Immunogenicity and Safety Study of a Booster Dose of GSK Biologicals' Infanrix Hexa™ (217744) in Healthy Infants Born to Mothers Vaccinated With Boostrix™ During Pregnancy or Immediately Post-delivery
Phase: PHASE4
Conditions: Diphtheria, Hepatitis B, Acellular Pertussis, Haemophilus Influenzae Type b, Tetanus, Poliomyelitis, Diphtheria-Tetanus-aPertussis-Hepatitis B-Poliomyelitis-Haemophilus Influenzae Type b Vaccines
Sponsor: GlaxoSmithKline

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Clinical Study Protocol
Sponsor
GlaxoSmithKline Biologicals
Rue de l'Institut 89
1330 Rixensart, Belgium.
Primary Study vaccine and 
number
GlaxoSmithKline (GSK) Biologicals’ combined
diphtheria-tetanus-acellular pertussis-hepatitis B-
inactivated poliovirus and Haemophilus influenzae type 
b (DTPa-HBV-IPV/Hib) vaccine (Infanrix hexa™) 
(217744).
Other Study vaccine
Pneumoccocal 13-valent Conjugate Vaccine 
(Diphtheria CRM197 Protein) (Prevenar 13®, 
Manufactured by Wyeth Pharmaceuticals Inc. 
Marketed by Pfizer Inc.).
eTrack study number and 
Abbreviated Title
201334 [DTPA (BOOSTRIX)-049 BST: 048]
EudraCT number
2014-001120-30
Date of protocol
Final Version 2: 14 March 2016
Date of protocol 
amendment
Amendment 1 Final 12 December 2016
Title
Immunogenicity and safety study of a booster dose of 
GSK Biologicals’ Infanrix hexa™(217744) in healthy 
infants born to mothers vaccinated with Boostrix™ 
during pregnancy or immediately post-delivery.
Detailed Title
A phase IV, open-label, non-randomised, multi-centre 
study to assess the immunogenicity and safety of a 
booster dose of Infanrix hexa™ in healthy infants born 
to mothers vaccinated with Boostrix™ during 
pregnancy or immediately post-delivery.
Co-ordinating authors
, Scientific Writers
Contributing authors
(Amended 12 December 
2016)
!
, Clinical and 
Epidemiology Project Leader (CEPL) 
!
, Clinical Research and 
Development Lead (CRDL)
!
and 
, Clinical 
Research and Development Lead (Project-Level 
CRDL)
!
, Project Statistician
!
and 
, Study 
Delivery Lead
!
, 
, Clinical 
Laboratory Sciences (CLS) Clinical Read-Out 
Team Leader

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eTrack study number and 
Abbreviated Title
201334 [DTPA (BOOSTRIX)-049 BST: 048]
EudraCT number
2014-001120-30
Detailed Title
A phase IV, open-label, non-randomised, multi-centre 
study to assess the immunogenicity and safety of a 
booster dose of Infanrix hexa™ in healthy infants born 
to mothers vaccinated with Boostrix™ during 
pregnancy or immediately post-delivery.
Contributing authors
!
, CLS Study Manager
!
 and 
, Global 
Clinical Regulatory Affairs Representative
!
, 
, 
and 
, Clinical Safety 
Representatives
!
, Global Patents Representative
!
, Study Data Manager
!
, 
, Oversight data 
Manager
!
and 
, 
Senior Manager, Biometrics
!
and 
, Vaccines 
Supply Coordinator
!
, Director, Global Medical Affairs
!
, Study Delivery Manager
!
and 
, Local Delivery 
Lead, Australia
!
and 
, Local 
Delivery Lead, Canada 
!
and 
 
 Local Delivery Lead, Spain
!
and 
, Local 
Delivery Lead, Czech Republic
!
, Director/Local Medical Lead, 
Czech Republic
!
, Local Delivery Lead, Finland
!
 and 
, Local 
Delivery Leads, Italy
GSK Biologicals’ Protocol DS v 14.1.1
Copyright 2016 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised 
copying or use of this information is prohibited.

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Protocol Amendment 1 Sponsor Signatory Approval
eTrack study number and 
Abbreviated Title
201334 [DTPA (BOOSTRIX)-049 BST: 048]
EudraCT number
2014-001120-30
Date of protocol amendment
Amendment 1 Final: 12 December 2016
Detailed Title 
A phase IV, open-label, non-randomised, multi-centre 
study to assess the immunogenicity and safety of a 
booster dose of Infanrix hexa™ in healthy infants 
born to mothers vaccinated with Boostrix™ during 
pregnancy or immediately post-delivery.
Sponsor signatory
Narcisa Mesaros, MD
Clinical and Epidemiology R&D Project Leader 
(CEPL), DTP, Polio, Hib containing vaccines
R&D Center Belgium
Signature
Date
 
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Protocol Amendment 1 Rationale
Amendment number:
Amendment 1
Rationale/background for changes: 
Given the fact that only infants born from mothers vaccinated in the study (116945 
[DTPA (BOOSTRIX)-047) and vaccinated in the previous study 201330 [DTPA 
(BOOSTRIX)-048 PRI] can be enrolled in the current study, the enrolment in these 
studies has an impact on this current study (e.g. cohorts to be investigated). Initially, 
the DTPA (BOOSTRIX)-047 and DTPA (BOOSTRIX)-048 PRI studies were opened 
only in countries using 3-dose primary vaccination series plus a booster vaccination at 
12 to 18 months of age against diphtheria, tetanus and pertussis in infants. 
Nevertheless, the 2-dose primary vaccination schedule with a booster vaccination at 11 
to 13 months of age in infants is also meaningful for different regions in the world (e.g. 
Europe). It was therefore decided to open the DTPA (BOOSTRIX)-047 and DTPA 
(BOOSTRIX)-048 PRI, and therefore the current booster study to countries using 2-
dose primary vaccination series with a booster vaccination at 11 to 13 months of age 
with the aim to increase the scientific value of the study and generate clinical data in 
diverse infant vaccination schedules. This protocol is amended to include the 
possibility to administer the booster vaccine dose at 11 to 13 months of age, in addition 
to the 12 to 18 months of age initially planned. 
The notion of end of study was clarified and the Section 11.5 describing the posting of 
information on public registry was revised accordingly.
An inclusion criterion was updated to specify that only infant having received the full 
vaccination series as per protocol requirement in the study DTPA (BOOSTRIX)-048 
PRI can be enrolled in the current study (and not only infant born from mother 
vaccinated in the DTPA (BOOSTRIX)-047).
Following a request from the Czech Republic, the phone call at 18 months may be 
replaced by a clinic visit if deemed preferable by the study team.
The vaccination sites were updated to allow vaccination either in the thigh or deltoid, 
according to the national recommendation, to comply with the Australian 
recommendations.
The names and functions of the contributing authors have been updated. In addition, 
minor updates including typos, abbreviations, clarifications of wording were done 
throughout the document.
 
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Protocol Amendment 1 Investigator Agreement
I agree:

To conduct the study in compliance with this protocol, any future protocol 
amendments or protocol administrative changes, with the terms of the clinical trial 
agreement and with any other study conduct procedures and/or study conduct 
documents provided by GlaxoSmithKline (GSK) Biologicals.

To assume responsibility for the proper conduct of the study at this site.

That I am aware of, and will comply with, ‘Good Clinical Practice’ (GCP) and all 
applicable regulatory requirements. 

To ensure that all persons assisting me with the study are adequately informed about 
the GSK Biologicals’ investigational vaccine and other study-related duties and 
functions as described in the protocol.

To acquire the reference ranges for laboratory tests performed locally and, if required 
by local regulations, obtain the laboratory’s current certification or Quality 
Assurance procedure manual.

To ensure that no clinical samples (including serum samples) are retained onsite or 
elsewhere without the approval of GSK Biologicals and the express written informed 
consent of the subject and/or the subject’s legally acceptable representative.

To perform no other biological assays on the clinical samples except those described 
in the protocol or its amendment(s).

To co-operate with a representative of GSK Biologicals in the monitoring process of 
the study and in resolution of queries about the data.

That I have been informed that certain regulatory authorities require the sponsor to 
obtain and supply, as necessary, details about the investigator’s ownership interest in 
the sponsor or the investigational vaccine, and more generally about his/her financial 
ties with the sponsor. GSK Biologicals will use and disclose the information solely 
for the purpose of complying with regulatory requirements.
Hence I:

Agree to supply GSK Biologicals with any necessary information regarding 
ownership interest and financial ties (including those of my spouse and dependent 
children).

Agree to promptly update this information if any relevant changes occur during the 
course of the study and for one year following completion of the study.

Agree that GSK Biologicals may disclose any information it has about such 
ownership interests and financial ties to regulatory authorities.

Agree to provide GSK Biologicals with updated Curriculum Vitae and other 
documents required by regulatory agencies for this study.
 
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eTrack study number and 
Abbreviated Title
201334 [DTPA (BOOSTRIX)-049 BST: 048]
EudraCT number
2014-001120-30
Date of protocol Amendment
Amendment 1 Final: 12 December 2016
Detailed Title
A phase IV, open-label, non-randomised, 
multi-centre study to assess the immunogenicity and 
safety of a booster dose of Infanrix hexa™ in healthy 
infants born to mothers vaccinated with Boostrix™ 
during pregnancy or immediately post-delivery.
Investigator name
Signature
Date
 
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Sponsor Information
1.
Sponsor
GlaxoSmithKline Biologicals
Rue de l'Institut 89
1330 Rixensart, Belgium.
2.
Sponsor Medical Expert for the Study
Refer to the local study contact information document.
3.
Sponsor Study Monitor
Refer to the local study contact information document.
4.
Sponsor Study Contact for Reporting of a Serious Adverse Event
GSK Biologicals Central Back-up Study Contact for Reporting SAEs: refer to protocol 
Section 8.3.2.
 
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SYNOPSIS
Detailed Title
A phase IV, open-label, non-randomised, multi-centre study 
to assess the immunogenicity and safety of a booster dose of 
Infanrix hexa™ in healthy infants born to mothers vaccinated 
with Boostrix™ during pregnancy or immediately post-
delivery.
Indication
Booster immunisation of infants against diphtheria, tetanus, 
pertussis, hepatitis B, poliomyelitis and disease caused by 
Haemophilus influenzae type b (Hib).
Rationale for the 
study and study 
design

Rationale for the study
Recent studies have shown that maternal combined reduced 
antigen content diphtheria-tetanus-acellular pertussis (dTpa)
vaccination during pregnancy results in high pertussis 
antibody concentrations in infants during the period between 
birth and the first vaccine dose. Although slightly decreased 
immune responses following the primary diphtheria-tetanus-
acellular pertussis (DTPa) vaccination has been observed in 
infants whose mothers received dTpa vaccine compared to 
those whose mothers did not receive dTpa vaccine, the 
differences did not persist following the booster vaccination in 
infants [Hardy-Fairbanks, 2013; Gall, 2011].
An analysis of data from the Clinical Practice Research 
Datalink (a primary care database of 520 general medical 
practices in England) demonstrates that maternal dTpa 
immunisation can decrease the incidence of infant pertussis. 
After a maternal pertussis vaccination programme was 
introduced in October 2012 in response to a pertussis outbreak 
in England, the number of pertussis cases in infants younger 
than three months of age and the number of hospitalisations 
decreased significantly [Amirthalingam, 2014].
In 2013, the Advisory Committee on Immunization Practices 
(ACIP) recommended that all women should be vaccinated 
with dTpa vaccine during each pregnancy, regardless of the 
previous immunisation schedule [CDC, 2013]. Similar 
recommendations have been implemented in 18 countries 
including United Kingdom, New Zealand, Israel, Mexico, 
Brazil, Colombia, Uruguay, Panama, Costa Rica, Argentina,
Australia and some provinces in Spain [Joint Committee on 
Vaccination and Immunization (JCVI), 2012; Pharmaceutical 
Management Agency (PHARMAC), 2012; TAG, 2013]. The 
National Advisory Committee on Immunization in Canada 
recommends that all pregnant women following 26 weeks of 
pregnancy who have not received a dose of pertussis-
containing vaccine in adulthood should be encouraged to 
 
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receive dTpa vaccination. In special circumstances, such as an 
outbreak situation, all pregnant women who are of 26 weeks 
gestation or greater may be offered dTpa vaccination 
irrespective of their immunisation history [Warshawsky, 
2014; Public Health Agency of Canada, 2014].
All infants born to pregnant women who participated in study 
116945 [DTPA (BOOSTRIX)-047] will be followed-up to 
study the immunogenicity and safety of GSK Biologicals’ 
combined diphtheria-tetanus-acellular pertussis-hepatitis B-
inactivated poliovirus and Haemophilus influenzae type b 
vaccine (DTPa-HBV-IPV/Hib), Infanrix hexa, given as 
primary and booster vaccination. Study 201330 [DTPA 
(BOOSTRIX)-048 PRI] will be conducted to assess the 
immunogenicity and safety of Infanrix hexa co-administered 
with Prevenar 13 as the primary vaccination course.
The present study will be performed to study the 
immunogenicity and safety of the booster dose of Infanrix 
hexa in infants who were born to mothers vaccinated with 
Boostrix during pregnancy or immediately post-delivery and 
who completed their primary vaccination series as per 
protocol requirement in study DTPA (BOOSTRIX)-048 PRI.
(Amended 12 December 2016)

Rationale for the study design
This phase IV study is a follow-up of the study 201330 
[DTPA (BOOSTRIX)-048 PRI]. The immunogenicity and 
safety of Infanrix hexa when given as a booster dose 
according to the routine national/ local immunization 
schedule or as specified in the SPM will be evaluated. 
Subjects will receive Prevenar 13 according to the routine 
national/ local immunization schedule or as specified in the 
SPM as a co-administered vaccine in this study. (Amended 
12 December 2016)
This study will have two groups:

dTpa Group: This group will consist of infants born to 
mothers belonging to the dTpa Group in study 116945 
[DTPA (BOOSTRIX)-047], i.e., mothers who received a 
single dose of Boostrix during pregnancy and a dose of 
placebo immediately post-delivery and infants who 
received full primary vaccination course as per protocol 
requirement in the study 201330 [DTPA (BOOSTRIX)-
048 PRI]. All infants in this group will receive a booster 
dose of Infanrix hexa co-administered with Prevenar 13
according to the routine national/ local immunization 
schedule or as specified in the SPM. (Amended 12 
December 2016)
 
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
Control Group: This group will consist of infants born to 
mothers belonging to the Control group in study 116945 
[DTPA (BOOSTRIX)-047], i.e., mothers who received a 
single dose of placebo during pregnancy and a dose of 
Boostrix immediately post-delivery and infants who 
received full primary vaccination course as per protocol 
requirement in the study 201330 [DTPA (BOOSTRIX)-
048 PRI]. All infants in this group will receive a booster 
dose of Infanrix hexa co-administered with Prevenar 13
according to the routine national/ local immunization 
schedule or as specified in the SPM. (Amended 12 
December 2016)
The study will be open-label since the treatment allocation is 
similar between the two groups. Also, the data related to the 
study groups will be unblinded at the end of study 116945 
[DTPA (BOOSTRIX)-047].
Currently, the effect of Boostrix administered to mothers 
during pregnancy or immediately post-delivery on the 
neurodevelopment of infants is unknown. Therefore, the 
neurodevelopment of the subjects will be studied at 9 months 
and 18 months of age in this study. To assess the 
neurodevelopmental status, the investigator or designate will 
complete a standardised developmental screening tool, Ages 
and Stages Questionnaire-3 (ASQ-3) via a paper questionnaire 
with subjects’ parent(s)/LAR(s) during the study visits or 
phone call [ASQ-3, 2016]. (Amended 12 December 2016)
Any subject who scores below the cut-off i.e., a score more 
than 2 Standard Deviations (SDs) below the mean score for 
the U.S. reference group (i.e., black zone in the score chart) in 
any of the five domains of the ASQ-3 (i.e., communication, 
gross motor, fine motor, problem solving, and personal-social) 
will be referred to a developmental specialist for formal 
neurodevelopmental assessment (e.g., using the Bayley Scale 
for Infant Development, Version III [BSID-III]) 
[Bayley-III, 2006]. An overall neurodevelopmental 
assessment in the areas of cognitive, language, motor, social-
emotional and adaptive behaviour will be rendered using 
BSID-III. A BSID-III score more than 2 SDs below the mean 
score for the U.S. reference group will be considered as a 
neurodevelopmental impairment.
Objectives
Primary

To assess the immunological response to Infanrix hexa in 
terms of seroprotection status for diphtheria, tetanus, 
hepatitis B, poliovirus and Hib antigens, and in terms of 
booster response for the pertussis antigens, one month 
 
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after the booster dose in infants born to mothers 
vaccinated with Boostrix during pregnancy or 
immediately post-delivery.
Secondary

To assess the persistence of antibodies to all vaccine 
antigens before the booster dose in infants born to 
mothers vaccinated with Boostrix during pregnancy or 
immediately post-delivery.

To assess the immunological response to Infanrix hexa
and Prevenar 13 in terms of antibody concentrations or 
titres against all antigens, one month after the booster 
dose in infants born to mothers vaccinated with Boostrix
during pregnancy or immediately post-delivery.

To assess the immunological response to Infanrix hexa in 
terms of seropositivity rates against pertussis antigens, 
one month after the booster dose in infants born to 
mothers vaccinated with Boostrix during pregnancy or 
immediately post-delivery.

To assess the safety and reactogenicity of Infanrix hexa
and Prevenar 13 in terms of solicited and unsolicited 
symptoms and serious adverse events (SAEs).

To assess the neurodevelopmental status of infants born 
to mothers vaccinated with Boostrix during pregnancy or 
immediately post-delivery, at 9 and 18 months of age.
Study design

Experimental design: Phase IV, open-label, non-
randomised, multi-centric, multi-country study with two 
parallel groups.

Duration of the study: The intended duration of the study, 
is approximately 9 to 10 months, per subject.

Epoch 001: Booster phase starting at Visit 1 (9 
months of age) and ending at telephone contact or at
Visit 3 (18 or 19 months of age), depending on the 
time of vaccination. (Amended 12 December 2016)

End of Study (EoS): Last testing results released of 
samples collected at Visit 3. (Amended 12 December 
2016)

Study groups: The study groups and epoch foreseen in the 
study are presented in Synopsis Table 1.

dTpa Group: This group will consist of infants born 
to mothers belonging to the dTpa Group in study 
116945 [DTPA (BOOSTRIX)-047] i.e., mothers who 
received a single dose of Boostrix during pregnancy 
 
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and a dose of placebo immediately post-delivery and 
infants who received full vaccination course in the 
study 201330 [DTPA (BOOSTRIX)-048 PRI]. All 
subjects in this group will receive a booster dose of 
Infanrix hexa co-administered with Prevenar 13
according to the routine national/ local 
immunization schedule or as specified in the SPM. 
(Amended 12 December 2016).

Control Group: This group will consist of infants 
born to mothers belonging to the Control group in 
study 116945 [DTPA (BOOSTRIX)-047] i.e.,
mothers who received a single dose of placebo 
during pregnancy and a dose of Boostrix immediately 
post-delivery and infants who received full
vaccination course in the study 201330 [DTPA 
(BOOSTRIX)-048 PRI]. All subjects in this group 
will receive a booster dose of Infanrix hexa co-
administered with Prevenar 13 according to the 
routine national/ local immunization schedule or as 
specified in the SPM. (Amended 12 December 
2016).
Synopsis Table 1
Study groups and epoch foreseen in the study
(Amended 12 December 2016)
Study Groups
Number of 
subjects*
Age (Min – Max)**
Epochs
Epoch 001
dTpa Group
340
11 months-19months
x
Control Group
340
11 months-19 months
x
*A maximum number of subjects
**Age at the time of vaccination depending on the routine national/ local immunization schedule or as specified 
in the SPM
The study groups and treatment foreseen in this study are given in Synopsis Table 2.
Synopsis Table 2
Study groups and treatment foreseen in the study
(Amended 12 December 2016)
Treatment name
Vaccine name
Study Groups
dTpa Group
Control Group
Infanrix hexa 
DTPa-HBV-IPV
X
x
Hib
X
x
Prevenar 13 
Prevenar 13
X
x

Control: uncontrolled (No active control or placebo. All 
subjects will receive the same vaccine)

Vaccination schedule: All subjects will receive a booster 
 
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dose of Infanrix hexa co-administered with Prevenar 13
between 11-18 months of age according to the routine 
national/ local immunization schedule or as specified in 
the SPM. (Amended 12 December 2016)

Treatment allocation: Non-randomised. All subjects will 
receive a booster dose of Infanrix hexa co-administered 
with Prevenar 13.

Blinding: Open-label.
Note: The study personnel operating SBIR and the site staff 
will remain blinded towards the treatment allocation of the 
mother in study 116945 [DTPA (BOOSTRIX)-047]. 
(Amended 12 December 2016)
The blinding of the study is given in Synopsis Table 3.
Synopsis Table 3
Blinding of study epoch
Study Epoch
Blinding
Epoch 001 
open

Sampling schedule: Blood samples will be drawn from all 
subjects at the following time points:

Pre-Bst: Before the booster dose administration, a 
volume of approximately 5 mL of whole blood (to 
provide approximately 1.7 mL of serum) will be 
collected.

Post-Bst: One month after the booster dose, 
approximately 5 mL of whole blood (to provide 
approximately 1.7 mL of serum) will be collected.

Type of study: extension of other protocol(s) 116945 
[DTPA (BOOSTRIX)-047] and 201330 [DTPA 
(BOOSTRIX)-048 PRI].

Data collection: Electronic Case Report Form (eCRF).

Safety monitoring: An independent data monitoring 
committee (IDMC) (including paediatricians and a 
statistician) will be put in place to oversee the safety 
aspects including neurodevelopmental status of infants 
born to mothers vaccinated with Boostrix during pregnancy 
or immediately post-delivery in the clinical study i.e., each 
SAE/incidence of grade 3 local and general solicited 
adverse events (AEs), unsolicited AEs will be reviewed by 
this committee as per approved IDMC charter. (Amended 
12 December 2016)
 
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Number of subjects
A maximum of 680 infants (approximately 340 infants in each 
group) aged 9 months will be enrolled in this study. Blood 
samples will be taken from all subjects in order to evaluate the 
immunogenicity endpoints.
Endpoints
Primary

Immunogenicity with respect to components of Infanrix 
hexa.

Anti-diphtheria, anti-tetanus, anti-HBs, anti-poliovirus 
type 1, anti-poliovirus type 2, anti-poliovirus type 3 
and anti-polyribosyl-ribitol phosphate (anti-PRP) 
seroprotection status, one month after the booster dose.

Booster response to PT, FHA and PRN antigens, one 
month after the booster dose.
Secondary

Immunogenicity with respect to components of Infanrix 
hexa and Prevenar 13.
Before the booster dose

Anti-diphtheria, anti-tetanus, anti-poliovirus type 1, 
anti-poliovirus type 2, anti-poliovirus type 3, anti-HBs 
and anti-PRP seroprotection status.

Anti-PT, anti-FHA, anti-PRN and anti-pneumococcal 
serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 
19F, 23F) seropositivity rates.

Anti-diphtheria, anti-tetanus, anti-PT, anti-FHA, anti-
PRN, anti-poliovirus type 1, anti-poliovirus type 2, 
anti-poliovirus type 3, anti-HBs and anti-
pneumococcal serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 
14, 18C, 19A, 19F, 23F) and anti-PRP antibody 
concentrations or titres.
One month after the booster dose

Anti-diphtheria, anti-tetanus, anti-poliovirus type 1, 
anti-poliovirus type 2, anti-poliovirus type 3, anti-HBs, 
anti-PRP, anti-PT, anti-FHA, anti-PRN and anti-
pneumococcal serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 
14, 18C, 19A, 19F, 23F) antibody concentrations or 
titres.

Anti-PT, anti-FHA, anti-PRN antibody seropositivity 
rates.
 
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
Solicited local and general symptoms.

Occurrence of solicited local/general symptoms during 
the 4-day (Day 0-Day 3) follow-up period after booster 
vaccination.

Unsolicited adverse events.

Occurrence of unsolicited symptoms during the 31-day 
(Day 0-Day 30) follow-up period after booster 
vaccination.

Serious adverse events.

Occurrence of reported SAEs from booster dose up to 
study end.

Neurodevelopmental status will be assessed at 9 and 18 
months of age adjusted for prematurity.

Proportion of infants with an ASQ-3 score in the black 
zone in any domain.

Proportion of infants with an ASQ-3 score in the black 
zone for gross motor skills.

Proportion of infants with an ASQ-3 score in the black 
zone for fine motor skills.

Proportion of infants with an ASQ-3 score in the black 
zone for communication.

Proportion of infants with an ASQ-3 score in the black 
zone for problem solving skills.

Proportion of infants with an ASQ-3 score in the black 
zone for personal-social skills.

Proportion of infants referred for formal 
neurodevelopmental evaluation using BSID-III.

Proportion of infants with at least one of the indicators 
of neurodevelopmental impairment using BSID-III.
 
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TABLE OF CONTENTS
PAGE
SPONSOR INFORMATION ............................................................................................7
SYNOPSIS......................................................................................................................8
LIST OF ABBREVIATIONS...........................................................................................22
GLOSSARY OF TERMS ...............................................................................................25
TRADEMARKS .............................................................................................................28
1.
INTRODUCTION....................................................................................................29
1.1.
Background ................................................................................................29
1.2.
Rationale for the study and study design ....................................................30
1.2.1.
Rationale for the study.................................................................30
1.2.2.
Rationale for the study design......................................................30
1.3.
Benefit: Risk Assessment ...........................................................................32
1.3.1.
Risk Assessment .........................................................................32
1.3.2.
Benefit Assessment.....................................................................33
1.3.3.
Overall Benefit: Risk Conclusion..................................................33
2.
OBJECTIVES.........................................................................................................33
2.1.
Primary objective ........................................................................................33
2.2.
Secondary objectives..................................................................................34
3.
STUDY DESIGN OVERVIEW ................................................................................35
4.
STUDY COHORT...................................................................................................37
4.1.
Number of subjects/centres ........................................................................37
4.2.
Inclusion criteria for enrolment....................................................................38
4.3.
Exclusion criteria for enrolment...................................................................38
5.
CONDUCT OF THE STUDY ..................................................................................40
5.1.
Regulatory and ethical considerations, including the informed 
consent process..........................................................................................40
5.2.
Subject identification and randomisation of treatment .................................41
5.2.1.
Subject identification....................................................................41
5.2.2.
Randomisation of treatment.........................................................41
5.2.2.1.
Treatment allocation to the subject.............................41
5.2.2.1.1.
Study group and treatment 
number allocation ...................................41
5.3.
Method of blinding ......................................................................................42
5.4.
General study aspects ................................................................................42
5.4.1.
Independent Data Monitoring Committee.....................................42
5.4.2.
Responsibilities............................................................................42
5.4.3.
Composition of the IDMC.............................................................43
5.4.4.
GSK Biologicals’ safety review team............................................43
5.5.
Outline of study procedures ........................................................................44
5.6.
Detailed description of study procedures ....................................................46
 
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5.6.1.
Procedures prior to study participation.........................................46
5.6.1.1.
Informed consent........................................................46
5.6.2.
Procedures during study participation..........................................47
5.6.2.1.
Check inclusion and exclusion criteria ........................47
5.6.2.2.
Collect demographic data...........................................47
5.6.2.3.
Medical history ...........................................................47
5.6.2.4.
Medication and vaccination history.............................47
5.6.2.5.
Physical examination..................................................47
5.6.2.6.
Check contraindications, warnings and 
precautions to vaccination ..........................................47
5.6.2.7.
Assess pre-vaccination body temperature..................48
5.6.2.8.
Record body length, weight and head 
circumference (Amended 12 December 2016) ...........48
5.6.2.9.
Treatment number allocation......................................48
5.6.2.10.
Sampling ....................................................................48
5.6.2.10.1.
Blood sampling for immune 
response assessments...........................48
5.6.2.11.
Study Vaccines administration....................................48
5.6.2.12.
Check and record concomitant 
medication/vaccination and intercurrent 
medical conditions......................................................49
5.6.2.13.
Assessment of neurodevelopmental status ................49
5.6.2.14.
Recording of AEs and SAEs.......................................50
5.6.2.15.
Study conclusion ........................................................50
5.7.
Biological sample handling and analysis.....................................................51
5.7.1.
Use of specified study materials ..................................................51
5.7.2.
Biological samples.......................................................................52
5.7.3.
Laboratory assays .......................................................................52
5.7.4.
Biological samples evaluation......................................................55
5.7.4.1.
Immunological read-outs ............................................55
5.7.5.
Immunological correlates of protection.........................................55
6.
STUDY VACCINES AND ADMINISTRATION ........................................................57
6.1.
Description of study vaccines......................................................................57
6.2.
Storage and handling of study vaccines......................................................59
6.3.
Dosage and administration of study vaccines .............................................59
6.4.
Replacement of unusable vaccine doses....................................................60
6.5.
Contraindications to vaccination .................................................................60
6.6.
Warnings and precautions ..........................................................................60
6.7.
Concomitant medications/products and concomitant vaccinations..............62
6.7.1.
Recording of concomitant medications/products and 
concomitant vaccinations.............................................................62
6.7.2.
Concomitant medications/products/vaccines that may lead 
to the elimination of a subject from ATP analyses........................63
6.8.
Intercurrent medical conditions that may lead to elimination of a 
subject from ATP analyses .........................................................................63
7.
HEALTH ECONOMICS ..........................................................................................63
8.
SAFETY.................................................................................................................64
8.1.
Safety definitions ........................................................................................64
8.1.1.
Definition of an adverse event......................................................64
 
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8.1.2.
Definition of a serious adverse event ...........................................65
8.1.3.
Solicited adverse events..............................................................66
8.1.3.1.
Solicited local (injection-site) adverse events..............66
8.1.3.2.
Solicited general adverse events................................66
8.1.4.
Clinical laboratory parameters and other abnormal 
assessments qualifying as adverse events or serious 
adverse events ............................................................................66
8.2.
Detecting and recording adverse events and serious adverse
events.........................................................................................................67
8.2.1.
Time period for detecting and recording adverse events 
and serious adverse events .........................................................67
8.2.2.
Post-Study adverse events and serious adverse events..............68
8.2.3.
Evaluation of adverse events and serious adverse events...........69
8.2.3.1.
Active questioning to detect adverse events 
and serious adverse events........................................69
8.2.3.2.
Assessment of adverse events...................................70
8.2.3.2.1.
Assessment of intensity..........................70
8.2.3.2.2.
Assessment of causality .........................71
8.2.3.3.
Assessment of outcomes............................................72
8.2.3.4.
Assessment of neurodevelopmental status ................73
8.2.3.5.
Medically attended visits.............................................73
8.3.
Reporting of serious adverse events...........................................................73
8.3.1.
Prompt reporting of serious adverse events to GSK 
Biologicals ...................................................................................73
8.3.2.
Contact information for reporting serious adverse events ............73
8.3.3.
Completion and transmission of SAE reports to GSK 
Biologicals ...................................................................................73
8.3.3.1.
Back-up system in case the electronic 
reporting system does not work..................................74
8.3.4.
Updating of SAE information after removal of write access 
to the subject’s eCRF...................................................................74
8.3.5.
Regulatory reporting requirements for serious adverse 
events..........................................................................................74
8.4.
Follow-up of adverse events and serious adverse events...........................75
8.4.1.
Follow-up of adverse events and serious adverse events............75
8.4.1.1.
Follow-up during the study..........................................75
8.4.1.2.
Follow-up after the subject is discharged from 
the study.....................................................................75
8.5.
Treatment of adverse events ......................................................................75
8.6.
Subject card................................................................................................75
9.
SUBJECT COMPLETION AND WITHDRAWAL.....................................................76
9.1.
Subject completion .....................................................................................76
9.2.
Subject withdrawal......................................................................................76
9.2.1.
Subject withdrawal from the study ...............................................76
10. STATISTICAL METHODS......................................................................................77
10.1.
Primary endpoint.........................................................................................77
10.2.
Secondary endpoints ..................................................................................77
10.3.
Determination of sample size......................................................................78
10.4.
Cohorts for Analyses ..................................................................................81
10.4.1.
Total enrolled cohort....................................................................81
 
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10.4.2.
Total vaccinated cohort................................................................81
10.4.3.
According-to-protocol cohort for analysis of safety.......................81
10.4.4.
According-to-protocol cohort for analysis of 
immunogenicity............................................................................81
10.5.
Derived and transformed data.....................................................................82
10.6.
Analysis of demographics...........................................................................84
10.7.
Analysis of immunogenicity.........................................................................84
10.8.
Analysis of safety........................................................................................85
10.9.
Interpretation of analyses............................................................................86
10.10. Conduct of analyses ...................................................................................86
10.10.1. Sequence of analyses..................................................................86
10.10.2. Statistical considerations for interim analyses..............................86
11. ADMINISTRATIVE MATTERS ...............................................................................87
11.1.
electronic Case Report Form instructions ...................................................87
11.2.
Study Monitoring by GSK Biologicals..........................................................87
11.3.
Record retention .........................................................................................88
11.4.
Quality assurance.......................................................................................88
11.5.
Posting of information on publicly available clinical trial registers and 
publication policy (Amended 12 December 2016).......................................89
11.6.
Provision of study results to investigators ...................................................89
12. COUNTRY SPECIFIC REQUIREMENTS...............................................................89
13. REFERENCES.......................................................................................................90
 
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LIST OF TABLES
PAGE
Table 1
Study groups and epoch foreseen in the study.......................................36
Table 2
Study groups and treatment foreseen in the study .................................36
Table 3
Blinding of study epoch ..........................................................................37
Table 4
List of study procedures .........................................................................45
Table 5
Intervals between study visits.................................................................46
Table 6
Biological samples .................................................................................52
Table 7
Humoral Immunity (Antibody determination)...........................................52
Table 8
Immunological read-outs........................................................................55
Table 9
Study vaccines.......................................................................................58
Table 10
Dosage and administration.....................................................................59
Table 11
Solicited local adverse events ................................................................66
Table 12
Solicited general adverse events............................................................66
Table 13
Reporting periods for collecting safety information .................................68
Table 14
Intensity scales for solicited symptoms...................................................70
Table 15
Timeframes for submitting serious adverse event reports to GSK 
Biologicals..............................................................................................73
Table 16
Exact 95% CI of the different values of observed response rate 
(booster response rate or seroprotection rate) for a sample size 
of 204-272 subjects)...............................................................................79
Table 17
Reference values (booster phase) .........................................................80
Table 18
GSK Biologicals’ laboratories .................................................................93
Table 19
Outsourced laboratories.........................................................................93
 
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LIST OF APPENDICES
PAGE
APPENDIX A CLINICAL LABORATORIES ..................................................................93
APPENDIX B AMENDMENTS AND ADMINISTRATIVE CHANGES TO THE 
PROTOCOL...........................................................................................94
 
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LIST OF ABBREVIATIONS
(Amended 12 December 2016)
ACIP: 
Advisory Committee on Immunization Practices
AE:
Adverse Event
Anti-HBs:
Antibodies against hepatitis B surface antigen
ASQ-3:
Ages and Stages Questionnaire-3
ATP:
According-To-Protocol
BSID-III:
Bayley Scale for Infant Development, Version III
CDC:
Centers for Disease Control and Prevention, USA
CI:
Confidence Interval
CLIA:
ChemiLuminescence ImmunoAssay
CLS:
Clinical Laboratory Sciences 
CRDL:
Clinical Research and Development Lead
DTP:
Diphtheria-Tetanus-Pertussis
dTpa:
Combined reduced antigen content diphtheria-tetanus-
acellular pertussis vaccine
DTPa:
Diphtheria-Tetanus-acellular Pertussis
DTPA-HBV-IPV/Hib:
Combined diphtheria-tetanus-acellular pertussis-hepatitis 
B-inactivated poliovirus and Haemophilus influenzae
type b vaccine (Infanrix hexa)
eCRF:
electronic Case Report Form 
ELISA: 
Enzyme-Linked ImmunoSorbent Assay
EL.U/mL:
ELISA Unit per milliter
EoS:
End of Study
EPAR:
European public assessment report 
FHA:
Filamentous Haemagglutinin
GCP:
Good Clinical Practice
 
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GMC:
Geometric Mean Concentration
GMT:
Geometric Mean Titre
GSK:
GlaxoSmithKline
HBs: 
Hepatitis B surface antigen
HBV:
Hepatitis B Virus
HHE:
Hypotonic-Hyporesponsiveness Episode
Hib:
Haemophilus influenzae type b
HIV:
Human Immunodeficiency Virus
IB:
Investigator Brochure
ICF:
Informed Consent Form
ICH:
International Conference on Harmonization
IDMC:
Independent Data Monitoring Committee
IEC:
Independent Ethics Committee
IgG/ IgM:
Immunoglobulin G/ M
IM:
Intramuscular
IMP:
Investigational Medicinal Products
IPV: 
Inactivated Poliovirus Vaccine
IRB:
Institutional Review Board
JCVI:
Joint Committee on Vaccination and Immunization
LAR:
Legally Acceptable Representative
LL:
Lower Limit
LSLV:
Last Subject Last Visit
MedDRA:
Medical Dictionary for Regulatory Activities
(m)IU:
(Milli)-international units
PI:
Product Information
 
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PRN:
Pertactin
PRP:
Hib capsular polysaccharide Polyribosyl-Ribitol 
Phosphate 
PT:
Pertussis Toxoid
RCC:
Reverse Cumulative Curve
RSI:
Reference Safety Safety Information
SAE:
Serious Adverse Event
SBIR:
Randomisation System on Internet
SD:
Standard Deviation
SDV:
Source Document Verification
SIDS:
Sudden Infant Death Syndrome
SPC:
Summary of Product characteristics
SPM:
Study Procedure Manual
SRT:
Safety Review Team
(e)TDF:
(electronic) Temperature Excursion decision Form
TT:
Tetanus Toxoid
TVC:
Total Vaccinated Cohort
UK:
United Kingdom
UL:
Upper Limit
USA: 
United States of America
WHO: 
World Health Organization
 
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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 unfavourable 
and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a medicinal product. 
For marketed medicinal products, this also includes 
failure to produce expected benefits (i.e., lack of 
efficacy), abuse or misuse.
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, organisation, institution or entity 
by the courts, the government or a government body, 
acting in accordance with powers conferred on them by 
law or regulation. The definition of a child in care can 
include a child cared for by foster parents or living in a 
care home or institution, provided that the arrangement 
falls within the definition above. The definition of a child 
in care does not include a child who is adopted or has an 
appointed legal guardian.
Eligible:
Qualified for enrolment into the study based upon strict 
adherence to inclusion/exclusion criteria.
End of Study: 
(Synonym of End of 
Trial)
(Amended 12 December 
2016)
For studies without collection of human biologicals 
samples or imaging data EoS is the Last Subject Last 
Visit (LSLV).
For studies with collection of Human Biologicals 
Samples or imaging data, EoS is defined as the date of 
the last testing/reading released of the Human 
Biological Samples or imaging data, related to primary 
and secondary endpoints. EoS must be achieved no later 
than 8 months after LSLV
 
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Epoch:
An epoch is a self-contained set of consecutive time
points or a single time point from a single protocol. Self-
contained means that data collected for all subjects at all 
time points within that epoch allows to draw a complete 
conclusion to define or precise the targeted label of the 
product. Typical examples of epochs are primary
vaccinations, boosters, yearly immunogenicity follow-
ups, and surveillance periods for efficacy or safety.
eTrack:
GSK’s tracking tool for clinical trials.
Evaluable:
Meeting all eligibility criteria, complying with the 
procedures defined in the protocol, and, therefore, 
included in the according-to-protocol (ATP) analysis (see 
Sections 6.7.2 and 10.4 for details on criteria for 
evaluability).
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 or placebo 
being tested or used as a reference in a clinical trial, 
including a product with a marketing authorisation 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 
authorised 
representative are used 
in some settings.)
An individual or juridical or other body authorised under 
applicable law to consent, on behalf of a prospective 
subject, to the subject's participation in the clinical trial.
Randomisation:
Process of random attribution of treatment 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:
AEs to be recorded as endpoints in the clinical study. The 
presence/occurrence/intensity of these events is actively 
 
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solicited from the subject or an observer during a 
specified post-vaccination follow-up period.
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 vaccine or as a control.
Subject number:
A unique number identifying a subject, assigned to each 
subject consenting to participate in the study.
Treatment:
Term used throughout the clinical study to denote a set of 
investigational product(s) or marketed product(s) or 
placebo intended to be administered to a subject, 
identified by a unique number, according to the study 
randomisation or treatment allocation.
Treatment number:
A number identifying a treatment to a subject, according 
to the study randomisation or 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 GlaxoSmithKline 
group of companies
Generic description
Infanrix hexa™
Combined diphtheria-tetanus-acellular pertussis-
hepatitis B-inactivated poliovirus vaccine and 
Haemophilus influenzae type b conjugate vaccine
(Amended 12 December 2016)
Trademarks not owned by the GlaxoSmithKline 
group of companies
Generic description
Prevenar 13® (Wyeth Pharmaceuticals Inc.; 
Marketed by Pfizer Inc. or Wyeth LLC, owner/Pfizer 
Canada Inc., Licensee)
Pneumococcal 13-valent conjugate vaccine 
(diphtheria CRM197 protein)
 
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1.
INTRODUCTION
1.1.
Background
Infants experience the highest rates of serious complications, hospitalisations and death 
due to pertussis. This is mainly because they are too young to have completed the 
primary diphtheria, tetanus and acellular pertussis (DTPa) immunisation series.
Since 2000, most deaths and hospitalisations related to pertussis have been in 
unvaccinated infants younger than three months of age [Murphy, 2008]. In 2012, there 
were 48,777 reported cases of pertussis in the United States (US). Infants younger than 
one year of age had the highest incidence compared to other studied age groups. Fifteen 
out of 20 deaths occurred in unvaccinated infants younger than three months of age. In 
2014, there were 28,660 reported cases of pertussis in the US. The incidence again was 
highest in infants younger than one year of age and all of nine deaths due to pertussis 
occurred in unvaccinated infants three months of age and younger [Centers for Disease 
Control and Prevention (CDC), 2015; CDC, 2013]. (Amended 12 December 2016)
In Canada, approximately 2500 cases were reported in 2012 [Public Health Agency of 
Canada, 2012]. The United Kingdom (UK) was amidst a large outbreak of pertussis in 
2012. A national increase in the laboratory-confirmed cases of pertussis has also been 
observed in England and Wales, with a large number of cases being reported in very 
young infants [Health Protection Report, 2013]. The incidence of pertussis in Spain has 
also gradually increased, with significant increase in 2012- 7.5/100,000 inhabitants, 
especially affecting infants <3 months of age who are too young to have received the 
primary three doses of pertussis vaccine [Sizaire, 2014]. The number of pertussis cases 
reported in Australia has also been increasing with nearly 40,000 cases reported in 2011 
and 2012. While the rates are highest in the primary school-aged children, due to the 
waning of vaccine-induced immunity, the impact of the disease remains greatest in 
infants under one year of age [Communicable Disease Control Directorate, 2011]. 
Transplacental transfer of maternal antibodies is considered to provide some degree of 
protection to infants in the first few months of their life [Englund, 1995]. Unfortunately, 
low levels of the maternal antibodies and rapid decay of the antibodies in the infants 
often leave them at high risk for pertussis. One way to confer protection to infants is to 
immunise mothers late during pregnancy. This concept of “boosting” maternal levels of 
antibody to pertussis has been suggested as early as 1995. However, findings suggest that 
pre-existing high levels of pertussis antibody in infants suppress the ultimate immune 
response to whole-cell diphtheria, tetanus and pertussis (DTP) vaccines [Englund, 1995]. 
Although slightly decreased immune responses following the primary DTPa vaccination 
has been observed in infants whose mothers received dTpa vaccine compared to those 
whose mothers did not receive dTpa vaccine, the differences did not persist following the 
booster vaccination in infants [Hardy-Fairbanks, 2013; Gall, 2011].
Please refer to the current Investigator Brochure for information regarding the pre-
clinical and clinical studies and the epidemiological information of Infanrix hexa.
 
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1.2.
Rationale for the study and study design
1.2.1.
Rationale for the study
Recent studies have shown that maternal combined reduced antigen content diphtheria-
tetanus-acellular pertussis (dTpa) vaccination during pregnancy results in high pertussis 
antibody concentrations in infants during the period between birth and the first vaccine 
dose. 
An analysis of data from the Clinical Practice Research Datalink (a primary care database 
of 520 general medical practices in England) demonstrates that maternal dTpa
immunisation can decrease the incidence of infant pertussis. After a maternal pertussis 
vaccination programme was introduced in October 2012 in response to a pertussis
outbreak in England, the number of pertussis cases in infants younger than three months 
of age and the number of hospitalisations decreased significantly [Amirthalingam, 2014].
In 2013, the Advisory Committee on Immunization Practices (ACIP) recommended that 
all women should be vaccinated with dTpa vaccine during each pregnancy, regardless of 
the previous immunisation schedule [CDC, 2013]. Similar recommendations have been 
implemented in 18 countries including UK, New Zealand, Israel, Mexico, Brazil, 
Colombia, Uruguay, Panama, Costa Rica, Argentina, Australia and some provinces in 
Spain [Joint Committee on Vaccination and Immunization (JCVI), 2012; Pharmaceutical 
Management Agency (PHARMAC), 2012; TAG, 2013]. The National Advisory 
Committee on Immunization in Canada recommends that all pregnant women following 
26 weeks of pregnancy who have not received a dose of pertussis-containing vaccine in 
adulthood should be encouraged to receive dTpa vaccination. In special circumstances, 
such as an outbreak situation, all pregnant women who are of 26 weeks gestation or 
greater may be offered dTpa vaccination irrespective of their immunization history
[Warshawsky, 2014; Public Health Agency of Canada, 2014].
All infants born to pregnant women who participated in study 116945 [DTPA 
(BOOSTRIX)-047] will be followed-up to study the immunogenicity and safety of 
GlaxoSmithKline (GSK) Biologicals’ combined diphtheria-tetanus-acellular pertussis-
hepatitis B-inactivated poliovirus and Haemophilus influenzae type b vaccine (DTPa-
HBV-IPV/Hib), Infanrix hexa, given as primary and booster vaccination. Study 201330 
[DTPA (BOOSTRIX)-048 PRI] will be conducted to assess the immunogenicity and 
safety of Infanrix hexa co-administered with Prevenar 13 as the primary vaccination 
course. (Amended 12 December 2016)
The present study will be performed to study the immunogenicity and safety of the 
booster dose of Infanrix hexa in infants who were born to mothers vaccinated with 
Boostrix during pregnancy or immediately post-delivery and who completed their 
primary vaccination series as per protocol requirement in study DTPA (BOOSTRIX)-
048 PRI.. (Amended 12 December 2016)
1.2.2.
Rationale for the study design
This phase IV study is a follow-up of the study 201330 [DTPA (BOOSTRIX)-048 PRI]
where infants in both the groups received Infanrix hexa co-administered with Prevenar 
 
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13 as part of the primary vaccination series. The immunogenicity and safety of Infanrix 
hexa when given as a booster dose according to the routine national/ local 
immunization schedule or as specified in the SPM will be evaluated. Subjects will 
receive Prevenar 13 according to the routine national/ local immunization schedule or 
as specified in the SPM as a co-administered vaccine in this study. (Amended 12 
December 2016)
This study will have two groups: 

dTpa Group: This group will consist of infants born to mothers belonging to the 
dTpa Group in study 116945 [DTPA (BOOSTRIX)-047], i.e., mothers who received 
a single dose of Boostrix during pregnancy and a dose of placebo immediately post-
delivery and infants who received full primary vaccination course as per protocol 
requirement in the study 201330 [DTPA (BOOSTRIX)-048 PRI]. All infants in this 
group will receive a booster dose of Infanrix hexa co-administered with Prevenar 13
according to the routine national/ local immunization schedule or as specified in 
the SPM. (Amended 12 December 2016).

Control Group: This group will consist of infants born to mothers belonging to the 
Control group in study 116945 [DTPA (BOOSTRIX)-047], i.e., mothers who 
received a single dose of placebo during pregnancy and a dose of Boostrix
immediately post-delivery and infants who received full primary vaccination course 
as per protocol requirement in the study 201330 [DTPA (BOOSTRIX)-048 PRI]. 
All infants in this group will receive a booster dose of Infanrix hexa co-administered 
with Prevenar 13 according to the routine national/ local immunization schedule 
or as specified in the SPM. (Amended 12 December 2016).
The study will be open-label since the treatment allocation is similar between the two 
groups. Also, the data related to the study groups will be unblinded at the end of study 
116945 [DTPA (BOOSTRIX)-047].
Currently, the effect of Boostrix administered to mothers during pregnancy or 
immediately post-delivery on the neurodevelopment of infants is unknown. Therefore, 
the neurodevelopment of the subjects will be studied at 9 months and 18 months of age in 
this study. To assess the neurodevelopmental status, the investigator or designate will 
complete a standardised developmental screening tool, Ages and Stages Questionnaire-3 
(ASQ-3) via a paper questionnaire with subjects’ parent(s)/LAR(s) during the study 
visits or phone call [ASQ-3, 2016]. (Amended 12 December 2016)
Any subject who scores below the cut-off i.e., a score more than 2 Standard Deviations 
(SDs) below the mean score for the U.S. reference group (i.e., black zone in the score 
chart) in any of the five domains of the ASQ-3 (i.e., communication, gross motor, fine 
motor, problem solving, and personal-social) will be referred to a developmental 
specialist for formal neurodevelopmental assessment (e.g., using the Bayley Scale for 
Infant Development, Version III [BSID-III]) [Bayley-III, 2006]. An overall 
neurodevelopmental assessment in the areas of cognitive, language, motor, social-
emotional and adaptive behaviour will be rendered using BSID-III. A BSID-III score 
more than 2 SDs below the mean score for the U.S. reference group will be considered as 
a neurodevelopmental impairment.
 
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1.3.
Benefit: Risk Assessment
Please refer to the current Investigator Brochure (IB) for the summary of potential risks 
and benefits of Infanrix hexa. (Amended 12 December 2016)
The following section outlines the risk assessment and mitigation strategy for this study 
protocol: 
1.3.1.
Risk Assessment
Important Potential/Identified 
Risk
Data/Rationale for Risk
Mitigation Strategy
Investigational study vaccine Infanrix hexa
Hypersensitivity including allergic 
reaction such as anaphylaxis
Acute allergic reactions such as a 
rare case of anaphylactic event 
may occur with any vaccine 
administration. These are serious, 
but rare occurrences estimated in 
the range of 1 to 10 cases per 
million of vaccinations, depending 
on the vaccine studied [Rüggeberg, 
2007].
Anaphylaxis following vaccine 
administration is an exclusion criterion 
for study participation and a 
contraindication to vaccination. The 
onset of vaccine-related allergic 
symptoms is typically quite prompt. In 
order to treat subjects with a serious 
allergic reaction to vaccination, all 
subjects will need to remain under 
observation (i.e., visibly followed; no 
specific procedure) at the vaccination 
centre for at least 30 minutes after 
vaccination.
Temperature of ≥ 40.0C within 
48 hours, not due to another 
identifiable cause
As outlined in the Infanrix 
hexa Reference Safety 
Information (RSI) from clinical 
trials and post-marketing safety 
data, this adverse event 
(AE)/serious adverse event (SAE) 
is recognized as well-characterized 
identified risks for Infanrix hexa.
(Amended 12 December 2016)
Subjects’ parents/LAR(s) should report 
any untoward symptoms experienced 
by the infant after receiving the vaccine 
immediately to the investigator.
Hypotonic-hyporesponsive 
episode
As outlined in the Infanrix hexa RSI 
from clinical trials and post-
marketing safety data, this AE/SAE 
is recognized as well-characterized 
identified risks for Infanrix hexa.
Subjects’ parents/LAR(s) should report 
any untoward symptoms experienced 
by the infant after receiving the vaccine 
immediately to the investigator.
Convulsions
As outlined in the Infanrix hexa RSI 
from clinical trials and post-
marketing safety data, this AE/SAE 
is recognized as well-characterized 
identified risks for Infanrix hexa.
Subjects’ parents/LAR(s) should report 
any untoward symptoms experienced 
by the infant after receiving the vaccine 
immediately to the investigator.
Encephalopathy
As outlined in the Infanrix hexa RSI 
from clinical trials and post-
marketing safety data, this AE/SAE 
is recognized as potential risk for 
Infanrix hexa.
Subjects’ parents/LAR(s) should report 
any untoward symptoms experienced 
by the infant after receiving the vaccine 
immediately to the investigator.
Study Procedures
Not applicable.
Other (Prevenar 13)
Hypersensitivity including allergic 
reaction such as anaphylaxis
Acute allergic reactions such as a 
rare case of anaphylactic event 
may occur with any vaccine 
Anaphylaxis following vaccine 
administration is an exclusion criterion 
for study participation and a 
 
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Important Potential/Identified 
Risk
Data/Rationale for Risk
Mitigation Strategy
administration. These are serious, 
but rare occurrences estimated in 
the range of 1 to 10 cases per 
million of vaccinations, depending 
on the vaccine studied [Rüggeberg, 
2007].
contraindication to vaccination. The 
onset of vaccine-related allergic 
symptoms is typically quite prompt. In 
order to treat subjects with a serious 
allergic reaction to vaccination, all 
subjects will need to remain under 
observation (i.e., visibly followed; no 
specific procedure) at the vaccination 
centre for at least 30 minutes after 
vaccination.
Temperature of ≥ 40.0C within 
48 hours, not due to another 
identifiable cause
As outlined in Prevenar 13
European public assessment report 
(EPAR), increased fever rates were 
observed when Prevenar 13 was 
co-administered with Infanrix hexa.
Subjects’ parents/LAR(s) should report 
any untoward symptoms experienced 
by the infant after receiving the vaccine 
immediately to the investigator.
(Amended 12 December 2016)
Hypotonic-hyporesponsive 
episode
As outlined in the Prevenar 13
summary of product characteristics 
(SPC), this AE/SAE is recognized 
as well-characterized identified 
risks for Prevenar 13.
Subjects’ parents/LAR(s) should report 
any untoward symptoms experienced 
by the infant after receiving the vaccine 
immediately to the investigator.
Convulsions
As outlined in the Prevenar 13
SPC, this AE/SAE is recognized as 
well-characterized identified risks 
for Prevenar 13.
Subjects’ parents/LAR(s) should report 
any untoward symptoms experienced 
by the infant after receiving the vaccine 
immediately to the investigator.
1.3.2.
Benefit Assessment
Diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis and Haemophilus influenzae type 
b (Hib) are common causes of diseases in children worldwide, with significant morbidity 
and mortality. A dramatic decline in the incidence of diphtheria, tetanus, pertussis, 
hepatitis B, poliomyelitis and Hib has been evidenced in countries in which infants are 
routinely immunised against these diseases. By receiving the Infanrix hexa vaccine, the 
subjects may be protected against the above mentioned diseases. In addition, the subjects 
will undergo a physical examination at Visit 2 before booster vaccination. In case the 
study doctor discovers any medical condition, the subject will be referred to the local 
healthcare system. The vaccine and study related tests will be provided free of cost to the 
subjects. (Amended 12 December 2016)
1.3.3.
Overall Benefit: Risk Conclusion
The benefit/risk profile of Infanrix hexa for primary and booster vaccination of infants 
against diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis and Haemophilus
influenzae type b continues to be favourable.
2.
OBJECTIVES
2.1.
Primary objective

To assess the immunological response to Infanrix hexa in terms of seroprotection 
status for diphtheria, tetanus, hepatitis B, poliovirus and Hib antigens, and in terms 
 
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of booster response for the pertussis antigens, one month after the booster dose in 
infants born to mothers vaccinated with Boostrix during pregnancy or immediately 
post-delivery.
Refer to Section 10.1 for the definition of the primary endpoint.
2.2.
Secondary objectives

To assess the persistence of antibodies to all vaccine antigens before the booster dose 
in infants born to mothers vaccinated with Boostrix during pregnancy or immediately 
post-delivery.

To assess the immunological response to Infanrix hexa and Prevenar 13 in terms of 
antibody concentrations or titres against all antigens, one month after the booster 
dose in infants born to mothers vaccinated with Boostrix during pregnancy or 
immediately post-delivery.

To assess the immunological response to Infanrix hexa in terms of seropositivity 
rates against pertussis antigens, one month after the booster dose in infants born to 
mothers vaccinated with Boostrix during pregnancy or immediately post-delivery.

To assess the safety and reactogenicity of Infanrix hexa and Prevenar 13 in terms of 
solicited and unsolicited symptoms and serious adverse events (SAEs).

To assess the neurodevelopmental status of infants born to mothers vaccinated with 
Boostrix during pregnancy or immediately post-delivery, at 9 and 18 months of age.
Refer to Section 10.2 for the definition of the secondary endpoints.
 
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3.
STUDY DESIGN OVERVIEW
(Amended 12 December 2016)
N: Maximum Number of subjects planned to be enrolled; Mo: Age in Months
*The neurodevelopmental status will be recorded when the subject is 9 months and 18 months of age. It is encouraged 
that subjects who are getting vaccinated at 18 months of age at Visit 2 or coming for Visit 3, complete their ASQ-3 
during their visit to the study centre. In case subjects complete Visit 3 before 18 months of age, the study staff will 
contact the parents/LAR(s) via phone and conduct an interview to complete the child’s ASQ-3 at 18 months of age. For 
Czech Republic, the phone call at 18 months may be replaced by a clinic visit if deemed preferable by the 
study team.
** Subjects have received either 2 or 3 doses of Infanrix hexa and Prevnar during the course of the study DTPA 
(Boostrix)-048, depending on the national/ local routine immunization schedule.
Refer to Section 5.6.2.13 for further details. 
Pre-Bst: Blood sample to be collected before the booster dose.
Post-Bst: Blood sample to be collected one month after the booster dose.
Protocol waivers or exemptions are not allowed with the exception 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 IV, open-label, non-randomised, multi-centric, multi-
country study with two parallel groups.

Duration of the study: The intended duration of the study, is approximately 9 to 10 
months, per subject.
Infanrix hexa
Prevenar 13
Infanrix hexa
Prevenar 13
Infanrix hexa
Prevenar 13**
dTpa Group (N =340)
Control Group (N =340)
Infanrix hexa
Prevenar 13
Infanrix hexa
Prevenar 13
Infanrix hexa
Prevenar 13**
Infanrix hexa
Prevenar 13
Infanrix hexa
Prevenar 13
Visit 1*
Visit 3
Day 0
Month 1
Pre-Bst
Post-Bst
Visits
Time-points
Blood sample:
dTpa Group (N =340)
Control Group (N =340)
Study 201330 [DTPA (BOOSTRIX)-048]
Epoch 001
Study 201334 [DTPA 
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11-18 Mo 12-19 Mo
9 Mo
Boostrix
dTpa Group (N = 340)
Control Group (N = 340)
Study 116945 [DTPA 
(BOOSTRIX)-047]
Boostrix
Placebo
Placebo
Randomisation (1:1)
Visit  2
TC*
18 Mo
 
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
Epoch 001: Booster phase starting at Visit 1 (9 months of age) and ending at 
telephone contact or at Visit 3 (18 or 19 months of age), depending on the time 
of vaccination.(Amended 12 December 2016)

End of Study (EoS): Last testing results released of samples collected at Visit 3.
(Amended 12 December 2016)

Study groups: The study groups and epoch foreseen in the study are presented in 
Table 1.

dTpa Group: This group will consist of infants born to mothers belonging to the 
dTpa Group in study 116945 [DTPA (BOOSTRIX)-047] i.e., mothers who 
received a single dose of Boostrix during pregnancy and a dose of placebo 
immediately post-delivery and infants who received full primary vaccination 
course as per protocol requirement in the study 201330 [DTPA (BOOSTRIX)-
048 PRI]. All subjects in this group will receive a booster dose of Infanrix hexa
co-administered with Prevenar 13 according to the routine national/ local
immunization schedule or as specified in the SPM. (Amended 12 December 
2016).

Control Group: This group will consist of infants born to mothers belonging to 
the Control group in study 116945 [DTPA (BOOSTRIX)-047] i.e., mothers who 
received a single dose of placebo during pregnancy and a dose of Boostrix
immediately post-delivery and infants who received full primary vaccination 
course as per protocol requirement in the study 201330 [DTPA (BOOSTRIX)-
048 PRI]. All subjects in this group will receive a booster dose of Infanrix hexa
co-administered with Prevenar 13 according to the routine national/ local 
immunization schedule or as specified in the SPM. (Amended 12 December 
2016).
Table 1
Study groups and epoch foreseen in the study
(Amended 12 December 2016)
Study groups
Number of 
subjects*
Age (Min/Max)**
Epoch
Epoch 001
dTpa Group
340
11 months-19 months
x
Control Group
340
11 months-19 months
x
*Maximum number of subjects
**Age at the time of vaccination depending on routine national/ local immunization schedule or as specified in 
the SPM
The study groups and treatment foreseen in the study is presented in Table 2.
Table 2
Study groups and treatment foreseen in the study
(Amended 12 December 2016)
Treatment name
Vaccine name
Study Groups
dTpa Group
Control Group
Infanrix hexa 
DTPa-HBV-IPV
x
x
Hib
x
x
Prevenar 13 
Prevenar 13
x
x
 
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
Control: uncontrolled (No active control or placebo. All subjects will receive the 
same vaccine)

Vaccination schedule: All subjects will receive a booster dose of Infanrix hexa co-
administered with Prevenar 13 between 11-18 months of age according to the 
routine national/ local immunization schedule or as specified in the SPM. 
(Amended 12 December 2016)

Treatment allocation: Non-randomised. All subjects will receive a booster dose of 
Infanrix hexa co-administered with Prevenar 13.

Blinding: Open-label. Note: The study personnel operating with the GSK 
Biologicals’ central Randomisation System on Internet (SBIR) and the site staff 
will remain blinded towards the treatment allocation of the mother in study 116945 
[DTPA (BOOSTRIX)-047]. (Amended 12 December 2016)
The blinding of study epoch is presented in Table 3.
Table 3
Blinding of study epoch
Study Epoch
Blinding
Epoch 001
open

Sampling schedule: Blood samples will be drawn from all subjects at the following 
time points:

Pre-Bst: Before the booster dose administration, a volume of approximately 5 
mL of whole blood (to provide approximately 1.7 mL of serum) will be 
collected.

Post-Bst: One month after the booster dose, approximately 5 mL of whole blood 
(to provide approximately 1.7 mL of serum) will be collected.

Type of study: extension of other protocol(s) 116945 [DTPA (BOOSTRIX)-047] 
and 201330 [DTPA (BOOSTRIX)-048 PRI].

Data collection: Electronic Case Report Form (eCRF).

Safety monitoring: An independent data monitoring committee (IDMC) (including 
paediatricians and a statistician) will be put in place to oversee the safety aspects
including neurodevelopmental status of infants born to mothers vaccinated with 
Boostrix during pregnancy or immediately post-delivery in the clinical study i.e.,
each SAE/incidence of grade 3 local and general solicited AEs, unsolicited AEs will 
be reviewed by this committee as per approved IDMC charter. (Amended 12
December 2016).
4.
STUDY COHORT
4.1.
Number of subjects/centres
A maximum of 680 infants aged 9 months will be enrolled in this study. Blood samples 
will be taken from all subjects in order to evaluate the immunogenicity endpoints. The 
tracking of recruitment of subjects into the study will be performed using SBIR.
 
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Overview of the recruitment plan:

Enrolment will be offered to all eligible infants born to mothers from the 116945 
[DTPA (BOOSTRIX)-047] study and having completed their primary vaccination 
series as per protocol requirement in study 201330 [DTPA (BOOSTRIX)-048 PRI].
(Amended 12 December 2016)

The study will be monitored by a local Study Monitor.

The treatment allocation and confirmation of the enrolment of subjects into the study 
will be tracked using SBIR.
4.2.
Inclusion criteria for enrolment
Deviations from inclusion criteria are not allowed because they can potentially jeopardise 
the scientific integrity of the study, regulatory acceptability 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:

Subjects’ parent(s)/LAR(s) who, in the opinion of the investigator, can and will 
comply, with the requirements of the protocol (e.g., completion of the diary cards, 
return for follow-up visits).

Written informed consent obtained from the parent(s)/LAR(s) of the subject prior to 
performing any study specific procedure.

A male or female child 9 months of age at the time of enrolment.

Healthy subjects as established by medical history and clinical examination before 
entering into the study.

Subjects born to mothers who were vaccinated in 116945 [DTPA (BOOSTRIX)-
047] study and having completed their primary vaccination series as per protocol 
requirement in study 201330 [DTPA (BOOSTRIX)-048 PRI]. (Amended 12
December 2016)
4.3.
Exclusion criteria for enrolment
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardise the scientific integrity of the study, regulatory acceptability 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:

Child in care
Please refer to the glossary of terms for the definition of child in care.

Concurrently participating in another clinical study, within three months prior to the 
booster vaccine dose and at any time during the present booster study, in which the 
subject has been or will be exposed to an investigational or a non-investigational 
vaccine/product (pharmaceutical product or device).
 
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
Chronic administration (defined as more than 14 days in total) of 
immunosuppressants or other immune-modifying drugs during the period within six 
months prior to the booster vaccine dose. For corticosteroids, this will mean 
prednisone ≥0.5mg/kg/day, or equivalent. Inhaled and topical steroids are allowed.

Administration of long-acting immune-modifying drugs at any time during the study 
period (e.g., infliximab).

A vaccine not foreseen by the study protocol administered during the period starting 
from 30 days before the booster dose of study vaccine and ending 30 days after*, 
with the exception of inactivated influenza vaccine and other vaccines given as a part 
of the national/regional immunisation schedule, that are allowed at any time during 
the study period.
*In case an emergency mass vaccination for an unforeseen public health threat (e.g.: 
a pandemic) is organised by the public health authorities, outside the routine 
immunisation program, the time period described above can be reduced if necessary 
for that vaccine provided it is licensed and used according to its SPC or Product 
Information (PI) and according to the local governmental recommendations and 
provided a written approval of the Sponsor is obtained.

Any confirmed or suspected immunosuppressive or immunodeficient condition, 
based on medical history and physical examination (no laboratory testing required).

Major congenital defects.

Serious chronic illness.

Administration of immunoglobulins and/or any blood products during the period 
within three months before the booster dose of study vaccines or planned 
administration during the study period.

Encephalopathy defined as an acute, severe central nervous system disorder 
occurring within seven days following vaccination with Infanrix hexa and generally 
consisting of major alterations in consciousness, unresponsiveness, generalised or 
focal seizures that persist more than a few hours, with failure to recover within 24 
hours.

History of Hib, diphtheria, tetanus, pertussis, pneumococcal, poliovirus and hepatitis 
B diseases since the conclusion visit of study 201330 [DTPA (BOOSTRIX)-048 
PRI].

Previous booster vaccination against Hib, diphtheria, tetanus, pertussis, 
pneumococcus, hepatitis B and/or poliovirus since the conclusion visit of study 
201330 [DTPA (BOOSTRIX)-048 PRI].

History of any reaction or hypersensitivity likely to be exacerbated by any 
component of the vaccines (e.g.: antigen, excipients).

Hypersensitivity to latex.

History of any neurological disorders or seizures.

Any condition that in the judgment of the investigator would make intramuscular 
injection unsafe.
 
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
Acute disease and/or fever at the time of vaccination.

Fever is defined as temperature 37.5°C/99.5°F for oral, axillary or tympanic 
route, or 38.0°C/100.4°F on rectal route. 

Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory 
infection) without fever may be enrolled at the discretion of the investigator.
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 Conference on 
Harmonization (ICH) Guideline for Good Clinical Practice (GCP), all applicable subject 
privacy requirements and the guiding principles of the Declaration of Helsinki. 
(Amended 12 December 2016)
The study has been designed and will be conducted in accordance with the ICH 
Harmonised Tripartite Guideline for clinical investigation of medicinal products in the 
paediatric population (ICH E11) and all other applicable ethical guidelines.
GSK will obtain favourable opinion/approval to conduct the study from the appropriate 
regulatory agency, in accordance with applicable regulatory requirements, prior to a site 
initiating the study in that country.
Conduct of the study includes, but is not limited to, the following:

Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and 
favourable opinion/approval of study protocol and any subsequent amendments.

Subject’s parent(s)/LAR(s) informed consent, as appropriate.

Investigator reporting requirements as stated in the protocol.
GSK will provide full details of the above procedures to the investigator, either verbally, 
in writing, or both.
Freely given and written or witnessed/thumb printed informed consent must be obtained 
from each subject’s parent(s)/LAR(s), as appropriate, prior to participation in the study.
GSK Biologicals will prepare a model Informed Consent Form (ICF) which will embody 
the ICH GCP and GSK Biologicals required elements. While it is strongly recommended 
that this model ICF is to be followed as closely as possible, the informed consent 
requirements given in this document are not intended to pre-empt any local regulations 
which require additional information to be disclosed for informed consent to be legally 
effective. Clinical judgement, local regulations and requirements should guide the final 
structure and content of the local version of the ICF.
 
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The investigator has the final responsibility for the final presentation of the ICF, 
respecting the mandatory requirements of local regulations. The ICF generated by the 
investigator with the assistance of the sponsor’s representative must be acceptable to 
GSK Biologicals and be approved (along with the protocol, and any other necessary 
documentation) by the IRB/IEC.
5.2.
Subject identification and randomisation of treatment
5.2.1.
Subject identification
Subjects will retain the same subject number as their mothers in the 116945 [DTPA 
(BOOSTRIX)-047] study and their own subject number in study 201330 [DTPA 
(BOOSTRIX)-048 PRI]. These subject numbers will also be used to identify blood 
samples collected in the study. (Amended 12 December 2016)
5.2.2.
Randomisation of treatment
5.2.2.1.
Treatment allocation to the subject
There will be no randomisation of subjects into groups in this study. The infants enrolled 
in this study will be allocated to the same groups as their mothers in the 116945 [DTPA 
(BOOSTRIX)-047] study and as themselves in study 201330 [DTPA (BOOSTRIX)-048 
PRI]. Subjects will retain the same subject number as their corresponding mothers from 
the 116945 [DTPA (BOOSTRIX)-047] study. (Amended 12 December 2016)
The treatment numbers will be allocated by dose.
5.2.2.1.1.
Study group and treatment number allocation
The target will be to enrol maximum of 680 eligible subjects aged 9 months 
(approximately 340 subjects in each group).
After obtaining the signed and dated ICF from the subject’s parent(s)/LAR(s) and having 
checked the eligibility of the subject, investigator or designate will complete a 
standardised developmental screening tool, Ages and Stages Questionnaire-3 via a 
paper questionnaire (at Visit 1) with subjects’ parent(s)/LAR(s). At Visit 2, the site staff 
in charge of the vaccine administration will access SBIR. Upon providing the subject 
identification number, the randomisation system will provide the treatment number to be 
used for vaccination. (Amended 12 December 2016)
The number of each administered treatment must be recorded in the eCRF on the Vaccine 
Administration screen.
When SBIR is not available, please refer to the SBIR user guide or the Study Procedures 
Manual (SPM) for specific instructions.
 
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5.3.
Method of blinding 
This study will be conducted in an open-label manner since the treatment allocation is 
similar between the two groups. Also, the data related to the study groups will be 
unblinded at the end of study 116945 [DTPA (BOOSTRIX)-047].
Note: The study personnel operating SBIR and the site staff will remain blinded towards 
the treatment allocation of the mother in study 116945 [DTPA (BOOSTRIX)-047] until 
the completion and unblinding of study 116945 [DTPA (BOOSTRIX)-047] to prevent 
the potential unblinding of the treatment allocation to the mother in 116945 [DTPA 
(BOOSTRIX)-047]. (Amended 12 December 2016)
The laboratory in charge of the laboratory testing will be blinded to the treatment, and 
codes will be used to link the subject 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.
5.4.1.
Independent Data Monitoring Committee
An IDMC will oversee the safety of infants born to mothers who were vaccinated with 
Boostrix during pregnancy or immediately post-delivery in the clinical study 116945 
[DTPA (BOOSTRIX)-047], infants who received primary vaccination series of Infanrix 
hexa and Prevenar13 as per protocol requirement in the study 201330 [DTPA 
(BOOSTRIX)-048 PRI] and booster vaccination in 201334 [DTPA (BOOSTRIX)-049 
BST: 048] study.
To facilitate the review, the IDMC will be provided with all relevant safety data 
including data on each SAE, grade 3 local and general solicited AEs, unsolicited AEs and 
neurodevelopmental status of infants born to mothers vaccinated with Boostrix during 
pregnancy or immediately post-delivery at specified times and access to data on request 
by an unblinded statistician. The frequency of the meeting will be documented in the 
IDMC charter (Amended 12 December 2016)
The operating rules of the IDMC are documented in a charter.
5.4.2.
Responsibilities
(Amended 12 December 2016)
The overall responsibility of the IDMC is to protect the ethical and safety interests of 
subjects recruited into this study while protecting as far as possible the scientific validity 
of the data.
 
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The details of the IDMC’s responsibilities and conduct of meetings will be provided in 
the IDMC charter. The IDMC charter will also clearly state who will conduct the 
statistical analysis (ICH E9). Key responsibilities of the IDMC are the following:

Prior to study start, the IDMC will review the protocol with special attention to 
safety monitoring procedures and will make recommendations for adjustments, if 
required.

The IDMC will be informed of any amendment to the initial protocol

The IDMC will review the unblinded safety data from the study (i.e., each SAE,
grade 3 local and general solicited AEs , unsolicited AEs and neurodevelopmental 
status), provide GSK Biologicals with indications on safety profiles and make 
recommendations on further study conduct.

The IDMC will review the final analysis provided by the sponsor. 
5.4.3.
Composition of the IDMC
(Amended 12 December 2016)
IDMC members will not participate in the study, neither as principal or co-investigators 
nor as study subject care physicians. They can also not provide medical care to a subject 
enrolled in the study. The IDMC will include medically qualified experts in the field 
under study (paediatrician and a biostatistician). The person specifically selected to chair 
the IDMC will be required not only to have appropriate training for the study but also to 
have experience serving on one or more IDMCs. The IDMC also may convene an ad-hoc 
meeting should it deem necessary for review of specific cases/safety concerns.
Neither the IDMC chair, nor the members are allowed to communicate with the 
investigators involved in the trial about data from the study. If needed, additional 
information should be obtained from the sponsor. The sponsor should inform the 
investigators in case of any safety concerns observed by the IDMC.
5.4.4.
GSK Biologicals’ safety review team
(Amended 12 December 2016)
At GSK Biologicals, a Safety Review Team (SRT) will include the Central Safety 
Physician and Safety Scientist, the Clinical Research and development Lead (CRDL)
and Biostatistician of the project as well as Epidemiology and Regulatory representatives. 
The SRT will be responsible for reviewing the blinded safety data related to the 
investigational product in this study and due to Boostrix vaccine received by the mother 
in 116945 [DTPA (BOOSTRIX)-047] study. The SRT review will be done on a regular 
basis to identify any potential safety issues or signals in order to evaluate and agree on 
action plans, if necessary.
The IDMC will provide recommendation to the sponsor which will be shared with the 
investigators.
 
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5.5.
Outline of study procedures
The list of study procedures is detailed in Table 4.
 
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Table 4
List of study procedures
(Amended 12 December 2016)
Age 
9 months
11-18 
months 
12-19 
months
18 months **
Epoch 
Epoch 001
Type of contact
Visit 1
Visit 2
Visit 3
Phone contact *
Time points
Months -2 to -9
Day 0 **
Month 1 **
Day 0 to Month7 **
Sampling time points
Pre-Bst
Post-Bst
Informed consent
●
Check inclusion/exclusion criteria
●
Collect demographic data
●
Medical history, including medication/vaccine 
history§
●
●
Physical examination
O
Check contraindications and warnings and 
precautions
O
Pre-vaccination body temperature
●
Measure/record length, weight and head 
circumference
●
Vaccine
Treatment number allocation
O
Recording of administered treatment number
●
Vaccine administration
●
Laboratory assays
Blood sampling for antibody determination 
(approx 5 mL)
●
●
Safety assessments
Record any concomitant medication/vaccination
●
●
Record any intercurrent medical conditions
●
Distribution of diary cards
●
Recording of solicited adverse events (Day 0-
Day 3) post-vaccination by subjects’ 
parent(s)/LAR(s) in the diary card
●
Recording of non-serious adverse events within 
31 days (Day 0-Day 30) post-vaccination, by 
subjects’ parent(s)/LAR(s) in the diary card
●
●
Recording of large injection-site reactions
●
Return of diary cards
O
Diary card transcription by investigator or site 
staff
●
Recording of neurodevelopmental status by the 
subjects’ parent(s)/LAR(s) in the ASQ-3 paper 
questionnaire
●
●**
●  **
●  **
Transcribe the information in ASQ-3 paper 
questionnaire, by the investigator
●
●**
●**
●**
Recording of SAEs and AEs/SAEs leading to 
withdrawal
●
●
●
●**
Recording of SAEs related to study participation 
or to a concurrent GSK medication/vaccine
●
●
●
●
Study Conclusion †
●
● 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.
* For Czech Republic, the phone call at 18 months may be replaced by a clinic visit if deemed preferable by the 
study team.
 
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** The neurodevelopmental status will be recorded when the subject is 9 and 18 months of age. It is encouraged that 
subjects who are getting vaccinated at 18 months of age at Visit 2 or coming for Visit 3, complete their ASQ-3 during 
their visit to the study centre. In case subjects complete Visit 3 before 18 months of age, the study staff will contact the 
parents/LAR(s) via phone and conduct an interview to complete the child’s ASQ-3 at 18 months of age. If the subject is 
referred to a developmental specialist for formal assessment, then this information needs to be recorded in the eCRF. 
Also, the overall assessment of delay by the specialist should be recorded in the eCRF.
§ History of all medications given to the infants after the end of 201330 [DTPA (BOOSTRIX)-048 PRI] until enrolment in 
this study will be recorded in the eCRF at Visit 1 and updated at Visit 2 for all new information
† Study conclusion will be at Visit 3 or after ASQ-3 is completed at 18 months of age.
Pre-Bst: Blood sample to be collected before the booster dose.
Post-Bst: Blood sample to be collected one month after the booster dose.
The intervals between study visits are presented in Table 5.
Table 5
Intervals between study visits
(Amended 12 December 2016)
Interval
Optimal length of interval 1
Allowed interval 2
BirthVisit 1
9 months old
9 months old +30 days *
Visit 1Visit 2
2-10 months **
2-10 months **
Visit 2 Visit 3
30 days **
21-48 days **
Phone contact
18 months old
18 months old 30 days  *
1 Whenever possible the investigator should arrange study visits within this interval.
2 Subjects will not be eligible for inclusion in the ATP cohort for analysis of immunogenicity if they make the study visit 
outside this interval.
* The allowed interval for Visit 1 and Phone contact is calculated depending on the official recommendation for 
age for completion of the ASQ-3 questionnaire (9 months and 0 days through 9 months and 30 days and 17 
months and 0 days through 18 months of age and 30 days). In case subjects who were born prematurely by three
or more weeks are enrolled, prematurity adjustment needs to be performed for the 9th and 18th month ASQ-3 
questionnaire completion. Refer to Section 5.6.2.13 and SPM for more details.
** The intervals required in the table are the minimum and maximum intervals for the study and the allowed 
intervals for inclusion in the ATP cohort will correspond to approximately 30 days before or after the time 
window corresponding to the national/ local immunization schedule or as specified in the SPM
If subjects return for the Visit 3 prior to 30 days, the parent(s)/LAR(s) should take home the diary card and continue to 
record unsolicited safety information until 30 days post-vaccination and mail/send it upon completion. Investigators will 
make an attempt to retrieve diary cards from subjects’ parent(s)/LAR(s) who have not mailed/sent them in.
5.6.
Detailed description of study procedures
5.6.1.
Procedures prior to study participation
5.6.1.1.
Informed consent
The signed/witnessed/thumb printed informed consent of the subject’s parent(s)/LAR(s)
must be obtained before study participation. Refer to Section 5.1 for the requirements on 
how to obtain informed consent, as appropriate.
At the end of the primary vaccination series study, 201330 [DTPA (BOOSTRIX)-048 
PRI], parent(s)/LAR(s) will be informed about this booster follow-up study [DTPA 
(BOOSTRIX)-049 BST: 048] in which their infants will receive a booster dose of the 
study vaccines. When the subject is approximately 9 months of age, the investigator or 
designee will complete a standardised developmental screening tool, Ages and Stages 
 
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Questionnaire-3 (ASQ-3) via a paper questionnaire with subjects’ parent(s)/LAR(s) 
during the Visit 1. (Amended 12 December 2016)
5.6.2.
Procedures during study participation
5.6.2.1.
Check inclusion and exclusion criteria
Check all inclusion and exclusion criteria as described in Sections 4.2 and 4.3 before 
enrolment. 
5.6.2.2.
Collect demographic data
Record demographic data such as the full date of birth in the subject’s eCRF at Visit 2.
(Amended 12 December 2016)
5.6.2.3.
Medical history
Obtain the subject’s medical history by interview and/or review of the subject’s medical 
records and record in the eCRF any pre-existing conditions or signs and/or symptoms 
present in a subject at Visit 1 and update with all new information at Visit 2.
All events that occur after the end of primary study 201330 [DTPA (BOOSTRIX)-048 
PRI] until enrolment in 201334 [DTPA (BOOSTRIX)-049 BST: 048] study will be 
recorded as part of the subject’s medical history.
5.6.2.4.
Medication and vaccination history
Obtain the subject’s medication and vaccination history by interview and/or review of the 
subject’s medical records and record in the eCRF any medication and vaccine 
administration at Visits 1 and update with all new information at Visit 2.
5.6.2.5.
Physical examination
(Amended 12 December 2016)
Perform a physical examination (including vital signs) prior to vaccination (Visit 2). The 
extent of the physical examination to be performed are as per investigator or delegate 
discretion to determine if the subject is healthy.
If it is determined that the subject’s health on the day of vaccination temporarily 
precludes vaccination, the visit will be rescheduled.
Treatment of any abnormality observed during this examination has to be performed 
according to local medical practice outside this study or by referral to an appropriate 
health care provider.
5.6.2.6.
Check contraindications, warnings and precautions to vaccination
Contraindications, warnings and precautions to vaccination must be checked at the
vaccination visit (Visit 2). Refer to Sections 6.5 and 6.6 for more details.
 
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5.6.2.7.
Assess pre-vaccination body temperature
The axillary, rectal, oral or tympanic body temperature of all subjects needs to be 
measured prior to any study vaccines administration. The preferred route for recording 
temperature in this study will be axillary/rectal. If the subject has fever [fever is defined 
as temperature 37.5°C/99.5°F for oral, axillary or tympanic route, or 38.0°C/100.4°F 
for rectal route] on the day of vaccination, the vaccination visit will be rescheduled 
within the allowed interval for this visit (see Table 5).
5.6.2.8.
Record body length, weight and head circumference (Amended 12
December 2016)
Record body weight (kg), height (cm) and head circumference (cm) of the subject at 
Visit 2 in the eCRF.
5.6.2.9.
Treatment number allocation
Treatment number allocation will be performed at Visit 2 as described in Section 5.2.2. 
The number of administered treatment must be recorded in the eCRF.
5.6.2.10.
Sampling
Refer to the Module on Biospecimen Management in the SPM for detailed instructions 
for the collection, handling and processing of the samples.
5.6.2.10.1. Blood sampling for immune response assessments
Blood samples will be taken during certain study visits as specified in Section 5.7.2:

Pre-Bst: Before the booster dose administration, a volume of approximately 
5 mL of whole blood (to provide approximately 1.7 mL of serum) will be 
collected.

Post-Bst: One month after the booster dose, approximately 5 mL of whole blood 
(to provide approximately 1.7 mL of serum) will be collected.

After centrifugation, serum samples should be kept at –20°C/–4°F or below until 
shipment. Refer to the SPM for more details on sample storage conditions.
5.6.2.11.
Study Vaccines administration

After completing all prerequisite procedures prior to vaccination, a booster dose of 
study vaccines will be administered intramuscularly (IM) either in the thigh or in the 
deltoid, according to the national recommendation /local practice (refer to Section 
6.3 for detailed description of the vaccines administration procedure). If the 
investigator or delegate determines that the subject’s health on the day of 
administration temporarily precludes vaccines administration, the visit will be 
rescheduled within the allowed interval for this visit (refer to Table 5). (Amended 12
December 2016)
 
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
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.
5.6.2.12.
Check and record concomitant medication/vaccination and intercurrent 
medical conditions 
Concomitant medication/vaccination must be checked and recorded in the eCRF as 
described in Section 6.7.
Intercurrent medical conditions must be checked and recorded in the eCRF as described 
in Section 6.8.
5.6.2.13.
Assessment of neurodevelopmental status
The parent(s)/LAR(s) will be asked to complete a standardised developmental screening 
tool known as ASQ-3 when the subject is 9 months and 18 months old [ASQ-3, 2016].
The ASQ-3 has been used globally and translated into different languages. The tool has 
been demonstrated to reliably and accurately identify children with delays who should 
receive further in-depth assessment. The ASQ-3 includes a series of questions designed 
to assess five areas of development: communication, gross motor, fine motor, problem 
solving, and personal-social. The questions target behaviours that are appropriate for 
particular developmental status. These behaviours are easy for the parent(s)/LAR(s) to 
observe and they are asked to indicate whether or not the subject can perform the 
behaviour. The ASQ-3 will be completed by the investigator or designee with the 
parent(s)/LAR(s) during the study visits or phone call when the subject is 9 and 18 
months of age, via a paper questionnaire *. These time- points comply with the 
recommended developmental screening assessment guidelines from the American 
Academy of Pediatrics [Council on Children with Disabilities, 2006]. The investigator or
designee may discuss the results with the parents if deemed necessary. (Amended 12
December 2016)
The ASQ-3 has narrow age intervals (9 months and 0 days through 9 months and 30 
days and 17 months and 0 days through 18 months of age and 30 days), so age must be 
calculated to the month and day from the date the ASQ-3 will be completed. (Amended 
12 December 2016)
If a baby was born three or more weeks prematurely, the number of weeks premature 
should be subtracted from the child’s actual age [ASQ, 2014]. Refer to the SPM for more 
details and examples.
Any subject who scores below the cut-off i.e., a score more than 2 Standard Deviations 
(SDs) below the mean score for the U.S. reference group (i.e., black zone in the score 
chart) in any of the five domains of the ASQ-3 (i.e., communication, gross motor, fine 
motor, problem solving, and personal-social) will be referred to a developmental 
specialist for formal neurodevelopmental assessment (e.g., using the Bayley Scale for 
Infant Development, Version III [BSID-III]) [Bayley-III, 2006]. An overall 
neurodevelopmental assessment in the areas of cognitive, language, motor, social-
emotional and adaptive behaviour will be rendered using BSID-III. A BSID-III score 
 
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more than 2 SDs below the mean score for the U.S. reference group will be considered as 
a neurodevelopmental impairment. If the subject is referred to a developmental specialist 
for formal assessment then this information should be recorded in the eCRF. Also, the 
overall assessment of delay by the specialist should be recorded in the eCRF.
*Note: It is encouraged that the parent(s)/LAR(s) of the subject complete the ASQ-3 
during their visit to the study centre at Visit 2 or Visit 3. In case the subject completes
Visit 3 before 18 months of age, the study staff will contact the parents/LAR(s) via phone 
to conduct an interview to complete the child’s ASQ-3 at 18 months of age. For Czech 
Republic, the phone call at 18 Months may be replaced by a clinic visit if deemed 
preferable by the study team. (Amended 12 December 2016)
5.6.2.14.
Recording of AEs and SAEs

Refer to Section 8.2 for procedures for the investigator to record AEs and SAEs. 
Refer to Section 8.3 for guidelines and how to report SAE reports to GSK 
Biologicals.

The subjects’ parent(s)/LAR(s) will be instructed to contact the investigator 
immediately should the subjects manifest any signs or symptoms they perceive as 
serious. 

Record large injection site reactions as described in 8.1.3.1.

At the vaccination visit (Visit 2), diary cards will be provided to the subject’s 
parent(s)/LAR(s). The subject’s parent(s)/LAR(s) will record body (axillary/rectal) 
temperature and any solicited local/general AEs (i.e., on the day of vaccination and 
during the next three days) or any unsolicited AEs (i.e., on the day of vaccination 
and during the next 30 days) occurring after vaccination. The subject’s 
parent(s)/LAR(s) will be instructed to return the completed diary card to the 
investigator at the next study visit.

Collect and verify completed diary cards during discussion with the subject’s 
parent(s)/LAR(s) at Visit 3.

Any unreturned diary cards will be sought from the subject’s parent(s)/LAR(s) 
through telephone call(s) or any other convenient procedure. The investigator/ 
designee will transcribe the collected information into the eCRF in English.
(Amended 12 December 2016)
5.6.2.15.
Study conclusion
The investigator will:

review data collected to ensure accuracy and completeness,

complete the Study Conclusion screen in the eCRF.
 
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5.7.
Biological sample handling and analysis
Please refer to the SPM and laboratory manual for details on biospecimen management 
(handling, storage and shipment). (Amended 12 December 2016)
Samples will not be labelled with information that directly identifies the subject but will 
be coded with the identification number for the subject (subject number).

Collected samples will be used for protocol mandated research and purposes related 
to the improvement, development and quality assurance of the laboratory tests 
described in this protocol. This may include the management of the quality of these 
tests, the maintenance or improvement of these tests, the development of new test 
methods, as well as making sure that new tests are comparable to previous methods 
and work reliably.

It is also possible that future findings may make it desirable to use the samples 
acquired in this study for future research, not described in this protocol. Therefore, 
all subjects in countries where this is allowed, will be asked to give a specific 
consent to allow GSK or a contracted partner to use the samples for future research. 
Future research will be subject to the laws and regulations in the respective countries 
and will only be performed once an independent Ethics Committee or Review Board 
has approved this research.
Information on further investigations and their rationale can be obtained from GSK 
Biologicals.
Any sample testing will be done in line with the consent of the individual subject’s 
parent(s)/LAR(s).
Refer also to the Investigator Agreement, where it is noted that the investigator cannot 
perform any other biological assays except those described in the protocol or its 
amendment(s).
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, 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 According-to-Protocol (ATP) analysis (See Section 
10.4 for the definition of cohorts to be analysed). The investigator must ensure that 
 
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his/her personnel and the laboratory(ies) under his/her supervision comply with this 
requirement. However, when GSK Biologicals 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. (Amended 12
December 2016)
5.7.2.
Biological samples
The biological sample to be collected, quantity and time point of collection are mentioned 
in Table 6.
Table 6
Biological samples
Sample type
Quantity
Unit
Time points
Blood
Approximately 5
ml
Visit 2 and Visit 3
5.7.3.
Laboratory assays
Please refer to APPENDIX A for the address of the clinical laboratories used for sample 
analysis.
Serological assays for the determination of antibodies will be performed at a GSK 
Biologicals’ laboratory or in a laboratory designated by GSK Biologicals using 
standardised and validated procedures (refer to Table 7).
Table 7
Humoral Immunity (Antibody determination)
(Amended 12 December 2016)
System
Component
Method
Kit / 
Manufacturer
Unit
Cut-off***
Laboratory  
†
SER
Corynebacterium 
diphtheriae.Diphtheria Toxoid 
Ab.IgG
ELI
NA
IU/ml
0.1
GSK 
Biologicals* 
SER
Clostridium tetani.Tetanus 
Toxoid Ab.IgG
ELI
NA
IU/ml
0.1
GSK 
Biologicals*
SER
Bordetella 
pertussis.Filamentous 
Hemaglutinin Ab.IgG
ELI
NA
EU/ml
5
GSK 
Biologicals* 
SER
Bordetella pertussis.Pertactin 
Ab.IgG
ELI
NA
EU/ml
5
GSK 
Biologicals* 
SER
Bordetella pertussis.Pertussis 
Toxin Ab.IgG
ELI
NA
EU/ml
5
GSK 
Biologicals*
SER
Hepatitis B Virus.Surface Ab
CLIA
ADVIA 
Centaur anti-
HBs2 
(Siemens 
Healthcare)
mIU/ml
6.2
GSK 
Biologicals*
SER
Poliovirus Sabin Type 1 Ab
NEU
NA
ED50
8
GSK 
Biologicals*
SER
Poliovirus Sabin Type 2 Ab
NEU
NA
ED50
8
GSK 
Biologicals*
SER
Poliovirus Sabin Type 3 Ab
NEU
NA
ED50
8
GSK 
 
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System
Component
Method
Kit / 
Manufacturer
Unit
Cut-off***
Laboratory  
†
Biologicals*
SER 
Haemophilus influenzae type 
b.Polyribosyl Ribitol 
Phosphate Ab 
ELI 
NA 
µg/ml 
0.15 
GSK 
Biologicals*
SER 
Streptococcus 
pneumoniae.Polysaccharide 
01 Ab.IgG
Streptococcus 
pneumoniae.Polysaccharide 
03 Ab.IgG
Streptococcus 
pneumoniae.Polysaccharide 
05 Ab.IgG
Streptococcus 
pneumoniae.Polysaccharide 
06A Ab.IgG 
Streptococcus 
pneumoniae.Polysaccharide 
06B Ab.IgG
Streptococcus 
pneumoniae.Polysaccharide 
07F Ab.IgG
Streptococcus 
pneumoniae.Polysaccharide 
09V Ab.IgG
Streptococcus 
pneumoniae.Polysaccharide 
14 Ab.IgG
Streptococcus 
pneumoniae.Polysaccharide 
18C Ab.IgG
Streptococcus 
pneumoniae.Polysaccharide 
19A Ab.IgG 
Streptococcus 
pneumoniae.Polysaccharide 
19F Ab.IgG
Streptococcus 
pneumoniae.Polysaccharide 
23F Ab.IgG
ELIF or 
multiplex
NA 
µg/ml 
0.05 or equivalent 
cut-off for the 
multiplex
GSK 
Biologicals*
 
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System
Component
Method
Kit / 
Manufacturer
Unit
Cut-off***
Laboratory  
†
SER
Streptococcus 
pneumoniae.Polysaccharide 
01 Ab.IgG
Streptococcus 
pneumoniae.Polysaccharide 
03 Ab.IgG
Streptococcus 
pneumoniae.Polysaccharide 
04 Ab.IgG
Streptococcus 
pneumoniae.Polysaccharide 
05 Ab.IgG
Streptococcus 
pneumoniae.Polysaccharide 
06A Ab.IgG
Streptococcus 
pneumoniae.Polysaccharide 
06B Ab.IgG
Streptococcus 
pneumoniae.Polysaccharide 
07F Ab.IgG
Streptococcus 
pneumoniae.Polysaccharide 
09V Ab.IgG
Streptococcus 
pneumoniae.Polysaccharide 
14 Ab.IgG
Streptococcus 
pneumoniae.Polysaccharide 
18C Ab.IgG
Streptococcus 
pneumoniae.Polysaccharide 
19A Ab.IgG
Streptococcus 
pneumoniae.Polysaccharide 
19F Ab.IgG
Streptococcus 
pneumoniae.Polysaccharide 
23F Ab.IgG
ELI
NA
µg/ml
0.15
WHO 
reference 
laboratory**
*GSK Biologicals laboratory refers to the Clinical Laboratory Sciences (CLS) in Rixensart, Belgium; Wavre, Belgium; 
Neomed Lab Inc, Canada.
** At the discretion of GSK Biologicals, pneumococcal testing may be done at a GSK Biologicals laboratory or the 
WHO reference laboratory
*** Assay cut-off and unit might be subject to change during the course of the study (e.g. in case of 
requalification, revalidation or standardization). In this case, this will be documented in the clinical report.
† Refer to the APPENDIX A for the laboratory addresses.
SER = Serum
ELI = Enzyme-linked immunosorbent assay (ELISA)
ELIF = 22F Inhibition ELISA
NEU = Neutralisation assay
CLIA = ChemiLuminescence ImmunoAssay 
IU/mL = International Units/millilitre
mIU/mL = milliInternational Units/millilitre
EL.U/mL = ELISA Units/millilitre
µg/ml = Micrograms/millilitre
 
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The GSK Biologicals’ clinical laboratories have established a Quality System supported 
by procedures. The activities of GSK Biologicals’ clinical laboratories are audited 
regularly for quality assessment by an internal (sponsor-dependent) but laboratory-
independent Quality Department.
5.7.4.
Biological samples evaluation
5.7.4.1.
Immunological read-outs
The immunological read-outs are presented in Table 8.
Table 8
Immunological read-outs
(Amended 12 December 2016)
Blood sampling time point
No. subjects
Component
Components
priority rank
Type of contact and 
time point
Sampling time point
Visit 2 (Day 0)
Pre-Bst
All
PT, FHA, PRN
D, T
HBs, PRP
Poliovirus types 1, 2, 3
13 pneumococcal serotypes
1
2
3
4
5
Visit 3 (Day 30)
Post-Bst
All
PT, FHA, PRN
HBs, PRP
D, T
Poliovirus types 1, 2, 3
13 pneumococcal serotypes
1
2
3
4
5
Pre-Bst: Blood sample to be collected before the booster dose.
Post-Bst: Blood sample to be collected one month after the booster dose 
In case of insufficient blood sample volume to perform assays for all antibodies, the 
samples will be analysed according to priority ranking provided in Table 8.
5.7.5.
Immunological correlates of protection
The following cut-offs are accepted as immunological correlates of protection:

Specific antibodies against diphtheria toxoid (anti-diphtheria) and tetanus toxoid 
(anti-tetanus) will be measured by Enzyme-linked immunosorbent assay (ELISA), 
for which the threshold of 0.1 International Units per ml (IU/ml) provides a 
conservative estimate of the percentage of subjects deemed to be protected
[Camargo, 1984; Melville-Smith, 1983].

Antibodies against the hepatitis B surface antigen (anti-HBs) will be measured using 
ChemiLuminescence ImmunoAssay (CLIA). The cut-off of the test is set at 
6.2 mIU/ml. An antibody concentration 10 mIU/ml defines seroprotection [CDC, 
1991].

Antibodies against poliovirus types 1, 2 and 3 will be determined by a virus 
micro-neutralisation test adapted from the World Health Organization Guidelines for 
WHO/EPI Collaborative Studies on Poliomyelitis [WHO, 1993]. Titres will be 
 
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expressed in terms of the reciprocal of the dilution resulting in 50% inhibition.
Samples with a titre greater than or equal to 1:8 will be considered as seropositive 
and protective.

Data from subjects given unconjugated Hib vaccine suggest that, in the absence of 
induction of immunological memory, a concentration of 0.15 g/mL is indicative of 
short-term protection, with 1 g/mL considered indicative of long-term protection 
[Käyhty, 1983; Anderson, 1984].

No serological correlate of protection against pertussis has been established [Plotkin, 
2010]. Antibodies against the pertussis components pertussis toxoid (PT), 
filamentous haemagglutinin (FHA) and pertactin (PRN) will be measured by ELISA. 
The seropositivity cut-off for all three pertussis antibodies in ELISA is 5 EL.U/ml. 
Subjects with antibody concentration below the cut-off will be considered 
seronegative.

Pneumococcal serotype specific total immunoglobulin G (IgG) antibodies 
(antibodies to 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F) will be each 
measured by 22F-inhibition ELISA [Concepcion, 2001] or multiplex. The antibody 
concentration for ELISA will be determined by logistic log comparison of the 
ELISA curves with a standard reference serum 89-SF available from the US Food 
and Drug Administration for which concentration of IgG and IgM to the serotypes 
are known in g/ml [Quataert, 1995]. The cut-off for ELISA is 0.05 g/ml. No 
correlate of protection is defined for the immune response to pneumococcal antigens. 
At the discretion of GSK Biologicals, this assay will be performed either at a GSK 
laboratory or at the WHO reference laboratory. The assay cut-off of the 22F-
inhibition ELISA test performed at the WHO reference laboratory is 0.15 g/ml.
The immunological assay results will be communicated to the investigator as soon as 
they become available.
The investigator is encouraged to share the immunological assay results for non-
responders with the study 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.
 
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6.
STUDY VACCINES AND ADMINISTRATION
6.1.
Description of study vaccines
The candidate vaccine to be used has been developed and manufactured by GSK 
Biologicals. 
The Quality Control Standards and Requirements for the candidate vaccine are described 
in separate Quality Assurance documents (e.g., release protocols, certificate of analysis) 
and the required approvals have been obtained. 
The vaccines are labelled and packed according to applicable regulatory requirements.
Commercial vaccines are assumed to comply with the specifications given in the 
manufacturer’s Summary of Product Characteristics.
The study vaccines, formulation and presentation is detailed in Table 9.
 
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Table 9
Study vaccines
Treatment 
name
Vaccines name
Formulation
Presentation
Volume to be 
administered*
Number of 
doses
Infanrix 
hexa 
DTPa-HBV-IPV
DT>=30IU; TT>=40IU; 
PT=25µg; FHA=25µg; 
PRN=8µg; 
HBsAg=10µg; 
Inactivated Poliovirus 
type 1 (Mahoney 
strain)=40DU; 
Inactivated Poliovirus 
type 2 (MEF-1 
strain)=8DU; 
Inactivated Poliovirus 
type 3 (Saukett strain); 
Aluminium=700µg 
Al3+
The DTPa-
HBV-IPV 
component is 
presented as 
a turbid white 
suspension in 
a pre-filled 
syringe.
0.5 ml *
1
Hib
PRP=10µg; 
TT~=25µg Aluminium 
as salts = 0.12 mg
The 
lyophilised Hib 
component is 
presented as 
a white pellet 
in a glass vial; 
it must be 
reconstituted 
before use 
with the liquid 
DTPa-HBV-
IPV 
component.
Prevenar 13
Prevenar 13
PS1=2.2µg CRM197; 
PS3=2.2µg CRM197; 
PS4=2.2µg CRM197; 
PS5=2.2µg CRM197; 
PS6A=2.2µg 
CRM197; 
PS6B=4.4µg 
CRM197; 
PS7F=2.2µg 
CRM197; 
PS9V=2.2µg 
CRM197; 
PS14=2.2µg 
CRM197; 
PS18C=2.2µg 
CRM197; 
PS19A=2.2µg 
CRM197; 
PS19F=2.2µg 
CRM197; 
PS23F=2.2µg 
CRM197; 
AlPO₄=125µg Al3+
Suspension 
for injection in 
a pre-filled 
syringe
0.5 ml
1
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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 authorised 
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 0.0 to +8.0C (for +2 to +8°C/+36 to 
+46°F label storage condition) impacting investigational medicinal products (IMPs) must 
be reported in the appropriate (electronic) temperature excursion decision form ([e]TDF). 
The impacted IMPs must not be used and must be stored in quarantine at label 
temperature conditions until usage approval has been obtained from the sponsor.
In case of temperature excursion below +2.0°C down to 0.0°C impacting IMP(s) there is 
no need to report in (e)TDF, but adequate actions must be taken to restore the +2 to 
+8°C/+36 to +46°F label storage temperature conditions. The impacted IMP(s) may still 
be administered, but the site should avoid re-occurrence of such temperature excursion.
Refer to the Module on Clinical Trial Supplies in the SPM for more details on actions to 
take.
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 study vaccines is given in Table 10.
Table 10
Dosage and administration
(Amended 12 December 2016)
Type of contact 
and time point
Volume to be 
administered
Study group
Treatment 
name
Route 1
Site
Side 3
Visit 2 (Day 0)
0.5 mL
dTpa Group and
Control Group
Infanrix hexa 
IM
Thigh or 
Deltoid 2
R
Visit 3 (Day 30)
0.5 mL
dTpa Group and
Control Group
Prevenar 13
IM
Thigh or 
Deltoid 2
L
1Intramuscular (IM)
2The vaccines should be administered in the thigh or deltoid, according to the national recommendations
/local practice
3Right (R), Left (L)
 
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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-randomisation when applicable), at least 10% additional vaccine doses will be 
supplied to replace those that are unusable. 
6.5.
Contraindications to vaccination
Since this is a booster study (single dose), contraindications have been included as part of 
the exclusion criteria.
The following events constitute contraindications to administration of Infanrix hexa at 
that point in time; if any of these events occur at the time scheduled for vaccination, the 
subject may be vaccinated at a later date, within the time window specified in the 
protocol (see Section 5.5), or the subject may be withdrawn at the discretion of the 
investigator (see Section 8.4). 

Acute disease and/or fever at the time of vaccination. 

Fever is defined as temperature 37.5°C/99.5°F for oral, axillary or tympanic 
route, or 38.0°C/100.4°F for rectal route. The preferred route for recording 
temperature in this study will be axillary/rectal.

Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory 
infection) without fever can be administered all vaccines/products.
6.6.
Warnings and precautions
The information below presents, in addition to the contraindications in Section 6.5, 
warnings and precautions to administration of Infanrix hexa.

As with other vaccines, administration of Infanrix hexa should be postponed in 
subjects suffering from acute severe febrile illness. The presence of a minor infection 
is not a contraindication.

Vaccination should be preceded by a review of the medical history (especially with 
regard to previous vaccination and possible occurrence of undesirable events) and a 
clinical examination.

If any of the following events are known to have occurred in temporal relation to 
receipt of pertussis-containing vaccine, the decision to give further doses of 
pertussis-containing vaccines should be carefully considered:

Temperature of 40.0°C within 48 hours, not due to another identifiable cause.

Collapse or shock-like state (hypotonic-hyporesponsiveness episode [HHE]) 
within 48 hours of vaccination. (Amended 12 December 2016)

Persistent, inconsolable crying lasting 3 hours, occurring within 48 hours of 
vaccination.

Convulsions with or without fever, occurring within three days of vaccination.
 
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
As with all injectable vaccines, appropriate medical treatment and supervision should 
always be readily available in case of a rare anaphylactic event following the
administration of the vaccine.

Infanrix hexa should be administered with caution to subjects with thrombocytopenia 
or a bleeding disorder since bleeding may occur following an intramuscular 
administration to these subjects.

In children with progressive neurological disorders, including infantile spasms, 
uncontrolled epilepsy or progressive encephalopathy, it is better to defer pertussis 
(Pa or Pw) immunization until the condition is corrected or stable. However, the 
decision to give pertussis vaccine must be made on an individual basis after careful 
consideration of the risks and benefits. 

Do not administer the vaccine intravascularly or intradermally.

A protective immune response may not be elicited in all vaccinees.

A history of febrile convulsions, a family history of convulsions or Sudden Infant 
Death Syndrome (SIDS) do not constitute contraindications for the use of Infanrix 
hexa. Vaccinees with a history of febrile convulsions should be closely followed up 
as such adverse events may occur within 2 to 3 days post vaccination.

Since the Hib capsular polysaccharide antigen is excreted in the urine, a positive 
urine test can be observed within 1-2 weeks following vaccination. Other tests 
should be performed in order to confirm Hib infection during this period.

Data from clinical studies indicate that, when Infanrix hexa is co-administered with 
pneumococcal conjugate vaccine, the rate of febrile reactions is higher compared to 
that occurring following the administration of Infanrix hexa alone.

Increased reporting rates of convulsions (with or without fever) and HHE were 
observed with concomitant administration of Infanrix hexa and Prevenar 13.
(Amended 12 December 2016)
Warnings and Precautions for the use of Prevenar13:

Prevenar 13 must not be administered intravascularly.

As with all injectable vaccines, appropriate medical treatment and supervision should 
always be readily available in case of a rare anaphylactic event following the
administration of the vaccine.

Prevenar13 should be administered with caution to subjects with thrombocytopenia 
or a bleeding disorder since bleeding may occur following an intramuscular 
administration to these subjects.

Prevenar 13 will only protect against Streptococcus pneumoniae serotypes included 
in the vaccine, and will not protect against other microorganisms that cause invasive 
disease, pneumonia, or otitis media. As with any vaccine, Prevenar 13 may not 
protect all individuals receiving the vaccine from pneumococcal disease.

Individuals with impaired immune responsiveness, whether due to the use of 
immuno-suppressive therapy, a genetic defect, human immunodeficiency virus 
 
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(HIV) infection, or other causes, may have reduced antibody response to active 
immunisation.

Increased reporting rates of convulsions (with or without fever) and HHE were 
observed with concomitant administration of Infanrix hexa and Prevenar 13.
(Amended 12 December 2016)
Refer to the latest approved product label/package insert for warnings and precautions for 
the use of Infanrix hexa and Prevenar 13.
6.7.
Concomitant medications/products and concomitant 
vaccinations
At each study visit/contact, the investigator should question 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 medication(s)/product(s)/vaccine(s) must be recorded in 
the eCRF.

All concomitant medications/products, except vitamins and dietary supplements, 
administered during the period starting from the administration of the dose of study 
vaccines (Visit 2) and ending at Visit 3 (Day 0 to Day 30)

Any concomitant vaccination administered in the period starting from the 
administration of the dose of study vaccines (Visit 2) and ending at the study visit 3
(Day 0 to Day 30).
Note: Medications/vaccinations listed prior to the dose of study vaccine are to be 
recorded as medical/vaccination history.

Prophylactic medication (i.e., medication administered in the absence of ANY 
symptom and in anticipation of a reaction to the vaccination).
E.g., an anti-pyretic is considered to be prophylactic when it is given in the absence 
of fever and any other symptom, to prevent fever from occurring [fever is defined as 
temperature 37.5°C/99.5°F for oral, axillary or tympanic route, or 
38.0°C/100.4°F for rectal route].

Any concomitant medications/products/vaccines listed in Section 6.7.2.

Any concomitant medications/products/vaccines relevant to a SAE to be reported as 
per protocol or administered at any time during the study period for the treatment of 
a SAE. In addition, concomitant medications relevant to SAEs need to be recorded 
on the expedited Adverse Event report.
 
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6.7.2.
Concomitant medications/products/vaccines that may lead to the 
elimination of a subject from ATP 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 
ATP analysis. See Section 10.4 for cohorts to be analysed.

Any investigational or non-registered product (drug or vaccine) other than the study 
vaccine(s) used within 30 days preceding the dose of study vaccine, or planned use 
during the study period.

Immunosuppressants or other immune-modifying drugs administered chronically 
(i.e., more than 14 days) during the study period. For corticosteroids, this will mean 
prednisone 0.5 mg/kg/day, or equivalent. 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 starting 
from 30 days before each dose of vaccine and ending 30 days after*, with the 
exception of inactivated influenza vaccine and other vaccines given as a part of the 
national immunisation schedule, that are allowed at any time during the study period.
*In case an emergency mass vaccination for an unforeseen public health threat (e.g.: 
a pandemic) is organised by the public health authorities, outside the routine 
immunisation program, the time period described above can be reduced if necessary 
for that vaccine provided it is licensed and used according to its SPC or PI and 
according to the local governmental recommendations and provided a written 
approval of the Sponsor is obtained.

Immunoglobulins and/or any blood products administered during the study period.
6.8.
Intercurrent medical conditions that may lead to elimination 
of a subject from ATP analyses
At each study visit subsequent to the vaccination visit, it must be verified if the subject 
has experienced or is experiencing any intercurrent medical condition. If it is the case, the 
condition(s) must be recorded in the eCRF.
Subjects may be eliminated from the ATP cohort for immunogenicity if, during the study, 
they incur a condition that has the capability of altering their immune response or are 
confirmed to have an alteration of their initial immune status (e.g., any confirmed or 
suspected immunosuppressive or immunodeficient condition).
7.
HEALTH ECONOMICS
Not applicable.
 
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8.
SAFETY
The investigator or site staff is/are responsible for the detection, documentation and 
reporting of events meeting the criteria and definition of an AE or SAE as provided in 
this protocol. 
Each subject’s parent(s)/LAR(s) will be instructed to contact the investigator immediately 
should 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 unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with 
the use of a medicinal product. For marketed medicinal products, this also includes 
failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse.
Examples of an AE include:

Significant or unexpected worsening or exacerbation of the condition/indication 
under study.

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 investigational 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 
investigational vaccine or a concurrent medication (overdose per se should not be 
reported as an AE/SAE).

Signs, symptoms temporally associated with vaccine administration.

Significant failure of expected pharmacological or biological action. 

Pre- or post-treatment events that occur as a result of protocol-mandated procedures 
(i.e., invasive procedures, modification of subject’s previous therapeutic regimen).
AEs to be recorded as endpoints (solicited AEs) are described in Section 8.1.3. All other 
AEs will be recorded as UNSOLICITED AEs.
 
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Examples of an AE DO NOT include:

Medical or surgical procedures (e.g., endoscopy, appendectomy); the condition that 
leads to the procedure is an AE/SAE.

Situations where an untoward medical occurrence did not occur (e.g., social and/or 
convenience admission to a hospital, admission for routine examination).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 

Pre-existing conditions or signs and/or symptoms present in a subject prior to the 
study vaccination. These events will be recorded in the medical history section of the 
eCRF.
8.1.2.
Definition of a serious adverse event 
A SAE is any untoward medical occurrence that:
a.
Results in death,
b.
Is life-threatening,
Note: The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in 
which the subject was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, had it been more severe.
c.
Requires hospitalisation or prolongation of existing hospitalisation,
Note: In general, hospitalisation signifies that the subject has been admitted at the 
hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician’s office or in an out-patient setting. Complications 
that occur during hospitalisation are also considered AEs. If a complication prolongs 
hospitalisation or fulfils any other serious criteria, the event will also be considered 
serious. When in doubt as to whether ‘hospitalisation’ occurred or was necessary, the 
AE should be considered serious.
Hospitalisation for elective treatment of a pre-existing condition (known or 
diagnosed prior to informed consent signature) that did not worsen from baseline is 
NOT considered an AE.
d.
Results in disability/incapacity
Note: The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhoea, influenza like illness, and accidental trauma (e.g., sprained 
ankle) which may interfere or prevent everyday life functions but do not constitute a 
substantial disruption.
Medical or scientific judgement should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalisation but may jeopardise the 
subject or may require medical or surgical intervention to prevent one of the other 
 
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outcomes listed in the above definition. These should also be considered serious. 
Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalisation.
8.1.3.
Solicited adverse events
8.1.3.1.
Solicited local (injection-site) adverse events
The following local (injection-site) AEs will be solicited:
Table 11
Solicited local adverse events
Pain at injection site
Redness at injection site
Swelling at injection site
N.B. If parent(s)/LAR(s) of infants observe any large injection site reaction [defined as 
any local swelling with diameter > 50 mm and/or any noticeable diffuse injection site 
swelling (diameter not measurable) and/or any noticeable increased circumference of the 
injected limb)], they will be asked to contact the study personnel and bring the subject for 
an evaluation by the investigator as soon as possible. The investigator will record detailed 
information describing the AE on a specific large swelling reaction sheet in the eCRF.
8.1.3.2.
Solicited general adverse events
The following general AEs will be solicited:
Table 12
Solicited general adverse events
Drowsiness
Fever
Irritability/Fussiness
Loss of appetite
Note: Temperature will be recorded in the evening. Should additional temperature 
measurements be performed at other times of day, the highest temperature will be 
recorded in the eCRF.
8.1.4.
Clinical laboratory parameters and other abnormal assessments 
qualifying as adverse events or serious adverse events 
In absence of diagnosis, abnormal laboratory findings (e.g., clinical chemistry, 
haematology, urinalysis) or other abnormal assessments (e.g., vital signs) that are judged 
by the investigator to be clinically significant will be recorded as AE or SAE if they meet 
the definition of an AE or SAE (refer to Sections 8.1.1 and 8.1.2). Clinically significant 
abnormal laboratory findings or other abnormal assessments that are present at baseline 
and significantly worsen following the start of the study will also be reported as AEs or 
SAEs. However, clinically significant abnormal laboratory findings or other abnormal 
assessments that are 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 
 
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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.
8.2.
Detecting and recording adverse events and serious 
adverse events 
8.2.1.
Time period for detecting and recording adverse events and
serious adverse events 
All AEs starting within 30 days following administration of the dose of study vaccines
(Day 0 to Day 30) must be recorded into the appropriate section of the eCRF, irrespective 
of intensity or whether or not they are considered vaccination-related.
The time period for collecting and recording SAEs will begin at the receipt of study 
vaccines and will end when the subject is discharged from the study. See Section 8.3 for 
instructions on reporting of SAEs.
All AEs/SAEs leading to withdrawal from the study will be collected and recorded from 
the time the subjects have been enrolled in the study.
(Amended 12 December 2016)
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’s parent(s)/LAR(s) consents to their child/wards participation in the 
study until she/he is discharged from the study.
An overview of the protocol-required reporting periods for AEs and SAEs is given in 
Table 13.
 
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Table 13
Reporting periods for collecting safety information
(Amended 12 December 2016)
Event
V 1
V2
4 d post V2
31 d 
post-V2
V3 
Phone contact *
Study Conclusion
Age of subject
9 months
11-18 months
12-19 months
18 months¶
Timepoint
Month -9 to -2
Day 0
Day 3
Day 30
Day 30
Day 0 to Month 7
Solicited local and 
general AEs
Large injection site 
reactions
Unsolicited AEs
Neurodevelopmental 
status¶
AEs/SAEs leading to 
withdrawal from the 
study
SAEs
SAEs related to study 
participation 
or concurrent GSK 
medication/vaccine
Pre-V: pre-vaccination; V: Visit; Post-V: post-visit; D: Day, M: Month; 
* For Czech Republic, the phone call at 18 months may be replaced by a clinic visit if deemed preferable by the 
study team. (Amended 12 December 2016)
¶ Neurodevelopmental status will be recorded at 9 months and 18 months of age. It is encouraged that subjects who 
are getting vaccinated at 18 months of age at Visit 2 or coming for Visit 3, complete their ASQ-3 during their visit to the 
study centre. In case subjects complete Visit 3 before 18 months of age, the study staff will contact the parents/LAR(s) 
via phone and conduct an interview to complete the child’s ASQ-3 at 18 months of age.
If the subject is referred to a developmental specialist for formal assessment, then this information needs to be 
recorded in the eCRF. Also, the overall assessment of delay by the specialist should be recorded in the eCRF.
8.2.2.
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 13. Investigators are not obligated to actively seek AEs 
or SAEs in former study participants. However, if the investigator learns of any SAE at 
any time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the investigational vaccine the investigator will promptly 
notify the Study Contact for Reporting SAEs.
 
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8.2.3.
Evaluation of adverse events and serious adverse events
8.2.3.1.
Active questioning to detect adverse events and serious adverse 
events
As a consistent method of collecting AEs, the subject’s parent(s)/LAR(s) should be asked 
a non-leading question such as:
‘Has your child acted differently or felt different in any way since receiving the vaccines
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 in the eCRF. The investigator is not allowed to send photocopies of the 
subject’s medical records to GSK Biologicals instead of appropriately completing the 
eCRF. However, there may be instances when copies of medical records for certain cases 
are requested by GSK Biologicals. In this instance, all subject identifiers will be blinded 
on the copies of the medical records prior to submission to GSK Biologicals.
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.
 
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8.2.3.2.
Assessment of adverse events
8.2.3.2.1.
Assessment of intensity
The intensity of the following solicited AEs will be assessed as described:
Table 14
Intensity scales for solicited symptoms
Adverse Event
Intensity grade
Parameter
Pain at injection site
0
None
1
Mild: Minor reaction to touch
2
Moderate: Cries/protests on touch
3
Severe: Cries when limb is moved/spontaneously painful
Redness at injection site
Record greatest surface diameter in mm
Swelling at injection site
Record greatest surface diameter in mm
Fever*
Record temperature in °C/°F
Irritability/Fussiness
0
Behaviour as usual
1
Mild: Crying more than usual/no effect on normal activity
2
Moderate: Crying more than usual/interferes with normal activity
3
Severe: Crying that cannot be comforted/prevents normal 
activity
Drowsiness
0
Behaviour as usual
1
Mild: Drowsiness easily tolerated
2
Moderate: Drowsiness that interferes with normal activity
3
Severe: Drowsiness that prevents normal activity
Loss of appetite
0
Appetite as usual
1
Mild: Eating less than usual/no effect on normal activity
2
Moderate: Eating less than usual/interferes with normal activity
3
Severe: Not eating at all
*Fever is defined as temperature 37.5°C/99.5°F for oral, axillary or tympanic route, or 38.0°C/100.4°F for rectal 
route. The preferred route for recording temperature in this study will be axillary/rectal.
The maximum intensity of local injection site redness/swelling will be scored at GSK 
Biologicals as follows:
0
:
Absent
1
:
5 mm
2
:
> 5 mm and 20 mm
3
:
> 20 mm
The maximum intensity of fever (oral, axillary or typmpanic route) will be scored at 
GSK Biologicals as follows: (Amended 12 December 2016)
0
=
< 37.5C
1
=
37.5C to 38.0C
2
=
> 38.0C to 39.0C
3
=
> 39.0C
 
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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.
The intensity should be assigned to one of the following categories:
1 (mild)
=
An AE which is easily tolerated by the subject, causing minimal 
discomfort and not interfering with everyday activities.
2 (moderate)
=
An AE which is sufficiently discomforting to interfere with 
normal everyday activities.
3 (severe)
=
An AE which prevents normal, everyday activities (in a young 
child, such an AE would, for example, prevent attendance at 
school/kindergarten/a day-care centre and would cause the 
parent(s)/LAR(s) to seek medical advice.)
An AE that is assessed as Grade 3 (severe) should not be confused with a SAE. Grade 
3 is a category used for rating the intensity of an event; and both AEs and SAEs can be 
assessed as Grade 3. An event is defined as ‘serious’ when it meets one of the pre-
defined outcomes as described in Section 8.1.2.
8.2.3.2.2.
Assessment of causality
The definitions for ‘NO’ and ‘YES’ have been written in such a way that all events that 
have been attributed a ‘NO’ can be pooled with events which in the primary vaccination 
study were determined to be ‘not related’ or ‘unlikely to be related’ to vaccination. Those 
events that are attributed a ‘YES’ can be pooled with those events that in the past were 
determined to have a ‘suspected’ or ‘probable’ relationship to vaccination in the primary 
vaccination study.
The investigator is obligated to assess the relationship between investigational vaccine
and the occurrence of each AE/SAE. The investigator will use clinical judgement to 
determine the relationship. 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 investigational vaccine will be considered and 
investigated. The investigator will also consult the IB and/or PI for marketed products to 
determine his/her assessment. (Amended 12 December 2016)
There may be situations when a SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK Biologicals. However, it is very 
important that the investigator always makes an assessment of causality for every event 
prior to submission of the Expedited Adverse Events Report to GSK Biologicals. The 
investigator may change his/her opinion of causality in light of follow-up information and 
update the SAE information accordingly. The causality assessment is one of the criteria 
used when determining regulatory reporting requirements.
In case of concomitant administration of multiple vaccines/products, it may not be 
possible to determine the causal relationship of general AEs to the individual vaccine
 
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administered. The investigator should, therefore, assess whether the AE could be causally 
related to vaccination rather than to the individual vaccines.
All solicited local (injection site) reactions will be considered causally related to 
vaccination. Causality of all other AEs should be assessed by the investigator using the 
following question:
Is there a reasonable possibility that the AE may have been caused by the investigational 
vaccine?
YES
:
There is a reasonable possibility that the vaccines contributed to the 
AE. 
NO
:
There is no reasonable possibility that the AE is causally related to 
the administration of the study vaccines. There are other, more 
likely causes and administration of the study vaccines is not 
suspected to have contributed to the AE.
If an event meets the criteria to be determined as ‘serious’ (see Section 8.1.2), additional 
examinations/tests will be performed by the investigator in order to determine ALL 
possible contributing factors for each SAE.
Possible contributing factors include:

Medical history.

Other medication.

Protocol required procedure.

Other procedure not required by the protocol.

Lack of efficacy of the vaccines, if applicable.

Erroneous administration.

Other cause (specify).
8.2.3.3.
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).
 
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8.2.3.4.
Assessment of neurodevelopmental status
The parent(s)/LAR(s) will be asked to complete a standardised developmental screening 
tool known as ASQ-3. Refer to Section 5.6.2.13 for more details. 
8.2.3.5.
Medically attended visits
For each solicited and unsolicited symptom the subject experiences, the subject’s 
parent(s)/LAR(s) will be asked if the subject received medical attention defined as 
hospitalisation, 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.
8.3.
Reporting of serious adverse events
8.3.1.
Prompt reporting of serious adverse events to GSK Biologicals
SAEs that occur in the time period defined in Section 8.2 will be reported promptly to 
GSK within the timeframes described in Table 15, once the investigator determines that 
the event meets the protocol definition of a SAE.
Table 15
Timeframes for submitting serious adverse event reports to GSK 
Biologicals
Type of Event
Initial Reports
Follow-up of Relevant Information on a
Previous Report
Timeframe
Documents
Timeframe
Documents
SAEs
24 hours*‡
electronic Expedited 
Adverse Events Report
24 hours*
electronic Expedited Adverse 
Events Report
* Timeframe allowed after receipt or awareness of the information.
‡ The investigator will be required to confirm review of the SAE causality by ticking the ‘reviewed’ box in the electronic 
Expedited Adverse Events Report within 72 hours of submission of the SAE.
8.3.2.
Contact information for reporting serious adverse events
Study Contact for Reporting SAEs
Refer to the local study contact information document.
Back-up Study Contact for Reporting SAEs
24/24 hour and 7/7 day availability:
GSK Biologicals Clinical Safety & Pharmacovigilance
Fax: 
 or 
Email address: 
8.3.3.
Completion and transmission of SAE reports to GSK Biologicals
Once an investigator becomes aware that a SAE has occurred in a study subject, the 
investigator (or designate) must complete the information in the electronic Expedited 
Adverse Events Report WITHIN 24 HOURS. The report will always be completed as 
thoroughly as possible with all available details of the event. Even if the investigator does 
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not have all information regarding a SAE, the report should still be completed within 24 
hours. Once additional relevant information is received, the report should be updated 
WITHIN 24 HOURS.
The investigator will always provide an assessment of causality at the time of the initial 
report. The investigator will be required to confirm the review of the SAE causality by 
ticking the ‘reviewed’ box in the electronic Expedited Adverse Events Report within 72 
hours of submission of the SAE.
8.3.3.1.
Back-up system in case the electronic reporting system does not work
If the electronic reporting system does not work, the investigator (or designate) must 
complete, then date and sign a paper Expedited Adverse Events Report and fax it to the 
Study Contact for Reporting SAEs (refer to the Sponsor Information) or to GSK 
Biologicals Clinical Safety and Pharmacovigilance department within 24 hours.
This back-up system should only be used if the electronic reporting system is not working 
and NOT if the system is slow. As soon as the electronic reporting system is working 
again, the investigator (or designate) must complete the electronic Expedited Adverse 
Events Report within 24 hours. The final valid information for regulatory reporting will 
be the information reported through the electronic SAE reporting system.
8.3.4.
Updating of SAE information after removal of write access to the 
subject’s eCRF
When additional SAE information is received after removal of the write access to the 
subject’s eCRF, new or updated information should be recorded on the appropriate paper 
report, with all changes signed and dated by the investigator. The updated report should 
be faxed to the Study Contact for Reporting SAEs (refer to the Sponsor Information) or 
to GSK Biologicals Clinical Safety and Pharmacovigilance department within the 
designated reporting time frames specified in Table 15.
8.3.5.
Regulatory reporting requirements for serious adverse events
The investigator will promptly report all SAEs to GSK in accordance with the procedures 
detailed in Section 8.3.1. GSK Biologicals has a legal responsibility to promptly notify, 
as appropriate, both the local regulatory authority and other regulatory agencies about the 
safety of a product under clinical investigation. Prompt notification of SAEs by the 
investigator to the Study Contact for Reporting SAEs is essential so that legal obligations 
and ethical responsibilities towards the safety of other subjects are met.
Investigator safety reports are prepared according to the current GSK policy and are 
forwarded to investigators as necessary. An investigator safety report is prepared for a 
SAE(s) that is both attributable to the investigational vaccine and unexpected. The 
purpose of the report is to fulfil specific regulatory and GCP requirements, regarding the 
product under investigation.
 
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8.4.
Follow-up of adverse events and serious adverse events
8.4.1.
Follow-up of adverse events and serious adverse events 
8.4.1.1.
Follow-up during the study
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject and provide additional relevant information on the subject’s condition to GSK 
Biologicals (within 24 hours for SAEs; refer to Table 15).
All SAEs documented at a previous visit/contact and designated as not recovered/not 
resolved or recovering/resolving will be reviewed at subsequent visits/contacts until the
end of the study.
All AEs documented at a previous visit/contact and designated as not recovered/not 
resolved or recovering/resolving will be reviewed at subsequent visit/contact until 30 
days after the vaccination.
8.4.1.2.
Follow-up after the subject is discharged from the study
The investigator will follow subjects:

with SAEs, or subjects withdrawn from the study as a result of an AE, until the event 
has resolved, subsided, stabilised, disappeared, or until the event is otherwise 
explained, or the subject is lost to follow-up. 
If the investigator receives additional relevant information on a previously reported SAE, 
he/she will provide this information to GSK Biologicals using electronic Expedited 
Adverse Events Report.
GSK Biologicals may request that the investigator performs or arranges the conduct of 
additional clinical examinations/tests and/or evaluations to elucidate as fully as possible 
the nature and/or causality of the AE or SAE. The investigator is obliged to assist. If a 
subject dies during participation in the study or during a recognised follow-up period, 
GSK Biologicals will be provided with any available post-mortem findings, including 
histopathology.
8.5.
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 an AE should 
be recorded in the subject’s eCRF (refer to Section 6.7).
8.6.
Subject card
Study 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’s 
parent(s)/LAR(s). In an emergency situation this card serves to inform the responsible 
 
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attending physician that the subject is in a clinical study and that relevant information 
may be obtained by contacting the investigator.
Subjects’ parent(s)/LAR(s) must be instructed to keep subject cards in their possession at 
all times.
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
Withdrawals will not be replaced.
9.2.1.
Subject withdrawal from the study
From an analysis perspective, a ‘withdrawal’ from the study refers to any subject who did 
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 a ‘withdrawal’ from the study when no study procedure has 
occurred, no follow-up has been performed and no further information has been collected 
for this subject from the date of withdrawal/last contact.
Investigators will make an attempt to contact those subjects who do not return for
scheduled visits or follow-up.
Information relative to the withdrawal will be documented in the eCRF. The investigator 
will document whether the decision to withdraw a subject from the study was made by 
the subject’s parent(s)/LAR(s), or by the investigator, as well as which of the following 
possible reasons was responsible for withdrawal:

Serious adverse event.

Non-serious adverse event.

Protocol violation (specify).

Consent withdrawal, not due to an adverse event*.

Moved from the study area.

Lost to follow-up.

Other (specify).
*In case a subject is withdrawn from the study because the subject’s parent(s)/LAR(s)
has withdrawn consent, the investigator will document the reason for withdrawal of 
consent, if specified by the subject’s parent(s)/LAR(s), in the eCRF.
 
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Subjects who are withdrawn from the study because of SAEs/AEs must be clearly 
distinguished from subjects who are withdrawn for other reasons. Investigators will 
follow subjects who are withdrawn from the study as result of a SAE/AE until resolution 
of the event (see Section 8.4.1.2).
10.
STATISTICAL METHODS
10.1.
Primary endpoint

Immunogenicity with respect to components of Infanrix hexa.

Anti-diphtheria, anti-tetanus, anti-HBs, anti-poliovirus type 1, anti-poliovirus 
type 2, anti-poliovirus type 3 and anti-polyribosyl-ribitol phosphate (anti-PRP) 
seroprotection status, one month after the booster dose.

Booster response to PT, FHA and PRN antigens, one month after the booster 
dose.
10.2.
Secondary endpoints

Immunogenicity with respect to components of Infanrix hexa and Prevenar 13.
Before the booster dose

Anti-diphtheria, anti-tetanus, anti-poliovirus type 1, anti-poliovirus type 2, anti-
poliovirus type 3, anti-HBs and anti-PRP seroprotection status.

Anti-PT, anti-FHA and anti-PRN and anti-pneumococcal serotypes (1, 3, 4, 5, 
6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F) seropositivity rates.

Anti-diphtheria, anti-tetanus, anti-PT, anti-FHA, anti-PRN, anti-poliovirus type 
1, anti-poliovirus type 2, anti-poliovirus type 3, anti-HBs and anti-pneumococcal 
serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F) and anti-PRP 
antibody concentrations or titres.
One month after the booster dose

Anti-diphtheria, anti-tetanus, anti-poliovirus type 1, anti-poliovirus type 2, anti-
poliovirus type 3, anti-HBs, anti-PRP, anti-PT, anti-FHA, anti-PRN and anti-
pneumococcal serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F) 
antibody concentrations or titres.

Anti-PT, anti-FHA, anti-PRN antibody seropositivity rates.
 
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
Solicited local and general symptoms.

Occurrence of solicited local/general symptoms during the 4-day (Day 0-Day 3) 
follow-up period after booster vaccination.

Unsolicited adverse events.

Occurrence of unsolicited symptoms during the 31-day (Day 0-Day 30) follow-
up period after booster vaccination.

Serious adverse events.

Occurrence of reported SAEs from booster dose up to study end.

Neurodevelopmental status will be assessed at 9 and 18 months of age adjusted for 
prematurity.

Proportion of infants with an ASQ-3 score in the black zone in any domain.

Proportion of infants with an ASQ-3 score in the black zone for gross motor 
skills.

Proportion of infants with an ASQ-3 score in the black zone for fine motor 
skills.

Proportion of infants with an ASQ-3 score in the black zone for communication.

Proportion of infants with an ASQ-3 score in the black zone for problem solving 
skills.

Proportion of infants with an ASQ-3 score in the black zone for personal-social 
skills.

Proportion of infants referred for formal neurodevelopmental evaluation using 
BSID-III.

Proportion of infants with at least one of the indicators of neurodevelopmental 
impairment using BSID-III.
10.3.
Determination of sample size
The sample size for this study is not derived from any power based calculation. The 
number of evaluable subjects for the study is based on the all infants who are willing to 
take part in the current study. Considering approximately 20-40% reduction in the 
number of evaluable subjects due to dropouts and protocol violations from the primary 
study, Table 16 gives the estimated sample size of evaluable subjects that can be 
expected and the precision achieved with this sample for various expected values of 
seroprotection/booster response rates in terms of exact 95% confidence interval (CI). 
 
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Table 16
Exact 95% CI of the different values of observed response rate 
(booster response rate or seroprotection rate) for a sample size of 
204-272 subjects)
Number of evaluable 
subjects
Observed 
seroprotection/response rate 
expressed as a percentage
Exact 2-sided 95% CI for this observed rate for a sample 
size of 204-272 subjects
Lower Limit (LL)
Upper Limit (UL)
272
80
74.9 
84.7
86
81.3
89.9
92
88.4
95.2
93
89.3
95.7
94
90.6
96.6
95
92.0
97.4
96
92.9
98.0
97
94.3
98.7
98
95.8
99.4
99
97.4
99.9
100
98.7
100.0
238
80
74.6
85.1
86
81.1
90.3
92
87.8
95.1
93
89.3
96.1
94
90.3
96.7
95
91.4
97.4
96
92.9
98.3
97
94.0
98.8
98
95.8
99.5
99
97.0
99.9
100
98.5
100.0
204
80
74.3
85.6
86
80.8
90.7
92
87.6
95.5
93
88.8
96.2
94
90.0
96.9
95
91.2
97.6
96
92.4
98.3
97
93.7
98.9
98
95.1
99.5
99
96.5
99.9
100
98.2
100
Reference study: 
DTPa-HBV-IPV 095 (Germany): Group primed with Infanrix hexa according to 2, 4, 6 schedule and received a booster 
dose of Infanrix hexa between 11-23 months.
DTPa-HBV-IPV 083 (Spain): Group primed with Infanrix hexa according to 2, 4, 6 schedule and received a booster 
dose of Infanrix hexa between 18-20 months of age.
DTPa-HBV-IPV 081 (Germany): Group primed with Infanrix hexa according to 3, 4, 5 schedule and received a booster 
dose of Infanrix hexa between 12-23 months of age.
The reference values (booster phase) considered for the above calculations are presented 
in Table 17.
 
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Table 17
Reference values (booster phase) 
(Amended 12 December 2016)
Reference Study
Observed seroprotection 
rates 
Booster response for Pertussis antigens
Observed Seroprotection rates
D
T
PT
FHA
PRN
PRP
HBs
Anti-IPV1
Anti-IPV2
Anti-IPV3
DTPa-HBV-IPV-095
100.0% 
[97.7, 100]
100.0% 
[97.7,100]
93.3%
[88.1, 96.8]
86.0%
[79.6, 91.0]
98.1%
[94.4, 99.6]
99.4%
[96.5,100]
100%
[97.7,100]
100%
[97.5,100]
100%
[97.5,100]
100%
[97.5,100]
DTPa-HBV-IPV 083 
[Full term infants 
(37 weeks)]
100.0%
[94.7, 100],
98.5%
[92.1, 100]
97%
[89.5,99.6]
98.5%
[92, 100]
98.5%
[92,100]
100%
[94.7,100]
98.5%
[92.1,100]
100%
[94.6,100]
100%
[94.6,100]
100%
[94.3,100]
DTPa-HBV-IPV 083 
[Pre-term infants 
(<37 weeks)]
100.0%
[95.7, 100]
100.0%
[95.7, 100]
100%
[95.7,100]
97.6%
[91.7, 99.7]
100%
[95.7,100]
100%
[95.7,100]
91.6%
[83.4,96.5]
100%
[95.5,100]
100%
[95.5,100]
100%
[95.1,100]
DTPa-HBV-IPV 081
100.0%
[96.8, 100]
100.0%
[96.8, 100]
98.2%
[93.8,99.8]
98.2%
[93.8,99.8]
99.1%
[95.2,100]
100%
[96.8,100]
99.1%
[95.2,100]
100%
[96.6,100]
100%
[96.6,100]
100%
[96.3,100]
217744/054
100.0%
[97.9,100.0]
100.0%
[97.9,100.0]
100.0%
[97.8,100.0]
100.0%
[97.8,100.0]
100.0%
[97.9,100.0]
100.0%
[97.9,100.0]
98.9 
(95.9,99.9)
100.0%
[97.6,100.0]
100.0%
[97.5,100.0]
100.0%
[97.5,100.0]
DTPa-HBV-IPV 095 (Germany): Group primed with Infanrix hexa according to 2,4,6 schedule and received a booster dose of Infanrix hexa between 11-23 months.
DTPa-HBV-IPV 083 (Spain): Group primed with Infanrix hexa according to 2,4,6 schedule and received a booster dose of Infanrix hexa between 18-20 months of age.
DTPa-HBV-IPV 081 (Germany): Group primed with Infanrix hexa according to 3,4,5 schedule and received a booster dose of Infanrix hexa between 12-23 months of age
217744/054: Group receiving DTPa-HBV-IPV/Hib according to 3,5,11 schedule in Italy and Germany
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10.4.
Cohorts for Analyses
Four cohorts are defined for the purpose of the analysis:

Total enrolled cohort

Total Vaccinated cohort (TVC).

ATP cohort for analysis of safety

ATP cohort for analysis of immunogenicity
10.4.1.
Total enrolled cohort
The Total enrolled cohort will include all enrolled subjects in the study.
10.4.2.
Total vaccinated cohort
The TVC will include all vaccinated subjects for whom data are available. (Amended 12
December 2016)

A safety analysis based on the TVC will include all subjects with booster vaccine 
administration documented. 

An immunogenicity analysis based on the TVC will include vaccinated subjects for 
whom data concerning immunogenicity endpoint measures are available.
10.4.3.
According-to-protocol cohort for analysis of safety
The ATP cohort for analysis of safety will include all subjects from the TVC who 
complied with the vaccine administration:

who have received all vaccine doses in the primary study 201330 [DTPA 
(BOOSTRIX)-048 PRI]. (Amended 12 December 2016)

who have received the booster dose of study vaccines in the current study.
(Amended 12 December 2016)

for whom administration route and site of study vaccines is known and according to 
the protocol.

who have not received a vaccine not specified or forbidden in the protocol.
10.4.4.
According-to-protocol cohort for analysis of immunogenicity
The ATP cohort for analysis of immunogenicity will include all evaluable subjects from 
the ATP cohort for analysis of safety:

Who meet all eligibility criteria.

Who received all doses of vaccine in the primary study 201330 [DTPA 
(BOOSTRIX)-048 PRI]. (Amended 12 December 2016)

Who comply with the procedures and intervals defined in the protocol (refer to Table 
5).
 
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
Who do not meet any of the criteria for elimination from an ATP analysis (refer to 
Section 6.7.2 during the study).

Who did not receive a product leading to elimination from an ATP analysis as listed 
in Section 6.7.2,

Who did not present with a medical condition leading to elimination from an ATP 
analysis as listed in Section 6.8,

For whom data concerning immunogenicity endpoint measures are available. This 
will include subjects for whom assay results are available for antibodies against at 
least one study vaccine antigen component after vaccination.

The interval between the vaccination visit and post-booster blood sampling, 
considered for inclusion of a subject will be 21–48 days. 
10.5.
Derived and transformed data
The cut-off value is defined by the laboratory before the analysis and is described in 
Section 5.7.3.

A seronegative subject is a subject whose antibody concentration/titre is below the 
assay cut-off.

A seropositive subject is a subject whose antibody concentration/titre is greater than 
or equal to the assay cut-off defined in Table 7.

A seroprotected subject is a subject whose antibody concentration/titre is greater than 
or equal to the level defining clinical protection. The following seroprotection 
thresholds are applicable:

Anti-diphtheria antibody concentrations 0.1 IU/ml.

Anti-tetanus antibody concentrations 0.1 IU/ml.

Anti-HBs antibody concentrations 10 mIU/mL.

Anti-poliovirus types 1, 2 and 3 antibody titres 8.

Anti-PRP antibody concentrations 0.15 µg/ml.

Other cut-offs to be considered:

Anti-PRP antibody concentrations 1.0 µg/ml.

Anti-diphtheria antibody concentrations 1.0 IU/ml.

Anti-tetanus antibody concentrations 1.0 IU/ml.

Anti-HBs antibody concentrations 100 mIU/mL.

For the pneumococcal antigens, the threshold used for statistical analysis will depend 
on the final selected assay.

Booster response to the PT, FHA and PRN antigens, is defined as:
 
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
initially seronegative subjects (pre-booster antibody concentration below cut-
off: < 5 ELISA EL.U/mL) with an increase of at least four times the cut-off one 
month after vaccination (post-booster antibody concentration 20 EL.U/mL), 
and

initially seropositive subjects with pre-booster antibody concentration
5 EL.U./mL and < 20 EL.U/mL with an increase of at least four times the pre-
booster antibody concentration one month after vaccination, and,

For initially seropositive subjects with pre-booster antibody concentration 
20 EL.U/mL with an increase of at least two times the pre-booster antibody 
concentration, one month after vaccination.
Note: Due to ongoing re-validation of pertussis assays and potential change in the assay 
unit, the definition of booster response may be subject to change.

The geometric mean titres (GMTs)/geometric mean concentrations (GMCs) 
calculations will be performed by taking the anti-log of the mean of the log10
titre/concentration transformations. Antibody titres/concentrations below the cut-off 
of the assay will be given an arbitrary value of half the cut-off for the purpose of 
GMT/GMC calculation. Note that as per assay specification for anti-HBs antibodies, 
results between the assay cut-off of 6.2 mIU/ml and 7.65 mIU/ml (= Lower limit of 
Quantification) will be quantified as 6.2 mIU/ml.
Handling of missing data:
Immunogenicity
For a given subject and a given immunogenicity measurement, missing or non-evaluable 
measurements will not be replaced. Therefore, an analysis will exclude subjects with 
missing or non-evaluable measurements.
Safety/reactogenicity

For a given subject and the analysis of solicited AEs, four days post-vaccination
(Day 0-Day 3), missing or non-evaluable measurements will not be replaced. 
Therefore the analysis of the solicited AEs based on the TVC will include only 
vaccinated subjects and doses with documented safety data (i.e., symptom screen 
completed). 

For a given subject, missing neurodevelopmental status will not be replaced. 
Therefore, an analysis will exclude subjects with missing or non-evaluable 
measurements

For analysis of unsolicited AEs, such as SAEs or AEs by primary Medical 
Dictionary for Regulatory Activities (MedDRA) term, and for the analysis of 
concomitant medications, all vaccinated subjects will be considered. Subjects, whose 
parent(s)/LAR(s) do not report the event or the concomitant medication, will be 
considered as subjects without the event or the concomitant medication, respectively.

For summaries reporting both solicited and unsolicited AEs, all vaccinated subjects 
 
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will be considered. Subjects, whose parent(s)/LAR(s) do not report the event or the 
concomitant medication, will be considered as subjects without the event or the 
concomitant medication, respectively.
10.6.
Analysis of demographics
Demographic characteristics (age in months, race, length [cm], weight [kg], head 
circumference [cm]), cohort description and withdrawal status will be summarised by 
group using descriptive statistics:

Frequency tables will be generated for categorical variables such as race, country or 
primary vaccination schedule; (Amended 12 December 2016)

Mean, median and standard error will be provided for continuous data such as age.
The distribution of subjects enrolled among the study sites will be tabulated as a whole 
and per group.
10.7.
Analysis of immunogenicity
The primary analysis will be based on the ATP cohort for analysis of immunogenicity. If 
in any vaccine group, the percentage of enrolled subjects excluded from this ATP cohort 
is more than 5%, a second analysis based on the TVC will be performed to complement 
the ATP analysis. All analyses will be descriptive.
For each group, at each time point that a blood sample result is available:

Seropositivity rates against PT, FHA and PRN antigens and pneumococcal antigens 
(1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F) with exact 95% CI [Clopper, 
1934] will be calculated.

Seroprotection rates against diphtheria toxoid, tetanus toxoid, HBs, PRP antigen and 
poliovirus types 1, 2, 3 antigens (with exact 95% CI [Clopper, 1934]) will be 
calculated.

Percentage of subjects with anti-pneumococcal serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 
14, 18C, 19A, 19F, 23F) antibody concentrations, depending on the GSK laboratory 
or WHO reference laboratory assay cut-offs, will be calculated along with its exact 
95% CI [Clopper, 1934].

Percentage of subjects with anti-D and anti-T antibody concentrations 1.0 IU/ml 
will be calculated along with its exact 95% CI [Clopper, 1934].

Percentage of subjects with anti-PRP antibody concentrations 1.0 g/ml and anti-
HBs antibody concentrations 100 mIU/mL will be calculated along with its exact 
95% CI [Clopper, 1934].

GMC/GMT with 95% CI will be tabulated for antibodies against each antigen.

The booster response rates to PT, FHA and PRN (with exact 95% CI) one month 
after the booster dose will be calculated.
The above summaries will be provided by country or primary vaccination schedule for 
countries involving more than 50 subjects.
 
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
The distribution of antibody concentrations/titres for each antigen will be displayed 
using reverse cumulative distribution curves (RCCs).

The distribution of antibody concentrations or titres of each antigen will be tabulated.
10.8.
Analysis of safety
The primary analysis will be based on the TVC. If more than 5% of enrolled subjects are 
excluded from the ATP cohort for analysis of safety, then a second analysis based on this 
ATP cohort will be performed to complement the TVC analysis. All analyses will be 
descriptive.

The percentage of subjects with at least one local symptom (solicited or unsolicited), 
with at least one general symptom (solicited or unsolicited) and with any symptom 
(solicited or unsolicited) during the 4-day (Day 0-Day 3) solicited follow-up period 
will be tabulated with exact 95% CI [Clopper, 1934]. The same calculations will be 
done for symptoms (solicited or unsolicited) rated as grade 3 in intensity, for 
symptoms (solicited or unsolicited) leading to medical advice and for symptoms 
(solicited or unsolicited) assessed as causally related to vaccination.

The incidence of local AEs (solicited and unsolicited) will be calculated at each 
injection site as well as overall (all sites considered) for each group.

The percentage of subjects reporting each individual solicited local and general 
symptom during the 4-day (Day 0-Day 3) solicited follow-up period will be 
tabulated after the vaccine dose, with exact 95% CI [Clopper, 1934]. The same 
calculations will be done for each individual solicited symptom rated as grade 3 in 
intensity and for each individual solicited symptom assessed as causally related to 
vaccination. (Amended 12 December 2016)

All computations mentioned above will be done for Grade ≥2 (solicited symptoms 
only) and grade 3 symptoms, for symptoms considered related to vaccination 
(general symptoms only), for grade 3 symptoms considered related to vaccination 
(general symptoms only) and for symptoms that resulted in a medically-attended 
visit.

Occurrence of fever and related fever will be reported per 0.5°C cumulative 
temperature increments as well as the occurrence of grade 3 fever (> 39.0°C axillary 
temperature) with causal relationship to vaccination.

The verbatim reports of unsolicited AEs will be reviewed by a physician and the 
signs and symptoms will be coded according to MedDRA. Every verbatim term will 
be matched with the appropriate Preferred Term. The percentage of subjects with 
unsolicited AEs occurring within 31-day (Day 0- Day 30) follow-up period after any 
dose with its exact 95% CI [Clopper, 1934] will be tabulated by group, and by 
preferred term. Similar tabulation will be done for unsolicited AEs rated as grade 3, 
for unsolicited AEs with causal relationship to vaccination and AEs/SAEs leading to 
withdrawal from the study.

The percentage of subjects who receive concomitant medication and antipyretic 
medication during the 4-day (Day 0- Day 3) follow-up period and during the entire 
 
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study period will be tabulated (with exact 95% CI [Clopper, 1934]) after the booster 
dose.

Any large injection site reaction (defined as any local swelling with diameter 
> 50 mm and/or any noticeable diffuse injection site swelling (diameter not 
measurable) and/or any noticeable increased circumference of the injected limb)
reported within 4 days (Day 0-Day 3) following the booster dose will be described in 
detail.

Subjects who experience at least one SAE from booster vaccination up to study end 
will be described in detail.

Subjects who report at least one SAE after the end of primary study 201330 [DTPA 
(BOOSTRIX)-048 PRI] and before 201334 [DTPA (BOOSTRIX)-049 BST: 048] 
study will be described in detail.

Withdrawal due to AEs and SAEs following vaccinations will be described in detail.

For the subjects who withdraw from the study after Visit 1 (after completion of 
ASQ-3 questionnaire but have not received booster vaccination), the analysis will be 
performed on the Total enrolled cohort.

Neurodevelopmental status of the subjects will be assessed depending on the ASQ-3 
score. The proportion of subjects in the black zone for any domain, for gross motor 
skills, fine motor skills, communication, problem solving skills and personal-social 
skills will be tabulated. The proportion of infants referred for formal 
neurodevelopmental evaluation using BSID-III and those with at least one indicators 
of neurodevelopmental impairment using BSID-III will also be tabulated. 
10.9.
Interpretation of analyses
All analyses will be conducted in a descriptive manner.
10.10.
Conduct of analyses
Any deviation(s) or change(s) from the original statistical plan outlined in this protocol 
will be described and justified in the final study report.
10.10.1.
Sequence of analyses
The final analyses of all data will be conducted when all data are available. This analysis 
will include the final analysis of immunogenicity and the final analysis of solicited and 
unsolicited symptoms, SAEs and neurodevelopmental status. A statistical report and a 
clinical report will be written at that time.
10.10.2.
Statistical considerations for interim analyses
No interim analysis is planned for this study.
 
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11.
ADMINISTRATIVE MATTERS
To comply with ICH GCP administrative obligations relating to data collection, 
monitoring, archiving data, audits, confidentiality and publications must be fulfilled.
11.1.
electronic Case Report Form instructions
A validated GSK defined electronic data collection tool will be used as the method for 
data collection.
In all cases, subject initials will not be collected nor transmitted to GSK. Subject data 
necessary for analysis and reporting will be entered/transmitted into a validated database 
or data system. Clinical data management will be performed in accordance with 
applicable GSK standards and data cleaning procedures.
While completed eCRFs are reviewed by a GSK Biologicals’ Site Monitor at the study 
site, omissions or inconsistencies detected by subsequent eCRF review may necessitate 
clarification or correction of omissions or inconsistencies with documentation and 
approval by the investigator or appropriately qualified designee. In all cases, the 
investigator remains accountable for the study data.
The investigator will be provided with a CD-ROM 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.
Study Monitoring by GSK Biologicals
GSK will monitor the study to verify that, amongst others, the: 

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol, any other 
study agreements, GCP and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents.
The investigator must ensure provision of reasonable time, space and qualified personnel 
for monitoring visits.
Direct access to all study-site related and source data is mandatory for the purpose of 
monitoring review. The monitor will perform a eCRF review and a Source Document 
Verification (SDV). By SDV we understand verifying eCRF entries by comparing them 
with the source data that will be made available by the investigator for this purpose.
The Source Documentation Agreement Form describes the source data for the different 
data in the eCRF. This document should be completed and signed by the site monitor and 
investigator and should be filed in the monitor’s and investigator’s study file. Any data 
 
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item for which the eCRF will serve as the source must be identified, agreed and 
documented in the source documentation agreement form.
For eCRF, the monitor freezes completed and approved screens at each visit.
Upon completion or premature discontinuation of the study, the monitor will conduct site 
closure activities with the investigator or site staff, as appropriate, in accordance with 
applicable regulations, GCP, and GSK procedures.
11.3.
Record retention
Following closure of the study, the investigator must maintain all site study records 
(except for those required by local regulations to be maintained elsewhere) in a safe and 
secure location. The records must be easily accessible, when needed (e.g., audit or 
inspection), and must be available for review in conjunction with assessment of the 
facility, supporting systems, and staff. Where permitted by applicable laws/regulations or 
institutional policy, some or all of these records can be maintained in a validated format 
other than hard copy (e.g., microfiche, scanned, electronic); however, caution needs to be 
exercised before such action is taken. The investigator must ensure that all reproductions 
are legible and are a true and accurate copy of the original and meet accessibility and 
retrieval standards, including re-generating a hard copy, if required. Furthermore, the 
investigator must ensure that an acceptable back-up of the reproductions exists and that 
there is an acceptable quality control procedure in place for making these reproductions.
GSK will inform the investigator/institution of the time period for retaining these records 
to comply with all applicable regulatory requirements. However, the 
investigator/institution should seek the written approval of the sponsor before proceeding 
with the disposal of these records. The minimum retention time will meet the strictest 
standard applicable to a particular site, as dictated by ICH GCP, any institutional 
requirements, applicable laws or regulations, or GSK standards/procedures.
The investigator/institution must notify GSK of any changes in the archival 
arrangements, including, but not limited to archival at an off-site facility, transfer of 
ownership of the records in the event the investigator leaves the site.
11.4.
Quality assurance
To ensure compliance with GCP and all applicable regulatory requirements, GSK may 
conduct a quality assurance audit. Regulatory agencies may also conduct a regulatory 
inspection of this study. Such audits/inspections can occur at any time during or after 
completion of the study. If an audit or inspection occurs, the investigator and institution 
agree to allow the auditor/inspector direct access to all relevant documents and to allocate 
his/her time and the time of his/her staff to the auditor/inspector to discuss findings and 
any relevant issues.
 
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11.5.
Posting of information on publicly available clinical trial 
registers and publication policy (Amended 12 December 
2016)
GSK assures that the key design elements of this protocol will be posted on the GSK 
website and in publicly accessible database(s) such as clinicaltrials.gov, in compliance 
with the current regulations.
GSK also assures that results of this study will be posted on the GSK website and in 
publicly accessible regulatory registry(ies) within the required time-frame, in 
compliance with the current regulations. The minimal requirement is to have primary 
endpoint summary results disclosed at latest 12 months post primary completion date 
(PCD) and to have secondary endpoint disclosed at latest 12 months after the last 
subject last visit (LSLV) as described in the protocol.
As per EU regulation, summaries of the results of GSK interventional studies (phase I-
IV) in paediatric population conducted in at least one EU member state will be posted 
on publicly available EMA 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.
11.6.
Provision of study results to investigators
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK Biologicals will also provide the investigator with the full summary of the study 
results. The investigator is encouraged to share the summary results with the study 
subjects, as appropriate.
12.
COUNTRY SPECIFIC REQUIREMENTS
Not applicable.
 
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13.
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avoid them. 2014. http://agesandstages.com/free-resources/articles/four-common-asq-
screening-mistakes-avoid/. Accessed: 21 August 2015 
Ages and stages Questionnaires, Third Edition (ASQ-3) Are the children in your program 
on track? 2016. http://www.brookespublishing.com/resource-center/screening-and-
assessment/asq/asq-3/.
Amirthalingam, G. et al. Effectiveness of maternal pertussis vaccination in England:an 
observational study. Lancet. 2014, 384(9953): 1521-28.
Anderson P. The protective levels of serum antibodies to the capsular polysaccharide of 
Haemophilus influenzae type b. J Infect Dis. 1984;149:1034-1035.
Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III). 2006. 
http://www.pearsonclinical.com/childhood/products/100000123/bayley-scales-of-infant-
and-toddler-development-third-edition-bayley-iii.html#tab-details.
Camargo ME, Silveira L, Furuta JA, Oliveira EPT and Germek OA. Immunoenzymatic 
assay of anti-diphtheric toxin antibodies in human serum. J Clin Microbiol. 1984; 20(4): 
772-4.
Canadian Immunisation Guide (Part 4). Pertussis Vaccine. Public Health Agency of 
Canada. 2014. http://www.phac-aspc.gc.ca/publicat/cig-gci/p04-pert-coqu-eng.php. 
Accessed: 21 August 2015.
Center for Disease Control and Prevention (CDC). Hepatitis B virus: A comprehensive 
strategy for eliminating transmission in the United States through universal childhood 
vaccination: Recommendations of the Immunization Practices Advisory Committee 
(ACIP). MMWR. 1991; 40(RR-13): 1–19.
Centers for Disease Control and Prevention (CDC). Pertussis (whopping cough) 
outbreaks. 2013, http://www.cdc.gov/pertussis/outbreaks/trends.html. Accessed: 21 
August 2015.
Center for Disease Control and Prevention (CDC). Final Pertussis Surveillance Report 
2014. Published in 2015. http://www.cdc.gov/pertussis/surv-reporting.html. Accessed: 21 
August 2015
Clopper C J, Pearson E S. The Use Of Confidence Or Fiducial Limits Illustrated In The 
Case Of The Binomial. Biometrika. 1934; 26(4):404-13.
Communicable Disease Control Directorate. Ongoing pertussis epidemic in Western 
Australia. 2011; 16 (1).
 
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Concepcion N and Frasch C. Pneumococcal type 22F polysaccharide absorption 
improves the specificity of a pneumococcal-polysaccharide enzyme-linked 
immunosorbent assay. Clin Diag Lab Immun. 2001; 8: 266-272.
Council on Children with Disabilities; Section on Developmental Behavioral Pediatrics; 
Bright Futures Steering Committee; Medical Home Initiatives for Children With Special 
Needs Project Advisory Committee. Identifying infants and young children with 
developmental disorders in the medical home: an algorithm for developmental 
surveillance and screening. Pediatrics. 2006;118(1):405-420.
Englund JA, Anderson EL, Reed GF et al. The effect of maternal antibody on the 
serologic response and the incidence of adverse reactions after primary immunization 
with acellular and whole-cell pertussis vaccines combined with diphtheria and tetanus 
toxoids. Pediatrics 1995, 96:580–84.
Gall SA, Myers J, Pichichero M. Maternal immunization with tetanus-diphtheria-
pertussis vaccine: effect on maternal and neonatal serum antibody levels. Am J Obstet 
Gynecol. 2011; 204:334.e1–334.e5.
Hardy-Fairbanks AJ, Pan SJ, Kirkland KB et al. Immune Responses in Infants Whose 
Mothers Received Tdap Vaccine During Pregnancy. Pediatr Infec Dis J. 2013; 32: 1257-
60.
Health Protection Report. Confirmed pertussis in England and Wales: data to end-
December 2012. 2013; 7(5).
Joint Committee on Vaccination and Immunization (JCVI). JVCI meeting on pertussis 
immunization: August 2012. Draft minutes of discussions on the immunization of 
pregnant women against pertussis. Published 28 September 2012. 
http://webarchive.nationalarchives.gov.uk/20130402145952/http://media.dh.gov.uk/netw
ork/261/files/2012/09/pertussis-teleconference-minute-to-committee-v4.pdf ; Accessed: 
21 August 2015.
Käyhty H, Peltola H, Karanko V and Makela PH. The protective level of serum 
antibodies to the capsular polysaccharide of Haemophilus influenzae type b. J Infect Dis 
1983;147:1100.
Melville-Smith ME, Seagroatt VA, Watkins JT. A comparison of enzyme-linked 
immunosorbent assay (ELISA) with the toxin neutralisation test in mice as a method for 
the estimation of tetanus antitoxin in human sera. J Biol Stand 1983; 11: 137-44.
Murphy TV, Slade BA, Border KR et al. Prevention of Pertussis, Tetanus, and Diphtheria 
Among Pregnant and Postpartum Women and Their Infants recommendations of the 
Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2008; 
57(RR-4):1-51.
New Zealand Pharmaceutical Management Agency (PHARMAC). Decision to amend the 
diphtheria, pertussis and tetanus vaccine (Boostrix) listing, 12 December 2012. 
http://www.pharmac.govt.nz/2012/12/12/; Accessed: 21 August 2015 .
 
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Plotkin SA. Correlates of protection Induced by Vaccination. Clin Vaccine Immunol. 
2010. 17 (7): 1055. DOI: 10. 1128/CVI.00131-10
Public Health Agency of Canada. Pertussis (whooping cough)-fact sheet. 2012. 
http://www.phac-aspc.gc.ca/id-mi/pertussis-coqueluche-eng.php Accessed: 21 August 
2015.
Quataert SA, Kirch CS, Quackenbush Wiedl LJ, Phipps DC, Strohmeyer, Cimino CO, et 
al. Assignment of weight-based antibody units to a human antipneumococcal standard 
reference serum, lot 89-S. Clin Diag Lab Immunol 1995; 2: 590-597.
Rüggeberg JU, Gold MS, Bayas JM, et al. Anaphylaxis: case definition and guidelines 
for data collection, analysis, and presentation of immunization safety data. Vaccine. 
2007; 25: 5675-84. 
Sizaire V, Garrido-Estepa M, Masa-Calles J, Martinez de Aragon MV. Increase of 
pertussis incidence in 2010 to 2012 after 12 years of low circulation in Spain. Euro 
Surveill 2014; 19(32): 20875. Available online: 
http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20875. Accessed: 21 
August 2015.
Technical Advisory Group (TAG) on Vaccine-preventable Diseases. Vaccination: a 
shared responsibility. Quito, Ecuador 3-5 July 2013.
Warshawsky B. NACI update on pertussis vaccination in pregnancy. Can Fam Physician. 
2014; 60(6): 521.
World Health Organisation (WHO). Standard Procedure for Determining Immunity to 
Poliovirus using the Microneutralisation Test (WHO/EPI/GEN 93.9) 1993.
 
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APPENDIX A
CLINICAL LABORATORIES
Table 18
GSK Biologicals’ laboratories
Laboratory
Address
GSK Biologicals Clinical Laboratory 
Sciences (CLS), Rixensart
Biospecimen Reception-B7/44
Rue de l'Institut, 89 -B-1330 Rixensart-Belgium
GSK Biologicals CLS, Wavre-Nord 
Noir Epine
Avenue Fleming, 20-B-1300 Wavre-Belgium
Table 19
Outsourced laboratories
(Amended 12 December 2016)
Laboratory
Address
NÉOMED-LABS Inc.
525, Cartier Ouest Laval, Quebec Canada H7V 
3S8
Q² Solutions Limited (UK)
The Alba Campus
Rosebank
Livingston
West Lothian, EH54 7EG
Scotland,
UK
Q² Solutions Nichols Institute
33608 Ortega Highway 
San Juan Capistrano,
CA 92675-2042
USA
CEVAC-University of Gent
De Pintelaan, 185 Gent
Belgium
 
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APPENDIX B
AMENDMENTS AND ADMINISTRATIVE CHANGES 
TO THE PROTOCOL
GlaxoSmithKline Biologicals SA
Vaccines R &D
Protocol Amendment 1
eTrack study number 
and Abbreviated Title
201334 [DTPA (BOOSTRIX)-049 BST: 048]
EudraCT number
2014-001120-30
Amendment number:
Amendment 1 
Amendment date:
12 December 2016
Co-ordinating author:
, Lead Scientific Writer
Rationale/background for changes: 
Given the fact that only infants born from mothers vaccinated in the study (116945 
[DTPA (BOOSTRIX)-047) and vaccinated in the previous study 201330 [DTPA 
(BOOSTRIX)-048 PRI] can be enrolled in the current study, the enrolment in these 
studies has an impact on this current study (e.g. cohorts to be investigated). Initially, 
the DTPA (BOOSTRIX)-047 and DTPA (BOOSTRIX)-048 PRI studies were opened 
only in countries using 3-dose primary vaccination series plus a booster vaccination at 
12 to 18 months of age against diphtheria, tetanus and pertussis in infants. 
Nevertheless, the 2-dose primary vaccination schedule with a booster vaccination at 11 
to 13 months of age in infants is also meaningful for different regions in the world (e.g. 
Europe). It was therefore decided to open the DTPA (BOOSTRIX)-047 and DTPA 
(BOOSTRIX)-048 PRI, and therefore the current booster study to countries using 2-
dose primary vaccination series with a booster vaccination at 11 to 13 months of age 
with the aim to increase the scientific value of the study and generate clinical data in 
diverse infant vaccination schedules. This protocol is amended to include the 
possibility to administered the booster vaccine dose at 11 to 13 months of age, in 
addition to the 12 to 18 months of age initially planned.
The notion of end of study was clarified and the Section 11.5 describing the posting of 
information on public registry was revised accordingly.
An inclusion criterion was updated to specify that only infant having received the full 
vaccination series as per protocol requirement in the study DTPA (BOOSTRIX)-048 
PRI can be enrolled in the current study (and not only infant born from mother 
vaccinated in the DTPA (BOOSTRIX)-047).
Following a request from the Czech Republic, the phone call at 18 months may be 
replaced by a clinic visit if deemed preferable by the study team.
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The vaccination sites were updated to allow vaccination either in the thigh or deltoid, 
according to the national recommendation, to comply with the Australian 
recommendations.
The names and functions of the contributing authors have been updated. In addition, 
minor updates including typos, abbreviations, clarifications of wording were done 
throughout the document.
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections:
Contributing authors: The following changes have been made:
!
, Clinical and Epidemiology Project Leader (CEPL) 
!
, Clinical Research and Development Lead (CRDL)
!
and 
, Clinical Research and Development Lead 
(Project-Level CRDL)
!
, Project Statistician
!
 and 
, Study Delivery Lead
!
, 
 , Clinical Laboratory Sciences (CLS) Clinical 
Read-Out Team Leader
!
, CLS Study Manager
!
 and 
, Global Clinical Regulatory Affairs
Representative
!
, 
, 
and 
, Clinical 
Safety Representatives
!
, Global Patents Representative
!
, Study Data Manager
!
, 
, Oversight data Manager Portfolio Data Manager
!
 and 
, Senior Manager, Biometrics
!
 and 
, Vaccines Supply Coordinator
!
, Director, Global Medical Affairs
!
, Study Delivery Manager
!
and 
, Local Delivery Lead, Australia
!
 and 
, Local Delivery Lead, Canada 
!
 and 
, Local Delivery Lead, 
Spain
!
 and 
, Local Delivery Lead, Czech Republic
!
, Director/Local Medical Lead, Czech Republic
!
, Local Delivery Lead, Finland
!
 and 
, Local Delivery Leads, Italy
Synopsis: Rationale for the study
The present study will be performed to study the immunogenicity and safety of the 
booster dose of Infanrix hexa in infants who were born to mothers vaccinated with 
Boostrix during pregnancy or immediately post-delivery and who completed their 
primary vaccination series as per protocol requirement in study DTPA (BOOSTRIX)-
048 PRI.
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PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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Synopsis: Rationale for the study design
This phase IV study is a follow-up of the study 201330 [DTPA (BOOSTRIX)-048 PRI].
The immunogenicity and safety of Infanrix hexa when given as a booster dose according 
to the routine national/ local immunization schedule or as specified in the SPM will be 
evaluated. Subjects will receive Prevenar 13 according to the routine national/ local 
immunization schedule or as specified in the SPM as a co-administered vaccine in this 
study.
This study will have two groups:

dTpa Group: This group will consist of infants born to mothers belonging to the 
dTpa Group in study 116945 [DTPA (BOOSTRIX)-047], i.e., mothers who received 
a single dose of Boostrix during pregnancy and a dose of placebo immediately post-
delivery and infants who participated in the received full primary vaccination course 
as per protocol requirement in the study 201330 [DTPA (BOOSTRIX)-048 PRI]. 
All infants in this group will receive a booster dose of Infanrix hexa co-administered 
with Prevenar 13 according to the routine national/ local immunization schedule 
or as specified in the SPM.

Control Group: This group will consist of infants born to mothers belonging to the 
Control group in study 116945 [DTPA (BOOSTRIX)-047], i.e., mothers who 
received a single dose of placebo during pregnancy and a dose of Boostrix
immediately post-delivery and infants who participated in the received full primary 
vaccination course as per protocol requirement in the study 201330 [DTPA 
(BOOSTRIX)-048 PRI]. All infants in this group will receive a booster dose of 
Infanrix hexa co-administered with Prevenar 13 according to the routine national/ 
local immunization schedule or as specified in the SPM.
The study will be open-label since the treatment allocation is similar between the two 
groups. Also, the data related to the study groups will be unblinded at the end of study 
116945 [DTPA (BOOSTRIX)-047].
Currently, the effect of Boostrix administered to mothers during pregnancy or 
immediately post-delivery on the neurodevelopment of infants is unknown. Therefore, 
the neurodevelopment of the subjects will be studied at 9 months and 18 months of age in 
this study. To assess for the neurodevelopmental status, the investigator or designate 
subject’s parent(s)/legally acceptable representatives [LAR(s)] will be asked to complete
a standardised developmental screening tool, Ages and Stages Questionnaire-3 (ASQ-3) 
via a paper questionnaire with subjects’ parent(s)/LAR(s) during the study visits or 
phone call and submit it to the centralised research coordinating centre or the site where 
the study will be conducted [ASQ-3, 2016].
Synopsis: Study design

Experimental design: Phase IV, open-label, non-randomised, uncontrolled multi-
centric, multi-country study with two parallel groups.

Duration of the study: The intended duration of the study, is approximately 9 to 10 
months, per subject.
 
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
Epoch 001: Booster phase starting at Visit 1 (9 months of age) and ending at 
telephone contact orVisit 3 or18 months of age) Visit 3 (13 18 or19 months of 
age), depending on the time of vaccination.

End of Study (EoS): Last testing results released of samples collected at Visit 3.

Study groups: The study groups and epoch foreseen in the study are presented in 
Synopsis Table 1.

dTpa Group: This group will consist of infants born to mothers belonging to the 
dTpa Group in study 116945 [DTPA (BOOSTRIX)-047] i.e., mothers who 
received a single dose of Boostrix during pregnancy and a dose of placebo 
immediately post-delivery and infants who participated in the received full 
primary vaccination course in the study 201330 [DTPA (BOOSTRIX)-048 PRI]. 
All subjects in this group will receive a booster dose of Infanrix hexa co-
administered with Prevenar 13 according to the routine national/ local 
immunization schedule or as specified in the SPM.

Control Group: This group will consist of infants born to mothers belonging to 
the Control group in study 116945 [DTPA (BOOSTRIX)-047] i.e., mothers who 
received a single dose of placebo during pregnancy and a dose of Boostrix
immediately post-delivery and infants who participated in the received full
primary vaccination course in the study 201330 [DTPA (BOOSTRIX)-048 PRI]. 
All subjects in this group will receive a booster dose of Infanrix hexa co-
administered with Prevenar 13 according to the routine national/ local 
immunization schedule or as specified in the SPM.
Synopsis Table 1: Study groups and epoch foreseen in the study
Study Groups
Number of 
subjects*
Age (Min – Max)**
Epochs
Epoch 001
dTpa Group
340
11 12 months- 18 19 months
x
Control Group
340
11 12 months-18 19 months
x
*A maximum number of subjects
**Age at the time of vaccination depending on the routine national/ local immunization schedule or as specified 
in the SPM
Synopsis Table 2: Study groups and treatment foreseen in the study
Treatment name
Vaccine name
Study Groups
dTpa Group
Control Group
Infanrix hexa 
DTPa-DTPA-HBV-
IPV
X
x
Hib
X
x
Prevenar 13 
Prevenar 13
X
x

Control: uncontrolled (No active control or placebo. All subjects will receive the 
same vaccine)

Vaccination schedule: All subjects will receive a booster dose of Infanrix hexa co-
administered with Prevenar 13 between 11 12-18 months of age according to the 
routine national/ local immunization schedule or as specified in the SPM. 
 
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
Blinding: Open-label.
Note: The study personnel operating SBIR and the site staff will remain blinded 
towards the treatment allocation of the mother in this study until the completion and 
unblinding of study 116945 [DTPA (BOOSTRIX)-047] , study 201330 [DTPA 
(BOOSTRIX)-048 PRI] and this study.

Safety monitoring: An independent data monitoring committee (IDMC) (including 
paediatricians and a statistician) will be put in place to oversee the safety aspects 
including neurodevelopmental status of infants born to mothers vaccinated with 
Boostrix during pregnancy or immediately post-delivery in the clinical study i.e., 
each SAE/incidence of grade 3 local and general solicited adverse events (AEs), 
unsolicited AEs will be reviewed by this committee as per approved IDMC charter.
List of abbreviations
CRDL:
Clinical Research and Development Lead
EL.U/mL:
ELISA Unit per milliter
EoS:
End of Study
EPAR:
European public assessment report 
GCP:
Good Clinical Practice
HHE:
Hypotonic-Hyporesponsiveness Episode
Hib:
Haemophilus influenzae type b
HIV:
Human Immunodeficiency Virus
HRV: 
Human Rotavirus Vaccine
IB:
Investigator Brochure
ICF:
Informed Consent Form
ICH:
International Conference on Harmonization
IEC:
Independent Ethics Committee
IgG/ IgM:
Immunoglobulin G/ M
IM:
Intramuscular
IMP:
Investigational Medicinal Products
IRB:
Institutional Review Board
JCVI:
Joint Committee on Vaccination and Immunization
 
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LL:
Lower Limit
LSLV:
Last Subject Last Visit
PI:
Product Information
RCC:
Reverse Cumulative Curve
RDE:
Remote Data Entry
RSI:
Reference Safety Safety Information
SDV:
Source Document Verification
SIDS:
Sudden Infant Death Syndrome
SPC:
Summary of Product characteristics
SPM:
Study Procedure Manual
SRT:
Safety Review Team
(e)TDF:
(electronic) Temperature Excursion decision Form
UK:
United Kingdom
UL:
Upper Limit
Glossary of terms
End of Study: 
(Synonym of End of 
Trial)
For studies without collection of human biologicals 
samples or imaging data EoS is the Last Subject Last 
Visit (LSLV).
For studies with collection of Human Biologicals 
Samples or imaging data, EoS is defined as the date of 
the last testing/reading released of the Human 
Biological Samples or imaging data, related to primary 
and secondary endpoints. EoS must be achieved no later 
than 8 months after LSLV
Trademarks
Trademarks not owned by the GlaxoSmithKline 
group of companies
Generic description
Prevenar 13® (Wyeth Pharmaceuticals Inc.; 
Marketed by Pfizer Inc. or Wyeth LLC, owner/Pfizer 
Canada Inc., Licensee)
Pneumococcal  Pneumoccocal 13-valent conjugate 
vaccine (diphtheria CRM197 protein)
 
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Section 1.1. Background
The incidence again was highest in infants younger than one year of age and all of nine 
deaths due to pertussis occurred in unvaccinated infants three months of age and younger 
[Centers for Disease Control and Prevention (CDC), 2015; CDC, 2013].
1.2.1 Rationale for the study
All infants born to pregnant women who participated in study 116945 [DTPA 
(BOOSTRIX)-047] will be followed-up to study the immunogenicity and safety of 
GlaxoSmithKline (GSK) Biologicals’ combined diphtheria-tetanus-acellular pertussis-
hepatitis B-inactivated poliovirus and Haemophilus influenzae type b vaccine (DTPa-
HBV-IPV/Hib), Infanrix hexa, given as primary and booster vaccination.  Study 201330 
[DTPA (BOOSTRIX)-048 PRI] will be conducted to assess the immunogenicity and 
safety of Infanrix hexa co-administered with Prevenar 13 as the primary vaccination 
course.
The present study will be performed to study the immunogenicity and safety of the 
booster dose of Infanrix hexa in infants who were born to mothers vaccinated with 
Boostrix during pregnancy or immediately post-delivery and who completed their 
primary vaccination series in study DTPA (BOOSTRIX)-048 PRI..
1.2.2. Rationale for the study design
This phase IV study is a follow-up of the study 201330 [DTPA (BOOSTRIX)-048 PRI] 
where infants in both the groups received Infanrix hexa co-administered with Prevenar 
13 as part of the primary vaccination series. The immunogenicity and safety of Infanrix 
hexa when given as a booster dose according to the routine national/ local 
immunization schedule or as specified in the SPM will be evaluated. Subjects will 
receive Prevenar 13 according to the routine national/ local immunization schedule or 
as specified in the SPM as a co-administered vaccine in this study.
This study will have two groups: 

dTpa Group: This group will consist of infants born to mothers belonging to the 
dTpa Group in study 116945 [DTPA (BOOSTRIX)-047], i.e., mothers who received 
a single dose of Boostrix during pregnancy and a dose of placebo immediately post-
delivery and infants who participated in the received full primary vaccination course
as per protocol requirement in the study 201330 [DTPA (BOOSTRIX)-048 PRI]. 
All infants in this group will receive a booster dose of Infanrix hexa co-administered 
with Prevenar 13 according to the routine national/ local immunization schedule 
or as specified in the SPM.

Control Group: This group will consist of infants born to mothers belonging to the 
Control group in study 116945 [DTPA (BOOSTRIX)-047], i.e., mothers who 
received a single dose of placebo during pregnancy and a dose of Boostrix
immediately post-delivery and infants who participated in the received full primary 
vaccination course as per protocol requirement in the study 201330 [DTPA 
(BOOSTRIX)-048 PRI]. All infants in this group will receive a booster dose of 
 
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Infanrix hexa co-administered with Prevenar 13 according to the routine national/ 
local immunization schedule or as specified in the SPM.
Currently, the effect of Boostrix administered to mothers during pregnancy or 
immediately post-delivery on the neurodevelopment of infants is unknown. Therefore, 
the neurodevelopment of the subjects will be studied at 9 months and 18 months of age in 
this study. To assess for the neurodevelopmental status, the investigator or designate
subject’s parent(s)/legally acceptable representatives [LAR(s)] will be asked to complete
a standardised developmental screening tool, Ages and Stages Questionnaire-3 (ASQ-3) 
via a paper questionnaire with subjects’ parent(s)/LAR(s) during the study visits or 
phone call and submit it to the centralised research coordinating centre or the site where 
the study will be conducted [ASQ-3, 2016].
1.3. Benefit: Risk assessment
Please refer to the current Investigator Brochure (IB) for the summary of potential risks 
and benefits of Infanrix hexa.
1.3.1. Risk assessment
Important Potential/Identified 
Risk
Data/Rationale for Risk
Mitigation Strategy
Investigational study vaccine Infanrix hexa
Temperature of ≥ 40.0C within 
48 hours, not due to another 
identifiable cause
As outlined in the Infanrix 
hexa Reference Safety 
Information (RSI) from clinical 
trials and post-marketing safety 
data, this adverse event 
(AE)/serious adverse event (SAE) 
is recognized as well-characterized 
identified risks for Infanrix hexa.
Subjects’ parents/LAR(s) should report 
any untoward symptoms experienced
by the infant after receiving the vaccine 
immediately to the investigator.
Other (Prevenar 13)
Temperature of ≥ 40.0C within 
48 hours, not due to another 
identifiable cause
As outlined in Prevenar 13
European public assessment report 
(EPAR), increased fever rates were 
observed when Prevenar 13 was 
co-administered with Infanrix hexa.
Subjects’ parents/legally acceptable 
representative(s) [LAR(s) should report 
any untoward symptoms experienced 
by the infant after receiving the vaccine 
immediately to the investigator.
1.3.2. Benefit assessment
Diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis and Haemophilus influenzae type 
b (Hib) are common causes of diseases in children worldwide, with significant morbidity 
and mortality. A dramatic decline in the incidence of diphtheria, tetanus, pertussis, 
hepatitis B, poliomyelitis and Hib has been evidenced in countries in which infants are 
routinely immunised against these diseases. By receiving the Infanrix hexa vaccine, the 
subjects may be protected against the above mentioned diseases. In addition, the subjects 
will undergo a history directed  physical examination at Visit 2 before booster 
vaccination. In case the study doctor discovers any medical condition, the subject will be 
referred to the local healthcare system. The vaccine and study related tests will be 
provided free of cost to the subjects.
 
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3. Study design overview
N: Maximum Number of subjects planned to be enrolled; Mo: Age in Months
*The neurodevelopmental status will be recorded when the subject is 9 months and 18 months of age. It is encouraged 
that subjects who are getting vaccinated at 18 months of age at Visit 2 or coming for Visit 3, complete their ASQ-3 
during their visit to the study centre. In case subjects complete Visit 3 before 18 months of age, the study staff will 
contact the parents/LAR(s) via phone and conduct an interview to complete the child’s ASQ-3 at 18 months of age. For 
Czech Republic, the phone call at 18 months may be replaced by a clinic visit if deemed preferable by the 
study team.
** Subjects have received either 2 or 3 doses of Infanrix hexa and Prevnar during the course of the study DTPA 
(Boostrix)-048, depending on the national/ local routine immunization schedule.
Refer to Section 5.6.2.13 for further details. 
Pre-Bst: Blood sample to be collected before the booster dose.
Post-Bst: Blood sample to be collected one month after the booster dose.

Experimental design: Phase IV, open-label, non-randomised, uncontrolled, multi-
centric, multi-country study with two parallel groups.

Duration of the study: The intended duration of the study, is approximately 9 to 10 
months, per subject.

Epoch 001: Booster phase starting at Visit 1 (9 months of age) and ending at 
telephone contact ( 18 months of age) or at Visit 3 (18 or 19 months of age)
(13-19 months of age), depending on the time of vaccination

End of Study (EoS): Last testing results released of samples collected at Visit 3.

Study groups: The study groups and epoch foreseen in the study are presented in 
Table 1.
Infanrix hexa
Prevenar 13
Infanrix hexa
Prevenar 13
Infanrix hexa
Prevenar 13**
dTpa Group (N =340)
Control Group (N =340)
Infanrix hexa
Prevenar 13
Infanrix hexa
Prevenar 13
Infanrix hexa
Prevenar 13**
Infanrix hexa
Prevenar 13
Infanrix hexa
Prevenar 13
Visit 1*
Visit 3
Day 0
Month 1
Pre-Bst
Post-Bst
Visits
Time-points
Blood sample:
dTpa Group (N =340)
Control Group (N =340)
Study 201330 [DTPA (BOOSTRIX)-048]
Epoch 001
Study 201334 [DTPA 
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11-18 Mo 12-19 Mo
9 Mo
Boostrix
dTpa Group (N = 340)
Control Group (N = 340)
Study 116945 [DTPA 
(BOOSTRIX)-047]
Boostrix
Placebo
Placebo
Randomisation (1:1)
Visit  2
TC*
18 Mo
 
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
dTpa Group: This group will consist of infants born to mothers belonging to the 
dTpa Group in study 116945 [DTPA (BOOSTRIX)-047] i.e., mothers who 
received a single dose of Boostrix during pregnancy and a dose of placebo 
immediately post-delivery and infants who participated in the received full
primary vaccination course as per protocol requirement in the study 201330 
[DTPA (BOOSTRIX)-048 PRI]. All subjects in this group will receive a booster 
dose of Infanrix hexa co-administered with Prevenar 13 according to the 
routine national/ local immunization schedule or as specified in the SPM.

Control Group: This group will consist of infants born to mothers belonging to 
the Control group in study 116945 [DTPA (BOOSTRIX)-047] i.e., mothers who 
received a single dose of placebo during pregnancy and a dose of Boostrix
immediately post-delivery and infants who participated in the received full
primary vaccination course as per protocol requirement in the study 201330 
[DTPA (BOOSTRIX)-048 PRI]. All subjects in this group will receive a booster 
dose of Infanrix hexa co-administered with Prevenar 13 according to the 
routine national/ local immunization schedule or as specified in the SPM. 
Table 1: Study groups and epoch foreseen in the study
Study groups
Number of 
subjects*
Age (Min/Max)**
Epoch
Epoch 001
dTpa Group
340
11 12 months-18 19 months
x
Control Group
340
11 12 months-18 19 months
x
*Maximum number of subjects
**Age at the time of vaccination depending on routine national/ local immunization schedule or as specified in 
the SPM
The study groups and treatment foreseen in the study is presented in Table 2.
Table 2: Study groups and treatment foreseen in the study
Treatment name
Vaccine name
Study Groups
dTpa Group
Control Group
Infanrix hexa 
DTP aDTPA-HBV-IPV
x
x
Hib
x
x
Prevenar 13 
Prevenar 13
x
x

Control: uncontrolled (No active control or placebo. All subjects will receive the 
same vaccine)

Vaccination schedule: All subjects will receive a booster dose of Infanrix hexa co-
administered with Prevenar 13 between 1112-18 months of age according to the 
routine national/ local immunization schedule or as specified in the SPM. 

Blinding: Open-label. Note: The study personnel operating GSK Biologicals’ central 
Randomisation System on Internet (SBIR) and the site staff will remain blinded 
towards the treatment allocation of the mother in this study until the completion and 
unblinding of study 116945 [DTPA (BOOSTRIX)-047], study 201330 [DTPA 
(BOOSTRIX)-048 PRI] and this study.
 
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
Safety monitoring: An independent data monitoring committee (IDMC) (including 
paediatricians and a statistician) will be put in place to oversee the safety aspects 
including neurodevelopmental status of infants born to mothers vaccinated with 
Boostrix during pregnancy or immediately post-delivery in the clinical study i.e., 
each SAE/incidence of grade 3 local and general solicited AEs, unsolicited AEs will 
be reviewed by this committee as per approved IDMC charter. 
4.1. Number of subjects/ centres
A maximum of 680 infants aged 9 months will be enrolled in this study. Blood samples 
will be taken from all subjects in order to evaluate the immunogenicity endpoints. The 
tracking of recruitment of subjects into the study will be performed using GSK 
Biologicals’ central randomisation system on Internet (SBIR).
Overview of the recruitment plan:

Enrolment will be offered to all eligible infants born to mothers from the 116945 
[DTPA (BOOSTRIX)-047] study and having completed their primary vaccination 
series as per protocol requirement in study 201330 [DTPA (BOOSTRIX)-048 PRI].
4.2. Inclusion criteria

Subjects born to mothers who were vaccinated in 116945 [DTPA (BOOSTRIX)-
047] study and having completed their primary vaccination series as per protocol 
requirement in study 201330 [DTPA (BOOSTRIX)-048 PRI].
5.1. Regulatory and ethical considerations, including the informed consent process
The study will be conducted in accordance with the International Conference on 
Harmonization (ICH) Guideline for Good Clinical Practice (GCP), all applicable subject 
privacy requirements and the guiding principles of the Declaration of Helsinki. 
5.2.1. Subject identification
Subjects will retain the same subject number as their mothers in the 116945 [DTPA 
(BOOSTRIX)-047] study and their own subject number in study 201330 [DTPA 
(BOOSTRIX)-048 PRI]. These subject numbers will also be used to identify blood 
samples collected in the study.
5.2.2.1. Treatment allocation to the subject
There will be no randomisation of subjects into groups in this study. The infants enrolled 
in this study will be allocated to the same groups as their mothers in the 116945 [DTPA 
(BOOSTRIX)-047] study and as themselves in study 201330 [DTPA (BOOSTRIX)-048 
PRI]. Subjects will retain the same subject number as their corresponding mothers from 
the 116945 [DTPA (BOOSTRIX)-047] study.
5.2.2.1.1. Study group and treatment number allocation
After obtaining the signed and dated ICF from the subject’s parent(s)/LAR(s) and having 
checked the eligibility of the subject, investigator or designate will complete a 
 
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standardised developmental screening tool, Ages and Stages Questionnaire-3 via a 
paper questionnaire (at Visit 1) with subjects’ parent(s)/LAR(s) will complete a 
standardised developmental screening tool, Ages and Stages Questionnaire-3 via a paper 
questionnaire (at Visit 1) at the study site. At Visit 2, the site staff in charge of the 
vaccine administration will access SBIR. Upon providing the subject identification 
number, the randomisation system will provide the treatment number to be used for the 
dose vaccination.
5.3. Method of blinding
Note: The study personnel operating SBIR and the site staff will remain blinded towards 
the treatment allocation of the mother in study 116945 [DTPA (BOOSTRIX)-047] in this 
study until the completion and unblinding of study 116945 [DTPA (BOOSTRIX)-047], 
study 201330 [DTPA (BOOSTRIX)-048 PRI] and this study to prevent the potential 
unblinding of the treatment allocation to the mother in 116945 [DTPA (BOOSTRIX)-
047].
5.4.1. Independent Data Monitoring Committee
An IDMC will oversee the safety of infants born to mothers who were vaccinated with 
Boostrix during pregnancy or immediately post-delivery in the clinical study 116945 
[DTPA (BOOSTRIX)-047], infants who received primary vaccination series of Infanrix 
hexa and Prevenar13 as per protocol requirement in the study 201330 [DTPA 
(BOOSTRIX)-048 PRI] and booster vaccination in 201334 [DTPA (BOOSTRIX)-049 
BST: 048] study.
To facilitate the review, the IDMC will be provided with all relevant safety data 
including data on each SAE, /incidence of grade 3 local and general solicited AEs, 
unsolicited AEs and neurodevelopmental status of infants born to mothers vaccinated 
with Boostrix during pregnancy or immediately post-delivery at specified times and 
access to data on request by an unblinded statistician. The frequency of the meeting will 
be decided and documented in the IDMC charter
The operating rules of the IDMC are will be documented in a charter.
5.4.2. Responsabilities
The overall responsibility of the IDMC is to protect the ethical and safety interests of 
patients subjects recruited into this study while protecting as far as possible the scientific 
validity of the data. 
The details of the IDMC’s responsibilities and conduct of meetings will be provided in 
the IDMC cCharter. The IDMC charter will also clearly state who will conduct the 
statistical analysis (ICH E9). Key responsibilities of the IDMC are the following:

The IDMC will be informed of any amendment to the initial protocol

The IDMC will review the unblinded safety data from the study (i.e., each 
SAE/incidence of, grade 3 local and general solicited AEs , unsolicited AEs and 
neurodevelopmental status), provide GSK Biologicals with indications on safety 
 
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profiles and make recommendations for consultation of regulatory authorities and on 
further study conduct.
5.4.3. Composition of the IDMC
IDMC members will not participate in the study, neither as principal or co-investigators 
nor as study patient subject care physicians. They can also not provide medical care to a 
patient subject enrolled in the study. The IDMC will include medically qualified experts 
in the field under study (paediatrician and a biostatistician). The person specifically 
selected to chair the IDMC will be required not only to have appropriate training for the 
study but also to have experience serving on one or more IDMCs. The IDMC also may 
convene an ad-hoc meeting should it deem necessary for review of specific cases/safety 
concerns.
5.4.4. GSK Biologicals’ safety review team
At GSK Biologicals, a Safety Review Team (SRT) will include, including the Central 
Safety Physician and Safety Scientist, the Clinical Research and development Lead 
(CRDL) and Biostatistician of the project as well as Epidemiology and Regulatory 
representatives. The SRT, as core members and the IDMC will be responsible for 
reviewing the blinded safety data related to the investigational product in this study and 
due to Boostrix vaccine as received by the mother in 116945 [DTPA (BOOSTRIX)-047] 
study. The SRT review will be done on a regular basis to identify any potential safety 
issues or signals in order to evaluate and agree on action plans, if necessary.
The IDMC will provide recommendation to the sponsor via the GSK Safety Review 
Team which will be shared with the investigators.
5.5. Outline of study procedures
Table 4 List of study procedures
Age 
9 months
1112-18 
months 
1213-19 
months
18 months ** 
Epoch 
Epoch 001
Type of contact
Visit 1
Visit 2
Visit 3
Phone contact *
Time points
Day 0
Months -2 to -9
Months 3 to 
9
Day 0 **
Months 4 to 
10
Month 1 **
9 Months
Day 0 to Month7 **
Sampling time points
Pre-Bst
Post-Bst
Physical examination  
O 
Recording of solicited adverse events (Day 0-
Day 3) post-vaccination by subjects’ 
parent(s)/LAR(s) in the diary card
●
* For Czech Republic, the phone call at 18 months may be replaced by a clinic visit if deemed preferable by the 
study team.
** The neurodevelopmental status will be recorded when the subject is 9 and 18 months of age.  It is encouraged that 
subjects who are getting vaccinated at 18 months of age at Visit 2 or coming for Visit 3, complete their ASQ-3 during 
their visit to the study centre. In case subjects complete Visit 3 before 18 months of age, the study staff will contact the 
parents/LAR(s) via phone and conduct an interview to complete the child’s ASQ-3 at 18 months of age. If the subject is 
referred to a developmental specialist for formal assessment, then this information needs to be recorded in the eCRF. 
Also, the overall assessment of delay by the specialist should be recorded in the eCRF.
§ History of all medications given to the infants after the end of 201330 [DTPA (BOOSTRIX)-048 PRI] until enrolment in 
this study will be recorded in the eCRF at Visit 1 and updated at Visit 2 for all new information
 
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Table 5: Intervals between study visits
Interval
Optimal length of interval 1
Allowed interval 2
BirthVisit 1
9 months old
9 months old* +30 days
Visit 1Visit 2
2 3-10 9 months **
2 3-10 months 
Visit 2 Visit 3
30 days
21-48 days
Phone contact
18 months old
18 months old* 30 days
1 Whenever possible the investigator should arrange study visits within this interval.
2 Subjects will not be eligible for inclusion in the ATP cohort for analysis of immunogenicity if they make the study visit 
outside this interval.
* The allowed interval for Visit 1 and Phone contact is calculated depending on the official recommendation for 
age for completion of the ASQ-3 questionnaire (9 months and 0 days through 9 months and 30 days and 17 
months and 0 days through 18 months of age and 30 days). In case subjects who were born prematurely by three 
or more weeks are enrolled, prematurity adjustment needs to be performed for the 9th and 18th month ASQ-3 
questionnaire completion. Refer to Section 5.6.2.13 and SPM for more details.
** The intervals required in the table are the minimum and maximum intervals for the study and the allowed 
intervals for inclusion in the ATP cohort will correspond to approximately 30 days before or after the time 
window corresponding to the national/ local immunization schedule or as specified in the SPM
If subjects return for the visits Visit 3 prior to 30 days, the parent(s)/LAR(s) should take home the diary card and 
continue to record unsolicited safety information until 30 days post-vaccination and mail/send it upon completion.
Investigators will make an attempt to retrieve diary cards from subjects’ parent(s)/LAR(s) who have not mailed/sent 
them in.
5.6.1.1. Informed consent
At the end of the primary vaccination series study, 201330 [DTPA (BOOSTRIX)-048 
PRI], parent(s)/LAR(s) will be informed about this booster follow-up study [DTPA 
(BOOSTRIX)-049 BST: 048] in which their infants will receive a booster dose of the 
study vaccines. When the subject is approximately 9 months of age, the investigator or 
designee subject’s parent(s)/legally acceptable representatives [LAR(s)] will be asked to
complete a standardised developmental screening tool, Ages and Stages Questionnaire-3 
(ASQ-3) via a paper questionnaire with subjects’ parent(s)/LAR(s) during the  (at Visit 
1) at the study site. 
5.6.2.2. Collect demographic data and vital signs
Record demographic data such as the full date of birth (age in months and race, length 
[cm], weight [kg] and head circumference [in (cm)]) in the subject’s eCRF at Visit 2. 
5.6.2.3. Medical history
Obtain the subject’s medical history by interview and/or review of the subject’s medical 
records and record in the eCRF any pre-existing conditions or signs and/or symptoms 
present in a subject prior to the study vaccination in the eCRF at Visit 1 and update with 
all new information at Visit 2.
All events that occur after the end of primary study 201330 [DTPA (BOOSTRIX)-048 
PRI] until enrolment in 201334 [DTPA (BOOSTRIX)-049 BST: 048] study and are not 
reported to the investigator will be recorded as part of the subject’s medical history and 
will be analysed in this study.
 
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5.6.2.4. Medication and vaccination history
Obtain the subject’s medication and vaccination history by interview and/or review of the 
subject’s medical records and record in the eCRF any medication and vaccine 
administration prior to the study vaccination in the eCRF at Visits 1 and update with all 
new information at Visit 2.
5.6.2.5. Physical examination
Perform a physical examination (including vital signs) prior to vaccination (Visit 2). The 
extend of the physical examination to be performed are as per investigator or delegate 
discretion to determine if the subject is healthy. 
If it is determined determines that that the subject’s health on the day of vaccination
temporarily precludes vaccination, the visit will be rescheduled. Collected information 
needs to be recorded in the eCRF.
5.6.2.8. Record body length, weight and head circumference
Record body weight (kg), height (cm) and head circumference (cm) of the subject at 
Visit 2 in the eCRF.
5.6.2.11 Study vaccines administration
After completing all prerequisite procedures prior to vaccination, a booster dose of study 
vaccines will be administered intramuscularly (IM) either in the thigh or in the deltoid, 
according to the national recommendation /local practice .
5.6.2.13. Assessment of neurodevelopmental status
The ASQ-3 will be completed by the investigator or designee with the parent(s)/LAR(s) 
during the study visits or phone call when the subject is 9 and 18 months of age, via a 
paper questionnaire and submitted to the centralised research coordinating centre or the 
site where the study will be conducted*. These time- points comply with the 
recommended developmental screening assessment guidelines from the American 
Academy of Pediatrics [Council on Children with Disabilities, 2006]. The investigator or 
designee may discuss the results with the parents if deemded necessary.
The ASQ-3 has narrow age intervals (9 months and 0 days through 9 months and 30 
days and 17 months and 0 days through 18 months of age and 30 days), so age must be 
calculated to the month and day from the date the ASQ-3 will be completed (i.e., at 9 
months  and 18 months of age).
*Note: It is encouraged that the parent(s)/LAR(s) of the subject complete the ASQ-3 
during their visit to the study centre at Visit 2 or Visit 3. In case the subject completes 
Visit 3 before 18 months of age, the study staff will contact the parents/LAR(s) via phone 
to conduct an interview to complete the child’s ASQ-3 at 18 months of age. For Czech 
Republic, the phone call at 18 Months may be replaced by a clinic visit if deemed 
preferable by the study team.
 
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5.6.2.14. Recording of AEs and SAEs

Any unreturned diary cards will be sought from the subject’s parent(s)/LAR(s) 
through telephone call(s) or any other convenient procedure. The investigator/ 
designee will transcribe the collected information into the eCRF in English. 
5.7. Biological sample handling and analysis
Please refer to the SPM and laboratory manual for details on biospecimen management 
(handling, storage and shipment).
5.7.1. Use of specified study materials
The use of other materials could result in the exclusion of the subject from the 
According-to-Protocol (ATP) analysis (See Section 10.4 for the definition of cohorts to 
be analysed).
 
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5.7.3. Laboratory assays
Table 7 Humoral immunity (antibody determination)
System
Component
Method
Kit / 
Manufacturer
Unit
Cut-off***
Laboratory  
†
SER
Corynebacterium 
diphtheriae.Diphtheria Toxoid 
Ab.IgG
ELI
NA
IU/ml
0.1
GSK 
Biologicals* 
SER
Clostridium tetani.Tetanus Toxoid 
Ab.IgG
ELI
NA
IU/ml
0.1
GSK 
Biologicals*
SER 
Haemophilus influenzae type 
b.Polyribosyl Ribitol Phosphate Ab 
ELI 
NA 
µg/ml 
0.15 
GSK 
Biologicals*
SER 
Streptococcus 
pneumoniae.Polysaccharide 01 
Ab.IgG
Streptococcus 
pneumoniae.Polysaccharide 03 
Ab.IgG
Streptococcus 
pneumoniae.Polysaccharide 05 
Ab.IgG
Streptococcus 
pneumoniae.Polysaccharide 06A 
Ab.IgG 
Streptococcus 
pneumoniae.Polysaccharide 06B 
Ab.IgG
Streptococcus 
pneumoniae.Polysaccharide 07F 
Ab.IgG
Streptococcus 
pneumoniae.Polysaccharide 09V 
Ab.IgG
Streptococcus 
pneumoniae.Polysaccharide 14 
Ab.IgG
Streptococcus 
pneumoniae.Polysaccharide 18C 
Ab.IgG
Streptococcus 
pneumoniae.Polysaccharide 19A 
Ab.IgG 
Streptococcus 
pneumoniae.Polysaccharide 19F 
Ab.IgG
Streptococcus 
pneumoniae.Polysaccharide 23F 
Ab.IgG
ELIF or 
multiplex
NA 
µg/ml 
0.05 or 
equivalent 
cut-off for the 
multiplex
GSK 
Biologicals*
 
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System
Component
Method
Kit / 
Manufacturer
Unit
Cut-off***
Laboratory  
†
SER
Streptococcus 
pneumoniae.Polysaccharide 01 
Ab.IgG
Streptococcus 
pneumoniae.Polysaccharide 03 
Ab.IgG
Streptococcus 
pneumoniae.Polysaccharide 04 
Ab.IgG
Streptococcus 
pneumoniae.Polysaccharide 05 
Ab.IgG
Streptococcus 
pneumoniae.Polysaccharide 06A 
Ab.IgG
Streptococcus 
pneumoniae.Polysaccharide 06B 
Ab.IgG
Streptococcus 
pneumoniae.Polysaccharide 07F 
Ab.IgG
Streptococcus 
pneumoniae.Polysaccharide 09V 
Ab.IgG
Streptococcus 
pneumoniae.Polysaccharide 14 
Ab.IgG
Streptococcus 
pneumoniae.Polysaccharide 18C 
Ab.IgG
Streptococcus 
pneumoniae.Polysaccharide 19A 
Ab.IgG
Streptococcus 
pneumoniae.Polysaccharide 19F 
Ab.IgG
Streptococcus 
pneumoniae.Polysaccharide 23F 
Ab.IgG
ELI
NA
µg/ml
0.15
WHO 
reference 
laboratory**
*GSK Biologicals laboratory refers to the Clinical Laboratory Sciences (CLS) in Rixensart, Belgium; Wavre, Belgium; 
Neomed Lab Inc, Canada.
** At the discretion of GSK Biologicals, pneumococcal testing may be done at a GSK Biologicals laboratory or the 
WHO reference laboratory
*** Assay cut-off and unit might be subject to change during the course of the study (e.g. in case of 
requalification, revalidation or standardization). In this case, this will be documented in the clinical report.
† Refer to the APPENDIX A for the laboratory addresses.
*** The cut-offs for some of the assays might be subject to change due to assay re-development.
SER = Serum
ELI = Enzyme-linked immunosorbent assay (ELISA)
ELIF = 22F Inhibition ELISA
NEU = Neutralisation assay
CLIA = ChemiLuminescence ImmunoAssay 
IU/mL = International Units/millilitre
mIU/mL = milliInternational Units/millilitre
EL.U/mL = ELISA Units/millilitre
 
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µg/ml = Micrograms/millilitre
Note: The assay cut-off for D, T, pertussis and PRP may be subject to change.
The unit for the pertussis assays may be subject to change.
5.7.4.1. Immunological  read-outs
Table 8: Immunological  read-outs
Blood sampling time point
No. subjects
Component
Components
priority rank
Type of contact and 
time point
Sampling time point
Visit 2 (Day 0 Month 3-9)
Pre-Bst
All
PT, FHA, PRN
D, T
HBs, PRP
Poliovirus types 1, 2, 3
13 pneumococcal serotypes
1
2
3
4
5
Visit 3 (Day 30 Month 4 -
10)
Post-Bst
All
Poliovirus types 1, 2, 3
13 pneumococcal serotypes
1
2
3
4
5
Section 6.3. Dosage and administration of study vaccines
Table 10 Dosage and administration
Type of contact 
and time point
Volume to be 
administered
Study group
Treatment 
name
Route 1
Site 2
Side 3
Visit 2 (Day 0 
Month 3-9)
0.5 mL
dTpa Group and
Control Group
Infanrix hexa 
IM
TThigh or 
Deltoid 2
R
Visit 2 (Day 30 
Month 3-9)
0.5 mL
dTpa Group and
Control Group
Prevenar 13
IM
TThigh or 
Deltoid 2
L
1Intramuscular (IM)
2 The vaccines should be administered in the thigh or deltoid, according to the national recommendations
Thigh (T)
3Right (R), Left (L)
6.6. Warnings and precautions
The information below presents, in addition to the contraindications in Section 6.5, 
warnings and precautions to administration of Infanrix hexa.

If any of the following events are known to have occurred in temporal relation to 
receipt of pertussis-containing vaccine, the decision to give further doses of 
pertussis-containing vaccines should be carefully considered:

Collapse or shock-like state (hypotonic-hyporesponsiveness episode [HHE]) 
within 48 hours of vaccination.

Increased reporting rates of convulsions (with or without fever) and hypotonic 
hyporesponsive episode (HHE) were observed with concomitant administration of 
Infanrix hexa and Prevenar 13.
 
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Warnings and Precautions for the use of Prevenar13:

Increased reporting rates of convulsions (with or without fever) and hypotonic 
hyporesponsive episode (HHE) were observed with concomitant administration of 
Infanrix hexa and Prevenar 13. 
6.7.1. Recording of concomitant medications/products and concomitant vaccinations

All concomitant medications/products, except vitamins and dietary supplements, 
administered during the period starting from the administration of the dose of study 
vaccines (Visit 2) and ending at the last study visit (Visit 3 (Day 0 to Day 30)).

Any concomitant vaccination administered in the period starting from the 
administration of the dose of study vaccines (Visit 2) and ending at the last study 
visit 3 (Day 0 to Day 30) (Visit 3).
8.2.1. Time period for detecting and recording adverse events and serious adverse 
events 
The time period for collecting and recording SAEs will begin at the receipt of study 
vaccines and will end 30 days following administration of the dose of study vaccines
when the subject is discharged from the study. See Section 8.3 for instructions on 
reporting of SAEs.
All AEs/SAEs leading to withdrawal from the study will be collected and recorded from 
the time the subjects have been enrolled in the study of the receipt of study vaccines.
Table 13 Reporting periods for collecting safety information
Event
V 1
V2
4 d post V2
31 d 
post-V2
V3 
Phone contact *
Study Conclusion
Age of subject
9 months
11 12-18 months
12 13-19 
months
18 months¶
Timepoint
Month -9 
to -2
M 3-9
Day 0
Day 3
Day 30
M 4-10
Day 30
Day 0 to Month 7
AEs/SAEs leading to 
withdrawal from the study
SAEs
* i.e., consent obtained for vaccination. Pre-V: pre-vaccination; V: Visit; Post-V: post-visit; D: Day, M: Month; 
* For Czech Republic, the phone call at 18 months may be replaced by a clinic visit if deemed preferable by the 
study team.
¶ Neurodevelopmental status will be recorded at 9 months and 18 months of age. It is encouraged that subjects who 
are getting vaccinated at 18 months of age at Visit 2 or coming for Visit 3, complete their ASQ-3 during their visit to the 
study centre. In case subjects complete Visit 3 before 18 months of age, the study staff will contact the parents/LAR(s)
via phone and conduct an interview to complete the child’s ASQ-3 at 18 months of age. 
If the subject is referred to a developmental specialist for formal assessment, then this information needs to be 
recorded in the eCRF. Also, the overall assessment of delay by the specialist should be recorded in the eCRF.
 
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8.2.3.2.1. Assessment of intensity
The maximum intensity of fever (oral, axillary or typmpanic route) will be scored at 
GSK Biologicals as follows:
8.2.3.2.2. Assessment of causality
The investigator will also consult the IB and/or PI Prescribing Information for marketed 
products to determine his/her assessment. 
 
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10.3. Determination of sample size
Table 17 Reference values (booster phase)
Reference Study
Observed seroprotection 
rates 
Booster response for Pertussis antigens
Observed Seroprotection rates
D
T
PT
FHA
PRN
PRP
HBs
Anti-IPV1
Anti-IPV2
Anti-IPV3
217744/054
100.0%
[97.9,100.0]
100.0%
[97.9,100.0]
100.0%
[97.8,100.0]
100.0%
[97.8,100.0]
100.0%
[97.9,100.0]
100.0%
[97.9,100.0]
98.9 
(95.9,99.9)
100.0%
[97.6,100.0]
100.0%
[97.5,100.0]
100.0%
[97.5,100.0]
217744/054: Group receiving DTPa-HBV-IPV/Hib according to 3,5,11 schedule in Italy and Germany
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10.4.2. Total vaccinated cohort
The Total Vaccinated cohort (TVC) will include all vaccinated subjects for whom data 
are available.
10.4.3. According-to-protocol cohort for analysis of safety
The ATP cohort for analysis of safety will include all subjects from the TVC who 
complied with the vaccine administration:

who have received all at least one vaccine doses in the primary study DTPA 
(BOOSTRIX)-048 PRI.

who have received the booster dose of study vaccines in the current study. 
10.4.4. According-to-protocol cohort for analysis of immunogenicity
The ATP cohort for analysis of immunogenicity will include all evaluable subjects from 
the ATP cohort for analysis of safety:

Who received all three doses of vaccine in the primary study 201330 201334 [DTPA 
(BOOSTRIX)-048 PRI].
10.6. analysis of demographics
Demographic characteristics (age in months, race, length [cm], weight [kg], head 
circumference [cm]), cohort description and withdrawal status will be summarised by 
group using descriptive statistics:

Frequency tables will be generated for categorical variables such as race, country or 
primary vaccination schedule;
10.7. analysis of immunogenicity
For serology results one month after the booster dose:

The booster response rates to PT, FHA and PRN (with exact 95% CI) one month 
after the booster dose will be calculated.
The above summaries will be provided by country or primary vaccination schedule for 
countries involving more than 50 subjects.

The distribution of antibody concentrations/titres for each antigen will be displayed 
using reverse cumulative distribution curves (RCCs).

The distribution of antibody concentrations or titres of each antigen will be tabulated.
The above summaries will be stratified based on country and primary vaccination 
schedule conducted as exploratory analysis.
10.8. Analysis of safety
The percentage of subjects reporting each individual solicited local and general symptom 
during the 4-day (Day 0-Day 3) solicited follow-up period will be tabulated after the 
 
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vaccine dose and overall, with exact 95% CI [Clopper, 1934]. The same calculations will 
be done for each individual solicited symptom rated as grade 3 in intensity and for each 
individual solicited symptom assessed as causally related to vaccination.
11.5. Posting of information on publicly available clinical trial registers and 
publication policy
GSK assures that the key design elements of this protocol will be posted on the GSK 
website and in publicly accessible database(s) such as clinicaltrials.gov, in compliance 
with the current regulations.
GSK also assures that results of this study will be posted on the GSK website and in 
publicly accessible regulatory registry(ies) within the required time-frame, in 
compliance with the current regulations. The minimal requirement is to have primary 
endpoint summary results disclosed at latest 12 months post primary completion date 
(PCD) and to have secondary endpoint disclosed at latest 12 months after the last 
subject last visit (LSLV) as described in the protocol.
As per EU regulation, summaries of the results of GSK interventional studies (phase I-
IV) in paediatric population conducted in at least one EU member state will be posted 
on publicly available EMA 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.
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.
Summaries of the results of GSK interventional studies (phase I-IV) are posted on 
publicly available results registers within six months of the primary completion date for 
studies of authorised vaccines and 18 months for studies of non-authorised vaccines.
GSK also aims to publish the results of these studies in the searchable, peer reviewed 
scientific literature. Manuscripts are submitted for publication within 24 months of the 
last subject’s last visit. At the time of publication, this protocol will be fully disclosed.
 
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Appendix A Clinical laboratories
Table 19 Outsources laboratories
Laboratory
Address
NÉOMED-LABS Inc.
525, Cartier Ouest Laval, Quebec Canada H7V 3S8
Q² Solutions Limited Clinical Trials (UK)
The Alba Campus
Rosebank
Livingston
West Lothian, EH54 7EG
Scotland,
Unit B1, Parkway West Industrial Estate
Cranford Lane–Heston, 
Middlesex TW5 9QA
UK
Q² Solutions Nichols Institute
33608 Ortega Highway 
San Juan Capistrano,
CA 92675-2042
USA
CEVAC-University of Gent
De Pintelaan, 185 Gent
Belgium
 
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