Evaluation of Immunogenicity, Safety and Reactogenicity of GSK Biologicals' dTpa Booster Vaccine (263855) (Boostrix) Administered as a Booster Dose in Healthy Russian Subjects
Phase: PHASE3
Conditions: Diphtheria-Tetanus-acellular Pertussis Vaccines
Sponsor: GlaxoSmithKline

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Clinical Study Protocol
Sponsor:
GlaxoSmithKline Biologicals SA
Rue de l’Institut, 89
1330 Rixensart, Belgium
Primary Study vaccine 
and number
GlaxoSmithKline (GSK) Biologicals’ combined reduced 
antigen content diphtheria, tetanus and acellular pertussis 
vaccine (dTpa), Boostrix (263855).
eTrack study number 
and Abbreviated Title
201532 [DTPA (BOOSTRIX)-050]
Investigational New Drug 
(IND) number
BB-IND-8461
EudraCT number
2015-003405-42
Date of protocol
Final Version 01: 21 January 2016
Date of protocol 
amendment
Amendment 01 Final: 02 February 2017
Amendment 02 Final: 07 August 2017
Amendment 03 Final: 31 October 2017
Title
Evaluation of immunogenicity, safety and reactogenicity 
of GSK Biologicals’ dTpa booster vaccine (263855) 
(Boostrix) administered as a booster dose in healthy 
Russian subjects.
Detailed Title
A phase III, open-label, single-group, multi-centre study 
to assess the immunogenicity, safety and reactogenicity 
of GSK Biologicals’ combined reduced antigen content 
diphtheria, tetanus and acellular pertussis (dTpa) vaccine, 
Boostrix, administered as a booster dose in healthy 
Russian subjects aged four years and older.
Co-ordinating authors
, Scientific Writer, contractor for GSK 
Biologicals and 
, Scientific Writer
Contributing authors
!
, Clinical and Epidemiology 
Project Leader
!
, Clinical Research and 
Development Lead, contractor for GSK Biologicals
!
, Clinical Research and 
Development Lead
!
/
, Lead
Statistician
!
, Project Statistician
!
/
, Study Delivery 
Lead

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eTrack study number 
and Abbreviated Title
201532 [DTPA (BOOSTRIX)-050]
Investigational New Drug 
(IND) number
BB-IND-8461
EudraCT number
2015-003405-42
Detailed Title
A phase III, open-label, single-group, multi-centre study 
to assess the immunogenicity, safety and reactogenicity 
of GSK Biologicals’ combined reduced antigen content 
diphtheria, tetanus and acellular pertussis (dTpa) vaccine, 
Boostrix, administered as a booster dose in healthy 
Russian subjects aged four years and older.
Contributing authors
(continued)
!
, Study Delivery Manager 
!
, Head of Clinical Operations, 
Vaccines
!
, Senior Clinical Research
Associate, Vaccines
!
, contractor for GSK Biologicals/
 
, Clinical Trial Supply Manager
!
/
, Clinical Read-out 
Team Leader
!
/
, Business and 
Decision Life Sciences contractor for GSK 
Biologicals.
!
, Project Data Manager
!
 and 
/
 
, Study Data Manager
!
, Oversight Data Manager
!
/
, Global Patents 
Representative
!
 and 
/
 
and 
, Clinical Safety 
Representatives
!
, Senior Regional Medical 
Manager
!
/
, Global 
Regulatory Affairs
GSK Biologicals’ Protocol DS v 15.0
© 2016-2017 GSK group of companies or its licensor.

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Protocol Amendment 3 Sponsor Signatory Approval
eTrack study number and 
Abbreviated Title
201532 [DTPA (BOOSTRIX)-050]
IND number
BB-IND-8461
EudraCT number
2015-003405-42
Date of protocol amendment
Amendment 3 Final: 31 October 2017
Detailed Title
A phase III, open-label, single-group, multi-centre 
study to assess the immunogenicity, safety and 
reactogenicity of GSK Biologicals’ combined 
reduced antigen content diphtheria, tetanus and 
acellular pertussis (dTpa) vaccine, Boostrix, 
administered as a booster dose in healthy Russian 
subjects aged four years and older.
Sponsor signatory
Signature
Date
 
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Protocol Amendment 3 Rationale
Amendment number:
Amendment 3
Rationale/background for changes:
This protocol amendment was developed in order to accommodate older adults 
(approximately 58 years old and older) who were born before national 
recommendations in Russia for infant DTP vaccination, as well as those born when 
DTP vaccination coverage was low. The protocol amendment would also clarify 
inconsistencies present in the Protocol Amendment 2, between the English version and 
the Russian version. Following which, adjustments to the text were made in the 
inclusion criteria to clarify the enrolment of subjects for age group eight years and 
above. The wording parent(s)/adoptive parent(s) were aligned according to the local 
regulations. References for laboratory assays were updated and certain sections were 
modified to align with the rest of the document.
 
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Protocol Amendment 3 Investigator Agreement
I agree:

To conduct the study in compliance with this protocol, any future protocol 
amendments or protocol administrative changes, with the terms of the clinical trial 
agreement and with any other study conduct procedures and/or study conduct 
documents provided by GlaxoSmithKline (GSK) Biologicals.

To assume responsibility for the proper conduct of the study at this site.

That I am aware of, and will comply with, ‘Good Clinical Practice’ (GCP) and all 
applicable regulatory requirements.

To ensure that all persons assisting me with the study are adequately informed about 
the GSK Biologicals’ study 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 parent(s)/adoptive parent(s) (Amended 
31 October 2017).

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
201532 [DTPA (BOOSTRIX)-050]
IND number
BB-IND-8461
EudraCT number
2015-003405-42
Date of protocol amendment
Amendment 3 Final: 31 October 2017
Detailed Title
A phase III, open-label, single-group, multi-centre 
study to assess the immunogenicity, safety and 
reactogenicity of GSK Biologicals’ combined 
reduced antigen content diphtheria, tetanus and 
acellular pertussis (dTpa) vaccine, Boostrix, 
administered as a booster dose in healthy Russian 
subjects aged four years and older.
Investigator name
Signature
Date
 
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Sponsor Information
1.
Sponsor
GlaxoSmithKline Biologicals
Rue de l’Institut, 89
1330 Rixensart, Belgium.
2.
Sponsor Medical Expert for the Study
Refer to the local study contact information document.
3.
Sponsor Study Monitor
Refer to the local study contact information document.
4.
Sponsor Study Contact for Reporting of a Serious Adverse Event
GSK Biologicals Central Back-up Study Contact for Reporting SAEs: refer to protocol 
Section 8.4.2.
 
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SYNOPSIS
Detailed Title
A phase III, open-label, single-group, multi-centre study to 
assess the immunogenicity, safety and reactogenicity of GSK 
Biologicals’ combined reduced antigen content diphtheria, 
tetanus and acellular pertussis (dTpa) vaccine, Boostrix, 
administered as a booster dose in healthy Russian subjects 
aged four years and older.
Indication
Booster immunisation against diphtheria, tetanus and pertussis 
diseases of individuals from age of four years onwards. The 
study population for this study will include individuals aged 
four years and older.
Rationale for the 
study and study 
design

Rationale for the study
In Russia, DTP vaccines have been indicated for active 
immunisation against diphtheria, tetanus and pertussis 
diseases in infants starting at the age of three months. Recent 
data shows that the coverage rate for DTP vaccine is 97% in 
Russia [WHO, 2015a]. However, like many developing 
countries, the DTP vaccination programme does not include 
older children, adolescents or adults and it is likely that a 
majority of the population will remain unprotected against 
such diseases in the future.
According to the World Health Organization (WHO), the 
incidence of pertussis disease in Russia was estimated at about 
4,705 cases per 100,000 population in 2014 [WHO, 2015b].
Studies have shown that childhood pertussis burden can be 
significantly reduced by vaccination of adolescents and adults 
[Ward, 2005; Ward, 2006]. Hence, boosting with reduced-
antigen-content diphtheria and tetanus toxoids and acellular 
pertussis vaccine (dTpa) instead of dT may prolong the 
immunity against pertussis infection. GlaxoSmithKline (GSK)
Biologicals has developed a dTpa vaccine for booster 
vaccination of children, adolescents and adults against 
diphtheria, tetanus and pertussis diseases, known as Boostrix.
Boostrix vaccine contains 0.5 mg Al (as aluminium phosphate 
and aluminium hydroxide) per 0.5 millilitre (ml) dose. 
Boostrix is currently not registered in Russia. This study will 
assess the immunogenicity, reactogenicity and safety of 
Boostrix in healthy Russian subjects aged four years and 
older. The data obtained from this study will be used to 
support the registration of Boostrix in Russia for individuals 
aged four years and older.

Rationale for the study design
The study is designed as an open-label, single group trial in 
which all the study subjects will receive a single dose of 
 
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Boostrix vaccine. An equal number of subjects are expected to 
be recruited in the following age categories: 4-9 years
(children), 10-17 years (adolescents), 18-64 years (adults) and 
65 years (elderly population).
Pertussis outbreaks have occurred in a number of European 
and non-European countries. This resurgence is observed 
across the age range with a notable increase in cases now 
being detected in adolescents and older age groups. It is also 
now recognized that immunity following either natural 
pertussis infection or vaccination is not long lived, and the 
acellular pertussis vaccines that have been widely used since 
the 1990s may be more prone to such waning. Consequently, 
adults and adolescents with pertussis are a potential source of 
infection for infants too young to have been fully vaccinated. 
Many countries recommend 'cocoon ' strategy, i.e. vaccination 
of family members and close contact of newborn (i.e. 
grandparents usually above 65 years old), in order to protect 
infants from acquiring pertussis. The ≥65 years (elderly 
population) have therefore been included in the study.
Objective
Primary

To assess the immune response to the dTpa vaccine in 
terms of seroprotection status for antibodies against 
diphtheria and tetanus antigens and in terms of 
seropositivity status for antibodies against the pertussis 
antigens [pertussis toxoid (PT), filamentous 
haemagglutinin (FHA) and pertactin (PRN)], one month 
after vaccination.
Secondary

To assess the immune response in terms of booster 
response to diphtheria, tetanus, PT, FHA, and PRN 
antigens, one month after vaccination.

To assess the immune response in terms of antibody 
concentrations to diphtheria, tetanus, PT, FHA, and PRN 
antigens, one month after vaccination.

To assess the reactogenicity and safety of Boostrix in 
terms of solicited symptoms (local and general), 
unsolicited adverse events (AEs) and serious adverse 
events (SAEs).
Study design

Experimental design: Phase III, open-label, non-
randomised, multi-centric, single-country study with a
single group.

Duration of the study:

Epoch 001: Primary Epoch starting at Visit 1 (Day 1) 
 
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and ending at Visit 2 (Day 31)

Primary Completion Date (PCD): Visit 2 (Day 31)

End of Study (EoS): Last testing results released of 
samples collected at Visit 2
Study groups: dTpa group: Subjects aged four years and older
Synopsis Table 1
Study groups and epochs foreseen in the study
Study Groups
Number of 
subjects
Age (Min)
Epochs
Epoch 001
dTpa Group
448
4 years
x
Synopsis Table 2
Study groups and treatment foreseen in the study
Treatment name
Vaccine name
Study Groups
dTpa group
Boostrix
dTpa
x

Control: uncontrolled (in terms of no active comparator)

Vaccination schedule: A single dose of Boostrix vaccine 
will be administered to all subjects at Visit 1 (Day 1)

Treatment allocation: Non-randomised and stratified by 
age

Blinding: open
Synopsis Table 3
Blinding of study epochs
Study Epoch
Blinding
Epoch 001
Open

Sampling schedule: A blood sample of approximately 5 ml
will be collected from all subjects before vaccination (at the 
Pre-Booster timepoint) and one month after vaccination 
(Post-Booster timepoint)

Type of study: self-contained

Data collection: Electronic Case Report Form (eCRF)
Number of subjects
Approximately 448 subjects aged four years and older will be 
enrolled in the study.
 
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Endpoints
Primary

Immunogenicity with respect to components of the study 
vaccine.

Anti-diphtheria* and anti-tetanus seroprotection status, 
one month after vaccination.

Anti-PT, anti-FHA and anti-PRN seropositivity status, 
one month after vaccination.
*Sera with ELISA concentrations <0.1 IU/ml will be tested 
for neutralising antibodies using a Vero-cell neutralisation 
assay.
Secondary

Booster response* to the diphtheria, tetanus and pertussis 
(PT, FHA and PRN) antigens, one month after vaccination.

Immunogenicity with respect to components of the study 
vaccine.

Anti-diphtheria** anti-tetanus, anti-PT, anti-FHA and 
anti-PRN antibody concentrations, one month after 
vaccination.

Solicited local and general symptoms.

Occurrence of each solicited local and general 
symptom during the 4-day (Day 1-4) follow-up period 
after vaccination.

Occurrence of large swelling reactions during the 4-
day (Day 1-4) follow-up period after vaccination.

Unsolicited adverse events (AEs).

Occurrence of unsolicited AEs during the 31-day (Day 
1-31) follow-up period after vaccination, according to 
the Medical Dictionary for Regulatory Activities 
(MedDRA) classification.

Serious adverse events (SAEs).

Occurrence of SAEs from the vaccination up to study 
end.
*Refer to section 10.5 for the definition of booster response.
**Sera with ELISA concentrations <0.1 IU/ml will be tested for 
neutralising antibodies using a Vero-cell neutralisation assay.
 
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TABLE OF CONTENTS
PAGE
SPONSOR INFORMATION ............................................................................................7
SYNOPSIS......................................................................................................................8
LIST OF ABBREVIATIONS...........................................................................................19
GLOSSARY OF TERMS ...............................................................................................21
TRADEMARKS .............................................................................................................25
1.
INTRODUCTION....................................................................................................26
1.1.
Background ................................................................................................26
1.2.
Rationale for the study and study design ....................................................26
1.2.1.
Rationale for the study.................................................................26
1.2.2.
Rationale for the study design......................................................27
1.3.
Benefit: Risk Assessment ...........................................................................27
1.3.1.
Risk Assessment .........................................................................28
1.3.2.
Benefit Assessment.....................................................................28
1.3.3.
Overall Benefit: Risk Conclusion..................................................29
2.
OBJECTIVES.........................................................................................................29
2.1.
Primary objective ........................................................................................29
2.2.
Secondary objectives..................................................................................29
3.
STUDY DESIGN OVERVIEW ................................................................................30
4.
STUDY COHORT...................................................................................................31
4.1.
Number of subjects/centres ........................................................................31
4.2.
Inclusion criteria for enrolment....................................................................32
4.3.
Exclusion criteria for enrolment...................................................................33
5.
CONDUCT OF THE STUDY ..................................................................................34
5.1.
Regulatory and ethical considerations, including the informed 
consent process..........................................................................................34
5.2.
Subject identification and randomisation.....................................................36
5.2.1.
Subject identification....................................................................36
5.2.2.
Randomisation of treatment.........................................................36
5.2.2.1.
Treatment allocation to the subject.............................36
5.2.2.1.1.
Study group and treatment 
number allocation ...................................36
5.3.
Method of blinding ......................................................................................37
5.4.
General study aspects ................................................................................37
5.5.
Outline of study procedures ........................................................................37
5.6.
Detailed description of study procedures ....................................................39
5.6.1.
Informed consent.........................................................................39
5.6.2.
Check inclusion and exclusion criteria .........................................39
5.6.3.
Collect demographic data ............................................................39
 
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5.6.4.
Medical history and vaccination history (Amended 31 
October 2017)..............................................................................39
5.6.5.
Physical examination ...................................................................40
5.6.6.
Urine pregnancy test....................................................................40
5.6.7.
Check contraindications, warnings and precautions to 
vaccination...................................................................................40
5.6.8.
Assess pre-vaccination body temperature ...................................40
5.6.9.
Sampling......................................................................................40
5.6.9.1.
Blood sampling for antibody determination.................41
5.6.10.
Study Vaccine administration.......................................................41
5.6.11.
Check and record concomitant medication/vaccination and 
intercurrent medical conditions ....................................................41
5.6.12.
Distribution of diary cards and recording of AEs, SAEs and 
pregnancies.................................................................................41
5.6.13.
Return of diary card and diary card transcription..........................42
5.6.14.
Recording of AEs, SAEs and pregnancies...................................42
5.6.15.
Study conclusion..........................................................................43
5.7.
Biological sample handling and analysis.....................................................43
5.7.1.
Use of specified study materials ..................................................44
5.7.2.
Biological samples.......................................................................44
5.7.3.
Laboratory assays .......................................................................44
5.7.4.
Biological samples evaluation......................................................45
5.7.4.1.
Immunological read-outs ............................................45
5.7.5.
Immunological correlates of protection.........................................46
6.
STUDY VACCINE AND ADMINISTRATION...........................................................47
6.1.
Description of study vaccine .......................................................................47
6.2.
Storage and handling of study vaccine .......................................................47
6.3.
Dosage and administration of study vaccine...............................................48
6.4.
Replacement of unusable vaccine doses....................................................48
6.5.
Contraindications to vaccination .................................................................49
6.6.
Warnings and precautions ..........................................................................49
6.7.
Concomitant medications/products and concomitant vaccinations..............49
6.7.1.
Recording of concomitant medications/products and 
concomitant vaccinations.............................................................49
6.7.2.
Concomitant medications/products/vaccines that may lead 
to the elimination of a subject from per protocol analyses ............50
6.8.
Intercurrent medical conditions that may lead to elimination of a 
subject from per protocol analyses..............................................................51
7.
HEALTH ECONOMICS ..........................................................................................51
8.
SAFETY.................................................................................................................51
8.1.
Safety definitions ........................................................................................51
8.1.1.
Definition of an adverse event......................................................51
8.1.2.
Definition of a serious adverse event ...........................................52
8.1.3.
Solicited adverse events..............................................................53
8.1.3.1.
Solicited local (injection-site) adverse events..............53
8.1.3.2.
Solicited general adverse events................................53
8.1.4.
Clinical laboratory parameters and other abnormal 
assessments qualifying as adverse events or serious 
adverse events ............................................................................54
 
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8.2.
Events or outcomes not qualifying as adverse events or serious 
adverse events ...........................................................................................55
8.2.1.
Pregnancy ...................................................................................55
8.3.
Detecting and recording adverse events, serious adverse events 
and pregnancies .........................................................................................56
8.3.1.
Time period for detecting and recording adverse events, 
serious adverse events and pregnancies.....................................56
8.3.2.
Post-Study adverse events and serious adverse events..............57
8.3.3.
Evaluation of adverse events and serious adverse events...........57
8.3.3.1.
Active questioning to detect adverse events 
and serious adverse events........................................57
8.3.3.2.
Assessment of adverse events...................................58
8.3.3.2.1.
Assessment of intensity..........................58
8.3.3.2.2.
Assessment of causality .........................60
8.3.3.3.
Assessment of outcomes............................................62
8.4.
Reporting of serious adverse events, pregnancies, and other events .........62
8.4.1.
Prompt reporting of serious adverse events and 
pregnancies to GSK Biologicals...................................................62
8.4.2.
Contact information for reporting serious adverse events, 
pregnancies and pIMDs...............................................................63
8.4.3.
Completion and transmission of SAE reports to GSK 
Biologicals ...................................................................................63
8.4.3.1.
Back-up system in case the electronic 
reporting system does not work..................................63
8.4.4.
Completion and transmission of pregnancy reports to GSK 
Biologicals ...................................................................................63
8.4.5.
Updating of SAE and pregnancy information after removal 
of write access to the subject’s eCRF ..........................................64
8.4.6.
Regulatory reporting requirements for serious adverse 
events..........................................................................................64
8.5.
Follow-up of adverse events, serious adverse events, and 
pregnancies................................................................................................64
8.5.1.
Follow-up of adverse events and serious adverse events............64
8.5.1.1.
Follow-up during the study..........................................64
8.5.1.2.
Follow-up after the subject is discharged from 
the study.....................................................................65
8.5.2.
Follow-up of pregnancies.............................................................65
8.6.
Treatment of adverse events ......................................................................65
8.7.
Subject card................................................................................................65
9.
SUBJECT COMPLETION AND WITHDRAWAL.....................................................66
9.1.
Subject completion .....................................................................................66
9.2.
Subject withdrawal......................................................................................66
9.2.1.
Subject withdrawal from the study ...............................................66
10. STATISTICAL METHODS......................................................................................67
10.1.
Primary endpoint.........................................................................................67
10.2.
Secondary endpoints ..................................................................................67
10.3.
Determination of sample size......................................................................68
10.4.
Cohorts for Analyses ..................................................................................72
10.4.1.
Total vaccinated cohort................................................................72
10.4.2.
Per protocol cohort for analysis of immunogenicity ......................72
 
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10.5.
Derived and transformed data.....................................................................73
10.6.
Analysis of demographics...........................................................................74
10.7.
Analysis of immunogenicity.........................................................................75
10.8.
Analysis of safety........................................................................................75
10.9.
Interpretation of analyses............................................................................76
10.10. Conduct of analyses ...................................................................................76
10.10.1. Sequence of analyses..................................................................76
10.10.2. Statistical considerations for interim analyses..............................76
11. ADMINISTRATIVE MATTERS ...............................................................................76
11.1.
Electronic Case Report Form instructions...................................................76
11.2.
Study Monitoring by GSK Biologicals..........................................................77
11.3.
Record retention .........................................................................................78
11.4.
Quality assurance.......................................................................................78
11.5.
Posting of information on publicly available clinical trial registers and 
publication policy ........................................................................................78
11.6.
Provision of study results to investigators ...................................................79
11.7.
Data Sharing...............................................................................................79
12. COUNTRY SPECIFIC REQUIREMENTS...............................................................79
13. REFERENCES.......................................................................................................80
 
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LIST OF TABLES
PAGE
Table 1
Study group and epoch foreseen in the study ........................................31
Table 2
Study group and treatment foreseen in the study ...................................31
Table 3
Blinding of study epoch ..........................................................................31
Table 4
Number of subjects required for enrolment.............................................36
Table 5
List of study procedures .........................................................................38
Table 6
Intervals between study visits.................................................................39
Table 7
Biological samples .................................................................................44
Table 8
Humoral Immunity (Antibody determination)...........................................45
Table 9
Immunological read-outs........................................................................46
Table 10
Study vaccine.........................................................................................47
Table 11
Dosage and administration.....................................................................48
Table 12
Solicited local adverse events ................................................................53
Table 13
Solicited general adverse events............................................................54
Table 14
Reporting periods for collecting safety information .................................57
Table 15
Intensity scales for solicited symptoms in children less than six 
years of age ...........................................................................................58
Table 16
Intensity scales for solicited symptoms in adults and children of 
six years of age or more.........................................................................59
Table 17
Timeframes for submitting serious adverse event and pregnancy 
reports to GSK Biologicals .....................................................................62
Table 18
Exact two-sided 95% CI for a sample size of 400 subjects 
according to the value observed for seroprotection status for 
diphtheria and tetanus............................................................................68
Table 19
Exact two-sided 95% CI for a sample size of 400 subjects 
according to the seropositivity for the pertussis antigens........................69
Table 20
Exact two-sided 95% CI for a sample size of 400 subjects 
according to the value observed for the primary endpoints and 
the Booster response to all antigens ......................................................69
 
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Table 21
Exact two-sided 95% CI for a sample size of 100 (per age 
category) subjects according to the value observed for the 
seroprotection status for diphtheria and tetanus, seropositivity for 
the pertussis antigens and booster response to all antigens. .................70
Table 22
Reference values ...................................................................................71
Table 23
Age stratification.....................................................................................74
 
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LIST OF APPENDICES
PAGE
APPENDIX A CLINICAL LABORATORIES ..................................................................82
APPENDIX B AMENDMENTS AND ADMINISTRATIVE CHANGES TO THE 
PROTOCOL...........................................................................................83
 
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LIST OF ABBREVIATIONS
AE:
Adverse Event
Al:
Aluminium
ATEAM:
Appropriate (electronic) temperature excursion decision 
form
CI:
Confidence Interval
CLS:
Clinical Laboratory Sciences
dT:
Reduced-antigen-content diphtheria and tetanus toxoid 
vaccine
DTPa:
Diphtheria, Tetanus, acellular Pertussis Vaccine
dTpa:
reduced-antigen-content diphtheria and tetanus toxoids 
and acellular pertussis vaccine
eCRF:
electronic Case Report Form
EoS:
End of Study
ELISA:
Enzyme-linked immunosorbent assay
FHA:
Filamentous Haemagglutinin
GMC:
Geometric Mean Concentration
GSK:
GlaxoSmithKline
IAF:
Inform Assent Form
IB
Investigator Brochure
ICF:
Inform Consent Form
ICH:
International Conference on Harmonisation
IEC:
Independent Ethics Committee
IMP:
Investigational Medicinal Product
IM:
Intramuscular
IND:
Investigational New Drug
IRB:
Institutional Review Board
IU:
International Unit(s)
MedDRA:
Medical Dictionary for Regulatory Activities
ml:
millilitre
PCD:
Primary Completion Date
PRN:
Pertactin
PP:
Per Protocol
PT:
Pertussis Toxoid
 
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RDE:
Remote Data Entry
RSI:
Reference Safety Information
SAE:
Serious Adverse Event
SBIR:
Randomisation System on Internet
SDV:
Source Document Verification
SmPC:
Summary of Product Characteristics
SPM:
Study Procedures Manual
Td:
Combined tetanus and diphtheria vaccine
TVC:
Total Vaccinated Cohort
WHO:
World Health Organization
 
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GLOSSARY OF TERMS
Adequate contraception:
Adequate contraception is defined as a contraceptive 
method with failure rate of less than 1% per year when 
used consistently and correctly and when applicable, in 
accordance with the product label for example:

abstinence from penile-vaginal intercourse, when this 
is their preferred and usual lifestyle,

combined estrogen and progesterone oral 
contraceptives,

injectable progestogen,

implants of etenogestrel or levonorgestrel,

contraceptive vaginal ring,

percutaneous contraceptive patches,

intrauterine device or intrauterine system,

male partner sterilisation prior to the female subject’s 
entry into the study, and this male is the sole partner 
for that subject,
The information on the male sterility can come from 
the site personnel’s review of the subject’s medical 
records; or interview with the subject on her medical 
history.

male condom combined with a vaginal spermicide 
(foam, gel, film, cream or suppository), and/or 
progesterone alone oral contraceptive.
Adequate contraception does not apply to subjects of 
child bearing potential with same sex partners, or for 
subjects who are and will continue to be abstinent from 
penile-vaginal intercourse on a long term and persistent 
basis, when this is their preferred and usual lifestyle.
Adverse event:
Any untoward medical occurrence in a patient or clinical 
investigation subject, temporally associated with the use 
of a medicinal product, whether or not considered related 
to the medicinal product.
An adverse event (AE) can therefore be any unfavourable 
and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a medicinal product. 
For marketed medicinal products, this also includes 
failure to produce expected benefits (i.e. lack of efficacy), 
abuse or misuse.
 
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Blinding:
A procedure in which one or more parties to the trial are 
kept unaware of the treatment assignment in order to 
reduce the risk of biased study outcomes. The level of 
blinding is maintained throughout the conduct of the trial, 
and only when the data are cleaned to an acceptable level 
of quality will appropriate personnel be unblinded or 
when required in case of a serious adverse event. In an 
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.
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 biological
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
Epoch:
An epoch is a set of consecutive timepoints or a single 
timepoint from a single protocol. Epochs are defined to 
support a main purpose which is either to draw 
conclusions on subject participation or to draw a 
complete conclusion to define or precise the targeted 
label of the product. Supporting means that data collected 
at the timepoints included in an epoch must be sufficient 
to fulfil the purpose of the epoch.
Typical examples of epochs are screening primary 
vaccinations, boosters, yearly immunogenicity follow-
ups, and surveillance periods for efficacy or safety.
eTrack:
GSK’s tracking tool for clinical trials.
 
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Evaluable:
Meeting all eligibility criteria, complying with the 
procedures defined in the protocol, and, therefore, 
included in the per protocol analysis (see Sections 6.7.2
and 10.4 for details on criteria for evaluability).
Immunological correlate 
of protection:
The defined immune response above which there is a high 
likelihood of protection in the absence of any host factors 
that might increase susceptibility to the infectious agent.
Investigational vaccine
(Synonym of 
Investigational Medicinal 
Product):
A pharmaceutical form of an active ingredient being 
tested 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.
Menarche:
Menarche is the onset of menses for the first time in a 
young female and is preceded by several changes 
associated with puberty including breast development and 
pubic hair growth. Menarche usually occurs within 1-2 
years of breast development, thelarche. However, a young 
female can become pregnant before her first menses. 
Thus, a conservative definition of non-childbearing 
potential in a pre-menarcheal female is a young female 
who has not yet entered puberty as evidenced by lack of 
breast development (palpable glandular breast tissue).
Menopause:
Menopause is the age associated with complete cessation 
of menstrual cycles, menses, and implies the loss of 
reproductive potential by ovarian failure. A practical 
definition accepts menopause after one year without 
menses with an appropriate clinical profile at the 
appropriate age e.g. >45 years.
Primary completion 
date:
The date that the final subject was examined or received 
an intervention for the purpose of final collection of data 
for all primary outcomes, whether the clinical trial was 
concluded according to the pre-specified protocol or was 
terminated.
Protocol amendment:
The International Conference on Harmonisation (ICH) 
defines a protocol amendment as: ‘A written description 
of a change(s) to or formal clarification of a protocol.’ 
GSK Biologicals further details this to include a change 
to an approved protocol that affects the safety of subjects, 
scope of the investigation, study design, or scientific 
integrity of the study.
Randomisation:
Process of random attribution of treatment to subjects in 
order to reduce bias of selection.
 
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Self-contained study:
Study with objectives not linked to the data of another 
study.
Site Monitor:
An individual assigned by the sponsor who is responsible 
for assuring proper conduct of clinical studies at one or 
more investigational sites.
Solicited adverse event:
AEs to be recorded as endpoints in the clinical study. The 
presence/occurrence/intensity of these events is actively 
solicited after study vaccine use from the subject or an 
observer during a specified post-vaccination follow-up 
period.
Study vaccine:
Any investigational vaccine being tested and/or any 
authorised use of a vaccine as a reference or administered 
concomitantly, in a clinical trial that evaluates the use of 
an investigational vaccine.
Subject:
Term used throughout the protocol to denote an 
individual who has been contacted in order to participate 
or participates in the clinical study, either as a recipient of 
the vaccine or as a control.
Subject number:
A unique number identifying a subject, assigned to each 
subject consenting to participate in the study.
Treatment:
Term used throughout the clinical study to denote a set of 
investigational product(s) or marketed product(s) or 
placebo intended to be administered to a subject.
Treatment number:
A number identifying a treatment to a subject, according 
to treatment allocation.
Unsolicited adverse 
event:
Any AE reported in addition to those solicited during the 
clinical study. Also any ‘solicited’ symptom with onset 
outside the specified period of follow-up for solicited 
symptoms will be reported as an unsolicited adverse 
event.
 
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TRADEMARKS
The following trademark is used in the present protocol.
Note: In the body of the protocol (including the synopsis), the name of the vaccine 
will be written without the superscript symbol ™ or ® and in italics.
Trademark of the GSK group of 
companies
Generic description
Boostrix
Combined reduced-antigen-content 
diphtheria, tetanus and acellular pertussis 
(dTpa) vaccine
 
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1.
INTRODUCTION
1.1.
Background
Universal immunisation of infants with multiple doses of paediatric diphtheria and 
tetanus toxoids and acellular pertussis (DTPa) vaccine, followed by a booster vaccination 
in the second year of life, and at school age is widely practised worldwide and has 
controlled the occurrence of diphtheria, tetanus and pertussis in infants. Boostrix is a 
vaccine indicated for active booster immunisation against tetanus, diphtheria, and 
pertussis. It is approved for use in the European Union as a single dose in individuals four 
years of age and older.
Pertussis (whooping cough) is a highly infectious respiratory disease caused by 
Bordetella pertussis bacterium. The most common complication seen in young infants for 
pertussis-related deaths is secondary bacterial pneumonia [CDC, 2015a]. Worldwide, 
around 16 million cases of pertussis [CDC, 2015b] and about 195,000 deaths per year 
have been reported [CDC, 2015a]. Pertussis continues to be a serious problem among 
unvaccinated or incompletely vaccinated infants [Forsyth, 2015]. As the vaccine-induced 
immunity to pertussis wanes with time, adolescents and adults may serve as a source of 
infection for neonates and infants too young to be immunised [de Greeff, 2010; 
Kowalzik, 2007].
Please refer to the current Investigator Brochure for information regarding the pre-
clinical and clinical studies and the epidemiological information of Boostrix.
1.2.
Rationale for the study and study design
1.2.1.
Rationale for the study
In Russia, DTP vaccines have been indicated for active immunisation against diphtheria, 
tetanus and pertussis diseases in infants starting at the age of three months. Recent data 
shows that the coverage rate for DTP vaccine is 97% in Russia [WHO, 2015a]. However, 
like many developing countries, the DTP vaccination programme does not include older 
children, adolescents or adults, and it is likely that a majority of the population will 
remain unprotected against such diseases in the future.
According to the World Health Organization (WHO), the incidence of pertussis disease 
in Russia was estimated at about 4,705 cases per 100,000 population in 2014 [WHO, 
2015b]. Studies have shown that childhood pertussis burden can be significantly reduced 
by vaccination of adolescents and adults [Ward, 2005; Ward, 2006]. Hence, boosting 
with reduced-antigen-content diphtheria and tetanus toxoids and acellular pertussis 
vaccine (dTpa) instead of diphtheria and tetanus toxoids (dT) may prolong the immunity 
against pertussis infection. GlaxoSmithKline (GSK) Biologicals has developed a dTpa 
vaccine for booster vaccination of children, adolescents and adults against diphtheria, 
tetanus and pertussis diseases, known as Boostrix. Boostrix was first licensed for use in 
Germany in 1999 and is indicated for booster vaccination in individuals aged four years 
and older [Mertsola, 2010]. Boostrix vaccine contains 0.5 mg Al (as aluminium 
 
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phosphate and aluminium hydroxide) per 0.5 millilitre (ml) dose. Boostrix is currently not 
registered in Russia. This study will assess the immunogenicity, reactogenicity and safety 
of Boostrix in healthy Russian subjects aged four years and older. The data obtained from 
this study will be used to support the registration of Boostrix in Russia for individuals 
aged four years and older. 
1.2.2.
Rationale for the study design
The study is designed as an open-label, single group trial in which all the study subjects 
will receive a single dose of Boostrix vaccine. An equal number of subjects are expected 
to be recruited in the following age categories: 4-9 years (children), 10-17 years
(adolescents), 18-64 years (adults) and 65 years (elderly population).
Pertussis outbreaks have occurred in a number of European and non-European countries. 
This resurgence is observed across the age range with a notable increase in cases now 
being detected in adolescents and older age groups. It is also now recognized that 
immunity following either natural pertussis infection or vaccination is not long lived, and 
the acellular pertussis vaccines that have been widely used since the 1990s may be more 
prone to such waning. Consequently, adults and adolescents with pertussis are a potential 
source of infection for infants too young to have been fully vaccinated. Many countries 
recommend 'cocoon ' strategy, i.e. vaccination of family members and close contact of 
newborn (i.e. grandparents usually above 65 years old), in order to protect infants from 
acquiring pertussis. The ≥65 years (elderly population) have therefore been included in 
the study.
1.3.
Benefit: Risk Assessment
Please refer to the current Investigator Brochure (IB) for the summary of the potential 
risks and benefits of Boostrix.
 
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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 (Boostrix)
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.
Syncope
As outlined in the Reference Safety 
Information (RSI), syncope (fainting) 
can occur following or even before any 
vaccination especially in adolescents 
as a psychogenic response to the 
needle injection.
It is important that procedures are 
in place to avoid injury from fainting. 
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.
Study Procedure
Risk from blood sampling.
Blood sampling associated risk of 
discomfort, syncope, infection at the 
site after or during venipuncture
Blood samples will be obtained by a 
trained professional and medical 
assistance will be available.
The potential risk of feeling faint, or 
experiencing mild local pain, 
bruising, irritation or redness at the 
site where blood was taken, is 
mentioned in the ICF. The amount 
of blood to be taken for sampling 
will not be harmful to the subject’s 
health.
1.3.2.
Benefit Assessment
Diphtheria, tetanus and pertussis are common causes of diseases in children worldwide, 
with significant morbidity and mortality. A dramatic decline in the incidence of 
diphtheria, tetanus, and pertussis has been evidenced in countries in which infants are 
routinely immunised against these diseases. Clinical trial and post-marketing data 
demonstrate the substantial benefit of Boostrix vaccination worldwide. By receiving the 
Boostrix vaccine, the subjects may be protected against diphtheria, tetanus and pertussis 
diseases.
 
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1.3.3.
Overall Benefit: Risk Conclusion
Based on the assessment of the extensive safety database following Boostrix vaccination 
and taking into account the measures taken to minimise risk to subjects participating in 
this study, the potential or identified risks identified in association with Boostrix
vaccination, are justified by the potential benefits (prevention) that may be afforded to 
subject(s) receiving Boostrix vaccination.
2.
OBJECTIVES
2.1.
Primary objective

To assess the immune response to the dTpa vaccine in terms of seroprotection status 
for antibodies against diphtheria and tetanus antigens and in terms of seropositivity 
status for antibodies against the pertussis antigens [pertussis toxoid (PT), filamentous 
haemagglutinin (FHA) and pertactin (PRN)], one month after vaccination.
Refer to Section 10.1 for the definition of the primary endpoint.
2.2.
Secondary objectives

To assess the immune response in terms of booster response* to diphtheria, tetanus, 
PT, FHA, and PRN antigens, one month after vaccination.

To assess the immune response in terms of antibody concentrations to diphtheria, 
tetanus, PT, FHA, and PRN antigens, one month after vaccination.

To assess the reactogenicity and safety of Boostrix in terms of solicited symptoms 
(local and general), unsolicited adverse events (AEs) and serious adverse events 
(SAEs).
*Refer to Section 10.5 for the definition of booster response.
Refer to Section 10.2 for the definition of the secondary endpoints.
 
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3.
STUDY DESIGN OVERVIEW
* An equal number of subjects are expected to be recruited in the following age categories: 4-9 years (children), 10-17
years (adolescents), 18-64 years (adults) and 65 years (elderly population) in order to evaluate data.
Protocol waivers or exemptions are not allowed unless necessary for the management of 
immediate safety concerns. Therefore, adherence to the study design requirements, 
including those specified in the outline of study procedures (Section 5.5), are essential 
and required for study conduct.

Experimental design: Phase III, open-label, non-randomised, multi-centric, single-
country study with a single group.

Duration of the study:

Epoch 001: Primary Epoch starting at Visit 1 (Day 1) and ending at Visit 2 
(Day 31)

Primary Completion Date (PCD): Visit 2 (Day 31)
Refer to glossary of terms for the definition of PCD.

End of Study (EoS): Last testing results released of samples collected at Visit 2.
Refer to glossary of terms for the definition of EoS.

Study groups: The study group and epoch foreseen in this study is presented in 
Table 1.
 
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Table 1
Study group and epoch foreseen in the study
Study group
Number of 
subjects
Age (Min)
Epoch
Epoch 001
dTpa Group
448
4 years
x
Table 2
Study group and treatment foreseen in the study
Treatment name
Vaccine/Product name
Study Group
dTpa Group
Boostrix
dTpa
x

Control: uncontrolled (in terms of no active comparator).

Vaccination schedule: A single dose of Boostrix vaccine will be administered to all 
subjects at Visit 1 (Day 1).

Treatment allocation: Non-randomised and stratified by age.

Blinding: open.
Table 3
Blinding of study epoch
Study Epoch
Blinding
Epoch 001
open

Sampling schedule: A blood sample of approximately 5 ml will be collected from all 
subjects before vaccination (at the Pre-Booster timepoint) and one month after
vaccination (Post-Booster timepoint).

Type of study: self-contained.

Data collection: Electronic Case Report Form (eCRF).
4.
STUDY COHORT
4.1.
Number of subjects/centres
Approximately 448 subjects are expected to be enrolled in this study. An equal number of 
subjects (approximately 112) are expected to be recruited in each of the following age 
categories: 4-9 years (children), 10-17 years (adolescents), 18-64 years (adults) and 65 
years (elderly population) in order to evaluate data. Refer to Section 10.1 for a detailed 
description of criteria used for the estimation of sample size.
Overview of the recruitment plan:

The study will take place at multiple centres in Russia.

The recruitment of subjects into the study will be tracked using GSK Biologicals’ 
central randomisation system on Internet (SBIR).

Recruitment will be monitored by the site monitor.
 
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4.2.
Inclusion criteria for enrolment
Deviations from inclusion criteria are not allowed because they can potentially jeopardize
the scientific integrity, regulatory acceptability of the study or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential.
All subjects must satisfy ALL the following criteria at study entry:

Subjects or subjects’ parent(s)/adoptive parent(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).

A male or female four years of age and older.

Written informed consent obtained from the subject/from the parent(s)/adoptive 
parent(s) of the subject prior to performing any study specific procedure.

Written informed assent obtained from subjects aged 14 years to <18 years.

Healthy subjects as established by medical history and physical examination before 
entering into the study.

Children 4-7 years of age with documented previous diphtheria, tetanus and pertussis 
vaccination (primary series and first booster) as per local recommendation prior to 
study enrolment, but should have not received any further diphtheria-tetanus 
containing booster planned at 6-7 years of age as per local recommendations or any 
other diphtheria, tetanus and pertussis containing vaccine.
OR

Subjects eight years of age and older who can report previous diphtheria, tetanus 
with or without pertussis vaccination – documented or to the best of their/subjects’ 
parent(s)/subjects’ adoptive parent(s) knowledge – and did not receive an additional 
diphtheria, tetanus with or without pertussis vaccination within five years prior to 
enrolment in the study will be enrolled. (Amended 31 October 2017)

Female subjects of non-childbearing potential may be enrolled in the study.

Non-childbearing potential is defined as pre-menarche, current tubal ligation, 
hysterectomy, ovariectomy or post-menopause.
Please refer to the glossary of terms for the definition of menarche and menopause.

Female subjects of childbearing potential may be enrolled in the study, if the subject:

has practiced adequate contraception within 30 days prior to vaccination, and

has a negative pregnancy test on the day of vaccination, and

has agreed to continue adequate contraception during the entire treatment period 
and for one month after completion of the vaccination.
Please refer to the glossary of terms for the definition of adequate contraception.
 
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4.3.
Exclusion criteria for enrolment
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity, regulatory acceptability of the study or subject safety. 
Therefore, adherence to the criteria as specified in the protocol is essential.
The following criteria should be checked at the time of study entry. If ANY exclusion 
criterion applies, the subject must not be included in the study:

Child in care
Please refer to the glossary of terms for the definition of child in care.

Use of any investigational or non-registered product (drug or vaccine) other than the 
study vaccine during the period starting 30 days before the dose of study vaccine, or
planned use during the study period.

History of previous or intercurrent diphtheria, tetanus or pertussis diseases since 
birth in subjects four to seven years of age.

History of previous or intercurrent diphtheria, tetanus or pertussis diseases within 
five years prior to enrolment in subjects aged eight years and above.

Chronic administration (defined as more than 14 days in total) of 
immunosuppressants or other immune-modifying drugs within six months prior to 
the vaccine dose. For corticosteroids, this will mean prednisone ≥20 mg/day (for 
adult subjects, ≥18 years of age) or ≥0.5 mg/kg/day (for paediatric subjects, aged 4-
17 years), 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).

Planned administration/administration of a vaccine not foreseen by the study 
protocol within the period starting 30 days before and ending 30 days after the dose 
of vaccine with the exception of inactivated influenza vaccine which can be given at 
any time during the study conduct as per the Summary of Product Characteristics 
(SmPC) and according to the local governmental recommendations.

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).

Any confirmed or suspected immunosuppressive or immunodeficient condition, 
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.

Hypersensitivity to latex.

History of encephalopathy (e.g. coma, decreased level of consciousness, prolonged 
seizures) after administration of a previous dose of pertussis vaccine that could not 
be attributed to another identifiable cause, progressive neurologic disorder, 
 
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uncontrolled epilepsy or progressive encephalopathy: pertussis vaccine should not be 
administered to individuals with these conditions until a treatment regimen has been 
established and the condition has stabilized.

Acute disease and/or fever at the time of enrolment.

Fever is defined as temperature 38.0°C. The preferred location for measuring 
temperature in this study will be the axilla.

Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory 
infection) without fever may, be enrolled at the discretion of the investigator.

Acute or chronic, clinically significant uncontrolled pulmonary, cardiovascular, 
hepatic or renal functional abnormality, as determined by physical examination
and/or laboratory screening tests.

Administration of immunoglobulins and/or any blood products within the three
months preceding the dose of study vaccine or planned administration during the 
study period.

Pregnant or lactating female.

Female planning to become pregnant or planning to discontinue contraceptive 
precautions during the study conduct.

Any medical condition that, in the opinion of the investigator, might interfere with 
the evaluations required by the study.

Any medical condition that in the judgment of the investigator would make
intramuscular injection unsafe.
5.
CONDUCT OF THE STUDY
5.1.
Regulatory and ethical considerations, including the 
informed consent process
The study will be conducted in accordance with all applicable regulatory requirements.
The study will be conducted in accordance with the ICH Guideline for GCP, all 
applicable subject privacy requirements and the guiding principles of the Declaration of 
Helsinki.
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.
 
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Conduct of the study includes, but is not limited to, the following:

Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and 
favourable opinion/approval of study protocol and any subsequent amendments.

Subject/subject’s parent(s)/adoptive parent (s) informed consent and subject 
informed assent, as appropriate.

Investigator reporting requirements as stated in the protocol.
GSK will provide full details of the above procedures to the investigator, either verbally, 
in writing, or both.
Freely given and written or witnessed informed consent must be obtained from each 
subject and/or each subject’s parent(s)/adoptive parent(s) and subject informed assent, as 
appropriate, prior to participation in the study.
GSK Biologicals will prepare a model Informed Consent Form (ICF) which will embody 
the ICH GCP and GSK Biologicals required elements. While it is strongly recommended 
that this model ICF is to be followed as closely as possible, the informed consent 
requirements given in this document are not intended to pre-empt any local regulations 
which require additional information to be disclosed for informed consent to be legally 
effective. Clinical judgement, local regulations and requirements should guide the final 
structure and content of the local version of the ICF.
In accordance with the ICH Harmonised Tripartite Guidelines for Good Clinical Practice, 
those subjects who can only be enrolled in the study with the consent of the subject’s 
parent(s)/adoptive parent(s) (e.g. minors), should be informed about the study to the 
extent compatible with the subject’s understanding and, if capable, the subject should 
sign and personally date a written informed assent form (IAF). It is required that the 
assent be signed by each subject, if capable, in addition to the informed consent that is to 
be signed by his/her legal representative. It should be assessed whether an assent is 
required depending of the age of the study population and the local requirements 
(Amended 31 October 2017).
GSK Biologicals strongly recommends that if the subject reaches the age of consent 
during the study they will be asked to provide consent at the next study visit (if 
applicable). This procedure should be applied according to local laws and regulations.
The investigator has the final responsibility for the final presentation of the ICF and IAF, 
respecting the mandatory requirements of local regulations. The ICF and IAF generated 
by the investigator with the assistance of the sponsor’s representative must be acceptable 
to GSK Biologicals and be approved (along with the protocol, and any other necessary 
documentation) by the IRB/IEC.
 
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5.2.
Subject identification and randomisation
5.2.1.
Subject identification
Subject identification numbers will be assigned sequentially to the subjects who have 
consented to participate in the study, according to the range of subject identification 
numbers allocated to each study centre.
5.2.2.
Randomisation of treatment
5.2.2.1.
Treatment allocation to the subject
The treatment numbers will be allocated by dose.
5.2.2.1.1.
Study group and treatment number allocation
The enrolment will be performed to ensure equal distribution of the population across the 
four age strata [4-9 years (children), 10-17 years (adolescents), 18-64 (adults) years and 
65 years (elderly population)]. Therefore, the expected distribution of subjects is as 
shown in Table 4.
Table 4
Number of subjects required for enrolment
Age Stratum
Vaccine
N
4-9 years
Boostrix
112
10-17 years
Boostrix
112
18-64 years
Boostrix
112
65 years
Boostrix
112
N = approximate number of subjects to be enrolled
Allocation of a treatment number to the subject at the investigator site will be performed 
using a randomisation system on internet (SBIR).
After obtaining the signed and dated ICF and IAF (if applicable) from the subject and 
having checked the eligibility of the subject, the study staff in charge of the vaccine
administration will access SBIR. Upon providing the age [4-9 years (children), 10-17
years (adolescents), 18-64 years (adults) and 65 years (elderly population)] and the 
subject identification number, the randomisation system will provide the treatment 
number to be used for the dose.
The number of each administered treatment must be recorded in the eCRF on the Vaccine 
Administration form.
When SBIR is not available, please refer to the SBIR user guide or the Study Procedures 
Manual (SPM) for specific instructions.
 
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5.3.
Method of blinding
This is an open-label study as all the subjects will receive a booster dose of Boostrix.
5.4.
General study aspects
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying SPM. The SPM provides the investigator and the site 
personnel with administrative and detailed technical information that does not impact the 
safety of the subjects.
5.5.
Outline of study procedures
The list of study procedures is presented in Table 5.
 
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Table 5
List of study procedures
Epoch
Epoch 001
Type of contact
Visit 1
Visit 2
Timepoints
Day 1
Day 31
Sampling timepoints
Pre-Bst
Post-Bst
Informed consent
●
Informed assent
O
Check if minor subject reaches legal age and needs to 
provide consent
O
Check inclusion/exclusion criteria
●
Collect demographic data
●
Medical history and vaccination history
●
Physical examination#
●
O
Urine pregnancy test 1
●
Check contraindications and warnings and precautions for 
vaccination
O
Pre-vaccination body temperature
●
Laboratory assays
Blood sampling for antibody determination (approx. 5 ml)
●
●
Vaccine
Treatment number allocation
O
Recording of administered treatment number
●
Vaccine administration
●
Observation of subject for minimum 30 minutes following 
vaccination
O
Safety assessments
Record any concomitant medication/vaccination
●
●
Record any intercurrent medical conditions
●
●
Distribution of diary cards
O
Recording of solicited adverse events within 4 days (Day 
1–4) post-vaccination by subjects/subjects’ 
parent(s)/adoptive parent(s)
●
Record large injection site reactions2
●
Recording of non-serious adverse events within 31 days 
(Day 1-31) post-vaccination, by subjects/subjects’ 
parent(s)/adoptive parent(s)
●
●
Return of dairy cards
O
Diary card transcription by investigator
●
Recording of serious adverse events (SAEs)
●
●
Recording of SAEs related to study participation or to a 
concurrent GSK medication/vaccine
●
●
Recording of pregnancies1
●
●
Recording of AEs leading to withdrawal from the study
●
●
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
# Physical examination after the vaccination visit, will be performed only if the subject/subject’s parent(s)/adoptive
parent(s) indicates during questioning that there might be some underlying pathology(ies) or if deemed necessary 
by the Investigator or delegate.
Pre-Bst: Before the administration of study vaccine; Post-Bst: one month after the administration of study vaccine.
1 Applicable to women of child-bearing potential.
2 Refer to the table notes under Table 12 for a detailed explanation on the reporting of large injection site reactions by 
the subject's/subjects' parent(s)/adoptive parent (s).
 
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The interval between study visits is presented in Table 6.
Table 6
Intervals between study visits
Interval
Optimal length of interval1
Allowed interval2
Visit 1Visit 2
30 days
21 days-48 days
1 Whenever possible the investigator should arrange study visits within this interval.
2 An interval of 21-48 days between Visit 1 and Visit 2 will be considered for the Per Protocol (PP) cohort of 
immunogenicity. Refer to Section 10.4 for the definition of the cohorts for analysis. If subjects return for the visits prior 
to 30 days, they should take the diary card home and continue to record unsolicited safety information until 30 days 
post-vaccination and mail/send it upon completion. Investigators should transcribe any data already collected on the 
cards prior to sending it back home with the subjects. Investigators will make an attempt to retrieve diary cards from 
subjects who have not mailed/sent them in.
5.6.
Detailed description of study procedures
5.6.1.
Informed consent
The signed/witnessed informed consent of the subject/subject’s parent(s)/adoptive parent
(s) must be obtained before study participation. The signed informed assent of the subject 
below the age of consent (i.e. minor) should be obtained in addition to the signed 
informed consent by his/her parent(s)/adoptive parent (s) according to local rules and 
regulations. Refer to Section 5.1 for the requirements on how to obtain informed consent 
and assent, as appropriate.
5.6.2.
Check inclusion and exclusion criteria
Check all inclusion and exclusion criteria as described in Sections 4.2 and 4.3 before 
enrolment.
5.6.3.
Collect demographic data
Record demographic data such as age at vaccination visit in months and years, gender 
and geographical ancestry in the subject’s eCRF.
5.6.4.
Medical history and vaccination history (Amended 31 October 
2017)
Obtain the subject’s medical history by interview and/or review of the subject’s medical 
records and record both any current and/or pre-existing conditions or signs and/or 
symptoms in a subject prior to the study vaccination in the eCRF.
Review the subject’s* childhood diphtheria, tetanus, with or without pertussis,
vaccinations to collect information on the vaccine name, route of administration, dose 
number and date of administration. This information should be recorded in the eCRF.
*For subjects eight years and older, with no documented previous diphtheria, tetanus, 
with or without pertussis, vaccinations, details are to be recorded to the best of 
their/subjects’ parent(s)/subjects’ adoptive parent(s) knowledge.
 
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5.6.5.
Physical examination
Perform a physical examination of the subject, including recording of height and weight 
(for calculation of BMI), assessment of body temperature and resting vital signs: 
systolic/diastolic blood pressure, heart rate and respiratory rate after at least 10 minutes of 
rest. Collected information needs to be recorded in the eCRF.
Physical examination after the vaccination visit, will be performed only if the subject 
indicates during questioning that there might be some underlying pathology(ies) or if 
deemed necessary by the Investigator or delegate.
Treatment of any abnormality observed during physical examination has to be performed 
according to local medical practice outside this study or by referral to an appropriate 
health care provider.
5.6.6.
Urine pregnancy test
Female subjects of childbearing potential are to have a urine pregnancy test prior to any 
study vaccine administration. The study vaccine may only be administered if the 
pregnancy test is negative.
Note: Pregnancy test must be performed even if the subject is menstruating at the time of 
the study visit.
5.6.7.
Check contraindications, warnings and precautions to 
vaccination
Contraindications, warnings and precautions to vaccination must be checked at the 
beginning of the vaccination visit. Refer to Sections 6.5 and 6.6 for more details.
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 the study vaccine administration. The preferred route for recording 
temperature in this study will be axillary. If the subject has fever [Fever is defined as 
temperature 38.0°C. The preferred location for measuring temperature in this study will 
be the axilla] on the day of vaccination, the vaccination visit will be rescheduled.
5.6.9.
Sampling
Refer to the Module on Biospecimen Management in the SPM for detailed instructions 
for the collection, handling and processing of the samples.
 
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5.6.9.1.
Blood sampling for antibody determination
Blood samples will be taken at Visit 1 and Visit 2 as specified in Section 5.5, List of 
Study Procedures.

A volume of approximately 5 ml of whole blood (to provide approximately 1. 7 ml
of serum) should be drawn from all subjects at the pre-booster and post-booster 
timepoint (Visit 1 and Visit 2). After centrifugation, serum samples should be kept at 
–20°C or below until shipment.
Refer to the Module on Biospecimen Management in the SPM for detailed instructions 
for the collection, handling and processing of the samples.
5.6.10.
Study Vaccine administration

After completing all prerequisite procedures prior to vaccination, the study vaccine 
will be administered intramuscularly in the deltoid muscle of the non-dominant arm 
(refer to Section 6.3 for detailed description of the vaccine administration 
procedure). If the investigator or delegate determines that the subject’s health on the 
day of administration temporarily precludes vaccine administration, the visit will be 
rescheduled.

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.
5.6.11.
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.
5.6.12.
Distribution of diary cards and recording of AEs, SAEs and 
pregnancies

Refer to Section 8.3 for procedures for the investigator or delegate to record AEs, 
SAEs, and pregnancies. Refer to Section 8.4 for guidelines and how to report SAE, 
and pregnancy reports to GSK Biologicals.

The subjects/subjects’ parent(s)/adoptive parent (s) will be instructed to contact the 
investigator or delegate immediately should they/the subjects manifest any signs or 
symptoms they perceive as serious.

At Visit 1, diary cards will be provided to the subject/subject’s parent(s)/adoptive 
parent(s). The subject/subject’s parent(s)/adoptive parent(s) will record body 
(preferably axillary) temperature and any solicited local/general AEs (i.e. on the day 
 
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of vaccination and during the next three days) or any unsolicited AEs (i.e. on the day 
of vaccination and during the next 30 days) occurring after vaccination. The 
subject/subject’s parent(s)/adoptive parent(s) will be instructed to return the 
completed diary card to the investigator or delegate at the next study visit.

Note: Diary cards can be filled in by a minor subject under the supervision of 
the subject’s parent(s)/adoptive parent(s) provided that the minor has the 
competency to assess and report the information to be provided in the diary card. 
The ultimate accountability for the completion of the diary cards remains with 
the subject’s parent(s)/adoptive parent(s). The investigator or delegate should 
discuss this accountability with the subject’s parent(s)/adoptive parent(s).

Collect and verify completed diary cards during discussion with the subject/subject’s 
parent(s)/adoptive parent(s) on Visit 2.

Note: If the diary card has been filled in by a minor subject, the investigator or 
delegate should verify the reported information during a discussion with the 
minor subject preferably in the presence of his/her parent(s)/adoptive parent(s).

After vaccination, if the subjects or the subject’s parents/adoptive parents observe 
any large injection site reaction (for subjects <6 years of age defined as a swelling 
with a diameter of >50 mm and for subjects 6 years of age swelling with a diameter 
of >100 mm, noticeable diffuse swelling or noticeable increase in limb 
circumference) during the 4-day follow-up (Day 1-4) period, they will be asked to 
contact study personnel and to visit the investigator's office for evaluation as soon as 
possible. The investigator or delegate will record detailed information describing the 
AE on a specific large injection site reaction screen in the eCRF.
5.6.13.
Return of diary card and diary card transcription

Any unreturned diary cards will be sought from the subject/subject’s 
parent(s)/adoptive parent(s) through telephone call(s) or any other convenient 
procedure. The investigator or delegate will transcribe the collected information into 
the eCRF in English.
5.6.14.
Recording of AEs, SAEs and pregnancies

Refer to Section 8.3 for procedures for the investigator or delegate to record AEs, 
SAEs, pregnancies. Refer to Section 8.4 for guidelines and how to report SAE and 
pregnancy reports to GSK Biologicals.

The subject/subjects’ parent(s)/adoptive parent(s) will be instructed to contact the 
investigator immediately should they/the subjects manifest any signs or symptoms 
they perceive as serious.
 
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5.6.15.
Study conclusion
The investigator will:

review data collected to ensure accuracy and completeness

complete the Study Conclusion screen in the eCRF.
5.7.
Biological sample handling and analysis
Please refer to the SPM for details on Biospecimen Management (handling, storage and 
shipment).
Samples will not be labelled with information that directly identifies the subject but will 
be coded with 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 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 Russia and will only be performed once an IEC or IRB has 
approved this research.
Information on further investigations and their rationale can be obtained from GSK 
Biologicals.
Any sample testing will be done in line with the consent of the individual 
subject/subject’s parent(s)/adoptive parent(s).
Refer also to the Investigator Agreement, where it is noted that the investigator cannot 
perform any other biological assays except those described in the protocol or its 
amendment(s).
If additional testing is performed, the marker priority ranking given in Section 5.7.4 may 
be changed.
Collected samples will be stored for a maximum of 20 years (counting from when the last 
subject performed the last study visit), unless local rules, regulations or guidelines require 
different timeframes or different procedures, which will then be in line with the subject 
consent. These extra requirements need to be communicated formally to and discussed 
and agreed with GSK Biologicals.
 
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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 per protocol (PP) 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 required for this study have been presented in Table 7.
Table 7
Biological samples
Sample type
Quantity
Unit
Timepoint
Blood
Approximately 5
ml
Pre-Bst1 and Post-Bst2
1Pre-Bst: Before the administration of study vaccine.
2 Post-Bst: one month after the administration of study vaccine.
5.7.3.
Laboratory assays
Please refer to APPENDIX A for the address of the clinical laboratories used for sample 
analysis.
All serology will be determined in GSK Biologicals’ laboratories or in a laboratory 
designated by GSK using standardized and validated procedures with adequate controls.
Refer to Table 8 for the assays used in antibody determination.
 
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Table 8
Humoral Immunity (Antibody determination)
System
Component
Method
Kit/Manufacturer
Unit
Cut-off†
Laboratory*
Serum
Corynebacterium 
diphtheriae.Diphtheria 
Toxoid Ab.IgG
ELI
NA
IU/ml
0.057
GSK Biologicals
or designated 
laboratory
Serum
Corynebacterium 
diphtheriae.Diphtheria 
Toxoid Ab
NEU
assay on 
Vero 
cells**
NA
IU/ml
0.004
GSK Biologicals
or designated 
laboratory
Serum
Clostridium 
tetani.Tetanus Toxoid 
Ab.IgG
ELI
NA
IU/ml
0.043
GSK Biologicals
or designated 
laboratory
Serum
Bordetella 
pertussis.Pertussis 
Toxin Ab.IgG
ELI
NA
IU/ml
2.693
GSK Biologicals
or designated 
laboratory
Serum
Bordetella 
pertussis.Filamentous 
Hemaglutinin Ab.IgG
ELI
NA
IU/ml
2.046
GSK Biologicals
or designated 
laboratory
Serum
Bordetella 
pertussis.Pertactin 
Ab.IgG
ELI
NA
IU/ml
2.187
GSK Biologicals
or designated 
laboratory
ELI: ELISA
NEU: Neutralisation assay
NA: Not Applicable
IU/ml: International Units per millilitre
†ELISA’s for diphtheria, tetanus and pertussis were re-developed and re-validated as per most recent CBER 
recommendations (Guidance for Industry “Bioanalytical Method Validation” from September 2013). The new assay cut-
off’s that apply are listed in the table. The neutralisation assay for Diphtheria is still under re-development and 
the assay cut-off might be subject to change during the course of the study. In this case, it will be documented 
in the clinical study report. (Amended 31 October 2017)
*GSK Biologicals laboratory refers to the Clinical Laboratory Sciences (CLS) in Rixensart, Belgium and Wavre, 
Belgium.
**Test on Vero-cells will be performed on pre- and post-vaccination samples with concentrations <0.1 IU/ml by ELISA.
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 9.
 
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Table 9
Immunological read-outs
Blood sampling timepoint
No. of subjects
Component
Components
priority rank
Type of contact and timepoint Sampling timepoint
Visit 1 (Day 1)
Pre-Bst1
All
PT, FHA, PRN, 
Diphtheria (ELISA), Tetanus 
Diphtheria (Vero-cell*) 
1
2
3
Visit 2 (Day 31)
Post-Bst1
All
PT, FHA, PRN, 
Diphtheria (ELISA), Tetanus 
Diphtheria (Vero-cell*) 
1
2
3
1.Pre-Bst: Before the administration of study vaccine; Post-Bst: one month after the administration of study vaccine.
* Test on Vero-cells will be performed on pre- and post-vaccination samples with concentrations <0.1 IU/ml by ELISA.
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 newly validated assay cut-off for anti-diphtheria is currently set at 0.057 IU/ml
and for anti-tetanus at 0.043 IU/ml. For both serology a threshold of 0.1 IU/ml
provides a conservative estimate of the percentage of subjects deemed to be 
protected [Camargo, 1984; Melville-Smith, 1983].

The cut-off of the Vero-cell neutralisation assay (performed for pre- and post-
vaccination serum samples when ELISA anti-diphtheria antibody concentrations are 
<0.1 IU/ml) is 0.004 IU/ml. Antibody concentrations 0.01 IU/ml are considered as 
protective [WHO, 1994]. Both the ELISA test (antibody concentrations 0.1 IU/ml) 
and Vero-cell test (antibody concentration 0.01 IU/ml) will define the 
seroprotection status for the primary endpoint. (Amended 31 October 2017)

No serological correlate of protection is defined for the immune response to pertussis 
antigens. Antibodies against the pertussis components PT, FHA and PRN will be 
measured by ELISA technique. The newly validated assay cut-off for anti-PT is 
2.693 IU/ml, for anti-FHA is 2.046 IU/ml and for anti-PRN is 2.187 IU/ml. Subjects 
with antibody concentration below this cut-off will be considered seronegative.
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/subjects’ parent(s)/adoptive parent(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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Non-responders are defined as:

Antibody concentrations <0.01 IU/ml post-booster for diphtheria antigen by Vero-
cell neutralisation assay and,

Antibody concentrations <0.1 IU/ml post-booster for tetanus antigen by ELISA 
assay.
6.
STUDY VACCINE AND ADMINISTRATION
6.1.
Description of study vaccine
The candidate vaccine to be used has been developed and manufactured by GSK 
Biologicals.
The Quality Control Standards and Requirements for the candidate vaccine are described 
in separate Quality Assurance documents (e.g. release protocols, certificate of analysis) 
and the required approvals have been obtained.
The vaccines are labelled and packed according to applicable regulatory requirements.
Table 10 presents the details of the study vaccine and administration.
Table 10
Study vaccine
Treatment 
name
Vaccine name
Formulation
Presentation
Volume to be 
administered
Number of 
doses
Boostrix
dTpa
DT>=2IU; TT>=20IU; 
PT=8µg; FHA=8µg; 
PRN=2.5µg; 
Aluminium=500µg 
Al3+
Pre-filled 
syringes, 
Homogeneous 
turbid white 
suspension
0.5 ml
1
DT: Diphtheria toxoid, TT: Tetanus toxoid, PT: Pertussis toxoid, FHA: Filamentous haemagglutinin, PRN: Pertactin, 
Aluminium as Al(OH)5.
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 authorised study 
personnel. The storage conditions will be assessed during pre-study activities under the 
responsibility of the sponsor study contact. The storage temperature should be 
continuously monitored with calibrated (if not validated) temperature monitoring 
device(s) and recorded. Refer to the Module on Clinical Trial Supplies in the SPM for 
more details on storage of the study vaccine.
Temperature excursions must be reported in degree Celsius.
 
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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) or above -15.0°C (for -20°C/-4°F label storage condition)
impacting investigational medicinal products (IMPs) must be reported in the appropriate 
(electronic) temperature excursion decision form (ATEAM). The impacted IMPs must 
not be used and must be stored in quarantine at label temperature conditions until usage 
approval has been obtained from the sponsor.
In case of temperature excursion below +2.0°C down to 0.0°C impacting IMP(s) there is 
no need to report in ATEAM, 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 vaccine
The vaccine will be administered as detailed in Table 11.
The vaccine will be administered as an IM injection into the deltoid muscle of the non-
dominant arm, i.e. in the left arm if the subject is right-handed or in the right arm if the 
subject is left-handed. In case it is not possible for a valid reason to inject in the 
non-dominant arm, an injection in the dominant arm may be performed. Boostrix should 
in no circumstances be administered intravascularly.
In order to ensure proper IM injection of the vaccine, a needle of 1-1½ inch length, 25 
gauge will be used [Zuckerman, 2000]. Needle of 21-25 gauge can be used depending on 
the age of the subjects.
Table 11
Dosage and administration
Type of contact and 
timepoint
Volume to 
be 
administered
Study 
Group
Treatment name
Route
Site 
Side 
Visit 1 (Day 1)
0.5 ml
dTpa 
Group
Boostrix
IM
Deltoid
Non-
dominant
IM: Intramuscular
6.4.
Replacement of unusable vaccine doses
In addition to the vaccine doses provided for the planned number of subjects (including 
over-randomisation when applicable), at least 5% additional vaccine doses will be 
supplied to replace those that are unusable.
 
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6.5.
Contraindications to vaccination
Since this is a single dose study, contraindications to vaccination are included in the 
exclusion criteria. Refer to Section 4.3.
The following events constitute contraindications to administration of Boostrix at that 
point in time; if any of these events occur at the time scheduled for vaccination, the 
subject may be vaccinated at a later date, within the time window specified in the 
protocol (see Section 6.7.1), or the subject may be withdrawn at the discretion of the 
investigator (see Section 6.7.2).

Acute disease and/or fever at the time of vaccination.

Fever is defined as temperature 38.0°C. The preferred location for measuring 
temperature in this study will be the axilla.

Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory 
infection) without fever can be administered the study vaccine.
6.6.
Warnings and precautions
As with all injectable vaccines, appropriate medical treatment should always be readily 
available in case of anaphylactic reactions following the administration of the vaccine. 
For this reason, the vaccinee should remain under medical supervision for 30 minutes 
after vaccination.
Boostrix vaccination should be administered with caution to subjects with 
thrombocytopenia or a bleeding disorder since bleeding may occur following an 
intramuscular (IM) administration to these subjects.
Boostrix vaccination should under no circumstances be administered intravenously.
6.7.
Concomitant medications/products and concomitant 
vaccinations
At each study visit/contact, the investigator or delegate should question the subject and/or 
the subject’s parent(s)/adoptive parent(s) about any medications/products taken and 
vaccinations received by the subject.
6.7.1.
Recording of concomitant medications/products and 
concomitant vaccinations
The following concomitant medication(s)/product(s)/vaccine(s) must be recorded in 
the eCRF

All concomitant medications/products, except vitamins and dietary supplements, 
administered during the period starting from the administration of study vaccine 
(Day 1) and ending at Visit 2 (Day 31).
 
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
Any concomitant vaccination administered in the period starting from the 
administration of study vaccine (Day 1) and ending at the last study visit [Visit 2 
(Day 31)].

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 38.0°C. The preferred location for measuring 
temperature in this study will be the axilla.

Any concomitant medications/products/vaccines listed in Section 6.7.2.

Any concomitant medications/products/vaccines relevant to a SAE to be reported as 
PP 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 in eCRF.
6.7.2.
Concomitant medications/products/vaccines that may lead to the 
elimination of a subject from per protocol analyses
The use of the following concomitant medications/products/vaccines will not require 
withdrawal of the subject from the study but may determine a subject’s evaluability in the 
PP analysis. See Section 10.4 for cohorts to be analysed.

Any investigational or non-registered product (drug or vaccine) other than the study 
vaccine used during the study period.

Immunosuppressants or other immune-modifying drugs administered chronically 
(i.e. more than 14 days) during the study period. For corticosteroids, this will mean 
prednisone 20 mg/day (for adult subjects) or 0.5 mg/kg/day (for paediatric 
subjects), 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 the dose of study vaccine (Day 1) and ending 31 days after the dose of vaccine 
administration, with the exception of influenza vaccine which is allowed throughout 
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 Summary of Product 
Characteristics (SmPC) 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.
 
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6.8.
Intercurrent medical conditions that may lead to elimination 
of a subject from per protocol analyses
At each study visit subsequent to the vaccination visit, it must be verified if the subject 
has experienced or is experiencing any intercurrent medical condition. If it is the case, the 
condition(s) must be recorded in the eCRF.
Subjects may be eliminated from the PP cohort for immunogenicity if, during the study, 
they incur a condition that has the capability of altering their immune response or are 
confirmed to have an alteration of their initial immune status.
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/subject’s parent(s)/adoptive parent(s) will be instructed to contact the 
investigator immediately should they/the subject manifest any signs or symptoms they 
perceive as serious.
8.1.
Safety definitions
8.1.1.
Definition of an adverse event
An AE is any untoward medical occurrence in a clinical investigation subject, temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with 
the use of a medicinal product. For marketed medicinal products, this also includes 
failure to produce expected benefits (i.e. lack of efficacy), abuse or misuse.
Examples of an AE include:

Significant or unexpected worsening or exacerbation of the condition/indication 
under study.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after investigational vaccine administration 
even though they may have been present prior to the start of the study.
 
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
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 
study vaccination. These events will be recorded in the medical history section of the 
eCRF.
8.1.2.
Definition of a serious adverse event
A SAE is any untoward medical occurrence that:
a.
Results in death,
b.
Is life-threatening,
Note: The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in 
which the subject was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, had it been more severe.
c.
Requires hospitalisation or prolongation of existing hospitalisation,
Note: In general, hospitalisation signifies that the subject has been admitted at the 
hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician’s office or in an out-patient setting. Complications 
that occur during hospitalisation are also considered AEs. If a complication prolongs 
hospitalisation or fulfils any other serious criteria, the event will also be considered
serious. When in doubt as to whether ‘hospitalisation’ occurred or was necessary, the 
AE should be considered serious.
 
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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, OR
Note: The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhoea, influenza like illness, and accidental trauma (e.g. sprained 
ankle) which may interfere or prevent everyday life functions but do not constitute a 
substantial disruption.
e.
Is a congenital anomaly/birth defect in the offspring of a study subject.
Medical or scientific judgement should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or 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 12
Solicited local adverse events
All age groups
Pain at injection site
Redness at injection site
Swelling at injection site
Note: If the subjects or the subject’s parent(s)/adoptive parent(s) observe any large 
injection site reaction (for subjects <6 years of age defined as a swelling with a diameter 
of > 50 mm and for subjects 6 years of age swelling with a diameter of >100 mm, 
noticeable diffuse swelling or noticeable increase in limb circumference) during the 4-
day (Day 1–4) follow-up period after vaccination, they will be asked to contact the study 
personnel and to visit the investigator’s office for evaluation as soon as possible. The 
investigator or delegate will record detailed information describing the AE on a specific 
large injection site reaction sheet in the eCRF.
8.1.3.2.
Solicited general adverse events
The following general AEs will be solicited:
 
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Table 13
Solicited general adverse events
Toddler/Child (<6 years)
Drowsiness
Fever
Irritability/Fussiness
Loss of appetite
Adult/Child (6 years)
Fatigue
Fever
Gastrointestinal symptoms †
Headache
†Gastrointestinal symptoms include nausea, vomiting, diarrhoea and/or abdominal pain.
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.
Subjects/parent(s)/adoptive parent(s) will be instructed to measure and record the body 
temperature by axillary route in the evening. Should additional temperature 
measurements be performed at other times of day, subjects/parent(s)/adoptive parent(s) 
will be instructed to record the highest temperature in the diary card.
8.1.4.
Clinical laboratory parameters and other abnormal assessments 
qualifying as adverse events or serious adverse events 
In absence of diagnosis, abnormal laboratory findings (e.g. clinical chemistry, 
haematology, urinalysis) or other abnormal assessments (e.g. vital signs) that are judged 
by the investigator to be clinically significant will be recorded as AE or SAE if they meet 
the definition of an AE or SAE (refer to Sections 8.1.1 and 8.1.2). Clinically significant 
abnormal laboratory findings or other abnormal assessments that are present at baseline 
and significantly worsen following the start of the study will also be reported as AEs or 
SAEs.
The investigator will exercise his or her medical and scientific judgement in deciding 
whether an abnormal laboratory finding or other abnormal assessment is clinically 
significant.
 
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8.2.
Events or outcomes not qualifying as adverse events or 
serious adverse events
8.2.1.
Pregnancy
Female subjects who become pregnant after the vaccination may continue the study at the 
discretion of the investigator.
While pregnancy itself is not considered an AE or SAE, any adverse pregnancy outcome 
or complication or elective termination of a pregnancy for medical reasons will be 
recorded and reported as an AE or a SAE.
Note: The pregnancy itself should always be recorded on an electronic pregnancy report.
The following should always be considered as SAE and will be reported as described in 
Sections 8.4.1 and 8.4.3:

Spontaneous pregnancy loss, including:

spontaneous abortion, (spontaneous pregnancy loss before/at 22 weeks of 
gestation)

ectopic and molar pregnancy

stillbirth (intrauterine death of foetus after 22 weeks of gestation)
Note: The 22 weeks’ cut-off in gestational age is based on WHO-ICD 10 noted in the 
EMA Guideline on pregnancy exposure [EMA, 2006]. It is recognized that national 
regulations might be different.

Any early neonatal death (i.e. death of a live born infant occurring within the first 
seven days of life).

Any congenital anomaly or birth defect (as per [CDC MACDP] guidelines) 
identified in the offspring of a study subject (either during pregnancy, at birth or 
later) regardless of whether the foetus is delivered dead or alive. This includes 
anomalies identified by prenatal ultrasound, amniocentesis or examination of the 
products of conception after elective or spontaneous abortion.
Furthermore, any SAE occurring as a result of a post-study pregnancy and considered by 
the investigator to be reasonably related to the study vaccine will be reported to GSK 
Biologicals as described in Section 8.4.3. While the investigator or delegate is not 
obligated to actively seek this information from former study participants, he/she may 
learn of a pregnancy through spontaneous reporting.
 
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8.3.
Detecting and recording adverse events, serious adverse 
events and pregnancies
8.3.1.
Time period for detecting and recording adverse events, serious 
adverse events and pregnancies
All AEs starting within 30 days following administration of the dose of study vaccine 
(Day 1-31) must be recorded onto the appropriate section of the eCRF, irrespective of 
intensity or whether or not they are considered vaccination-related.
The time period for collecting and recording SAEs will begin at the receipt of study 
vaccine and will end 30 days following administration of the dose of study vaccine for 
each subject. See Section 8.4 for instructions on reporting of SAEs.
All AEs/SAEs leading to withdrawal from the study will be collected and recorded from 
the time of the receipt of study vaccine.
SAEs that are related to the study vaccine will be collected and recorded from the time of 
the 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 subject consents to participate in the study until she/he is discharged from the 
study.
The time period for collecting and recording pregnancies will begin at the receipt of study 
vaccine and will end 30 days following administration of the dose of study vaccine. All 
pregnancies recorded during this period will be followed up as detailed in sections 8.2.1, 
8.4 and 8.5.2.
An overview of the protocol-required reporting periods for AEs, SAEs, and pregnancies 
is given in Table 14.
 
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Table 14
Reporting periods for collecting safety information
Event
Timepoint
Pre-Bst 
(consent 
obtained)
Vaccination
(Day 1)
Post Bst
(Day 1-4)
Post Bst
(Day1-31)
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/vaccination
Pregnancies*
Pre-Bst: Before the administration of study vaccine; Post-Bst: After the administration of study vaccine.
*This refers to collecting information on pregnancy as an event and not as an outcome, which will be collected after the 
end of the study.
8.3.2.
Post-Study adverse events and serious adverse events
A post-study AE/SAE is defined as any event that occurs outside of the AE/SAE 
reporting period defined in Table 14. Investigator(s) or delegate(s) is/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.
8.3.3.
Evaluation of adverse events and serious adverse events
8.3.3.1.
Active questioning to detect adverse events and serious adverse 
events
As a consistent method of collecting AEs, the subject or the subject’s parent(s)/adoptive 
parent(s) should be asked a non-leading question such as:
‘Have you felt different in any way since receiving the vaccine(s)/product(s) or since the 
previous visit?’
‘Has your child acted differently or felt different in any way since receiving the 
vaccine(s)/product(s) or since the last visit?’
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g. hospital progress notes, laboratory and diagnostics reports) relative 
to the event. The investigator or delegate will then record all relevant information 
regarding an AE/SAE in the eCRF. The investigator or delegate is not allowed to send 
 
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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.
8.3.3.2.
Assessment of adverse events
8.3.3.2.1.
Assessment of intensity
The intensity of the following solicited AEs will be assessed as described:
Table 15
Intensity scales for solicited symptoms in children less than six
years of age
Toddler/Child (<6 years)
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
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 38.0°C. The preferred location for measuring temperature in this study will be the 
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Table 16
Intensity scales for solicited symptoms in adults and children of six
years of age or more
Adult/Child (6 years)
Adverse Event
Intensity grade
Parameter
Pain at injection site
0
None
1
Mild: Any pain neither interfering with nor preventing 
normal every day activities.
2
Moderate: Painful when limb is moved and interferes with 
every day activities.
3
Severe: Significant pain at rest. Prevents normal every 
day activities.
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
Headache
0
Normal
1
Mild: Headache that is easily tolerated
2
Moderate: Headache that interferes with normal activity
3
Severe: Headache that prevents normal activity
Fatigue
0
Normal
1
Mild: Fatigue that is easily tolerated
2
Moderate: Fatigue that interferes with normal activity
3
Severe: Fatigue that prevents normal activity
Gastrointestinal symptoms
0
Normal
(nausea, vomiting, diarrhoea and/or 
abdominal pain)
1
Mild: Gastrointestinal symptoms that are easily tolerated
2
Moderate: Gastrointestinal symptoms that interfere with 
normal activity
3
Severe: Gastrointestinal symptoms that prevent normal 
activity
* Fever is defined as temperature 38.0°C. The preferred location for measuring temperature in this study will be the
axilla.
The maximum intensity of local injection site redness/swelling for toddlers and children 
<6 years of age 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 local injection site redness/swelling for adults and children 6 
years of age will be scored at GSK Biologicals as follows:
0
:
Absent
1
:
20 mm
2
:
>20 mm and 50 mm
3
:
>50 mm
 
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The maximum intensity of fever will be scored at GSK Biologicals as follows:
0
=
<38C
1
=
38.0C to 39.0C
2
=
>39.0C to 40.0C
3
=
>40.0C
The investigator will assess the maximum intensity that occurred over the duration of the 
event for all unsolicited AEs (including SAEs) recorded during the study. The assessment 
will be based on the investigator’s clinical judgement.
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)/adoptive parent(s) to seek medical advice. In 
adults/adolescents, such an AE would, for example, prevent attendance 
at work/school and would necessitate the administration of corrective 
therapy.
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.
8.3.3.2.2.
Assessment of causality
The investigator is obligated to assess the relationship between study vaccine and the 
occurrence of each AE/SAE using clinical judgement. In case of concomitant 
administration of multiple vaccines/products, if possible, the investigator should specify 
if the AE could be causally related to a specific vaccine/product administered (i.e 
investigational, control/placebo or co-administered vaccine). When causal relationship to 
a specific vaccine(s)/product(s) cannot be determined the investigator should indicate the 
AE to be related to all products.
Alternative plausible causes, such as natural history of the underlying diseases, 
concomitant therapy, other risk factors, and the temporal relationship of the event to the 
study vaccine will be considered and investigated. The investigator will also consult the 
IB and/or SmPC for marketed products to determine his/her assessment.
There may be situations when a SAE has occurred and the investigator has minimal 
information to include in the initial report to 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 
 
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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.
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 vaccine contributed to the AE.
NO
:
There is no reasonable possibility that the AE is causally related to the 
administration of the study vaccine. There are other, more likely causes
and administration of the study vaccine is not suspected to have 
contributed to the AE.
If an event meets the criteria to be determined as ‘serious’ (see Section 8.1.2), additional 
examinations/tests will be performed by the investigator in order to determine ALL 
possible contributing factors for each SAE.
Possible contributing factors include:

Medical history.

Other medication.

Protocol required procedure.

Other procedure not required by the protocol.

Lack of efficacy of the vaccine, if applicable.

Erroneous administration.

Other cause (specify).
 
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8.3.3.3.
Assessment of outcomes
The investigator will assess the outcome of all unsolicited AEs (including SAEs) 
recorded during the study as:

Recovered/resolved.

Recovering/resolving.

Not recovered/not resolved.

Recovered with sequelae/resolved with sequelae.

Fatal (SAEs only).
8.4.
Reporting of serious adverse events, pregnancies, and 
other events
8.4.1.
Prompt reporting of serious adverse events and pregnancies to 
GSK Biologicals
SAEs that occur in the time period defined in Section 8.3 will be reported promptly to 
GSK within the timeframes described in Table 17, once the investigator determines that 
the event meets the protocol definition of a SAE.
Pregnancies that occur in the time period defined in Section 8.3 will be reported promptly 
to GSK within the timeframes described in Table 17, once the investigator becomes 
aware of the pregnancy.
Table 17
Timeframes for submitting serious adverse event and pregnancy 
reports to GSK Biologicals
Type of Event
Initial Reports
Follow-up of Relevant Information on a 
Previous Report
Timeframe
Documents
Timeframe
Documents
SAEs
24 hours*‡
electronic Expedited 
Adverse Events Report
24 hours*
electronic Expedited Adverse 
Events Report
Pregnancies
2 weeks*
electronic pregnancy report
2 weeks*
electronic pregnancy report
* Timeframe allowed after receipt or awareness of the information.
‡ The investigator will be required to confirm review of the SAE causality by ticking the ‘reviewed’ box in the electronic 
Expedited Adverse Events Report within 72 hours of submission of the SAE.
 
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8.4.2.
Contact information for reporting serious adverse events,
pregnancies and pIMDs
Study Contact for Reporting SAEs and pregnancies
Refer to the local study contact information document.
Back-up Study Contact for Reporting SAEs and pregnancies
24/24 hour and 7/7 day availability:
GSK Biologicals Clinical Safety & Pharmacovigilance
Outside US & Canada sites:
Fax: 
 or 
Email address: 
8.4.3.
Completion and transmission of SAE reports to GSK Biologicals
Once an investigator becomes aware that a SAE has occurred in a study subject, the 
investigator (or designate) must complete the information in the electronic Expedited 
Adverse Events Report WITHIN 24 HOURS. The report will always be completed as 
thoroughly as possible with all available details of the event. Even if the investigator or 
delegate does not have all information regarding a SAE, the report should still be 
completed within 24 hours. Once additional relevant information is received, the report 
should be updated WITHIN 24 HOURS.
The investigator will always provide an assessment of causality at the time of the initial 
report. The investigator will be required to confirm the review of the SAE causality by 
ticking the ‘reviewed’ box in the electronic Expedited Adverse Events Report within 72 
hours of submission of the SAE.
8.4.3.1.
Back-up system in case the electronic reporting system does not work
If the electronic reporting system does not work, the investigator (or designate) must 
complete, then date and sign a paper Expedited Adverse Events Report and fax it to the 
Study Contact for Reporting SAEs (refer to the Sponsor Information) or to GSK 
Biologicals Clinical Safety and Pharmacovigilance department within 24 hours.
This back-up system should only be used if the electronic reporting system is not working 
and NOT if the system is slow. As soon as the electronic reporting system is working 
again, the investigator (or designate) must complete the electronic Expedited Adverse 
Events Report within 24 hours. The final valid information for regulatory reporting will 
be the information reported through the electronic SAE reporting system.
8.4.4.
Completion and transmission of pregnancy reports to GSK 
Biologicals
Once the investigator becomes aware that a subject is pregnant, the investigator (or 
designate) must complete the required information onto the electronic pregnancy report 
WITHIN 2 WEEKS.
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Note: Conventionally, the estimated gestational age (EGA) of a pregnancy is dated from 
the first day of the last menstrual period (LMP) of the cycle in which a woman conceives. 
If the LMP is uncertain or unknown, dating of EGA and the estimated date of delivery 
(EDD) should be estimated by ultrasound examination and recorded in the pregnancy 
report.
8.4.5.
Updating of SAE and pregnancy information after removal of 
write access to the subject’s eCRF
When additional SAE and pregnancy information is received after removal of the write 
access to the subject’s eCRF, new or updated information should be recorded on the 
appropriate paper report, with all changes signed and dated by the investigator. The
updated report should be faxed to the Study Contact for Reporting SAEs (refer to the 
Sponsor Information) or to GSK Biologicals Clinical Safety and Pharmacovigilance 
department within the designated reporting time frames specified in Table 17.
8.4.6.
Regulatory reporting requirements for serious adverse events
The investigator will promptly report all SAEs to GSK in accordance with the procedures 
detailed in Section 8.4.1. GSK Biologicals has a legal responsibility to promptly notify, 
as appropriate, both the local regulatory authority and other regulatory agencies about the 
safety of a product under clinical investigation. Prompt notification of SAEs by the 
investigator to the Study Contact for Reporting SAEs is essential so that legal obligations 
and ethical responsibilities towards the safety of other subjects are met.
Investigator safety reports are prepared according to the current GSK policy and are 
forwarded to investigators as necessary. An investigator safety report is prepared for a 
SAE(s) that is both attributable to the study vaccine and unexpected. The purpose of the 
report is to fulfil specific regulatory and GCP requirements, regarding the product under 
investigation.
8.5.
Follow-up of adverse events, serious adverse events, and 
pregnancies
8.5.1.
Follow-up of adverse events and serious adverse events
8.5.1.1.
Follow-up during the study
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject and provide additional relevant information on the subject’s condition to GSK 
Biologicals (within 24 hours for SAEs; refer to Table 17).
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.
 
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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 vaccination.
8.5.1.2.
Follow-up after the subject is discharged from the study
The investigator will follow subjects:

with SAEs or subjects withdrawn from the study as a result of an AE, until the event 
has resolved, subsided, stabilised, disappeared, or until the event is otherwise 
explained, or the subject is lost to follow-up.
If the investigator receives additional relevant information on a previously reported SAE, 
he/she will provide this information to GSK Biologicals using a paper/electronic 
Expedited Adverse Events Report and/or pregnancy report as applicable.
GSK Biologicals may request that the investigator performs or arranges the conduct of 
additional clinical examinations/tests and/or evaluations to elucidate as fully as possible 
the nature and/or causality of the AE or SAE. The investigator is obliged to assist. If a 
subject dies during participation in the study or during a recognised follow-up period, 
GSK Biologicals will be provided with any available post-mortem findings, including 
histopathology.
8.5.2.
Follow-up of pregnancies
Pregnant subjects will be followed to determine the outcome of the pregnancy. At the end 
of the pregnancy, whether full-term or premature, information on the status of the mother 
and child will be forwarded to GSK Biologicals using the pregnancy report and the 
Expedited Adverse Events Report if applicable. Generally, the follow-up period doesn’t 
need to be longer than six to eight weeks after the estimated date of delivery.
Regardless of the reporting period for SAEs for this study, if the pregnancy outcome is a 
SAE, it should always be reported as SAE.
8.6.
Treatment of adverse events
Treatment of any AE is at the sole discretion of the investigator and according to current 
good medical practice. Any medication administered for the treatment of a SAE should 
be recorded in Expedited Adverse Event Report of the subject’s eCRF (refer to Section 
6.7).
8.7.
Subject card
Study subjects/subjects’ parent(s)/adoptive parent(s) must be provided with the address 
and telephone number of the main contact for information about the clinical study.
The investigator (or designate) must therefore provide a “subject card” to each 
subject/subject’s parent(s)/adoptive parent(s). In an emergency situation this card serves 
 
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to inform the responsible attending physician that the subject is in a clinical study and 
that relevant information may be obtained by contacting the investigator.
Subjects/subjects’ parent(s)/adoptive parent(s) must be instructed to keep subject cards in 
their possession at all times during the study duration.
9.
SUBJECT COMPLETION AND WITHDRAWAL
9.1.
Subject completion
A subject who 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 
or delegate will document whether the decision to withdraw a subject from the study was 
made by the subject himself/herself, by the subject’s parent(s)/adoptive parent(s), or by 
the investigator, as well as which of the following possible reasons was responsible for 
withdrawal:

Serious adverse event.

Unsolicited non-serious adverse event.

Solicited adverse event

Protocol violation (specify).

Consent withdrawal, not due to an adverse event*.

Moved from the study area.
 
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
Lost to follow-up.

Other (specify).
*In case a subject is withdrawn from the study because he/she/the subject’s 
parent(s)/adoptive parent(s) has withdrawn consent, the investigator or delegate will 
document the reason for withdrawal of consent, if specified by the subject/subject’s 
parent(s)/adoptive parent(s), in the eCRF.
Subjects who are withdrawn from the study because of SAEs/AEs must be clearly 
distinguished from subjects who are withdrawn for other reasons. Investigators will 
follow subjects who are withdrawn from the study as result of a SAE/AE until resolution 
of the event (see Section 8.5.1.2).
10.
STATISTICAL METHODS
10.1.
Primary endpoint

Immunogenicity with respect to components of the study vaccine.

Anti-diphtheria* and anti-tetanus seroprotection status, one month after 
vaccination.

Anti-PT, anti-FHA and anti-PRN seropositivity status, one month after 
vaccination.
*Sera with ELISA concentrations <0.1 IU/ml will be tested for neutralising antibodies 
using a Vero-cell neutralisation assay.
10.2.
Secondary endpoints

Booster response* to the diphtheria, tetanus and pertussis (PT, FHA and PRN) 
antigens, one month after vaccination.

Immunogenicity with respect to components of the study vaccine.

Anti-diphtheria** anti-tetanus, anti-PT, anti-FHA and anti-PRN antibody 
concentrations, one month after vaccination.

Solicited local and general symptoms.

Occurrence of each solicited local and general symptom during the 4-day (Day 
1-4) follow-up period after vaccination.

Occurrence of large swelling reactions during the 4-day (Day 1-4) follow-up 
period after vaccination.

Unsolicited adverse events.

Occurrence of unsolicited AEs during the 31-day (Day 1-31) follow-up period 
after vaccination, according to the Medical Dictionary for Regulatory Activities 
(MedDRA) classification.
 
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
Serious adverse events.

Occurrence of SAEs from the vaccination up to study end.
*Refer to Section 10.5 for the definition of booster response.
**Sera with ELISA concentrations <0.1 IU/ml will be tested for neutralising antibodies 
using a Vero-cell neutralisation assay.
10.3.
Determination of sample size
The primary objective of the study is to assess the immunological response to the study 
vaccine in terms of seroprotection status for diphtheria, tetanus and in terms of 
seropositivity for the pertussis antigens, one month after vaccination.
According to Russian regulations, for the purpose of product registration, the minimum 
sample size required is 100 subjects in each age group. Therefore, the total number of 
evaluable subjects is 400 [100 subjects in each age group, 4-9 years (children), 10- 17
years (adolescents), 18-64 years (adults) and 65 years (elderly population)]. Assuming a 
drop-out rate of 10%, to compensate for subject attrition due to early withdrawal, a total 
of 448 subjects (112 in each age group) will be enrolled in to the study in order to obtain 
the desired number of evaluable subjects for analysis.
Table 18, Table 19, Table 20 present the exact two-sided 95% confidence interval (CI) 
for a sample size of 400 subjects, according to the value observed for the seroprotection 
status for diphtheria and tetanus, seropositivity for the pertussis antigens and booster 
response to all antigens.
In addition, Table 21 presents the exact two-sided 95% CI for a sample size of 100 
subjects (per age category), according to the value observed for the seroprotection status 
for diphtheria and tetanus, seropositivity for the pertussis antigens and booster response 
to all antigens.
Table 18
Exact two-sided 95% CI for a sample size of 400 subjects according 
to the value observed for seroprotection status for diphtheria and 
tetanus
Observed rate expressed as a 
percentage (number of subjects 
reporting seroprotection for 
diphtheria and tetanus antigens)
Exact two-sided 95% CI for this observed rate for a sample size of 400 
subjects
Lower Limit
Upper Limit
90(360)
86.6
92.8
91.1(364)
87.8
93.6
95(380)
92.4
96.9
96.2(385)
93.9
97.9
99.5(398)
98.2
99.9
100(400)
99.1
100
Reference data: Please refer Table 22.
 
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Table 19
Exact two-sided 95% CI for a sample size of 400 subjects according 
to the seropositivity for the pertussis antigens
Observed rate expressed as a 
percentage (number of subjects 
reporting seropositivity for the pertussis 
antigens)
Exact two-sided 95% CI for this observed rate for a sample size of 
400 subjects
Lower Limit
Upper Limit
90(360)
86.6
92.8
95(380)
92.4
96.9
98.6(394)
96.8
99.4
99.1(396)
97.5
99.7
99.5(398)
98.2
99.9
100(400)
99.1
100
Reference data: Please refer Table 22.
Table 20
Exact two-sided 95% CI for a sample size of 400 subjects according 
to the value observed for the primary endpoints and the Booster 
response to all antigens
Observed rate expressed as a 
percentage (number of subjects 
reporting Booster response to all 
antigens)
Exact two-sided 95% CI for this observed rate for a sample size of 400 
subjects
Lower Limit
Upper Limit
75(300)
70.5
79.2
79(316)
74.7
82.9
80(320)
75.7
83.8
80.6(322)
76.3
84.3
81.2(325)
77.1
85
84.6(338)
80.6
87.9
85(340)
81.1
88.4
89.3(357)
85.8
92.1
90(360)
86.6
92.8
92.1(368)
88.9
94.5
92.8(371)
89.8
95.1
94.3(377)
91.5
96.3
95(380)
92.4
96.9
96.8(387)
94.5
98.3
98.9(396)
97.5
99.7
99.5(398)
98.2
99.9
100(400)
99.1
100
Reference data: Please refer Table 22.
 
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Table 21
Exact two-sided 95% CI for a sample size of 100 (per age category) 
subjects according to the value observed for the seroprotection 
status for diphtheria and tetanus, seropositivity for the pertussis 
antigens and booster response to all antigens.
Observed rate expressed as a 
percentage (number of subjects 
reporting Booster response to all 
antigens)
Exact two-sided 95% CI for this observed rate for a sample size of 100 
subjects
Lower Limit
Upper Limit
75(75)
65.3
83.1
79(79)
69.7
86.5
80(80)
70.8
83.8
81(81)
71.9
88.2
84(84)
75.3
90.6
85(85)
76.5
91.4
89(89)
81.2
94.4
90(90)
82.4
95.1
92(92)
84.8
96.5
94(94)
87.4
97.8
95(95)
88.7
98.4
96(96)
90.1
98.9
98(98)
93.0
99.8
99(99)
94.6
100.0
100(100)
96.4
100.0
Reference data: Please refer Table 22.
 
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Table 22
Reference values
Study
Country
Population
(Age in 
Years)
Vaccination History
N
D
T
PT
FHA
PRN
D 
VR
T 
VR
PT 
VR
FHA 
VR
PRN 
VR
DTPA (BOOSTRIX-045) 114778
Mexico, 
Chile
10-15
5/6X DTPa
319
100
100
99.1
100
100
79
84.6
92.8
96.5
99.7
DTPA (BOOSTRIX-002) 
263855/002
Australia
<40
Heterogeneous
214
96.2
100
99.5
100
100
-
-
96.2
100
99.1
DTPA (BOOSTRIX-002) 
263855/002
Australia
≥40
Heterogeneous
214
91.1
99.5
98.6
100
99.1
-
-
94.3
99.5
98.1
DTPA (BOOSTRIX-004) 
263855/004
Finland
10-14
4XDTPw
447
100
100
98.4
100
100
-
-
92.1
96.8
98.9
DTPA (BOOSTRIX-029) 
263855/029
Belgium
10-18
4XDTPw
218
99.5
100
100
100
100
80.6
81.2
89.3
97.7
98.1
(APV-118 ) 208355/118
Germany
4-6
4XDTPa
172
100
100
100
100
100
-
-
98.3
91.1
94.8
DTPA (BOOSTRIX-034) 
263855/034
Belgium
≥40
Heterogeneous
139
99.3
100
100
100
100
89.6
85.9
98.5
99.3
97.7
DTPA (BOOSTRIX)-041 BST 029 
(113055)
Belgium
20-28
4XDTPw + booster 
DTPa
60
100
100
100
100
100
-
-
94.1
96.0
67.3
N = number of subjects included in the PP cohort for immunogenicity
D and T: % of subjects with antibody concentration 0.1 IU/ml; PT, FHA and PRN: % of subjects with antibody concentration 5 EL.U/ml.
VR= Vaccine response:
Booster responses to the diphtheria and tetanus antigens, defined as:
For subjects with pre-vaccination concentration below seroprotection cut-off (<0.1 IU/ml): antibody concentrations at least ≥0.4 IU/ml one month after vaccination.
For subjects with pre-vaccination concentration equal or above seroprotection cut-off (≥0.1 IU/ml): an increase in antibody concentrations of at least four times the pre-vaccination 
concentration one month after vaccination.
Booster response to the PT, FHA and PRN antigens, defined as:
For initially seronegative subjects (pre-vaccination concentration below cut-off: <5 EL.U/ml): antibody concentrations at least four times the cut-off (post-vaccination concentration ≥20 
EL.U/ml) 
For initially seropositive subjects with pre-vaccination concentration ≥5 EL.U/ml and <20 EL.U/ml: an increase in antibody concentrations of at least four times the pre-vaccination 
concentration.
For initially seropositive subjects with pre-vaccination concentration ≥20 EL.U/ml: an increase in antibody concentrations of at least two times the pre-vaccination concentration.
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10.4.
Cohorts for Analyses
Two cohorts are defined for the purpose of analysis:

The Total vaccinated cohort (TVC).

PP cohort for analysis of immunogenicity.
10.4.1.
Total vaccinated cohort

The TVC analysis will be performed per treatment actually administered. A safety 
analysis based on the TVC will include all subjects with the study vaccine 
administration documented.

An immunogenicity analysis based on the TVC will include all subjects vaccinated 
and for whom data concerning at least one immunogenicity endpoint measure is 
available.
10.4.2.
Per protocol cohort for analysis of immunogenicity
The PP cohort for immunogenicity will include all evaluable subjects:

Who have received the dose of study vaccine.

For whom administration site of study vaccine is known and according to the 
protocol.

Who have not received a vaccine not specified or forbidden in the protocol.

Who meet all eligibility criteria.

Who comply with the procedures and intervals defined in the protocol (Refer to 
Table 6).

Who are within the maximum interval (the interval between Visit 1 and blood 
sampling at Visit 2, considered for inclusion of a subject will be 21–48 days) allowed 
as defined in the protocol.

Who do not meet any of the criteria for elimination from an PP analysis (refer to 
Section 6.7.2).

Who did not receive a product leading to exclusion from an PP analysis (refer to 
Section 6.7.2).

Who did not present with a medical condition leading to exclusion from an PP
analysis (refer to Section 6.8).

For whom data concerning immunogenicity endpoint measures are available. This 
will include subjects for whom assay results are available for antibodies against at 
least one study vaccine antigen component.
 
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10.5.
Derived and transformed data

A seronegative subject is a subject whose antibody concentration is below the assay 
cut-off value.

A seropositive subject is a subject whose antibody concentration is greater than or 
equal to the assay cut-off value.

A seroprotected subject is a subject whose antibody concentration 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 for ELISA assay and 0.1 
IU/ml for Vero-cell assay. (Amended 31 October 2017)

Anti-tetanus antibody concentrations 0.1 IU/ml.

Other cut-offs to be considered:

Anti-diphtheria antibody concentrations 1.0 IU/ml.

Anti-tetanus antibody concentrations 1.0 IU/ml.

Booster response to Diphtheria and Tetanus antigens is defined as:

for subjects with pre-vaccination antibody concentration <0.1 IU/ml (i.e. below 
the seroprotection cut-off), antibody concentrations at least ≥0.4 IU/ml, one 
month after vaccination, and

for subjects with pre-vaccination antibody concentration ≥0.1 IU/ml (i.e. equal 
or above the seroprotection cut-off), an increase in antibody concentrations of at 
least four times the pre-vaccination concentration, one month after vaccination.

Booster 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 four times the assay cut-off,

for subjects with pre-vaccination antibody concentration between the assay cut-
off and below four times the assay cut-off, post-vaccination antibody 
concentration four times the pre-vaccination antibody concentration, and

for subjects with pre-vaccination antibody concentration four times the assay 
cut-off, post-vaccination antibody concentration two times the pre-vaccination 
antibody concentration.

The geometric mean concentration (GMC) calculations are performed by taking the 
anti-log of the mean of the log10 concentration transformations. Antibody 
concentrations below the cut-off of the assay will be given an arbitrary value of half 
the cut-off for the purpose of GMC calculation.
 
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Handling of missing data:
Immunogenicity:

For a given subject and a given immunogenicity measurement, missing or non-
evaluable measurements will not be replaced.
Reactogenicity and Safety:

For a given subject and the analysis of solicited symptoms during the 4-day post-
vaccination follow-up period, missing or non-evaluable measurements will not be 
replaced. Therefore, the analysis of the solicited symptoms 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 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 summaries reporting both solicited and unsolicited AEs, 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.
10.6.
Analysis of demographics
Demographic characteristics (age at vaccination visit in years, gender and geographical 
ancestry, body mass index in kg/m2), cohort description and withdrawal status will be 
summarised using descriptive statistics:

Frequency tables will be generated for categorical variable such as centre.

Mean, median, standard deviation will be provided for continuous data such as age.

The distribution of subjects based on age stratification will be tabulated (as seen in
Table 23).
In addition, the above analysis will also be done for sub-groups based on age as an 
exploratory analysis.
Table 23
Age stratification
Age groups
Number of subjects
4-9 years
112
10-17 years
112
18-64 years
112
≥65 years
112
 
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10.7.
Analysis of immunogenicity
The primary analysis will be based on the PP cohort for analysis of immunogenicity. If, 
the percentage of vaccinated subjects with serological results excluded from the PP
cohort for analysis of immunogenicity is 5% or more, a second analysis based on the 
TVC will be performed to complement the PP analysis.
For all subjects and each antigen:

Seropositivity/seroprotection rate at pre-vaccination and one month post-vaccination 
will be calculated with exact 95% CIs.

GMCs at pre-vaccination and one month post-vaccination will be tabulated with
95% CIs.

Booster response rate one month post-vaccination will be calculated with exact 
95% CIs for diphtheria, tetanus and pertussis antigens.
In addition, the above analysis will also be done based on age stratification (Refer Table 
23) as an exploratory analysis.
Finally, antibody concentrations distribution at pre-vaccination and one month post-
vaccination will be displayed using reverse cumulative curves (RCC).
10.8.
Analysis of safety
The analysis will be based on the TVC.

The percentage of subjects reporting each individual solicited local and general 
symptom during the 4-day (Day 1-4) follow-up period after booster vaccination will 
be tabulated. 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.

Occurrence of fever during the 4-day follow-up period after vaccination will be 
reported per 0.5°C cumulative increments.

In addition, the above analysis will also be done for sub groups based on age
stratification (Refer Table 23) as an exploratory analysis.

The percentage of subjects with at least one local symptom (solicited or unsolicited), 
with at least one general symptom (solicited or unsolicited) and with any symptom 
(solicited or unsolicited) during the 4-day (Day 1-4) follow-up period after booster 
vaccination will be tabulated with exact 95% CI after booster vaccination. 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 consultation and 
for symptoms (solicited or unsolicited) assessed as causally related to vaccination.

The percentage of subjects who started to receive at least one concomitant 
medication (i.e. any medication, antipyretic medication, prophylactic antipyretics) 
during the 4-day (Day 1-4) and 31-day (Day 1-31) follow-up period after vaccination 
will be tabulated with exact 95% CI.
 
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
The verbatim reports of unsolicited AEs will be reviewed by a clinical research and 
development lead 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 the 31-day (Day 1-31) 
follow-up period after booster dose with its exact 95% CI will be tabulated by 
Preferred Term. Similar tabulation will be done for unsolicited AEs rated as grade 3 
and for unsolicited AEs with causal relationship to vaccination.

Any large injection site reaction (for subjects <6 years of age defined as a swelling 
with a diameter of >50 mm and for subjects 6 years of age swelling with a diameter 
of >100 mm, noticeable diffuse swelling or noticeable increase in limb 
circumference) onset during the 4-day (Day 1-4) follow-up period after vaccination 
will be described in detail.

SAEs and withdrawal due to AEs and SAEs will be described in detail.
10.9.
Interpretation of analyses
All analysis 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
Analysis of the single booster dose will be performed at the end of the study when all 
data are available. An integrated clinical study report containing all data will be written 
and made available to the investigators.
10.10.2.
Statistical considerations for interim analyses
All analyses will be conducted on final data and therefore no statistical adjustment for 
interim analyses is required.
11.
ADMINISTRATIVE MATTERS
To comply with ICH GCP administrative obligations relating to data collection, 
monitoring, archiving data, audits, confidentiality, public disclosure requirements and 
publications must be fulfilled.
11.1.
Electronic Case Report Form instructions
A validated GSK defined electronic data collection tool will be used as the method for 
data collection.
 
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In all cases, subject initials will not be collected nor transmitted to GSK. Subject data 
necessary for analysis and reporting will be entered/transmitted into a validated database 
or data system. Clinical data management will be performed in accordance with 
applicable GSK standards and data cleaning procedures.
While completed eCRFs are reviewed by a GSK Biologicals’ Site Monitor at the study 
site, omissions or inconsistencies detected by subsequent eCRF review may necessitate 
clarification or correction by the investigator or appropriately qualified designee. In all 
cases, the investigator remains accountable for the study data.
The investigator will be provided with 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 other items, the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol, any other 
study agreements, GCP and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents.
The investigator must ensure provision of reasonable time, space and qualified personnel 
for monitoring visits.
Direct access to all study-site related and source data is mandatory for the purpose of 
monitoring review. The monitor will perform eCRF review and a Source Document 
Verification (SDV). By SDV we understand verifying eCRF entries by comparing them 
with the source data that will be made available by the investigator for this purpose.
The Source Documentation Agreement Form describes the source data for the different 
data in the eCRF. This document should be completed and signed by the site monitor and 
investigator and should be filed in the investigator’s study file. Any data item for which 
the eCRF will serve as the source must be identified, agreed and documented in the 
source documentation agreement form.
Upon completion or premature discontinuation of the study, the monitor will conduct site 
closure activities with the investigator or site staff, as appropriate, in accordance with 
applicable regulations, GCP, and GSK procedures.
 
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11.3.
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. The minimum retention time will 
meet the strictest standard applicable to a particular site, as dictated by ICH GCP, any 
institutional requirements, applicable laws or regulations, or GSK standards/procedures, 
otherwise, the minimum retention period will default to 25 years after completion of the 
study report.
The investigator/institution must notify GSK of any changes in the archival 
arrangements, including, but not limited to archival at an off-site facility, transfer of 
ownership of the records in the event the investigator leaves the site.
11.4.
Quality assurance
To ensure compliance with GCP and all applicable regulatory requirements, GSK may 
conduct a quality assurance audit. Regulatory agencies may also conduct a regulatory 
inspection of this study. Such audits/inspections can occur at any time during or after 
completion of the study. If an audit or inspection occurs, the investigator and institution 
agree to allow the auditor/inspector direct access to all relevant documents and to allocate 
his/her time and the time of his/her staff to the auditor/inspector to discuss findings and 
any relevant issues.
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 PCD and to have secondary endpoint 
 
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disclosed at latest 12 months after the last subject last visit (LSLV) as described in the 
protocol.
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.
11.7.
Data Sharing
Under the framework of the SHARE initiative, results of GSK studies may be combined 
with non-GSK studies, to investigate further about the study product(s) and other 
product(s), and/or the disease/condition under investigation and related diseases and 
conditions.
12.
COUNTRY SPECIFIC REQUIREMENTS
Not applicable.
 
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13.
REFERENCES
Camargo ME, Silveira L, Furuta JA, et al. Immunoenzymatic assay of anti-diphtheric 
toxin antibodies in human serum. J Clin Microbiol 1984; 20(4): 772-4.
Centers for Disease Control and Prevention Metropolitan Atlanta Congenital Defects 
Program (CDC MACDP) guidelines. Birth defects and genetic diseases branch 6-digit 
code for reportable congenital anomalies; 
http://www.cdc.gov/ncbddd/birthdefects/documents/MACDPcode0807.pdf. Accessed on 
02 February 2017.
Centers for Disease Control and Prevention (CDC)2015(a). Epidemiology and Prevention 
of Vaccine-Preventable Diseases, 13th Edition. April 2015.
http://www.cdc.gov/vaccines/pubs/pinkbook/downloads/pert.pdf. Accessed on 02 
February 2017.
Centers for Disease Control and Prevention CDC 2015(b). 
http://www.cdc.gov/pertussis/fast-facts.html. Accessed on 02 February 2017.
de Greeff SC, Mooi FR, Westerhof A et al. Pertussis Disease Burden in the Household: 
How to Protect Young Infants. Clin Infect Dis. 2010; 50(10): 1339–1345.
Efstratiou A. & Maple P.A.C., 1994. Diphtheria. Laboratory diagnosis of Diphtheria. 
The expended programme on immunization in the European region of WHO. WHO 
ICP/EPI 038 (C). World Health Organization, Geneva, Switzerland. (Amended 31 
October 2017)
EMA Guideline on the exposure to medicinal products during pregnancy: need for post-
authorisation data (Doc. Ref. EMEA/CHMP/313666/2005) ‘adopted at Community level 
in May 2006);
http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_g
uideline/2009/11/WC500011303.pdf. Accessed on 02 February 2017.
Forsyth KD, Plotkin S, Tan T, et al. Strategies to Decrease Pertussis. Pediatrics. 
2015;135(6): e1475 -82 (doi: 10.1542/peds.2014-3925).
Kowalzik F, Barbosa AP, Fernandes VR, et al. Prospective multinational study of 
pertussis infection in hospitalised infants and their household contacts. Pediatric 
Infectious Disease Journal 2007; 26(3): 238–242.
Melville-Smith ME, Seagroatt VA and 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.
Mertsola J, Meeren OVD, He Q et al. Decennial Administration of a Reduced Antigen 
Content Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine in Young 
Adults. Clinical Infectious Diseases 2010; 51(6):656–662.
 
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Rüggeberg JU, Gold MS, Bayas JM, et al. Anaphylaxis: case definition and guidelines 
for data collection, analysis, and presentation of immunisation safety data. Vaccine 2007; 
25(31): 5675-84.
Ward JI, Cherry JD, Chang SJ, et al. Efficacy of an acellular pertussis vaccine among 
adolescents and adults. New England Journal of Medicine 2005; 353(15): 1555–1563.
Ward JI, Cherry JD, Chang SJ, et al. Bordetella pertussis infections in vaccinated and 
unvaccinated adolescents and adults, as assessed in a national prospective randomised 
acellular pertussis vaccine trial (APERT), Clinical Infectious Diseases 2006; 43(2): 151–
157.
WHO National Immunization Coverage Scorecards 2015. 2015a. 
http://www.who.int/immunization/global_vaccine_action_plan/WHA_Scorecards_DTP_
coverage_2014.pdf. Accessed on 02 February 2017.
WHO vaccine-preventable diseases: monitoring system. 2015 global summary. 2015b. 
http://apps.who.int/immunization_monitoring/globalsummary/countries?countrycriteria%
5Bcountry%5D%5B%5D=RUS&commit=OK. Accessed on 02 February 2017.
Zuckerman JN. The importance of injecting vaccines into muscles. BMJ 2000; 321: 
1237-38.
 
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APPENDIX A
CLINICAL LABORATORIES
Table 24
GSK Biologicals’ laboratories
Laboratory
Address
GSK Biologicals Clinical Laboratory 
Sciences, Rixensart
Biospecimen Reception-B7/44
Rue de l'Institut, 89-B-1330 Rixensart-Belgium
GSK Biologicals Clinical Laboratory
Sciences, Wavre-Nord Noir Epine
Avenue Fleming, 20-B-1300 Wavre-Belgium
 
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APPENDIX B
AMENDMENTS AND ADMINISTRATIVE 
CHANGES TO THE PROTOCOL
GlaxoSmithKline Biologicals SA
Vaccines R &D
Protocol Amendment 1
eTrack study number 
and Abbreviated Title
201532 [DTPA (BOOSTRIX)-050]
IND number
BB-IND-8461
EudraCT number
2015-003405-42
Amendment number:
Amendment 1
Amendment date:
02 February 2017
Co-ordinating author:
, Scientific Writer
Rationale/background for changes:
The protocol has been amended to implement the following changes:
!
The age at inclusion to study has been changed from 3 to 4 years of age in order to 
be in compliant with Boostrix’s approved EU label wherein it is indicated for 
booster vaccination in individuals aged four years and older.
!
Wording “parents/Legally Acceptable Representative(s) (LAR[s])” is replaced by 
the wording “parent(s)/adoptive parent(s)”. As per Russian legislation, only 
parents or adoptive parents can give consent for the enrolment of their child in a 
clinical trial. No other person is allowed to give consent on behalf of a minor to 
participate in a clinical trial.
!
The age groups are amended according to the approved Boostrix EU label and 
physiological particularities i.e., from 3-9 to 4-9 years (children), 10-19 to 10-17 
years (adolescents), 20-64 to 18-64 years (adults) and ≥65 years (elderly 
population).
!
To reflect the upgrade to new version for protocol (15.0), ICF (8.0), eCRF, SPM 
and overall changes in the functions.
!
The inclusion criteria has been amended in order to clarify the following,
#
Children from four to seven years of age who have received diphtheria, 
tetanus and pertussis vaccination prior to study enrolment as per local 
recommendations will be enrolled
!
Subjects eight years of age and older who have received diphtheria, tetanus and 
pertussis vaccination to the best of their/subjects’ parent(s)/subjects’ adoptive 
parent(s) knowledge and did not receive an additional diphtheria, tetanus or 
pertussis vaccination within 5 years prior to enrolment in the study will be 
enrolled.
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Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections:
Title page:
Detailed Title
A phase III, open-label, single-group, multi-centre 
study to assess the immunogenicity, safety and 
reactogenicity of GSK Biologicals’ combined reduced 
antigen content diphtheria, tetanus and acellular 
pertussis (dTpa) vaccine, Boostrix™, administered as 
a booster dose in healthy Russian subjects aged three
four years and older.
Contributing authors
!
, Clinical and
Epidemiology Project Leader Project Level 
Clinical Research and Development Lead
!
, Clinical Research and 
Development Lead, contractor for GSK 
Biologicals
!
/
, Lead 
Statistician
!
, Project Statistician
!
/
, Study 
Delivery Lead
!
, Study Delivery Manager
!
, Senior Local Study Manager
Head of Clinical Operations, Vaccines
!
, Senior Clinical Reserach 
Associate, Vaccines
!
, Vaccine Supply Coordinator,
contractor for GSK Biologicals/
,
Clinical Trial Supply Manager
!
/
, Clinical Read-
out Team Leader
!
, Business and Decision Life 
Sciences contractor for GSK BiologicalsCLS 
Study Manager
!
, Project Data Manager
!
 and 
/
 
, Study Data Manager
!
, Oversight Data Manager
!
/
, Global Patents 
Representative
!
and 
/
 
and 
, Clinical Safety 
Representatives
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!
, Senior Regional Medical 
Manager
!
/
, Global 
Regulatory Affairs
List of abbreviations:
ATEAM
Appropriate (electronic) temperature excursion decision 
form
ATP
According To Protocol
eTDF
Electronic temperature excursion decision form
LAR
Legally Acceptable Representative
PI
Product Prescribing Information
List of abbreviations:
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.
Legally acceptable 
representative
(The terms legal 
representative or legally 
authorized 
representative are used 
in some settings.)
An individual or juridical or other body authorized under 
applicable law to consent, on behalf of a prospective 
subject, to the subject's participation in the clinical trial 
(as per Russian legislation, it is parent(s)/adoptive 
parent(s).
Synopsis
Indication
Booster immunisation against diphtheria, tetanus and pertussis 
diseases of individuals from age of four years onwards. The 
study population for this study will include individuals aged 
three four years and above older.
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Synopsis and Section 1.2.1 Rationale for the study
Boostrix vaccine contains 0.5 mg Al (as aluminium phosphate and aluminium hydroxide) 
per 0.5 millilitre (ml) dose. Boostrix is currently not registered in Russia. This study will 
assess the immunogenicity, reactogenicity and safety of Boostrix in healthy Russian 
subjects aged three four years and older. The data obtained from this study will be used 
to support the registration of Boostrix in Russia for individuals aged 3 4 years and 
olderabove. Although Boostrix is indicated for individuals aged 4 years onwards, in this 
study, individuals aged 3 years and above have been selected with the intention to 
increase the coverage rate of the vaccine which may also help reduce the pertussis burden 
in Russia.
Synopsis and Section 1.2.1 Rationale for the study design
The study is designed as an open-label, single group trial in which all the study subjects 
will receive a single dose of Boostrix vaccine. An equal number of subjects are expected 
to be recruited in the following age categories: 43-9 years (children), 10-19 17 years
(adolescents), 2018-64 years (adults) and 65 years (elderly population).in order to 
support the registration of Boostrix in Russia
The ≥65 years (elderly population) has been included in the study to ensure cocooning 
effect. Pertussis outbreaks have occurred in a number of European and non-European 
countries. Whilst this resurgence is observed across the age range with a notable 
increase in cases now being detected in adolescents and older age groups. It is also 
now recognized that immunity following either natural pertussis infection or 
vaccination is not long lived, and the acellular pertussis vaccines that have been widely 
used since the 1990s may be more prone to such waning. Consequently, adults and 
adolescents with pertussis are a potential source of infection for infants too young to 
have been fully vaccinated. Many countries recommend 'cocoon ' strategy, i.e. 
vaccination of family members and close contact of newborn (i.e. grandparents usually 
above 65 years old), in order to protect infants from acquiring pertussis.
Section 1.3. Benefit: Risk Assessment
Important 
Potential/Identified Risk
Data/Rationale for Risk
Mitigation Strategy
Investigational study vaccine (Boostrix)
Temperature of ≥40.0C within 
48 hours of vaccination, not due 
to another identifiable cause
As outlined in the RSI from clinical trials 
and post-marketing safety data, this 
AE/SAE is recognised as well-
characterised identified risks for 
Boostrix.
Subjects/Subjects’ parents/legally 
acceptable representative [LAR(s)]
adoptive parent should report any 
untoward symptoms experienced, after 
receiving the vaccine immediately to 
the investigator.
Hypotonic-hyporesponsive 
episode
As outlined in the Boostrix RSI from 
clinical trials and post-marketing safety 
data, this AE/SAE is recognised as 
well-characterised identified risks for 
Boostrix
All SAEs should be reported 
immediately to GSK. It is important 
that procedures are in place to avoid 
injury from fainting. All subjects will 
need to remain under observation (i.e. 
visibly followed; no specific procedure) 
at the vaccination centre for at least 30 
 
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Important 
Potential/Identified Risk
Data/Rationale for Risk
Mitigation Strategy
minutes after vaccination.
Convulsions with or without fever 
occurring within 3 days of 
vaccination
As outlined in the Boostrix RSI from 
clinical trials and post-marketing safety 
data, this AE/SAE is recognised as 
well-characterised identified risks for 
the vaccine.
Subjects/Subjects’ parents/legally 
acceptable representative [LAR(s)] 
adoptive parent should report any 
untoward symptoms experienced, after 
receiving the vaccine immediately to 
the investigator.
Extensive swelling of vaccinated 
limb
Given that the active ingredients of 
Boostrix are conjugated to tetanus 
toxoid carrier protein, an exaggerated 
local (Arthus-like) reaction are 
occasionally reported following receipt 
of a diphtheria- or tetanus- containing 
vaccine. These reactions present as 
extensive painful swelling, often from 
shoulder to elbow. They generally 
begin from 2 to 8 hours after injections 
and are reported most often in adults, 
particularly those who have received 
frequent doses of diphtheria or tetanus 
toxoid.
Subjects/Subjects’ parents/legally 
acceptable representative [LAR(s)]
adoptive parent should report any 
untoward symptoms experienced, after 
receiving the vaccine immediately to 
the investigator.
Encephalopathy of unknown 
aetiology, occurring within 7 days 
following previous vaccination 
with pertussis containing vaccine
As outlined in the Boostrix RSI from 
clinical trials and post-marketing safety 
data, this AE/SAE is recognised as 
potential risk for Boostrix
Subjects/Subjects’ parents/legally 
acceptable representative [LAR(s)]
adoptive parent should report any 
untoward symptoms experienced, after 
receiving the vaccine immediately to 
the investigator.
Adequate human data on use 
during pregnancy/lactation are 
not available. Animal studies do 
not indicate direct or indirect 
harmful effects with respect to 
pregnancy, embryonal/foetal 
development, parturition or post-
natal development
Monitoring of spontaneous reports
GSK is closely monitoring pregnancy 
outcomes in spontaneous reports 
including pregnancy registries
Study Procedure
Risk from blood sampling.
Blood sampling associated risk of 
discomfort, syncope, infection at the 
site after or during venipuncture
Blood samples will be obtained by a 
trained professional and medical 
assistance will be available.
The potential risk of feeling faint, or 
experiencing mild local pain, 
bruising, irritation or redness at the 
site where blood was taken, is 
mentioned in the ICF. The amount 
of blood to be taken for sampling 
will not be harmful to the subject’s 
health.
 
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Synopsis and Section 3. Study design overview
BS: Blood Sampling 
* An equal number of subjects are expected to be recruited in the following age categories: 34-9 years (children), 10-
1917 years (adolescents), 2018-64 years (adults) and 65 years (elderly population) in order to evaluate data.
Synopsis and Table 1
Study groups and epochs foreseen in the study
Study Groups
Number of 
subjects*
Age (Min/Max)
Epochs
Epoch 001
dTpa Group
448
34 years
x
* Approximate number
Control: uncontrolled (in terms of no active comparator
Synopsis and Section 4. Study cohort
Approximately 448 subjects are expected to be enrolled in this study. An equal number of 
subjects (approximately 112) are expected to be recruited in each of the following age 
categories: 43-9 years (children), 10-19 17 years (adolescents), 2018-64 years (adults)
and 65 years (elderly population) in order to evaluate data. Refer to Section 10.1 for a 
detailed description of criteria used for the estimation of sample size.
Section 4.2. Inclusion criteria for enrolment

Subjects or subjects’ parent(s)/adoptive parent 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).

A male or female threefour years of age and older.

Written informed assent obtained from subjects aged 10 14 years to <18 years.
 
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
Written informed consent obtained from the subject/from the parent(s)/adoptive 
parentLAR(s) of the subject prior to performing any study specific procedure.

Children three four to seven years of age who have previously received primary and 
booster diphtheria, tetanus and pertussis vaccination in the first two years of life, as 
per local recommendations. Children four to seven years of age who have received 
diphtheria, tetanus and pertussis vaccination prior to study enrolment as per local 
recommendations.

Subjects eight years of age and older who have completed their routine childhood 
diphtheria, tetanus and pertussis vaccinations to the best of their/subjects’ 
parent(s)/adoptive parent LAR(s) knowledge and as per local recommendations and 
did not receive a booster dose of the vaccine(s) within 5 years prior to enrolment in 
the study. Subjects eight years of age and older who have received diphtheria, 
tetanus and pertussis vaccination to the best of their/subjects’ parent(s)/subjects’ 
adoptive parent(s) knowledge and did not receive an additional diphtheria, tetanus or 
pertussis vaccination within 5 years prior to enrolment in the study will be enrolled.
Section 4.3. Exclusion criteria for enrolment

History of previous or intercurrent diphtheria, tetanus or pertussis diseases since 
birth in subjects three four to seven years of age.

Chronic administration (defined as more than 14 days in total) of 
immunosuppressants or other immune-modifying drugs within six months prior to 
the vaccine dose. For corticosteroids, this will mean prednisone ≥20 mg/day (for 
adult subjects, ≥18 years of age) or ≥0.5 mg/kg/day (for paediatric subjects, aged 34-
17 years), or equivalent. Inhaled and topical steroids are allowed.
Section 5.1. Regulatory and ethical considerations, including the informed consent 
process
Conduct of the study includes, but is not limited to, the following:

Subject/subject’s parent(s)/adoptive parent LAR(s) informed consent and subject 
informed assent, as appropriate.
Freely given and written or witnessed informed consent must be obtained from each 
subject and/or each subject’s parent(s)/adoptive parentLAR(s) and subject informed 
assent, as appropriate, prior to participation in the study. 
Section 5.2. Subject identification and randomisation
The enrolment will be performed to ensure equal distribution of the population across the 
four age strata [43-9 years (children), 10-19 17 years (adolescents), 2018-64 years 
(adults) and 65 years (elderly population)]. Therefore, the expected distribution of 
subjects is as shown in Table 4.
 
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Table 4
Number of subjects required for enrolment
Age Stratum
Vaccine
N
43-9 years
Boostrix
112
10-19 17 years
Boostrix
112
2018-64 years
Boostrix
112
65 years
Boostrix
112
N = approximate number of subjects to be enrolled
After obtaining the signed and dated ICF and IAF (if applicable) from the subject and 
having checked the eligibility of the subject, the study staff in charge of the vaccine
administration will access SBIR. Upon providing the age [43-9 years (children), 10-19 
17 years (adolescents), 2018-64 years (adults) and 65 years (elderly population)] and 
the subject identification number, the randomisation system will provide the treatment 
number to be used for the dose.
Section 5.5. Outline of study procedures
Table 5
List of study procedures
Epoch
Epoch 001
Type of contact
Visit 1
Visit 2
Timepoints
Day 01
Day 3031
Sampling timepoints
Pre-Bst
Post-Bst
Recording of solicited adverse events within 4 days (Day 
1–4) post-vaccination by subjects/subjects’ 
parent(s)/adoptive parent LAR(s)
● 
Recording of non-serious adverse events within 31 days 
(Day 1-31) post-vaccination, by subjects/subjects’ 
parent(s)/adoptive parent LAR(s)
● 
● 
● 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.
# Physical examination after the vaccination visit, will be performed only if the subject indicates during questioning that 
there might be some underlying pathology(ies) or if deemed necessary by the Investigator or delegate.
Pre-Bst: Before the administration of study vaccine; Post-Bst: one month after the administration of study vaccine.
1 Applicable to women of child-bearing potential
2 Refer to the table notes under Table 12 for a detailed explanation on the reporting of large injection site reactions by 
the subject's/subjects' parent(s)/adoptive parent LAR(s).
Section 5.6.1. Informed consent
The signed/witnessed informed consent of the subject/subject’s parent(s)/adoptive parent
LAR(s) must be obtained before study participation. The signed informed assent of the 
subject below the age of consent (i.e. minor) should be obtained in addition to the signed 
informed consent by his/her parent(s)/adoptive parent LAR(s) according to local rules 
and regulations. Refer to Section 5.1 for the requirements on how to obtain informed 
consent and assent, as appropriate.
 
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Section 5.6.4. Medical history and vaccination history
Obtain the subject’s medical history by interview and/or review of the subject’s medical 
records and record both any current and/or past any pre-existing conditions or signs 
and/or symptoms present in a subject prior to the study vaccination in the eCRF.
Review the subject’s childhood diphtheria, tetanus and pertussis vaccinations to collect 
information on the vaccine name, route of administration, dose number and date of 
administration. This information should be recorded in the eCRF.
Section 5.6.9.1 Blood sampling for antibody determination

A volume of approximately 5 ml of whole blood (to provide approximately 1.7 ml of 
serum) should be drawn from all subjects included in the immunogenicity analysis of 
humoral immune response at the pre-booster and post-booster timepoint (Visit 1 and 
Visit 2). After centrifugation, serum samples should be kept at –20°C or below until 
shipment.
Section 5.6.12. Distribution of diary cards and recording of AEs, SAEs, and 
pregnancies

The subjects/subjects’ parent(s)/adoptive parent LAR(s) will be instructed to contact 
the investigator immediately should they/the subjects manifest any signs or 
symptoms they perceive as serious. 

At Visit 1, diary cards will be provided to the subject/subject’s parent(s)/adoptive 
parent LAR (s). The subject/subject’s parent(s)/adoptive parent LAR(s) will record 
body (preferably 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 vaccination. The 
subject/subject’s parent(s)/adoptive parent LAR(s) will be instructed to return the 
completed diary card to the investigator at the next study visit.

Note: Diary cards can be filled in by a minor subject under the supervision of 
the subject’s parent(s)/adoptive parent LAR(s) provided that the minor has the 
competency to assess and report the information to be provided in the diary card. 
The ultimate accountability for the completion of the diary cards remains with 
the subject’s parent(s)/adoptive parent LAR (s). The investigator should discuss 
this accountability with the subject’s parent(s)/adoptive parent LAR (s).

Collect and verify completed diary cards during discussion with the subject/subject’s 
parent(s)/adoptive parent LAR(s) on Visit 2.

Note: If the diary card has been filled in by a minor subject, the investigator or 
delegate should verify the reported information during a discussion with the 
minor subject preferably in the presence of his/her parent(s)/adoptive parent
LAR(s).

After vaccination, if the subjects or the subject’s parents/adoptive parent LAR
observe any large injection site reaction (defined as a swelling with a diameter of > 
50 mm for subjects <6 years of age and >100 mm for subjects 6 years of age, 
 
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noticeable diffuse swelling or noticeable increase in limb circumference) during the 
4-day follow-up (Day 1-4) period, they will be asked to contact study personnel and 
to visit the investigator's office for evaluation as soon as possible. The investigator 
will record detailed information describing the AE on a specific large injection site 
reaction screen in the eCRF.
Section 5.6.13. Return of diary card and diary card transcription

Any unreturned diary cards will be sought from the subject/subject’s 
parent(s)/adoptive parent LAR(s) through telephone call(s) or any other convenient 
procedure. The investigator will transcribe the collected information into the eCRF 
in English.
Section 5.6.14. Recording of AEs, SAEs and pregnancies

The subjects/subjects’ parent(s)/adoptive parentLAR(s) will be instructed to contact 
the investigator immediately should they/the subjects manifest any signs or 
symptoms they perceive as serious. 
Section 5.7. Biological sample handling and analysis
Any sample testing will be done in line with the consent of the individual 
subject/subject’s parent(s)/adoptive parent LAR(s).
Section 6.1. Description of Study vaccine
Boostrix is indicated for booster immunisation against diphtheria, tetanus and pertussis 
diseases of individuals aged four years and above. However, in this study, the study 
population will include individuals aged three years and above. This age has been 
selected with the intention to increase the coverage rate of the vaccine which may also 
help reduce the pertussis burden in Russia which was estimated at about 4,705 cases per 
100,000 population in 2014 [WHO, 2015b].
Section 6.2. Storage and handling of study vaccine
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) or above -15.0°C (for -20°C/-4°F label storage condition) 
impacting investigational medicinal products (IMPs) must be reported in the appropriate 
(electronic) temperature excursion decision form (ATEAM [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 ATEAM, 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.
 
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Section 6.7. Concomitant medications/products and concomitant vaccinations
At each study visit/contact, the investigator or delegate should question the subject and/or 
the subject’s parent(s)/adoptive parentLAR(s) about any medications/products taken and 
vaccinations received by the subject.
Section 6.7.1. Recording of concomitant medications/products and concomitant 
vaccinations

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 in eCRF.
*SAEs that are required to be reported per protocol.
Section 8. Safety
Each subject/subject’s parent(s)/adoptive parentLAR(s) will be instructed to contact the 
investigator immediately should they/the subject manifest any signs or symptoms they 
perceive as serious.
Section 8.1.3.1. Solicited local (injection site) adverse events
Note: If the subjects or the subject’s parent(s)/adoptive parentLAR(s) observe any large 
injection site reaction (defined as a swelling with a diameter of >50 mm for subjects <6 
years of age and >100 mm for subjects 6 years of age, noticeable diffuse swelling or 
noticeable increase in limb circumference) during the 4-day (Day 1–4) follow-up period 
after vaccination, they will be asked to contact the study personnel and to visit the 
investigator’s office for evaluation as soon as possible. The investigator will record 
detailed information describing the AE on a specific large injection site reaction sheet in 
the eCRF.
Section 8.1.3.2. Solicited general adverse events
Table 13
Solicited general adverse events
Toddler/Child (<6 years)
Drowsiness
Fever
Irritability/Fussiness
Loss of appetite
Adult/Child (6 years)
Fatigue
Fever
Gastrointestinal symptoms †
Headache
†Gastrointestinal symptoms include nausea, vomiting, diarrhoea and/or abdominal pain.
 
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Subjects/parent(s)/adoptive parentLAR(s) will be instructed to measure and record the 
axillary, rectal or oral body temperature by axillary route in the evening. Should 
additional temperature measurements be performed at other times of day, 
subjects/parent(s)/adoptive parentLAR(s) will be instructed to record the highest 
temperature in the diary card.
Section 8.3.1. Time period for detecting and recording adverse events, serious 
adverse events and pregnancies
All pregnancies recorded during this period will be followed up as detailed in section 
8.2,See section 8.4 for instructions on reporting of pregnancies.and 8.5.2.
Table 14
Reporting periods for collecting safety information
Event
Pre-Bst 
(consent 
obtained)
Vaccination
(Day 1)
4 days Post Bst
(Day 1-4) 
31 days Post Bst
(Day1-31) 
Study Conclusion
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/vaccination
Pregnancies*
Pre-Bst: Before the administration of study vaccine; Post-Bst: one month after the administration of study vaccine.
*This refers to collecting information on pregnancy as an event and not as an outcome, which will be collected 
after the end of the study.
Section 8.3.3.1. Active questioning to detect adverse events and serious adverse 
events
As a consistent method of collecting AEs, the subject or the subject’s parent(s)/adoptive 
parentLAR(s) should be asked a non-leading question such as:
Section 8.3.3.2.1
Table 15
Intensity scales for solicited symptoms in children less than 6 years of 
age 
Toddler/Child (< 6 years)
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
 
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Table 16
Intensity scales for solicited symptoms in adults and children of 6 
years of age or more
Adults/Child (6 years)
Adverse Event
Intensity grade
Parameter
Pain at injection site
0
None
1
Mild: Any pain neither interfering with nor preventing 
normal every day activities.
2
Moderate: Painful when limb is moved and interferes with 
every day activities.
3
Severe: Significant pain at rest. Prevents normal every 
day activities.
The maximum intensity of local injection site redness/swelling for toddler and children < 
6 years of age will be scored at GSK Biologicals as follows:
The intensity should be assigned to one of the following categories:
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)/adoptive parentLAR(s) to seek medical advice. 
In adults/adolescents, such an AE would, for example, prevent 
attendance at work/school and would necessitate the 
administration of corrective therapy.
Section 8.7. Subject card
Study subjects/subjects’ parent(s)/adoptive parentLAR(s) must be provided with the 
address and telephone number of the main contact for information about the clinical 
study.
The investigator (or designate) must therefore provide a “subject card” to each 
subject/subject’s parent(s)/adoptive parentLAR(s). In an emergency situation this card 
serves to inform the responsible attending physician that the subject is in a clinical study 
and that relevant information may be obtained by contacting the investigator.
Subjects/subjects’ parent(s)/adoptive parentLAR(s) must be instructed to keep subject 
cards in their possession at all times during the study duration.
Section 9.2.1. Subject withdrawal from the study
Information relative to the withdrawal will be documented in the eCRF. The investigator 
will document whether the decision to withdraw a subject from the study was made by 
the subject himself/herself, by the subject’s parent(s)/adoptive parentLAR(s), or by the 
investigator, as well as which of the following possible reasons was responsible for 
withdrawal:
 
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*In case a subject is withdrawn from the study because he/she/the subject’s 
parent(s)/adoptive parentLAR(s) has withdrawn consent, the investigator will document 
the reason for withdrawal of consent, if specified by the subject/subject’s 
parent(s)/adoptive parentLAR(s), in the eCRF.
Section 10.3. Determination of sample size
According to Russian regulations, for the purpose of product registration, the minimum 
sample size required is 100 subjects in each age group. Therefore, the total number of 
evaluable subjects is 400 [100 subjects in each age group, 43-9 years (children), 10-19 17
years (adolescents), 2018-64 years (adults) and 65 years (elderly population)]. 
Assuming a drop-out rate of 10%, to compensate for subject attrition due to early 
withdrawal, a total of 448 subjects (112 in each age group) will be enrolled in to the study 
in order to obtain the desired number of evaluable subjects for analysis.
Section 10.6. Analysis of demographics
Table 23
Age stratification
Age groups
Number of subjects
43-9 years
112
10-1917 years
112
2018-64 years
112
≥65 years
112
 
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GlaxoSmithKline Biologicals SA
Vaccines R &D
Protocol Amendment 2
eTrack study number 
and Abbreviated Title
201532 [DTPA (BOOSTRIX)-050]
IND number
BB-IND-8461
EudraCT number
2015-003405-42
Amendment number:
Amendment 2
Amendment date:
07 August 2017
Co-ordinating author:
, Scientific Writer
Rationale/background for changes:
This protocol amendment was developed after the comments from the Russian 
regulatory authorities [Ministry of Health (MoH)]. Adjustments to the text were made 
in certain sections for better readability and to clarify the inclusion and exclusion 
criteria for enrolment of subjects and the conduct of the study. In addition, adjustments 
for the reporting period and assessment of adverse events in the safety sections were 
made for consistency. Typos and errors were corrected throughout the document. The 
newly re-developed and re-validated GSK’s DTPa ELISA cut-offs were updated as per 
the most recent CBER recommendation (2017).

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Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections:
Title page:
Contributing authors
!
, Clinical Research and 
Development Lead
!
, Senior Local Study Manager
Head of Clinical Operations, Vaccines
!
, Senior Clinical Reserach 
Research Associate, Vaccines
Copyright 2016-2017 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised 
copying or use of this information is prohibited. © 2016-2017 GSK group of companies or its licensor.
Synopsis:
Rationale for the 
study and study 
design
Studies have shown that childhood pertussis burden can be 
significantly reduced by vaccination of adolescents and adults 
[Ward, 2005; Ward, 2006]. Hence, boosting with reduced-
antigen-content diphtheria and tetanus toxoids and acellular 
pertussis vaccine (dTpa) instead of DTdT may prolong the 
immunity against pertussis infection.
The ≥ 65 years (elderly population) has been included in the 
study to ensure cocooning effect. Pertussis outbreaks have 
occurred in a number of European and non-European 
countries. Whilst tThis resurgence is observed across the age 
range with a notable increase in cases now being detected in 
adolescents and older age groups. It is also now recognised 
that immunity following either natural pertussis infection or 
vaccination is not long lived, and the acellular pertussis 
vaccines that have been widely used since the 1990s may be 
more prone to such waning. Consequently, adults and 
adolescents with pertussis are a potential source of infection 
for infants too young to have been fully vaccinated. Many 
countries recommend 'cocoon ' strategy, i.e. vaccination of 
family members and close contact of newborn (i.e. 
grandparents usually above 65 years old), in order to protect 
infants from acquiring pertussis. The ≥65 years (elderly 
population) have therefore been included in the study.
Study design
!
Experimental design: Phase III, open-label, non-
randomised, multi-centric, single-country study with a 
single group.
!
Duration of the study:
#
Epoch 001: Primary Epoch starting at Visit 1 (Day 1) 
and ending at Visit 2 (Day 31)
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
Primary Completion Date (PCD): Visit 2 (Day 31)

End of Study (EoS): Last testing results released of 
samples collected at Visit 2

Study groups: dTpa group: Subjects aged four years and 
older
Synopsis Table 4
Study groups and epochs foreseen in the study
Study Groups
Number of 
subjects*
Age (Min)
Epochs
Epoch 001
dTpa Group
448
4 years
x
List of abbreviations
dT:
Reduced-antigen-content diphtheria and tetanus toxoid 
vaccine
ELISA:
Enzyme-linked immunosorbent assay
IAF:
Inform Assent Form
IB
Investigator Brochure
ICF:
Inform Consent Form
PI:
Prescribing Information
Trademarks:
Trademark of the GSKlaxoSmithKline
group of companies
Generic description
Boostrix
Combined reduced-antigen-content 
diphtheria, tetanus and acellular pertussis 
(dTpa) vaccine
Section 1.2.1: Rationale for the study
Studies have shown that childhood pertussis burden can be significantly reduced by 
vaccination of adolescents and adults [Ward, 2005; Ward, 2006]. Hence, boosting with 
reduced-antigen-content diphtheria and tetanus toxoids and acellular pertussis vaccine 
(dTpa) instead of diphtheria and tetanus toxoids (DdT) may prolong the immunity against 
pertussis infection.
Section 1.2.2: Rationale for the study design
The ≥ 65 years (elderly population) has been included in the study to ensure cocooning 
effect. Pertussis outbreaks have occurred in a number of European and non-European 
countries. Whilst tThis resurgence is observed across the age range with a notable 
increase in cases now being detected in adolescents and older age groups. It is also now 
recognized that immunity following either natural pertussis infection or vaccination is not 
long lived, and the acellular pertussis vaccines that have been widely used since the 
 
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1990s may be more prone to such waning. Consequently, adults and adolescents with 
pertussis are a potential source of infection for infants too young to have been fully 
vaccinated. Many countries recommend 'cocoon ' strategy, i.e. vaccination of family 
members and close contact of newborn (i.e. grandparents usually above 65 years old), in 
order to protect infants from acquiring pertussis. The ≥65 years (elderly population) 
have therefore been included in the study.
Section 1.3: Benefit: Risk Assessment
Please refer to the Prescribing information (PI) current Investigator Brochure (IB) for 
the summary of the potential risks and benefits of Boostrix.
Section 3: Study design and overview

Duration of the study:

Epoch 001: Primary Epoch starting at Visit 1 (Day 1) and ending at Visit 2 
(Day 31)
Section 4.2: Inclusion criteria for enrolment

Children four to seven years of age who have received diphtheria, tetanus and 
pertussis vaccination prior to study enrolment as per local recommendations.

Children 4-7 years of age with documented previous diphtheria, tetanus and 
pertussis vaccination (primary series and first booster) as per local 
recommendation prior to study enrolment, but should have not received any 
further diphtheria-tetanus containing booster planned at 6-7 years of age as per 
local recommendations or any other diphtheria, tetanus and pertussis containing 
vaccine.
OR

Subjects eight years of age and older who have received can report previous
diphtheria, tetanus and pertussis vaccination – documented or to the best of 
their/subjects’ parent(s)/subjects’ adoptive parent(s) knowledge – and did not receive 
an additional diphtheria, tetanus or pertussis vaccination within five years prior to 
enrolment in the study will be enrolled.
Section 4.3: Exclusion criteria for enrolment

Planned administration/administration of a vaccine not foreseen by the study 
protocol within the period starting 30 days before and ending 30 days after the dose 
of vaccine with the exception of inactivated influenza vaccine which can be given at 
any time during the study conduct as per the Summary of Product Characteristics 
(SmPC) or PI and according to the local governmental recommendations.

Acute or chronic, clinically significant uncontrolled pulmonary, cardiovascular, 
hepatic or renal functional abnormality, as determined by physical examination, 
and/or laboratory screening tests.
 
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Section 5.3: Method of blinding
This is an open-label study as all the subjects will receive a booster dose of Boostrix.
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.
Table 5: Footnote
Physical examination after the vaccination visit, will be performed only if the 
subject/subject’s parent(s)/adoptive parent(s) indicates during questioning that there 
might be some underlying pathology(ies) or if deemed necessary by the Investigator or 
delegate.
Section 5.6.4: Medical history and vaccination history
Obtain the subject’s medical history by interview and/or review of the subject’s medical 
records and record both any current and/or past pre-existing conditions or signs and/or 
symptoms in a subject prior to the study vaccination in the eCRF.
Review the subject’s* childhood diphtheria, tetanus and pertussis vaccinations to collect 
information on the vaccine name, route of administration, dose number and date of 
administration. This information should be recorded in the eCRF.
*For subjects eight years and older, with no documented previous diphtheria, tetanus 
and pertussis vaccinations, details are to be recorded to the best of their/subjects’ 
parent(s)/subjects’ adoptive parent(s) knowledge.
Section 5.6.12: Distribution of dairy cards and recording of AEs, SAEs and 
pregnancies

Refer to Section 8.3 for procedures for the investigator or delegate to record AEs, 
SAEs, and pregnancies. Refer to Section 8.4 for guidelines and how to report SAE, 
and pregnancy reports to GSK Biologicals.

The subjects/subjects’ parent(s)/adoptive parent (s) will be instructed to contact the 
investigator or delegate immediately should they/the subjects manifest any signs or 
symptoms they perceive as serious. 

At Visit 1, diary cards will be provided to the subject/subject’s parent(s)/adoptive 
parent(s). The subject/subject’s parent(s)/adoptive parent(s) will record body 
(preferably axillary) temperature and any solicited local/general AEs (i.e. on the day 
of vaccination and during the next three days) or any unsolicited AEs (i.e. on the day 
of vaccination and during the next 30 days) occurring after vaccination. The 
subject/subject’s parent(s)/adoptive parent(s) will be instructed to return the 
completed diary card to the investigator or delegate at the next study visit.

Note: Diary cards can be filled in by a minor subject under the supervision of 
the subject’s parent(s)/adoptive parent(s) provided that the minor has the 
competency to assess and report the information to be provided in the diary card. 
 
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The ultimate accountability for the completion of the diary cards remains with 
the subject’s parent(s)/adoptive parent(s). The investigator or delegate should 
discuss this accountability with the subject’s parent(s)/adoptive parent(s).

After vaccination, if the subjects or the subject’s parents/adoptive parents observe 
any large injection site reaction (defined as a swelling with a diameter of >50 mm for 
subjects <6 years of age and >100 mm for subjects 6 years of age for subjects <6 
years of age defined as a swelling with a diameter of >50 mm and for subjects 6 
years of age swelling with a diameter of >100 mm, noticeable diffuse swelling or 
noticeable increase in limb circumference) during the 4-day follow-up (Day 1-4) 
period, they will be asked to contact study personnel and to visit the investigator's 
office for evaluation as soon as possible. The investigator or delegate will record 
detailed information describing the AE on a specific large injection site reaction 
screen in the eCRF.
Throughout the document for the procedures for the investigator, “or delegate” was 
added as appropriately.
Section 5.6.13: Return of dairy card and dairy card transcription

Any unreturned diary cards will be sought from the subject/subject’s 
parent(s)/adoptive parent(s) through telephone call(s) or any other convenient 
procedure. The investigator or delegate will transcribe the collected information into 
the eCRF in English.
Section 5.6.14: Recording of AEs, SAEs and pregnancies

Refer to Section 8.3 for procedures for the investigator or delegate to record AEs, 
SAEs, pregnancies. Refer to Section 8.4 for guidelines and how to report SAE and 
pregnancy reports to GSK Biologicals.

The subject/subjects’ parent(s)/adoptive parent(s) will be instructed to contact the 
investigator immediately should they/the subjects manifest any signs or symptoms 
they perceive as serious.
Section 5.7.3: Laboratory assays
All serology will be determined in GSK Biologicals’ laboratories or in a laboratory 
designated by GSK using standardized and validated procedures with adequate 
controls.
Refer to Table 8 for the assays used in antibody determination.
 
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Table 8
Humoral Immunity (Antibody determination)
System
Component
Method
Kit / Manufacturer
Unit
Cut-
off†
Laboratory*
Serum
Corynebacterium 
diphtheriae.Diphtheria 
Toxoid Ab.IgG 
ELI
NA 
IU/ml
0.057.1 
GSK Biologicals
or designated 
laboratory
Serum
Corynebacterium 
diphtheriae.Diphtheria 
Toxoid Ab 
NEU assay 
on Vero 
cells**
NA 
IU/ml 
0.004
GSK Biologicals
or designated 
laboratory
Serum
Clostridium 
tetani.Tetanus Toxoid 
Ab.IgG 
ELI 
NA 
IU/ml 
0.043.1 
GSK Biologicals 
or designated 
laboratory 
Serum
Bordetella 
pertussis.Pertactin 
Ab.IgG 
ELI 
NA 
IU/ml
EU/ml$
2.6935 
GSK Biologicals 
or designated 
laboratory
Serum
Bordetella 
pertussis.Filamentous 
Hemaglutinin Ab.IgG 
ELI 
NA 
IU/ml
EU/ml$
2.0465 
GSK Biologicals
or designated 
laboratory
Serum
Bordetella 
pertussis.Pertussis 
Toxin Ab.IgG 
ELI 
NA 
IU/ml
EU/ml$
2.1875 
GSK Biologicals
or designated 
laboratory
ELI: ELISA
NEU: Neutralisation assay
NA: Not Applicable
IU/ml: International Units per millilitre
The assay cut-off for diphtheria, tetanus and pertussis may be subject to change.
EU/ml: ELISA units per millilitre
$The unit for the pertussis assays may be subject to change.
†Assays for diphtheria, tetanus and pertussis were re-developed and re-validated as per most recent CBER 
recommendations (Guidance for Industry “Bioanalytical Method Validation” from September 2013). The new 
assay cut-off’s that apply are listed in the table.
*GSK Biologicals laboratory refers to the Clinical Laboratory Sciences (CLS) in Rixensart, Belgium and Wavre, 
Belgium.
**Test on Vero-cells will be performed on pre- and post-vaccination samples with concentrations <0.1 IU/ml by ELISA.
Section 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 newly validated assay cut-off for anti-diphtheria is currently set at 0.1 IU/ml 
(ELISA)0.057 IU/ml and for anti-tetanus at 0.043 IU/ml. For both serology a 
threshold of 0.1 IU/ml which provides a conservative estimate of the percentage of 
subjects deemed to be protected [Camargo, 1984; Melville-Smith, 1983].

The cut-off of the Vero-cell neutralisation assay (performed for pre- and post-
vaccination serum samples when ELISA anti-diphtheria antibody concentrations are 
<0.1 IU/ml) is 0.004 IU/ml. Antibody concentrations 0.01 IU/ml are considered as 
protective [Camargo, 1984]. The ELISA test will define the seroprotection status for 
the primary endpoint.
 
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
No serological correlate of protection is defined for the immune response to 
pertussis antigens. Antibodies against the pertussis components PT, FHA and PRN 
will be measured by ELISA technique. The current cut-off for all three pertussis 
antibody assay is 5 ELISA Units per ml (EL.U/ml). The newly validated assay cut-
off for anti-PT is 2.693 IU/ml, for anti-FHA is 2.046 IU/ml and for anti-PRN is 
2.187 IU/ml. Subjects with antibody concentration below this cut-off will be 
considered seronegative. [Granstrom, 1987; Karpinsky, 1987].
Non-responders are defined as:

Antibody concentrations <0.01 IU/ml post-booster for diphtheria antigen by Vero-cell 
neutralisation assay and,

Antibody concentrations <0.1 IU/ml post-booster for tetanus antigen by ELISA assay
Section 6.3: Dosage and administration of study vaccine
The vaccine will be administered as an IM injection into the deltoid muscle of the non-
dominant arm, i.e. in the left arm if the subject is right-handed or in the right arm if the 
subject is left-handed. In case it is not possible for a valid reason to inject in the 
non-dominant arm, an injection in the dominant arm may be performed. Boostrix
should in no circumstances be administered intravascularly.
Section 6.5: Contraindications to vaccination
Since this is a single dose study, contraindications to vaccination are included in the 
exclusion criteria. Refer to Section 4.3.
The following events constitute contraindications to further administration of Boostrix. 
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 8.5).
The following events constitute contraindications to administration of Boostrix at that 
point in time; if any of these events occur at the time scheduled for vaccination, the 
subject may be vaccinated at a later date, within the time window specified in the 
protocol (see Section 6.7.1), or the subject may be withdrawn at the discretion of the 
investigator (see Section 6.7.2).
Section 6.6: Warnings and precautions
Refer to the package insert of Boostrix. As with all injectable vaccines, appropriate 
medical treatment should always be readily available in case of anaphylactic reactions 
following the administration of the vaccine. For this reason, the vaccinee should 
remain under medical supervision for 30 minutes after vaccination.
Boostrix vaccination should be administered with caution to subjects with 
thrombocytopenia or a bleeding disorder since bleeding may occur following an 
intramuscular (IM) administration to these subjects.
Boostrix vaccination should under no circumstances be administered intravenously.
 
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Section 6.7.2: Concomitant medications/products/vaccines that may lead to the 
elimination of a subject from per protocol 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 program, the time period described above can be reduced if necessary 
for that vaccine provided it is licensed and used according to its Summary of Product 
Characteristics (SmPC) or PI and according to the local governmental 
recommendations and provided a written approval of the Sponsor is obtained.
Section 8.1.3.1: Solicited local (injection-site) adverse events
Note: If the subjects or the subject’s parent(s)/adoptive parent(s) observe any large 
injection site reaction (defined as a swelling with a diameter of > 50 mm for subjects <6 
years of age and >100 mm for subjects 6 years of age, for subjects <6 years of age 
defined as a swelling with a diameter of > 50 mm and for subjects 6 years of age 
swelling with a diameter of >100 mm, noticeable diffuse swelling or noticeable increase 
in limb circumference) during the 4-day (Day 1–4) follow-up period after vaccination, 
they will be asked to contact the study personnel and to visit the investigator’s office for 
evaluation as soon as possible. The investigator or delegate will record detailed 
information describing the AE on a specific large injection site reaction sheet in the 
eCRF.
Section 8.2.1: Pregnancy
Furthermore, any SAE occurring as a result of a post-study pregnancy and considered by 
the investigator to be reasonably related to the study vaccine will be reported to GSK 
Biologicals as described in Section 8.4.3. While the investigator or delegate is not 
obligated to actively seek this information from former study participants, he/she may 
learn of a pregnancy through spontaneous reporting.
Section 8.3.1: Time period for detecting and recording adverse events, serious 
adverse events and pregnancies
All AEs starting within three 30 days following administration of the dose of study 
vaccine (Day 1-4 Day 1-31) must be recorded onto the appropriate section of the eCRF, 
irrespective of intensity or whether or not they are considered vaccination-related.
Section 8.3.2: Post-Study adverse events and serious adverse events
A post-study AE/SAE is defined as any event that occurs outside of the AE/SAE 
reporting period defined in Table 14. Investigator(s) or delegate(s) is/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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Section 8.3.3.1: Active questioning to detect adverse events and serious adverse 
events
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 or delegate will then record all relevant information 
regarding an AE/SAE in the eCRF. The investigator or delegate 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.
Section 8.3.3.2.1: Assessment of intensity
The maximum intensity of fever 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
0
=
<38C
1
=
38.0C to 39.0C
2
=
>39.0C to 40.0C
3
=
>40.0C
Section 8.3.3.2.2: Assessment of causality
Alternative plausible causes, such as natural history of the underlying diseases, 
concomitant therapy, other risk factors, and the temporal relationship of the event to the 
study vaccine will be considered and investigated. The investigator will also consult the 
IB and/or SmPC and/or PI for marketed products to determine his/her assessment.
Section 8.4.3: Completion and transmission of SAE reports to GSK Biologicals
Once an investigator becomes aware that a SAE has occurred in a study subject, the 
investigator (or designate) must complete the information in the electronic Expedited 
Adverse Events Report WITHIN 24 HOURS. The report will always be completed as 
thoroughly as possible with all available details of the event. Even if the investigator or 
delegate does not have all information regarding a SAE, the report should still be 
completed within 24 hours. Once additional relevant information is received, the report 
should be updated WITHIN 24 HOURS.
Section 9.2.1: Subject withdrawal from the study
Information relative to the withdrawal will be documented in the eCRF. The investigator 
or delegate will document whether the decision to withdraw a subject from the study was 
made by the subject himself/herself, by the subject’s parent(s)/adoptive parent(s), or by 
the investigator, as well as which of the following possible reasons was responsible for 
withdrawal:
 
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*In case a subject is withdrawn from the study because he/she/the subject’s 
parent(s)/adoptive parent(s) has withdrawn consent, the investigator or delegate will 
document the reason for withdrawal of consent, if specified by the subject/subject’s 
parent(s)/adoptive parent(s), in the eCRF.
Section 10.5: Derived and transformation data

A seroprotected subject is a subject whose antibody concentration is greater than or 
equal to the level defining clinical protection. The following seroprotection 
thresholds are applicable:

Anti-Ddiphtheria antibody concentrations assay cut-off 0.1 IU/ml.

Anti-Ttetanus antibody concentrations assay cut-off 0.1 IU/ml.

Booster response to Diphtheria and Tetanus antigens is defined as:

for initially seronegative subjects with pre-vaccination antibody concentration
<0.1 IU/ml (i.e. below the seroprotection cut-off) (pre-vaccination 
concentration below assay cut-off), antibody concentrations at least four times 
the assay cut-off ≥0.4 IU/ml, one month after vaccination, and

for initially seropositive subjects with pre-vaccination antibody concentration 
≥0.1 IU/ml (i.e. equal or above the seroprotection cut-off), an increase in 
antibody concentrations of at least four times the pre-vaccination concentration, 
one month after vaccination.

Booster response to PT, FHA and PRN antigens is defined as:

for subjects with pre-vaccination antibody concentration below (i.e. <) the assay 
cut-off, post-vaccination concentration four times the assay cut-off,

for subjects with pre-vaccination antibody concentration between the assay cut-
off and below (i.e.) four times the assay cut-off, post-vaccination antibody 
concentration four times the pre-vaccination antibody concentration, and

for subjects with pre-vaccination antibody concentration four times the assay 
cut-off, post-vaccination antibody concentration two times the pre-vaccination 
antibody concentration.
Section 10.7: Analysis of immunogenicity

Booster response rate one month post-vaccination will be calculated with exact 
95% CIs for diphtheria, tetanus and pertussis antigens.
Section 10.8: Analysis of safety
The overall incidence percentage of subjects with at least one local symptom (solicited 
or unsolicited), with at least one general symptom (solicited or unsolicited) and with any 
symptom (solicited or unsolicited) during the 4-day (Day 1-4) follow-up period after 
booster vaccination will be tabulated with exact 95% CI after booster vaccination.
Any large injection site reaction (defined as a swelling with a diameter of >50 mm for 
subjects <6 years of age and >100 mm for subjects 6 years of age for subjects <6 years 
 
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of age defined as a swelling with a diameter of > 50 mm and for subjects 6 years of 
age swelling with a diameter of >100 mm, noticeable diffuse swelling or noticeable 
increase in limb circumference) onset during the 4-day (Day 1-4) follow-up period after 
vaccination will be described in detail.
Section 13: Reference
Granström M, Thoren M, Blennow M, et al. Acellular Pertussis Vaccine in Adults: 
Adverse Reactions and Immune Response. Eur J Clin Microbiol 1987;6(1):18-21.
Karpinsky KF, Hayward S and Tryphonas H. Statistical considerations in the quantitation 
of serum immunoglobulin levels using the enzyme-linked immunosorbent assay 
(ELISA). J Immunol Methods, 1987; 103: 189-94.
Appendix A: Clinical Laboratories
Table 26
Outsourced Laboratories
Laboratory
Address
NÉOMED-LABS Inc (formerly GSK 
GVCL Laval)
525, Blvd Cartier Ouest Laval
Quebec
Canada CH7V 3S8
Q² Solutions 
Unit B1, Parkway West Industrial Estate Cranford 
Lane – Heston,
Middlesex TW5 9Q4
UK
Throughout the document 100.4F was removed since the scale Fahrenheit is not 
used for measuring temperature in Russia.
 
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GlaxoSmithKline Biologicals SA
Vaccines R &D
Protocol Amendment 3
eTrack study number 
and Abbreviated Title
201532 [DTPA (BOOSTRIX)-050]
IND number
BB-IND-8461
EudraCT number
2015-003405-42
Amendment number:
Amendment 3
Amendment date:
31 October 2017
Co-ordinating author:
, Scientific Writer
Rationale/background for changes:
This protocol amendment was developed in order to accommodate older adults 
(approximately 58 years old and older) who were born before national 
recommendations in Russia for infant DTP vaccination. The protocol amendment will 
also clarify inconsistencies present in the Protocol Amendment 2, between the English 
version and the Russian version. Following which, adjustments to the text were made 
in the inclusion criteria to clarify the enrolment of subjects for age group eight years 
and above.
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections:
Protocol Amendment 3 Investigator Agreement
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
parent(s)/adoptive parent(s).
Section 4.2: Inclusion criteria for enrolment
Subjects eight years of age and older who can report previous diphtheria, tetanus and 
with or without pertussis vaccination – documented or to the best of their/subjects’ 
parent(s)/subjects’ adoptive parent(s) knowledge – and did not receive an additional 
diphtheria, tetanus with or without pertussis vaccination within five years prior to 
enrolment in the study will be enrolled.
Section 5.1: Regulatory and ethical considerations, including the informed consent 
process
In accordance with the ICH Harmonised Tripartite Guidelines for Good Clinical Practice, 
those subjects who can only be enrolled in the study with the consent of the subject’s 
parent(s)/adoptive parent(s) legally acceptable representative (e.g. minors), should be 
informed about the study to the extent compatible with the subject’s understanding and, if 
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capable, the subject should sign and personally date a written informed assent form 
(IAF). It is required that the assent be signed by each subject, if capable, in addition to the 
informed consent that is to be signed by his/her legal representative. It should be assessed 
whether an assent is required depending of the age of the study population and the local 
requirements.
Section 5.6.4: Medical history and vaccination history
Review the subject’s* childhood diphtheria, tetanus, with or without and pertussis,
vaccinations to collect information on the vaccine name, route of administration, dose 
number and date of administration. This information should be recorded in the eCRF.
*For subjects eight years and older, with no documented previous diphtheria, tetanus, 
with or without and pertussis, vaccinations, details are to be recorded to the best of 
their/subjects’ parent(s)/subjects’ adoptive parent(s) knowledge.
Section 5.7.3: Laboratory assays (Table 8: footnote)
ELISA’s Assays for diphtheria, tetanus and pertussis were re-developed and re-validated as per most recent CBER 
recommendations (Guidance for Industry “Bioanalytical Method Validation” from September 2013). The new assay cut-
off’s that apply are listed in the table. The neutralisation assay for Diphtheria is still under re-development and 
the assay cut-off might be subject to change during the course of the study. In this case, it will be documented 
in the clinical study report.
Section 5.7.5: Immunological correlates of protection
The cut-off of the Vero-cell neutralisation assay (performed for pre- and post-vaccination
serum samples when ELISA anti-diphtheria antibody concentrations are <0.1 IU/ml) is 
0.004 IU/ml. Antibody concentrations 0.01 IU/ml are considered as protective [WHO, 
1994 Camargo, 1984]. Both, the ELISA test (antibody concentrations ≥0.1 IU/ml) and 
Vero-cell test (antibody concentrations ≥0.01 IU/ml) will define the seroprotection 
status for the primary endpoint.
Section 10.5: Derived and transformed data
Anti-diphtheria antibody concentrations 0.1 IU/ml for ELISA assay and ≥0.01 IU/ml 
for Vero-cell assay.
Section 13: References
Efstratiou A. & Maple P.A.C., 1994. Diphtheria. Laboratory diagnosis of Diphtheria. 
The expended programme on immunization in the European region of WHO. WHO 
ICP/EPI 038 (C). World Health Organization, Geneva, Switzerland.
 
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