s eCRF.
 
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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 first study vaccination in the eCRF.
5.6.5.
Physical examination
Perform a history directed physical examination. This is a physical examination that will 
include measurement of heart rate, blood pressure, and temperature (preferably axilla). If 
the investigator determines that the subject’s health on the day of vaccination temporarily 
precludes vaccination, the visit will be rescheduled.
Physical examination at each study visit subsequent to the first vaccination 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.
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.
Pregnancy test
Female subjects of childbearing potential are to have a urine pregnancy test prior to any 
study vaccine(s) administration. The study vaccine(s) 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 each vaccination visit. Refer to Sections 6.5 and 6.6 for more details. 
5.6.8.
Assess pre-vaccination body temperature
The body temperature (preferably axilla) of each subject needs to be measured prior to 
any study vaccine(s) administration. If the subject has a fever (fever is defined as 
temperature 38.0°C regardless the location of measurement) on the day of vaccination, 
the vaccination visit will be rescheduled within the allowed interval for this visit as 
described in Table 5.
5.6.9.
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 subject 
records and the eCRF.
 
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5.6.10.
Sampling
Please refer to the Biospecimen Management section of the SPM and the central 
laboratory manual for detailed instructions for the collection, handling, processing, 
storage, and shipment of the samples.
5.6.10.1.
Blood sampling for immune response assessments
Blood samples will be taken during certain study visits as specified in Section 5.5 outline
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 time point. After 
centrifugation, serum samples should be kept at -20°C or below until shipment. 
Refer to the SPM and the central laboratory manual for details.

An overall volume of up to approximately 60 mL will be collected during the entire 
study period for immune response assessments, with the exception of the 
MenACWY study group, which will have an overall volume of approximately 
40 mL collected during the entire study period for immune response assessments.
5.6.11.
Study vaccines administration

After completing all prerequisite procedures prior to vaccination, 1 dose of study 
vaccine(s) will be administered IM in the deltoid (refer to Section 6.3 for detailed 
description of the administration procedure). If the investigator or delegate 
determines that the subject’s health on the day of administration temporarily 
precludes vaccine(s) administration, the visit will be rescheduled within the allowed 
interval for this visit (refer to Table 5).

The subjects will be observed closely for at least 30 minutes following the 
administration of the vaccine(s), with appropriate medical treatment readily available 
in case of anaphylaxis.
5.6.12.
Check and record concomitant medication/vaccination and 
intercurrent medical conditions
Concomitant medication/vaccination must be checked and recorded in the subject records 
and the eCRF as described in Section 6.7.
Intercurrent medical conditions must be checked and recorded in the subject records and 
the eCRF as described in Section 6.8.
5.6.13.
Recording of adverse events, serious adverse events, 
pregnancies, and adverse events of special interest

Refer to Section 8.3 for procedures for the investigator to record adverse events 
(AEs), medically attended AEs, SAEs, pregnancies, and AESIs. Refer to Section 8.4
for guidelines and how to report SAE, pregnancy, and AESI reports to PPD.
 
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
The subjects/subjects’ parent(s)/LAR(s) will be instructed to contact the investigator 
immediately should they/the subjects manifest any signs or symptoms they perceive 
as serious. 
5.6.13.1.
Subject diary
A pDiary hereafter referred to as Subject Diary will be used in this study to capture 
solicited AEs. 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 AEs 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/subject’s parent(s)/LAR(s) enters information into the Subject Diary, this 
person’s identity must be documented in the Subject Diary. Any individual that makes 
entries into the Subject Diary must receive training on completion of the Subject Diary at 
the time of the visit 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/subject’s parent(s)/LAR(s) should be trained on how to self-measure local 
solicited AEs and body temperature. 
The measurement of solicited local AEs is to be performed using the ruler provided by 
the site.
The subject/subject’s parent(s)/LAR(s) should be instructed how to perform body 
temperature (preferably axilla) measurement using the thermometer provided by the site, 
and to record the body temperature in the evening. If the subject feels unusually hot or 
cold during the day, the subject or parent(s)/LAR(s) should check the body temperature. 
If the subject has a fever, the highest body temperature observed that day should be 
recorded in the Subject Diary.
5.6.13.2.
Post-vaccination reminders
Reminder calls or alerts are not intended to be an interview for collection of safety data. 
If the subject/subject’s 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.
5.6.13.2.1. Subject diary reminder calls
Subject Diary reminder calls will be performed at 3 and 5 days (±1 day) after each 
vaccination (i.e., Day 4 and Day 6 after the first vaccination and accordingly after the 
second vaccination). (Amended 29 Aug 2018) The purpose of this call is to remind the 
subject/subject’s parent(s)/LAR(s) about completion of the Subject Diary. The call 
follows the Subject Diary Reminder Telephone Call Script provided to the site. The 
 
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subject/subject’s parent(s)/LAR(s) should be reminded to contact the site via the 
telephone number provided in the informed consent to discuss medical questions.
5.6.13.3.
Safety follow-up calls
Safety follow-up calls will be performed on Day 15 and Day 75. Please see Table 5 for 
the intervals allowed between study visits.
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/subject’s parent(s)/LAR(s) will be 
interviewed according to the script, and information relating to unsolicited AE (including 
SAEs, AESIs, medically attended AEs, and/or AEs leading to withdrawal) and 
concomitant medications or vaccinations associated with those events. All safety 
information described by the subject must be written down in a designated location 
within the source document and not written on the script used for the telephone call.
The site should schedule the next study clinic visit with the subject/subject’s 
parent(s)/LAR(s).
The subject/subject’s parent(s)/LAR(s) will be instructed to contact the site as soon as 
possible to report potential unsolicited AEs that required hospitalization, emergency 
room visit, or visit to/by a health care provider that were of concern. The detailed 
information about the reported unsolicited AEs will be collected by qualified site 
personnel during the interview and will be documented in the subject’s records.
5.6.14.
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 Biospecimen Management section of the SPM and the central 
laboratory manual for detailed instructions for the collection, handling, processing, 
storage, and shipment of the samples.
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.
 
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
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 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/subject’s parent(s)/LAR(s).
Refer also to the Amendment 2 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). 
If additional testing is performed, the marker priority ranking given in Section 5.7.4 may 
be changed.
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.
5.7.1.
Use of specified study materials
When materials are provided by GSK Biologicals’ selected 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 10.5.5 for the 
definition of analysis sets to be analyzed). The investigator must ensure that his/her 
personnel and the laboratory(ies) under his/her supervision comply with this requirement. 
However, when GSK Biologicals’ selected 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.
5.7.2.
Biological samples
The collection of blood samples during the study are defined in Table 6.
 
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Table 6
Biological samples
Sample type
Quantity
(per sample)
Unit
Study group
Time points
Blood
20
mL
MenABCWY
Visit 1 (Day 1)
Visit 2 (Day 31)
Visit 4 (Day 91)
Blood
20
mL
rMenBOMV+ACWY_S1
Visit 1 (Day 1)
Visit 2 (Day 31)
Visit 4 (Day 91)
Blood
20
mL
rMenBOMV+ACWY_D2
Visit 1 (Day 1)
Visit 2 (Day 31)
Visit 4 (Day 91)
Blood
20
mL
rMenBOMV
Visit 1 (Day 1)
Visit 2 (Day 31)
Visit 4 (Day 91)
Blood
20
mL
MenACWY
Visit 1 (Day 1)
Visit 2 (Day 31)
1S refers to administration in the same arm (approximately 2.5 cm apart).
2D refers to administration in 2 different arms.
5.7.3.
Laboratory assays
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 measures of immunogenicity used in this study are standard (i.e. widely used and 
generally recognized as reliable, accurate, and relevant [able to describe the quality and 
extent of the immune response]). Testing will be conducted by the GSK or designated 
laboratory in a blinded manner towards the treatment arm and to the study visit.
 
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Table 7
Humoral immunity (antibody determination)
System
Component
Method
Kit/ 
Manufacturer
Unit1
Cut-off1
Laboratory2
Humoral
Neisseria meningitidis
Serogroup B M14459 
(fHbp)
hSBA
In-house
1/Dilution
LLOQ
GSK 
Biologicals or a 
laboratory 
designated by 
GSK 
Biologicals3
Neisseria meningitidis
Serogroup B 96217 
(NadA)
1/Dilution
LLOQ
Neisseria meningitidis 
Serogroup B NZ98/254 
(PorA P1.4)
1/Dilution
LLOQ
Neisseria meningitidis
Serogroup B 
M07-0241084 (NHBA)
1/Dilution
LLOQ
Neisseria meningitidis
Serogroup A 
1/Dilution
LLOQ
Neisseria meningitidis
Serogroup C 
1/Dilution
LLOQ
Neisseria meningitidis
Serogroup W-135 
1/Dilution
LLOQ
Neisseria meningitidis
Serogroup Y 
1/Dilution
LLOQ
1Assay cut-offs and units will be determined following the completion of the qualification of hSBA for each of the 
8 serogroups. In case testing is performed at another GSK designated laboratory, the assay cut-offs may also need 
to be adapted accordingly. Any of these changes will be documented in a protocol amendment or in the clinical 
study report.
2Refer to Appendix B for the possible laboratory addresses.
3GSK Biologicals laboratory refers to the Clinical Laboratory Sciences in Rixensart, Belgium; Wavre, Belgium; 
Marburg, Germany.
GSK = GlaxoSmithKline; hSBA = serum bactericidal assay using human complement; LLOQ = lower limit of 
quantitation
Additional exploratory testing on the vaccine(s) 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.
 
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5.7.4.
Biological samples evaluation
5.7.4.1.
Immunological read-outs
Table 8
Immunological read-outs
Blood sampling time point
No. 
subjects1
Component
Components priority 
rank2
Type of contact and 
time point
Sampling time point
Visit 1 (Day 1)
Pre-Vacc 1
500
Serogroup B M14459
Serogroup B M07-0241084
Serogroup B 96217
Serogroup B NZ98/254
Serogroup C
Serogroup Y
Serogroup W-135
Serogroup A
1
2
3
4
5
6
7
8
Visit 2 (Day 31)
Post-Vacc 1 1
500
Serogroup B M14459
Serogroup B M07-0241084
Serogroup B 96217
Serogroup B NZ98/254
Serogroup C
Serogroup Y
Serogroup W-135
Serogroup A
1
2
3
4
5
6
7
8
Visit 4 (Day 91)3
Post-Vacc 2
400
Serogroup B M14459
Serogroup B M07-0241084
Serogroup B 96217
Serogroup B NZ98/254
Serogroup C
Serogroup Y
Serogroup W-135
Serogroup A
1
2
3
4
5
6
7
8
1Approximate number of subjects.
2Priority ranking for the serum bactericidal assay using human complement (hSBA) testing using the 8 indicator 
strains may be subject to change following the selection of the most appropriate hSBA format for each of the 
8 serogroups. This will be documented in a protocol amendment or the clinical study report.
3No blood collection and assays will be performed at this time point for the MenACWY treatment group.
Pre-Vacc: pre-vaccination; Post-Vacc: post-vaccination
In case of insufficient blood sample volume to perform assays for all antibodies, the 
samples will be analyzed according to priority ranking provided in Table 8. 
5.7.5.
Immunological correlates of protection
No generally accepted immunological correlate of protection has been demonstrated so 
far against N. meningitidis serogroups A, B, W-135, and Y.
An hSBA titer ≥4 is a generally accepted correlate of protection against invasive 
meningococcal disease caused by N. meningitidis serogroup C.
Assessment of the protection level will be performed 1 month after the last vaccination 
for the primary objective.
 
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The immunological assay results will be communicated to the investigator as soon as 
they become available and in any case no later than 12 months after the visit date at 
which sampling allows the assessment of protection.
The investigator is encouraged to share the immunological assay results for 
non-responders with the study subjects/subjects’ parent(s)/LAR(s).
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.
6.
STUDY VACCINES ADMINISTRATION
6.1.
Description of study vaccines
All vaccines to be used have been developed and manufactured by GSK Biologicals. 
The formulations of the study vaccines are shown in Table 9.
 
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Table 9
Study vaccines 
Treatment name
Vaccine name
Formulation
Presentation
Volume to be administered
Number of doses
MenABCWY 
MenACWY lyo 
MenA=10µg,CRM197=16.7-33.3µg;
MenC=5µg,CRM197=7.1-12.5µg;
MenW=5µg,CRM197=3.3-8.3µg;
MenY=5µg,CRM197=5.6-10µg;
NaH2PO4=0.328mg; Sucrose=12.5mg 
Lyophilized 
component in a vial
0.5 mL
2
rMenB+OMV NZ 
rp936-741=50µg;
rp287-953=50µg;
rp961c=50µg;
OMV NZ98/254=25µg;
Al(OH)3=1.5mg; Histidine=776µg;
NaCl=3.125mg; Sucrose=10mg; Water=0.5mL 
Suspension for 
injection in a 
pre-filled syringe
rMenB+OMV NZ 
rMenB+OMV NZ
rp936-741=50µg;
rp287-953=50µg;
rp961c=50µg;
OMV NZ98/254=25µg;
Al(OH)3=1.5mg; Histidine=776µg;
NaCl=3.125mg; Sucrose=10mg; Water=0.5mL 
Suspension for 
injection in a 
pre-filled syringe
0.5 mL
2
MenACWY
MenA lyo
MenA=10µg,CRM197=16.7-33.3µg;
KH2PO4=5mM; Sucrose=12.5mg
Lyophilized 
component in a vial
0.5 mL
1 or 2
MenCWY liquid
MenC=5µg,CRM197=7.1-12.5µg;
MenW=5µg,CRM197=3.3-8.3µg;
MenY=5µg,CRM197=5.6-10µg;
NaCl=4.5mg; Na3PO4=10mM;
NaH2PO4=2.5mM; Na2HPO4=7.5mM;
Water=0.5mL 
Liquid component in 
a vial
Note: MenACWY is approved in adults as a single dose injection. In this study, for study groups rMenBOMV+ACWY_S and rMenBOMV+ACWY_D, 2 injections of MenACWY 
will be administered.
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The Quality Control Standards and Requirements for each vaccine are described in 
separate Quality Assurance documents (e.g. certificate of analysis) and the required 
approvals have been obtained. 
The vaccines are labelled and packed according to applicable regulatory requirements.
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 label 
storage condition) impacting the study vaccines must be reported in the appropriate
(electronic) temperature excursion decision form (Advanced Temperature Excursion 
Analysis and Management [ATEAM]). The impacted study vaccines must not be used 
and must be stored in quarantine at label temperature conditions until usage approval has 
been obtained from GSK Biologicals/PPD.
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.
6.3.
Dosage and administration of study vaccines
The dosage and administration of the study vaccines are presented in Table 10.
In addition to the Investigator Brochure for MenABCWY and SmPCs for the commercial 
MenACWY and rMenB+OMV NZ vaccines, please also refer to the Critical Expert 
Overview document, which addresses the off-label administration of the MenACWY and 
rMenB+OMV NZ vaccines in this study.
 
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Table 10
Dosage and administration
Type of contact 
and time point
Study group
Treatment name
Volume to be 
administered
Route1
Site
Location
Directionality2
Laterality3
Visit 1 (Day 1)
MenABCWY
MenABCWY4
0.5 mL
IM
Deltoid
Upper or lower
Non-dominant 
rMenBOMV+ACWY_S5
rMenB+OMV NZ
0.5 mL
Upper Deltoid (approximately 2.5 cm above 
MenACWY injection)
Upper
Non-dominant
MenACWY6
0.5 mL
Lower Deltoid (approximately 2.5 cm below 
rMenB+OMV NZ injection)
Lower
Non-dominant
rMenBOMV+ACWY_D7
rMenB+OMV NZ 
0.5 mL
Deltoid
Upper or lower
Non-dominant
MenACWY6
0.5 mL
Deltoid
Upper or lower
Dominant
rMenBOMV
rMenB+OMV NZ 
0.5 mL
Deltoid
Upper or lower
Non-dominant
MenACWY
MenACWY6
0.5 mL
Deltoid
Upper or lower
Non-dominant
Visit 3 (Day 61)
MenABCWY
MenABCWY4
0.5 mL
IM
Deltoid
Upper or lower
Non-dominant
rMenBOMV+ACWY_S5
rMenB+OMV NZ 
0.5 mL
Upper Deltoid (approximately 2.5 cm above 
MenACWY injection)
Upper
Non-dominant
MenACWY6
0.5 mL
Lower Deltoid (approximately 2.5 cm below 
rMenB+OMV NZ injection)
Lower
Non-dominant
rMenBOMV+ACWY_D7
rMenB+OMV NZ 
0.5 mL
Deltoid
Upper or lower
Non-dominant
MenACWY6
0.5 mL
Deltoid
Upper or lower
Dominant
rMenBOMV
rMenB+OMV NZ 
0.5 mL
Deltoid
Upper or lower
Non-dominant
1Intramuscular (IM)
2Directionality is a qualifier for further detailing the location of the vaccine(s) administration (e.g. Upper, Lower)
3The non-dominant arm is the preferred arm of injection. In case it is not possible to administer the vaccine(s) in the non-dominant arm, an injection in the dominant arm may be 
performed.
4MenABCWY is to be reconstituted as a 0.5 mL solution between MenACWY lyo (lyophilized component) and rMenB+OMV NZ (liquid component) by trained staff.
5S refers to administration in the same arm (approximately 2.5 cm apart).
6MenACWY is to be reconstituted as a 0.5 mL solution between Men A lyo (lyophilized component) and Men CWY liquid (liquid component) by trained staff.
7D refers to administration in 2 different arms.
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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 10% additional vaccine doses will be 
supplied to replace those that are unusable.
6.5.
Contraindications to subsequent vaccination
The following events constitute absolute contraindications to further administration of 
MenABCWY, rMenB+OMV NZ, or MenACWY. If any of these events occur during the 
study, the subject must not receive additional doses of vaccine(s) but may continue other 
study procedures at the discretion of the investigator (see Section 8.5). 

Anaphylaxis following the administration of vaccine(s).

Pregnancy (see Section 8.2.1).

Any occurrence of an event listed in the exclusion criteria, which must always be 
re-assessed by the investigator before administration of the second dose of study 
vaccine(s). Refer to Section 4.3.

Subjects who experience any SAE judged to be possibly or probably related to study 
vaccine(s), including hypersensitivity reactions.

Subjects who develop any new condition which, in the opinion of the investigator, 
may pose additional risk to the subject if he/she continues to participate in the study.

Any condition that in the judgment of the investigator would make IM injection 
unsafe.
The following events constitute contraindications to administration of MenABCWY, 
rMenB+OMV NZ, or MenACWY 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). 

Body temperature elevation (i.e. fever) within 3 days prior to intended study 
vaccination. Fever is defined as temperature 38.0°C.

Significant acute illness (e.g. acute severe febrile illness) within 7 days prior to 
vaccination.

Administration of any other vaccine 14 days (for inactivated vaccines), 28 days (for 
live vaccines), or 7 days (for influenza vaccines) prior to vaccination.
Additionally, the following event warrants the delay of blood sample collection for 
immunogenicity assessments in this study.

Receipt of systemic antibiotics with the previous 3 days before blood sample 
collection.
In the event that a subject meets the criterion for delay of blood sample collection, blood 
sample collection may proceed once the appropriate window for delay has passed.
 
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6.6.
Warnings and precautions
Please also refer to the Investigator Brochure for MenABCWY. Please refer to the 
approved SmPCs for the commercial MenACWY and rMenB+OMV NZ vaccines.
6.7.
Concomitant medications/products and concomitant 
vaccinations
At each study contact, the investigator or delegate should question the subject and/or the 
subject’s 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 medications/products and concomitant vaccines must be 
recorded in the subject records and the eCRF.

All concomitant medications/products, except vitamins and dietary supplements, 
administered through 30 days post-vaccination.

Any concomitant vaccination administered in the period starting 28 days before the 
first dose of study vaccine(s) and ending at the last study visit (Day -28 to Day 91).

Prophylactic medication (i.e. medication administered in the absence of ANY 
symptom and in anticipation of a reaction to the vaccination).
For example, an antipyretic 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 temperature 38.0°C regardless the location of measurement). The 
preferred location for measuring temperature in this study is the axilla.

Any concomitant medications/products/vaccines listed in Section 6.7.2.

Any concomitant medications/products administered for treatment of an AE to be 
recorded as per protocol-specified reporting period (see Table 11).

Any concomitant medications/products/vaccines relevant to an SAE/AESI to be 
reported as per protocol or administered at any time during the study period for the 
treatment of an SAE/AESI. In addition, concomitant medications relevant to SAEs 
and AESIs need to be recorded on the Expedited Adverse Events Report.

The use of antipyretic and/or other medications to prevent (prophylactic use) and/or 
treat fever during the first 7 days after vaccination to be recorded in the eCRF as well.
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 10.5 for analyses sets to be analyzed.
 
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
Any investigational or non-registered product (drug or vaccine) other than the study 
vaccine(s) used during the study period. 

Immunosuppressants or other immune-modifying drugs administered chronically (i.e. 
more than 14 consecutive days in total) during the study period. Inhaled and topical 
steroids are allowed.

Long-acting immune-modifying drugs administered at any time during the study 
period (e.g. infliximab).

A vaccine not foreseen by the study protocol administered during the period of 
14 days (for inactivated vaccines), 28 days (for live vaccines), or 7 days (for 
influenza vaccines) before or after administration of the study vaccine(s) at Visit 1 
and Visit 3*.
*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 SmPC and according 
to local governmental recommendations and provided a written approval of the 
sponsor is obtained.

Drug and/or alcohol abuse that, in the opinion of the investigator, will interfere with 
the results of the study or pose additional risk to the subject.
6.8.
Intercurrent medical conditions that may lead to elimination 
of a subject from per-protocol analyses
At each study visit/safety call subsequent to the first vaccination/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 subject 
records and the eCRF.
Subjects may be eliminated from the per-protocol cohort for immunogenicity if, during 
the study, they incur a condition that has the capability of altering their immune response 
(i.e. human immunodeficiency virus or hematological malignancies) or are confirmed to 
have an alteration of their initial immune status.
For analysis purposes, intercurrent conditions will be identified using AEs reported in the 
eCRFs during the study.
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 AE or SAE as provided in 
this protocol. 
 
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Each subject/subject’s parent(s)/LAR(s) will be instructed to contact the investigator 
immediately should they/the subject manifest any signs or symptoms they perceive as 
serious.
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 unfavorable 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 vaccine 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
vaccine(s) or a concurrent medication (overdose per se should not be reported as an 
AE/SAE).

Signs, symptoms temporally associated with study vaccine(s) administration.

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).
Adverse events 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 
first 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 
An SAE is any untoward medical occurrence that:
a.
Results in death,
b.
Is life-threatening,
Note: The term “life-threatening” in the definition of “serious” refers to an event in 
which the subject was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, had it been more severe.
c.
Requires 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, diarrhea, 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 AEs”) 
occurring in the hours and days following a vaccination, to be collected by the 
subjects/parent(s)/LAR(s) for 7 consecutive days, using a pre-defined Subject Diary.
The following solicited AEs are included in the Subject Diary. 
 
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8.1.3.1.
Solicited local adverse events
Solicited local (injection site) AEs for this study are pain, erythema, swelling, and 
induration. The preferred location for measuring temperature in this study is the axilla.
Solicited local AEs will be recorded and collected according to which vaccine was 
administered and the site of administration (e.g. upper or lower deltoid and the arm used 
for administration).
8.1.3.2.
Solicited systemic adverse events
Solicited systemic AEs for this study are fever (body temperature ≥38.0°C), nausea, 
myalgia, arthralgia, headache, and fatigue.
8.1.3.3.
Other solicited adverse events
The use of analgesics/antipyretics (preferably paracetamol) for either prophylactic or 
treatment purposes will also be recorded as other solicited events in the Subject Diary and 
verified onto specific eCRFs and subject medical records.
The study staff must review the data entered into the Subject Diary as described in 
Section 11.2.
Note: Any solicited AE that meets any of the following criteria must be entered into 
subjects’ source document (see Section 11.2) and also as an AE event on the Adverse 
Event eCRF:

Solicited local or systemic AE that continues beyond day 7 after vaccination. 

Solicited local or systemic AE that leads to a visit to a healthcare provider (medically 
attended AE, see Section 8.3.3.4).

Solicited local or systemic AE leading to the subject withdrawing from the study or 
the subject being withdrawn from the study by the investigator (AE leading to 
withdrawal).

Solicited local or systemic AE that otherwise meets the definition of an SAE (see 
Section 8.1.2).
8.1.4.
Unsolicited adverse events
An unsolicited AE is an AE that was not solicited using a Subject Diary and that was 
spontaneously communicated by a subjects/parent(s)/LAR(s) who has signed the 
informed consent or a solicited local or systemic AE that continues beyond the solicited 
period at day 7 after vaccination.
Unsolicited AEs will be collected during interview with the subjects/parent(s)/LAR(s) 
and by review of available medical records at the next visit. Unsolicited AEs will be 
reviewed at the safety follow-up calls as well.
Subjects/parent(s)/LAR(s) will be instructed to contact the site as soon as possible to 
report potential unsolicited AEs that required hospitalization, emergency room visit, or 
 
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visit to/by a health care provider that were of concern to the subjects/parent(s)/LAR(s). 
The detailed information about the reported unsolicited AEs will be collected by qualified 
site personnel during the interview and will be documented in the subject’s records.
Unsolicited AEs (including those of concern to subjects/parent(s)/LAR(s) and those 
which led to a medical visit but were not of concern) will be collected during the visit 
interview.
Unsolicited AEs that are not medically attended nor perceived as a concern by 
subjects/parent(s)/LAR(s) will be collected during interview with the 
subjects/parent(s)/LAR(s) 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 
Only immunogenicity blood samples will be collected in this study (i.e. no routine 
clinical laboratory assessments will be performed per protocol). Should any local 
laboratory tests be performed during the study for a subject, AEs will be recorded as 
follows.
In absence of diagnosis, abnormal laboratory findings (e.g. clinical chemistry, 
hematology, urinalysis) or other abnormal assessments that are judged by the investigator 
to be clinically significant will be recorded as an 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 associated with the disease being studied, unless judged by the 
investigator as more severe than expected for the subject’s condition, or 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.
8.1.6.
Adverse events of special interest
Adverse events of special interest are predefined (serious or non-serious) AEs of 
scientific and medical concern specific to the product or program, for which ongoing 
monitoring and rapid communication by the investigator to the sponsor can be 
appropriate, because such an event might warrant further investigation in order to 
characterize and understand it. 
Arthritis is the only AESI in this study as described in Section 1.3.1 and Section 8.1.6.1.
8.1.6.1.
Arthritis
Cases of arthritis are defined according to the following ad-hoc definition:
 
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
Presence of physical examination findings of swelling, redness, heat, or limitation in 
range of motion
and/or

Presence of diagnostic imaging studies interpreted by a health care provider as 
demonstrating evidence of joint inflammation and/or arthrocentesis results evidencing 
inflammation 
Due to the heterogeneity of the presentation of arthritis, which can be either acute or 
chronic, the threshold of duration of 6 weeks is to be considered.
The list of preferred terms corresponding to the diagnosis of arthritis are those included in 
the Medical Dictionary for Regulatory Activities (MedDRA) Standardized MedDRA
Queries Narrow “Arthritis.” For any new diagnosis of arthritis (serious or non-serious) in 
a study subject, the investigator (or designate) must complete an electronic Expedited 
Adverse Events Report and an ad-hoc eCRF page on arthritis to further characterize this 
AESI.
8.2.
Events or outcomes not qualifying as adverse events or 
serious adverse events
8.2.1.
Pregnancy
Female subjects who are pregnant or lactating at the time of vaccination must not receive 
additional doses of study vaccine(s) but may continue other study procedures 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 an SAE.
Note: The pregnancy itself should always be recorded on a paper pregnancy report.
The following should always be considered as SAEs 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 fetus after 22 weeks of gestation).
Note: the 22 weeks cut-off in gestational age is based on the World Health 
Organization-International Classification of Diseases 10 noted in the European 
Medicines Agency guideline on pregnancy exposure [EMA, 2006]. It is recognized 
that national regulations might be different.
 
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
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 fetus 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 vaccine(s) will be reported to 
PPD 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.
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
The time period for collecting and recording AEs will begin at the time of informed 
consent signature and through study discharge. 
All AEs starting within 30 days following administration of each dose of study vaccine(s)
must be recorded into the subject records and 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 will begin at the time of informed 
consent signature and will end 30 days following administration of the last dose of study 
vaccine(s) for each subject. See Section 8.4 for instructions on reporting of SAEs.
All medically attended AEs will be collected and recorded from the time of informed 
consent signature.
All AEs/SAEs leading to withdrawal from the study will be collected and recorded from 
the time of informed consent signature.
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 time of 
informed consent signature and will end 30 days following administration of the last dose 
of study vaccine(s). See Section 8.4 for instructions on reporting of pregnancies.
 
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The time period for collecting and recording of AESIs will begin at the time of informed 
consent signature and will end 30 days following administration of the last dose of study 
vaccine(s). See Section 8.4 for instructions on reporting of AESIs.
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
Event
Visit 1
Safety 
Call 1
Visit 2
Visit 3
Safety 
Call 2
Visit 4 
Study 
Conclusion
Day 1
Day 7
Day 15
Day 31
Day 61
Day 67
Day 75
Day 91
Solicited local and 
systemic AEs1,2
Unsolicited AEs1,2,3
Medically attended 
AEs1,3
AESI3
AEs/SAEs leading to 
withdrawal from the 
study1,3
SAEs1,3
SAEs related to study 
participation or concurrent 
GSK medication/vaccine3
Pregnancies3
1All concomitant medications/products, except vitamins and dietary supplements, administered during the entire study 
period (Day 1 to Day 91), and used to treat an AE or a SAE, should be recorded in the electronic case report form and 
subject medical records.
2Safety information will not be collected at the Visit 3 time point for the MenACWY group administered only 1 dose of 
vaccine at Visit 1 (no Visit 3 performed).
3All AEs/SAEs, including those related to study participation or to a concurrent GSK medication/vaccine should be 
recorded starting from informed consent form signature, if a separate visit occurs before Visit 1 (maximum 5 days before 
Visit 1).
AE = adverse event; AESI = adverse event of special interest; GSK = GlaxoSmithKline; 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 
 
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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 vaccine(s), the investigator will promptly notify the 
Study Contact for Reporting SAEs.
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 subject’s parent(s)/LAR(s)
should be asked a non-leading question such as:
“Have you felt different in any way since receiving the vaccine(s) or since the previous 
visit?”
OR
“Has your child acted differently or felt different in any way since receiving the 
vaccine(s) or since the last 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 PPD instead of appropriately completing the eCRF. 
However, there may be instances when copies of medical records for certain cases are 
requested by PPD. In this instance, all subject identifiers will be blinded on the copies of 
the medical records prior to submission to PPD.
The investigator will attempt to establish a diagnosis pertaining to the event based on 
signs, symptoms, and/or other clinical information. In such cases, the diagnosis should be 
documented as the AE/SAE and not the individual signs/symptoms.
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 in Table 12.
 
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Table 12
Intensity scales for solicited symptoms
Adverse Event
Intensity 
grade
Parameter
Pain at injection site
0
None
1
Mild: Any pain neither interfering with nor preventing normal every day activities
2
Moderate: Painful when limb is moved and interferes with every day activities
3
Severe: Significant pain at rest. Prevents normal every day activities
Erythema at injection site
Swelling at injection site
Induration at injection site
0
Grade 0: ˂25 mm surface diameter
1
Grade 1: 25-50 mm surface diameter
2
Grade 2: 51-100 mm surface diameter
3
Grade 3: >100 mm surface diameter
Fever1
Record temperature in °C
Nausea
0
None
1
Mild: Nausea present but not interfering with oral intake
2
Moderate: Nausea leading to decreased oral intake
3
Severe: Nausea leading to minimal to no oral intake
Myalgia
0
None
1
Mild: Myalgia present but does not interfere with activity
2
Moderate: Myalgia that interferes with normal activity
3
Severe: Myalgia that prevents normal activity
Arthralgia
0
None
1
Mild: Arthralgia present but does not interfere with activity
2
Moderate: Arthralgia that interferes with normal activity
3
Severe: Arthralgia that prevents normal activity
Headache
0
None
1
Mild: Headache present but does not interfere with activity
2
Moderate: Headache that interferes with normal activity
3
Severe: Headache that prevents normal activity
Fatigue
0
None
1
Mild: Fatigue that does not interfere with activity
2
Moderate: Fatigue that causes some interference with activity
3
Severe: Fatigue that prevents daily activity
1The preferred route for measuring and recording temperature in this study is the axilla. When there is no other 
alternative, the temperature may be recorded by another route. If the temperature is taken by another route (oral, 
rectal, or tympanic), the route should be documented. Fever is defined as a body temperature 38C.
Note: Temperature will be recorded in the evening. If additional temperature measurements are to be performed at 
other times of the day, the highest temperature measured will be recorded in the eCRF.
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.
Every effort should be made by the investigator to evaluate safety information reported 
by a subject for an underlying diagnosis and to capture this diagnosis as the event in the 
AE page. In other words, the practice of reporting only symptoms (e.g. “cough” or “ear 
pain”) are better reported according to the underlying cause (e.g. “asthma exacerbation” 
or “otitis media”).
 
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The severity of 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 vaccine(s) 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) 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 vaccine(s) will be considered and investigated. The investigator will also consult 
the Investigator Brochure and/or SmPC 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 PPD. 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 PPD. 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.
All solicited AEs 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(s)
contributed to the AE. 
NO:
There is no reasonable possibility that the AE is causally related to 
the administration of the study vaccine(s). There are other, more 
likely causes and administration of the study vaccine(s) 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 
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Possible contributing factors include:

Medical history

Other medication

Protocol required procedure

Other procedure not required by the protocol

Lack of efficacy of the vaccine(s), 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/subject’s 
parent(s)/LAR(s) will be asked if he/she or the subject 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
and source documents. 
8.4.
Reporting of serious adverse events, pregnancies, and 
other events
8.4.1.
Prompt reporting of serious adverse events, pregnancies, and 
other events
Serious AEs that occur in the time period defined in Section 8.3 will be reported 
promptly to PPD 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 PPD within the timeframes described in Table 13, once the investigator becomes aware 
of the pregnancy. 
 
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Adverse events of special interest that occur in the time period defined in Section 8.3 will 
be reported promptly to PPD within the timeframes described in Table 13, once the 
investigator determines that the event meets the protocol definition of an AESI.
Table 13
Timeframes for submitting serious adverse event, pregnancy, and 
other events reports
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*
paper pregnancy notification 
report 
2 weeks*
paper pregnancy follow-up report
AESIs
24 hours** ‡
electronic Expedited 
Adverse Events Report
24 hours*
electronic Expedited Adverse 
Events Report
* Timeframe allowed after receipt or awareness of the information.
**Timeframe allowed once the investigator determines that the event meets the protocol definition of a AESI.
‡ The investigator will be required to confirm review of the SAE/AESI causality by ticking the “reviewed” box in the 
electronic Expedited Adverse Events Report within 72 hours of submission of the SAE/AESI.
AESI = adverse event of special interest; SAE = serious adverse event
8.4.2.
Contact information for reporting serious adverse events,
pregnancies, and adverse events of special interest
Study Contact for Reporting SAEs, AESIs, and pregnancies
Refer to the local study contact information document.
Back-up Study Contact for Reporting SAEs, AESIs, and pregnancies
24/24 hour and 7/7 day availability:
PPD Pharmacovigilance
EMEA SAE Hotline: 
 
EMEA SAE fax:
Email address: 
8.4.3.
Completion and transmission of SAE reports
Once an investigator becomes aware that an 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 an 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.
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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 PPD 
Pharmacovigilance (at 
) 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
Once the investigator becomes aware that a subject is pregnant, the investigator (or 
designate) must complete the required information onto the paper pregnancy report 
WITHIN 2 WEEKS. The investigator (or designate) must complete and fax a pregnancy 
notification form to PPD Pharmacovigilance (at 
) after entering or 
updating information within the paper pregnancy report. (Amended 29 Aug 2018)
Note: Conventionally, the estimated gestational age of a pregnancy is dated from the first 
day of the last menstrual period of the cycle in which a woman conceives. If the last 
menstrual period is uncertain or unknown, dating of estimated gestational age and the 
estimated date of delivery should be estimated by ultrasound examination and recorded in 
the pregnancy report.
8.4.5.
Reporting of adverse events of special interest
Once an AESI is diagnosed (serious or non-serious) in a study subject, the investigator 
(or designate) must complete the information in the electronic Expedited Adverse Events 
Report WITHIN 24 HOURS after he/she becomes aware of the diagnosis. The report 
allows to specify that the event is an AESI and whether it is serious or non-serious. 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 an AESI, 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 AESI causality by 
ticking the “reviewed” box in the electronic Expedited Adverse Events Report within 
72 hours of submission of the AESI.
Refer to Section 8.4.3.1 for back-up system in case the electronic reporting system does 
not work.
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8.4.6.
Updating of serious adverse event, pregnancy, and adverse 
events of special interest information after removal of write 
access to the subject’s electronic case report form
When additional SAE, pregnancy, or AESI 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
Study Contact Information in Section 8.4.2) within the designated reporting time frames 
specified in Table 13.
8.4.7.
Regulatory reporting requirements for serious adverse events
The investigator will promptly report all SAEs to PPD in accordance with the procedures 
detailed in Section 8.4.1. PPD 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 PPD policy and are 
forwarded to investigators as necessary. An investigator safety report is prepared for an
SAE(s) that is both attributable to the study vaccine(s) 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 PPD
(within 24 hours for SAEs; refer to Table 13).
All SAEs and AESIs (serious or non-serious) 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.
8.5.1.2.
Follow-up after the subject is discharged from the study
The investigator will follow subjects:
 
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
with SAEs, AESIs (serious or non-serious), or subjects withdrawn from the study as a 
result of an AE, until the event has resolved, subsided, stabilized, 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 PPD using an electronic Expedited Adverse 
Events Report and/or pregnancy report as applicable.
PPD 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, PPD 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 PPD using the paper pregnancy report and the Expedited 
Adverse Events Report if applicable. Generally, the follow-up period does not need to be 
longer than 6 to 8 weeks after the estimated date of delivery.
Regardless of the reporting period for SAEs for this study, if the pregnancy outcome is an
SAE, it should always be reported as an 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 SAEs/AESIs 
should be recorded in Expedited Adverse Events Report of the subject’s eCRF (refer to 
Section 6.7).
8.7.
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/subject’s 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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9.
SUBJECT COMPLETION AND WITHDRAWAL
9.1.
Subject completion
A subject who returns for the concluding visit foreseen in the protocol is considered to 
have completed the study.
9.2.
Subject withdrawal
Subjects withdrawn from the study will not be replaced.
9.2.1.
Subject withdrawal from the study
From an analysis perspective, a “withdrawal” from the study refers to when a subject 
does not come back for the concluding visit 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 “withdrawn” 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 to contact those subjects who do not return for 
scheduled visits or follow-up. At a minimum, the investigator will contact the subject or 
subject’s parent(s)/LAR(s) via 3 telephone calls and a certified letter to the last known 
address.
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 subject’s parent(s)/LAR(s), or by the investigator, as 
well as which of the following possible reasons was responsible for withdrawal:

Serious AE

Unsolicited non-serious AE

Solicited AE

Protocol violation (specify)

Consent withdrawal, not due to an AE*

Moved from the study area

Lost to follow-up

Other (specify)
*In case a subject is withdrawn from the study because he/she/the subject’s 
parent(s)/LAR(s) has withdrawn consent, the investigator will document the reason for
 
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withdrawal of consent, if specified by the subject/subject’s 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 an SAE/AE until 
resolution of the event (see Section 8.5.1.2).
9.2.2.
Subject withdrawal from study vaccines
A “withdrawal” from the study vaccine(s) refers to when a subject does not receive the 
complete treatment, i.e. when no further planned dose is administered from the date of 
withdrawal. A subject withdrawn from the study vaccine(s) may not necessarily be 
withdrawn from the study as further study procedures or follow-up may be performed 
(safety or immunogenicity) if planned in the study protocol. 
Information relative to premature discontinuation of the study vaccine(s) will be 
documented on the Vaccine Administration page/screen of the eCRF. The investigator 
will document whether the decision to discontinue further vaccination/treatment was 
made by the subject himself/herself, by the subject’s parent(s)/LAR(s), or by the 
investigator, as well as which of the following possible reasons was responsible for 
withdrawal:

Serious AE

Unsolicited non-serious AE

Solicited AE

Not willing to be vaccinated

Other (specify)
9.3.
Screen failures
Screen failures are subjects who withdraw or are withdrawn from the study following 
informed consent, but before randomization to study treatment. Information relative to 
screen failures will be documented on the Screening Conclusion page/screen of the 
eCRF. The investigator will document whether the screen failure decision was made by 
the subject himself/herself, by the subject’s parent(s)/LAR(s), or by the investigator, as 
well as which of the following possible reasons was responsible for the screen failure:

Consent withdrawal, not due to an SAE

Eligibility criteria not fulfilled (inclusion and exclusion criteria)

Lost to follow-up

Migrated or moved from the study area

Other (specify)

Protocol violation
 
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
SAE not related to study participation or to a GSK concurrent medication

SAE related to study participation or to a GSK concurrent medication
10.
STATISTICAL METHODS
10.1.
Primary endpoint

Immune responses against N. meningitidis serogroup B* test strains and 
N. meningitidis serogroups A, C, W-135, and Y, as measured by hSBA, 1 month after 
the last vaccination in all study groups

hSBA GMTs against each of the N. meningitidis serogroup B test strains and 
against N. meningitidis serogroups A, C, W-135, and Y

hSBA GMTs against all of N. meningitidis serogroup B test strains (pooled) 

Percentage of subjects with hSBA titers ≥the lower limit of quantitation 
(LLOQ) against each of the N. meningitidis serogroup B test strains and against 
N. meningitidis serogroups A, C, W-135, and Y 

Percentage of subjects with a 4-fold increase in hSBA titers against 
N. meningitidis serogroups B test strains and against N. meningitidis serogroups 
A, C, W-135, and Y 

hSBA geometric mean ratios (GMRs) against each of the N. meningitidis
serogroup B test strains and against N. meningitidis serogroups A, C, W-135,
and Y at 1 month after the last vaccination against baseline (Day 1)
*Serogroup B strains that will be tested are M14459 (factor H binding protein; fHbp), 
96217 (Neisserial adhesin A; NadA), NZ98/254 (PorA), and M07-0241084 (Neisseria 
heparin binding antigen; NHBA) and will be pooled to estimate the effect of immune 
interference due to stress to lymph nodes.
Note: A 4-fold rise is defined as: 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 
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 4 times the LLOQ; and 
c) for individuals whose pre-vaccination titers are ≥the LLOQ, the post-vaccination titers
must be at least 4 times the pre-vaccination titer.
The ratios of GMTs between study groups will be analyzed to evaluate effect of treatment 
as described below:
a.
Immune interference due to stress to lymph nodes (lymph-node effect) in 
rMenBOMV+ACWY_S versus rMenBOMV+ACWY_D study groups, on the 
pooled B strains, and individually by serogroup A, C, W-135, Y, and B test strains.
b.
Other unknown interference in the MenABCWY versus rMenBOMV+ACWY_S 
study groups, by serogroup A, C, W-135, Y, and B test strains.
 
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c.
The difference in immune response compared to control groups in 
rMenBOMV+ACWY_S versus rMenBOMV and MenACWY, 
rMenBOMV+ACWY_D versus rMenBOMV and MenACWY, and MenABCWY 
versus rMenBOMV and MenACWY study groups, by serogroup A, C, W-135, Y, 
and B test strains.
10.2.
Secondary endpoints
Immunogenicity Endpoints

Immune responses against N. meningitidis serogroup B* test strains and 
N. meningitidis serogroups A, C, W-135, and Y, as measured by hSBA, 1 month 
after the first vaccination in all groups (except for subjects in the MenACWY group)

hSBA GMTs against each of the N. meningitidis serogroup B test strains and 
against N. meningitidis serogroups A, C, W-135, and Y

hSBA GMTs against all of N. meningitidis serogroup B test strains (pooled)

Percentage of subjects with hSBA titers ≥the LLOQ against each of the 
N. meningitidis serogroup B test strains and against N. meningitidis serogroups 
A, C, W-135, and Y 

Percentage of subjects with a 4-fold increase in hSBA titers against 
N. meningitidis serogroups B test strains and against N. meningitidis serogroups 
A, C, W-135, and Y

hSBA GMRs against each of the N. meningitidis serogroup B test strains and 
against N. meningitidis serogroups A, C, W-135, and Y at 1 month after the first 
vaccination against baseline (Day 1)
*Serogroup B tests strains that will be tested are M14459 (fHbp), 96217 (NadA), 
NZ98/254 (PorA), and M07-0241084 (NHBA).
Notes, as described in Section 10.1, also apply to the secondary endpoints.
The ratios of GMTs between study groups will be analyzed to evaluate effect of treatment 
as described below:
a.
Immune interference due to stress to lymph nodes (lymph-node effect) in 
rMenBOMV+ACWY_S versus rMenBOMV+ACWY_D study groups, on the 
pooled B strains, and individually by serogroup A, C, W-135, Y, and B test strains.
b.
Other unknown interference in MenABCWY versus rMenBOMV+ACWY_S study 
groups, by serogroup A, C, W-135, Y, and B test strains.
c.
The difference in immune response compared to control groups in 
rMenBOMV+ACWY_S versus rMenBOMV, rMenBOMV+ACWY_D versus 
rMenBOMV, and MenABCWY versus rMenBOMV study groups, by serogroup B 
test strains.
 
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Safety Endpoints

Solicited local and systemic AEs in all study groups

Occurrence of solicited local and systemic AEs during the 7 days (including the 
day of vaccination) after each vaccination (Day 1 to Day 7 and Day 61 to 
Day 67 [Day 1 to Day 7 only for subjects in the MenACWY group])

Unsolicited AEs in all study groups

Occurrence of unsolicited AEs during the 30 days (including the day of 
vaccination) after each vaccination (Day 1 to Day 31 and Day 61 to Day 91 
[Day 1 to Day 31 only for subjects in the MenACWY group])

SAEs, medically attended AEs, AEs leading to withdrawal, and AESIs, in all study
groups from informed consent signature to Visit 4 (Day 91)
10.3.
Tertiary endpoint
Endpoints related to the tertiary objective will be described in a separate statistical 
analysis plan. (Amended 29 Aug 2018)
10.4.
Determination of sample size
The sample size is for exploratory statistical analysis purposes only. There are no formal 
confirmatory hypotheses to be tested. The text in this section describes what can be 
observed with the current sample size.
Sample size calculation was performed using PASS 12 and SAS 9.2 (SAS Institute Inc., 
Cary, NC, USA).
The potential immune interference due to immunological stress to lymph nodes is 
assumed to result in decreases to all of the 4 B test strains but to various extents. In a 
previous study (MenABCWY-011 [V102_15]), the GMT ratios ranged from 74% (-0.13 
on log10 scale) to 50% (-0.3 log10 scale) with a mean of 64% (-0.19 on log10 scale). 
Because of this consistent decrease in GMT ratios in the MenABCWY group in 
comparison to the MenB group across the 4 serogroups, the presence of the lymph-node 
effect will be tested globally on all the serogroups together. A multivariate analysis of 
V102_15 data provided an estimate of σ = 0.435 (on log10 scale) for the standard 
deviation (SD) of the averaged GMTs across the 4 serogroups of the MenABCWY arm. 
That variability is higher than what would be expected by dividing the variance of a 
single serogroup by 4 due to the correlations existing between serogroups.
Therefore, assuming a SD of σ = 0.435 (in log form), group sample sizes of 100 in each 
study group will achieve a power of approximately 80% to reject the null hypothesis of 
equal means when the population mean difference is -0.130 (log GMT ratio 74%) with a 
SD of 0.435 for both groups and a significance level (alpha) of 10% using a 1-sided 
2-sample equal-variance t-test. This calculation ignores the potential correlation that 
might exist between serogroups of the MenABCWY when pooled together.
 
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The numerical results for the 2-sample t-test assuming equal variance (alternative 
hypothesis: δ < 0) is shown in Table 14.
Table 14
Sample size calculation results
Power
N1
N2
δ
σ
Alpha
Beta
0.650
100
100
-0.145
0.435
0.025
0.350
0.759
100
100
-0.145
0.435
0.050
0.241
0.819
100
100
-0.145
0.435
0.075
0.181
0.858
100
100
-0.145
0.435
0.100
0.142
0.620
100
100
-0.140
0.435
0.025
0.380
0.733
100
100
-0.140
0.435
0.050
0.267
0.797
100
100
-0.140
0.435
0.075
0.203
0.839
100
100
-0.140
0.435
0.100
0.161
0.589
100
100
-0.135
0.435
0.025
0.411
0.706
100
100
-0.135
0.435
0.050
0.294
0.773
100
100
-0.135
0.435
0.075
0.227
0.818
100
100
-0.135
0.435
0.100
0.182
0.557
100
100
-0.130
0.435
0.025
0.443
0.678
100
100
-0.130
0.435
0.050
0.322
0.748
100
100
-0.130
0.435
0.075
0.252
0.796
100
100
-0.130
0.435
0.100
0.204
The sample size calculation shows that with a power range of 80% to 90%, a global 
lymph-node effect is detectable when the GMT ratio is between 64% 
(approximately -0.19 on log10 scale) and 74% (-0.13) pooling 4 variants of B test strains
together and using a 1-sided false-positive error rate of 10%.
A decrease in GMT ratios below 74% is acceptable as, for a lower mean ratio, the 
presence of a marginal lymph-node effect can be compensated with an increase in sample 
size in a formal non-inferiority study.
Assuming a rare event occurring at the rate of 1 out of 100, a sample size of 500 subjects 
in the study will have a probability of 99.3% to detect a rare AE.
A total of approximately 500 subjects (approximately 100 subjects in each group) are 
planned for enrollment into the study.
10.5.
Analysis sets
10.5.1.
All Enrolled Set
All subjects who signed an informed consent, underwent screening procedures, and have 
a subject number assigned.
 
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10.5.2.
All Exposed Set
All subjects in the All Enrolled Set who receive any study vaccination. (Amended 
29 Aug 2018)
10.5.3.
Safety Set
10.5.3.1.
Solicited Safety Set (solicited local and systemic adverse events and 
other solicited adverse events)
All subjects in the All Exposed Set with any solicited AE data.
10.5.3.2.
Unsolicited Safety Set (unsolicited adverse events)
All subjects in the All Exposed Set who attended at least 1 visit or had at least 1 safety 
call or at least 1 follow-up event (such as withdrawal from the study) after receiving any 
study vaccination.
10.5.3.3.
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[s] a subject received, 
rather than the vaccine[s] to which the subject may have been randomized).
10.5.4.
Full Analysis Set, Immunogenicity
Each Full Analysis Set (FAS) will be defined by visit and by serogroup.
10.5.4.1.
Full Analysis Set 1
All subjects in the All Exposed Set who provided evaluable serum samples and whose 
assay results are available for at least 1 serogroup or B strain at Visit 4 for all study 
groups except the MenACWY group, or at Visit 2 for the MenACWY group. (Amended 
29 Aug 2018)
10.5.4.2.
Full Analysis Set 2
All subjects in the All Exposed Set who provided evaluable serum samples and whose 
assay results are available for at least 1 serogroup or B strain at Visit 2 for all study 
groups except the MenACWY group. (Amended 29 Aug 2018)
10.5.4.3.
Full Analysis Set 3
All subjects in the All Exposed Set who provided evaluable serum samples and whose 
assay results are available for at least 1 serogroup or B strain at Visit 4 for all study 
groups except the MenACWY group, or at Visit 2 for the MenACWY group, and at 
baseline for all study groups. (Amended 29 Aug 2018)
 
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10.5.4.4.
Full Analysis Set 4
All subjects in the All Exposed Set who provided evaluable serum samples and whose 
assay results are available for at least 1 serogroup or B strain at Visit 2 and at baseline
for all study groups except the MenACWY group. (Amended 29 Aug 2018)
10.5.5.
Per-Protocol Set, Immunogenicity
Per-Protocol Set (PPS) 1, PPS 2, PPS 3, and PPS 4 are the corresponding subsets of 
FAS 1, FAS 2, FAS 3, and FAS 4, respectively, who have no major protocol violations.
A major deviation is defined as a protocol deviation that is considered to have a 
significant impact on the immunogenicity result of the subject.
All protocol deviations will be identified prior to the analysis and a clinical judgment will 
be necessary to classify each deviation as “major” or not. These deviations and the 
judgment regarding their use will be listed and summarized in the final report.
A list of key major deviations is provided below, but not limited to:

Subjects enrolled who did not meet entry criteria including age at enrollment 

Subjects incorrectly vaccinated 

Subjects who did not receive study vaccinations as planned in protocol

Subjects who did not have blood draws as planned in protocol

Subjects with a blood draw outside of allowed time window

Subjects with a vaccination done outside of allowed time window
These key major deviations will be assessed based on the data collected in the eCRFs. 
The complete list of protocol deviations considered major for this study will be detailed 
in the statistical analysis plan and be reported in the final report.
10.5.6.
Other analysis sets
No additional analysis sets are planned.
10.5.7.
Subgroups
There are no intended subgroups for analysis.
10.6.
Derived and transformed data

Immunogenicity

The assay cut-off values will be defined by the laboratory before analysis and 
will be documented in a protocol amendment or in the clinical study report.

For the primary and secondary endpoints (see Section 10.1 and Section 10.2
, respectively), the percentage of subjects with hSBA titers ≥ LLOQ and with a 
 
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4-fold increase in hSBA titers against each of the N. meningitidis serogroup B 
test strains and against N. meningitidis serogroups A, C, W-135, and Y will be 
determined.

The GMT 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. 

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: for safety analyses, subjects who missed reporting 
symptoms (solicited/unsolicited) or concomitant medications will be analyzed 
further. The main safety analyses will contain missing data (missing safety 
values will not be imputed) but further analyses to assess the missing 
mechanism will be specified in the statistical analysis plan.

For the analysis of solicited symptoms, missing or non-evaluable measurements 
will not be replaced. Therefore the analysis of the solicited symptoms based on 
the All Exposed Set will include only subjects/doses with documented safety 
data (i.e. symptom screen/sheet completed). 

Solicited AEs will be assessed as described in Table 12 and Section 10.9.2.
10.7.
Analysis of demographics
Demographic characteristics (age, gender, and ethnic origin) will be tabulated per study 
group for each analysis set as described in the statistical analysis plan.
The mean of continuous variables (plus range and SD) of the enrolled subjects, as a 
whole and per study group, will be calculated.
The distribution of discrete variables will be tabulated as a whole and per study group as
described in the statistical analysis plan.
10.8.
Analysis of immunogenicity
The primary and secondary immunogenicity analyses will be based on the PPS. If the 
difference between PPS and FAS is greater than 10%, a second analysis based on the 
FAS will be performed to complement the PPS analysis.
Titers below the LLOQ will be handled based on the assay procedure and will be 
described in the statistical analysis plan.
One of the main objectives of the study is to estimate the extent of a potential immune 
interference, due to immunological stress to lymph nodes in the arm where the 
combination vaccine is administered in comparison to injections in 2 different arms of 
individual vaccines. The sample size defines the conditions under which the observed 
 
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reduction in immune response will be attributed to a true lymph-node effect or is the 
consequence of natural variability. An acceptable probability of falsely detecting the 
lymph-node effect was set to 10% (1-sided test). The minimum probability of detecting 
the lymph node is set to 80%.
Criteria for the Statistical Test
rMenBOMV+ACWY_S will be declared statistically inferior if the 2-sided 80% 
confidence intervals (CIs) of the ratio of the GMT with rMenBOMV+ACWY_D as 
control is lower than 1. The lymph-node effect would therefore be the most probable 
cause for the decrease observed.
Analysis of hSBA GMT
An analysis of covariance (ANCOVA) model will be used to analyze post-vaccination 
log-transformed titers of hSBA for both the primary and secondary objectives (i.e. the 
hSBA at 1 month after the last vaccination and the hSBA at 1 month after the first 
vaccination, respectively). The ANCOVA model will be fitted to each serogroup/strain 
individually, and in addition the serogroup B strains will be grouped together to perform 
a pooled analysis. The GMTs obtained through the ANCOVA model will be called 
“adjusted” and the “unadjusted” GMTS will be obtained through descriptive statistics. 
Unadjusted and adjusted GMTs and associated 2-sided 80% CIs will be computed for 
each study group and for each strain at each visit. The fixed-effect model will include the 
age strata, treatment, serogroup, and center as fixed effects. The pre-vaccination log-
transformed titer with centering at zero will be included as a continuous covariate. An 
interaction between serogroup and pre-vaccination log-transformed titer centered at zero 
will be included in the model. For each study group, adjusted GMTs and their 80% CIs 
will be obtained by exponentiating (base 10) the least squares means and the lower and 
upper limits of the 80% CIs of the log-transformed titers (base 10).
The following contrasts will be computed to investigate possible effects on the immune 
response based on strains common to each treatment group:
a.
rMenBOMV+ACWY_S versus rMenBOMV+ACWY_D (test for immune 
interference, due to immunological stress to lymph node)
b.
MenABCWY versus rMenBOMV+ACWY_S (test for other unknown 
immunological interference)
c.
rMenBOMV+ACWY_S versus rMenBOMV
d.
rMenBOMV+ACWY_S versus MenACWY
e.
rMenBOMV+ACWY_D versus rMenBOMV
f.
rMenBOMV+ACWY_D versus MenACWY
g.
MenABCWY versus rMenBOMV
h.
MenABCWY versus MenACWY
In addition, the distribution of antibody titers for each strain will be displayed using 
reverse cumulative distribution curves.
 
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Analysis of Percentage of Subjects With Titers Above LLOQ and a 4-fold Increase
The percentage of subjects with titers above the LLOQ and a 4-fold increase as well as 
the associated 2-sided 80% Clopper-Pearson CIs will be computed by study group at each 
visit [Clopper, 1934]. In addition, differences in percentages and 2-sided 80% CIs 
between the groups will be calculated and the associated CI for the difference will be 
constructed using the method of Miettinen and Nurminen [Miettinen, 1985].
Unadjusted and adjusted GMTs and associated 2-sided 80% CIs will be computed for 
each group and for each strain at each visit. For each study group, adjusted GMTs and 
their 80% CIs will be obtained by exponentiating (base 10) the least square means and 
the lower and upper limits of the 80% CIs of the log-transformed titers (base 10).
The fixed-effect model for the individual serogroups/strains will include the age strata, 
treatment, and center as fixed effects. The fixed-effect model for the pooled analysis will 
include the age strata, treatment, strain, and center as fixed effects. The pre-vaccination 
log-transformed titer with centering at zero will be included as a continuous covariate. An 
interaction between serogroup and pre-vaccination log-transformed titer centered at zero 
will be included in the model.
Additionally, the group GMT ratios will be computed. The 2-sided 80% CIs for the group 
GMT ratio will be constructed by exponentiating the group difference of the least squares 
means of the log-transformed titers and the lower and upper limits of the 80% CI.
10.9.
Analysis of safety
The analysis will be based on the Safety Sets.
10.9.1.
Analysis of extent of exposure
The frequency and percentage of exposed subjects will be summarized overall and by 
study group.
10.9.2.
Analysis of local and systemic adverse events
All solicited AEs will be summarized according to defined severity grading scales (see 
Table 12).
Frequencies and percentages of subjects experiencing each AE will be presented for each 
symptom severity. Summary tables showing the occurrence of any local or systemic AE 
overall and at each time point will also be presented. Local AEs will be assessed 
according to which vaccine was administered and the site of administration (e.g. upper or 
lower deltoid and the arm used for administration).
Post-vaccination solicited AEs reported from day 1 to day 7 will be summarized for the 
intervals days 1 to 3, days 4 to 7, and days 1 to 7 by maximal severity and by study 
group, excluding the 30-minute post-vaccination measurement, which will be 
summarized separately. In addition, solicited AEs ongoing after day 7 will be presented 
as unsolicited AEs. 
 
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Body temperature will be classified as <38°C (no fever) and ≥38°C (fever), as well as by 
0.5°C increments from 36.0°C up to ≥40°C.
Erythema, induration, and swelling will be categorized as none (<25 mm), 25 to 50 mm
(mild), 51 to 100 mm (moderate), and >100 mm (severe local reactions). The severity of 
pain will be categorized as none, mild (transient with no limitation in normal daily 
activity), moderate (some limitation in normal daily activity), and severe (unable to 
perform normal daily activity). 
If an AE occurs more than once for a subject, it will be counted in the summary only 
once, according to the maximal severity. Summary tables showing the occurrence of any 
local or systemic AEs overall will be presented.
10.9.3.
Analysis of other adverse events
Unsolicited Adverse Events 
This analysis applies to all AEs occurring during the study, judged either as probably 
related, possibly related, or not related to vaccination by the investigator, recorded in the 
Adverse Events eCRF, with a start date on or after the date of first vaccination. Adverse 
events starting prior to the first vaccination will only be listed. The original verbatim 
terms used by investigators to identify AEs in the eCRFs will be mapped to preferred 
terms using the MedDRA dictionary. The AEs will then be grouped by MedDRA 
preferred terms into frequency tables according to system organ class.
All reported AEs, as well as AEs judged by the investigator as at least possibly related to 
study vaccine(s), will be summarized according to system organ class and preferred term 
within system organ class. These summaries will be presented by study group and by 
interval of study observation. When an AE occurs more than once for a subject, the 
maximal severity and strongest relationship to the study group will be counted.
Separate summaries will be produced for the following categories:

SAEs

AEs that are possibly or probably related to vaccine(s)

AEs leading to withdrawal

AEs leading to a medically attended visit

AESI
Data listings of all AEs will be provided by subject. In addition, AEs in the categories 
above will be provided as listed data.
10.10.
Interpretation of analyses
All analyses will be descriptive.
 
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10.11.
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.
10.11.1.
Sequence of analyses
The final study analysis will only be performed when all data up to the end of the study 
will be available and cleaned. Individual data listings will be provided and a clinical 
study report will be written.
Any outcome of exploratory testing will be reported in an annex/addendum to the final 
study report. (Amended 29 Aug 2018)
10.11.2.
Statistical considerations for interim analyses
Not applicable.
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 PPD 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 PPD. 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 PPD standards and data cleaning procedures.
While completed eCRFs are reviewed by a PPD 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
Subject Diaries will be the only source document allowed for solicited local and systemic 
AEs (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.
 
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The investigator or delegated staff should monitor the Subject’s Diary status throughout 
the study for compliance and any solicited local and systemic AEs that were of concern 
to the subject.

No corrections or additions to the information recorded by the 
subject/parent(s)/LAR(s) within the Subject Diary will be allowed after it is delivered 
to the site.

Any blank or illegible fields on the Subject Diary must be described as missing in the 
eCRF.
The following additional rules apply to documentation of Subject Diary information 
collected in the eCRFs:
The site must enter all readable entries in the Subject Diary into the eCRF, including 
those values that may be biologically implausible (e.g. body temperature: 400°C).
Any illegible or implausible data should be reviewed with the subject/parent(s)/LAR(s). 
If an underlying solicited or unsolicited AE is described on review with the subject, this 
should be described in the source document and reported as an unsolicited AE in the 
Adverse Event eCRF (e.g. if the subject above confirms body temperature of 40°C on the 
day in which body temperature: 400°C was written into his/her Subject Diary, this fever 
of 40°C should be recorded in the Adverse Event eCRF).
Any newly described safety information (including a solicited AE) must not be written 
into the Subject Diary and must be described in the study file as a verbally reported AE. 
Any AE reported in this fashion must be described as an unsolicited AE and therefore 
entered on the Adverse Event eCRF.
11.3.
Study monitoring
PPD 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. By Source Data Verification we understand verifying eCRF entries by 
comparing them with the source data that will be made available by the investigator for 
this purpose. 
 
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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 PPD procedures.
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.
PPD 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 PPD standards/procedures, 
otherwise, the minimum retention period will default to 25 years after completion of the 
study report.
The investigator/institution must notify PPD 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 and/or 
PPD 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.
 
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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 PCD and to have secondary endpoint 
disclosed at latest 12 months after the LSLV as described in the protocol.
As per EU regulation, summaries of the results of GSK interventional studies 
(Phase I-IV) in adolescent and adult populations conducted in at least 1 EU member state 
will be posted on publicly available European Medicines Agency registers within 
6 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 6 months 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.
PPD 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.
12.
COUNTRY SPECIFIC REQUIREMENTS
Not applicable.
 
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13.
REFERENCES
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
Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of 
binomial. Biometrika. 1934; 26: 404-413.
EMA Guideline on the exposure to medicinal products during pregnancy: need for 
post-authorisation 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
European Centre for Disease Prevention and Control (ECDC). Annual Epidemiological 
Report 2016 – Invasive meningococcal disease. [Internet]. Stockholm: ECDC; 2016 
[cited 05-DEC-2017]. Available from 
https://ecdc.europa.eu/sites/portal/files/documents/Invasive%20meningococcal%20diseas
e%20AER.pdf .
Institute of Medicine (IOM). 2011. Adverse Effects of Vaccines: Evidence and Causality. 
Washington DC: The National Academies Press.
Magnus P, Brubakk O, Nyland H, et al. Vaccination as teenagers against meningococcal 
disease and the risk of the chronic fatigue syndrome. Vaccine. 2009; 27: 23-27.
Miettinen OS, Nurminen M. Comparative analysis of two rates. Stat Med. 1985; 4: 
213-226.
Prymula R, Esposito S, Zuccotti GV, et al. A phase 2 randomized controlled trial of a 
multicomponent meningococcal serogroup B vaccine (I). Hum Vaccin Immunother. 2014; 
10: 1993-2014.
Rosenstein NE, Perkins BA, Stephens DS, et al. Meningococcal disease. N Engl J Med.
2001; 344: 1378-88.
Tingle AJ, Allen M, Petty RE, et al. Rubella-associated arthritis. I. Comparative study of 
joint manifestations associated with natural rubella infection and RA 27/3 rubella 
immunisation. Ann Rheum Dis. 1986: 45: 110-114.
 
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Appendix A
LABORATORY ASSAYS
Serum bactericidal assay using human complement (hSBA)
The functional measure of immunogenicity used in this study, serum bactericidal activity, 
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.
Serum bactericidal activity against rMenB+OMV NZ, MenACWY, and MenABCWY 
will be determined by performing an assay using plasma or serum as the source of 
exogenous complement, and measuring hSBA titers using standardized procedures 
against a standard panel consisting of Neisseria meningitidis serogroup A, C, W-135, Y 
and serogroup B test strains following study vaccination.
Each of the serogroup B test strains measures bactericidal activity primarily directed 
against one of the major meningococcal antigens included in rMenB+OMV NZ and in 
the combination MenABCWY vaccine: strain M14459 measures serum bactericidal 
activity against the factor H binding protein variant 1.1; strain M07-0241084 measures 
bactericidal activity against Neisseria heparin binding antigen; strain 96217 measures 
bactericidal activity against antigen Neisserial adhesin A; and strain NZ98/254 measures 
activity against PorA P1.4, which is the immunodominant antigen in the OMV NZ 
vaccine component.
 
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Appendix B
CLINICAL LABORATORIES
Table 15
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 AND ADMINISTRATIVE 
CHANGES TO THE PROTOCOL
GlaxoSmithKline Biologicals SA
Vaccines R &D
Protocol Amendment 1
eTrack study number 
and abbreviated title
208205 MENABCWY-016 (V102_19)
EudraCT number
2017-005128-12
Amendment number:
Amendment 1, substantial
Amendment date:
15 May 2018
Co-ordinating author:
, Principal Medical Writer, PPD, for GSK 
Biologicals
Rationale/background for changes: 
!
The protocol has been updated based on feedback received from the State 
Institute for Drug Control (SUKL) regarding contraception requirements, 
exclusion of other vaccines before and after study vaccine(s) administration, 
exclusion of subjects with medical bleeding conditions, and to indicate that 
paracetamol is the preferred antipyretic/analgesic.
!
The distribution and return of Subject Diaries has been clarified.
!
The protocol was updated to include the use of a pregnancy notification form
and to clarify that paper pregnancy forms will be used.
!
Clarifications have been made to the analysis population definitions and the 
modeling analysis plans.
!
Other minor changes have been made to correct typos, and improve clarity 
and alignment within the document.
Minor administrative edits (e.g. typos, abbreviations) have not been listed here.
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections:
Glossary of terms:
(Note: The alphabetical order was updated in the main text.)
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Highly effective Adequate
contraception:
Highly effective contraceptive methods, defined as 
contraceptive methods with a failure rate of less than 
1% per year according to the Pearl Index, when used 
consistently and correctly and in accordance with the 
product label, when applicable. These methods include:

combined (estrogen and progestogen containing) 
hormonal contraception associated with inhibition 
of ovulation:

oral

intravaginal (i.e. contraceptive vaginal ring)

percutaneous delivery system (i.e. transdermal
patch)

progestogen-only hormonal contraception associated 
with inhibition of ovulation:

injectable

implantable

intrauterine device

intrauterine hormone-releasing system

bilateral tubal occlusion

vasectomized partner (provided that partner is the 
sole sexual partner of the female subject and that the 
vasectomized partner has received medical 
assessment of the surgical success, i.e. documented 
sterility). The documentation on male sterility can 
come from the site personnel’s: review of subject’s 
medical records, medical examination of the subject 
and/or semen analysis, or medical history interview 
provided by her or her partner.

sexual abstinence (defined as refraining from 
penile-vaginal intercourse during the entire period 
of risk associated with the study treatments). 
Periodic abstinence (e.g. calendar, ovulation, 
symptothermal, post-ovulation methods) and 
withdrawal are not acceptable methods of 
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: 
 
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
abstinence from penile-vaginal intercourse, when this 
is their preferred and usual lifestyle,

combined estrogen 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.
Highly effective 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.
 
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Section 1.3.1 Risk assessment
Important 
potential/identified 
risk
Data/Rationale for risk
Mitigation strategy
Investigational vaccine: rMenB+OMV NZ
Important identified 
risk:
Fever
Fever may occur following 
vaccination. Fever is listed in 
the rMenB+OMV NZ SmPC. 
Any febrile illness constitutes a 
contraindication to administration 
of the vaccine at the time 
scheduled for vaccination (see 
Section 6.5). Prophylactic use of 
analgesic/antipyretic medications
(preferably paracetamol) during 
the first 7 days after vaccination 
is allowed on a voluntary basis, 
but must be recorded in the 
source document and 
Concomitant Medications 
electronic case report form 
(eCRF) field (see Section 6.7.1).
Important potential risk:
Decrease of 
immunogenicity 
secondary to 
prophylactic use of 
paracetamol
Prophylactic use of 
paracetamol reduces the 
incidence and severity of fever 
without affecting the 
immunogenicity of either 
rMenB+OMV NZ or routine 
vaccines [Prymula, 2014]. The 
effect of antipyretics other than 
paracetamol on the immune 
response has not been studied. 
Prophylactic use of 
analgesic/antipyretic medications
(preferably paracetamol) to 
reduce febrile reactions during 
the first 7 days after vaccination 
is allowed on a voluntary basis, 
but must be recorded in the 
source document and 
Concomitant Medications eCRF 
field (see Section 6.7.1).
Synopsis and Section 4.2 Inclusion criteria for enrollment
7. Female subjects of childbearing potential may be enrolled in the study, if the subject:

has practiced highly effective adequate contraception for 30 days prior to 
vaccination, and

has a negative pregnancy test on the day of vaccination, and

has agreed to continue highly effective adequate contraception during the entire 
treatment period and for 2 months after completion of the vaccination series. 
Please refer to the glossary of terms for the definition of highly effective adequate
contraception.
 
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Synopsis and Section 4.3 Exclusion criteria for enrollment
Each subject must not have:
(Note: These 2 new criteria have been added to the previous 23 exclusion criteria.)
24. Administration of a vaccine not foreseen by the study protocol in the period starting 
14 days (for inactivated vaccines), 28 days (for live vaccines), or 7 days (for 
influenza vaccines) before each dose and ending 14 days (for inactivated vaccines), 
28 days (for live vaccines), or 7 days (for influenza vaccines) after each dose of 
study vaccine(s) administration.
25. Thrombocytopenia, bleeding disorders, or be receiving anticoagulant therapy.
Synopsis and Section 5.5 Outline of study procedures
Table 4 List of study procedures
(Note: Bold italicized text could not be applied to the individual table cells. Cells that 
were edited are shaded in the excerpt below.)
Epoch
Epoch 001
Type of contact
Visit 1
Safety call 1 
Visit 2
Visit 3
Safety call 2
Visit 4
Time points
Day 1
Day 15
Day 31
Day 61
Day 75
Day 91
Sampling time points
Pre-Vacc 1 
Post-Vacc 
1 
Post-Vacc 2 
Distribution of pDiary
○
○4,6
Review of pDiary
○
○4 
○4 
Return of pDiary
○6
○4,6
○4,6
4This study procedure will not be performed at this time point for the MenACWY group, administered only 1 dose of 
vaccine at Visit 1 (no Visit 3 performed) 
6Subjects who receive a single dose of MenACWY only will return their pDiary at Visit 2 (Day 31). All subjects 
in the other treatment groups will return their first pDiary at Visit 3 (Day 61) and will receive a second pDiary 
for the remainder of the study.
○ is used to indicate a study procedure that does not require documentation in the individual eCRF.
Pre-Vacc: pre-vaccination; Post-Vacc: post-vaccination
 
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Table 5 Intervals between study visits
Interval
Optimal length of 
interval
Allowed interval (Min – Max)1
Visit 1 (Day 1) Safety call 1 (Day 15)
14 days
11 days – 17 days (Days 12 – 18)
Visit 1 (Day 1) Visit 2 (Day 31)
30 days
23 days – 40 days (Days 24 – 41)
Visit 1 (Day 1) Visit 3 (Day 61)
60 days
53 days – 70 days (Days 54 – 71)
Visit 3 (Day 61) Safety call 2 (Day 75)
14 days
11 days – 17 days (Days 72 – 78)
Visit 3 (Day 61) Visit 4 (Day 91)
30 days
23 days – 40 days (Days 84 – 101)
1Safety call time intervals will not be used for the assessment of protocol deviations. The Study Day ranges shown 
in the table are based on optimal intervals; the actual Study Day ranges for Safety Call 2 and Visit 4 will be 
based on when Visit 3 occurs.
Section 6.5 Contraindications to subsequent vaccination
The following events constitute contraindications to administration of MenABCWY, 
rMenB+OMV NZ, or MenACWY 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). 

Body temperature elevation (i.e. fever) within 3 days prior to intended study
vaccination. Fever is defined as temperature 38.0°C.

Significant acute illness (e.g. acute severe febrile illness) within 7 days prior to 
vaccination.

Administration of any other vaccine 14 days (for inactivated vaccines), or 28 days 
(for live vaccines), or 7 days (for influenza vaccines) prior to vaccination, with the 
exception of flu vaccination.
Synopsis and Section 6.7.2 Concomitant medications/products/vaccines that may lead to 
the elimination of a subject from the per-protocol analyses
(Note: Only the bullet point text was added to the synopsis.)

A vaccine not foreseen by the study protocol administered during the period of 
14 days (for inactivated vaccines), 28 days (for live vaccines), or 7 days (for 
influenza vaccines) before or after administration of the study vaccine(s) at Visit 1 
and Visit 3*.
*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 SmPC 
and according to local governmental recommendations and provided a written 
approval of the sponsor is obtained.
 
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Section 6.8 Intercurrent medical conditions that may lead to elimination of a subject from 
per-protocol analyses
For analysis purposes, intercurrent conditions will be identified using AEs reported in 
the eCRFs during the study.
Section 8.1.3.3 Other solicited adverse events
The use of analgesics/antipyretics (preferably paracetamol) for either prophylactic or 
treatment purposes will also be recorded as other solicited events in the Subject Diary and 
verified onto specific eCRFs and subject medical records.
Section 8.2.1 Pregnancy
Note: The pregnancy itself should always be recorded on a paper an electronic pregnancy 
report.
Section 8.3.3.2.1 Assessment of intensity
Table 12 Intensity scales for solicited symptoms
Note: Temperature will be recorded in the evening. If additional temperature 
measurements are to be performed at other times of the day, the highest temperature and 
the time when the temperature was measured will be recorded in the eCRF.
Section 8.4.1 Prompt reporting of serious adverse events, pregnancies, and other events
Table 13 Timeframes for submitting serious adverse event, pregnancy, and other 
events reports
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*
paper pregnancy 
notification report
electronic pregnancy report
2 weeks*
paper pregnancy follow-up 
report electronic pregnancy 
report
AESIs
24 hours** ‡
electronic Expedited 
Adverse Events Report
24 hours*
electronic Expedited Adverse 
Events Report
Section 8.4.4 Completion and transmission of pregnancy reports
Once the investigator becomes aware that a subject is pregnant, the investigator (or 
designate) must complete the required information onto the paper electronic pregnancy 
report WITHIN 2 WEEKS. The investigator (or designate) must complete and fax a 
pregnancy notification form to PPD Pharmacovigilance (at 
) after 
entering or updating information within the pregnancy eCRF.
Section 8.5.2 Follow-up of pregnancies
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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 PPD using the paper electronic pregnancy report and the 
Expedited Adverse Events Report if applicable. Generally, the follow-up period does not 
need to be longer than 6 to 8 weeks after the estimated date of delivery.
Synopsis and Section 10.2 Secondary endpoints
Safety Endpoints

Unsolicited local and systemic AEs in all study groups

Adverse events, SAEs, medically attended AEs, AEs leading to withdrawal, and 
AESIs, in all study groups from informed consent signature to Visit 4 (Day 91)
Section 10.4.3.2 Unsolicited Safety Set (unsolicited adverse events)
All subjects in the All Exposed Set who attended at least 1 visit or had at least 1 safety 
call or at least 1 follow-up event (such as withdrawal from the study) after receiving 
any study vaccination with unsolicited AE data.
Section 10.4.4.1 Full Analysis Set 1
All subjects in the All Exposed Set who provided evaluable serum samples and whose 
assay results are available for at least 1 serogroup at Visit 4 for all study groups except 
the MenACWY group, or at Visit 2 for the MenACWY group.
Section 10.4.4.2 Full Analysis Set 2
All subjects in the All Exposed Set who provided evaluable serum samples and whose 
assay results are available for at least 1 serogroup at Visit 2 for all study groups except 
the MenACWY group.
Section 10.4.4.3 Full Analysis Set 3
All subjects in the All Exposed Set who provided evaluable serum samples and whose 
assay results are available for at least 1 serogroup at Visit 4 for all study groups except 
the MenACWY group, or at Visit 2 for the MenACWY group, and at baseline for all 
study groups.
Section 10.4.4.4 Full Analysis Set 4
All subjects in the All Exposed Set who provided evaluable serum samples and whose 
assay results are available for at least 1 serogroup at Visit 2 and at baseline for all study 
groups except the MenACWY group.
 
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Section 10.5 Derived and transformed data

Reactogenicity and Safety

Handling of missing data: for safety analyses, subjects who missed reporting 
symptoms (solicited/unsolicited) or concomitant medications will be analyzed 
further. The main safety analyses will contain missing data (missing safety 
values will not be imputed) but further analyses to assess the missing 
mechanism will be specified in the statistical analysis plan. subjects who 
missed reporting symptoms (solicited/unsolicited or concomitant medications)
will be treated as subjects without symptoms (solicited/unsolicited or 
concomitant medications, respectively). In case of significant non-compliance 
with study procedures for reporting symptoms, the statistical analysis plan will 
be reassessed to ensure more accurate reporting of study data by further 
analysis.
Section 10.7 Analysis of immunogenicity
Analysis of hSBA GMT
An analysis of covariance (ANCOVA) model will be used to analyze post-vaccination 
log-transformed titers of hSBA for both the primary and secondary objectives (i.e. the 
hSBA at 1 month after the last vaccination and the hSBA at 1 month after the first 
vaccination, respectively). The ANCOVA model will be fitted to each serogroup/strain 
individually, and in addition the serogroup B strains will be grouped together to 
perform a pooled analysis. The GMTs obtained through the ANCOVA model will be 
called “adjusted” and the “unadjusted” GMTS will be obtained through descriptive 
statistics. Unadjusted and adjusted GMTs and associated 2-sided 80% CIs will be 
computed for each study group and for each strain at each visit. The fixed-effect model 
will include the age strata, treatment, serogroup, and center as fixed effects. The 
pre-vaccination log-transformed titer with centering at zero will be included as a 
continuous covariate. An interaction between serogroup and pre-vaccination 
log-transformed titer centered at zero will be included in the model. For each study 
group, adjusted GMTs and their 80% CIs will be obtained by exponentiating (base 10) 
the least squares means and the lower and upper limits of the 80% CIs of the 
log-transformed titers (base 10).
Section 10.7 Analysis of immunogenicity
Analysis of Percentage of Subjects With Titers Above LLOQ and a 4-fold Increase
The fixed-effect model for the individual serogroups/strains will include the age strata, 
treatment, and center as fixed effects. The fixed-effect model for the pooled analysis 
will include the age strata, treatment, strain serogroup, and center as fixed effects. The 
pre-vaccination log-transformed titer with centering at zero will be included as a 
continuous covariate. An interaction between serogroup and pre-vaccination 
log-transformed titer centered at zero will be included in the model.
 
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Section 10.8.2 Analysis of local and systemic adverse events
(Note: The greater than or equal to sign [≥] has been edited to a greater than [>] sign in 
the first sentence.)
Erythema, induration, and swelling will be categorized as none (<25 mm), 25 to 50 mm
(mild), 51 to 100 mm (moderate), and >100 mm (severe local reactions). The severity of 
pain will be categorized as none, mild (transient with no limitation in normal daily 
activity), moderate (some limitation in normal daily activity), and severe (unable to 
perform normal daily activity). 
 
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GlaxoSmithKline Biologicals SA
Vaccines R &D
Protocol Amendment 2
eTrack study number 
and abbreviated title
208205 MENABCWY-016 (V102_19)
EudraCT number
2017-005128-12
Amendment number:
Amendment 2, substantial
Amendment date:
29 August 2018
Co-ordinating author:
 Principal Medical Writer, PPD, for GSK 
Biologicals
Rationale/background for changes: 
!
A tertiary objective was added to allow potential exploratory evaluation of 
immune responses induced by the study vaccine(s) against a panel of strains 
of Neisseria species in a subset of subjects.
!
Protocol Clarification Letter 1 was incorporated, which removed reference to 
a pregnancy electronic case report form.
!
The window for Subject Diary reminder calls was clarified.
!
Other minor changes were made to correct typos, and improve clarity and 
alignment within the document.
Minor administrative edits (e.g. typos, abbreviations) have not been listed here.
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections:
Synopsis, Objectives
Tertiary
!
To further characterize the immune response induced by the study vaccine(s)
against an additional panel of strains of Neisseria species in a subset of subjects. 
Note: This tertiary objective is exploratory and suitable assays may or may not be 
developed. The tertiary objective will be assessed in a subset of subjects using 
remaining serum after the primary and secondary analyses have been completed; no 
additional blood samples will be collected from subjects. Any outcome of exploratory 
testing that would be of scientific/medical relevance will be reported in an 
annex/addendum to the final study report.

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Synopsis, Method of evaluation
Tertiary
!
Endpoints related to the tertiary objective will be described in a separate statistical 
analysis plan. 
Section 2.3 Tertiary objective (newly added header and section)
2.3 Tertiary objective
!
To further characterize the immune response induced by the study vaccine(s)
against an additional panel of strains of Neisseria species in a subset of subjects. 
Note: This tertiary objective is exploratory and suitable assays may or may not be 
developed. The tertiary objective will be assessed in a subset of subjects using 
remaining serum after the primary and secondary analyses have been completed; no 
additional blood samples will be collected from subjects. Any outcome of exploratory 
testing that would be of scientific/medical relevance will be reported in an 
annex/addendum to the final study report.
Refer to Section 10.3 for the definition of the tertiary endpoint and to Section 10.11.1 
for the reporting of tertiary endpoint results.
Section 5.6.13.2.1 Subject diary reminder calls
Subject Diary reminder calls will be performed at 3 and 5 days (±1 day) after each 
vaccination (i.e., Day 4 and Day 6 after the first vaccination and accordingly after the 
second vaccination). The purpose of this call is to remind the subject/subject’s 
parent(s)/LAR(s) about completion of the Subject Diary. The call follows the Subject 
Diary Reminder Telephone Call Script provided to the site. The subject/subject’s 
parent(s)/LAR(s) should be reminded to contact the site via the telephone number 
provided in the informed consent to discuss medical questions.
Section 8.4.4 Completion and transmission of pregnancy reports
Once the investigator becomes aware that a subject is pregnant, the investigator (or 
designate) must complete the required information onto the paper pregnancy report 
WITHIN 2 WEEKS. The investigator (or designate) must complete and fax a pregnancy 
notification form to PPD Pharmacovigilance (at 
) after entering or 
updating information within the paper pregnancy report eCRF.

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Section 10.3 Tertiary endpoint (newly added header and section; heading numbers were 
updated in subsequent sections accordingly)
10.3 Tertiary endpoint
Endpoints related to the tertiary objective will be described in a separate statistical 
analysis plan.
Section 10.5.2 All Exposed Set
All subjects in the All Enrolled Set who receive a any study vaccination.
Section 10.5.4.1 Full Analysis Set 1
All subjects in the All Exposed Set who provided evaluable serum samples and whose 
assay results are available for at least 1 serogroup or B strain at Visit 4 for all study 
groups except the MenACWY group, or at Visit 2 for the MenACWY group.
Section 10.5.4.2 Full Analysis Set 2
All subjects in the All Exposed Set who provided evaluable serum samples and whose 
assay results are available for at least 1 serogroup or B strain at Visit 2 for all study 
groups except the MenACWY group.
Section 10.5.4.3 Full Analysis Set 3
All subjects in the All Exposed Set who provided evaluable serum samples and whose 
assay results are available for at least 1 serogroup or B strain at Visit 4 for all study 
groups except the MenACWY group, or at Visit 2 for the MenACWY group, and at 
baseline for all study groups.
Section 10.5.4.4 Full Analysis Set 4
All subjects in the All Exposed Set who provided evaluable serum samples and whose 
assay results are available for at least 1 serogroup or B strain at Visit 2 and at baseline 
for all study groups except the MenACWY group.
Section 10.11.1 Sequence of analyses
Any outcome of exploratory testing will be reported in an annex/addendum to the final 
study report.
 
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Protocol Amendment 2 Final
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29-AUG-2018