Clinical trial NCT02422264
Conditions: Acellular Pertussis Tetanus Poliomyelitis Diphtheria Diphtheria-Tetanus-aPertussis-Hepatitis B-Poliomyelitis-Haemophilus Influenzae Type b Vaccines
Sponsor: GlaxoSmithKline
Start date: 2016-01-22; Completion date: 2018-03-07
Enrollment: 601 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the immunogenicity and safety of GSK Biologicals' Infanrix hexa, given in the primary vaccination schedule to infants born to pregnant women who participated in study 116945 \[DTPA (BOOSTRIX)-047\]. This study will help us evaluate if the presence of transplacentally transferred maternal antibodies interfere with the immune response to primary vaccination with Infanrix hexa and a co-administered pneumococcal conjugate vaccine given as a part of this study in infants.

Detailed description:

Arms: arm 1: This group will consist of infants born to mothers belonging to the dTpa Group in study 116945 \[DTPA (BOOSTRIX)-047\] i.e. who received a single dose of BoostrixTM during pregnancy and a dose of placebo immediately post-delivery. All infants in this group will receive Infanrix hexaTM co-administered with Prevenar 13®. arm 2: This group will consist of infants born to mothers belonging to the Control group in study 116945 \[DTPA (BOOSTRIX)-047\], i.e. who received a single dose of placebo during pregnancy and a dose of BoostrixTM immediately post-delivery. All infants in this group will receive Infanrix hexaTM co-administered with Prevenar 13®.
Interventions: intervention 1: Infanrix hexa intervention 2: Prevnar13
Intervention descriptions: intervention 1: • All subjects will receive Infanrix hexa at 2 and 4, at 3 and 5, at 2, 4 and 6 months or at 2, 3 and 4 months, depending on the immunisation schedule of the country. Infanrix hexa is administered intramuscularly to the right thigh. intervention 2: • All subjects will receive Infanrix hexa co-administered with Prevenar13\* at 2 and 4, at 3 and 5, at 2, 4 and 6 months or at 2, 3 and 4 months, depending on the immunisation schedule of the country. \*In some countries/regions with an Infanrix hexa 3-dose vaccination schedule, Prevenar 13 could be administered as 2-doses or 3-doses primary vaccination schedule (according to the routine national immunisation schedule). Prevnar13 is administered intramuscularly to the left thigh.

Protocol documents:
Prot_000.pdf: 
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Primary Study vaccine and 
number 
Clinical Study Protocol 
Sponsor: 
GlaxoSmithKline Biologicals 
Rue de l'Institut 89 
1330 Rixensart, Belgium. 
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 
201330 [DTPA (BOOSTRIX)-048 PRI] 
EudraCT number 
2014-001117-41 
Date of protocol 
Final Version 01: 13 February 2015 
Date of protocol 
amendment 
Amendment 1 Final: 06 September 2016 
Title 
Immunogenicity and safety study of GSK Biologicals’ 
combined diphtheria-tetanus-acellular pertussis- 
hepatitis B-inactivated poliovirus and Haemophilus 
influenzae type b vaccine (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 
Infanrix hexa™ administered as primary vaccination 
in healthy infants born to mothers given Boostrix™ 
during pregnancy or post-delivery in 116945 [DTPA 
(BOOSTRIX)-047]. 
Co-ordinating author 
, Scientific Writer 
Contributing authors 
(Amended 06 September 
2016) 
• 
, Clinical Research and Development 
Lead (CRDL) 
• 
, Clinical and 
Epidemiology Project Leader (CEPL) 
• 
, 
and 
, Project-Level CRDLs 
• 
PPD 
• 
PPD 
, Project Statistician 
, 
and 
, Study Delivery Leads 
PPD 
PPD 


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eTrack study number and 
Abbreviated Title 
201330 [DTPA (BOOSTRIX)-048 PRI] 
EudraCT number 
2014-001117-41 
Date of protocol 
Final Version 01: 13 February 2015 
Date of protocol 
amendment 
Amendment 1 Final: 06 September 2016 
Title 
Immunogenicity and safety study of GSK Biologicals’ 
combined diphtheria-tetanus-acellular pertussis- 
hepatitis B-inactivated poliovirus and Haemophilus 
influenzae type b vaccine (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 
Infanrix hexa™ administered as primary vaccination 
in healthy infants born to mothers given Boostrix™ 
during pregnancy or post-delivery in 116945 [DTPA 
(BOOSTRIX)-047]. 
Contributing authors 
(Amended 06 September 
• 
PPD 
, PPD 
CLS Study Managers 
and 
2016) 
• 
and 
, Global Clinical 
Regulatory Affairs Representatives 
• 
PPD 
, PPD 
and PPD 
, Clinical Safety Representatives 
• 
, Global Patents Representative 
• 
and 
Study Data Managers 
• 
, Project Data Manager 
• 
and 
Senior Managers, Biometrics 
• 
and 
, Clinical Trial Supplies 
Managers 
• 
, Director, Global Medical Affairs 
• 
and 
, Local Delivery Leads 
• 
and 
, Local Delivery Leads 
• 
and 
, Local Delivery Leads 
• 
, Local Delivery Lead 
• 
, Local Delivery Lead 
• 
and 
, Local Delivery Leads 
GSK Biologicals’ Protocol DS v 14.1.1 
Copyright 2015-2016 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised 
copying or use of this information is prohibited. 
PPD 
PPD 
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Protocol Amendment 1 Sponsor Signatory Approval 
 
eTrack study number and 
Abbreviated Title 
201330 [DTPA (BOOSTRIX)-048 PRI] 
 
EudraCT number 
2014-001117-41 
 
Date of protocol amendment 
Amendment 1 Final: 06 September 2016 
 
Detailed Title 
A phase IV, open-label, non-randomised, multi- 
centre study to assess the immunogenicity and safety 
of Infanrix hexa™ administered as primary 
vaccination in healthy infants born to mothers given 
Boostrix™ during pregnancy or post-delivery in 
116945 [DTPA (BOOSTRIX)-047]. 
 
Sponsor signatory 
Narcisa Mesaros, MD 
 
Clinical and Epidemiology R&D Project Leader 
(CEPL), DTP, Polio, Hib containing vaccines 
R&D Center Belgium 
 
 
Signature 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For internal use only 
 
 
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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 previous study 
(116945 [DTPA (BOOSTRIX)-047) can be enrolled in the current study, the enrolment 
in DTPA (BOOSTRIX)-047 study has an impact on this current study (e.g. cohorts to 
be investigated). Initially, the DTPA (BOOSTRIX)-047 study was opened only in 
countries using 3-dose primary vaccination series against diphtheria, tetanus and 
pertussis in infants. Nevertheless, the 2-dose primary vaccination schedule 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 therefore the current study to 
countries using 2-dose primary vaccination series in infants with the aim to increase the 
scientific value of the study and generate clinical data in diverse infant vaccination 
schedules. 
 
The notion of end of study was added and Section 11.5 describing the posting of 
information on public registry was revised accordingly. 
 
The names and functions of the contributing authors have been updated. The name of 
GSK Biologicals’ Global Vaccines Clinical Laboratories (GVCL) department has been 
updated to Clinical Laboratory Sciences (CLS) and the name of outsourced laboratory 
(Quest Diagnostic laboratory is now called Q² Solutions) has also been updated. In 
addition, minor updates including typos, abbreviations, clarifications of wording were 
done throughout the document. 


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I agree: 
Protocol Amendment 1 Investigator Agreement 
 
• 
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 an updated Curriculum Vitae and other 
documents required by regulatory agencies for this study. 


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eTrack study number and 
Abbreviated Title 
201330 [DTPA (BOOSTRIX)-048 PRI] 
 
EudraCT number 
2014-001117-41 
Date of protocol amendment 
Amendment 1 Final: 06 September 2016 
Detailed Title 
A phase IV, open-label, non-randomised, multi- 
centre study to assess the immunogenicity and safety 
of Infanrix hexa™ administered as primary 
vaccination in healthy infants born to mothers given 
Boostrix™ during pregnancy or post-delivery in 
116945 [DTPA (BOOSTRIX)-047]. 
Investigator name 
Signature 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For internal use only 
 
 
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1. Sponsor 
Sponsor Information 
 
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 Infanrix hexa™ 
administered as primary vaccination in healthy infants born to 
mothers given Boostrix™ during pregnancy or post-delivery 
in 116945 [DTPA (BOOSTRIX)-047]. 
 
Indication 
Primary 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 of Diphtheria-Tetanus- 
acellular Pertussis (DTPa) vaccination series. 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]. 
 
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]. (Amended 06 
September 2016) 
 
In 2013, the Advisory Committee on Immunisation Practices 
(ACIP) recommended that all women should be vaccinated 
with dTpa vaccine during each pregnancy, regardless of the 
previous immunisation schedule [CDC, 2013b]. Similar 
recommendations have been implemented in many countries 
including UK, New Zealand, Israel, Mexico, Brazil, 
Colombia, Uruguay, Panama, Costa Rica, Argentina and some 
provinces in Australia and Spain [Joint Committee on 
Vaccination and Immunisation (JCVI), 2012; Pharmaceutical 
Management Agency (PHARMAC), 2012; TAG, 2013]. The 
National Advisory Committee on Immunisation in Canada 


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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 immunisation history [Warshawsky, 
2014; Public Health Agency of Canada, 2014]. (Amended 06 
September 2016) 
 
In line with these recommendations, study 116945 [DTPA 
(BOOSTRIX)-047] will be conducted to evaluate the 
immunogenicity and safety of GlaxoSmithKline (GSK) 
Biologicals’ dTpa vaccine, Boostrix, in pregnant women, as 
well as the transfer of maternal antibodies against pertussis 
to the foetus (cord blood sample at delivery). Subjects will 
receive a dose of Boostrix during pregnancy or immediately 
post-delivery. (Amended 06 September 2016) 
 
All infants born to pregnant women who participate in study 
116945 [DTPA (BOOSTRIX)-047] will be offered enrolment 
in the present study. This study will be conducted to evaluate 
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 in the primary 
vaccination schedule. This will help us evaluate if the 
presence of transplacentally transferred maternal antibodies 
interfere with the immune response to primary vaccination 
with Infanrix hexa and a co-administered pneumococcal 
conjugate vaccine given as a part of this study in infants. 
 
• 
Rationale for the study design 
This phase IV study is a follow-up of the study 116945 
[DTPA (BOOSTRIX)-047]. The immunogenicity and safety 
of Infanrix hexa when administered as a part of the primary 
vaccination schedule, according to the routine national 
immunisation schedule (3 doses given at 2, 4 and 6 months 
of age or at 2, 3 and 4 months of age or 2 doses given at 3 
and 5 months of age or at 2 and 4 months of age) will be 
evaluated. As part of the study, subjects will also receive 
Prevenar 13 according to the routine national immunisation 
schedule. The immunogenicity and safety of the booster dose 
of the same vaccines in infants in the second year of their life 
will be assessed in another follow-up study DTPA 
(BOOSTRIX)-049. (Amended 06 September 2016) 


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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. who received a single 
dose of Boostrix during pregnancy and a dose of placebo 
immediately post-delivery. All infants in this group will 
receive Infanrix hexa co-administered with Prevenar 13 
according to the routine national immunisation 
schedule. (Amended 06 September 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. who received a single 
dose of placebo during pregnancy and a dose of Boostrix 
immediately post-delivery. All infants in this group will 
receive Infanrix hexa co-administered with Prevenar 13 
according to the routine national immunisation 
schedule. (Amended 06 September 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]. 
 
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 
vaccine response for the pertussis antigens, one month 
after the last dose of the primary vaccination in infants 
born to mothers vaccinated with Boostrix during 
pregnancy or immediately post-delivery. 
Secondary 
 
• 
To assess persistence of antibodies against diphtheria, 
tetanus and pertussis antigens, before the first dose of 
Infanrix hexa 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 last dose 
of the primary vaccination in infants born to mothers 
vaccinated with Boostrix during pregnancy or 
immediately post-delivery. 
*In some countries/regions with an Infanrix hexa 3-dose 
vaccination schedule, Prevenar 13 could be 


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Study design 
 
(Amended 06 
September 2016) 
administered as 2-doses or 3-doses primary vaccination 
schedule (according to the routine national 
immunisation schedule). In such an instance, the 
evaluation will be performed one month after the last 
Infanrix hexa dose regardless of Prevenar 13 
vaccination. In the countries/regions with an Infanrix 
hexa 2-dose schedule, Prevenar 13 is co-administered at 
the same time as Infanrix hexa. (Amended 06 
September 2016) 
• 
To assess the immunological response to Infanrix hexa in 
terms of seropositivity rates against pertussis antigens, 
one month after the last dose of the primary vaccination 
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). 
• 
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 3 months, per subject, for subjects 
vaccinated according to the 2 and 4, the 3 and 5 or the 2, 
3 and 4 months schedule and approximately 5 months, 
per subject, for those vaccinated according to 2, 4 and 6 
month schedule. 
 
Epoch 001: Primary starting at Visit 1 (Day 0) and 
ending at Visit 4 (Month 3 or 5 depending on the 
vaccination schedule). 
• 
End of Study (EoS): Last testing results released of 
samples collected at Visit 4. 
• 
Study groups: The study groups and epoch foreseen in the 
study are presented below. 
 
dTpa Group: This group will consist of infants born 
to mothers belonging to the dTpa Group in study 
116945 [DTPA (BOOSTRIX)-047]. All subjects in 
this group will receive Infanrix hexa co-administered 
with Prevenar 13 according to the routine national 
immunisation schedule. 
 
Control Group: This group will consist of infants 
born to mothers belonging to the Control group in 
study 116945 [DTPA (BOOSTRIX)-047]. All 
subjects in this group will receive Infanrix hexa co- 


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administered with Prevenar 13 according to the 
routine national immunisation schedule. 
 
Synopsis Table 1 
Study groups and epoch foreseen in the study (Amended 06 
September 2016) 
 
Study Groups 
Number of 
subjects 
Age (Min - Max)* 
Epoch 
Epoch 001 
dTpa Group 
340 
6 -14 weeks 
x 
Control Group 
340 
6 -14 weeks 
x 
*Up to and including 14 weeks and 6 days of age. 
 
Synopsis Table 2 
Study groups and treatments foreseen in the study (Amended 
06 September 2016) 
 
Treatment names 
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. 
• 
Vaccination schedules: All subjects will receive either 3 
doses of Infanrix hexa co-administered with Prevenar 
13* at 2, 4 and 6 months or 2, 3 and 4 months, either 2 
doses of Infanrix hexa co-administered with Prevenar 
13 at 3 and 5 months or at 2 and 4 months, depending 
on the immunisation schedule of the country. 
*In some countries/regions with an Infanrix hexa 3 
doses routine national immunisation schedule, Prevenar 
13 could be administered as 2-doses or 3-doses primary 
vaccination schedule (according to the routine national 
immunisation schedule). (Amended 06 September 2016) 
• 
Treatment allocation: non-randomised. All subjects will 
receive Infanrix hexa co-administered with Prevenar 13. 
• 
Blinding: Open-label. Note: The study personnel 
operating GSK Biologicals’ randomisation system on 
internet (SBIR) and the site staff will remain blinded 
towards the treatment allocation to subjects in study 
116945 [DTPA (BOOSTRIX)-047]. 
 
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 timepoints (Amended 06 


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Number of subjects 
(Amended 06 
September 2016) 
September 2016): 
 
Pre-Pri: Before the first Infanrix hexa vaccine 
administration, a volume of approximately 2 mL of 
whole blood (to provide approximately 0.7 mL of 
serum) will be collected from all study participants. 
(Amended 06 September 2016) 
 
Post-Pri: One month after the last dose of Infanrix 
hexa primary vaccination, approximately 5 mL of 
whole blood (to provide approximately 1.7 mL of 
serum) will be collected from all study participants. 
(Amended 06 September 2016) 
• 
Type of study: extension of other protocol(s) 116945 
[DTPA (BOOSTRIX)-047]. 
• 
Data collection: Electronic Case Report Form (eCRF). 
• 
Safety monitoring: An independent data monitoring 
committee (IDMC) (including paediatrician and 
statistician) will be put in place to oversee the safety of 
infants born to mothers who were vaccinated with Boostrix 
during pregnancy in the clinical study 116945 [DTPA 
(BOOSTRIX)-047] 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 
IDMC approved charter. (Amended 06 September 2016) 
The target will be to enrol maximum of 680 eligible subjects 
aged 6-14 weeks (up to and including 14 weeks and 6 days of 
age) (approximately 340 subjects in each group). 
 
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 last dose of 
primary vaccination.
 Vaccine response to PT, FHA and PRN antigens, one 
month after the last dose of primary vaccination.
Secondary 
 
• 
Persistence of antibodies before the first dose of Infanrix 
hexa. 
 Anti-diphtheria and anti-tetanus seroprotection status,


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anti-PT, anti-FHA, anti-PRN seropositivity status and 
antibody concentrations. 
• 
Immunogenicity with respect to components of Infanrix 
hexa and Prevenar 13. 
 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, one month after the last dose of primary 
vaccination.
• 
Immunogenicity with respect to components of Infanrix 
hexa. 
 Anti-PT, anti-FHA, anti-PRN antibody seropositivity 
status, one month after the last dose of primary 
vaccination.
• 
Solicited local and general symptoms. 
 Occurrence of solicited local/general symptoms during 
the 4-day (Day 0-Day 3) follow-up period after each 
vaccination.
• 
Unsolicited adverse events. 
 Occurrence of unsolicited symptoms during the 31-day 
(Day 0-Day 30) follow-up period after each 
vaccination.
• 
Serious adverse events. 
 Occurrence of SAEs from first vaccination dose to 
study end.


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TABLE OF CONTENTS 
 
PAGE 
 
SPONSOR INFORMATION ............................................................................................ 7 
SYNOPSIS ...................................................................................................................... 8 
LIST OF ABBREVIATIONS ........................................................................................... 23 
GLOSSARY OF TERMS (AMENDED 06 SEPTEMBER 2016) ...................................... 26 
TRADEMARKS ............................................................................................................. 29 
1. 
INTRODUCTION .................................................................................................... 30 
1.1. 
Background ................................................................................................ 30 
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 ...................................................... 32 
1.3. 
Benefit : Risk Assessment .......................................................................... 32 
1.3.1. 
Risk Assessment ......................................................................... 33 
1.3.2. 
Benefit Assessment ..................................................................... 34 
1.3.3. 
Overall Benefit:Risk Conclusion ................................................... 35 
2. 
OBJECTIVES ......................................................................................................... 35 
2.1. 
Primary objective ........................................................................................ 35 
2.2. 
Secondary objectives .................................................................................. 35 
3. 
STUDY DESIGN OVERVIEW ................................................................................ 36 
4. 
STUDY COHORT ................................................................................................... 39 
4.1. 
Number of subjects/centres ........................................................................ 39 
4.2. 
Inclusion criteria for enrolment .................................................................... 39 
4.3. 
Exclusion criteria for enrolment ................................................................... 40 
5. 
CONDUCT OF THE STUDY .................................................................................. 41 
5.1. 
Regulatory and ethical considerations, including the informed 
consent process .......................................................................................... 41 
5.2. 
Subject identification and randomisation of treatment .................................. 42 
5.2.1. 
Subject identification .................................................................... 42 
5.2.2. 
Randomisation of treatment ......................................................... 43 
5.2.2.1. 
Treatment allocation to the subject ............................. 43 
5.2.2.1.1. 
Study group and treatment 
number allocation ................................... 43 
5.2.2.1.2. 
Treatment number allocation for 
subsequent doses ................................... 43 
5.3. 
Method of blinding....................................................................................... 43 
5.4. 
General study aspects ................................................................................ 44 
5.4.1. 
Independent Data Monitoring Committee ..................................... 44 
5.4.2. 
Responsibilities ............................................................................ 44 
5.4.3. 
Composition of the IDMC (Amended 06 September 2016) ........... 45 
5.4.4. 
GSK Biologicals’ safety review team ............................................ 45 


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5.5. 
Outline of study procedures ........................................................................ 46 
5.6. 
Detailed description of study procedures ..................................................... 49 
5.6.1. 
Informed consent ......................................................................... 49 
5.6.2. 
Check inclusion and exclusion criteria .......................................... 49 
5.6.3. 
Collect demographic data ............................................................ 49 
5.6.4. 
Medical history ............................................................................. 49 
5.6.5. 
Medication and vaccination history ............................................... 49 
5.6.6. 
History directed physical examination .......................................... 50 
5.6.7. 
Check contraindications, warnings  and  precautions  to 
vaccination ................................................................................... 50 
5.6.8. 
Assess pre-vaccination body temperature .................................... 50 
5.6.9. 
Record body weight, height and head circumference ................... 50 
5.6.10. 
Study group and treatment number allocation .............................. 50 
5.6.11. 
Sampling ...................................................................................... 50 
5.6.11.1. Blood sampling for immune response 
assessments .............................................................. 50 
5.6.12. 
Study vaccine administration ....................................................... 51 
5.6.13. 
Check and record concomitant medication/vaccination and 
intercurrent medical conditions ..................................................... 51 
5.6.14. 
Recording of AEs and SAEs ........................................................ 51 
5.6.15. 
Study conclusion .......................................................................... 52 
5.7. 
Biological sample handling and analysis ..................................................... 52 
5.7.1. 
Use of specified study materials ................................................... 53 
5.7.2. 
Biological samples ....................................................................... 53 
5.7.3. 
Laboratory assays........................................................................ 53 
5.7.4. 
Biological samples evaluation ...................................................... 56 
5.7.4.1. 
Immunological read-outs ............................................ 56 
5.7.5. 
Immunological correlates of protection ......................................... 56 
6. 
STUDY VACCINES AND ADMINISTRATION ........................................................ 58 
6.1. 
Description of study vaccine ........................................................................ 58 
6.2. 
Storage and handling of study vaccine ........................................................ 59 
6.3. 
Dosage and administration of study vaccines .............................................. 59 
6.4. 
Replacement of unusable vaccine doses .................................................... 60 
6.5. 
Contraindications to subsequent vaccination............................................... 60 
6.6. 
Warnings and precautions .......................................................................... 61 
6.7. 
Concomitant medications/products and concomitant vaccinations .............. 62 
6.7.1. 
Recording of concomitant medications/products and 
concomitant vaccinations ............................................................. 63 
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 ......................................................................... 64 
7. 
HEALTH ECONOMICS .......................................................................................... 64 
8. 
SAFETY ................................................................................................................. 64 
8.1. 
Safety definitions ........................................................................................ 64 
8.1.1. 
Definition of an adverse event ...................................................... 64 
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 


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8.1.3.2. 
Solicited general adverse events ................................ 67 
8.1.4. 
Clinical laboratory parameters and other abnormal 
assessments qualifying as adverse events or serious 
adverse events ............................................................................ 67 
8.2. 
Detecting and recording adverse events, 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 .............. 70 
8.2.3. 
Evaluation of adverse events and serious adverse events ........... 71 
8.2.3.1. 
Active questioning to detect adverse events 
and serious adverse events ........................................ 71 
8.2.3.2. 
Assessment of adverse events ................................... 72 
8.2.3.2.1. 
Assessment of intensity .......................... 72 
8.2.3.2.2. 
Assessment of causality ......................... 73 
8.2.3.3. 
Assessment of outcomes ............................................ 74 
8.2.3.4. 
Medically attended visits ............................................. 75 
8.3. 
Reporting of serious adverse events and other events ................................ 75 
8.3.1. 
Prompt reporting of serious adverse events and other 
events to GSK Biologicals ............................................................ 75 
8.3.2. 
Contact information for reporting serious adverse events ............. 75 
8.3.3. 
Completion and transmission of SAE reports to GSK 
Biologicals ................................................................................... 75 
8.3.3.1. 
Back-up system in case the electronic reporting 
system does not work ................................................. 76 
8.3.4. 
Updating of SAE information after removal of write access 
to the subject’s eCRF ................................................................... 76 
8.3.5. 
Regulatory   reporting   requirements   for   serious   adverse 
events .......................................................................................... 76 
8.4. 
Follow-up of adverse events and serious adverse events ........................... 77 
8.4.1. 
Follow-up of adverse events and serious adverse events ............ 77 
8.4.1.1. 
Follow-up during the study .......................................... 77 
8.4.1.2. 
Follow-up after the subject is discharged from 
the study ..................................................................... 77 
8.5. 
Treatment of adverse events ....................................................................... 77 
8.6. 
Subject card ................................................................................................ 78 
9. 
SUBJECT COMPLETION AND WITHDRAWAL ..................................................... 78 
9.1. 
Subject completion ...................................................................................... 78 
9.2. 
Subject withdrawal ...................................................................................... 78 
9.2.1. 
Subject withdrawal from the study ................................................ 78 
9.2.2. 
Subject withdrawal from investigational vaccine ........................... 79 
9.3. 
Extension study .......................................................................................... 79 
10. STATISTICAL METHODS ...................................................................................... 80 
10.1. Primary endpoint ......................................................................................... 80 
10.2. Secondary endpoints .................................................................................. 80 
10.3. Determination of sample size ...................................................................... 80 
10.4. Cohorts for analyses ................................................................................... 84 
10.4.1. 
Total vaccinated cohort ................................................................ 84 
10.4.2. 
ATP cohort for analysis of safety .................................................. 84 
10.4.3. 
ATP cohort for analysis of immunogenicity ................................... 84 
10.5. Derived and transformed data ..................................................................... 85 


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10.6. Analysis of demographics ........................................................................... 86 
10.7. Analysis of immunogenicity ......................................................................... 86 
10.8. Analysis of safety ........................................................................................ 87 
10.9. Interpretation of analyses ............................................................................ 88 
10.10. Conduct of analyses ................................................................................... 88 
10.10.1. Sequence of analyses .................................................................. 88 
10.10.2. Statistical considerations for interim analyses .............................. 89 
11. ADMINISTRATIVE MATTERS ............................................................................... 89 
11.1. electronic Case Report Form instructions .................................................... 89 
11.2. Study monitoring by GSK Biologicals .......................................................... 89 
11.3. Record retention ......................................................................................... 90 
11.4. Quality assurance ....................................................................................... 90 
11.5. Posting of information on publicly available clinical trial registers and 
publication policy (Amended 06 September 2016) ...................................... 91 
11.6. Provision of study results to investigators .................................................... 91 
12. COUNTRY SPECIFIC REQUIREMENTS ............................................................... 91 
13. REFERENCES ....................................................................................................... 92 


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LIST OF TABLES 
 
PAGE 
 
Table 1 
Study groups and epoch foreseen in the study (Amended 06 
September 2016) ................................................................................... 38 
Table 2 
Study groups and treatments foreseen in the study (Amended 06 
September 2016) ................................................................................... 38 
Table 3 
Blinding of study epoch .......................................................................... 39 
Table 4 
List of study procedures for infants receiving a 3-dose schedule 
of Infanrix hexa (Amended 06 September 2016) .................................... 46 
Table 5 
List of study procedures for infants receiving a 2-dose schedule 
of Infanrix hexa (Amended 06 September 2016) .................................... 47 
Table 6 
Intervals between study visits for subjects vaccinated with 
Infanrix hexa at 2, 4 and 6 months of age (Amended 06 
September 2016) ................................................................................... 48 
Table 7 
Intervals between study visits for subjects vaccinated with 
Infanrix hexa at 2, 3 and 4 months of age (Amended 06 
September 2016) ................................................................................... 48 
 
Table 8 
Intervals between study visits for subjects vaccinated with 
Infanrix hexa at 2 and 4 months of age (Amended 06 September 
2016)...................................................................................................... 48 
 
Table 9 
Intervals between study visits for subjects vaccinated with 
Infanrix hexa at 3 and 5 months of age (Amended 06 September 
2016)......................................................................................................  49 
 
Table 10 
Biological samples.................................................................................. 53 
 
Table 11 
Humoral Immunity (Antibody determination) (Amended 06 
September 2016) ................................................................................... 54 
 
Table 12 
Immunological read-outs (Amended 06 September 2016) ...................... 56 
 
Table 13 
Study vaccines (Amended 06 September 2016) ..................................... 58 
 
Table 14 
Dosage and administration (Amended 06 September 2016) ................... 60 
 
Table 15 
Solicited local adverse events ................................................................ 66 
 
Table 16 
Solicited general adverse events ............................................................ 67 
 
Table 17 
Reporting periods for adverse events and serious adverse 
events for subjects vaccinated with Infanrix hexa at 2, 4 and 6 
months of age (Amended 06 September 2016) ...................................... 68 


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Table 18 
Reporting periods for adverse events and serious adverse 
events for subjects vaccinated with Infanrix hexa at 2, 3 and 4 
months of age (Amended 06 September 2016) ...................................... 69 
Table 19 
Reporting periods for adverse events and serious adverse 
events for subjects vaccinated with Infanrix hexa at 2 and 4 
months of age or at 3 and 5 months of age (Amended 06 
September 2016) ................................................................................... 70 
Table 20 
Intensity scales for solicited symptoms in infants less than 6 
years of age ........................................................................................... 72 
Table 21 
Timeframes  for  submitting  serious  adverse  events  to  GSK  
Biologicals .............................................................................................. 75 
Table 22 
Exact 95% CI of the different values of observed response rate 
(vaccine response rate or seroprotection rate) for a sample size 
of 238-300 subjects) ............................................................................... 81 
Table 23 
Reference values ................................................................................... 83 
Table 24 
GSK Biologicals’ laboratories (Amended 06 September 2016) ............... 95 
Table 25 
Outsourced laboratories (Amended 06 September 2016) ....................... 95 


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LIST OF FIGURES 
 
PAGE 
 
Figure 1 
Study design diagram for infants receiving a 3-dose schedule of 
Infanrix hexa (Amended 06 September 2016) ........................................ 36 
Figure 2 
Study design diagram for infants receiving a 2-dose schedule of 
Infanrix hexa (Amended 06 September 2016) ........................................ 37 


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LIST OF APPENDICES 
 
PAGE 
 
APPENDIX A CLINICAL LABORATORIES ................................................................... 95 
APPENDIX B AMENDMENTS AND ADMINISTRATIVE CHANGES TO THE 
PROTOCOL ........................................................................................... 96 


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LIST OF ABBREVIATIONS 
(Amended 06 September 2016) 
 
ACIP: 
Advisory Committee on Immunization Practices 
 
AE: 
Adverse Event 
 
Anti-HBs: 
Antibodies against hepatitis B surface antigen 
 
ATP: 
According-To-Protocol 
 
CDC: 
Centers for Disease Control and Prevention, USA 
 
CEVAC: 
Centre for Vaccinology, Ghent University and Hospital 
 
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: 
ELISA Units 
 
EOS 
End of study 
 
EPAR: 
European Public Assessment Report 
 
FHA: 
Filamentous Haemagglutinin 
 
GMC: 
Geometric Mean Concentration 
 
GMT: 
Geometric Mean Titre 


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GSK: 
GlaxoSmithKline 
HBs: 
Hepatitis B surface antigen 
HBV: 
Hepatitis B Virus 
HHE: 
Hypotonic Hyporesponsive Episode 
Hib: 
Haemophilus influenzae type b 
HRV: 
Human Rotavirus Vaccine 
IDMC: 
Independent Data Monitoring Committee 
IM: 
intramuscular 
IMP: 
Investigational Medicinal Product 
IPV: 
Inactivated Poliovirus Vaccine 
LAR: 
Legally Acceptable Representative 
MedDRA: 
Medical Dictionary for Regulatory Activities 
(m)IU: 
(Milli)-international units 
PRN: 
Pertactin 
PRP: 
Hib capsular polysaccharide Polyribosyl-Ribitol 
Phosphate 
PT: 
Pertussis Toxoid 
RDE: 
Remote Data Entry 
RSI: 
Reference Safety Information 
SAE: 
Serious Adverse Event 
SBIR: 
Randomisation System on Internet 
SCID: 
Severe Combined immunodeficiency Disease 
SDV: 
Source Document Verification 
SIDS: 
Sudden Infant Death Syndrome 
SPC: 
Summary of Product Characteristics 
SPM: 
Study Procedures Manual 
 


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SRT 
Safety Review Team 
 
[e]TDF: 
(electronic) Temperature excursion Decision Form 
 
TT: 
Tetanus Toxoid 
 
TVC: 
Total Vaccinated Cohort 
 
USA/US: 
United States of America 
 
WHO: 
World Health Organization 


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GLOSSARY OF TERMS (AMENDED 06 September 2016) 
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) 
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 


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8 months after LSLV 
 
Epoch: 
An epoch is a self-contained set of consecutive timepoints 
or a single timepoint from a single protocol. Self-contained 
means that data collected for all subjects at all timepoints 
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: 
 
Intercurrent medical 
condition: 
 
Investigational vaccine: 
 
(Synonym of 
Investigational 
Medicinal Product) 
 
 
Legally acceptable 
representative 
 
(The terms legal 
representative or legally 
authorized 
representative are used 
in some settings.) 
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. 
 
A condition that has the capability of altering a subject’s 
immune response or are confirmed to have an 
immunodeficiency condition during the study. 
 
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. 
 
An individual or juridical or other body authorized under 
applicable law to consent, on behalf of a prospective 
subject, to the subject's participation in the clinical trial. 
 
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. 


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Site Monitor: 
An individual assigned by the sponsor who is responsible 
for assuring proper conduct of clinical studies at one or 
more investigational sites. 
 
Solicited adverse event: 
AEs to be recorded as endpoints in the clinical study. The 
presence/occurrence/intensity of these events is actively 
solicited from the subject or an observer during a specified 
post-vaccination follow-up period. 
 
Subject: 
Term used throughout the protocol to denote an individual 
who has been contacted in order to participate or 
participates in the clinical study, either as a recipient of the 
vaccines or as a control. 
 
Subject number: 
A unique number identifying a subject, assigned to each 
subject consenting to participate in the study. 
 
Treatment: 
Term used throughout the clinical study to denote a set of 
investigational product(s) or marketed product(s) or 
placebo intended to be administered to a subject, 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. 
 
 
 
 
 
 
 
 
Infanrix hexa™ 
Combined diphtheria-tetanus-acellular 
pertussis-hepatitis B-inactivated poliovirus 
vaccine and Haemophilus influenzae type b 
conjugate vaccine 
Prevenar 13® (Wyeth Pharmaceuticals Inc.; 
Marketed by Pfizer Inc.) 
Pneumococcal 13-valent conjugate 
vaccine (diphtheria CRM197 protein) 
(Amended 06 September 2016) 
Generic description 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
Generic description 
Trademarks of the GlaxoSmithKline 
group of companies 


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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 
2013, there were 24,231 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 [CDC, 2013a; CDC, 
2013b]. 
 
In Canada, approximately 2500 cases were reported in 2012 [Public Health Agency of 
Canada, 2012]. The United Kingdom 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, 2012]. 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. 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, the findings that pre-existing high levels 
of pertussis antibody in infants suppress the ultimate immune response to whole-cell 
diphtheria, tetanus and pertussis (DTP) vaccines lessened the enthusiasm for this 
approach [Englund, 1995]. 
 
Please refer to the current Investigator Brochure for information regarding the pre-clinical 
and clinical studies and the epidemiological information of Infanrix hexa. 
 
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 


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antibody concentrations in infants during the period between birth and the first vaccine 
dose of DTPa vaccination series. 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]. 
 
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]. 
(Amended 06 September 2016) 
 
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, 2013b]. Similar recommendations have been 
implemented in 18 countries including UK, New Zealand, Israel, Mexico, Brazil, 
Colombia, Uruguay, Panama, Costa Rica, Argentina and some provinces in Australia and 
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 immunisation history 
[Warshawsky, 2014; Public Health Agency of Canada, 2014]. (Amended 06 September 
2016) 
 
In line with these recommendations, study 116945 [DTPA (BOOSTRIX)-047] will be 
conducted to evaluate the immunogenicity and safety of GlaxoSmithKline (GSK) 
Biologicals’ dTpa vaccine, Boostrix, in pregnant women, as well as the transfer of 
maternal antibodies against pertussis to the foetus (cord blood sample at delivery). 
Subjects will receive a dose of Boostrix during pregnancy or immediately post-delivery. 
(Amended 06 September 2016) 
 
All infants born to pregnant women who participate in study 116945 [DTPA 
(BOOSTRIX)-047] will be offered enrolment in the present study. This study will be 
conducted to evaluate 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 in the primary 
vaccination schedule. This will help us evaluate if the presence of transplacentally 
transferred maternal antibodies interfere with the immune response to primary 
vaccination with Infanrix hexa and a co-administered pneumococcal conjugate vaccine 
given as a part of this study in infants. 


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1.2.2. 
Rationale for the study design 
 
This phase IV study is a follow-up of the study 116945 [DTPA (BOOSTRIX)-047]. The 
immunogenicity and safety of Infanrix hexa when administered as a part of the primary 
vaccination schedule, according to the routine national immunisation schedule (3 doses 
given at 2, 4 and 6 months of age or at 2, 3 and 4 months of age or 2 doses given at 3 
and 5 months of age or at 2 and 4 months of age) will be evaluated. As part of the study 
subjects will also receive Prevenar 13 according to the routine national immunisation 
schedule. The immunogenicity and safety of the booster dose of the same vaccines in 
infants in the second year of their life will be assessed in another follow-up study DTPA 
(BOOSTRIX)-049. (Amended 06 September 2016) 
 
This study will have two groups (Amended 06 September 2016): 
 
• 
dTpa Group: This group will consist of infants born to mothers belonging to the 
dTpa Group in study 116945 [DTPA (BOOSTRIX)-047] i.e. who received a single 
dose of Boostrix during pregnancy and a dose of placebo immediately post-delivery. 
All infants in this group will receive Infanrix hexa co-administered with Prevenar 13 
according to the routine national immunisation schedule. 
• 
Control Group: This group will consist of infants born to mothers belonging to the 
Control group in study 116945 [DTPA (BOOSTRIX)-047], i.e. who received a 
single dose of placebo during pregnancy and a dose of Boostrix immediately post- 
delivery. All infants in this group will receive Infanrix hexa co-administered with 
Prevenar 13 according to the routine national immunisation schedule. 
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]. 
 
1.3. 
Benefit : Risk Assessment 
Please refer to the current Investigator Brochure for the summary of potential risks and 
benefits of Infanrix hexa. 


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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 06 September 2016) 
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. 
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. 
Apnoea in infants born 
prematurely 
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. 
Medically stable* prematurely born infants, born 
after a gestation period of 27-36 weeks may be 
enrolled in the study at the discretion of the 
investigator. The need for respiratory monitoring 
for 48-72 hours should be considered when 
administering the primary immunisation series 
to very preterm infants (born ≤ 28 weeks of 
gestation) and particularly for those with a 
previous history of respiratory immaturity. 
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. 


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Important 
Potential/Identified Risk 
Data/Rationale for Risk 
Mitigation Strategy 
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 
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 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 06 September 2016) 
Apnoea in infants born 
prematurely 
As outlined in Prevenar 13 EPAR 
this AE/SAE is recognized as 
well-characterized identified risks 
for Prevenar 13. 
Medically stable* prematurely born infants, born 
after a gestation period of 27-36 weeks may be 
enrolled in the study at the discretion of the 
investigator. 
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. 
*Medically stable refers to the condition of premature infants who do not require significant medical support or ongoing 
management for debilitating disease and who have demonstrated a clinical course of sustained recovery by the time 
they receive the first dose of study vaccine. 
 
1.3.2. 
Benefit Assessment 
 
Diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis and Haemophilus influenzae type 
b 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 Haemophilus influenzae type b 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 the first 
study visit. In case the study doctor discovers any medical condition, the subject will be 
referred to the local healthcare system. The vaccine and study tests will be provided free 
of cost to the subjects. 


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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 
of vaccine response to the pertussis antigens, one month after the last dose of the 
primary vaccination 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 persistence of antibodies against diphtheria, tetanus and pertussis antigens, 
before the first dose of Infanrix hexa 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 last dose 
of the primary vaccination 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 last dose of the primary 
vaccination 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). 
*In some countries/regions with an Infanrix hexa 3-dose vaccination schedule, 
Prevenar 13 could be administered as 2-doses or 3-doses primary vaccination 
schedule (according to the routine national immunisation schedule). In such an 
instance, the evaluation will be performed one month after the last Infanrix hexa 
dose regardless of Prevenar 13 vaccination. In the countries/regions with an 
Infanrix hexa 2-dose schedule, Prevenar 13 is co-administered at the same time as 
Infanrix hexa. (Amended 06 September 2016) 
Refer to Section 10.2 for the definition of the secondary endpoints. 


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3. 
STUDY DESIGN OVERVIEW 
Figure 1 
Study design diagram for infants receiving a 3-dose schedule of 
Infanrix hexa (Amended 06 September 2016) 
 
 
N: Maximum number of subjects planned to be enrolled 
M = Month, Mo = age in months 
Timepoints have been numbered based on the different vaccination schedules. D0, M1, M2 and M3 timepoints reflect 
for subjects who will be vaccinated according to the 2, 3 and 4 month schedule while D0, M2, M4 and M5 timepoints 
reflect for subjects who will be vaccinated according to the 2, 4 and 6 month schedule. 
* In some countries/regions with an Infanrix hexa 3-dose schedule, Prevenar 13 is given as a 2-dose schedule at 2 
and 4 months of age as a part of the routine immunisation programme 
Pre-Pri = Blood sample to be collected before the first dose of the primary vaccination course 
Post-Pri = Blood sample to be collected one month after the last dose of the primary vaccination course 


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Figure 2 
Study design diagram for infants receiving a 2-dose schedule of 
Infanrix hexa (Amended 06 September 2016) 
 
 
N: Maximum number of subjects planned to be enrolled 
M = Month, Mo = age in months 
Pre-Pri = Blood sample to be collected before the first dose of the primary vaccination course 
Post-Pri = Blood sample to be collected one month after the last dose of the primary vaccination course 
Subjects will be vaccinated either at 2 and 4 months of age or 3 and 5 months of age, according to the routine 
national immunisation schedule 
 
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 3 months, 
per subject, for subjects vaccinated according to the 2 and 4, the 3 and 5 or the 2, 3 
and 4 months schedule and approximately 5 months, per subject, for those vaccinated 
according to 2, 4 and 6 month schedule. (Amended 06 September 2016) 
 Epoch 001: Primary starting at Visit 1 (Day 0) and ending at Visit 4 (Month 3 or 
5, depending on the vaccination schedule). (Amended 06 September 2016) 


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• 
End of Study (EoS): Last testing results released of samples collected at Visit 4. 
Refer to the glossary of terms for the definition of EoS. (Amended 06 September 
2016) 
• 
Study groups: The study groups and epoch foreseen in the study are presented in 
Table 1. 
 
Table 1 
Study groups and epoch foreseen in the study (Amended 06 
September 2016) 
 
Study Groups 
Number of 
subjects 
Age (Min - Max)* 
Epoch 
Epoch 001 
dTpa Group 
340 
6-14 weeks 
x 
Control Group 
340 
6-14 weeks 
x 
*Up to and including 14 weeks and 6 days of age. 
 
The study groups and treatment foreseen in the study are presented in Table 2. 
 
Table 2 
Study groups and treatments foreseen in the study (Amended 06 
September 2016) 
 
Treatment names 
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 
• 
Vaccination schedules: All subjects will receive either 3 doses of Infanrix hexa co- 
administered with Prevenar 13* at 2, 4 and 6 months or 2, 3 and 4 months, either 2 
doses of Infanrix hexa co-administered with Prevenar 13 at 3 and 5 months or 2 
and 4 months, depending on the immunisation schedule of the country. 
 
*In some countries/regions with an Infanrix hexa 3 doses routine national 
immunisation schedule, Prevenar 13 could be administered as 2-doses or 3-doses 
primary vaccination schedule (according to the routine national immunisation 
schedule). (Amended 06 September 2016) 
• 
Treatment allocation: non-randomised. All subjects will receive Infanrix hexa co- 
administered with Prevenar 13. 
• 
Blinding: Open-label. Note: The study personnel operating GSK Biologicals’ 
randomisation system on internet (SBIR) and the site staff will remain blinded 
towards the treatment allocation to subjects in study 116945 [DTPA (BOOSTRIX)- 
047]. (Amended 06 September 2016) 
 
The blinding of study epoch is presented in Table 3. 


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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 
timepoints (Amended 06 September 2016): 
 
Pre-Pri: Before the first Infanrix hexa vaccine administration, a volume of 
approximately 2 mL of whole blood (to provide approximately 0.7 mL of serum) 
will be collected from all study participants. 
 
Post-Pri: One month after the last dose of Infanrix hexa primary vaccination, 
approximately 5 mL of whole blood (to provide approximately 1.7 mL of serum) 
will be collected from all study participants. 
• 
Type of study: extension of other protocol(s) 116945 [DTPA (BOOSTRIX)-047]. 
• Data collection: Electronic Case Report Form (eCRF). 
• 
Safety monitoring: An independent data monitoring committee (IDMC) (including 
paediatrician and statistician) will be put in place to oversee the safety of infants born 
to mothers who were vaccinated with Boostrix during pregnancy in the clinical study 
116945 [DTPA (BOOSTRIX)-047] i.e. each SAE/incidence of grade 3 local and 
general solicited AEs, unsolicited AEs will be reviewed by this committee as per 
IDMC approved charter. (Amended 06 September 2016) 
 
4. 
STUDY COHORT 
 
4.1. 
Number of subjects/centres 
A maximum of 680 infants aged 6-14 weeks (up to and including 14 weeks and 6 days 
of age) 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. (Amended 06 September 2016) 
 
Overview of the recruitment plan: 
 
• 
Enrolment will be terminated when all the eligible infants born to pregnant women 
from the 116945 [DTPA (BOOSTRIX)-047] study are enrolled. (Amended 06 
September 2016) 
• 
The study will be monitored by a local Study Monitor. 
• 
The treatment allocation and 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 jeopardize 
the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential. 


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All subjects must satisfy ALL the following criteria at study entry: 
 
• 
Subjects’ parent(s)/Legally Acceptable Representative(s) [LAR(s)] who, in the 
opinion of the investigator, can and will comply, with the requirements of the 
protocol (e.g. completion of the 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 between, 6 and 14 weeks of age (including 6 weeks and up to and 
including 14 weeks and 6 days of age) at the time of the first vaccination. (Amended 
06 September 2016) 
• 
Healthy subjects as established by medical history and clinical examination before 
entering into the study. 
• Born to a mother enrolled in study 116945 [DTPA (BOOSTRIX)-047]. 
• Medically stable* prematurely born infants, born after a gestation period of 27-36 
weeks may be enrolled in the study at the discretion of the investigator. 
*Medically stable refers to the condition of premature infants who do not require 
significant medical support or ongoing management for debilitating disease and who 
have demonstrated a clinical course of sustained recovery by the time they receive 
the first dose of study vaccine. 
 
4.3. 
Exclusion criteria for enrolment 
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardize 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. 
 
• 
Chronic administration (defined as more than 14 days in total) of 
immunosuppressants or other immune-modifying drugs during the period starting at 
birth prior to the first 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). 
• 
Administration of any chronic drug therapy to be continued during the study period. 
• 
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/regional immunisation schedule, that are allowed at any time during the 
study period. 


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*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 package 
insert (PI) and according to the local governmental recommendations and provided a 
written approval of the Sponsor is obtained. 
• 
Concurrently participating in another clinical study, at any time during the study 
period, in which the subject has been or will be exposed to an investigational or a 
non-investigational vaccine/product (pharmaceutical product or device). 
• 
Previous vaccination against Hib, diphtheria, tetanus, pertussis, pneumococcus, 
and/or poliovirus since birth. 
• 
History of Hib, diphtheria, tetanus, pertussis, pneumococcal, poliovirus and hepatitis 
B diseases. 
• 
Any confirmed or suspected immunosuppressive or immunodeficient condition 
including severe combined immunodeficiency disease (SCID), based on medical 
history and physical examination (no laboratory testing required). 
• 
Family history of congenital or hereditary immunodeficiency. 
• 
History of any reaction or hypersensitivity likely to be exacerbated by any 
component of the vaccine. 
• 
Major congenital defects 
• 
Serious chronic illness. 
• 
History of any neurological disorders or seizures. 
• 
Acute disease and/or fever at the time of enrolment. 
 
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. 
 
Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory 
infection) without fever may, be enrolled at the discretion of the investigator. 
• 
Administration of immunoglobulins and/or any blood products during the period 
starting at birth before the first dose of study vaccines or planned administration 
during the study period. 
• 
Hypersensitivity to latex. 
 
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. 


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The study will be conducted in accordance with the ICH Guideline for Good Clinical 
Practice (GCP), all applicable subject privacy requirements and the guiding principles of 
the Declaration of Helsinki. 
 
The study has been designed and will be conducted in accordance with the ICH 
Harmonised Tripartite Guideline for clinical investigation of medicinal products in the 
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. 
• 
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. 
 
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. These subject numbers will also be used to identify blood 
samples collected in the study. 


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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. Subjects will retain the same subject number as their 
corresponding mothers from the 116945 [DTPA (BOOSTRIX)-047] study. 
 
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 6-14 weeks (up to and 
including 14 weeks and 6 days of age) (approximately 340 subjects in each group). 
(Amended 06 September 2016) 
The central randomisation system on internet (SBIR) will be used at the investigator site 
to track enrolment to confirm or to cancel the vaccination and to give the treatment 
number associated with the vaccination. 
 
After obtaining the signed and dated ICF from the subject’s parent(s)/LAR(s) and having 
checked the eligibility of the subject, the site staff in charge of the vaccine administration 
will access SBIR. Upon providing the subject identification number, the randomisation 
system will provide the treatment number to be used for the first dose. 
 
The number of each administered treatment must be recorded in the eCRF on the Vaccine 
Administration screen. 
 
When SBIR is not available, please refer to the SBIR user guide or the Study Procedures 
Manual (SPM) for specific instructions. 
 
5.2.2.1.2. 
Treatment number allocation for subsequent doses 
 
For each dose subsequent to the first dose, the study staff in charge of the vaccine 
administration will access SBIR, provide the subject identification number and the 
system will provide a treatment number to be allocated. 
 
The number of each administered treatment must be recorded in the eCRF on the Vaccine 
Administration screen. 
 
5.3. 
Method of blinding 
This study will be conducted in an open-label manner since the treatment 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]. 


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Note: The study personnel operating SBIR and the site staff will remain blinded towards 
the treatment allocation to subjects in study 116945 [DTPA (BOOSTRIX)-047]. 
(Amended 06 September 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 in the clinical study 116945 [DTPA (BOOSTRIX)-047]. 
 
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 and unsolicited AEs at 
specified times and access to data on request by an unblinded statistician. (Amended 06 
September 2016) 
The operating rules of the IDMC will be documented in a charter. 
 
5.4.2. 
Responsibilities 
 
(Amended 06 September 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. 
 
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 and unsolicited AEs), provide GSK 
Biologicals with indications on safety profiles and make recommendations for 
consultation of regulatory authorities and on further study conduct. 


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• 
The IDMC will review the final analysis provided by the sponsor. 
 
5.4.3. 
Composition of the IDMC (Amended 06 September 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 06 September 2016) 
 
At GSK Biologicals, a Safety Review Team (SRT) will include the Central Safety 
Physician, the Clinical Research and Development Lead (CRDL) and Biostatistician of 
the project as well as Epidemiology and Regulatory representative. 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 via the GSK SRT. 


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5.5. 
Outline of study procedures 
(Amended 06 September 2016) 
 
The list of study procedures for infants receiving a 3-dose and a 2-dose schedule of 
Infanrix hexa is detailed below in Table 4 and Table 5, respectively. 
 
Table 4 
List of study procedures for infants receiving a 3-dose schedule of 
Infanrix hexa (Amended 06 September 2016) 
 
Age 
2 months 
3 or 4 
months 
4 or 6 
months 
5 or 7 
months 
Epoch 
Epoch 001 
Type of contact 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Timepoints 
Day 0 
Month 1 
or 2# 
Month 2 
or 4# 
Month 3 
or 5# 
Sampling timepoints 
Pre-Pri 
Post-Pri 
Informed consent 
● 
Check inclusion/exclusion criteria 
● 
Collect demographic data 
● 
Medical history, including medication/vaccine history* 
● 
History directed physical examination 
● 
Check contraindications and warnings and precautions 
O 
O 
O 
Record pre-vaccination body temperature 
● 
● 
● 
Record body weight, height and head circumference 
● 
● 
Study group and treatment number allocation 
● 
Treatment number allocation for subsequent doses 
O 
O 
Recording of administered treatment number 
● 
● 
● 
Blood sampling for antibody determination 
● 
● 
Vaccine administration** 
● 
● 
● 
Record any concomitant medication/vaccination 
● 
● 
● 
● 
Record any intercurrent medical conditions 
● 
● 
● 
Distribution of diary cards 
O 
O 
O 
Recording of solicited adverse events (Day 0- Day 3) by subjects’ 
parent(s)/LAR(s) 
● 
● 
● 
Recording of non-serious adverse events (Day 0-Day 30) by 
subjects’ parent(s)/LAR(s) 
● 
● 
● 
● 
Return of diary cards 
O 
O 
O 
Diary card transcription by investigator or site staff 
● 
● 
● 
Recording of SAEs 
●● 
● 
● 
● 
Recording of SAEs related to study participation or to a 
concurrent GSK medication/vaccine 
● 
● 
● 
● 
Withdrawals due to AEs/SAEs 
● 
● 
● 
● 
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. 
Pre-Pri: Blood sample to be collected before the first dose of the primary vaccination course ( 2 mL). 
Post-Pri: Blood sample to be collected one month after the last dose of the primary vaccination course ( 5 mL). 
# Depending on the immunisation schedule of the country. 
* History of all medications given to the infants will be recorded in the eCRF. 
** In some countries/regions with an Infanrix hexa 3-dose schedule, Prevenar 13 is given as a 2-dose schedule at 2 
and 4 months of age as a part of the routine immunisation programme. 


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Timepoints have been numbered based on the different vaccination schedules. D0, M1, M2 and M3 timepoints reflect 
for subjects who will be vaccinated according to the 2, 3 and 4 month schedule while D0, M2, M4 and M5 timepoints 
reflect for subjects who will be vaccinated according to the 2, 4 and 6 month schedule. 
 
Table 5 
List of study procedures for infants receiving a 2-dose schedule of 
Infanrix hexa (Amended 06 September 2016) 
 
Age 
2 or 3 months# 
4 or 5 
months# 
5 or 6 
months# 
Epoch 
Epoch 001 
Type of contact 
Visit 1 
Visit 2 
Visit 3** 
Visit 4 
Timepoints 
Day 0 
Month 2 
Month 3 
Sampling timepoints 
Pre-Pri 
Post-Pri 
Informed consent 
● 
Check inclusion/exclusion criteria 
● 
Collect demographic data 
● 
Medical history, including medication/vaccine 
history* 
● 
History directed physical examination 
● 
Check contraindications and warnings and 
precautions 
O 
O 
Record pre-vaccination body temperature 
● 
● 
Record body weight, height and head 
circumference 
● 
● 
Study group and treatment number allocation 
● 
Treatment number allocation for subsequent doses 
O 
Recording of administered treatment number 
● 
● 
Blood sampling for antibody determination 
● 
● 
Vaccine administration 
● 
● 
Record any concomitant medication/vaccination 
● 
● 
● 
Record any intercurrent medical conditions 
● 
● 
Distribution of diary cards 
O 
O 
Recording of solicited adverse events (Day 0- Day 
3) by subjects’ parent(s)/LAR(s) 
● 
● 
Recording of non-serious adverse events (Day 0- 
Day 30) by subjects’ parent(s)/LAR(s) 
● 
● 
● 
Return of diary cards 
O 
O 
Diary card transcription by investigator or site staff 
● 
● 
Recording of SAEs 
● 
● 
● 
Recording of SAEs related to study participation or 
to a concurrent GSK medication/vaccine 
● 
● 
● 
Withdrawals due to AEs/SAEs 
● 
● 
● 
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. 
Pre-Pri: Blood sample to be collected before the first dose of the primary vaccination course ( 2 mL). 
Post-Pri: Blood sample to be collected one month after the last dose of the primary vaccination course ( 5 
mL). 
# Depending on the immunisation schedule of the country. 
* History of all medications given to the infants will be recorded in the eCRF. 
** Subject receiving 2 doses of Infanrix hexa will not attend the Visit 3 
 
The intervals between study visits for subjects receiving 3 doses of Infanrix hexa at 2, 4 
and 6 months and 2, 3 and 4 months are presented in Table 6 and Table 7, respectively. 
The intervals between study visits for subjects receiving 2 doses of Infanrix hexa at 2 


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and 4 months and at 3 and 5 months are presented in Table 8 and Table 9, respectively. 
(Amended 06 September 2016) 
 
Table 6 
Intervals between study visits for subjects vaccinated with Infanrix 
hexa at 2, 4 and 6 months of age (Amended 06 September 2016) 
 
Interval 
Optimal length of interval 1 
Allowed interval2† 
Birth Visit 1 
60 days 
42-104 days 
Visit 1Visit 2 
60 days 
52 - 78 days 
Visit 2Visit 3 
60 days 
52 - 78 days 
Visit 3Visit 4 
30 days * 
21 -48 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. 
† Date of previous visit/contact is the reference date 
*If subjects return for the visits 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. 
 
Table 7 
Intervals between study visits for subjects vaccinated with Infanrix 
hexa at 2, 3 and 4 months of age (Amended 06 September 2016) 
 
Interval 
Optimal length of interval 1 
Allowed interval2† 
BirthVisit 1 
60 days 
42-104 days 
Visit 1Visit 2 
30 days 
21 -48 days 
Visit 2Visit 3 
30 days 
21 -48 days 
Visit 3Visit 4 
30 days * 
21 -48 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. 
† Date of previous visit/contact is the reference date 
*If subjects return for the visits 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. 
 
Table 8 
Intervals between study visits for subjects vaccinated with Infanrix 
hexa at 2 and 4 months of age (Amended 06 September 2016) 
 
Interval 
Optimal length of interval 1 
Allowed interval2† 
Birth Visit 1 
60 days 
42-104 days 
Visit 1Visit 2 
60 days 
52-78 days 
Visit 2Visit 4** 
30 days* 
21- 48 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. 
† Date of previous visit/contact is the reference date 
*If subjects return for the visits 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. 
** Subject receiving 2 doses of Infanrix hexa will not attend the Visit 3 


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Table 9 
Intervals between study visits for subjects vaccinated with Infanrix 
hexa at 3 and 5 months of age (Amended 06 September 2016) 
 
Interval 
Optimal length of interval 1 
Allowed interval2† 
Birth Visit 1 
90 days 
42-104 days 
Visit 1Visit 2 
60 days 
52-78 days 
Visit 2Visit 4** 
30 days* 
21-48 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. 
† Date of previous visit/contact is the reference date 
*If subjects return for the visits 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. 
** Subject receiving 2 doses of Infanrix hexa will not attend the Visit 3 
5.6. 
Detailed description of study procedures 
 
5.6.1. 
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. 
 
Note: At Visit 4, parent(s)/LAR(s) will be informed about the booster follow-up study 
DTPA (BOOSTRIX)-049 BST: 048 in which their infants will receive a booster dose of 
the study vaccines according to the national immunisation programme. (Amended 06 
September 2016) 
 
5.6.2. 
Check inclusion and exclusion criteria 
 
Check all inclusion and exclusion criteria as described in Sections 4.2 and 4.3 before 
enrolment. 
 
5.6.3. 
Collect demographic data 
 
Record demographic data such as (age in weeks and race) in the subject’s eCRF. 
 
5.6.4. 
Medical history 
 
Obtain the subject’s medical history by interview and/or review of the subject’s medical 
records and record any pre-existing conditions or signs and/or symptoms present in a 
subject prior to the first study vaccination in the eCRF. 
 
5.6.5. 
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 any medication and vaccine administration prior to 
the study vaccination in the eCRF. 


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5.6.6. 
History directed physical examination 
 
Perform a history directed physical examination. If the investigator determines 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. 
 
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. 
 
5.6.7. 
Check contraindications, warnings and precautions to 
vaccination 
 
Contraindications, warnings and precautions to vaccination must be checked at the 
beginning of each vaccination visit. Refer to Sections 6.5 and 6.6 for more details. 
 
5.6.8. 
Assess pre-vaccination body temperature 
 
The axillary, rectal, oral or tympanic body temperature of all subjects needs to be 
measured prior to any study vaccine administration. The preferred route for recording 
temperature in this study will be rectal/axillary. 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 6 and Table 7 as applicable). 
 
5.6.9. 
Record body weight, height and head circumference 
 
(Amended 06 September 2016) 
 
Record body weight (kg), height (cm) and head circumference (cm) of the infant at Visit 
1 and Visit 4 in the eCRF. 
 
5.6.10. 
Study group and treatment number allocation 
 
Study group and treatment number allocation will be performed as described in Section 
5.2.2. The number of each administered treatment must be recorded in the eCRF. 
 
5.6.11. 
Sampling 
 
Refer to the Module on Biospecimen Management in the SPM for detailed instructions 
for the collection, handling and processing of the samples. 
 
5.6.11.1. 
Blood sampling for immune response assessments 
 
Blood samples will be taken during certain study visits as specified in Section 5.5 List of 
Study Procedures. 


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• 
Pre-Pri: Before the first Infanrix hexa vaccine administration, a volume of 
approximately 2 mL of whole blood (to provide approximately 0.7 mL of serum) will 
be collected. (Amended 06 September 2016) 
• 
Post-Pri: One month after the last dose of Infanrix hexa primary vaccination at Visit 
4, approximately 5 mL of whole blood (to provide approximately 1.7 mL of serum) 
will be collected. (Amended 06 September 2016) 
• 
After centrifugation, serum samples should be kept at –20°C/ –4°F or below until 
shipment. Refer to the SPM and laboratory manual for more details on sample 
storage conditions. (Amended 06 September 2016) 
 
5.6.12. 
Study vaccine administration 
 
(Amended 06 September 2016) 
 
• 
After completing all prerequisite procedures prior to vaccination, study vaccines will 
be administered intramuscularly (IM) in the thigh as described in Section 6.3. If the 
investigator or delegate determines that the subject’s health on the day of 
administration temporarily precludes vaccination, the visit will be rescheduled within 
the allowed interval for this visit (see Table 6 to Table 9, as applicable). 
• 
The subjects will be observed closely for at least 30 minutes following the 
administration of the vaccine with appropriate medical treatment readily available in 
case of anaphylaxis. 
 
5.6.13. 
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. 
 
5.6.14. 
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. 
 
• 
At each vaccination visit, diary cards will be provided to the subject’s 
parent(s)/LAR(s) with instructions by the study staff. The subject’s parent(s)/LAR(s) 
will record body (rectal/axillary) temperature and any solicited local/general AEs 
(i.e. on the day of vaccination and during the next 3 days) or any unsolicited AEs 
(i.e. on the day of vaccination and during the next 30 days occurring after 


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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 the next visit. (Amended 06 September 2016) 
• 
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 or site 
staff will transcribe the collected information into the eCRF in English. 
 
5.6.15. 
Study conclusion 
 
The investigator will: 
 
• 
review data collected to ensure accuracy and completeness, 
• 
ask each subject’s parent(s)/LAR(s) if they are interested to allow the subject to 
participate in the follow-up study DTPA (BOOSTRIX)-049 BST: 048. Refer to the 
Section 9.3 for more details. (Amended 06 September 2016) 
• 
complete the Study Conclusion screen in the eCRF. 
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 06 September 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). 


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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 ATP analysis (See Section 10.4 for the definition of 
cohorts to be analysed). The investigator must ensure that his/her personnel and the 
laboratory(ies) under his/her supervision comply with this requirement. However, when 
GSK Biologicals does not provide material for collecting and storing clinical samples, 
appropriate materials from the investigator’s site must be used. Refer to the Module on 
Clinical Trial Supplies in the SPM. 
 
5.7.2. 
Biological samples 
 
The biological samples are presented in Table 10. 
 
Table 10 
Biological samples 
 
Sample type 
Quantity 
Unit 
Timepoint 
Blood 
2 * 
ml 
Visit 1 
Blood 
5 * 
ml 
Visit 4 
* Approximately 
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 11). 


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Table 11 
Humoral Immunity (Antibody determination) (Amended 06 
September 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* 
or CEVAC 
SER 
Clostridium tetani.Tetanus 
Toxoid Ab.IgG 
ELI 
NA 
IU/ml 
0.1 
GSK 
Biologicals* 
or CEVAC 
SER 
Bordetella pertussis.Filamentous 
Hemaglutinin Ab.IgG 
ELI 
NA 
EU/ml 
5 
GSK 
Biologicals* or
CEVAC 
SER 
Bordetella pertussis.Pertactin 
Ab.IgG 
ELI 
NA 
EU/ml 
5 
GSK 
Biologicals* or
CEVAC 
SER 
Bordetella pertussis.Pertussis 
Toxin Ab.IgG 
ELI 
NA 
EU/ml 
5 
GSK 
Biologicals* 
or CEVAC 
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 
Poliovirus Sabin Type 2 Ab 
Poliovirus Sabin Type 3 Ab 
NEU 
NA 
ED50 
8 
GSK 
Biologicals* 
SER 
Haemophilus influenzae type 
b.Polyribosyl Ribitol Phosphate 
Ab 
ELI 
NA 
µg/ml 
0.15 
GSK 
Biologicals* 
or CEVAC 
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 
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 
† 
Streptococcus 
pneumoniae.Polysaccharide 
18C Ab.IgG 
Streptococcus 
pneumoniae.Polysaccharide 19A 
Ab.IgG 
Streptococcus 
pneumoniae.Polysaccharide 19F 
Ab.IgG 
Streptococcus 
pneumoniae.Polysaccharide 23F 
Ab.IgG 
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. 
** At the discretion of GSK Biologicals, pneumococcal testing may be done at a GSK Biologicals laboratory or the 
World Health Organisation (WHO) reference laboratory. 


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*** 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 = Neutralization assay 
CLIA = ChemiLuminescence ImmunoAssay 
CEVAC: Centre for Vaccinology, Ghent University and Hospital 
IU/mL = International Units/millilitre 
mIU/mL = milliInternational Units/millilitre 
EL.U/mL = ELISA Units/millilitre 
µg/ml = Micrograms/millilitre 
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 
 
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 12. 
 
Table 12 
Immunological read-outs (Amended 06 September 2016) 
 
Blood sampling timepoint 
No. subjects 
Component 
Components 
priority rank 
Type of contact and 
timepoint 
Sampling timepoint 
Visit 1 (Day 0) 
Pre-Pri 
All 
PT, FHA, PRN 
1 
D, T 
2 
Visit 4 (Month 3 or Month 
Post-Pri 
All 
PT, FHA, PRN 
1 
5)* 
HBs, PRP 
2 
D, T 
3 
Poliovirus types 1, 2, 3 
4 
13 pneumococcal serotypes 
5 
Pre-Pri: Blood sample to be collected before the first dose of the primary vaccination course. 
Post-Pri: Blood sample to be collected one month after the last dose of the primary vaccination course, depending on 
the vaccination schedule. 
* Depending on the vaccination schedule 
 
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). 
The assay cut-off of ELISA is currently set at 0.1 International Units per ml (IU/ml), 
which provides a conservative estimate of the percentage of subjects deemed to be 
protected [Camargo, 1984; Melville-Smith, 1983]. 


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• 
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 
expressed in terms of the reciprocal of the dilution resulting in 50% inhibition. 
Antibody titres greater than or equal to 1:8 are considered as 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 currently 
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 assay. 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 vaccine 
The candidate vaccine 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 vaccine are labelled and packed according to applicable regulatory requirements. 
 
Commercial vaccine are assumed to comply with the specifications given in the 
manufacturer’s SPC. 
 
The study vaccines, formulation and presentation is detailed in Table 13. 
 
Table 13 
Study vaccines (Amended 06 September 2016) 
 
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)=32DU; 
Aluminium=700µg Al3+ 
The DTPa-HBV- 
IPV component 
is presented as 
a turbid white 
suspension in a 
pre-filled 
syringe. 
0.5 ml * 
2 or 3** 
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; 
Suspension for 
injection in a 
pre-filled 
syringe 
0.5 ml 
2 or 3 *** 


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Treatment 
name 
Vaccines name 
Formulation 
Presentation 
Volume to be 
administered* 
Number 
of  
doses 
PS19A=2.2µg CRM197; 
PS19F=2.2µg CRM197; 
PS23F=2.2µg CRM197; 
AlPO₄=125µg Al3+ 
*After reconstitution 
** In some countries, Infanrix hexa is given as a 2-dose schedule at 2 and 4 months of age or at 3 and 5 
months of age. In other countries Infanrix hexa is given as a 3-dose schedule at 2, 4 and 6 months of age or at 
2, 3 and 4 months of age as recommended by the routine immunisation programme. 
*** I Prevenar 13 is administered at the same schedule as Infanrix hexa except in some countries/regions with an 
Infanrix hexa 3-dose schedule where Prevenar 13 is given as a 2-dose schedule at 2 and 4 months of age as a part 
of the routine immunisation programme. 
(Amended 06 September 2016) 
 
6.2. 
Storage and handling of study vaccine 
The study vaccine must be stored at the respective label storage temperature conditions in 
a safe and locked place. Access to the storage space should be limited to authorized study 
personnel. The storage conditions will be assessed during pre-study activities under the 
responsibility of the sponsor study contact. The storage temperature should be 
continuously monitored with calibrated (if not validated) temperature monitoring 
device(s) and recorded. Refer to the Module on Clinical Trial Supplies in the SPM for 
more details on storage of the study vaccine. 
 
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 vaccine. 
 
6.3. 
Dosage and administration of study vaccines 
The dosage and administration of study vaccines is given in Table 14. 


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Table 14 
Dosage and administration (Amended 06 September 2016) 
 
Type of contact 
and timepoint 
Volume to be 
administered 
Study group Treatment 
name 
Route 1 
Site 
Side 
Visit 1 (Day 0), 
Visit 2 (Month 2), 
Visit 3 (Month 4)* 
Or 
Visit 1 (Day 0), 
Visit 2 (Month 1), 
Visit 3 (Month 
2)** 
0.5 ml 
dTpa Group 
and Control 
Group 
Infanrix 
hexa 
IM 
Thigh 
Right 
Visit 1 (Day 0), 
Visit 2 (Month 2), 
Visit 3 (Month 4)* 
Or 
Visit 1 (Day 0), 
Visit 2 (Month 2)† 
Or 
Visit 1 (Day 0), 
Visit 2 (Month 
1), Visit 3 
(Month 2** 
0.5 ml 
dTpa Group 
and Control 
Group 
Prevenar 
13 
IM 
Thigh 
Left 
Visit 1 (Day 0), 
Visit 2 (Month 
2)*** 
0.5 ml 
dTpa Group 
and Control 
Group 
Infanrix 
hexa 
IM 
Thigh 
Right 
Visit 1 (Day 0), 
Visit 2 (Month 
2)*** 
0.5 ml 
dTpa Group 
and Control 
Group 
Prevenar 
13 
IM 
Thigh 
Left 
1Intramuscular (IM) 
*For subjects vaccinated with Infanrix hexa at 2, 4 and 6 months of age 
** For subjects vaccinated Infanrix hexa at 2, 3 and 4 months of age 
*** For subjects vaccinated with Infanrix hexa at 2 and 4 months of age or at 3 and 5 months of age. These 
subjects will receive Prevenar 13 at the same vaccination schedule. 
† In some countries/regions with an Infanrix hexa 3-dose schedule, Prevenar 13 is given as a 2-dose schedule at 2 
and 4 months of age as a part of the routine immunisation programme. 
 
6.4. 
Replacement of unusable vaccine doses 
In addition to the vaccine doses provided for the planned number of subjects, at least 5% 
additional vaccine doses will be supplied to replace those that are unusable. 
 
6.5. 
Contraindications to subsequent vaccination 
The following events constitute absolute contraindications to further administration of 
Infanrix hexa. If any of these events occur during the study, the subject must not receive 
additional doses of vaccine but may continue other study procedures at the discretion of 
the investigator (see Section 8.4). 
 
• 
Anaphylaxis following the administration of vaccine. 
• 
Hypersensitivity reaction to any component of the vaccine(s) and any excipients in 
the formulation. 


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• 
Any condition that in the judgment of the investigator would make intramuscular 
injection unsafe. 
• 
Contraindication to Infanrix hexa: 
 
Encephalopathy defined as an acute, severe central nervous system disorder 
occurring within 7 days following vaccination 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. 
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 Table 6 to Table 9 as applicable), or the subject may be withdrawn at the 
discretion of the investigator (see Section 8.4). (Amended 06 September 2016) 
 
• 
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 rectal/axillary. 
 
Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory 
infection) without fever can be administered all vaccines. 
 
6.6. 
Warnings and precautions 
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) within 48 
hours of vaccination. 
 
Persistent, inconsolable crying lasting  3 hours, occurring within 48 hours of 
vaccination. 
 
Convulsions with or without fever, occurring within 3 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) immunisation 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. 
• 
The potential risk of apnoea and the need for respiratory monitoring for 48-72 hours 
should be considered when administering the primary immunisation series to very 
preterm infants (born ≤ 28 weeks of gestation) and particularly for those with a 
previous history of respiratory immaturity. As the benefit of vaccination is high in 
these infants, vaccination should not be withheld or delayed. 
• 
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 hypotonic 
hyporesponsive episode (HHE) were observed with concomitant administration of 
Infanrix hexa and Prevenar 13. 
Refer to the approved product label/package insert for warnings and precautions for the 
use of Prevenar 13. 
 
6.7. 
Concomitant medications/products and concomitant 
vaccinations 
At each study visit, the investigator should question the subject’s parent(s)/LAR(s) about 
any medications/products taken and vaccinations received by the subject. 


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6.7.1. 
Recording of concomitant medications/products and 
concomitant vaccinations 
 
The following concomitant medications/products/vaccines must be recorded in the 
eCRF. 
 
• 
All concomitant medications/products, except vitamins and dietary supplements, 
administered in the period starting from the first dose of study vaccines (Visit 1) and 
ending at the last study visit (Visit 4). 
• 
Any concomitant vaccination administered in the period starting from the 
administration of the first dose of study vaccines (Visit 1) and ending at the last study 
visit (Visit 4). Note: Medications/vaccinations listed prior to the first dose of study 
vaccines 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. 
 
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 
vaccines used within 30 days preceding the first dose of study vaccines, or planned 
use during the study period. 
• 
Immunosuppressants or other immune-modifying drugs administered chronically 
(i.e. more than 14 days) since birth. 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 


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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 programme, the time period described above can be reduced if 
necessary for that vaccine provided it is licensed and used according to its SmPC or 
Prescribing Information and according to the local governmental recommendations 
and provided a written approval of the Sponsor is obtained. 
• 
Immunoglobulins and/or any blood products administered during the study period. 
6.8. 
Intercurrent medical conditions that may lead to elimination 
of a subject from ATP analyses 
At each study visit subsequent to the first vaccination, 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 (e.g. any 
confirmed or suspected immunosuppressive or immunodeficient condition) or are 
confirmed to have an alteration of their initial immune status. 
 
7. 
HEALTH ECONOMICS 
Not applicable. 
 
8. 
SAFETY 
The investigator or site staff is/are responsible for the detection, documentation and 
reporting of events meeting the criteria and definition of an 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 


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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. 
• 
New conditions detected or diagnosed after investigational vaccine 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. 
 
Examples of an AE DO NOT include: 
 
• 
Medical or surgical procedures (e.g. endoscopy, appendectomy); the condition that 
leads to the procedure is an AE/SAE. 
• 
Situations where an untoward medical occurrence did not occur (e.g. social and/or 
convenience admission to a hospital, admission for routine examination). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 
• 
Pre-existing conditions or signs and/or symptoms present in a subject prior to the 
first study vaccination. These events will be recorded in the medical history section 
of the eCRF. 
 
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. 


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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 
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 15 
 Solicited local adverse events 
Pain at injection site 
Redness at injection site 
Swelling at injection site 


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8.1.3.2. 
Solicited general adverse events 
The following general AEs will be solicited: 
Table 16 
 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 etc ) 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 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, 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 each dose of study vaccine 
(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 first receipt of study 
vaccine and will end 30 days following administration of the last dose of study vaccine 
for each subject. See Section 8.3 for instructions on reporting of SAEs. 


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All AEs/SAEs leading to withdrawal from the study will be collected and recorded from 
the time of the first receipt of study vaccine. 
 
SAEs that are related to the investigational vaccine will be collected and recorded from 
the time of the first receipt of study vaccine until the subject is discharged from the study. 
 
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 subjects’ 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 17, Table 18 and Table 19. (Amended 06 September 2016) 
 
Table 17 
Reporting periods for adverse events and serious adverse events for 
subjects vaccinated with Infanrix hexa at 2, 4 and 6 months of age 
(Amended 06 September 2016) 
 
Event 
Pre- 
V1* 
V1 3 d 
post 
V1 
30 d 
post
-V1 
V2 3 d 
post
V2 
30 d 
post- 
V2 
V3 
3 d 
post 
V3 
30 d 
post-V3 
V4 
Study Conclusion 
D0 
D 30
M2 
M 4 
M5 
Solicited local 
and general 
AEs 
Unsolicited AEs 
AEs/SAEs 
leading to 
withdrawal from 
the study 
SAEs† 
SAEs related to 
study participation 
or concurrent GSK 
medication/ 
vaccine† 
* i.e. consent obtained. Pre-V: pre-vaccination; V: vaccination; Post-V: post-vaccination; D: Day, M: Month 
† AEs/SAEs reported from the administration of first dose of primary vaccination until the end of study will be recorded 
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Table 18 
Reporting periods for adverse events and serious adverse events for 
subjects vaccinated with Infanrix hexa at 2, 3 and 4 months of age 
(Amended 06 September 2016) 
 
Event 
Pre- 
V1* 
V1 3 d 
post 
V1 
30 d 
post
-V1 
V2 3 d 
post
V2 
30 d 
post- 
V2 
V3 
3 d 
post 
V3 
30 d 
post-V3 
V4 
Study Conclusion 
D0 
D 30
M1 
M2 
M3 
Solicited local 
and general 
AEs 
Unsolicited AEs 
AEs/SAEs 
leading to 
withdrawal from 
the study 
SAEs† 
SAEs related to 
study participation 
or concurrent GSK 
medication/ 
vaccine† 
* i.e. consent obtained. Pre-V: pre-vaccination; V: vaccination; Post-V: post-vaccination; D: Day, M: Month 
† AEs/SAEs reported from the administration of first dose of primary vaccination until the end of study will be recorded 
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Table 19 Reporting periods for adverse events and serious adverse events for 
subjects vaccinated with Infanrix hexa at 2 and 4 months of age or at 
3 and 5 months of age (Amended 06 September 2016) 
 
Event 
Pre- 
V1* 
V1 
3 d 
post 
V1 
30 d 
post- 
V1 
V2 
3 d 
post 
V2 
30 d 
post- 
V2 
V4 
Study Conclusion 
D0 
D 30 
M2 
M3 
Solicited local 
and general 
AEs 
Unsolicited 
AEs 
AEs/SAEs 
leading to 
withdrawal 
from the study 
SAEs† 
SAEs related to 
study 
participation 
or concurrent 
GSK medication/ 
vaccine† 
* i.e. consent obtained. Pre-V: pre-vaccination; V: vaccination; Post-V: post-vaccination; D: Day, M: Month 
† AEs/SAEs reported from the administration of first dose of primary vaccination until the end of study will be 
recorded and analysed in this study (i.e. a part of 201330 [DTPA (BOOSTRIX)-048 PRI] study). 
 
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 17, Table 18 or Table 19 (Amended 06 September 
2016). 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 20 
Intensity scales for solicited symptoms in infants less than 6 years 
of age 
 
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 rectal/axillary. 
 
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 tympanic route) will be scored at GSK 
Biologicals as follows: (Amended 06 September 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 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 to determine his/her assessment. 
 
There may be situations when a SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK Biologicals. However, it is very 
important that the investigator always makes an assessment of causality for every event 
prior to submission of the Expedited Adverse Events Report to GSK Biologicals. The 
investigator may change his/her opinion of causality in light of follow-up information and 
update the SAE information accordingly. The causality assessment is one of the criteria 
used when determining regulatory reporting requirements. 
 
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 
administered. The investigator should, therefore, assess whether the AE could be causally 
related to vaccination rather than to the individual vaccines. 


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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 vaccine, 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. 
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 in the 
eCRF. 
 
8.3. 
Reporting of serious adverse events and other events 
 
8.3.1. 
Prompt reporting of serious adverse events and other 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 21, once the investigator determines that 
the event meets the protocol definition of a SAE. 
 
Table 21 
Timeframes for submitting serious adverse events 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: PPD 
or PPD 
              
Email address: PPD 
 
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 
not have all information regarding a SAE, the report should still be completed within 24 


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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 21. 
 
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 21). 
 
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 visits/contacts until 30 
days after the last 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. 
• 
with other non-serious AEs, until the end of the study period or they are lost to 
follow-up. 
 
If the investigator receives additional relevant information on a previously reported SAE, 
he/she will provide this information to GSK Biologicals using a electronic Expedited 
Adverse Events Report as applicable. 
 
GSK Biologicals may request that the investigator performs or arranges the conduct of 
additional clinical examinations/tests and/or evaluations to elucidate as fully as possible 
the nature and/or causality of the AE or SAE. The investigator is obliged to assist. If a 
subject dies during participation in the study or during a 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). 


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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 
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). 


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• 
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. 
 
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). 
 
9.2.2. 
Subject withdrawal from investigational vaccine 
 
A ‘withdrawal’ from the investigational vaccine refers to any subject who does not 
receive the complete treatment, i.e. when no further planned dose is administered from 
the date of withdrawal. A subject withdrawn from the investigational vaccine may not 
necessarily be withdrawn from the study as further study procedures or follow-up may be 
performed (safety or immunogenicity) if planned in the study protocol. 
 
Information relative to premature discontinuation of the investigational vaccine will be 
documented on the Vaccine Administration screen of the eCRF. The investigator will 
document whether the decision to discontinue further vaccination 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. 
• 
Other (specify). 
 
9.3. 
Extension study 
At the end of the study (study conclusion visit), the investigator will ask each subject’s 
parent(s)/LAR(s) if they are interested to allow the subject to participate in the follow-up 
study DTPA (BOOSTRIX)-049 BST: 048. If a subject’s parent(s)/LAR(s) are not 
interested in allowing their child to participate in the follow-up study the reason for 
refusal will be documented in the subject’s eCRF. 


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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 last dose of primary vaccination. 
 
Vaccine response to PT, FHA and PRN antigens, one month after the last dose 
of primary vaccination. 
 
10.2. 
Secondary endpoints 
• 
Persistence of antibodies before the first dose of Infanrix hexa. 
 
Anti-diphtheria and anti-tetanus seroprotection status, anti-PT, anti-FHA, anti- 
PRN seropositivity status and antibody concentrations. 
• 
Immunogenicity with respect to components of Infanrix hexa and Prevenar 13. 
 
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, one month after the last dose of primary 
vaccination. 
• 
Immunogenicity with respect to components of Infanrix hexa. 
 
Anti-PT, anti-FHA, anti-PRN antibody seropositivity status, one month after the 
last dose of primary vaccination. 
• 
Solicited local and general symptoms. 
 
Occurrence of solicited local/general symptoms during the 4-day (Day 0-Day 3) 
follow-up period after each vaccination. 
• 
Unsolicited adverse events. 
 
Occurrence of unsolicited symptoms during the 31-day (Day 0-Day 30) follow- 
up period after each vaccination. 
• 
Serious adverse events. 
 
Occurrence of SAEs from first vaccination dose to study end. 
10.3. 
Determination of sample size 
The sample size for this study is not derived from any power based calculation. The 
sample size would consist of all infants whose mothers were enrolled in the study 116945 
[DTPA (BOOSTRIX)-047]. Considering approximately 10%-30% reduction in the 
number of evaluable subjects due to drop-outs and protocol violations from the initial 


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study, the table below gives the estimated sample size of evaluable subjects that can be 
expected and the precision achieved with this sample for various expected values. 
 
Table 22 
Exact 95% CI of the different values of observed response rate 
(vaccine response rate or seroprotection rate) for a sample size of 
238-300 subjects) 
 
Number of 
evaluable 
subjects 
Observed response rate 
expressed as a percentage 
Exact 2-sided 95% CI for this observed rate for a sample size of 300 
subjects 
Lower Limit (LL) 
Upper Limit (UL) 
300 
70 
64.5 
75.1 
75 
69.7 
79.8 
80 
75.0 
84.4 
85 
80.4 
88.8 
92 
88.3 
94.8 
93 
89.5 
95.6 
94 
90.7 
96.4 
95 
91.9 
97.2 
96 
93.1 
97.9 
97 
94.4 
98.6 
98 
95.7 
99.3 
99 
97.1 
99.8 
100 
98.8 
100.0 
272 
70 
64.4 
75.6 
75 
69.4 
80.0 
80 
74.9 
84.7 
85 
80.5 
89.3 
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 
70 
63.9 
75.9 
75 
69.2 
80.6 
80 
74.6 
85.1 
85 
80.1 
89.5 
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 
Reference study: 
217744/070: Group receiving DTPa-HBV-IPV/Hib full-term infants according to 2, 4, 6 schedule in Spain. 
217744/078: Group receiving DTPa-HBV-IPV/Hib +Prevenar according to 2, 3, 4 schedule in Germany. 


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217744/054: Group receiving DTPa-HBV-IPV/Hib according to 3,5,11 schedule in Italy and Germany 
[Hardy-Fairbanks, 2013]. Based on this reference, the confidence interval of lower response rate also included in case 
of any immune interference. 
 
The reference values are presented in Table 23. 


 
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Table 23 Reference values 
 
Study Group 
Schedule 
(months) 
N 
D 
T 
PT VR 
FHA VR 
PRN VR 
HBs 
POLIO 
TYPE 1 
POLIO TYPE 2 
POLIO TYPE 3 
PRP 
217744/070 
DTPa-HBV-IPV/Hib 
pre-term 
2,4,6 
93 
100 
100 
98.9 
100 
100 
93.4 
100 
100 
100 
92.5 
DTPa-HBV-IPV/Hib 
full-term 
2,4,6 
89 
100 
100 
98.9 
100 
98.9 
95.2 
100 
100 
100 
97.8 
217744/078 
DTPa-HBV-IPV/Hib 
2,3,4 
138 
100 
100 
100 
97.8 
97.8 
97.8 
100 
98.4 
99.2 
95.7 
DTPa-HBV-IPV/Hib 
+ Prevenar 
2,3,4 
141 
100 
100 
98.6 
94.8 
95.0 
97.9 
100 
99.3 
100 
93.6 
217744/054 
DTPa-HBV-IPV/Hib 
3,5,11 
177 
97.6 
99.4 
95.9 
97.5 
98.2 
96.4 
97.4 
94.7 
99.3 
92.8 
N = number of subjects included in the ATP cohort for immunogenicity 
D and T: % with antibody concentration  0.1 IU/ml; HBs: % with antibody concentration 10 mIU/ml; polio: % with antibody titre 1:8; PRP: % with antibody concentrations 
0.15µg/ml. 
VR= Vaccine response: 1) Pre-vaccination seronegative subjects: appearance of antibodies (concentration cut-off) 2) Pre-vaccination seropositive subjects: post-vaccination 
concentration pre-vaccination concentration 
Pre-term infants (gestation period < 37 weeks) 
Full-term infants (gestation period ≥ 37 weeks) 
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10.4. 
Cohorts for analyses 
Three cohorts are defined for the purpose of the analysis: 
 
• 
Total vaccinated cohort (TVC). 
• 
ATP cohort for analysis of safety 
• 
ATP cohort for analysis of immunogenicity 
 
10.4.1. 
Total vaccinated cohort 
 
The TVC will include all vaccinated subjects for whom data are available. (Amended 06 
September 2016) 
• 
A safety analysis based on the TVC will include all subjects with at least one vaccine 
administration documented. 
• 
An immunogenicity analysis based on the TVC will include vaccinated subjects for 
whom data concerning immunogenicity endpoint measures are available. 
 
10.4.2. 
ATP 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 at least one dose of study vaccines according to their random 
assignment. 
• 
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. 
 
10.4.3. 
ATP cohort for analysis of immunogenicity 
 
The ATP cohort for immunogenicity will include all evaluable subjects from the ATP 
cohort for safety: 
 
• 
who meet all eligibility criteria; 
• 
who comply with the procedures and intervals defined in the protocol. 
• 
who do not meet any of the criteria for elimination from an ATP analysis (refer to 
Section 6.7.2) during the study; 
• 
who do not receive a product leading to exclusion from an ATP analysis as listed in 
Section 6.7.2; 
• 
who do not present with a medical condition leading to exclusion from an ATP 
analysis as listed in Section 6.8; 
• 
who are born full term (full term is defined  37 weeks of gestation); 


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• 
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 vaccines antigen component. 
 
The interval between the last vaccination visit and post-primary 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 the 
laboratory assays section (Section 5.7.1). 
 
• 
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 11. 
• 
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. 
• 
Vaccine response to the PT, FHA and PRN antigens, is defined as: 
 
appearance of antibodies in subjects who were initially seronegative (i.e., with 
concentrations <cut-off value). 
 
at least maintenance of pre-vaccination antibody concentrations in subjects who 
were initially seropositive (i.e., with concentrations cut-off value). 
• 
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 


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of the assay will be given an arbitrary value of half the cut-off for the purpose of 
GMT/GMC calculation. 
 
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 4 days post-vaccination, 
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 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, who 
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 
will be considered. Subjects, who 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 weeks, race, height [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; 
• 
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. 


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For each group, at each timepoint 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. 
For serology results one month after last vaccination dose: 
• 
The vaccine response rates to PT, FHA and PRN (with exact 95% CI) will be 
calculated. 
• 
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. 
Additional summaries will be provided based on country. 
 
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 doses and 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] after each 
vaccine dose and overall. 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. 


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• 
The percentage of doses and 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 each 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. 
• 
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 the 31-day follow- 
up (Day 0 – Day 30) will be tabulated (with exact 95% CI [Clopper, 1934]) after 
each vaccine dose and overall. 
• 
SAEs reported from first vaccination dose up to study end will be described in detail. 
• 
Withdrawal due to AEs and SAEs following vaccinations will be described in detail. 
 
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 and SAEs. A statistical report and a clinical report will be written 
at that time. 


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10.10.2. 
Statistical considerations for interim analyses 
 
No interim analysis is planned for this study. 
 
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 


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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 
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 


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his/her time and the time of his/her staff to the auditor/inspector to discuss findings and 
any relevant issues. 
 
11.5. 
Posting of information on publicly available clinical trial 
registers and publication policy (Amended 06 September 
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 
monthsin 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 
Infanrix hexa and Prevenar 13 vaccines should be administered to the infants according 
to the immunisation schedules of the participating countries. 


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13. 
REFERENCES 
Amirthalingam, G. et al. Effectiveness of maternal pertussis vaccination in England:an 
observational study. Lancet 2014. Available at http://dx.doi.org/10.1016/S0140- 
6736(14)60686-3). Accessed on 06 September 2016. 
 
Anderson P. The protective levels of serum antibodies to the capsular polysaccharide of 
Haemophilus influenzae type b. J Infect Dis 1984;149:1034-1035. 
 
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 on 06 September 2016. 
 
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. 
 
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(a), http://www.cdc.gov/pertussis/outbreaks/trends.html. Accessed on 06 
September 2016. 
 
Center for Disease Control and Prevention (CDC). Final Pertussis Surveillance Report 
2012.Published in 2013(b). http://www.cdc.gov/pertussis/downloads/pertuss-surv-report- 
2012.pdf. Accessed on 06 September 2016 
 
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). 
 
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. 
 
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. 


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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://transparency.dh.gov.uk/2012/09/28/jcvi-pertussis/ ; Accessed on 06 September 
2016. 
 
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 on 06 September 2016. 
 
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 on 06 
September 2016. 
 
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. 
 
Technical Advisory Group (TAG) on Vaccine-preventable Diseases. Vaccination: a 
shared responsibility. Quito, Ecuador 3-5 July 2013. 


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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 24 
GSK Biologicals’ laboratories (Amended 06 September 2016) 
 
Laboratory 
Address 
GSK Biologicals Clinical 
Sciences Laboratory, 
Rixensart 
Biospecimen Reception - B7/44 
Rue de l'Institut, 89 - B-1330 Rixensart - 
Belgium 
GSK Biologicals Clinical 
Sciences Laboratory, Wavre- 
Nord Noir Epine 
Avenue Fleming, 20 - B-1300 Wavre - 
Belgium 
 
 
Table 25 
Outsourced laboratories (Amended 06 September 2016) 
 
Laboratory 
Address 
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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PPD 
PPD 
PPD 
PPD 
APPENDIX B AMENDMENTS AND ADMINISTRATIVE CHANGES TO THE 
PROTOCOL 
 
GlaxoSmithKline Biologicals SA 
Vaccines R &D 
Protocol Amendment 1 
eTrack study number 
and Abbreviated Title 
201330 [DTPA (BOOSTRIX)-048 PRI] 
EudraCT number 
2014-001117-41 
Amendment number: 
Amendment 1 
Amendment date: 
06 September 2016 
Co-ordinating authors: 
PPD 
, Lead Scientific Writer and PPD 
, Scientific Writer 
Rationale/background for changes: 
Given the fact that only infants born from mothers vaccinated in the previous study 
(116945 [DTPA (BOOSTRIX)-047) can be enrolled in the current study, the enrolment 
in DTPA (BOOSTRIX)-047 study has an impact on this current study (e.g. cohorts to 
be investigated). Initially, the DTPA (BOOSTRIX)-047 study was opened only in 
countries using 3-dose primary vaccination series against diphtheria, tetanus and 
pertussis in infants. Nevertheless, the 2-dose primary vaccination schedule 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 therefore the current study to 
countries using 2-dose primary vaccination series in infants with the aim to increase the 
scientific value of the study and generate clinical data in diverse infant vaccination 
schedules. 
The notion of end of study was added and Section 11.5 describing the posting of 
information on public registry was revised accordingly. 
The names and functions of the contributing authors have been updated. The name of 
GSK Biologicals’ Global Vaccines Clinical Laboratories (GVCL) department has been 
updated to Clinical Laboratory Sciences (CLS) and the name of outsourced laboratory 
(Quest Diagnostic laboratory is now called Q² Solutions) has also 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) 
• 
, 
and 
, Project-Level CRDLs 


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PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
and 
PPD 
PPD 
and 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
, 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
• 
, PPD 
Leads 
and 
, Study Delivery 
• 
and 
GVCL CLS Study Project Managers 
• 
and 
, Global Clinical Regulatory Affairs Representatives 
• 
and 
, Clinical Safety Representatives 
• 
and 
Study Data Managers 
• 
, Project Data Manager 
• 
and 
Senior Managers, Biometrics 
• 
and 
,Vaccines Supply Coordinator Clinical Trial Supplies 
Managers 
• 
, Study Delivery Manager 
• 
, Local Delivery Leads 
• 
, Local Delivery Leads 
• 
and 
, Local Delivery Leads 
• 
, Local Delivery Lead 
• 
, Local Delivery Lead 
• 
and 
, Local Delivery Leads 
List of Abbreviations: The following changes have been made 
 
CEVAC: 
Centre for Vaccinology, Ghent University and Hospital 
 
CLS: 
Clinical Laboratory Sciences 
 
CRDL: 
Clinical Research and Development Lead 
 
DTPa--A-HBV-IPV/Hib: 
Combined diphtheria-tetanus-acellular pertussis-hepatitis 
B-inactivated poliovirus and Haemophilus influenzae 
type b vaccine (Infanrix hexa) 
 
EL.U: 
ELISA Units 
 
EOS 
End of study 
 
EPAR: 
European Public Assessment Report 
 
HHE: 
Hypotonic Hyporesponsive Episode 
 
IM: 
Intramuscular 
 
IMP: 
Investigational Medicinal Product 
 
(m)IU: 
(Milli)-international units 
 
RSI: 
Reference Safety Information 


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SCID: 
Severe Combined immunodeficiency Disease 
 
SDV: 
Source Document Verification 
 
SIDS: 
Sudden Infant Death Syndrome 
 
SPM: 
Study Procedures Manual 
 
SRT 
Safety Review Team 
 
[e]TDF: 
(electronic) Temperature excursion Decision Form 
 
Glossary of terms: The definition of End of study (EoS) was added. 
 
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: The following change has been made 
 
 
 
 
 
Synopsis and Section 1.2.1: Rationale for the study: 
An analysis of data from the Clinical Practice Research Datalink (a primary care database 
of 520 general medical practices in England) demonstrates that maternal dTpaTdap 
immunisation can decrease the incidence of infant pertussis. 
 
The National Advisory Committee on Immunisation 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 dTpadTap 
vaccination. In special circumstances, such as an outbreak situation, all pregnant women 
who are of 26 weeks gestation or greater may be offered dTpadTap vaccination 
irrespective of their immunisation history [Warshawsky, 2014; Public Health Agency of 
Canada, 2014]. 
Prevenar 13® (Wyeth Pharmaceuticals Inc.; 
Marketed by Pfizer Inc.) 
Pneumococcal Pneumoccocal 13-valent 
conjugate vaccine (diphtheria CRM197 
protein) 
Generic description 
Trademarks not owned by the 
GlaxoSmithKline group of companies 


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In line with these recommendations, study 116945 [DTPA (BOOSTRIX)-047] will be 
conducted to evaluate the immunogenicity and safety of GlaxoSmithKline (GSK) 
Biologicals’ dTpa vaccine, Boostrix, in pregnant women, as well as the transfer of 
maternal antibodies against pertussis to the foetus (cord blood sample at delivery). 
Subjects will receive a dose of Boostrix during pregnancy or immediately post-delivery. 
 
Synopsis and Section 1.2.2: Rationale for the study design: 
This phase IV study is a follow-up of the study 116945 [DTPA (BOOSTRIX)-047]. The 
immunogenicity and safety of Infanrix hexa when administered as a part of the primary 
vaccination schedule, according to the routine national immunisation schedule (3 doses 
given at 2, 4 and 6 months of age or at 2, 3 and 4 months of age or 2 doses given at 3 
and 5 months of age or at 2 and 4 months of age) will be evaluated. As part of the study 
subjects will also receive Prevenar 13 according to the routine national immunisation 
schedule as part of the study. The immunogenicity and safety of the booster dose of the 
same vaccines in infants in the second year of their life will be assessed in another 
follow-up study DTPA (BOOSTRIX)-049. 
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. who received a single 
dose of Boostrix during pregnancy and a dose of placebo immediately post-delivery. 
All infants in this group will receive Infanrix hexa co-administered with Prevenar 13 
according to the routine national immunisation schedule. 
• 
Control Group: This group will consist of infants born to mothers belonging to the 
Control group in study 116945 [DTPA (BOOSTRIX)-047], i.e. who received a 
single dose of placebo during pregnancy and a dose of Boostrix immediately post- 
delivery. All infants in this group will receive Infanrix hexa co-administered with 
Prevenar 13 according to the routine national immunisation schedule. 
Section 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/legally acceptable 
representative(s) [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. 


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Synopsis and Section 2.2: Secondary objectives 
 
• 
To assess the safety and reactogenicity of Infanrix hexa and Prevenar 13 in terms of 
solicited and unsolicited symptoms and serious adverse events (SAEs). 
*In some countries/regions with an Infanrix hexa 3-dose vaccination schedule, 
Prevenar 13 could be administered as 2-doses or 3-doses primary vaccination 
schedule (according to the routine national immunisation schedule)is administered 
as 2-dose schedule at 2 and 4 months of age. In such an instance, the evaluation will 
be performed one month after the last Infanrix hexa dose regardless of Prevenar 
13 vaccinationschedule2 or 3 months after the last dose of primary vaccination in 
infants according to the vaccination schedule. In the countries/regions with an 
Infanrix hexa 2-dose schedule, Prevenar 13 is co-administered at the same time as 
Infanrix hexa. 
 
Synopsis and Section 3. Study Design Overview 
 
Figure 1: Study design diagram for infants receiving a 3-dose schedule of Infanrix 
hexa 
 
N: Maximum number of subjects planned to be enrolled 
M = Month, Mo = age in months 


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Timepoints have been numbered based on the different vaccination schedules. D0, M1, M2 and M3 timepoints reflect 
for subjects who will be vaccinated according to the 2, 3 and 4 month schedule while D0, M2, M4 and M5 timepoints 
reflect for subjects who will be vaccinated according to the 2, 4 and 6 month schedule. 
* In some countries/regions with an Infanrix hexa 3-dose schedule, Prevenar 13 is given as a 2-dose schedule at 2 
and 4 months of age as a part of the routine immunisation programme. 
Pre-Pri = Blood sample to be collected before the first dose of the primary vaccination course 
Post-Pri = Blood sample to be collected one month after the last dose of the primary vaccination course 
 
 
Figure 2: Study design diagram for infants receiving a 2-dose schedule of Infanrix 
hexa 
 
N: Maximum number of subjects planned to be enrolled 
M = Month, Mo = age in months 
Pre-Pri = Blood sample to be collected before the first dose of the primary vaccination course 
Post-Pri = Blood sample to be collected one month after the last dose of the primary vaccination course 
Subjects will be vaccinated either at 2 and 4 months of age or 3 and 5 months of age, according to the routine 
national immunisation schedule 
 
• 
Duration of the study: The intended duration of the study is approximately 3 months, 
per subject, for subjects vaccinated according to the 2 and 4, the 3 and 5 or the 2, 3 
and 4 months schedule and approximately 5 months, per subject, for those vaccinated 
according to 2, 4 and 6 month schedule. 
Epoch 001: Primary starting at Visit 1 (Day 0) and ending at Visit 4 (Month 3 or 5, 
depending on the vaccination schedule). 
• 
End of Study (EoS): Last testing results released of samples collected at Visit 4. 


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Table 1: Study groups and epoch foreseen in the study 
 
Study Groups 
Number of 
subjects 
Age (Min - Max)* 
Epoch 
Epoch 001 
dTpa Group 
340 
6 -14 weeks 
x 
Control Group 
340 
6 -14 weeks 
x 
*Up to and including 14 weeks and 6 days of agebut not including 12 weeks of age. 
 
Table 2: Study groups and treatments foreseen in the study 
 
Treatment names 
Vaccine name 
Study Groups 
dTpa Group 
Control Group 
Infanrix hexa 
DTPaA-HBV-IPV 
x 
x 
• 
Vaccination schedules: All subjects will receive either 3 doses of Infanrix hexa co- 
administered with Prevenar 13* at 2, 4 and 6 months or 2, 3 and 4 months, either 2 
doses of Infanrix hexa co-administered with Prevenar 13 at 3 and 5 months or 2 
and 4 months, depending on the immunisation schedule of the country. 
 
*In some countries/regions with an Infanrix hexa 3 doses routine national 
immunisation schedule, Prevenar 13 could be administered as 2-doses or 3-doses 
primary vaccination schedule (according to the routine national immunisation 
schedule)is given as a 2-dose schedule at 2 and 4 months of age as a part of the 
routine immunisation programme. 
• 
Blinding: Open-label. Note: The study personnel operating GSK Biologicals’ 
randomisation system on internet (SBIR) and the site staff will remain blinded 
towards the treatment allocation to subjects in study 116945 [DTPA (BOOSTRIX)- 
047] and study 201330 [DTPA (BOOSTRIX)-048 PRI]. 
• 
Sampling schedule: Blood samples will be drawn from all subjects at the following 
timepoints: 
 
Pre-Pri: Before the first Infanrix hexa vaccine administration, a volume of 
approximately 2 mL of whole blood (to provide approximately 0.7 mL of serum) 
will be collected from all study participants. 
 
Post-Pri: One month after the last dose of Infanrix hexa dose of primary 
vaccination, approximately 5 mL of whole blood (to provide approximately 
1.7 mL of serum) will be collected from all study participants. 
 
Safety monitoring: An independent data monitoring committee (IDMC) 
(including paediatrician and statistician) will be put in place to oversee the 
safety of infants born to mothers who were vaccinated with Boostrix during 
pregnancy in the clinical study 116945 [DTPA (BOOSTRIX)-047] i.e. each 
SAE/incidence of grade 3 local and general solicited AEes, unsolicited AEs will 
be reviewed by this committee as per IDMC approved charter. 
Synopsis and Section 4.1: Number of Subjects/centers 
 
A maximum of 680 infants aged 6-1412 weeks (up to and including 14 weeks and 6 days 
of age but not including 12 weeks) will be enrolled in this study. Blood samples will be 


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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. 
 
Overview of the recruitment plan: 
 
• 
Enrolment will be terminated when all the eligible infants born to pregnant 
womensubjects from the 116945 [DTPA (BOOSTRIX)-047] study are enrolled. 
Section 4.2: Inclusion criteria for enrolment 
 
• 
A male or female between, 6 and 14 weeks of age (including 6 weeks and up to but 
not including 14 weeks and including 14 weeks and 6 days of age) at the time of the 
first vaccination. 
Section 5.2.2.1.1:Study group and treatment number allocation 
 
The target will be to enrol maximum of 680 eligible subjects aged 6-1412 weeks (up to 
and including 14 weeks and 6 days of age but not including 12 weeks) (approximately 
340 subjects in each group). 
 
Section 5.3:Method of Blinding 
 
This study will be conducted in an open-label manner since the treatmentallocation 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 to subjects in study 116945 [DTPA (BOOSTRIX)-047] and study 
201330 [DTPA (BOOSTRIX)-048 PRI]. 
 
Section 5.4.1: Independent Data Monitoring Committee 
 
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 and unsolicited 
AEs at specified times and access to data on request by an unblinded statistician. 
 
Section 5.4.2: Responsibilities 
 
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 Chartercharter. 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 and unsolicited AEs), provide 


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GSK Biologicals with indications on safety profiles and make recommendations for 
consultation of regulatory authorities and on further study conduct. 
Section 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. 
 
Section 5.4.4: GSK Biologicals’ safety review team 
 
At GSK Biologicals, a Safety Review Team (SRT) will includeing the Central Safety 
Physician, the Clinical Research and Development Lead (CRDL) and Biostatistician of 
the project as well as Epidemiology and Regulatory representative. 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 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. 
 
Section 5.5: Outline of Study Procedures 
 
The list of study procedures for infants receiving a 3-dose and a 2-dose schedule of 
Infanrix hexa is detailed below in Table 4 and Table 5, respectively. 
 
Table 4: List of study procedures for infants receiving a 3-dose schedule of Infanrix 
hexa 
 
Age 
2 months 
3 or 4 
months 
4 or 6 
months 
5 or 7 
months 
Epoch 
Epoch 001 
Type of contact 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Timepoints 
Day 0 
Month 1 
or 2# 
Month 2 
or 4# 
Month 3 
or 5# 
Sampling timepoints 
Pre-Pri 
Post-Pri 
Record pre-vaccination body temperature 
● 
● 
● 
Recording of serious adverse events (SAEs) 
● 
● 
● 
● 
** In some countries/regions with an Infanrix hexa 3-dose schedule, Prevenar 13 is given as a 2-dose schedule at 2 
and 4 months of age as a part of the routine immunisation programme. 


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Table 5: List of study procedures for infants receiving a 2-dose schedule of Infanrix 
hexa 
 
Age 
2 or 3 months# 
4 or 5 
months# 
5 or 6 
months# 
Epoch 
Epoch 001 
Type of contact 
Visit 1 
Visit 2 
Visit 3** 
Visit 4 
Timepoints 
Day 0 
Month 2 
Month 3 
Sampling timepoints 
Pre-Pri 
Post-Pri 
Informed consent 
● 
Check inclusion/exclusion criteria 
● 
Collect demographic data 
● 
Medical history, including medication/vaccine 
history* 
● 
History directed physical examination 
● 
Check contraindications and warnings and 
precautions 
O 
O 
Record pre-vaccination body temperature 
● 
● 
Record body weight, height and head 
circumference 
● 
● 
Study group and treatment number allocation 
● 
Treatment number allocation for subsequent doses 
O 
Recording of administered treatment number 
● 
● 
Blood sampling for antibody determination 
● 
● 
Vaccine administration 
● 
● 
Record any concomitant medication/vaccination 
● 
● 
● 
Record any intercurrent medical conditions 
● 
● 
Distribution of diary cards 
O 
O 
Recording of solicited adverse events (Day 0- Day 
3) by subjects’ parent(s)/LAR(s) 
● 
● 
Recording of non-serious adverse events (Day 0- 
Day 30) by subjects’ parent(s)/LAR(s) 
● 
● 
● 
Return of diary cards 
O 
O 
Diary card transcription by investigator or site staff 
● 
● 
Recording of SAEs 
● 
● 
● 
Recording of SAEs related to study participation or 
to a concurrent GSK medication/vaccine 
● 
● 
● 
Withdrawals due to AEs/SAEs 
● 
● 
● 
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. 
Pre-Pri: Blood sample to be collected before the first dose of the primary vaccination course ( 2 mL). 
Post-Pri: Blood sample to be collected one month after the last dose of the primary vaccination course ( 5 
mL). 
# Depending on the immunisation schedule of the country. 
* History of all medications given to the infants will be recorded in the eCRF. 
** Subject receiving 2 doses of Infanrix hexa will not attend the Visit 3 
 
The intervals between study visits for subjects receiving 3 doses of Infanrix 
hexavaccinated at 2, 4 and 6 months and 2, 3 and 4 months are presented in Table 6 and 
Table 7, respectively. the intervals between study visits for subjects receiving 2 doses of 
Infanrix hexa at 2 and 4 months and at 3 and 5 months are presented in Table 8 and 
Table 9, respectively. 


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Table 6: Intervals between study visits for subjects vaccinated with Infanrix hexa at 
2, 4 and 6 months of age 
 
Interval 
Optimal length of interval 1 
Allowed interval2† 
Birth Visit 1 
60 days 
42-83104 days 
 
Table 7: Intervals between study visits for subjects vaccinated with Infanrix hexa at 
2, 3 and 4 months of age 
 
Interval 
Optimal length of interval 1 
Allowed interval2† 
BirthVisit 1 
60 days 
42-83104 days 
 
Table 8:Intervals between study visits for subjects vaccinated with Infanrix hexa at 2 
and 4 months of age 
 
Interval 
Optimal length of interval 1 
Allowed interval2† 
Birth Visit 1 
60 days 
42-104 days 
Visit 1Visit 2 
60 days 
52-78 days 
Visit 2Visit 4** 
30 days* 
21-48 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. 
† Date of previous visit/contact is the reference date 
*If subjects return for the visits 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. 
** Subject receiving 2 doses of Infanrix hexa will not attend the Visit 3 
 
Table 9: Intervals between study visits for subjects vaccinated with Infanrix hexa at 3 
and 5 months of age 
 
Interval 
Optimal length of interval 1 
Allowed interval2† 
Birth Visit 1 
90 days 
42-104 days 
Visit 1Visit 2 
60 days 
52-78 days 
Visit 2Visit 4** 
30 days* 
21-48 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. 
† Date of previous visit/contact is the reference date 
*If subjects return for the visits 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. 
** Subject receiving 2 doses of Infanrix hexa will not attend the Visit 3 
 
Section 5.6.1: Informed consent 
 
Note: At Visit 4, parent(s)/LAR(s) will be informed about the booster follow-up study 
DTPA (BOOSTRIX)-049 BST: 048 in which their infants will receive a booster dose of 
the study vaccines according to the national immunisation programmeduring their 
second year of life. If they allow their child/ward to participate in the follow-up study, 
they will be contacted when the subject is approximately 9 months of age to complete a 


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standardised developmental screening tool, Ages and Stages Questionnaire-3 either 
through a secure, Internet-based system that provides automated scoring, or via a paper 
questionnaire and submit it to the centralised research coordinating centre or the site 
where the study will be conducted. A separate signed/witnessed/thumb printed informed 
consent of the subject’s parent(s)/LAR(s) for this procedure will be obtained after the 
completion of all study related activities of this study (i.e this informed consent process 
will be a part of DTPA (BOOSTRIX)-049 BST: 048 study). 
 
Section 5.6.9: Record body weight, height andding head circumference 
Section 5.6.11.1: Blood sampling for immune response assessments 
• 
Pre-Pri: Before the first Infanrix hexa vaccine administrationat Visit 1, a volume of 
approximately 2 mL of whole blood (to provide approximately 0.7 mL of serum) will 
be collected. 
• 
Post-Pri: One month after the last dose of Infanrix hexa dose of primary vaccination 
at Visit 4, 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 and laboratory manual for more details on sample 
storage conditions. 
Section 5.6.12: Study Vaccine vaccine administration 
 
• 
After completing all prerequisite procedures prior to vaccination, study vaccines will 
be administered intramuscularly (IM) in the deltoid of the thigh as described in 
Section 6.3. If the investigator or delegate determines that the subject’s health on the 
day of administration temporarily precludes vaccination, the visit will be rescheduled 
within the allowed interval for this visit (see Table 6 to Table 9,and Table 6 as 
applicable). 
Section 5.6.14: Recording of AEs and SAEs 
 
• 
Collect and verify completed diary cards during discussion with the subject’s 
parent(s)/LAR(s) at the next visitVisits 2, 3 and 4. 
Section 5.6.15: Study conclusion 
 
The investigator will: 
 
• 
ask each subject’s parent(s)/LAR(s) if they are interested to allow the subject to 
participate in the follow-up study DTPA (BOOSTRIX)-049 BST: 048. Refer to the 
Section 9.3 for more details. 
Section 5.7: Biological sample handling and analysis 
 
Please refer to the SPM and laboratory manual for details on biospecimen management 
(handling, storage and shipment). 


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Section 5.7.3: Laboratory assays 
 
Table 11: 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* 
or CEVAC 
SER 
Clostridium tetani.Tetanus 
Toxoid Ab.IgG 
ELI 
NA 
IU/ml 
0.1 
GSK 
Biologicals* 
or CEVAC 
SER 
Haemophilus influenzae type 
b.Polyribosyl Ribitol Phosphate 
Ab 
ELI 
NA 
µg/ml 
0.15 
GSK 
Biologicals* 
or CEVAC 
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 
ELIF or 
multiplex 
NA 
µg/ml 
0.05 or 
equivalent 
cut-off for 
the 
multiplex 
GSK 
Biologicals* 
SER 
Streptococcus 
pneumoniae.Polysaccharide 01 
Ab.IgG 
ELI 
NA 
µg/ml 
0.15 
WHO 
reference 
laboratory** 


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System 
Component 
Method 
Kit / 
Manufacturer 
Unit 
Cut-off*** 
Laboratory 
† 
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 
*GSK Biologicals laboratory refers to the Clinical Laboratory Sciences (CLS)Global Vaccines Clinical Laboratories 
(GVCL) in Rixensart, Belgium; Wavre, Belgium; Laval, Canada. 
** At the discretion of GSK Biologicals, pneumococcal testing may be done at a GSK Biologicals laboratory or the 
World Health Organisation (WHO) reference laboratory. 
*** The cut-offs for some of the assays might be subject to change due to assay re-development 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. 


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Table 12: Immunological read-outs 
 
Blood sampling timepoint 
No. subjects 
Component 
Components 
priority rank 
Type of contact and 
timepoint 
Sampling timepoint 
Visit 1 (Day 0) 
Pre-Pri 
All 
PT, FHA, PRN 
1 
D, T 
2 
Visit 4 (Month 3 or Month 
Post-Pri 
All 
PT, FHA, PRN 
1 
5)Visit 4 ()* 
HBs, PRP 
2 
D, T 
3 
Poliovirus types 1, 2, 3 
4 
13 pneumococcal serotypes 
5 
* Depending on the vaccination schedule 
 
Table 13: 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)=32DU; 
Aluminium=700µg Al3+ 
The DTPa-HBV- 
IPV component 
is presented as 
a turbid white 
suspension in a 
pre-filled 
syringe. 
0.5 ml * 
2 or 3** 
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 
2 or 3 *** 
*After reconstitution 


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** In some countries, Infanrix hexa is given as a 2-dose schedule at 2 and 4 months of age or at 3 and 5 
months of age. In other countries Infanrix hexa is given as a 3-dose schedule at 2, 4 and 6 months of age or at 
2, 3 and 4 months of age as recommended by the routine immunisation programme. 
*** ¶I Prevenar 13 is administered at the same schedule as Infanrix hexa except in some countries/regions with an 
Infanrix hexa 3-dose schedule where Prevenar 13 is given as a 2-dose schedule at 2 and 4 months of age as a part 
of the routine immunisation programme. 
 
Table 14: Dosage and administration 
 
Type of contact 
and timepoint 
Volume to be 
administered 
Study group Treatment 
name 
Route 1 
Site 
Side 
Visit 1 (Day 0), 
Visit 2 (Month 2), 
Visit 3 (Month 4)* 
Or 
Visit 1 (Day 0), 
Visit 2 (Month 1), 
Visit 3 (Month 
2)** 
0.5 ml 
dTpa Group 
and Control 
Group 
Infanrix 
hexa 
IM 
Thigh 
Right 
Visit 1 (Day 0), 
Visit 2 (Month 2), 
Visit 3 (Month 4)* 
Or 
Visit 1 (Day 0), 
Visit 32 (Month 
2)† 
Or 
Visit 1 (Day 0), 
Visit 2 (Month 
1), Visit 3 
(Month 2** 
0.5 ml 
dTpa Group 
and Control 
Group 
Prevenar 
13 
IM 
Thigh 
Left 
Visit 1 (Day 0), 
Visit 2 (Month 
2)*** 
0.5 ml 
dTpa Group 
and Control 
Group 
Infanrix 
hexa 
IM 
Thigh 
Right 
Visit 1 (Day 0), 
Visit 2 (Month 
2)*** 
0.5 ml 
dTpa Group 
and Control 
Group 
Prevenar 
13 
IM 
Thigh 
Left 
1Intramuscular (IM) 
2Thigh (T), 
*For subjects vaccinated with Infanrix hexa at 2, 4 and 6 months of age 
** For subjects vaccinated Infanrix hexa at 2, 3 and 4 months of age 
*** For subjects vaccinated with Infanrix hexa at 2 and 4 months of age or at 3 and 5 months of age. These 
subjects will receive Prevenar 13 at the same vaccination schedule. 
† In some countries/regions with an Infanrix hexa 3-dose schedule, Prevenar 13 is given as a 2-dose schedule at 2 
and 4 months of age as a part of the routine immunisation programme. 
 
Section 6.5: Contraindications to subsequent vaccination 
 
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 Table 6 to Table 9and Table 7 as applicable), or the subject may be 
withdrawn at the discretion of the investigator (see Section 8.4). 


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Section 6.7.2: Concomitant medications/products/vaccines that may lead to the 
elimination of a subject from ATP analyses 
 
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 programme, the time period described above can be reduced if 
necessary for that vaccine provided it is licensed and used according to its SmPC or 
Prescribing Information and according to the local governmental recommendations 
and provided a written approval of the Sponsor is obtained. 
Section 8.1.2: Definition of a serious adverse event 
 
A SAE is any untoward medical occurrence that: 
 
d. Results in disability/incapacity, OR 
Section 8.2.1: Time period for detecting and recording adverse events and serious 
adverse events 
 
An overview of the protocol-required reporting periods for AEs and SAEs is given in 
Table 17, and Table 18 and Table 19. 
 
Table 17: Reporting periods for adverse events and serious adverse events for 
subjects vaccinated with Infanrix hexa at 2, 4 and 6 months of age 
 
Table 18: Reporting periods for adverse events and serious adverse events for 
subjects vaccinated with Infanrix hexa at 2, 3 and 4 months of age 


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Table 19: Reporting periods for adverse events and serious adverse events for subjects 
vaccinated with Infanrix hexa at 2 and 4 months of age or at 3 and 5 months of age 
 
Event 
Pre- 
V1* 
V1 3 d post 
V1 
30 d 
post-V1 
V2 3 d post
V2 
30 d 
post-V2 
V4 
Study Conclusion 
D0 
D 30 
M2 
M3 
Solicited local and general 
AEs 
Unsolicited AEs 
AEs/SAEs leading to 
withdrawal from the study 
SAEs† 
SAEs related to study 
participation 
or concurrent GSK 
medication/ 
vaccine† 
* i.e. consent obtained. Pre-V: pre-vaccination; V: vaccination; Post-V: post-vaccination; D: Day, M: Month 
† AEs/SAEs reported from the administration of first dose of primary vaccination until the end of study will be 
recorded and analysed in this study (i.e. a part of 201330 [DTPA (BOOSTRIX)-048 PRI] study). 
 
Section 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 17, or Table 18 or Table 19. 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. 
 
Section 8.2.3.2.1: Assessment of intensity 
 
The maximum intensity of fever (oral, axillary or tympanic route) will be scored at GSK 
Biologicals as follows: 
 
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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Section 10.3: Determination of sample size 
Table 23: Reference values 
Study Group 
Schedule 
(months) 
N 
D 
T 
PT VR 
FHA VR 
PRN VR 
HBs 
POLIO 
TYPE 1 
POLIO TYPE 2 
POLIO 
TYPE 3 
PRP 
DTPa-HBV- 
IPV/Hib 
3,5,11 
177 
10097.6 
10099.4 
10095.9 
10097.5 
10098.2 
10096.4 
10097.4 
10094.7 
10099.3 
10092.8 
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Section 10.4: Cohorts for aAnalyses 
 
Section 10.4.1: Total vaccinated cohort 
The Total Vaccinated cohort (TVC) will include all vaccinated subjects for whom data 
are available. 
 
Section 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 
monthsin 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 6 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 24: GSK Biologicals’ laboratories 
 
Laboratory 
Address 
GSK Biologicals Global 
Vaccine Clinical Laboratory, 
North America- Laval 
Biospecimen Reception - Clinical Serology 
525 Cartier blvd West - Laval - Quebec - 
Canada - H7V 3S8 
GSK Biologicals Global 
Vaccine Clinical Laboratory 
Clinical Sciences 
Laboratory, Rixensart 
Biospecimen Reception - B7/44 
Rue de l'Institut, 89 - B-1330 Rixensart - 
Belgium 
GSK Biologicals Global 
Vaccine Clinical Laboratory 
Clinical Sciences 
Laboratory, Wavre-Nord Noir 
Epine 
Avenue Fleming, 20 - B-1300 Wavre - 
Belgium 
 
Table 25: Outsourced laboratories 
 
Laboratory 
Address 
Q2 Solutions Quest diagnostics 
LimitedClinical Trials (UK) 
The Alba Campus 
Rosebank 
Livingston 
West Lothian, EH54 7EG 
Scotland, UKUnit B1, Parkway West Industrial Estate 
Cranford Lane – Heston, 
Middlesex TW5 9QA 
UK 
Q² SolutionsQuest Diagnostics Nichols Institute 33608 Ortega Highway 
San Juan Capistrano, 
CA 92675-2042 
USA 


 
0 
b3ee276et2atna85a83565efce2509b826bffd43 2.0 9/7/2016 I :25:00 PM . • 
CONFIDENTIAL  
201330 [DTPA (BOOSTRIX)-048 PRI] 
Protocol Amendment 1 Final 
Protocol Amendment 1 Sponsor Signatory Approval 
eTrack study number and 
201330 [DTPA (BOOSTRIX)-048 PRI] 
Abbreviated Title 
EudraCT number 
2014-001117-41 
 
Date of protocol amendment 
Amendment 1 Final: 06 September 2016 
 
Detailed Title 
 A phase IV, open-label, non-randomised, multi- 
centre study to assess the immunogenicity and safety 
oflnfanrix hexa™ administered as primary 
vaccination in healthy infants born to mothers given 
Boostrix™ during pregnancy or post-delivery in 
116945 [DTPA (BOOSTRIX)-04 7]. 
 
Sponsor signatory 
Narcisa Mesaros, MD 
 
 
 
p_ _ 
Clinical and Epidemiology R&D Project Leader 
(CEPL), DTP, Polio, Hib containing vaccines 
_   o 
n c6-• .. u   1  :.. _""-  - 
- 
- 
- 
- 
 
 
 
Signature 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For internal use only 
 
 
 
• •··············•Checksum••········ ·· ··••! Ver.1Created On • . 
  
 
........ .....,..  
_ 
 
 
06-SEP-2016 
3 
b3ee276ef2af0a85a83565efce2509b826bffd43 

SAP_001.pdf: 
CONFIDENTIAL 
201330 [DTPA (BOOSTRIX)-048 PRI] 
Statistical Analysis Plan Final 
16 July 2018 
Page 1 of 57 
 
 
 
Statistical Analysis Plan 
Detailed Title: 
A phase IV, open-label, non-randomised, multicentre 
study to assess the immunogenicity and safety of 
Infanrix hexa™ administered as primary vaccination in 
healthy infants born to mothers vaccinated with 
Boostrix™ during pregnancy or immediately post- 
delivery. 
eTrack study number and 
Abbreviated Title 
201330 [DTPA (BOOSTRIX)-048 PRI] 
Scope: 
All analyses as planned per protocol and for study 
report 
Date of Statistical Analysis 
Plan 
16-Jul-2018 Final 
Co-ordinating author: 
PPD 
 
Reviewed by: 
PPD 
 
R&D Project Leader) 
PPD 
 
Lead (CRDL) 
PPD 
(Lead Statistician) 
PPD 
PPD 
(Scientific writer) 
PPD 
(Regulatory Affair) 
PPD 
(Safety Scientist) 
VxRD Medical Vx Office of Medical Governance and 
Bioethics Public Disclosure Global (Public disclosure) 
Approved by: 
PPD 
(Clinical and Epidemiology 
R&D Project Leader) 
PPD 
, Clinical Research and Development 
Lead (CRDL) 
PPD 
(Scientific writer) 
PPD 
(Lead Statistical analyst) 
PPD 
(Lead Statistician) 
APP 9000058193 Statistical Analysis Plan Template ( Effective date: 14 April 2017) 
 


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Statistical Analysis Plan Final 
16 July 2018 
Page 2 of 57 
 
 
TABLE OF CONTENTS 
 
PAGE 
 
LIST OF ABBREVIATIONS ............................................................................................. 8 
1. 
DOCUMENT HISTORY .......................................................................................... 10 
2. 
STUDY DESIGN .................................................................................................... 10 
3. 
OBJECTIVES ......................................................................................................... 14 
3.1. 
Primary objective ........................................................................................ 14 
3.2. 
Secondary objectives .................................................................................. 14 
4. 
ENDPOINTS .......................................................................................................... 15 
4.1. 
Primary endpoints ....................................................................................... 15 
4.2. 
Secondary endpoints .................................................................................. 15 
5. 
ANALYSIS SETS ................................................................................................... 16 
5.1. 
Definition..................................................................................................... 16 
5.1.1. 
All enrolled subjects ..................................................................... 16 
5.1.2. 
Total vaccinated cohort (TVC) ..................................................... 16 
5.1.3. 
ATP cohort for analysis of safety .................................................. 16 
5.1.4. 
ATP cohort for analysis of immunogenicity................................... 17 
5.2. 
Criteria for eliminating data from Analysis Sets ........................................... 17 
5.2.1. 
Elimination from Total vaccinated cohort (TVC) ........................... 17 
5.2.2. 
Elimination from ATP cohort for safety ......................................... 17 
5.2.2.1. 
Excluded subjects....................................................... 17 
5.2.3. 
Elimination from ATP cohort for immunogenicity .......................... 18 
5.2.3.1. 
Excluded subjects....................................................... 18 
6. 
STATISTICAL ANALYSES ..................................................................................... 20 
6.1. 
Demography ............................................................................................... 20 
6.1.1. 
Analysis of demographics/baseline characteristics planned 
in the protocol .............................................................................. 20 
6.1.2. 
Additional considerations ............................................................. 20 
6.2. 
Exposure. ................................................................................................... 20 
6.2.1. 
Analysis of exposure planned in the protocol ............................... 20 
6.2.2. 
Additional considerations ............................................................. 20 
6.3. 
Immunogenicity........................................................................................... 21 
6.3.1. 
Analysis of immunogenicity planned in the protocol ..................... 21 
6.3.2. 
Additional considerations ............................................................. 22 
6.4. 
Analysis of safety ........................................................................................ 23 
6.4.1. 
Analysis  of  safety   and   reactogenicity   planned   in   the 
protocol ........................................................................................ 23 
6.4.2. 
Additional considerations ............................................................. 25 
6.4.2.1. 
Combined Solicited and Unsolicited Adverse 
Events ........................................................................ 25 
7. 
ANALYSIS INTERPRETATION .............................................................................. 25 
8. 
CONDUCT OF ANALYSES .................................................................................... 25 
8.1. 
Sequence of analyses ................................................................................. 25 


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8.2. 
Statistical considerations for interim analyses ............................................. 25 
9. 
CHANGES FROM PLANNED ANALYSES ............................................................. 26 
10. LIST OF FINAL REPORT TABLES, LISTINGS AND FIGURES ............................. 28 
11. ANNEX 1 STANDARD DATA DERIVATION RULE AND STATISTICAL 
METHODS ............................................................................................................. 29 
11.1. Statistical Method References .................................................................... 29 
11.2. Standard data derivation ............................................................................. 29 
11.2.1. 
Date derivation ............................................................................ 29 
11.2.2. 
Dose number ............................................................................... 29 
11.2.3. 
Demography ................................................................................ 30 
11.2.4. 
Immunogenicity............................................................................ 31 
11.2.5. 
Safety .......................................................................................... 32 
11.2.6. 
Number of decimals displayed ..................................................... 34 
12. ANNEX 3: STUDY SPECIFIC MOCK TFL .............................................................. 35 


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LIST OF TABLES 
PAGE 
 
Table 1 
Study groups and epoch foreseen in the study ....................................... 12 
 
Table 2 
Study groups and treatments foreseen in the study ................................ 12 
 
Table 3 
Blinding of study epoch .......................................................................... 12 
 
Table 4 
Intensity scales for solicited symptoms in infants less than 6 
years of age ........................................................................................... 33 


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LIST OF FIGURES 
 
PAGE 
 
Figure 1 
Study design diagram for infants receiving a 3-dose schedule of 
Infanrix hexa .......................................................................................... 10 
Figure 2 
Study design diagram for infants receiving a 2-dose schedule of 
Infanrix hexa .......................................................................................... 11 


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LIST OF TEMPLATES 
PAGE 
Template 1 
Number of subjects enrolled by center (Total vaccinated cohort) ............ 35 
Template 2 
Number of subjects enrolled by country (Total vaccinated cohort) .......... 36 
Template 3 
Number of subjects vaccinated, completed and withdrawn with 
reason for withdrawal (Total vaccinated cohort)...................................... 36 
Template 4 
Number of subjects at each visit and list of withdrawn subjects 
(Total Vaccinated Cohort) ...................................................................... 37 
Template 5 
Number of subjects enrolled into the study as well as excluded 
from ATP analyses with reasons for exclusion ....................................... 38 
Template 6 
Deviations from specifications for age and intervals between 
study visits for subjects vaccinated with Infanrix hexa(<2> dose 
schedule - 1 dose/visit) (Total Vaccinated Cohort) .................................. 39 
Template 7 
Summary   of   demographic    characteristics    (Total    vaccinated 
cohort) .................................................................................................... 40 
Template 8 
Summary of vital signs characteristics (Total Vaccinated Cohort) ........... 41 
Template 9 
Study population (TVC) .......................................................................... 42 
Template 10 Seropositivity rates and GMCs for anti-PT, anti-FHA and anti- 
PRN antibodies before the first dose and 1 month after the last 
dose of the primary vaccination (ATP cohort for immunogenicity)........... 42 
Template 11 Seropositivity, seroprotection and GMC rates for <anti-tetanus> 
antibodies before the first dose and 1 month after the last dose of 
the primary vaccination (ATP cohort for immunogenicity) ....................... 43 
Template 12 Seroprotection rates for anti-poliovirus type 1,2,3 antibodies 
before the first dose and 1 month after the last dose of the 
primary vaccination (ATP cohort for immunogenicity) ............................. 44 
Template 13 Vaccine responses for anti-PT, anti-FHA and anti-PRN antibody 
concentration 1 month after the last dose of the primary 
vaccination course (ATP cohort for immunogenicity) .............................. 45 
Template 14 Reverse cumulative curve for anti-diphtheria antibody 
concentration before first dose and 1 month post last dose of the 
primary vaccination course (ATP cohort for immunogenicity) ................. 46 
Template 15 Number and percentage of subjects who received study vaccine 
doses by vaccination group (Total vaccinated cohort) ............................ 47 
Template 16 Compliance   in   returning   symptom   sheets   (Total   vaccinated  
cohort) .................................................................................................... 47 


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Template 17 Percentage and nature of <grade 3>symptoms (solicited and 
unsolicited) reported during the 4-day (Days 0-3) post- 
vaccination period following each dose and overall (Total 
vaccinated cohort) .................................................................................. 48 
Template 18 Percentage of solicited local symptoms reported during the 4-day 
(Day 0-3) post-vaccination period following each dose and 
overall (Total vaccinated cohort)............................................................. 49 
Template 19 Percentage of solicited general symptoms reported during the 4- 
day (Days 0-3) post-vaccination period following each dose and 
overall (Total vaccinated cohort)............................................................. 52 
Template 20 Percentage of Unsolicited symptoms experienced by subjects 
classified by MedDRA Primary System Organ Class and 
Preferred Term within the 31-day (Days 0-30) after any dose 
(Total vaccinated cohort) ........................................................................ 54 
Template 21 Number (%) of subjects with serious adverse events from the 
Day 0 to end of the study (Total Vaccinated cohort) ............................... 54 
Template 22 Solicited and unsolicited adverse events experienced by subjects 
classified by MedDRA Primary System Organ Class and 
Preferred Term within the 31-day (Days 0-30) post-vaccination 
period - SAE excluded (Total vaccinated cohort) .................................... 55 
Template 23 Number and percentage of subjects taking a concomitant 
medication and antipyretic medication during the 4-day (Days 0- 
3) follow-up period post-vaccination by dose and overall (Total 
vaccinated cohort) .................................................................................. 56 
Template 24 Minimum and maximum activity dates (Total vaccinated cohort) ............ 56 
Template 25 Number of enrolled subjects by age category at visit1 ............................ 57 
Template 26 Listing of SAEs from Day 0 up study (Total vaccinated cohort) ............... 57 
Template 27 Listing of dropouts due to AEs, SAEs and solicited symptoms 
(Total vaccinated cohort) ........................................................................ 57 


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Page 8 of 57 
 
 
LIST OF ABBREVIATIONS 
 
AE 
Adverse event 
Anti-HBs 
Antibodies against hepatitis B surface antigen 
ATP 
According-To-Protocol 
CI 
Confidence Interval 
CRDL 
Clinical Research and Development Lead 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CTRS 
Clinical Trial Registry Summary 
dTpa 
Combined reduced antigen content diphtheria-tetanus-acellular 
pertussis vaccine 
DTPa 
Diphtheria-Tetanus-acellular Pertussis 
eCRF 
electronic Case Report Form 
Eli Type 
Internal GSK database code for type of elimination code 
ELISA 
Enzyme-linked immunosorbent assay 
EOS 
End of study 
EPAR 
European Public Assessment Report 
FHA 
Filamentous Haemagglutinin 
GMC 
Geometric mean antibody concentration 
GMT 
Geometric mean antibody titer 
GSK 
GlaxoSmithKline 
HBs 
Hepatitis B surface antigen 
HBV 
Hepatitis B Virus 
Hib 
Haemophilus influenzae type b 
IDMC 
Independent Data Monitoring Committee 
IM 
Intramuscular 


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Statistical Analysis Plan Final 
16 July 2018 
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IMP 
Investigational Medicinal Product 
IPV 
Inactivated Poliovirus Vaccine 
IU/ml 
International units per milliliter 
LAR 
Legally Acceptable Representative 
LL 
Lower Limit of the confidence interval 
MedDRA 
Medical Dictionary for Regulatory Activities 
NA 
Not Applicable 
PRN 
Pertactin 
PRP 
Hib capsular polysaccharide Polyribosyl-Ribitol Phosphate 
PT 
Pertussis Toxoid 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SBIR 
GSK Biological’s Internet Randomization System 
SD 
Standard Deviation 
SR 
Study Report 
SRT 
Safety Review Team 
TFL 
Tables Figures and Listings 
TOC 
Table of Content 
TVC 
Total Vaccinated Cohort 
UL 
Upper Limit of the confidence interval 
WHO 
World Health Organization 


CONFIDENTIAL 
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Statistical Analysis Plan Final 
16 July 2018 
Page 10 of 57 
 
 
1. 
DOCUMENT HISTORY 
 
Date 
Description 
Protocol Version 
16-JUL-2018 
Final Version 
Amendment 1 Final - 06-SEP-2016 
2. 
STUDY DESIGN 
Figure 1 
Study design diagram for infants receiving a 3-dose schedule of 
Infanrix hexa 
 
 
N: Maximum number of subjects planned to be enrolled 
M = Month, Mo = age in months 
Timepoints have been numbered based on the different vaccination schedules. D0, M1, M2 and M3 timepoints reflect 
for subjects who will be vaccinated according to the 2, 3 and 4 month schedule while D0, M2, M4 and M5 timepoints 
reflect for subjects who will be vaccinated according to the 2, 4 and 6 month schedule. 
* In some countries/regions with an Infanrix hexa 3-dose schedule, Prevenar 13 is given as a 2-dose schedule at 2 and 
4 months of age as a part of the routine immunisation programme 
Pre-Pri = Blood sample to be collected before the first dose of the primary vaccination course 
Post-Pri = Blood sample to be collected one month after the last dose of the primary vaccination course 


CONFIDENTIAL 
201330 [DTPA (BOOSTRIX)-048 PRI] 
Statistical Analysis Plan Final 
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Page 11 of 57 
 
 
Figure 2 
Study design diagram for infants receiving a 2-dose schedule of 
Infanrix hexa 
 
 
N: Maximum number of subjects planned to be enrolled 
M = Month, Mo = age in months 
Pre-Pri = Blood sample to be collected before the first dose of the primary vaccination course 
Post-Pri = Blood sample to be collected one month after the last dose of the primary vaccination course 
Subjects will be vaccinated either at 2 and 4 months of age or 3 and 5 months of age, according to the routine national 
immunisation schedule 
 
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 of the protocol), 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 3 months, 
per subject, for subjects vaccinated according to the 2 and 4, the 3 and 5 or the 2, 3 
and 4 months schedule and approximately 5 months, per subject, for those 
vaccinated according to 2, 4 and 6 month schedule. 


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• 
Epoch 001: Primary starting at Visit 1 (Day 0) and ending at Visit 4 (Month 3 or 5, 
depending on the vaccination schedule). 
• 
End of study (EOS): Last testing results released of samples collected at Visit 4. 
• 
Study groups: The study groups and epoch foreseen in the study are presented in 
Table 1. 
Table 1 
Study groups and epoch foreseen in the study 
 
Study Groups 
Number of 
subjects 
Age (Min - Max)* 
Epoch 
Epoch 001 
dTpa Group 
340 
6-14 weeks 
x 
Control Group 
340 
6-14 weeks 
x 
*Up to and including 14 weeks and 6 days of age. 
 
The study groups and treatment foreseen in the study are presented in Table 2. 
 
Table 2 
Study groups and treatments foreseen in the study 
 
Treatment names 
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 
• 
Vaccination schedules: All subjects will receive either 3 doses of Infanrix hexa co- 
administered with Prevenar 13* at 2, 4 and 6 months or 2, 3 and 4 months, either 2 
doses of Infanrix hexa co-administered with Prevenar 13 at 3 and 5 months or 2 and 
4 months, depending on the immunisation schedule of the country. 
*In some countries/regions with an Infanrix hexa 3 doses routine national 
immunisation schedule, Prevenar 13 could be administered as 2-doses or 3-doses 
primary vaccination schedule (according to the routine national immunisation 
schedule). 
• 
Treatment allocation: non-randomised. All subjects will receive Infanrix hexa co- 
administered with Prevenar 13. 
• 
Blinding: Open-label. Note: The study personnel operating GSK Biologicals’ 
randomisation system on internet (SBIR) and the site staff will remain blinded 
towards the treatment allocation to subjects in study 116945 [DTPA (BOOSTRIX)- 
047]. 
• 
The blinding of study epoch is presented in Table 3. 
Table 3 
Blinding of study epoch 
 
Study Epoch 
Blinding 
Epoch 001 
open 


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• 
Sampling schedule: Blood samples will be drawn from all subjects at the following 
timepoints: 
 
Pre-Pri: Before the first Infanrix hexa vaccine administration, a volume of 
approximately 2 mL of whole blood (to provide approximately 0.7 mL of 
serum) will be collected from all study participants. 
 
Post-Pri: One month after the last dose of Infanrix hexa primary vaccination, 
approximately 5 mL of whole blood (to provide approximately 1.7 mL of 
serum) will be collected from all study participants. 
• 
Type of study: extension of other protocol(s) 116945 [DTPA (BOOSTRIX)-047]. 
• 
Data collection: Electronic Case Report Form (eCRF). 
• 
Safety monitoring: An independent data monitoring committee (IDMC) (including 
paediatrician and statistician) will be put in place to oversee the safety of infants 
born to mothers who were vaccinated with Boostrix during pregnancy in the clinical 
study 116945 [DTPA (BOOSTRIX)-047] i.e. each SAE/incidence of grade 3 local 
and general solicited AEs, unsolicited AEs will be reviewed by this committee as per 
IDMC approved charter. 


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3. 
OBJECTIVES 
 
3.1. 
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 
of vaccine response to the pertussis antigens, one month after the last dose of the 
primary vaccination in infants born to mothers vaccinated with Boostrix during 
pregnancy or immediately post-delivery. 
Refer to Section 4.1 for the definition of the primary endpoint. 
 
3.2. 
Secondary objectives 
• 
To assess persistence of antibodies against diphtheria, tetanus and pertussis antigens, 
before the first dose of Infanrix hexa 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 last dose 
of the primary vaccination 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 last dose of the primary 
vaccination 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). 
*In some countries/regions with an Infanrix hexa 3-dose vaccination schedule, 
Prevenar 13 could be administered as 2-doses or 3-doses primary vaccination 
schedule (according to the routine national immunisation schedule). In such an 
instance, the evaluation will be performed one month after the last Infanrix hexa 
dose regardless of Prevenar 13 vaccination. In the countries/regions with an Infanrix 
hexa 2-dose schedule, Prevenar 13 is co-administered at the same time as Infanrix 
hexa. 
Refer to Section 4.2 for the definition of the secondary endpoints. 


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4. 
ENDPOINTS 
 
4.1. 
Primary endpoints 
• 
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 last dose of primary vaccination. 
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. 
 
Vaccine response to PT, FHA and PRN antigens, one month after the last dose 
of primary vaccination. 
Vaccine response to the PT, FHA and PRN antigens, is defined as: 
 
appearance of antibodies in subjects who were initially seronegative (i.e., 
with concentrations <cut-off value). 
 
at least maintenance of pre-vaccination antibody concentrations in 
subjects who were initially seropositive (i.e., with concentrations cut-off 
value). 
 
4.2. 
Secondary endpoints 
• 
Persistence of antibodies before the first dose of Infanrix hexa. 
 
Anti-diphtheria and anti-tetanus seroprotection status, anti-PT, anti-FHA, anti- 
PRN seropositivity status and antibody concentrations. 
• 
Immunogenicity with respect to components of Infanrix hexa and Prevenar 13. 
 
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, one month after the last dose of primary 
vaccination. 
• 
Immunogenicity with respect to components of Infanrix hexa. 
 
Anti-PT, anti-FHA, anti-PRN antibody seropositivity status, one month after the 
last dose of primary vaccination. 


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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 each vaccination. 
• 
Unsolicited adverse events. 
 
Occurrence of unsolicited symptoms during the 31-day (Day 0-Day 30) follow- 
up period after each vaccination. 
• 
Serious adverse events. 
 
Occurrence of SAEs from first vaccination dose to study end. 
5. 
ANALYSIS SETS 
 
5.1. 
Definition 
 
5.1.1. 
All enrolled subjects 
 
• 
All subjects for whom study invasive procedure has been achieved and informed 
consent has been obtained. 
 
5.1.2. 
Total vaccinated cohort (TVC) 
 
The TVC will include all vaccinated subjects for whom data are available. 
 
• 
A safety analysis based on the TVC will include all subjects with at least one vaccine 
administration documented. 
• 
An immunogenicity analysis based on the TVC will include vaccinated subjects for 
whom data concerning immunogenicity endpoint measures are available. 
 
5.1.3. 
ATP 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 at least one dose of study vaccines according to their random 
assignment. 
• 
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. 


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5.1.4. 
ATP cohort for analysis of immunogenicity 
 
The ATP cohort for immunogenicity will include all evaluable subjects from the ATP 
cohort for safety: 
 
• 
who meet all eligibility criteria; 
• 
who comply with the procedures and intervals defined in the protocol. 
• 
who do not meet any of the criteria for elimination from an ATP analysis (refer to 
Section 6.7.2 of the protocol) during the study; 
• 
who do not receive a product leading to exclusion from an ATP analysis as listed in 
Section 6.7.2 of the protocol; 
• 
who do not present with a medical condition leading to exclusion from an ATP 
analysis as listed in Section 6.8 of the protocol; 
• 
who are born full term (full term is defined  37 weeks of gestation); 
• 
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 vaccines antigen component. 
The interval between the last vaccination visit and post-primary blood sampling, 
considered for inclusion of a subject will be 21–48 days. 
 
5.2. 
Criteria for eliminating data from Analysis Sets 
Elimination codes are used to identify subjects to be eliminated from analysis. Detail is 
provided below for each sets. 
 
5.2.1. 
Elimination from Total vaccinated cohort (TVC) 
 
Code 1030 (Study vaccine not administered at all) and code 900 (invalid informed 
consent or fraud data) will be used for identifying subjects eliminated from TVC. 
 
5.2.2. 
Elimination from ATP cohort for safety 
 
5.2.2.1. 
Excluded subjects 
 
All eliminations from the primary study 116945 [DTPA(BOOSTRIX)-047] will be 
applicable for this follow up study except for the visit specific elimination codes (2090, 
2100 and 2120) in other words the code 1050, 1060, 1070 assigned to the mother in study 
116945 [DTPA(BOOSTRIX)-047] will be inherited to the infant. 


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A subject will be excluded from the ATP cohort for safety and immunogenicity under the 
following conditions 
 
Code 
Decode => Condition under which the code is used 
900 
Questionable subject => Invalid informed consent or fraudulent data. In case informed 
consent is obtained retrospectively the subject is not eliminated. 
1030 
Study vaccine dose not administered at all but subject number allocated => subjects 
enrolled but not vaccinated 
1040 
Administration of vaccine(s) forbidden in the protocol 
Concurrently participating in another clinical study, at any time during the study period, in 
which the subject has been or will be exposed to an investigational or a non-investigational 
vaccine/product (pharmaceutical product or device). 
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/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 package insert (PI) and according 
to the local governmental recommendations and provided a written approval of the 
Sponsor is obtained. 
1050 
Randomisation failure (subject who received a vaccine not compatible with randomization) 
This code is inherited from the mother. 
1060 
Randomisation code broken at the investigator site OR at GSK Safety department. This 
code is inherited from the mother. 
1070 
Incomplete vaccination course before treatment withdrawal: =>for instance 
only part of the multiple planned administrations at one visit has been administered. For 
instance, Prevenar not administered while Infanrix hexa is. 
when no study vaccination at a visit, no other study vaccination can occur up to 
conclusion/drop-out (Ex. No vaccination at visit 2, but vaccinations at visits 1 and 3 would 
lead to assignment of code 1070). Note that the code would not be proposed for a subject 
who had vaccination as planned but missed the last vaccination(s) due to drop-out. In the 
example given previously, the code would not be proposed if the subject had missed also 
the vaccination at visit 3). 
This code is also inheritated from the mother 
Site or route of study vaccine administration wrong or unknown. 
1080 
Vaccine temperature deviation (vaccine administration not as per protocol) => Infanrix 
hexa vaccine administered despite a Good Manufacturing Practices (GMP) no-go 
temperature deviation 
1090 
Expired vaccine administered (vaccine administration not as per protocol)=> Subjects who 
received an expired Infanrix hexa 
5.2.3. 
Elimination from ATP cohort for immunogenicity 
 
5.2.3.1. 
Excluded subjects 
 
All eliminations from the primary study 116945 [DTPA(BOOSTRIX)-047] will be 
applicable for this follow up study except for the visit specific elimination codes (2090, 
2100 and 2120). 
 
A subject will be excluded from the ATP cohort for immunogenicity when he/she is 
excluded from the ATP cohort for safety (see Section 5.1.3) 


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The following additional codes will be used: 
 
Code 
Decode => Condition under which the code is used 
2010 
Protocol violation (inclusion/exclusion criteria) including age and excluding codes 
mentioned below. 
A male or female between, 6 and 14 weeks of age (including 6 weeks and up to and 
including 14 weeks and 6 days of age) at the time of the first vaccination. 
Healthy subjects as established by medical history and clinical examination before entering 
into the study. 
This code is also inheritated from the mother 
2040 
Administration of any medication forbidden by the protocol=> 
Immunosuppressants or other immune-modifying drugs administered chronically (i.e. more 
than 14 days) since birth. 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). 
This code is also inheritated from the mother 
2050 
Underlying medical condition forbidden by the protocol => 
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 (e.g. any 
confirmed or suspected immunosuppressive or immunodeficient condition) or are 
confirmed to have an alteration of their initial immune status. 
2080 
Vaccination done but: noncompliance with vaccination schedules (dates of vaccination not 
corresponding to protocol intervals or unknown vaccination dates) 
Intervals between study visits for subjects vaccinated with Infanrix hexa at 2, 4 and 6 
months of age is 42-104 days from birth to visit 1, 52-78 days from visit 1 to visit 2, 52-78 
days from visit 2 to visit 3. 
Intervals between study visits for subjects vaccinated with Infanrix hexa at 2, 3 and 4 
months of age is 42-104 days from birth to visit 1, 21-48 days from visit 1 to visit 2, 21-48 
days from visit 2 to visit 3. 
Intervals between study visits for subjects vaccinated with Infanrix hexa at 2 and 4 months 
of age is 42 to 104 days from birth to visit 1, 52-78 days from visit 1 to visit 2. 
Intervals between study visits for subjects vaccinated with Infanrix hexa at 3 and 5 months 
of age is 42 to 104 days from birth to visit 1, 52-78 days from visit 1 to visit 2. 
2090 
Blood sample taken but: noncompliance with blood sampling schedules (dates of blood 
sampling not corresponding to adapted protocol intervals or unknown blood 
sample/vaccination dates) => 21-48 days from last vaccination visit to visit 4 
2100 
Serological results not available for antigens POST vaccination (including lost samples, 
blood sample not done, unable to test, absence of parallelism) => no immunogenicity 
results available at visit 4. 
2120 
Obvious incoherence, abnormal serology evolution or error in data (incoherence between 
CRF and results, wrong sample labelling) 


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6. 
STATISTICAL ANALYSES 
Note that standard data derivation rule and stat methods are described in annex 1 (see 
Section 11) and will not be repeated below. 
 
6.1. 
Demography 
 
6.1.1. 
Analysis of demographics/baseline characteristics planned in the 
protocol 
 
Demographic characteristics (age in weeks, race, height [cm], weight [kg], head 
circumference [cm], body mass index in [kg/m2]), cohort description and withdrawal 
status will be summarised by group using descriptive statistics: 
• 
Frequency tables will be generated for categorical variables such as race; 
• 
Mean, median and standard deviation 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. 
 
6.1.2. 
Additional considerations 
 
Gender, country, schedule of vaccination will also be summarised by group using above 
mentioned descriptive statistics. 
 
All demography summaries will be generated for the TVC. The summary of age, height, 
weight, head circumference, gender will also be provided for the ATP cohort for 
immunogenicity. 
Number and reason for elimination from ATP cohorts will be tabulated by group. 
 
Quartile 1 and quartile 3 will be provided for continuous data such as age in weeks, race, 
height [cm], weight [kg], head circumference [cm], body mass index in [kg/m2]. 
 
6.2. 
Exposure. 
 
6.2.1. 
Analysis of exposure planned in the protocol 
 
NA 
 
6.2.2. 
Additional considerations 
 
The number of doses administered will be summarized by vaccine. 


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6.3. 
Immunogenicity 
 
6.3.1. 
Analysis of immunogenicity planned in the protocol 
 
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 timepoint 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. 
For serology results one month after last vaccination dose: 
• 
The vaccine response rates to PT, FHA and PRN (with exact 95% CI) will be 
calculated. 
• 
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. 
Additional summaries will be provided based on country. 
Handling of missing data: 
 
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. 


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6.3.2. 
Additional considerations 
 
Considering that RCC are available and the percentage of subjects with 
titres/concentration above key thresholds are available, the distribution of antibody 
concentrations or titres of each antigen will not be tabulated. 
 
In addition to the percentage of seroprotected or seropositive subjects, the percentage of 
subjects above the following cut-off will be summarized 
 
 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. 
 Anti-pneumococcal serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F) 
 0.35 µg/mL. 
In light of the number of subjects enrolled in each country, the analysis by country will 
be replaced with analysis by schedule (2 doses ie 2,4 months combined with 3,5 months 
versus 3 doses i.e. 2,3,4 months combined with 2,4,6 months). 
 
In addition subgroups analysis according to gestational age (27-32 weeks and 33-36 
weeks) and age of the mother (18-24 year, 25-34 year and 35-45 year) will be performed. 
 
The sub-group analyses will be limited to descriptive tables of GMT/GMC and the 
percentage of subjects with titres/concentration above key thresholds for ATP cohort of 
immunogenicity. 


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Deviations from specifications for age and intervals between study visits for subjects 
vaccinated with Infanrix hexa by dose schedule (2 dose schedule and 3 dose schedule 
separately) will be tabulated. 
 
6.4. 
Analysis of safety 
 
6.4.1. 
Analysis of safety and reactogenicity planned in the protocol 
 
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 doses and 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] after each 
vaccine dose and overall. 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. 


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• 
The percentage of doses and 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 each 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. 
• 
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) 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 the 31-day follow- 
up (Day 0 – Day 30) will be tabulated (with exact 95% CI [Clopper, 1934]) after 
each vaccine dose and overall. 
• 
SAEs reported from first vaccination dose up to study end will be described in detail. 
• 
Withdrawal due to AEs and SAEs following vaccinations will be described in detail. 
Handling of missing data: 
 
• 
For a given subject and the analysis of solicited AEs 4 days post-vaccination, 
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 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, who 
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 
will be considered. Subjects, who do not report the event or the concomitant 
medication, will be considered as subjects without the event or the concomitant 
medication, respectively. 


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6.4.2. 
Additional considerations 
 
6.4.2.1. 
Combined Solicited and Unsolicited Adverse Events 
 
For clintrial.gov and EudraCT posting purposes, a summary of combined solicited and 
unsolicited non-serious adverse events will be produced by System Organ Class and 
preferred terms and according to occurrence of each event. 
 
A summary of subjects with all combined solicited (regardless of their duration) and 
unsolicited adverse events will be provided. Solicited adverse events will be coded by 
MedDRA as per the following codes. 
 
Solicited symptom 
Lower level term code 
Corresponding Lower level term decode 
PA 
10022086 
Injection site pain 
RE 
10022098 
Redness at injection site 
SW 
10053425 
Swelling at injection site 
TE 
10016558 
Temperature/Fever 
FU 
10022998 
Irritability/Fussiness 
DR 
10013649 
Drowsiness 
LO 
10003028 
Loss of appetite 
7. 
ANALYSIS INTERPRETATION 
All analyses will be conducted in a descriptive manner. 
 
8. 
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. 
 
8.1. 
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 and SAEs. A clinical study report containing all data will be 
written and made available to the investigators. 
 
Description 
Analysis 
ID 
Disclosure Purpose 
(CTRS=public 
posting, SR=study 
report, internal, 
public posting) 
Dry run 
review 
needed 
(Y/N) 
Study Headline 
Summary 
(SHS)requiring 
expedited 
communication to 
upper management 
(Yes/No) 
Reference 
for TFL 
Final 
E1_01 
SR 
Yes 
Yes 
TFL TOC 
8.2. 
Statistical considerations for interim analyses 
NA 


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9. 
CHANGES FROM PLANNED ANALYSES 
• 
During the course of the study, the assays used to measure the anti-D, anti-T, anti- 
PT, anti-FHA and anti-PRN IgG concentrations were re-developed and re-validated 
and both assay units and assay cut-offs were adapted. The new ELISA’s for PT, FHA 
and PRN were calibrated against the WHO International Standard (NIBSC 06/140). 
This allowed the expression of concentrations measured with the new ELISA’s in 
international units per milliliter (IU/mL) instead of the formerly used ELISA units 
per milliliter (ELU/mL). The newly validated DTPa ELISA’s used in the study have 
a lower assay cut-off as compared to the one described in the protocol. The current 
assay cut-off is 0.057 IU/mL for anti-D, 0.043 IU/mL for anti- T, 2.693 IU/mL for 
anti-PT, 2.046 IU/mL for anti-FHA and 2.187 IU/mL for anti- PRN. An agreement 
between the old and new ELISAs was shown with regards to the two thresholds of 
clinical relevance for the DI/TE response (0.1 IU/mL and 1.0 IU/mL) and therefore 
the clinical endpoints and anti-D and anti-T are unchanged. In the absence of a 
correlate of protection for the B. pertussis antigens, the pertussis endpoints were 
redefined based on the assay cut-off (see section 5.7.5 of protocol). 
• 
In addition, following CBER feedback on the anti-D re-validated assay, a calibration 
factor of 0.543 was applied in the analysis of anti-D in order to align the ELISA 
assay to the WHO 10/262 reference samples which are measured as 2 IU/mL by Di 
neutralization. Assay since 54 WHO 10/262 reference samples measured by GSK re- 
validated ELISA led to GMC was about two fold (1.841) higher than the expected 
value (2 IU/mL). 


CONFIDENTIAL 
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Statistical Analysis Plan Final 
16 July 2018 
Page 27 of 57 
 
 
• 
Note: Due to re-validation of all assays, the cut-offs presented in Table 11 of the 
protocol of few antigens have changed. Below table has an updated threshold. 
 
Antigen 
Threshold for positivity 
• 
Anti-PT 
• 
2.693 IU/mL 
• 
Anti-FHA 
• 
2.046 IU/mL 
• 
Anti-PRN 
• 
2.187 IU/mL 
• 
Anti-D 
• 
0.057 IU/mL 
• 
Anti-T 
• 
0.043 IU/mL 
• 
Anti-polio 
• 
8 dilution 
• 
Anti-PRP 
• 
0.066 µg/mL 
• 
Anti-HBs 
• 
6.2 mIU/mL 
• 
Anti-pneumococcal serotypes (1) 
• 
0.080 µg/mL 
• 
Anti-pneumococcal serotypes (3) 
• 
0.075 µg/mL 
• 
Anti-pneumococcal serotypes (4) 
• 
0.061 µg/mL 
• 
Anti-pneumococcal serotypes (5) 
• 
0.198 µg/mL 
• 
Anti-pneumococcal serotypes (6A) 
• 
0.111 µg/mL 
• 
Anti-pneumococcal serotypes (6B) 
• 
0.102 µg/mL 
• 
Anti-pneumococcal serotypes (7F) 
• 
0.063 µg/mL 
• 
Anti-pneumococcal serotypes (9V) 
• 
0.066 µg/mL 
• 
Anti-pneumococcal serotypes (14) 
• 
0.160 µg/mL 
• 
Anti-pneumococcal serotypes (18C) 
• 
0.111 µg/mL 
• 
Anti-pneumococcal serotypes (19A) 
• 
0.199 µg/mL 
• 
Anti-pneumococcal serotypes (19F) 
• 
0.163 µg/mL 
• 
Anti-pneumococcal serotypes (23F) 
• 
0.073 µg/mL 


CONFIDENTIAL 
201330 [DTPA (BOOSTRIX)-048 PRI] 
Statistical Analysis Plan Final 
16 July 2018 
Page 28 of 57 
 
 
10. 
LIST OF FINAL REPORT TABLES, LISTINGS AND 
FIGURES 
The TFL TOC (Tables Figures and Listings Table Of Contents) provides the list of 
tables/listings and figures needed for the study report (synopsis, in-text, post-text) and for 
public disclosure (CTRS). 
 
The following group names will be used in the TFLs: 
 
Group 
order in 
tables 
Group label in 
tables 
Group definition for footnote 
Pooled Groups label 
in tables 
Pooled 
definition for 
footnote 
1 
dTpa Group 
Infants born to mothers belonging to 
the dTpa Group in study 116945 
[DTPA (BOOSTRIX)-047] where 
mothers received dTpa during 
pregnancy. All subjects in this group 
will receive Infanrix hexa co- 
administered with Prevenar 13 
according to the routine national 
immunisation schedule. 
NA 
NA 
2 
Control Group 
Infants born to mothers belonging to 
the Control group in study 116945 
[DTPA (BOOSTRIX)-047] where 
mothers received placebo during 
pregnancy. All subjects in this group 
will receive Infanrix hexa co- 
administered with Prevenar 13 
according to the routine national 
immunisation schedule. 
NA 
NA 
 
Tables will be generated on ATP cohort for immunogenicity with the following sub- 
group names inherited from the study 116945 [DTPA (BOOSTRIX)-047] 
 
Sub-group order in 
tables 
Sub-group label in tables 
Sub-group definition for footnote 
1 
18-24Y 
18-24 years old subjects 
2 
25-34Y 
25-34 years old subjects 
3 
35-45Y 
35-45 years old subjects 
4 
27-32W 
27-32 weeks of gestation of foetus at dose 1 
5 
33-36W 
33-36 weeks of gestation of foetus at dose 1 


CONFIDENTIAL 
201330 [DTPA (BOOSTRIX)-048 PRI] 
Statistical Analysis Plan Final 
16 July 2018 
Page 29 of 57 
 
 
11. 
ANNEX 1 STANDARD DATA DERIVATION RULE AND 
STATISTICAL METHODS 
 
11.1. 
Statistical Method References 
• 
The exact two-sided 95% CIs for a proportion within a group will be the Clopper- 
Pearson exact CI [Clopper CJ, Pearson ES. The use of confidence or fiducial limits 
illustrated in the case of binomial. Biometrika. 1934; 26:404-413]. 
• 
The 95% CI for geometric mean titers/concentrations (GMTs/GMCs) will be 
obtained within each group separately. The 95% CI for the mean of log-transformed 
titer/concentration will be first obtained assuming that log-transformed values were 
normally distributed with unknown variance. The 95% CI for the GMTs/GMCs will 
be then obtained by exponential-transformation of the 95% CI for the mean of log- 
transformed titer/concentration. 
 
11.2. 
Standard data derivation 
 
11.2.1. 
Date derivation 
 
• 
SAS date derived from a character date: In case day is missing, 15 is used. In case 
day & month are missing, 30 June is used. 
• 
Onset day for an event for the infant (AE, medication, vaccination, …): The onset 
day is the number of days from date of last study dose & the onset/start date of the 
event. This is 0 for an event starting on the same day of last study dose. There could 
also be events reported in the infant before delivery (anomalies diagnosed during 
pregnancy at ultrasound investigation), for these cases onset day will be negative ‘-‘ 
days. See SAS date derived in case the start date of the event is incomplete. 
• 
Duration: Duration of an event is expressed in days. It is the number of days 
between the start & the stop dates + 1. Therefore duration is 1 day for an event 
starting & ending on the same day. 
 
11.2.2. 
Dose number 
 
The study dose number is defined in reference to the number of study visits at which 
vaccination occurred. More specifically dose 1 refers to all vaccines administered at the 
first vaccination visit while dose 2 corresponds to all vaccinations administered at the 
second vaccination visit even if this is the first time a product is administered to the 
subject. 


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16 July 2018 
Page 30 of 57 
 
 
Relative dose: the relative dose for an event (AE, medication, vaccination) is the most 
recent study dose given before an event. In case the event takes place on the day a study 
dose is given, the related dose will be that of the study dose, even if the event actually 
took place before vaccination. For instance, if an adverse event begins on the day of the 
study vaccination but prior to administration of the vaccine, it will be assigned to this 
dose. In case a study dose is not administered and an event occurs after the subsequent 
study dose (e.g. 3rd study dose), the relative dose of the event will be study dose 
associated to the subsequent study dose (e.g. dose 3). 
 
The number of doses for a product is the number of time the product was administered to 
a subject. 
 
The incidence per dose is the number of vaccination visits at which an event (vaccination 
visit is a visit at which study vaccine was administered) was reported among all 
vaccination visits. 
 
11.2.3. 
Demography 
 
Age: Age at the reference activity, computed as the number of units between the date of 
birth and the reference activity. 
 
Conversion of weight to kg 
 
The following conversion rule is used: 
Weight in Kilogram= weight in Pounds / 2.2 
Weight in Kilogram =weight in oncs / 35.2 
The result is rounded to 2 decimals. 
Conversion of height to cm 
 
The following conversion rule is used: 
 
Height in Centimetres = Height in Feet * 30.48 
Height in Centimetres = Height in Inch * 2.54 
The result is rounded to the unit (i.e no decimal) 
Conversion of temperature to °C 
The following conversion rule is used: 
 
Temperature in °Celsius = ((Temperature in °Fahrenheit -32) *5)/9 
The result is rounded to 1 decimal. 


CONFIDENTIAL 
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Page 31 of 57 
 
 
11.2.4. 
Immunogenicity 
 
For a given subject and given immunogenicity measurement, missing or non-evaluable 
measurements will not be replaced. Therefore, an analysis will exclude subjects with 
missing or non-evaluable measurements. 
 
The Geometric Mean Concentrations/Titres (GMC/Ts) calculations are performed by 
taking the anti-log of the mean of the log titre transformations. Antibody titres below the 
cut-off of the assay will be given an arbitrary value of half the cut-off of the assay for the 
purpose of GMT calculation. The cut-off value is defined by the laboratory before the 
analysis and is described in the protocol. 
 
A seronegative subject is a subject whose antibody titre is below the cut-off value of the 
assay. A seropositive subject is a subject whose antibody titre is greater than or equal to 
the cut-off value of the assay. 
 
The assay cut-off is the value under which there is no quantifiable result available. For an 
assay with a specific ‘cut_off’, numerical immunogenicity result is derived from a 
character field (rawres): 
 
If rawres is ‘NEG’ or ‘-’ or ‘(-)’, numeric result= cutt_off/2, 
if rawres is ‘POS’ or ‘+’ or ‘(+)’, numeric result = cut_off, 
if rawres is ‘< value’ and value<=cut_off, numeric result =cut_off/2, 
if rawres is ‘< value’ and value>cut_off, numeric result =value, 
if rawres is ‘> value’ and value<cut_off, numeric result =cut_off/2, 
if rawres is ‘> value’ and value>=cut_off, numeric result =value, 
if rawres is ‘<= value’ or ‘>= value’ and value<cut_off, numeric result =cut_off/2, 
if rawres is ‘<= value’ or ‘>= value’ and value>=cut_off, numeric result =value, 
if rawres is a value < cut_off, numeric result = cut_off/2, 
if rawres is a value >= cut_off, numeric result = rawres, 
if rawres is a value >= cut_off, numeric result = rawres, 
else numeric result is left blank. 
All CI computed will be two-sided 95% CI. 


CONFIDENTIAL 
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Statistical Analysis Plan Final 
16 July 2018 
Page 32 of 57 
 
 
11.2.5. 
Safety 
 
For analysis of solicited, unsolicited adverse events such as serious adverse events or 
adverse events by primary MedDRA term, and for the analysis of concomitant 
medications, all vaccinated subjects will be considered. Subjects who did not report the 
event or the concomitant medication will be considered as subjects without the event or 
the concomitant medication respectively. 
 
For a given subject and the analysis of solicited adverse events within 4 days post- 
vaccination, missing or non-evaluable measurements will not be replaced. Therefore, the 
analysis of the solicited adverse events based on the Total Vaccinated Cohort will include 
only vaccinated subjects for doses with documented safety data (i.e., symptom screen 
completed). More specifically the following rules will be used: 
 
• 
Subjects who documented the absence of a solicited adverse events after one dose 
will be considered not having that adverse events after that dose. 
• 
Subjects who documented the presence of a solicited symptom and fully or partially 
recorded daily measurement over the solicited period will be included in the 
summaries at that dose and classified according to their maximum observed daily 
recording over the solicited period. 
• 
Subjects who documented the presence of a solicited symptom after one dose 
without having recorded any daily measurement will be assigned to the lowest 
intensity category at that dose (i.e., 37.5°C for fever or grade 1 for other symptoms). 
• 
Doses without symptom sheets documented will be excluded. 
• 
The intensity of the following solicited adverse events will be assessed as described 
in the below table 


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16 July 2018 
Page 33 of 57 
 
 
Table 4 
Intensity scales for solicited symptoms in infants less than 6 years 
of age 
 
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 rectal/axillary. 
 
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 tympanic route) will be scored at GSK 
Biologicals as follows: 
 
Grade 
Temperature 
0 
<37.5C 
1 
37.5C to 38.0C 
2 
>38.0C to 39.0C 
3 
> 39.0C 
The investigator will assess the maximum intensity that occurred over the duration of the 
event for all unsolicited AEs (including SAEs) recorded during the study. The assessment 
will be based on the investigator’s clinical judgement. 


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16 July 2018 
Page 34 of 57 
 
 
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 in the protocol. 
The way the percentage of subjects will be derived will depend on the event analysed 
(see table below for details). As a result, the N value will differ from one table to another. 
 
Event 
N used for deriving % per subject 
N used for deriving % per dose 
Concomitant 
vaccination 
All subjects with study vaccine 
administered 
All study visits with study vaccine 
administered 
Solicited general AEs 
All subjects with at least one solicited 
general AE documented as either present 
or absent (i.e., symptom screen 
completed) 
All study visits with study vaccine 
administered and with at least one 
solicited general AE documented as 
either present or absent (i.e., symptom 
screen completed) 
Solicited local AEs 
All subjects with at least one solicited local 
AE documented as either present or 
absent (i.e., symptom screen completed) 
All study visits with study vaccine 
administered and with at least one 
solicited local AE documented as either 
present or absent (i.e., AE screen 
completed) 
Unsolicited AEs 
All subjects with study vaccine 
administered 
All study visits with study vaccine 
administered 
Concomitant medication 
All subjects with study vaccine 
administered 
All study visits with study vaccine 
administered 
11.2.6. 
Number of decimals displayed: 
 
The following decimal description from the decision rules will be used for the 
demography, immunogenicity and safety/reactogenicity. 
 
Display Table 
Parameters 
Number of decimal digits 
Demographic 
characteristics 
Mean, median age 
1 
Demographic 
characteristics 
SD (age) 
1 
Immunogenicity 
GMT/GMC 
3 for anti-D, anti-T and anti- 
PRP 
2 for Strepto antigens 
1 for anti-PT, anti-FHA and anti- 
PRN, anti-HBs, anti-Polio 1, 
anti-Polio 2 and anti-Polio 3 
Reactogenicity 
Mean, Min, Q1, Median, Q3, Max for duration 
1 
All summaries 
% of count, including LL & UL of CI 
1 


CONFIDENTIAL 
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Page 35 of 57 
 
 
12. 
ANNEX 3: STUDY SPECIFIC MOCK TFL 
The following drafted study specific mocks will be used. 
 
The data display, title and footnote is for illustration purpose and will be adapted to the 
study specificity as indicated in the TFL TOC. 
 
These templates were copied from recent studies. Note that there may be few changes 
between the study specific SAP mock TFL and the final TFLs as editorial/minor changes 
do not require a SAP amendment. 
 
Template 1 
Number of subjects enrolled by center (Total vaccinated cohort) 
 
dTpa Group 
Control group 
Total 
Center 
n 
N 
n 
% 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD   
All 
dTpa Group = This group will consist of infants born to mothers belonging to the dTpa Group in study 116945 [DTPA 
(BOOSTRIX)-047]. All subjects in this group will receive Infanrix hexa co-administered with Prevenar 13 according to 
the routine national immunisation schedule. 
Control Group: This group will consist of infants born to mothers belonging to the Control group in study 116945 [DTPA 
(BOOSTRIX)-047]. All subjects in this group will receive Infanrix hexa co-administered with Prevenar 13 according to 
the routine national immunisation schedule. 
n = number of subjects included in each group or in total for a given center or for all centers 
All = sum of all subjects in each group or in total (sum of all groups) 
% = n/All x 100 


CONFIDENTIAL 
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Page 36 of 57 
 
 
Template 2 
Number of subjects enrolled by country (Total vaccinated cohort) 
 
dTpa Group 
Control group 
Total 
Country 
n 
N 
n 
% 
Australia 
Belgium 
Canada 
Czechia 
Finland 
Italy 
Spain 
All 
dTpa Group = This group will consist of infants born to mothers belonging to the dTpa Group in study 116945 [DTPA 
(BOOSTRIX)-047]. All subjects in this group will receive Infanrix hexa co-administered with Prevenar 13 according to 
the routine national immunisation schedule. 
Control Group: This group will consist of infants born to mothers belonging to the Control group in study 116945 [DTPA 
(BOOSTRIX)-047]. All subjects in this group will receive Infanrix hexa co-administered with Prevenar 13 according to 
the routine national immunisation schedule. 
n = number of subjects included in each group or in total for a given country or for all countries 
All = sum of all subjects in each group or in total (sum of all groups) 
% = n/All x 100 
 
Template 3 
Number of subjects vaccinated, completed and withdrawn with 
reason for withdrawal (Total vaccinated cohort) 
 
dTpa Group Control 
Group 
Total 
Number of subjects vaccinated 
Number of subjects completed 
Number of subjects withdrawn 
Reasons for withdrawal: 
Serious Adverse Event 
Non-serious adverse event 
Protocol violation 
Consent withdrawal (not due to an adverse event) 
Migrated/moved from study area 
Lost to follow-up (subjects with incomplete vaccination course) 
Lost to follow-up (subjects with complete vaccination course) 
Others 
dTpa Group = This group will consist of infants born to mothers belonging to the dTpa Group in study 116945 [DTPA 
(BOOSTRIX)-047]. All subjects in this group will receive Infanrix hexa co-administered with Prevenar 13 according to 
the routine national immunisation schedule. 
Control Group: This group will consist of infants born to mothers belonging to the Control group in study 116945 [DTPA 
(BOOSTRIX)-047]. All subjects in this group will receive Infanrix hexa co-administered with Prevenar 13 according to 
the routine national immunisation schedule. 
Vaccinated = number of subjects who were vaccinated in the study 
Completed = number of subjects who completed last study visit 
Withdrawn = number of subjects who did not come for last study visit 


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PP
Template 4 
Number of subjects at each visit and list of withdrawn subjects 
(Total Vaccinated Cohort) 
 
Group 
VISIT 
N 
Withdrawn Subject 
numbers 
Reason for withdrawal 
dTpa Group 
VISIT 1 
508 
no. PP  
CONSENT WITHDRAWAL 
no. PP  
CONSENT WITHDRAWAL 
no. PPD 
CONSENT WITHDRAWAL 
no. PPD 
CONSENT WITHDRAWAL 
VISIT 2 
504 
no. PPD 
CONSENT WITHDRAWAL 
no. PPD 
CONSENT WITHDRAWAL 
no. PPD 
SERIOUS ADVERSE EXPERIENCE 
VISIT 3 
501 
no. P 
MIGRATION FROM STUDY AREA 
no. PP  
CONSENT WITHDRAWAL 
no. PP  
MIGRATION FROM STUDY AREA 
no. PP  
CONSENT WITHDRAWAL 
no. PP  
MIGRATION FROM STUDY AREA 
no. PP  
MIGRATION FROM STUDY AREA 
no. PPD 
CONSENT WITHDRAWAL 
no. PPD 
MIGRATION FROM STUDY AREA 
no. PPD 
MIGRATION FROM STUDY AREA 
Control 
Group 
VISIT 1 
257 
no. PP  
PROTOCOL VIOLATION 
no. PPD 
CONSENT WITHDRAWAL 
VISIT 2 
255 
no. PPD 
CONSENT WITHDRAWAL 
VISIT 3 
254 
no. PP  
MIGRATION FROM STUDY AREA 
no. PP  
LOST TO FOLLOW-UP 
no.PPD 
LOST TO FOLLOW-UP 
no. PP  
CONSENT WITHDRAWAL 
no. PP  
MIGRATION FROM STUDY AREA 
no. PPD 
LOST TO FOLLOW-UP 
no. PPD 
ADVERSE EXPERIENCE 
dTpa Group = This group will consist of infants born to mothers belonging to the dTpa Group in study 116945 [DTPA 
(BOOSTRIX)-047]. All subjects in this group will receive Infanrix hexa co-administered with Prevenar 13 according to 
the routine national immunisation schedule. 
Control Group: This group will consist of infants born to mothers belonging to the Control group in study 116945 [DTPA 
(BOOSTRIX)-047]. All subjects in this group will receive Infanrix hexa co-administered with Prevenar 13 according to 
the routine national immunisation schedule. 
N = number of subjects who are still in the study up to the visit 
Withdrawn = subject who did not return after the visit 


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Template 5 
Number of subjects enrolled into the study as well as excluded from 
ATP analyses with reasons for exclusion 
 
Total 
dTpa 
Group 
Control 
Group 
Title 
N 
n s % 
N 
n s N 
n 
s 
Total enrolled cohort 
1200 
300 
300 
Invalid informed consent or fraud data (code 900) 
Study vaccine dose not administered AT ALL but subject number 
allocated (code 1030) 
TVC 
1200 
100 300 
300 
Administration of vaccine(s) forbidden in the protocol (code 1040) 
2 2 
0 0 
0 
0 
Randomisation code broken at the investigator site OR at GSK Safety 
department (1060) 
Study vaccine dose not administered according to protocol (code 1070) 
73 73 
23 23 
16 16 
Vaccine temperature deviation (code 1080) 
Expired vaccine administered (code 1090) 
10 11 
3 3 
1 
1 
Protocol violation (inclusion/exclusion criteria) (code 2010) 
1 1 
1 1 
0 
0 
Administration of any medication forbidden by the protocol (code 2040) 
1 1 
0 0 
1 
1 
Underlying medical condition forbidden by the protocol (code 2050) 
1 1 
0 0 
0 
0 
Concomitant infection related to the vaccine which may influence 
immune response 
(2060) 
Concomitant infection not related to the vaccine which may influence 
immune response (code 2070) 
0 1 
0 0 
0 
1 
Noncompliance with vaccination schedule (including wrong and unknown 
dates) (code 2080) 
14 16 
6 7 
3 
4 
Noncompliance with blood sampling schedule (including wrong and 
unknown dates) 
(code 2090) 
12 16 
3 5 
4 
5 
Essential serological data missing (code 2100) 
87 95 
20 22 
23 26 
Obvious incoherence, abnormal serology evolution or error in data (code 
2120) 
1 1 
0 0 
0 
0 
ATP cohort for analysis of immunogenicity 
998 
83.2 244 
252 
dTpa Group = This group will consist of infants born to mothers belonging to the dTpa Group in study 116945 [DTPA 
(BOOSTRIX)-047]. All subjects in this group will receive Infanrix hexa co-administered with Prevenar 13 according to 
the routine national immunisation schedule. 
Control Group: This group will consist of infants born to mothers belonging to the Control group in study 116945 [DTPA 
(BOOSTRIX)-047]. All subjects in this group will receive Infanrix hexa co-administered with Prevenar 13 according to 
the routine national immunisation schedule. 
Note: Subjects may have more than 1 elimination code assigned 
n = number of subjects with the elimination code assigned excluding subjects who have been assigned a lower 
elimination code number 
s = number of subjects with the elimination code assigned 
% = percentage of subjects in the per protocol set (ATP) relative to the TVC(ES) 


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Template 6 
Deviations from specifications for age and intervals between study 
visits for subjects vaccinated with Infanrix hexa(<2> dose schedule - 
1 dose/visit) (Total Vaccinated Cohort) 
 
Age 
VAC:1-VAC:2 
VAC:2-SER:2 
Group 
Protocol 
Protocol 
Protocol 
from 6 to 14 weeks and 6 
days 
from 52 to 78 days 
from 21 to 48 days 
dTpa Group 
N 
n 
% 
range 
Control Group 
N 
n 
% 
range 
dTpa Group = This group will consist of infants born to mothers belonging to the dTpa Group in study 116945 [DTPA 
(BOOSTRIX)-047]. All subjects in this group will receive Infanrix hexa co-administered with Prevenar 13 according to 
the routine national immunisation schedule. 
Control Group: This group will consist of infants born to mothers belonging to the Control group in study 116945 [DTPA 
(BOOSTRIX)-047]. All subjects in this group will receive Infanrix hexa co-administered with Prevenar 13 according to 
the routine national immunisation schedule. 
N = total number of subjects with available results 
n(%) = number(percentage) of subjects with results outside of the interval 
range = minimum-maximum for age and intervals 
VAC:1 = vaccination at visit 1 
VAC:2 = vaccination at visit 2 
SER:2 = blood sample collected before the first dose and 1 month after the last dose of the primary vaccination course 
2 dose schedule = subjects who received 2 dose of Infanrix hexa at 2,4 months of age or 3,5 months of age, co- 
administered with Prevenar 13 (according to the routine national immunisation schedule of the country). 


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Template 7 
Summary of demographic characteristics (Total vaccinated cohort) 
 
dTpa Group 
N = 
Control Group 
N = 
Total 
N = 
Characteristics 
Parameters or Categories 
Value or n % 
Value or 
n 
% 
Value or 
n 
% 
Age (week) at vaccination 
dose: 1 
Mean 
SD 
Median 
Q1 
Q3 
Gender 
Female 
Male 
Geographic Ancestry 
African Heritage / African American 
American Indian or Alaskan Native 
Asian - Central / South Asian 
Heritage 
Asian - East Asian Heritage 
Asian - Japanese Heritage 
Asian - South East Asian Heritage 
Native Hawaiian or Other Pacific 
Islander 
White - Arabic / North African 
Heritage 
White - Caucasian / European 
Heritage 
Other (Hispanic) 
Dose schedule 
2 dose schedule 
3 dose schedule 
Maternal age group 
18-24Y 
25-34Y 
35-45Y 
Gestational week of foetus at 
dose 1 
27-32W 
33-36W 
dTpa Group = This group will consist of infants born to mothers belonging to the dTpa Group in study 116945 [DTPA 
(BOOSTRIX)-047]. All subjects in this group will receive Infanrix hexa co-administered with Prevenar 13 according to 
the routine national immunisation schedule. 
Control Group: This group will consist of infants born to mothers belonging to the Control group in study 116945 [DTPA 
(BOOSTRIX)-047]. All subjects in this group will receive Infanrix hexa co-administered with Prevenar 13 according to 
the routine national immunisation schedule. 
N = total number of subjects 
n(%) = number(percentage) of subjects in a given category 
Value = value of the considered parameter 
SD = standard deviation 
Q1 = Quartile 1 
Q2 = Quartile 3 
2 dose schedule = subjects who received 2 dose of Infanrix hexa at 2,4 months of age or 3,5 months of age, 
co-administered with Prevenar 13 (according to the routine national immunisation schedule of the country). 
3 dose schedule = subjects who received 3 dose of Infanrix hexa at 2,3,4 months of age or 2,4,6 months of age, 
co-administered with Prevenar 13.Prevenar 13 could be administered as 2-doses or 3-doses primary vaccination 
schedule (according to the routine national immunisation schedule of the country). 
18-24Y = 18-24 years old subjects 
25-34Y = 25-34 years old subjects 
35-45Y = 35-45 years old subjects 
27-32W = 27-32 weeks of gestation of foetus at dose 1 
33-36W = 33-36 weeks of gestation of foetus at dose 1 


CONFIDENTIAL 
201330 [DTPA (BOOSTRIX)-048 PRI] 
Statistical Analysis Plan Final 
16 July 2018 
Page 41 of 57 
 
 
Template 8 
Summary of vital signs characteristics (Total Vaccinated Cohort) 
 
dTpa Group 
(N = 335) 
Control Group 
(N = 336) 
Total 
(N = 671) 
Characteristics 
Parameters 
Value 
Value 
Value 
Height (cm) 
Mean 
SD 
Median 
Q1 
Q3 
Unknown 
Weight (kg) 
Mean 
SD 
Median 
Q1 
Q3 
Unknown 
Head circumference (cm) Mean 
SD 
Median 
Q1 
Q3 
Unknown 
Body mass index in 
[kg/m2] 
Mean 
SD 
Median 
Q1 
Q3 
Unknown 
dTpa Group = This group will consist of infants born to mothers belonging to the dTpa Group in study 116945 [DTPA 
(BOOSTRIX)-047]. All subjects in this group will receive Infanrix hexa co-administered with Prevenar 13 according to 
the routine national immunisation schedule. 
Control Group: This group will consist of infants born to mothers belonging to the Control group in study 116945 [DTPA 
(BOOSTRIX)-047]. All subjects in this group will receive Infanrix hexa co-administered with Prevenar 13 according to 
the routine national immunisation schedule. 
N = total number of subjects 
Value = value of the considered parameter 
SD = standard deviation 
Height (cm) = height expressed in centimeters 
Weight (kg) = weight expressed in kilograms 
Head circumference(cm) = head circumference expressed in centimeters. 
Body mass index in [kg/m2] = body mass index expressed in kilograms per meter square 
SD = standard deviation 
Q1 = Quartile 1 
Q2 = Quartile 3 


CONFIDENTIAL 
201330 [DTPA (BOOSTRIX)-048 PRI] 
Statistical Analysis Plan Final 
16 July 2018 
Page 42 of 57 
 
 
Template 9 
Study population (TVC) 
 
Study population (Total vaccinated cohort) 
Number of subjects 
dTpa group 
Control group 
Planned, N 
225 
225 
Randomised, N (Total Vaccinated Cohort) 
224 
227 
Completed, n (%) 
224 (100) 
227 (100) 
Demographics 
dTpa group 
Control group 
N (Total Vaccinated Cohort) 
224 
227 
Females: Males 
97:127 
115:112 
Mean Age, weeks (SD) 
8.8 (1.1) 
8.8 (1.1) 
Median Age, weeks (minimum, maximum) 
9 (7, 11) 
9 (7, 11) 
Most frequent race: Asian - East Asian Heritage, n (%) 
224 (100) 
226 (99.6) 
dTpa Group = This group will consist of infants born to mothers belonging to the dTpa Group in study 116945 [DTPA 
(BOOSTRIX)-047]. All subjects in this group will receive Infanrix hexa co-administered with Prevenar 13 according to 
the routine national immunisation schedule. 
Control Group: This group will consist of infants born to mothers belonging to the Control group in study 116945 [DTPA 
(BOOSTRIX)-047]. All subjects in this group will receive Infanrix hexa co-administered with Prevenar 13 according to 
the routine national immunisation schedule. 
N = total number of subjects enrolled in the study 
n/% = number/percentage of subjects in a given category 
SD = Standard Deviation 
Mean Age = age calculated from Date of birth to first study vaccination 
 
Template 10 Seropositivity rates and GMCs for anti-PT, anti-FHA and anti-PRN 
antibodies before the first dose and 1 month after the last dose of 
the primary vaccination (ATP cohort for immunogenicity) 
 
≥ assay cut-off* 
GMC 
95% CI 
Antibody 
Group 
Timing 
N n 
% 
LL 
UL 
value 
LL 
UL 
Anti-PT 
dTpa Group 
Pre-Pri 
Post-Pri 
Control Group 
Pre-Pri 
Post-Pri 
Anti-FHA 
dTpa Group 
Pre-Pri 
Post-Pri 
Control Group 
Pre-Pri 
Post-Pri 
Anti-PRN 
dTpa Group 
Pre-Pri 
Post-Pri 
Control Group 
Pre-Pri 
Post-Pri 
dTpa Group = This group will consist of infants born to mothers belonging to the dTpa Group in study 116945 [DTPA 
(BOOSTRIX)-047]. All subjects in this group will receive Infanrix hexa co-administered with Prevenar 13 according to 
the routine national immunisation schedule. 
Control Group: This group will consist of infants born to mothers belonging to the Control group in study 116945 [DTPA 
(BOOSTRIX)-047]. All subjects in this group will receive Infanrix hexa co-administered with Prevenar 13 according to 
the routine national immunisation schedule. 
*Assay cut-off is 2.693 IU/mL for anti- PT, 2.046 IU/mL for anti-FHA and 2.187 IU/mL for anti-PRN 
GMC = geometric mean antibody concentration calculated on all subjects 
N = number of subjects with available results 
n(%)=number(percentage) of subjects with antibody concentrations above the specified cut-off 
95% CI = exact 95% confidence interval; LL = Lower Limit, UL = Upper Limit 
Pre-Pri = blood sample to be collected before the first dose of the primary vaccination course 
Post-Pri = blood sample to be collected 1 month after the last dose of the primary vaccination course 


CONFIDENTIAL 
201330 [DTPA (BOOSTRIX)-048 PRI] 
Statistical Analysis Plan Final 
16 July 2018 
Page 43 of 57 
 
 
Template 11 Seropositivity, seroprotection and GMC rates for <anti-tetanus> 
antibodies before the first dose and 1 month after the last dose of 
the primary vaccination (ATP cohort for immunogenicity) 
 
≥ assay cut-off* 
 0.1 IU/mL 
 1.0 IU/mL 
GMC 
95% CI 
95% CI 
95% CI 
95% CI 
Antibody Group 
Timing 
N 
n 
% 
LL 
UL n 
% 
LL UL n 
% 
UL UL value LL 
UL 
Anti- 
tetanus 
dTpa 
Group 
Pre-Pri 
Post-Pri 
Control 
Group 
Pre-Pri 
Post-Pri 
Anti- 
diphtheria 
dTpa 
Group 
Pre-Pri 
Post-Pri 
Control 
Group 
Pre-Pri 
Post-Pri 
dTpa Group = This group will consist of infants born to mothers belonging to the dTpa Group in study 116945 [DTPA 
(BOOSTRIX)-047]. All subjects in this group will receive Infanrix hexa co-administered with Prevenar 13 according to 
the routine national immunisation schedule. 
Control Group: This group will consist of infants born to mothers belonging to the Control group in study 116945 [DTPA 
(BOOSTRIX)-047]. All subjects in this group will receive Infanrix hexa co-administered with Prevenar 13 according to 
the routine national immunisation schedule. 
*Assay cut-off is 0.043 IU/mL for anti-tetanus and 0.057 IU/mL for anti- diphtheria 
GMC = geometric mean antibody concentration calculated on all subjects 
N = number of subjects with available results 
n(%)=number(percentage) of subjects with antibody concentrations above the specified cut-off 
95% CI = exact 95% confidence interval; LL = Lower Limit, UL = Upper Limit 
Pre-Pri = blood sample to be collected before the first dose of the primary vaccination course 
Post-Pri = blood sample to be collected 1 month after the last dose of the primary vaccination course 


CONFIDENTIAL 
201330 [DTPA (BOOSTRIX)-048 PRI] 
Statistical Analysis Plan Final 
16 July 2018 
Page 44 of 57 
 
 
Template 12 Seroprotection rates for anti-poliovirus type 1,2,3 antibodies before 
the first dose and 1 month after the last dose of the primary 
vaccination (ATP cohort for immunogenicity) 
 
 8 
GMT 
95% CI 
95% CI 
Antibody 
Group 
Timing 
N 
n 
% 
UL 
UL 
value 
LL 
UL 
anti-poliovirus type 1 
dTpa Group Pre-Pri 
Post-Pri 
Control 
Group 
Pre-Pri 
Post-Pri 
anti-poliovirus type 2 
dTpa Group Pre-Pri 
Post-Pri 
Control 
Group 
Pre-Pri 
Post-Pri 
anti-poliovirus type 3 
dTpa Group Pre-Pri 
Post-Pri 
Control 
Group 
Pre-Pri 
Post-Pri 
dTpa Group = This group will consist of infants born to mothers belonging to the dTpa Group in study 116945 [DTPA 
(BOOSTRIX)-047]. All subjects in this group will receive Infanrix hexa co-administered with Prevenar 13 according to 
the routine national immunisation schedule. 
Control Group: This group will consist of infants born to mothers belonging to the Control group in study 116945 [DTPA 
(BOOSTRIX)-047]. All subjects in this group will receive Infanrix hexa co-administered with Prevenar 13 according to 
the routine national immunisation schedule. 
GMT = geometric mean antibody concentration calculated on all subjects 
N = number of subjects with available results 
n(%)=number(percentage) of subjects with antibody concentrations above the specified cut-off 
95% CI = exact 95% confidence interval; LL = Lower Limit, UL = Upper Limit 
Pre-Pri = blood sample to be collected before the first dose of the primary vaccination course 
Post-Pri = blood sample to be collected 1 month after the last dose of the primary vaccination course 


CONFIDENTIAL 
201330 [DTPA (BOOSTRIX)-048 PRI] 
Statistical Analysis Plan Final 
16 July 2018 
Page 45 of 57 
 
 
Template 13 Vaccine responses for anti-PT, anti-FHA and anti-PRN antibody 
concentration 1 month after the last dose of the primary vaccination 
course (ATP cohort for immunogenicity) 
 
Vaccine response 
95% CI 
Antibody 
Group 
Pre-Pri* 
status 
N 
n 
% 
LL 
UL 
anti-PT 
dTpa Group 
S- 
S+ (≥cut-off IU/mL) 
Total 
Control Group 
S- 
S+ (≥cut-off IU/mL) 
Total 
anti-FHA 
dTpa Group 
S- 
S+ (≥cut-off IU/mL) 
Total 
Control Group 
S- 
S+ (≥cut-off IU/mL) 
Total 
anti-PRN 
dTpa Group 
S- 
S+ (≥cut-off IU/mL) 
Total 
Control Group 
S- 
S+ (≥cut-off IU/mL) 
Total 
dTpa Group = This group will consist of infants born to mothers belonging to the dTpa Group in study 116945 [DTPA 
(BOOSTRIX)-047]. All subjects in this group will receive Infanrix hexa co-administered with Prevenar 13 according to 
the routine national immunisation schedule. 
Control Group: This group will consist of infants born to mothers belonging to the Control group in study 116945 [DTPA 
(BOOSTRIX)-047]. All subjects in this group will receive Infanrix hexa co-administered with Prevenar 13 according to 
the routine national immunisation schedule. 
S- = Initially seronegative subjects (antibody concentration below assay cut-off for anti-PT, anti-FHA, anti-PRN) 
S+ = Initially seropositive (antibody concentration above assay cut-off for anti-PT, anti-FHA, anti-PRN) 
Total = subjects either seropositive or ser1gative at pre-vaccination 
Vaccine response to PT, FHA and PRN antigens is defined as: 
For subjects with pre-vaccination antibody concentration below the assay cut-off, post-vaccination antibody 
concentration equal or above the assay cut-off, 
For subjects with pre-vaccination antibody concentration equal or above the assay cut-off, post-vaccination antibody 
concentration equal or above the pre-vaccination antibody concentration 
N = number of subjects with pre- and post-vaccination results available 
n(%) = number(percentage) of subjects with booster response 
95% CI = 95% confidence interval; LL = Lower Limit, UL = Upper Limit 
*Pre-Pri = blood sample to be collected before the first dose of the primary vaccination course 
Note: The assay cut-off is 2.693 IU/mL for anti-PT, 2.046 IU/mL for anti-FHA, and 2.187 IU/mL for anti-PRN. 


CONFIDENTIAL 
201330 [DTPA (BOOSTRIX)-048 PRI] 
Statistical Analysis Plan Final 
16 July 2018 
Page 46 of 57 
 
 
Template 14 Reverse cumulative curve for anti-diphtheria antibody concentration 
before first dose and 1 month post last dose of the primary 
vaccination course (ATP cohort for immunogenicity) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
dTpa Group = This group will consist of infants born to mothers belonging to the dTpa Group in study 116945 [DTPA 
(BOOSTRIX)-047]. All subjects in this group will receive Infanrix hexa co-administered with Prevenar 13 according to 
the routine national immunisation schedule. 
Control Group: This group will consist of infants born to mothers belonging to the Control group in study 116945 [DTPA 
(BOOSTRIX)-047]. All subjects in this group will receive Infanrix hexa co-administered with Prevenar 13 according to 
the routine national immunisation schedule. 
Pre-Pri = blood sample to be collected before the first dose of the primary vaccination course 
Post-Pri = blood sample to be collected 1 month after the last dose of the primary vaccination course 
Note: The groups shown in figure are indicative only. Actual groups may differ. 


CONFIDENTIAL 
201330 [DTPA (BOOSTRIX)-048 PRI] 
Statistical Analysis Plan Final 
16 July 2018 
Page 47 of 57 
 
 
Template 15 Number and percentage of subjects who received study vaccine 
doses by vaccination group (Total vaccinated cohort) 
 
dTpa group N = 
Control group N = 
Total number of doses received 
n 
% 
n 
% 
0 
1 
2 
3 
Any 
dTpa Group = This group will consist of infants born to mothers belonging to the dTpa Group in study 116945 [DTPA 
(BOOSTRIX)-047]. All subjects in this group will receive Infanrix hexa co-administered with Prevenar 13 according to 
the routine national immunisation schedule. 
Control Group: This group will consist of infants born to mothers belonging to the Control group in study 116945 [DTPA 
(BOOSTRIX)-047]. All subjects in this group will receive Infanrix hexa co-administered with Prevenar 13 according to 
the routine national immunisation schedule. 
N = number of subjects in each group or in total included in the considered cohort 
n(%) = number(percentage) of subjects receiving the specified total number of doses 
Any = number and percentage of subjects receiving at least 1 dose 
Template 16 Compliance in returning symptom sheets (Total vaccinated cohort) 
 
Dose 
Group 
Number of 
doses 
Doses NOT 
according to 
protocol 
Number of 
general SS 
Compliance % 
general SS 
Number of 
local SS 
Compliance % 
local SS 
1 
dTpa group 
Control group 
2 
dTpa group 
Control group 
3 
dTpa group 
Control group 
Total 
dTpa group 
Control group 
dTpa Group = This group will consist of infants born to mothers belonging to the dTpa Group in study 116945 [DTPA 
(BOOSTRIX)-047]. All subjects in this group will receive Infanrix hexa co-administered with Prevenar 13 according to 
the routine national immunisation schedule. 
Control Group: This group will consist of infants born to mothers belonging to the Control group in study 116945 [DTPA 
(BOOSTRIX)-047]. All subjects in this group will receive Infanrix hexa co-administered with Prevenar 13 according to 
the routine national immunisation schedule. 
SS = Symptom sheets used for the collection of local and general solicited AEs 
Compliance % = (number of doses with symptom sheet return / number of administered doses) X 100 


CONFIDENTIAL 
201330 [DTPA (BOOSTRIX)-048 PRI] 
Statistical Analysis Plan Final 
16 July 2018 
Page 48 of 57 
 
 
Template 17 Percentage and nature of <grade 3>symptoms (solicited and 
unsolicited) reported during the 4-day (Days 0-3) post-vaccination 
period following each dose and overall (Total vaccinated cohort) 
 
Any symptom 
General symptoms 
Local symptoms 
95% CI 
95% CI 
95% CI 
Group 
N 
n 
% 
LL 
UL N 
n 
% 
LL 
UL 
N 
n 
% 
LL 
UL 
Dose 1 
dTpa group 
Control group 
Dose 2 
dTpa group 
Control group 
Dose 3 
dTpa group 
Control group 
Overall/dose 
dTpa group 
Control group 
Overall/subject dTpa group 
Control group 
dTpa Group = This group will consist of infants born to mothers belonging to the dTpa Group in study 116945 [DTPA 
(BOOSTRIX)-047]. All subjects in this group will receive Infanrix hexa co-administered with Prevenar 13 according to 
the routine national immunisation schedule. 
Control Group: This group will consist of infants born to mothers belonging to the Control group in study 116945 [DTPA 
(BOOSTRIX)-047]. All subjects in this group will receive Infanrix hexa co-administered with Prevenar 13 according to 
the routine national immunisation schedule. 
For each dose and overall/subject: 
N= number of subjects with at least 1 administered dose 
n(%) = number(percentage) of subjects presenting at least 1 type of symptom whatever the study vaccine administered 
For overall/dose: 
N= number of administered doses 
n(%) = number(percentage) of doses followed by at least 1 type of symptom whatever the study vaccine administered 
95% CI = exact 95% confidence interval, LL = Lower Limit, UL = Upper Limit 


CONFIDENTIAL 
201330 [DTPA (BOOSTRIX)-048 PRI] 
Statistical Analysis Plan Final 
16 July 2018 
Page 49 of 57 
 
 
Template 18 Percentage of solicited local symptoms reported during the 4-day 
(Day 0-3) post-vaccination period following each dose and overall 
(Total vaccinated cohort) 
 
each group 
dTpa group 
Control group 
95 % CI 
95 % CI 
Symptom 
Product 
Type 
N n % LL 
UL 
N n % LL 
UL 
Each dose 
Pain 
Total 
All 
Grade 2 or 3 
Grade 3 
Medical advice 
Infanrix hexa 
All 
Grade 2 or3 
Grade 3 
Medical advice 
Prevenar 13 
All 
Grade 2 or 3 
Grade 3 
Medical advice 
Redness 
Total 
All 
(mm) 
> 5.0 
> 20.0 
Medical advice 
Infanrix hexa 
All 
> 5.0 
> 20.0 
Medical advice 
Prevenar 13 
All 
> 5.0 
> 20.0 
Medical advice 
Swelling 
Total 
All 
(mm) 
> 5.0 
> 20.0 
Medical advice 
Infanrix hexa 
All 
> 5.0 
> 20.0 
Medical advice 
Prevenar 13 
All 
> 5.0 
> 20.0 
Medical advice 
Overall/Dose 
Pain 
Total 
All 
Grade 2 or 3 
Grade 3 
Medical advice 
Infanrix hexa 
All 
Grade 2 or 3 
Grade 3 
Medical advice 


CONFIDENTIAL 
201330 [DTPA (BOOSTRIX)-048 PRI] 
Statistical Analysis Plan Final 
16 July 2018 
Page 50 of 57 
 
 
 
  
each group 
dTpa group 
Control group 
95 % CI 
95 % CI 
Symptom 
Product 
Type 
N n % LL 
UL 
N n % LL 
UL 
Prevenar 13 
All 
Grade 2 or 3 
Grade 3 
Medical advice 
Redness (mm) 
Total 
All 
> 5.0 
> 20.0 
Medical advice 
Infanrix hexa 
All 
> 5.0 
> 20.0 
Medical advice 
Prevenar 13 
All 
> 5.0 
> 20.0 
Medical advice 
Swelling (mm) 
Total 
All 
> 5.0 
> 20.0 
Medical advice 
Infanrix hexa 
All 
> 5.0 
> 20.0 
Medical advice 
Prevenar 13 
All 
> 5.0 
> 20.0 
Medical advice 
Overall/Subject 
Pain 
Total 
All 
Grade 2 or 3 
Grade 3 
Medical advice 
Infanrix hexa 
All 
Grade 2 or 3 
Grade 3 
Medical advice 
Prevenar 13 
All 
Grade 2 or 3 
Grade 3 
Medical advice 
Redness (mm) 
Total 
All 
> 5.0 
> 20.0 
Medical advice 
Infanrix hexa 
All 
> 5.0 
> 20.0 
Medical advice 


CONFIDENTIAL 
201330 [DTPA (BOOSTRIX)-048 PRI] 
Statistical Analysis Plan Final 
16 July 2018 
Page 51 of 57 
 
 
 
each group 
dTpa group 
Control group 
95 % CI 
95 % CI 
Symptom 
Product 
Type 
N n % LL 
UL 
N n % LL 
UL 
Prevenar 13 
All 
> 5.0 
> 20.0 
Medical advice 
Swelling (mm) 
Total 
All 
> 5.0 
> 20.0 
Medical advice 
Infanrix hexa 
All 
> 5.0 
> 20.0 
Medical advice 
Prevenar 13 
All 
> 5.0 
> 20.0 
Medical advice 
dTpa Group = This group will consist of infants born to mothers belonging to the dTpa Group in study 116945 [DTPA 
(BOOSTRIX)-047]. All subjects in this group will receive Infanrix hexa co-administered with Prevenar 13 according to 
the routine national immunisation schedule. 
Control Group: This group will consist of infants born to mothers belonging to the Control group in study 116945 [DTPA 
(BOOSTRIX)-047]. All subjects in this group will receive Infanrix hexa co-administered with Prevenar 13 according to 
the routine national immunisation schedule. 
For each dose and overall/subject: 
N= number of subjects with at least 1 documented dose 
n(%) = number(percentage) of subjects reporting the symptom at least once 
For Overall/dose: 
N= number of documented doses 
n(%) = number(percentage) of doses followed by at least 1 type of symptom 
95%CI= Exact 95% confidence interval; LL = lower limit, UL = upper limit 


CONFIDENTIAL 
201330 [DTPA (BOOSTRIX)-048 PRI] 
Statistical Analysis Plan Final 
16 July 2018 
Page 52 of 57 
 
 
Template 19 Percentage of solicited general symptoms reported during the 4-day 
(Days 0-3) post-vaccination period following each dose and overall 
(Total vaccinated cohort) 
 
dTpa group 
Control group 
95 % CI 
95 % CI 
Symptom 
Type 
N 
n 
% 
LL 
UL 
N 
n 
% 
LL UL 
Each dose 
Drowsiness 
All 
Grade 2 or 3 
Grade 3 
Related 
Grade 3*Related 
Medical advice 
Irritability 
All 
Grade 2 or 3 
Grade 3 
Related 
Grade 3*Related 
Medical advice 
Loss of appetite 
All 
Grade 2 or 3 
Grade 3 
Related 
Grade 3*Related 
Medical advice 
Temperature/(Axillary) (°C) 
All 
>37.5 
>38.0 
>38.5 
>39.0 
>39.5 
Related 
>39*Related 
Medical advice 
Overall/dose 
Drowsiness 
All 
Grade 2 or 3 
Grade 3 
Related 
Grade 3*Related 
Medical advice 
Irritability 
All 
Grade 2 or 3 
Grade 3 
Related 
Grade 3*Related 
Medical advice 
Loss of appetite 
All 
Grade 2 or 3 
Grade 3 
Related 
Grade 3*Related 
Medical advice 


CONFIDENTIAL 
201330 [DTPA (BOOSTRIX)-048 PRI] 
Statistical Analysis Plan Final 
16 July 2018 
Page 53 of 57 
 
 
 
dTpa group 
Control group 
95 % CI 
95 % CI 
Symptom 
Type 
N 
n 
% 
LL 
UL 
N 
n 
% 
LL UL 
Temperature/(Axillary) (°C) 
All 
>37.5 
>38.0 
>38.5 
>39.0 
>39.5 
Related 
>39*Related 
Medical advice 
Overall/subject 
Drowsiness 
All 
Grade 2 or 3 
Grade 3 
Related 
Grade 3*Related 
Medical advice 
Irritability 
All 
Grade 2 or 3 
Grade 3 
Related 
Grade 3*Related 
Medical advice 
Loss of appetite 
All 
Grade 2 or 3 
Grade 3 
Related 
Grade 3*Related 
Medical advice 
Temperature/(Axillary) (°C) 
All 
>37.5 
>38.0 
>38.5 
>39.0 
>39.5 
Related 
>39*Related 
Medical advice 
dTpa Group = This group will consist of infants born to mothers belonging to the dTpa Group in study 116945 [DTPA 
(BOOSTRIX)-047]. All subjects in this group will receive Infanrix hexa co-administered with Prevenar 13 according to 
the routine national immunisation schedule. 
Control Group: This group will consist of infants born to mothers belonging to the Control group in study 116945 [DTPA 
(BOOSTRIX)-047]. All subjects in this group will receive Infanrix hexa co-administered with Prevenar 13 according to 
the routine national immunisation schedule. For each dose and overall/subject: 
N= number of subjects with at least 1 documented dose 
n(%) = number(percentage) of subjects reporting the symptom at least once 
For Overall/dose: 
N= number of documented doses 
n(%) = number(percentage) of doses followed by at least 1 type of symptom 
95%CI= Exact 95% confidence interval; LL = lower limit, UL = upper limit 
Related: Symptoms which is assessed by the investigator as related to vaccination 


CONFIDENTIAL 
201330 [DTPA (BOOSTRIX)-048 PRI] 
Statistical Analysis Plan Final 
16 July 2018 
Page 54 of 57 
 
 
Template 20 Percentage of Unsolicited symptoms experienced by subjects 
classified by MedDRA Primary System Organ Class and Preferred 
Term within the 31-day (Days 0-30) after any dose (Total vaccinated 
cohort) 
 
dTpa Group 
N = 
Control Group N = 
Primary System Organ Class (CODE) 
Preferred Term (CODE) 
n* 
n 
% 
n* 
n 
% 
At least 1 symptom 
<each SOC> 
<each PT term> 
dTpa Group = This group will consist of infants born to mothers belonging to the dTpa Group in study 116945 [DTPA 
(BOOSTRIX)-047]. All subjects in this group will receive Infanrix hexa co-administered with Prevenar 13 according to 
the routine national immunisation schedule. 
Control Group: This group will consist of infants born to mothers belonging to the Control group in study 116945 [DTPA 
(BOOSTRIX)-047]. All subjects in this group will receive Infanrix hexa co-administered with Prevenar 13 according to 
the routine national immunisation schedule. For each dose and overall/subject: 
At least 1 symptom = at least 1 symptom experienced (regardless of the MedDRA Preferred Term) 
N = number of subjects with the administered dose 
n* = number of events reported 
n(%) = number(percentage) of subjects reporting the symptom at least once 
95% CI = exact 95% confidence interval; LL = Lower Limit, UL = Upper Limit 
 
Template 21 Number (%) of subjects with serious adverse events from the Day 0 
to end of the study (Total Vaccinated cohort) 
 
Type of Event 
Primary System Organ 
Class 
Preferred Term 
(CODE) 
dTpa Group 
N = 
Control Group N = 
n* 
n 
% 
n* 
n 
% 
SAE 
At least 1 symptom 
<each SOC> 
<each PT> 
Related SAE 
At least 1 symptom 
<each SOC> 
<each PT> 
Fatal SAE 
At least 1 symptom 
<each SOC> 
<each PT> 
Related Fatal SAE At least 1 symptom 
<each SOC> 
<each PT> 
dTpa Group = This group will consist of infants born to mothers belonging to the dTpa Group in study 116945 [DTPA 
(BOOSTRIX)-047]. All subjects in this group will receive Infanrix hexa co-administered with Prevenar 13 according to 
the routine national immunisation schedule. 
Control Group: This group will consist of infants born to mothers belonging to the Control group in study 116945 [DTPA 
(BOOSTRIX)-047]. All subjects in this group will receive Infanrix hexa co-administered with Prevenar 13 according to 
the routine national immunisation schedule. For each dose and overall/subject: 
N = number of subjects with the administered dose 
n* = number of events reported 
n/% = number/percentage of subjects reporting the symptom at least once 


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201330 [DTPA (BOOSTRIX)-048 PRI] 
Statistical Analysis Plan Final 
 
 
Template 22 Solicited and unsolicited adverse events experienced by subjects 
classified by MedDRA Primary System Organ Class and Preferred 
Term within the 31-day (Days 0-30) post-vaccination period - SAE 
excluded (Total vaccinated cohort) 
 
dTpa Group 
N = 
Control Group N= 
Primary System Organ 
Class (CODE) 
Preferred Term (CODE) 
n* 
n 
% 
n* 
n 
% 
At least 1 symptom 
<each SOC> 
<each PT term> 
dTpa Group = This group will consist of infants born to mothers belonging to the dTpa Group in study 116945 [DTPA 
(BOOSTRIX)-047]. All subjects in this group will receive Infanrix hexa co-administered with Prevenar 13 according to 
the routine national immunisation schedule. 
Control Group: This group will consist of infants born to mothers belonging to the Control group in study 116945 [DTPA 
(BOOSTRIX)-047]. All subjects in this group will receive Infanrix hexa co-administered with Prevenar 13 according to 
the routine national immunisation schedule. For each dose and overall/subject: 
At least 1 symptom = at least 1 symptom experienced (regardless of the MedDRA Preferred Term) 
N = number of subjects with the administered dose 
n* = number of events reported 
n/% = number/percentage of subjects reporting the symptom at least once 


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201330 [DTPA (BOOSTRIX)-048 PRI] 
Statistical Analysis Plan Final 
 
 
Template 23 Number and percentage of subjects taking a concomitant 
medication and antipyretic medication during the 4-day (Days 0-3) 
follow-up period post-vaccination by dose and overall (Total 
vaccinated cohort) 
 
dTpa group 
Control group 
95% CI 
95% CI 
N 
n 
% 
LL 
UL 
N 
n 
% 
LL 
UL 
Each dose 
Any 
Any antipyretic 
Prophylactic antipyretic 
Overall/dose 
Any 
Any antipyretic 
Prophylactic antipyretic 
Overall/subject 
Any 
Any antipyretic 
Prophylactic antipyretic 
dTpa Group = This group will consist of infants born to mothers belonging to the dTpa Group in study 116945 [DTPA 
(BOOSTRIX)-047]. All subjects in this group will receive Infanrix hexa co-administered with Prevenar 13 according to 
the routine national immunisation schedule. 
Control Group: This group will consist of infants born to mothers belonging to the Control group in study 116945 [DTPA 
(BOOSTRIX)-047]. All subjects in this group will receive Infanrix hexa co-administered with Prevenar 13 according to 
the routine national immunisation schedule. For each dose and overall/subject: 
For each dose and overall/subject: 
N= number of subjects with at least 1 administered dose 
n(%) = number(percentage) of subjects who started to take the specified concomitant medication at least once during 
the menti1d period 
For overall/dose: 
N= number of administered doses 
n(%) = number(percentage) of doses after which the specified concomitant medication was started at least once during 
the menti1d period 
95% CI = exact 95% confidence interval, LL = Lower Limit, UL = Upper Limit 
Template 24 Minimum and maximum activity dates (Total vaccinated cohort) 
 
Visit 
Minimum date 
Maximum date 
1 
19JUN2007 
29DEC2007 
2 
24JUL2007 
08FEB2008 
3 
24AUG2007 
18MAR2008 
4 
25MAR2008 
22NOV2008 
Database Lock Date = 31MAR2009 


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CONFIDENTIAL 
201330 [DTPA (BOOSTRIX)-048 PRI] 
Statistical Analysis Plan Final 
 
 
Template 25 Number of enrolled subjects by age category at visit1 
 
dTpa group 
N = 
Control group 
N = 
Total 
N = 
Characteristics 
Categories 
n 
n 
n 
Age category 
Infants (6 weeks – 14 weeks and 6 days) 
Missing 
dTpa Group = This group will consist of infants born to mothers belonging to the dTpa Group in study 116945 [DTPA 
(BOOSTRIX)-047]. All subjects in this group will receive Infanrix hexa co-administered with Prevenar 13 according to 
the routine national immunisation schedule. 
Control Group: This group will consist of infants born to mothers belonging to the Control group in study 116945 [DTPA 
(BOOSTRIX)-047]. All subjects in this group will receive Infanrix hexa co-administered with Prevenar 13 according to 
the routine national immunisation schedule. For each dose and overall/subject: 
N = Number of enrolled subjects 
n = number of enrolled subjects included in each group or in total for a given age category or for all age categories 
Missing = subjects who are enrolled in the study but not vaccinated and for which age is unknown 
Template 26 Listing of SAEs from Day 0 up study (Total vaccinated cohort) 
 
Group Su 
b 
No. 
Cas 
e Id 
Age at 
onset 
(Week 
) 
Se 
x 
Verbati 
m 
Preferre 
d term 
Syste 
m 
Organ 
Class 
ME 
D 
type 
Dos 
e 
Day 
of 
onse 
t 
Duratio 
n 
Intensit 
y 
Causalit 
y 
Outcom 
e 
dTpa 
group 
Contro 
l group 
dTpa Group = This group will consist of infants born to mothers belonging to the dTpa Group in study 116945 [DTPA 
(BOOSTRIX)-047]. All subjects in this group will receive Infanrix hexa co-administered with Prevenar 13 according to 
the routine national immunisation schedule. 
Control Group: This group will consist of infants born to mothers belonging to the Control group in study 116945 [DTPA 
(BOOSTRIX)-047]. All subjects in this group will receive Infanrix hexa co-administered with Prevenar 13 according to 
the routine national immunisation schedule. For each dose and overall/subject: 
Med type = Type of medical advice; HO= Hospitalisation, ER = Emergency room 
 
Template 27 Listing of dropouts due to AEs, SAEs and solicited symptoms (Total 
vaccinated cohort) 
 
Group 
Sub. No. 
Country 
Gender 
AE Description SAE 
Causality 
Outcome 
Type of 
discontinuation 
dTpa 
group 
PP  
Germany F 
SUBJECT DIED Y 
Fatal 
Study at 
visit/contact: 
VISIT11 (Y5) 
Control 
group 
PP  
Germany F 
SUBJECT DIED Y 
Fatal 
Study at 
visit/contact: 
VISIT11 (Y5)