Clinical trial NCT02377349
Conditions: Diphtheria-Tetanus-acellular Pertussis Vaccines
Sponsor: GlaxoSmithKline
Start date: 2015-10-14; Completion date: 2017-10-24
Enrollment: 688 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to assess the immunogenicity and safety of Boostrix™ when compared to a placebo given during 27-36 weeks of gestation in healthy women aged 18-45 years. Infants born to mothers enrolled in this study will be followed-up in two separate clinical studies: 201330 \[DTPA (BOOSTRIX)-048 PRI\] and 201334 \[DTPA (BOOSTRIX)-049 BST: 048\].

Detailed description:
The protocol was amended to include Spain in the study. The reasons for the Spain-specific amendment are listed below:

* Based on the feedback from the Spanish Ethics Committee, the evaluation related to the acceptance of cocooning was added in the protocol.
* The objectives and endpoints to include cocooning were added in the protocol.
* The eligibility criteria for participation of household contacts were defined in the protocol.
* The study procedures for household contacts were included.

Arms: arm 1: This group will consist of pregnant women who will receive a single dose of Boostrix™ at 27-36 weeks (i.e. completed 27 weeks until 36 weeks) of gestation (Visit 1) and will receive a dose of the placebo post-delivery (within 72 hours). arm 2: This group will consist of pregnant women who will receive a single dose of placebo at 27-36 weeks (i.e. completed 27 weeks until 36 weeks) of gestation (Visit 1) and will receive a dose of Boostrix™ post-delivery (within 72 hours).
Interventions: intervention 1: Boostrix™ intervention 2: Saline placebo
Intervention descriptions: intervention 1: One dose administered intramuscularly in the deltoid muscle of the non-dominant arm. intervention 2: One dose administered intramuscularly in the deltoid muscle of the non-dominant arm.

Protocol documents:
Prot_000.pdf: 
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Clinical Study Protocol
Sponsor:
GlaxoSmithKline Biologicals
Rue de l'Institut 89
1330 Rixensart, Belgium.
Primary Study vaccine and 
number
GlaxoSmithKline (GSK) Biologicals’ combined 
reduced-antigen-content diphtheria, tetanus and 
acellular pertussis (dTpa) vaccine (Boostrix™) 
(263855).
Other Study vaccine
Placebo
eTrack study number and 
Abbreviated Title
116945 [DTPA (BOOSTRIX)-047]
EudraCT number
2014-001119-38
Date of protocol
Final Version 01: 28 January 2015
Date of protocol amendment
Amendment 1 Final: 29 May 2015
Amendment 2 Final: 15 July 2015
Title
Immunogenicity and safety study of GSK Biologicals’ 
dTpa vaccine, Boostrix™ (263855) in pregnant 
women.
Detailed Title
A Phase IV, observer-blind, randomised, cross-over, 
placebo-controlled, multicentre study to assess the 
immunogenicity and safety of a single dose of 
Boostrix™ in pregnant women.
Co-ordinating author
, Scientific Writer
 
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eTrack study number and 
Abbreviated Title
116945 [DTPA (BOOSTRIX)-047]
EudraCT number
2014-001119-38
Date of protocol
Final Version 01: 28 January 2015
Date of protocol amendment
Amendment 1 Final: 29 May 2015
Amendment 2 Final: 15 July 2015
Title
Immunogenicity and safety study of GSK Biologicals’ 
dTpa vaccine, Boostrix™ (263855) in pregnant 
women.
Detailed Title
A Phase IV, observer-blind, randomised, cross-over, 
placebo-controlled, multicentre study to assess the 
immunogenicity and safety of a single dose of 
Boostrix™ in pregnant women.
Contributing authors

, Project-Level CRDL

, Clinical Research and 
Development Lead (CRDL)

, Medical Director, 
Vaccines, Spain

, Medical Affairs 
Manager, Vaccines, Spain

, Project Statistician

 and 
, 
Study Delivery Leads

, GVCL Project Manager

and 
, Global
Clinical Regulatory Affairs Representatives

 and 
, Clinical 
Safety Representatives

, Global Patents Representative

, Study Data Manager

, Senior Manager, 
Biometrics

, Vaccines Supply Coordinator

, Director, Global Medical Affairs

, Study Delivery Manager

, Local Delivery Lead (LDL), 
Australia

, LDL, Canada

, LDL, Spain
GSK Biologicals’ Protocol DS v 14.1.1
Copyright 2015 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised copying or 
use of this information is prohibited.
 
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Protocol Amendment 2 Sponsor Signatory Approval
eTrack study number and 
Abbreviated Title
116945 [DTPA (BOOSTRIX)-047]
EudraCT number
2014-001119-38
Date of protocol amendment
Amendment 2 Final: 15 July 2015
Detailed Title 
A Phase IV, observer-blind, randomised, cross-over, 
placebo-controlled, multicentre study to assess the 
immunogenicity and safety of a single dose of 
Boostrix™ in pregnant women.
Sponsor signatory
Htay Htay Han, Project Level CRDL, Rotavirus and 
Tdap Maternal vaccination, GlaxoSmithKline 
Biologicals.
Signature
Date
 
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Protocol Amendment 2 Rationale
Amendment number:
Amendment 2
Rationale/background for changes:
The protocol is being amended to include Spain in the study. The reasons for this 
Spain-specific amendment are listed below:

Based on the feedback from the Spanish Ethics Committee, the evaluation related 
to the acceptance of cocooning has been added in the protocol.

The objectives and endpoints to include cocooning are added in the protocol.

The eligibility criteria for participation of household contacts are defined in the 
protocol.

The study procedures for household contacts are included.

The list of contributing authors has been updated.
 
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Protocol Amendment 2 Investigator Agreement
I agree:

To conduct the study in compliance with this protocol, any future protocol 
amendments or protocol administrative changes, with the terms of the clinical trial 
agreement and with any other study conduct procedures and/or study conduct 
documents provided by GlaxoSmithKline (GSK) Biologicals.

To assume responsibility for the proper conduct of the study at this site.

That I am aware of, and will comply with, ‘Good Clinical Practice’ (GCP) and all 
applicable regulatory requirements. 

To ensure that all persons assisting me with the study are adequately informed about 
the GSK Biologicals’ investigational vaccine(s) and other study-related duties and 
functions as described in the protocol.

To acquire the reference ranges for laboratory tests performed locally and, if required 
by local regulations, obtain the laboratory’s current certification or Quality 
Assurance procedure manual.

To ensure that no clinical samples (including serum samples) are retained onsite or 
elsewhere without the approval of GSK Biologicals and the express written informed 
consent of the subject and/or the subject’s legally acceptable representative. 

To perform no other biological assays on the clinical samples except those described 
in the protocol or its amendment(s). 

To co-operate with a representative of GSK Biologicals in the monitoring process of 
the study and in resolution of queries about the data.

That I have been informed that certain regulatory authorities require the sponsor to 
obtain and supply, as necessary, details about the investigator’s ownership interest in 
the sponsor or the investigational vaccine(s), 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
116945 [DTPA (BOOSTRIX)-047]
EudraCT number
2014-001119-38
Date of protocol amendment
Amendment 2 Final: 15 July 2015
Detailed Title
A Phase IV, observer-blind, randomised, cross-over, 
placebo-controlled, multicentre study to assess the 
immunogenicity and safety of a single dose of 
Boostrix™ in pregnant women.
Investigator name
Signature
Date
 
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Sponsor Information
Sponsor
GlaxoSmithKline Biologicals
Rue de l'Institut 89
1330 Rixensart, Belgium
Sponsor Medical Expert for the Study
Refer to the local study contact information document.
Sponsor Study Monitor
Refer to the local study contact information document.
Sponsor Study Contact for Reporting of a Serious Adverse Event
GSK Biologicals Central Back-up Study Contact for Reporting SAEs: refer to protocol 
Section 8.3.2
GSK Biologicals’ Central Safety Physician On-Call Contact information for 
Emergency Unblinding.
GSK Biologicals Central Safety Physician and Back-up Phone contact: refer to 
protocol Section 8.7. 
 
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SYNOPSIS
Detailed Title
A Phase IV, observer-blind, randomised, cross-over, placebo-
controlled, multicentre study to assess the immunogenicity 
and safety of a single dose of Boostrix™ in pregnant women.
Indication
Booster immunisation against diphtheria, tetanus and pertussis 
diseases. The study population for this study will include 
pregnant women.
Rationale for the 
study and study 
design (Amended: 15
July 2015)

Rationale for the study
On June 22, 2011, the Advisory Committee on Immunization 
Practices (ACIP) made recommendations for use of dTap 
vaccine in unvaccinated pregnant women and updated 
recommendations on cocooning and special situations [CDC, 
2011]. In 2013, the ACIP recommended the combined 
reduced antigen content diphtheria-tetanus-acellular pertussis 
vaccine (dTap) vaccine for pregnant women during every 
pregnancy irrespective of previous history of dTap 
vaccination [CDC, 2011]. Following the initial 
recommendation in the US by ACIP, temporary dTap 
immunisation programmes for pregnant women have been 
implemented in 18 countries including UK, New Zealand, 
Israel, Mexico, Brazil, Colombia, Uruguay, Panama, Costa 
Rica, Argentina and some provinces in Australia and Spain
[Joint Committee on Vaccination and Immunization (JCVI), 
2012; Pharmaceutical Management Agency (PHARMAC), 
2012; TAG, 2013]. Since 2013, vaccination during pregnancy 
is also recommended in Belgium between the 24th and 32nd
week of pregnancy [CSS, 2013]. The National Advisory 
Committee on Immunization in Canada recommends that all 
pregnant women following 26 weeks of pregnancy who have 
not received a dose of pertussis-containing vaccine in 
adulthood should be encouraged to receive dTap vaccination. 
In special circumstances, such as an outbreak situation, all 
pregnant women who are 26 weeks gestation or greater may 
be offered dTap vaccination irrespective of their immunisation 
history. [Warshawsky, 2014; Public Health Agency of 
Canada, 2014].
The important impact of maternal immunisation in decreasing 
the incidence of infant pertussis has been demonstrated 
recently by the Public Health England (PHE) pertussis 
maternal immunisation program in an analysis of data from 
the Clinical Practice Research Datalink (a primary care 
database of 520 English general practices). After a maternal 
pertussis vaccination program was introduced in October 2012 
in response to a pertussis outbreak, the number of pertussis 
 
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cases in infants younger than 3 months of age and the number 
of hospitalizations decreased significantly [Amirthalingam, 
2014]. A study conducted to assess the safety of pertussis 
vaccination during pregnancy in UK using the Clinical 
Practice Research Datalink showed no evidence of an 
increased risk of stillbirth or any adverse events related to 
pregnancy [Donegan, 2014]. Another randomized, double-
blind, placebo controlled trial conducted using Adacel (dTap, 
Sanofi Pasteur) in 33 pregnant women aged 18 to 45 years at 
30 to 32 weeks gestation did not find increased risk of adverse 
events among women or their infants [Munoz, 2014].
In light of these recommendations and observations, further 
clinical evaluation of the safety and immunogenicity of 
reduced antigen-content acellular pertussis vaccines in 
pregnant women is scientifically warranted. 
GSK Biologicals’ reduced-antigen-content dTpa vaccine, 
Boostrix, first licensed for use in Germany in 1999, is 
indicated for booster vaccination for individuals from the age 
of four years onwards. The immunogenicity, reactogenicity 
and safety of this vaccine have been established in a number 
of clinical trials in the different populations for which it is 
indicated [Minh, 1999; Turnbull, 2001; Van Damme, 2004; 
Meyer, 2008]. 
Review of reports to Vaccine Adverse Event Reporting 
System in pregnant women who received a dose of dTap 
vaccine did not identify any concerning patterns in maternal, 
infant, or foetal outcomes [Zheteyeva, 2012]. In addition, a 
clinical study concluded that administering dTap during 
pregnancy increased antibody concentrations against 
diphtheria and pertussis antigens and maternal immunisation 
with dTap may prevent neonatal pertussis infection [Gall, 
2011]. GSK has performed reproductive and developmental 
toxicity studies in female rats and rabbits. The developmental 
toxicity study to assess embryo-foetal and pre- and postnatal 
development in female rats at a dose approximately 40 times 
the human dose (on a mL/kg basis) revealed no evidence of 
harm to the foetus due to Boostrix. The study conducted on 
rabbits to evaluate the effects of Boostrix on female fertility, 
implantation and embryo-foetal development did not show 
adverse effects on embryo-foetal development or survival.
Considering the multiple countries which have recently 
instituted recommendations regarding the use of dTap vaccine 
in pregnant women along with the limited safety data of 
Boostrix in pregnant women currently available, an 
 
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investigation of safety and immunogenicity of Boostrix in a 
clinical trial is warranted. 

Rationale for the study design
In order to support the use of Boostrix in pregnant women, 
this phase IV, observer-blind, placebo-controlled and 
randomised study will be conducted to assess the 
immunogenicity and safety of the vaccine given during 27-36 
weeks of gestation in healthy women aged 18-45 years. This 
period of pregnancy is considered to be outside the critical 
susceptibility window for organogenesis. Transfer of maternal 
antibodies to the infants is also seen to be optimal in this 
trimester.
The subjects in this study will be randomised to two groups: 

dTpa Group: This group will consist of pregnant women 
who will receive a single dose of Boostrix at 27-36 weeks 
(i.e. completed 27 weeks until 36 weeks) of gestation 
(Visit 1).

Control Group: This group will consist of pregnant 
women who will receive a single dose of placebo (saline 
water) at 27-36 weeks (i.e. completed 27 weeks until 36 
weeks) of gestation (Visit 1).
The study will adopt a cross-over study design. Subjects in the 
dTpa group who receive a single dose of Boostrix at 27-36 
weeks of gestation will receive a dose of the placebo post-
delivery (within 72 hours); while subjects in the Control group 
who receive placebo at 27-36 weeks of gestation will receive 
a dose of Boostrix post-delivery (within 72 hours).
Infants born to mothers enrolled in this study will be 
followed-up in two separate clinical studies: DTPA 
(BOOSTRIX)-048 PRI and DTPA (BOOSTRIX)-049 BST: 
048. Infants will be given the primary vaccination course of 
Infanrix hexa in DTPA (BOOSTRIX)-048 PRI study and a 
booster dose in the second year of life in DTPA 
(BOOSTRIX)-049 study in order to generate safety and 
immunogenicity data. The impact of maternal Boostrix
vaccination on immune response of infants to primary and 
booster DTPa vaccination will also be evaluated in these 
studies.
Since pregnant women are a vulnerable population and the 
experience of clinical trials in this population is limited, high 
quality of obstetric, perinatal and infant care will be a 
requirement for all trial sites, ensuring optimal data collection 
 
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as well as access to emergency facilities, if required. In 
addition, sites that can guarantee high compliance with 
long-term follow-up of the children will be selected.

Rationale for the use of placebo
Since this study will be conducted in countries where dTap 
vaccination for pregnant women is not yet widely 
implemented and in the absence of an established active 
control for pertussis vaccination in this population, a placebo 
will be used. Based on the cross-over study design, pregnant 
women who receive placebo in the Control Group will receive 
a dose of Boostrix post-delivery. Vaccinating the mothers with 
dTpa vaccine post-delivery may provide some degree of 
protection against pertussis due to the cocooning effect [CDC, 
2013]. This is also in line with the ACIP recommendations 
which state that women should be administered a dose of 
dTpa vaccine immediately postpartum in case dTpa vaccine 
was not administered during pregnancy.
In addition, all the eligible household contacts of the infants 
born to pregnant women enrolled in Spain will be eligible to 
receive a single dose of Boostrix as part of an assessment of 
cocooning.
Objectives
(Amended: 15 July
2015)
Primary

To demonstrate that the maternally transferred antibodies 
against pertussis in the dTpa Group is superior to that in 
the Control Group in terms of geometric mean 
concentrations (GMCs) for the pertussis antibodies, in the 
cord blood sample.
Criterion:

The lower limit (LL) of the 95% confidence interval 
(CI) of the GMC ratio [dTpa Group divided by 
Control Group] for anti-pertussis toxoid (anti-PT), 
anti-filamentous haemagglutinin (anti-FHA) and 
anti-pertactin (anti-PRN) antibodies is ≥ 1.5.
Secondary

To assess the safety of a single dose of Boostrix in 
pregnant women, administered during 27-36 weeks of 
gestation, in terms of the outcomes of pregnancy and 
listed pregnancy-related adverse events of 
interest/neonate-related events of interest up to study end
(Visit 4).

To assess the immunogenicity of a single dose of 
 
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Boostrix administered during pregnancy in terms of 
seropositivity status for antibodies against pertussis, in 
the cord blood sample.

To assess the immunogenicity of a single dose of 
Boostrix administered during pregnancy in terms of 
seroprotection/seropositivity status, vaccine response and 
GMCs for antibodies against diphtheria, tetanus and 
pertussis, one month post-vaccination.

To evaluate the reactogenicity of a single dose of 
Boostrix administered during pregnancy and post-
delivery in terms of solicited symptoms during the 8-day 
(Day 0 – Day 7) follow-up period after vaccination.

To assess the safety of a single dose of Boostrix 
administered during pregnancy and post-delivery in terms 
of unsolicited symptoms during the 31-day (Day 0 – Day 
30) follow-up period after vaccination and serious 
adverse events (SAEs) during the period from Visit 1 up 
to Visit 4.

To assess the acceptance rate of a single dose of 
Boostrix among eligible household contacts of the 
infants born to pregnant women enrolled in Spain, as 
part of an assessment of cocooning.

To assess the safety of a single dose of Boostrix in terms 
of SAEs among the vaccinated household contacts of 
the infants born to pregnant women in Spain, as part of 
an assessment of cocooning, from the day of 
vaccination till 30 days after the vaccination.
Study design

Experimental design: Phase IV, observer-blind, 
randomised, placebo-controlled, multi-centric, multi-
country study with two cross-over groups.

Duration of the study: The intended duration of the study 
will be approximately 5 months for each subject.

Epoch 001: Booster vaccination starting at Screening 
visit (Day -14 to 0) and ending at Visit 4 (post-
delivery Month 2).

Study groups: The study groups are defined as follows: 

dTpa Group: This group will consist of pregnant 
women who will receive a single dose of Boostrix at 
27-36 weeks (i.e. completed 27 weeks until 36 
weeks) of gestation (Visit 1) and will receive a dose 
of the placebo post-delivery (within 72 hours).

Control Group: This group will consist of pregnant 
 
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women who will receive a single dose of placebo at 
27-36 weeks (i.e. completed 27 weeks until 36 
weeks) of gestation (Visit 1) and will receive a dose 
of Boostrix post-delivery (within 72 hours).
Synopsis Table 1
Study groups and epochs foreseen in the study
Study groups
Number of 
subjects
Age (Min/Max)
Epoch
Epoch 001
dTpa Group
340
18 years - 45 years
x
Control Group
340
18 years - 45 years
x
Synopsis Table 2
Study groups and treatment foreseen in the study (Amended: 
15 July 2015)
Treatment name
Vaccine name
Study Groups
dTpa Group
Control Group
Boostrix*
dTpa
x
x
Placebo for dTpa vaccine
Placebo
x
x
*All eligible household contacts of the infants born to pregnant women enrolled in Spain will be eligible to 
receive a single dose of Boostrix as part of an assessment of cocooning.
Synopsis Table 3
Blinding of study epoch
Study Epoch
Blinding
Epoch 001
observer-blind

Sampling schedule: Blood samples will be collected at the 
following time-points:

Pre-Vacc (Visit 1): Before the booster vaccination, 
approximately 5 mL of blood sample will be collected 
from all subjects.

Post-Vacc (Visit 2): One month after the booster 
vaccination, approximately 5 mL of blood sample will 
be collected from all subjects.

Cord blood (Visit 3): approximately 2.5mL of blood 
sample from the umbilical cord will be collected from 
all subjects.

Type of study: self-contained.

Data collection: Electronic Case Report Form (eCRF).

Safety monitoring: An independent data monitoring 
committee (IDMC) (including obstetrician, paediatrician, 
statistician and a neonatologist) will be put in place to 
oversee the safety aspects of Boostrix in the clinical study 
i.e. each SAE/congenital anomaly/foetal malformation 
case/incidence of grade 3 local and general solicited 
adverse events (AEs) will be reviewed by this committee.
 
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Number of subjects
The target will be to enrol approximately 680 eligible subjects 
who will be randomly assigned to two study groups in a 1: 1 
ratio (approximately 340 subjects in each group).
Endpoints
(Amended: 15 July
2015)
Primary

Immunogenicity with respect to components of the study 
vaccine received during pregnancy, one month post 
vaccination

Anti-PT, anti-FHA and anti-PRN antibody 
concentrations.
Secondary

Outcome of pregnancy in terms of pregnancy outcomes up 
to study end (Visit 4).

Pregnancy outcomes will include live birth with no 
congenital anomalies, live birth with congenital 
anomalies, still birth with no congenital anomalies, 
still birth with congenital anomalies, elective 
termination with no congenital anomalies and elective 
termination with congenital anomalies.

Outcome of pregnancy in terms of listed pregnancy-related 
adverse events of interest/ neonate-related events of interest 
up to study end (Visit 4).

Listed pregnancy-related adverse events of interest/
neonate-related events of interest will include 
gestational diabetes, pregnancy-related hypertension, 
premature rupture of membranes, preterm premature 
rupture of membranes, premature labour, premature 
uterine contractions, intrauterine growth 
restriction/poor foetal growth, pre-eclampsia, 
eclampsia, vaginal or intrauterine haemorrhage, 
maternal death, preterm birth, neonatal death, small for 
gestational age, neonatal hypoxic ischaemic 
encephalopathy and failure to thrive/growth 
deficiency.
Immunogenicity with respect to components of the study 
vaccine received during pregnancy, one month post 
vaccination

Anti-D, anti-T, anti-PT, anti-FHA and anti-PRN
seroprotection/seropositivity status and antibody 
concentrations.

Vaccine response to PT, FHA and PRN
 
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
Vaccine response to anti-D and anti-T

Immunogenicity with respect to components of the study 
vaccine, in the cord blood sample.

Anti-PT, anti-FHA and anti-PRN seropositivity status.

Solicited local and general symptoms (at Visit 1 and Visit 
3).

Occurrence of each solicited local/general symptoms 
during the 8-day (Day 0-Day 7) follow-up period after 
the vaccination.

Unsolicited adverse events (at Visit 1 and Visit 3).

Occurrence of unsolicited AEs within 31 days (Day 0 
– Day 30) after any vaccination, according to the 
Medical Dictionary for Regulatory Activities 
(MedDRA) classification.

Serious adverse events (SAEs).

Occurrence of serious adverse events from Dose 1 up 
to study end (Visit 4).

Percentage of household contacts of the infants born to 
pregnant women vaccinated in Spain who accepted 
Boostrix vaccine as part of an assessment of cocooning 
among the eligible household contacts.

Occurrence of SAEs among the vaccinated household 
contacts of the infants born to pregnant women in Spain, 
as part of an assessment of cocooning, from the day of 
vaccination till 30 days after vaccination.
 
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TABLE OF CONTENTS
PAGE
SPONSOR INFORMATION ............................................................................................7
SYNOPSIS......................................................................................................................8
LIST OF ABBREVIATIONS...........................................................................................23
GLOSSARY OF TERMS (AMENDED: 15 JULY 2015)..................................................25
TRADEMARKS .............................................................................................................31
1.
INTRODUCTION....................................................................................................32
1.1.
Background ................................................................................................32
1.2.
Rationale for the study and study design ....................................................33
1.2.1.
Rationale for the study.................................................................33
1.2.2.
Rationale for the study design (Amended: 15 July 2015) .............34
1.2.3.
Rationale for the use of placebo ..................................................35
1.3.
Benefit: Risk Assessment ...........................................................................35
1.3.1.
Risk Assessment .........................................................................36
1.3.2.
Benefit Assessment .....................................................................36
1.3.3.
Overall Benefit:Risk Conclusion...................................................36
2.
OBJECTIVES.........................................................................................................37
2.1.
Primary Objective .......................................................................................37
2.2.
Secondary objectives (Amended: 15 July 2015) .........................................37
3.
STUDY DESIGN OVERVIEW (AMENDED: 15 JULY 2015) ...................................38
4.
STUDY COHORT...................................................................................................40
4.1.
Number of subjects/centres ........................................................................40
4.2.
Inclusion criteria for enrolment (Amended: 15 July 2015)............................41
4.3.
Exclusion criteria for enrolment (Amended: 15 July 2015) ..........................42
5.
CONDUCT OF THE STUDY ..................................................................................45
5.1.
Regulatory and ethical considerations, including the informed 
consent process..........................................................................................45
5.2.
Subject identification and randomisation of treatment .................................45
5.2.1.
Subject identification....................................................................45
5.2.2.
Randomisation of treatment.........................................................46
5.2.2.1.
Treatment allocation to the subject.............................46
5.2.2.1.1.
Study group and treatment 
number allocation (Amended: 15 
July 2015)...............................................46
5.2.2.1.2.
Treatment number allocation for 
subsequent doses ..................................47
5.3.
Method of blinding ......................................................................................47
5.4.
General study aspects ................................................................................47
5.4.1.
Independent Data Monitoring Committee.....................................47
5.4.2.
Responsibilities............................................................................48
 
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5.4.3.
Composition of the IDMC.............................................................48
5.4.4.
GSK Biologicals’ Safety Review Team.........................................48
5.5.
Outline of study procedures (Amended: 15 July 2015)................................49
5.6.
Detailed description of study procedures (Amended: 15 July 2015)............52
5.6.1.
Study procedures for study subjects: ...........................................52
5.6.1.1.
Procedures prior to study participation........................52
5.6.1.1.1.
Informed consent....................................52
5.6.1.2.
Procedures during the screening visit.........................52
5.6.1.2.1.
Check inclusion and exclusion 
criteria.....................................................52
5.6.1.2.2.
Collect demographic data .......................52
5.6.1.2.3.
Medical history........................................52
5.6.1.2.4.
Pregnancy screening..............................52
5.6.1.2.5.
History directed physical 
examination ............................................53
5.6.1.2.6.
Record height and weight .......................53
5.6.1.3.
Procedures during the study.......................................53
5.6.1.3.1.
Check contraindications, warnings 
and precautions to vaccination ...............53
5.6.1.3.2.
Assess pre-vaccination body 
temperature ............................................53
5.6.1.3.3.
Study group and treatment 
number allocation ...................................53
5.6.1.3.4.
Sampling ................................................53
5.6.1.3.5.
Study Vaccine administration 
(Amended: 15 July 2015)........................54
5.6.1.3.6.
Check and record concomitant 
medication/vaccination and 
intercurrent medical conditions ...............54
5.6.1.3.7.
Physical examination of the 
newborn..................................................55
5.6.1.3.8.
Breastfeeding status...............................55
5.6.1.3.9.
Recording of AEs, SAEs, 
pregnancies, pregnancy-related 
AEs and neonate-related AEs.................55
5.6.1.3.10.
Study conclusion ....................................56
5.6.2.
Study procedures for household contacts in Spain ......................56
5.6.2.1.
Informed Consent.......................................................56
5.6.2.2.
Check inclusion and exclusion criteria ........................56
5.6.2.3.
Collect demographic data...........................................56
5.6.2.4.
Medical history ...........................................................56
5.6.2.5.
Urine pregnancy test ..................................................56
5.6.2.6.
Assess pre-vaccination body temperature..................56
5.6.2.7.
Vaccine administration ...............................................57
5.6.2.8.
Recording of SAEs and pregnancies ..........................57
5.7.
Biological sample handling and analysis.....................................................57
5.7.1.
Use of specified study materials ..................................................58
5.7.2.
Biological samples.......................................................................58
5.7.3.
Laboratory assays .......................................................................58
5.7.4.
Biological samples evaluation......................................................60
5.7.4.1.
Immunological read-outs ............................................60
5.7.5.
Immunological correlates of protection.........................................60
 
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6.
STUDY VACCINES AND ADMINISTRATION ........................................................61
6.1.
Description of study vaccines......................................................................61
6.2.
Storage and handling of study vaccine .......................................................61
6.3.
Dosage and administration of study vaccines .............................................62
6.4.
Replacement of unusable vaccine doses....................................................62
6.5.
Contraindications to vaccination .................................................................62
6.6.
Warnings and precautions ..........................................................................63
6.7.
Concomitant medications/products and concomitant vaccinations..............63
6.7.1.
Recording of concomitant medications/products and 
concomitant vaccinations.............................................................63
6.7.2.
Concomitant medications/products/vaccines that may lead 
to the elimination of a subject from ATP analyses........................64
6.8.
Intercurrent medical conditions that may lead to elimination of a 
subject from ATP analyses .........................................................................64
7.
HEALTH ECONOMICS ..........................................................................................64
8.
SAFETY.................................................................................................................65
8.1.
Safety definitions ........................................................................................65
8.1.1.
Definition of an adverse event......................................................65
8.1.2.
Definition of a serious adverse event ...........................................66
8.1.3.
Solicited adverse events..............................................................67
8.1.3.1.
Solicited local (injection-site) adverse events..............67
8.1.3.2.
Solicited general adverse events................................67
8.1.4.
Clinical laboratory parameters and other abnormal 
assessments qualifying as adverse events or serious 
adverse events ............................................................................67
8.1.5.
Pregnancy outcomes ...................................................................68
8.2.
Detecting and recording adverse events, serious adverse events, 
pregnancies, pregnancy-related AEs and neonate-related AEs ..................69
8.2.1.
Time period for detecting and recording adverse events, 
serious adverse events, pregnancies, pregnancy-related 
AEs and neonate-related AEs (Amended: 15 July 2015) .............69
8.2.2.
Adverse events of specific interest (adverse pregnancy 
outcomes, listed pregnancy-related adverse events of 
interest/neonate-related events of interest)..................................71
8.2.3.
Post-Study adverse events and serious adverse events..............72
8.2.4.
Evaluation of adverse events and serious adverse events...........72
8.2.4.1.
Active questioning to detect adverse events 
and serious adverse events........................................72
8.2.4.2.
Assessment of adverse events...................................73
8.2.4.2.1.
Assessment of intensity..........................73
8.2.4.2.2.
Assessment of causality .........................74
8.2.4.3.
Assessment of outcomes............................................75
8.2.4.4.
Medically attended visits.............................................76
8.3.
Reporting of serious adverse events, pregnancies and other events ..........76
8.3.1.
Prompt reporting of serious adverse events, pregnancies 
and other events to GSK Biologicals............................................76
8.3.2.
Contact information for reporting serious adverse events, 
pregnancies and other events......................................................77
8.3.3.
Completion and transmission of SAE reports to GSK 
Biologicals ...................................................................................77
 
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8.3.3.1.
Back-up system in case the electronic reporting 
system does not work.................................................77
8.3.4.
Completion and transmission of pregnancy reports to GSK 
Biologicals ...................................................................................77
8.3.5.
Updating of SAE and pregnancy information after removal 
of write access to the subject’s eCRF ..........................................78
8.3.6.
Regulatory reporting requirements for serious adverse 
events..........................................................................................78
8.4.
Follow-up of adverse events, serious adverse events and 
pregnancies................................................................................................78
8.4.1.
Follow-up of adverse events and serious adverse events ............78
8.4.1.1.
Follow-up during the study..........................................78
8.4.1.2.
Follow-up after the subject is discharged from 
the study.....................................................................79
8.4.2.
Follow-up of pregnancies.............................................................79
8.5.
Treatment of adverse events ......................................................................79
8.6.
Unblinding...................................................................................................79
8.7.
Emergency unblinding ................................................................................80
8.8.
Subject card (Amended: 15 July 2015) .......................................................81
9.
SUBJECT COMPLETION AND WITHDRAWAL.....................................................81
9.1.
Subject completion .....................................................................................81
9.2.
Subject withdrawal......................................................................................81
9.2.1.
Subject withdrawal from the study................................................81
9.2.2.
Subject withdrawal from investigational vaccine...........................82
9.3.
Extension study ..........................................................................................82
10. STATISTICAL METHODS......................................................................................83
10.1.
Primary endpoint.........................................................................................83
10.2.
Secondary endpoints (Amended: 15 July 2015)..........................................83
10.3.
Determination of sample size......................................................................84
10.4.
Cohorts for Analyses...................................................................................85
10.4.1.
Total Vaccinated cohort ...............................................................85
10.4.2.
According-To-Protocol cohort for analysis of safety .....................86
10.4.3.
ATP cohort for analysis of immunogenicity ..................................86
10.4.4.
Total cohort for household contacts in Spain ...............................86
10.5.
Derived and transformed data.....................................................................86
10.6.
Analysis of demographics (Amended: 15 July 2015)...................................88
10.6.1.
Analysis of eligible household contacts........................................88
10.7.
Analysis of immunogenicity.........................................................................89
10.7.1.
Within group assessment:............................................................89
10.7.2.
Between group assessment:........................................................89
10.8.
Analysis of safety (Amended: 15 July 2015) ...............................................90
10.9.
Interpretation of analyses............................................................................91
10.10. Conduct of analyses ...................................................................................91
10.10.1. Sequence of analyses..................................................................91
10.10.2. Statistical considerations for interim analyses..............................91
11. ADMINISTRATIVE MATTERS ...............................................................................91
11.1.
electronic Case Report Form instructions ...................................................92
11.2.
Study Monitoring by GSK Biologicals..........................................................92
11.3.
Record retention .........................................................................................93
 
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11.4.
Quality assurance.......................................................................................93
11.5.
Posting of information on publicly available clinical trial registers and 
publication policy ........................................................................................93
11.6.
Provision of study results to investigators ...................................................94
12. COUNTRY SPECIFIC REQUIREMENTS...............................................................94
13. REFERENCES.......................................................................................................95
 
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LIST OF TABLES
PAGE
Table 1
Study groups and epoch foreseen in the study.......................................39
Table 2
Study groups and treatment foreseen in the study (Amended:  15 
July 2015) ..............................................................................................39
Table 3
Blinding of study epoch ..........................................................................39
Table 4
List of study procedures for study subjects (Amended: 15 July 
2015)......................................................................................................49
Table 5
List of study procedures for household contacts in Spain.......................51
Table 6
Intervals between study visits (Amended: 15 July 2015) ........................51
Table 7
Biological samples .................................................................................58
Table 8
Humoral Immunity (Antibody determination)...........................................59
Table 9
Immunological read-outs........................................................................60
Table 10
Study vaccines.......................................................................................61
Table 11
Dosage and administration (Amended: 15 July 2015) ............................62
Table 12
Solicited local adverse events ................................................................67
Table 13
Reporting periods for adverse events, serious adverse events, 
pregnancies, pregnancy-related adverse events and neonate-
related adverse events (Amended: 15 July 2015)...................................70
Table 14
Intensity scales for solicited symptoms in adults.....................................73
Table 15
Timeframes for submitting serious adverse event and other 
events reports to GSK Biologicals ..........................................................76
Table 16
Power to rule out the null hypothesis (H0: group GMC ratio < 1.5) 
that dTpa Group is not superior to the Control Group (N= 272
evaluable subjects per group) ................................................................84
Table 17
Precision achieved with a sample of 300 subjects in each group 
for the various possible expected pregnancy outcomes and listed 
pregnancy-related adverse events of interest/ neonate-related 
events of interest in terms of exact 95 percent CI...................................85
Table 18
GSK Biologicals’ laboratories .................................................................99
Table 19
Outsourced laboratories.........................................................................99
 
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LIST OF APPENDICES
PAGE
APPENDIX A CLINICAL LABORATORIES ..................................................................99
APPENDIX B OBSTETRICAL RISK ASSESSMENT FORM ......................................100
APPENDIX C Definitions and evaluations of selected terms and adverse events 
of interest in pregnant women participating in clinical trials 
(adapted from [Munoz, 2013]) ..............................................................104
APPENDIX D AMENDMENTS AND ADMINISTRATIVE CHANGES TO THE 
PROTOCOL.........................................................................................123
 
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LIST OF ABBREVIATIONS
ACIP: 
Advisory Committee on Immunization Practices
AE:
Adverse Event
ATP:
According-To-Protocol
CDC:
Centers for Disease Control and Prevention, USA
CI:
Confidence Interval
dT:
Reduced antigen content diphtheria and tetanus toxoids
DTP:
Diphtheria-Tetanus-Pertussis
dTpa/dTap:
Combined reduced antigen content diphtheria-tetanus-
acellular pertussis vaccine
DTPa:
Diphtheria-Tetanus-acellular Pertussis
eCRF:
electronic Case Report Form
EDD:
Estimated date of delivery
EGA:
Estimated gestational age
ELISA: 
Enzyme-Linked ImmunoSorbent Assay
eTDF:
Electronic Temperature excursion Decision Form
FHA:
Filamentous Haemagglutinin
GCP:
Good Clinical Practice
GMC:
Geometric Mean Concentration
GSK:
GlaxoSmithKline
IB:
Investigator Brochure
ICF:
Informed Consent Form
ICH:
International Conference on Harmonisation
IDMC:
Independent Data Monitoring Committee
IEC:
Independent Ethics Committee
IMP:
Investigational Medicinal Product
 
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IRB:
Institutional Review Board
IU/ml: 
International Units per ml
LAR:
Legally Acceptable Representative
LL:
Lower Limit
LMP: 
Last menstrual period
LSC:
Local Study Contact
LSLV:
Last Subject Last Visit
MACDP:
Metropolitan Atlanta Congenital Defects Program
MedDRA:
Medical Dictionary for Regulatory Activities
PRN:
Pertactin
PT:
Pertussis Toxoid
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
 
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GLOSSARY OF TERMS (Amended: 15 July 2015)
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,

oral contraceptives, either combined or progestogen 
alone,

injectable progestogen,

implants of etenogestrel or levonorgestrel,

estrogenic 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),

male condom combined with a female diaphragm, 
either with or without a vaginal spermicide (foam, 
gel, film, cream, or suppository). 
Adequate contraception does not apply to subjects of 
child bearing potential with same sex partners, 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.
Blinding:
A procedure in which one or more parties to the trial are 
kept unaware of the treatment assignment in order to 
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blinding is maintained throughout the conduct of the trial, 
and only when the data are cleaned to an acceptable level 
of quality will appropriate personnel be unblinded or 
when required in case of a serious adverse event. In an 
observer-blind study, the subject and the site and sponsor 
personnel involved in the clinical evaluation of the 
subjects are blinded while other study personnel may be 
aware of the treatment assignment (see Section 5.3 for 
details on observer-blinded studies). 
Child in care:
A child who has been placed under the control or 
protection of an agency, 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.
Congenital anomalies:
The collection of congenital anomalies is based on the 
Centers for Disease Control and Prevention (CDC) 
Metropolitan Atlanta Congenital Defects Program 
(MACDP) guidelines [CDC, 2007] and include 
morphological, functional, chromosomal or genetic 
anomalies, regardless of whether detected at birth or not, 
the foetus is delivered dead or alive, or defects are 
identified by prenatal ultrasound, amniocentesis or 
examination of the products of conception.
Live-born neonates with transient (postural) defects, 
infectious conditions or biochemical disorders are 
classified as being without congenital anomalies unless 
there is a reasonable possibility that the condition reflects 
an unrecognised congenital birth defect. 
Eclampsia:
Features of pre-eclampsia accompanied by new-onset 
generalized seizures.
Elective termination:
Expulsion of products of conception with medical or 
surgical assistance. The termination of the pregnancy can 
be elective or therapeutic.
Eligible:
Qualified for enrolment into the study based upon strict 
adherence to inclusion/exclusion criteria.
Epoch:
An epoch is a self-contained set of consecutive time-
points or a single time-point from a single protocol. Self-
 
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contained means that data collected for all subjects at all 
time-points within that epoch allows to draw a complete 
conclusion to define or precise the targeted label of the 
product. Typical examples of epochs are primary 
vaccinations, boosters, yearly immunogenicity follow-
ups, and surveillance periods for efficacy or safety.
eTrack:
GSK’s tracking tool for clinical trials.
Evaluable:
Meeting all eligibility criteria, complying with the 
procedures defined in the protocol, and, therefore, 
included in the according-to-protocol (ATP) analysis (see 
Sections 6.7.2 and 10.4 for details on criteria for 
evaluability).
Failure to thrive/growth 
deficiency:
Inability to maintain expected growth rate over time, 
evaluated by plotting individual weight gain and growth 
on standard growth charts for the population.
Gestational diabetes:
Onset or first recognition of abnormal glucose tolerance 
during pregnancy (the diagnosis is based on 
administration of glucose challenge test at 24-28 weeks 
gestation).
Household contact
People living under the same roof with the infant.
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.
Intrauterine growth 
restriction/poor foetal 
growth:
Estimated or actual birth weight below the 10th percentile 
for gestational age.
Investigational vaccine:
(Synonym of 
Investigational Medicinal 
Product)
A pharmaceutical form of an active ingredient or placebo 
being tested or used as a reference in a clinical trial, 
including a product with a marketing authorisation when 
used in a way different from the approved form, or when 
used for an unapproved indication, or when used to gain 
further information about an approved use. 
Live birth:
Delivery of a live infant, regardless of maturity or birth 
weight, as determined by the presence of spontaneous 
respirations, a heartbeat, and spontaneous movement.
 
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Maternal death: 
Death of a woman while pregnant or within 42 days of 
termination of pregnancy, irrespective of the duration and 
site of the pregnancy, from any cause related to or 
aggravated by the pregnancy or its management, but not 
from accidental or incidental causes.
Menarche:
Menarche is the onset of menses for the first time in a 
young female and is preceded by several changes 
associated with puberty including breast development 
and pubic hair growth. Menarche usually occurs within 
1-2 years of breast development, thelarche. However, a 
young female can become pregnant before her first 
menses. Thus, a conservative definition of non-
childbearing potential in a pre-menarcheal female is a 
young female who has not yet entered puberty as 
evidenced by lack of breast development (palpable 
glandular breast tissue).
Menopause:
Menopause is the age associated with complete 
cessation of menstrual cycles, menses, and implies the 
loss of reproductive potential by ovarian failure. A 
practical definition accepts menopause after 1 year 
without menses with an appropriate clinical profile at 
the appropriate age e.g. > 45 years.
Neonatal death: 
Death of newborn at any time from birth to 28 days of 
life, regardless of gestational age.
Neonatal hypoxic 
ischaemic 
encephalopathy:
A disturbance of neurological function in the earliest days 
of life in the term infant manifested by difficulty in 
initiation and maintaining respiration, depression of tone 
and reflexes, abnormal level of consciousness and often 
seizures, which may follow an intrapartum hypoxic insult 
or due to another cause.
Post-partum 
haemorrhage:
Excessive blood loss after delivery i.e. estimated blood 
loss in excess of 500 ml after vaginal delivery and 
estimated blood loss in excess of 1000 ml after Caesarean 
delivery. The other symptoms are ≥10% drop in 
haematocrit, need for blood transfusion, symptomatic 
hypotension, dizziness, pallor and oligouria.
Pre-eclampsia:
Hypertension (>140 and/or >90 mmHg) and proteinuria 
(>300 mg in a 24 hr urine specimen) occurring after the 
20th week of gestation. 
 
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Pregnancy-related 
hypertension:
Hypertension (>140 and/or >90 mmHg) occurring after , 
20 weeks of gestation and up to 6 weeks postpartum 
combined with abnormalities such as proteinuria 
(>300 mg in a 24 hr urine specimen).
Premature labour:
Cervical change in the presence of regular uterine 
contractions that occur before 37 weeks of gestation. 
Premature rupture of 
membranes:
Spontaneous rupture of foetal membranes that occurs 
before the onset of labour. 
Premature uterine 
contraction:
Uterine contractions without cervical change.
Preterm birth:
Birth before 37 weeks of gestation.
Preterm premature 
rupture of membranes:
Spontaneous rupture of foetal membranes that occurs 
before the onset of labour before 37 weeks of gestation.
Primary completion 
date:
The date that the final subject was examined or received 
an intervention for the purpose of final collection of data 
for the primary outcome, whether the clinical trial 
concluded according to the pre-specified protocol or was 
terminated.
Protocol administrative 
change:
A protocol administrative change addresses changes to 
only logistical or administrative aspects of the study. 
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.
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.
Small for gestational age:
Birth weight less than 10% for infants of same gestational 
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Solicited adverse event:
Adverse events to be recorded as endpoints in the clinical 
study. The presence/occurrence/intensity of these events 
is actively solicited from the subject or an observer during 
a specified post-vaccination follow-up period.
Solicited adverse event:
AEs to be recorded as endpoints in the clinical study. The 
presence/occurrence/intensity of these events is actively 
solicited from the subject or an observer during a 
specified post-vaccination follow-up period.
Stillbirth:
Death of the foetus(es) at ≥22 weeks of gestation, 
occurring antepartum or intrapartum.
Subject number:
A unique number identifying a subject, assigned to each 
subject consenting to participate in the study.
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.
Treatment number:
A number identifying a treatment to a subject, according 
to the study randomisation or treatment allocation.
Treatment:
Term used throughout the clinical study to denote a set of 
investigational product(s) or marketed product(s) or 
placebo intended to be administered to a subject, 
identified by a unique number, according to the study 
randomisation or treatment allocation.
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.
Vaginal or intrauterine 
haemorrhage:
Vaginal or intrauterine haemorrhage that encompasses 
antepartum (i.e. bleeding from the genital tract after 24 
weeks of gestation), intrapartum, and postpartum 
bleeding (i.e. within 24 hours post-delivery).  
 
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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 ™ and in italics.
Trademark of the GlaxoSmithKline 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
Pertussis, “whooping cough”, caused by Bordetella pertussis is a highly contagious and
potentially life-threatening respiratory illness that is a cause of morbidity and mortality in 
infants less than six months of age. It is also a cause of morbidity in adolescents and 
adults. Compared to older children and adults, infants aged less than 12 months have 
higher rates of pertussis disease and the largest burden of pertussis-related deaths. Most 
of these cases, including hospitalisations and deaths, occur in infants less than two 
months of age as they are too young to be vaccinated [CDC, 2011].
Since 2011, increased pertussis cases or outbreaks have been reported in several 
countries. In the United States of America, forty nine states and Washington D.C. 
reported increases in the pertussis cases in 2012 compared to 2011 [CDC, 2015]. The 
incidence of pertussis among infants exceeds that observed among children and 
adolescents [CDC, 2012]. The number of pertussis cases reported in Australia has also 
been increasing with nearly 40,000 cases reported in 2011 and 2012. While the rates are 
highest in the primary school-aged children, due to the waning of vaccine-induced 
immunity, the impact of the disease remains greatest in infants under one year of age 
[Communicable Disease Control Directorate, 2011]. 
The United Kingdom is also in the midst of a large outbreak of pertussis. A national 
increase in the laboratory-confirmed cases of pertussis has been observed in England and 
Wales, with a large number of cases being reported in very young infants [Health 
Protection Report, 2012].
Different vaccination strategies can be implemented to protect infants against pertussis. 
Universal vaccination of pre-school children, adolescents, adults, or selective 
immunisation of unvaccinated postpartum mothers and other family members
(cocooning) not only protects the vaccinated group, but also increases herd immunity and 
hence reduces the risk of disease transmission to unvaccinated or incompletely vaccinated 
infants. However, due to difficulties of full implementation, these strategies are not very 
effective to control the outbreak of pertussis in infants less than 6 months of age [Mooi, 
2007].
Transfer of maternal antibodies against pertussis may have some protective effect in the 
infants. However, low levels of the maternal antibodies and rapid decay of the antibodies 
in the infants often still leave the infant at high risk for pertussis. If the maternal antibody 
levels are increased by maternal immunisation either before or during pregnancy, this 
approach might provide some degree of protection to the mother and infant during a 
vulnerable period immediately after birth [Leuridian, 2011]. 
Several studies have suggested that presence of maternal pertussis antibodies can inhibit 
active pertussis-specific antibody production in the child, known as blunting. This 
blunting effect might reduce protection after the first months of life. However, data 
suggest that blunting is overcome after the third dose of the primary vaccination and the 
potential benefit of protection from maternal antibodies in newborn infants outweighs the 
 
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potential risk of blunting the infant’s response to DTPa vaccine [CDC, 2011; Hardy-
y-Fairbanks, 2013]. Also, studies have shown that use of acellular pertussis vaccines 
(DTPa) compared to whole-cell diphtheria-tetanus-pertussis (DTP) vaccines confer 
higher levels of antibodies in women before pregnancy. These DTPa vaccines are 
unlikely to adversely affect pertussis antibody responses among infants born to mothers 
with high antibody levels [Englund, 1995]. 
1.2.
Rationale for the study and study design
1.2.1.
Rationale for the study
On June 22, 2011, the Advisory Committee on Immunization Practices (ACIP) made 
recommendations for use of dTap vaccine in unvaccinated pregnant women and updated 
recommendations on cocooning and special situations [CDC, 2011]. In 2013, the ACIP 
recommended the combined reduced antigen content diphtheria-tetanus-acellular 
pertussis vaccine (dTap) vaccine for pregnant women during every pregnancy 
irrespective of previous history of dTap vaccination [CDC, 2013]. Following the initial 
recommendation in the US by ACIP, temporary dTap immunisation programmes for 
pregnant women have been implemented in 18 countries including UK, New Zealand, 
Israel, Mexico, Brazil, Colombia, Uruguay, Panama, Costa Rica, Argentina and some 
provinces in Australia and Spain [Joint Committee on Vaccination and Immunization 
(JCVI), 2012; Pharmaceutical Management Agency (PHARMAC), 2012; TAG, 2013]. 
Since 2013, vaccination during pregnancy is also recommended in Belgium between the 
24th and 32nd week of pregnancy [CSS, 2013]. The National Advisory Committee on 
Immunization in Canada recommends that all pregnant women following 26 weeks of 
pregnancy who have not received a dose of pertussis-containing vaccine in adulthood 
should be encouraged to receive dTap vaccination. In special circumstances, such as an 
outbreak situation, all pregnant women who are 26 weeks gestation or greater may be 
offered dTap vaccination irrespective of their immunisation history [Warshawsky, 2014;
Public Health Agency of Canada, 2014].
The important impact of maternal immunisation in decreasing the incidence of infant 
pertussis has been demonstrated recently by the Public Health England (PHE) pertussis 
maternal immunisation program in an analysis of data from the Clinical Practice 
Research Datalink (a primary care database of 520 English general practices). After a 
maternal pertussis vaccination program was introduced in October 2012 in response to a 
pertussis outbreak, the number of pertussis cases in infants younger than 3 months of age 
and the number of hospitalizations decreased significantly [Amirthalingam, 2014]. A 
study conducted to assess the safety of pertussis vaccination during pregnancy in UK 
using the Clinical Practice Research Datalink showed no evidence of an increased risk of 
stillbirth or any adverse events related to pregnancy [Donegan, 2014]. Another 
randomized, double-blind, placebo controlled trial conducted using Adacel (dTap, Sanofi 
Pasteur) in 33 pregnant women aged 18 to 45 years at 30 to 32 weeks gestation did not 
find increased risk of adverse events among women or their infants [Munoz, 2014].
 
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In light of these recommendations and observations, further clinical evaluation of the 
safety of reduced antigen-content acellular pertussis vaccines in pregnant women is 
scientifically warranted.
GSK Biologicals’ reduced-antigen-content dTpa vaccine, Boostrix, first licensed for use 
in Germany in 1999, is indicated for booster vaccination for individuals from the age of 
four years onwards. The immunogenicity, reactogenicity and safety of this vaccine have
been established in a number of clinical trials in the different populations for which it is 
indicated [Minh, 1999; Turnbull, 2001; Van Damme, 2004; Meyer, 2008]. 
Review of reports to Vaccine Adverse Event Reporting System in pregnant women who 
received a dose of dTap vaccine did not identify any concerning patterns in maternal, 
infant, or foetal outcomes [Zheteyeva, 2012]. In addition, a clinical study concluded that 
administering dTap during pregnancy increased antibody concentrations against 
diphtheria and pertussis antigens and maternal immunisation with dTap may prevent 
neonatal pertussis infection [Gall, 2011]. GSK has performed reproductive and 
developmental toxicity studies in female rats and rabbits. The developmental toxicity 
study to assess embryo-foetal and pre- and postnatal development in female rats at a dose 
approximately 40 times the human dose (on a mL/kg basis) revealed no evidence of harm 
to the foetus due to Boostrix. The study conducted on rabbits to evaluate the effects of 
Boostrix on female fertility, implantation and embryo-foetal development did not show 
adverse effects on embryo-foetal development or survival.
Considering the multiple countries which have recently instituted recommendations 
regarding the use of dTap vaccine in pregnant women along with the limited safety data 
of Boostrix in pregnant women currently available, an investigation of safety and 
immunogenicity of Boostrix in a controlled clinical trial is warranted. 
Please refer to the current Investigator Brochure for information regarding the pre-clinical 
and clinical studies and the epidemiological information of Boostrix.
1.2.2.
Rationale for the study design (Amended: 15 July 2015)
In order to support the use of Boostrix in pregnant women, this phase IV, observer-blind, 
placebo-controlled and randomised study will be conducted to assess the immunogenicity 
and safety of the vaccine given during 27-36 weeks of gestation in healthy women aged 
18-45 years. This period of pregnancy is considered to be outside the critical 
susceptibility window for organogenesis. Transfer of maternal antibodies to the infants is 
also seen to be optimal in this trimester.
The subjects in this study will be randomised to two groups:

dTpa Group: This group will consist of pregnant women who will receive a single 
dose of Boostrix at 27-36 weeks (i.e. completed 27 weeks until 36 weeks) of 
gestation (Visit 1).

Control Group: This group will consist of pregnant women who will receive a single 
dose of placebo (saline water) at 27-36 weeks (i.e. completed 27 weeks until 36 
weeks) of gestation (Visit 1).
 
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The study will adopt a cross-over study design. Subjects in the dTpa group who receive a 
single dose of Boostrix at 27-36 weeks of gestation will receive a dose of the placebo 
post-delivery (within 72 hours); while subjects in the Control group who receive placebo 
at 27-36 weeks of gestation will receive a dose of Boostrix post-delivery (within 72 
hours).
Infants born to mothers enrolled in this study will be followed-up in two separate clinical 
studies: DTPA (BOOSTRIX)-048 PRI and DTPA (BOOSTRIX)-049 BST: 048. Infants 
will be given the primary vaccination course of Infanrix hexa in DTPA (BOOSTRIX)-
048 PRI study and a booster dose in the second year of life in DTPA (BOOSTRIX)-049 
BST: 048 study in order to generate safety and immunogenicity data. The impact of 
maternal Boostrix vaccination on immune response of infants to primary and booster 
dTpa vaccination will also be evaluated in these studies.
Since pregnant women are a vulnerable population and the experience of clinical trials in 
this population is limited, high quality of obstetric, perinatal and infant care will be a 
requirement for all trial sites, ensuring optimal data collection as well as access to 
emergency facilities, if required. In addition, sites that can guarantee high compliance 
with long-term follow-up of the children will be selected.
In addition, all the eligible household contacts of the infants born to pregnant women 
enrolled in Spain will be eligible to receive a single dose of Boostrix as part of an 
assessment of cocooning.
1.2.3.
Rationale for the use of placebo
Since this study will be conducted in countries where dTap vaccination for pregnant 
women is not yet widely implemented and in the absence of an established active control 
for pertussis vaccination in this population, a placebo will be used. Based on the cross-
over study design, pregnant women who receive placebo in the Control Group will 
receive a dose of Boostrix post-delivery. Vaccinating the mothers with dTpa vaccine 
post-delivery may provide some degree of protection against pertussis due to the 
cocooning effect [CDC, 2013]. This is also in line with the ACIP recommendations 
which state that women should be administered a dose of dTpa vaccine immediately 
postpartum in case dTpa vaccine was not administered during pregnancy. 
1.3.
Benefit: Risk Assessment
Please refer to the Investigator’s brochure for information regarding the summary of 
potential risks and benefits of Boostrix.
The following section outlines the risk assessment and mitigation strategy for this study 
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1.3.1.
Risk Assessment
Important Potential/Identified 
Risk
Data/Rationale for Risk
Mitigation Strategy
Investigational 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, 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.
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. 
Any untoward symptoms experienced 
by the subject after receiving the 
vaccine should be reported to the 
investigator.
Study Procedures
Not applicable
Other
Not applicable
1.3.2.
Benefit Assessment
By receiving the Boostrix vaccine, the subjects may have the benefit of being protected 
against diphtheria, tetanus and pertussis diseases. 
1.3.3.
Overall Benefit:Risk Conclusion
The benefit:risk profile of Boostrix for vaccination of subjects against diphtheria, tetanus, 
and pertussis continues to be favourable.
 
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2.
OBJECTIVES
2.1.
Primary Objective

To demonstrate that the maternally transferred antibodies against pertussis in the 
dTpa Group is superior to that in the Control Group in terms of geometric mean 
concentrations (GMCs) for the pertussis antibodies, in the cord blood sample.
Criterion:

The lower limit (LL) of the 95% confidence interval (CI) of the GMC ratio 
[dTpa Group divided by Control Group] for anti-pertussis toxoid (anti-PT), anti-
filamentous haemagglutinin (anti-FHA) and anti-pertactin (anti-PRN) antibodies 
is ≥ 1.5.
Refer to Section 10.1 for the definition of the primary endpoint.
2.2.
Secondary objectives (Amended: 15 July 2015)

To assess the safety of a single dose of Boostrix in pregnant women, administered 
during 27-36 weeks of gestation, in terms of the outcomes of pregnancy and listed 
pregnancy-related adverse events of interest/neonate-related events of interest up to 
study end (Visit 4).

To assess the immunogenicity of a single dose of Boostrix administered during 
pregnancy in terms of seropositivity status for antibodies against pertussis, in the 
cord blood sample.

To assess the immunogenicity of a single dose of Boostrix administered during 
pregnancy in terms of seroprotection/seropositivity status, vaccine response and 
GMCs for antibodies against diphtheria, tetanus and pertussis, one month post-
vaccination.

To evaluate the reactogenicity of a single dose of Boostrix administered during 
pregnancy and post-delivery in terms of solicited symptoms during the 8-day (Day 0 
– Day 7) follow-up period after vaccination.

To assess the safety of a single dose of Boostrix administered during pregnancy and 
post-delivery in terms of unsolicited symptoms during the 31-day (Day 0 – Day 30) 
follow-up period after vaccination and serious adverse events (SAEs) during the 
period from Visit 1 up to Visit 4.

To assess the acceptance rate of a single dose of Boostrix among eligible 
household contacts of the infants born to pregnant women enrolled in Spain, as 
part of an assessment of cocooning.

To assess the safety of a single dose of Boostrix in terms of SAEs among the 
vaccinated household contacts of the infants born to pregnant women in Spain, as 
part of an assessment of cocooning, from the day of vaccination till 30 days after 
the vaccination.
Refer to Section 10.2 for the definition of the secondary endpoints.
 
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3.
STUDY DESIGN OVERVIEW (AMENDED: 15 JULY 2015)
N: Number of subjects planned to be enrolled
Pre-vacc: Blood sample to be collected before the dose of the booster vaccination in pregnant women (Visit 1).
Post-vacc: Blood sample to be collected one month after the booster vaccination in pregnant women (Visit 2).
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the outline of study procedures (Section 5.5), are essential and required for 
study conduct. 

Experimental design: Phase IV, observer-blind, randomised, placebo-controlled, 
multi-centric, multi-country study with two cross-over groups. All eligible 
household contacts of the infants born to pregnant women enrolled in Spain will 
be eligible to receive a single dose of Boostrix as part of an assessment of 
cocooning.

Duration of the study: The intended duration of the study will be approximately 5 
months for each subject.

Epoch 001: Booster vaccination starting at Screening visit (Day -14 to 0) and 
ending at Visit 4 (post-delivery Month 2).

Study groups: The study groups are defined as follows: 

dTpa Group: This group will consist of pregnant women who will receive a 
single dose of Boostrix at 27-36 weeks (i.e. completed 27 weeks until 36 weeks) 
of gestation (Visit 1) and will receive a dose of the placebo post-delivery (within 
72 hours).
 
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
Control Group: This group will consist of pregnant women who will receive a 
single dose of placebo at 27-36 weeks (i.e. completed 27 weeks until 36 weeks) 
of gestation (Visit 1) and will receive a dose of Boostrix post-delivery (within 72 
hours).
The study groups and epoch foreseen in the study are presented in Table 1.
Table 1
Study groups and epoch foreseen in the study
Study groups
Number of 
subjects
Age (Min/Max)
Epoch
Epoch 001
dTpa Group
340
18 years - 45 years
x
Control Group
340
18 years - 45 years
x
The study groups and treatment foreseen in the study are presented in Table 2.
Table 2
Study groups and treatment foreseen in the study (Amended: 
15 July 2015)
Treatment name
Vaccine name
Study Groups
dTpa Group
Control Group
Boostrix *
dTpa
x
x
Placebo for dTpa vaccine
Placebo
x
x
*All eligible household contacts of the infants born to pregnant women enrolled in Spain will be eligible to 
receive a single dose of Boostrix as part of an assessment of cocooning.

Control: placebo control

Vaccination schedule:

All subjects will receive a single dose of Boostrix or placebo at 27-36 weeks (i.e. 
completed 27 weeks until 36 weeks) of gestation (Visit 1). Subjects who receive 
Boostrix at Visit 1 will receive a dose of placebo post-delivery (Visit 3) while 
those who receive placebo at Visit 1 will receive Boostrix post-delivery (Visit 
3).

All eligible household contacts of the infants born to pregnant women enrolled 
in Spain will be eligible to receive a single dose of Boostrix as part of an 
assessment of cocooning. Although the vaccine can be administered anytime 
during the study, it is recommended that the vaccine is administered 
preferably 2 weeks before birth of the infant.

Treatment allocation: randomised.

Blinding: Observer-blind. Refer to Section 5.3 for details of the of blinding 
procedure.
The blinding of study epoch is presented in Table 3.
Table 3
Blinding of study epoch
Study Epoch
Blinding
Epoch 001
observer-blind
 
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
Sampling schedule: Blood samples will be collected at the following time-points:

Pre-Vacc (Visit 1): Before the booster vaccination, approximately 5 mL of blood 
sample will be collected from all subjects.

Post-Vacc (Visit 2): One month after the booster vaccination, approximately
5 mL of blood sample will be collected from all subjects.

Cord blood (Visit 3): approximately 2.5 mL of blood sample from the umbilical 
cord will be collected from all subjects.

Type of study: self-contained

Data collection: Electronic Case Report Form (eCRF).

Safety monitoring: An independent data monitoring committee (IDMC) (including 
obstetrician, paediatrician, statistician and a neonatologist) will be put in place to 
oversee the safety aspects of Boostrix in the clinical study i.e. each SAE/congenital 
anomaly/foetal malformation case/incidence of grade 3 local and general solicited 
adverse events (AEs) will be reviewed by this committee (See Section 5.4.1 for 
details).
4.
STUDY COHORT
4.1.
Number of subjects/centres
Approximately 680 pregnant women between 18-45 years will be enrolled in this study. 
These subjects should be 27-36 weeks of gestation at the time of vaccination. Age of the 
pregnant women, gestational age of the foetus, centre and country will be the 
minimization factor for randomisation of pregnant women. Blood samples will be taken 
from all subjects in order to evaluate the immunogenicity endpoints.
The subjects will be enrolled into the two groups in a 1:1 ratio.
Refer to Section 10.3 for a detailed description of the criteria used in the estimation of 
sample size.
Overview of the recruitment plan:

Enrolment will be terminated when the target number of subjects will be achieved.

The study will be monitored by a local Study Monitor.

The treatment allocation and enrolment of subjects into the study will be tracked
using a randomisation system on internet (SBIR).

Centre, age of the pregnant women (18- <25 years, 25- <35 years and 35- 45 
years), gestational age of foetus (27-32 weeks and 33-36 weeks) and country will be 
the minimization factor for randomisation. 
 
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4.2.
Inclusion criteria for enrolment (Amended: 15 July 2015)
Deviations from inclusion criteria are not allowed because they can potentially jeopardise 
the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential.
All subjects must satisfy ALL the following criteria at study entry:
Inclusion criteria for study subjects:

Subjects who, in the opinion of the investigator, can and will comply with the 
requirements of the protocol (e.g. completion of the diary cards, return for follow-up 
visits).

Written informed consent obtained from the subject prior to performing any study 
specific procedure, as per local regulations.

A healthy pregnant woman between, and including, 18 and 45 years of age at the 
time of screening.

Pregnant subjects at 270/7-366/7 weeks (completed 27 weeks but not 37 weeks) of 
gestation at the time of vaccination (Visit 1), as established by ultrasound 
examination.

Not at high risk for complications, as determined by the obstetrical algorithm for 
identification of eligible subjects and the Obstetrical Risk Assessment Form.

No significant foetal abnormalities, as observed by the level II ultrasound testing 
conducted after 18 weeks of gestation.

Nuchal translucency scan, serum testing and any other prenatal tests, if conducted, 
should suggest normal pregnancy.

Willing to have the infant born immunised with Infanrix hexa and Prevenar 13, as 
per national recommendations, in the follow-up clinical studies DTPA 
(BOOSTRIX)-048 PRI and DTPA (BOOSTRIX)-049 BST: 048.

Subjects who do not plan to give their child for adoption or place the child in care.
Inclusion criteria for household contacts in Spain:

Household contacts living in the same house as that of the infant.

Household contacts or parent(s)/LAR(s) of the household contacts who, in the 
opinion of the investigator, can and will comply with the requirements of the 
protocol (e.g. reporting of SAEs).

Written informed consent obtained from the household contacts or the 
parent(s)/LAR(s) prior to vaccination, as per local regulations.

Household contacts who are eligible to receive a booster dose of DTP-containing 
vaccine according to the Summary of Product Characteristics (SmPC) of Boostrix 
and according to the local governmental recommendations in Spain.
 
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
Female household contacts 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 household contacts of childbearing potential may be enrolled in the study , 
if the household contact

has practiced adequate contraception for 30 days prior to vaccination,

has a negative pregnancy test on the day of vaccination and

has agreed to continue adequate contraception for 2 months after receiving
the vaccine dose.
Please refer to the glossary of terms for the definition of adequate contraception.
Please refer to APPENDIX B for the Obstetrical Risk Assessment Form.
4.3.
Exclusion criteria for enrolment (Amended: 15 July 2015)
Deviations from exclusion criteria are not allowed because they can potentially jeopardise 
the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential.
The following criteria should be checked at the time of study entry. If ANY exclusion 
criterion applies, the subject must not be included in the study:
Exclusion criteria for study subjects:

Subjects diagnosed with multiple pregnancies (twins, triplets etc.).

Previous vaccination containing diphtheria, tetanus or pertussis antigens or 
diphtheria and tetanus toxoids at any time during the current pregnancy.

Women with co-morbid medical or obstetric conditions that in the opinion of the 
investigator have the potential to complicate the pregnancy course and outcomes [for 
eg., such as hypertension (requiring medications), uterine anomalies and bleeding 
disorders etc.].

Gestational diabetes as determined by glucose tolerance test conducted after 20 
weeks of gestation, as per local recommendations of the country [Canadian Diabetes 
Association 2013 Clinical Practice Guidelines for the Prevention and Management 
of diabetes in Canada, 2013; International Association of Diabetes and Pregnancy 
Study groups Consensus Panel, 2010; GEDE, 2006].

History of early onset (<34 weeks of gestation) of eclampsia/pre-eclampsia in 
previous pregnancy.

History of major congenital anomalies in previous pregnancies.
 
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
Use of any investigational or non-registered product (drug or vaccine) other than the 
study vaccine anytime during the current pregnancy or planned use during the study 
period.

Any medical condition that in the judgment of the investigator would make 
intramuscular injection unsafe.

Chronic administration (defined as more than 14 days in total) of 
immunosuppressants or other immune-modifying drugs during the period starting six 
months prior to the first vaccine. For corticosteroids, this will mean prednisone 
20 mg/day, or equivalent. Inhaled and topical steroids are allowed.

Administration of long-acting immune-modifying drugs at any time during the study 
period (e.g. infliximab).

Planned administration/administration of a vaccine not foreseen by the study 
protocol in the period within the period starting 30 days before and 30 days after the 
dose of vaccine with the exception of seasonal influenza vaccine that can be 
administered anytime during the study period.

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).

Serious underlying medical condition [e.g., immunosuppressive disease or therapy, 
human immunodeficiency virus infection, collagen vascular disease, epilepsy, 
diabetes mellitus, chronic hypertension, moderate to severe asthma, lung/heart 
disease, liver/kidney disease, infections including TORCHES (toxoplasmosis, 
rubella, cytomegalovirus, herpes simplex, syphilis) infections].

History of an encephalopathy of unknown aetiology, occurring within 7 days 
following previous vaccination with pertussis-containing vaccine.

History of transient thrombocytopenia or neurological complications (for 
convulsions or hypotonic-hyporesponsive episodes) following an earlier 
immunisation against diphtheria and/or tetanus

Significant mental illness (e.g. schizophrenia, psychosis and major depression).

Family history (first degree relatives only) of congenital anomalies, recurrent 
pregnancy losses (two or more consecutive losses) and unexplained neonatal death(s)
in the subject.

Any confirmed or suspected immunosuppressive or immunodeficient condition, 
based on medical history and physical examination (no laboratory testing required).

History of any reaction or hypersensitivity likely to be exacerbated by any 
component of the vaccine.

History of febrile illness within the past 72 hours.

History of physician-diagnosed or laboratory-confirmed pertussis within the past five 
years.
 
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
Anything that would prevent subject from completing the study or put the subject at 
risk, as determined by the investigator.

Acute disease and/or fever at the time of enrolment.

Fever is defined as temperature 37.5°C /99.5°F for oral, axillary or tympanic 
route, or 38.0°C /100.4°F on rectal route.

Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory 
infection) without fever may be enrolled at the discretion of the investigator.

Administration of immunoglobulins and/or any blood products within the 3 months 
preceding the dose of study vaccine, or planned administration during the study 
period, with the exception of anti-D (Rh)-immunoglobulin.

History of chronic excessive alcohol consumption and/or drug abuse.
Exclusion criteria for household contacts in Spain:

Child in care.
Please refer to the glossary of terms for the definition of child in care.

Concurrently participating in another clinical study, at any time during the study 
period, in which the household contact has been or will be exposed to an 
investigational or a non-investigational product (pharmaceutical product or 
device).

Use of any investigational or non-registered product (drug or vaccine) other than 
the study vaccine within 30 days preceding the dose of study vaccine, or planned 
use during the study period.

History of any reaction or hypersensitivity likely to be exacerbated by any 
component of the vaccine.

History of an encephalopathy of unknown aetiology, occurring within 7 days 
following previous vaccination with pertussis-containing vaccine.

Acute disease and/or fever at the time of enrolment.

Fever is defined as temperature 37.5°C /99.5°F for oral, axillary or 
tympanic route, or 38.0°C /100.4°F on rectal route. The preferred route of 
recording temperature will be axillary in household contacts.

Household contacts with a minor illness (such as mild diarrhoea, mild upper 
respiratory infection) without fever may be enrolled at the discretion of the
investigator.

Anything that would put the household contact at risk, as determined by the 
investigator.

Pregnant or lactating household contacts.

Household contacts planning to become pregnant or planning to discontinue 
contraceptive precautions prior to 2 months post-vaccination.
 
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5.
CONDUCT OF THE STUDY
5.1.
Regulatory and ethical considerations, including the 
informed consent process
The study will be conducted in accordance with all applicable regulatory requirements.
The study will be conducted in accordance with the ICH Guideline for Good Clinical 
Practice (GCP), all applicable subject privacy requirements and the guiding principles of 
the Declaration of Helsinki. 
GSK will obtain favourable opinion/approval to conduct the study from the appropriate 
regulatory agency, in accordance with applicable regulatory requirements, prior to a site 
initiating the study in that country.
Conduct of the study includes, but is not limited to, the following:

Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and 
favourable opinion/approval of study protocol and any subsequent amendments.

Subject informed consent.

Investigator reporting requirements as stated in the protocol.
GSK will provide full details of the above procedures to the investigator, either verbally, 
in writing, or both.
Freely given and written or witnessed/ thumb printed informed consent must be obtained 
from each subject, 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.
5.2.
Subject identification and randomisation of treatment
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.
 
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5.2.2.
Randomisation of treatment
The randomisation of supplies within blocks will be performed at GSK Biologicals, using 
MATerial EXcellence (MATEX), a program developed for use in Statistical Analysis 
System (SAS®) (Cary, NC, USA) by GSK Biologicals. Entire blocks will be shipped to 
the study centres /warehouse(s).
To allow GSK Biologicals to take advantage of greater rates of recruitment than 
anticipated at individual centres in this multi-centre study and to thus reduce the overall 
study recruitment period, an over-randomisation of supplies will be prepared. 
5.2.2.1.
Treatment allocation to the subject
The treatment numbers will be allocated by component. 
5.2.2.1.1.
Study group and treatment number allocation (Amended: 15 July 2015)
The target will be to enrol approximately 680 eligible subjects who will be randomly 
assigned to two study groups in a (1: 1) ratio (approximately 340 subjects in each group).
Allocation of the subject to a study group at the investigator site will be performed using 
a randomisation system on internet (SBIR). The randomisation algorithm will use a 
minimisation procedure accounting for centre, age (18- <25 years, 25- <35 years and 
35- 45 years), gestational age (27-32 weeks and 33-36 weeks) and country.
Minimisation factors will have equal weight in the minimisation algorithm.
After obtaining the signed and dated ICF from the subject and having checked the 
eligibility of the subject, the site staff in charge of the vaccine administration will access 
SBIR. Upon providing the subject identification number, the randomisation system will 
determine the study group and will provide the treatment number to be used for each 
dose.
The number of each administered treatment must be recorded in the eCRF on the Vaccine 
Administration screen.
When SBIR is not available, please refer to the SBIR user guide or the Study Procedures 
Manual (SPM) for specific instructions.
All the eligible household contacts of infants born to pregnant women enrolled in 
Spain will be eligible to receive a single dose of Boostrix as part of an assessment of 
cocooning. For specific instructions with respect to treatment allocation of the 
household contacts in Spain, refer to the SPM.
 
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5.2.2.1.2.
Treatment number allocation for subsequent doses 
For each dose subsequent to the first dose, the study staff in charge of the vaccine 
administration will access SBIR, provide the subject identification number, and the 
system will provide a treatment number consistent with the allocated study group.
The number of each administered treatment must be recorded in the eCRF on the Vaccine 
Administration screen.
5.3.
Method of blinding 
Data will be collected in an observer-blind manner. By observer-blind, it is meant that 
during the course of the study, the vaccine recipient and those responsible for the 
evaluation of any study endpoint (e.g. safety, reactogenicity) will all be unaware of which 
vaccine was administered. To do so, vaccine preparation and administration will be done 
by authorised medical personnel who will not participate in any of the study clinical 
evaluation assays.
The laboratory in charge of the laboratory testing will be blinded to the treatment, and 
codes will be used to link the subject and study (without any link to the treatment 
attributed to the subject) to each sample.
5.4.
General study aspects
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying SPM. The SPM provides the investigator and the site 
personnel with administrative and detailed technical information that does not impact the 
safety of the subjects.
5.4.1.
Independent Data Monitoring Committee
An IDMC will monitor the safety aspects of Boostrix in the clinical study. An IDMC 
including an obstetrician, paediatrician, statistician and a neonatologist will be in charge 
of monitoring the safety aspects of the study and the committee will meet at regular 
intervals to review data on other adverse pregnancy outcomes. The frequency of the 
meeting will be decided in consultation with the chairman of the committee. 
To facilitate the review, the IDMC will be provided with all relevant safety data including 
data on congenital anomaly/foetal malformation/ incidence of grade 3 local and general 
solicited adverse events, withdrawals due to adverse experiences and SAE data at 
specified times and access to data on request by an unblinded statistician. The GSK staff 
and other study staff will be blinded during this study.
The IDMC will have access to the individual codes and may at its discretion, decode the 
cases to identify the product administered to any subject and evaluate whether enrolment 
in the study should be halted or if any additional safety follow-ups are required for 
subject safety. 
 
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The operating rules of the IDMC will be established by GSK and will be documented by 
a charter.
5.4.2.
Responsibilities
The overall responsibility of the IDMC is to protect the ethical and safety interests of 
subjects recruited into this study while protecting as far as possible the scientific validity 
of the data. 
The details of the IDMC responsibilities and conduct of meetings will be provided in the 
IDMC Charter. The IDMC charter will also clearly state who will conduct the statistical 
analysis (ICH E9). Key responsibilities of the IDMC include:

Prior to study start, the IDMC will review the protocol with special attention to 
safety monitoring procedures and will make recommendations for adjustments, if 
required.

The IDMC will review the safety data from the study (i.e. each SAE/congenital 
anomaly/foetal malformation/incidence of grade 3 local and general solicited adverse 
events), provide GSK Biologicals with indications on safety profiles and make 
recommendations for consultation of regulatory Authorities and on further study 
conduct.

The IDMC will review the final analysis provided by the sponsor. 
5.4.3.
Composition of the IDMC
IDMC members will not participate in the study, neither as principal or co-investigators 
nor as study patient care physicians. They can also not provide medical care to a subject
enrolled in the study. The IDMC will include medically qualified experts in the field 
under study (obstetrician, paediatrician, neonatologist) and a biostatistician. The person 
specifically selected to chair the IDMC will be required not only to have appropriate 
training for the study but also to have experience serving on one or more IDMCs. The 
IDMC also may convene an ad-hoc meeting should it deem necessary for review of 
specific cases/safety concerns.
Neither the IDMC Chair nor the members are allowed to communicate with the 
investigators involved in the trial about data from the study. If needed, additional 
information should be obtained from the Sponsor. The sponsor should inform the 
investigators in case of any safety concerns observed by the IDMC.
5.4.4.
GSK Biologicals’ Safety Review Team
A Safety Review Team, including the Central Safety Physician, the CRDL and 
Biostatistician of the project, as well as Epidemiology and Regulatory representatives as 
core members and the IDMC will be responsible for reviewing the blinded safety data 
related to the investigational product on a regular basis to identify any potential safety 
issues or signals in order to evaluate and agree on action plans, if necessary.
 
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The IDMC will provide recommendation to the sponsor via the GSK Safety Review 
Team.
5.5.
Outline of study procedures (Amended: 15 July 2015)
The list of study procedures are presented in Table 4 and Table 5.
Table 4
List of study procedures for study subjects (Amended: 15 July 2015)
Epoch
Epoch 001
Type of contact
Screening Visit
Visit 1
Visit 2
Visit 3
Visit 4
Time-points
Day -14 to 0
Day 0
Day 30
At birth
Post-
delivery 
Month 2
Sampling time-points
Pre-Vacc
Post-Vacc Cord blood
Informed consent
●
Collect demographic data
●
Medical history, including medication 
history and previous
diphtheria/tetanus/pertussis vaccination 
history*
O
●
Pregnancy screening**
●
Data collection on household 
contacts §
●
History directed physical examination
O
●
O
Check inclusion/exclusion criteria
O
●
Pre-vaccination body temperature
●
●
Measure/record height and weight
●
Check contraindications and warnings 
and precautions
O
O
Study group and treatment number 
allocation
O
Recording of administered treatment 
number
●
●
Treatment number allocation for 
subsequent dose (Cross-over dose)
O
Blood sampling for antibody 
determination
●
●
●
Vaccine administration
●
●
Distribution of diary cards
O
O
O
Record any concomitant 
medication/vaccination
●
●
●
●
Physical examination of newborn, 
including length, weight, head 
circumference and Apgar Score
●
Record breastfeeding status
●
Recording and follow up of pregnancy-
related adverse events and neonate-
related events
●
●
●
●
Record any intercurrent medical 
conditions
●
●
●
●
Recording of solicited adverse events 
(Days 0-7) by subjects in diary card
●
●
 
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Epoch
Epoch 001
Type of contact
Screening Visit
Visit 1
Visit 2
Visit 3
Visit 4
Time-points
Day -14 to 0
Day 0
Day 30
At birth
Post-
delivery 
Month 2
Sampling time-points
Pre-Vacc
Post-Vacc Cord blood
Recording of non-serious adverse events 
(Day 0– Day 30), by subjects
●
●
●
Recording of large injection site 
reactions
●
●
Return of diary cards
O
O
O
Diary card transcription by 
investigator/designee
●
●
●
Recording of serious adverse events 
(SAEs) # and AEs leading to withdrawal
●
●
●
●
Recording of SAEs related to study 
participation or to a concurrent GSK 
medication/vaccine
●
●
●
●
●
Recording of new pregnancies
●
●
Screening conclusion
●
Study Conclusion
●
Note: The procedures to be conducted during screening visit and Visit 1 may be combined.
In case a woman gives birth to an infant between Visit 1 (Day 0) and Visit 2 (Day 30), the procedures for Visit 2 and 
Visit 3 will be combined. A blood sample from the mother must be taken before the cross-over vaccination is given to 
her.
● is used to indicate a study procedure that requires documentation in the individual eCRF.
○ is used to indicate a study procedure that does not require documentation in the individual eCRF.
Pre-vacc: Blood sample to be collected before the dose of the booster vaccination in pregnant women (Visit 1).
Post-vacc: Blood sample to be collected one month after the booster vaccination in pregnant women (Visit 2).
† Father of the child should also sign the informed consent form, if required by the local laws.
* History of all medications, excluding the vitamins and supplements taken by the mother during her pregnancy before 
receiving the first dose of study vaccine will be recorded in the eCRF.
** Pregnancy screening will include checking of records of ultrasound testing, nuchal translucency scan, serum testing 
and any other prenatal tests (if performed). Refer to Section 4.2 for details regarding pregnancy screening. 
# Including adverse pregnancy outcomes and listed pregnancy-related/neonate-related AEs of interest.
§Information will be obtained by interviewing the mother after she agrees to participate in the study. These 
details can be collected at any of the study visits..
 
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Table 5
List of study procedures for household contacts in Spain
Epoch
Epoch 001
Type of contact
Screening Visit *
Visit 1
Visit 2
Visit 3
Visit 4
Time-points
Day -14 to 0
Day 0
Day 30
At birth
Post-delivery 
Month 2
Informed consent
●#
Check inclusion/exclusion criteria
●#
Collect demographic data
●#
Medical history and previous DTP-
containing vaccination history
●#
Urine pregnancy test in female 
household contacts of child bearing 
potential
●#
Pre-vaccination body temperature
●#
Vaccine administration**
●#
Recording of administered 
treatment number
●#
Recording of serious adverse 
events (SAEs) and pregnancies ‡
●
●
●
●
Recording of SAEs related to study 
participation or to a concurrent GSK 
medication/vaccine
●
●
●
●
● is used to indicate a study procedure that requires documentation in the individual eCRF.
*Screening visit will not be applicable for household contacts.
**The vaccine for household contacts should be administered only after vaccination of the mother (study 
subject).
#The procedures for household contacts can be performed anytime during the study, it is recommended that 
the vaccine is administered preferably 2 weeks before birth of the infant.
‡The SAEs and pregnancies in household contacts should be reported from the date of vaccination till 30 days 
after vaccination.
The intervals between study visits are presented in Table 6.
Table 6
Intervals between study visits (Amended: 15 July 2015)
Interval*
Optimal length of interval 1
Allowed interval2
Screening Visit Visit 1
-14 to 0 days
-28 to 0 days
Visit 1 Visit 2
30 days
21- 48 days
Visit 3 Visit 4
60 days
45 - 75 days
1. Whenever possible the investigator should arrange study visits within this interval.
2. Subjects will not be eligible for inclusion in the ATP cohort for analysis of immunogenicity if they make the study visit 
outside this interval. In case a mother gives birth to an infant before 21 days post-vaccination, she will be excluded 
from the ATP cohort for analysis of immunogenicity.
*Household contacts can be vaccinated anytime during the study, it is recommended that the vaccine is
administered preferably 2 weeks before birth of the infant.
 
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5.6.
Detailed description of study procedures (Amended: 15 July
2015)
5.6.1.
Study procedures for study subjects:
5.6.1.1.
Procedures prior to study participation
5.6.1.1.1.
Informed consent
The signed/witnessed/thumb printed informed consent of the subject must be obtained 
before study participation. The father of the child should also sign the informed consent 
form, if required by the local laws. 
Refer to Section 5.1 for the requirements on how to obtain informed consent.
5.6.1.2.
Procedures during the screening visit
5.6.1.2.1.
Check inclusion and exclusion criteria
Check all inclusion and exclusion criteria as described in Sections 4.2 and 4.3 before 
enrolment. 
5.6.1.2.2.
Collect demographic data
Record demographic data such as date of birth, gender, geographic ancestry and ethnicity 
in the subject’s eCRF.
5.6.1.2.3.
Medical history
Obtain the subject’s medical history by interview and/or review of the subject’s medical 
records and record any pre-existing conditions or signs and/or symptoms present in a 
subject prior to the first study vaccination in the eCRF. History of any medication taken 
by the subject during her current pregnancy and history of previous diphtheria, tetanus, 
pertussis or DTPa vaccination history in the past five years should be recorded in the 
eCRF.
5.6.1.2.4.
Pregnancy screening
Pregnancy screening including checking of records of ultrasound testing, nuchal 
translucency scan, serum testing and any other prenatal tests (if performed) should be 
recorded in the eCRF. The procedures to be conducted during screening visit and Visit 1 
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5.6.1.2.5.
History directed physical examination
Perform a history directed physical examination. If the investigator determines that the 
subject’s health on the day of vaccination temporarily precludes vaccination, the visit will 
be rescheduled. Collected information needs to be recorded in the eCRF.
Treatment of any abnormality observed during this examination has to be performed 
according to local medical practice outside this study or by referral to an appropriate 
health care provider.
5.6.1.2.6.
Record height and weight 
Record the subject’s height and weight in the subject’s eCRF.
5.6.1.3.
Procedures during the study
Note that some of the procedures to be performed during the study (such as recording 
medical history, checking inclusion/exclusion criteria and history directed physical 
examination) will also be performed at screening and are described in Section 5.6.1.2.
5.6.1.3.1.
Check contraindications, warnings and precautions to vaccination 
Contraindications, warnings and precautions to vaccination must be checked at the 
beginning of each vaccination visit. Refer to Sections 6.5 and 6.6 for more details. 
5.6.1.3.2.
Assess pre-vaccination body temperature
The axillary, rectal, oral or tympanic body temperature of all subjects needs to be 
measured prior to any study vaccine administration. The preferred route for recording 
temperature in this study will be oral/axillary. If the subject has fever [fever is defined as 
temperature 37.5°C/99.5°F for oral route on the day of vaccination], the vaccination 
visit will be rescheduled within the allowed interval for this visit (see Table 6).
5.6.1.3.3.
Study group and treatment number allocation
Study group and treatment number allocation will be performed as described in 
Section 5.2.2. The number of each administered treatment must be recorded in the eCRF 
at Visit 1. The treatment number allocation for the subsequent (cross-over) dose will be 
performed at Visit 3. The number of the administered treatment (cross-over dose) must be 
recorded in the eCRF at Visit 3.
5.6.1.3.4.
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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Blood sampling for immune response assessments
Blood samples will be taken during certain study visits as specified in Section 5.5 List of 
Study Procedures.

A volume of approximately 5 mL of whole blood (to provide approximately 1.7 mL 
of serum) should be drawn from all subjects for each analysis of humoral immune 
response at Visit 1 and Visit 2. In case a woman gives birth to an infant before 
Visit 2, a blood sample must be collected from the subject before the cross-over 
vaccination is given to the subject.

A volume of approximately 2.5mL of whole blood (to provide approximately
0.75 mL of serum) from the umbilical cord will be collected from all subjects at 
Visit 3.
After centrifugation, serum samples should be kept at –20°C/ –4°F or below until 
shipment. Refer to the SPM for more details on sample storage conditions.
5.6.1.3.5.
Study Vaccine administration (Amended: 15 July 2015)

After completing all prerequisite procedures prior to vaccination, one dose of study 
vaccine will be administered intramuscularly (IM) in the deltoid of the non-dominant 
arm (refer to Section 6.3 for detailed description of the vaccine administration 
procedure). If the investigator or delegate determines that the subject’s health on the 
day of administration temporarily precludes vaccine administration, the visit will be 
rescheduled within the allowed interval for this visit (refer to Table 6).

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.

The investigators will discuss with the subjects regarding the benefits of cocooning 
i.e. up to date vaccination of the baby’s siblings with DTP-containing vaccines and 
vaccinating all the household contacts (people living under the same roof) eligible 
to receive DTP-containing vaccines as per Summary of Product Characteristics 
(SmPC) of Boostrix and local governmental recommendations in Spain in order to 
reduce the potential risk of pertussis in neonates. The subjects will be requested to 
provide the number of household contacts. Additionally the subjects will also be 
requested for the number of household contacts who refused the visit to site and 
the reason for refusal for subsequent eligibility determination and vaccination will 
be documented.
5.6.1.3.6.
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 
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5.6.1.3.7.
Physical examination of the newborn
At Visit 3 or after the birth of the child, physical examination of the newborn will be 
done. The body weight, length, head circumference and Apgar Score will be recorded in 
the eCRF.
5.6.1.3.8.
Breastfeeding status
At Visit 4, the breastfeeding status (i.e. breast milk or formula milk) will be recorded in 
the eCRF.
5.6.1.3.9.
Recording of AEs, SAEs, pregnancies, pregnancy-related AEs and
neonate-related AEs

Refer to Section 8.2 for procedures for the investigator to record AEs, SAEs, 
pregnancies and pregnancy-related AEs and neonate-related AEs. Refer to Section 
8.3 for guidelines and how to report SAE reports and pregnancies to GSK 
Biologicals.

The subjects will be instructed to contact the investigator immediately should they 
manifest any signs or symptoms they perceive as serious. 

At each vaccination visit, diary cards will be provided to the subject. The subject will 
record body (oral/axillary) temperature and any solicited local/general AEs (i.e. on 
the day of vaccination and during the next 7 days) or any unsolicited AEs (i.e. on the 
day of vaccination and during the next 30 days occurring after vaccination. The 
subject will be instructed to return the completed diary card to the investigator at the 
next study visit.

All pregnancy-related AEs and neonate-related AEs will be captured in the diary 
card from the first receipt of study vaccine/placebo and will end at Visit 4. 

All adverse pregnancy outcomes, listed pregnancy-related and neonate-related AEs 
of interest will be reported as SAEs. Refer to Section 8.2.2 for details regarding 
listed pregnancy-related and neonate-related AEs of interest.

Collect and verify completed diary cards during discussion with the subject on 
Visits 2, 3 and 4.

After vaccination, if the subjects observe any large injection site reaction (defined as 
swelling with a diameter > 100 mm, noticeable diffuse swelling or noticeable 
increase of arm circumference) during the 8-day follow-up (Day 0-Day 7) 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 in the eCRF.

Any unreturned diary cards will be sought from the subject through telephone call(s) 
or any other convenient procedure. The investigator will transcribe the collected 
information into the eCRF in English.
 
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5.6.1.3.10. Study conclusion
The investigator will:

review data collected to ensure accuracy and completeness

complete the Study Conclusion screen in the eCRF.
5.6.2.
Study procedures for household contacts in Spain
5.6.2.1.
Informed Consent
The signed/witnessed/thumb printed informed consent of the household 
contact/parent(s)/LAR(s) must be obtained before study participation. If the household 
contact is below 18 years of age, the parent(s)/LAR(s) should sign the informed consent 
form, if required by the local laws. The subject has to visit the site to complete the 
informed consent process.
Refer to Section 5.1 for the requirements on how to obtain informed consent.
5.6.2.2.
Check inclusion and exclusion criteria
Check all inclusion and exclusion criteria for household contacts as described in 
Sections 4.2 and 4.3 before enrolment. 
5.6.2.3.
Collect demographic data
Record demographic data such as age, gender, ethnicity and relationship to the infant 
in the household contact’s eCRF.
5.6.2.4.
Medical history
Obtain the household contact’s medical history by interview and/or review of the 
medical records and record any pre-existing conditions or signs and/or symptoms 
present in a household contact prior to the vaccination in the household contact’s 
eCRF.
5.6.2.5.
Urine pregnancy test
Female household contacts of childbearing potential are to have a urine pregnancy test 
prior to study vaccine administration. The study vaccine may only be administered if 
the pregnancy test is negative. Note: The urine pregnancy test must be performed even 
if the household contact is menstruating at the time of the study visit.
5.6.2.6.
Assess pre-vaccination body temperature
The axillary, rectal, oral or tympanic body temperature of all household contacts needs 
to be measured prior to any study vaccine administration. The preferred route for 
 
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recording temperature in household contacts will be axillary. If the household contact
has fever [fever is defined as temperature 37.5°C/99.5°F for axillary route on the day 
of vaccination], the vaccination visit will be rescheduled within the allowed interval for 
this visit.
5.6.2.7.
Vaccine administration
After completing all prerequisite procedures prior to vaccination, one dose of Boostrix 
will be administered intramuscularly (IM) in the deltoid of the non-dominant arm 
(refer to Section 6.3 for detailed description of the vaccine administration procedure). 
If the investigator or delegate determines that the household contact’s health on the 
day of administration temporarily precludes vaccine administration, the visit will be 
rescheduled within the allowed interval for this visit. Although the vaccine can be 
administered anytime during the study, it is recommended that the household contact is
vaccinated preferably 2 weeks before birth of the infant. The reason for refusal of 
vaccination by eligible household contacts will be recorded, if applicable.
The household contacts 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.
5.6.2.8.
Recording of SAEs and pregnancies
Refer to Section 8.2 for procedures for the investigator to record SAEs and 
pregnancies. Refer to Section 8.3 for guidelines and how to report SAE and pregnancy
reports to GSK Biologicals.
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 in countries where this is allowed, will be asked to give a specific 
consent to allow GSK or a contracted partner to use the samples for future research. 
Future research will be subject to the laws and regulations in the respective countries 
 
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and will only be performed once an independent Ethics Committee or Review Board 
has approved this research.
Information on further investigations and their rationale can be obtained from GSK 
Biologicals. 
Any sample testing will be done in line with the consent of the individual subject.
Refer also to the Investigator Agreement, where it is noted that the investigator cannot 
perform any other biological assays except those described in the protocol or its 
amendment(s). 
If additional testing is performed, the marker priority ranking given in Section 5.7.4 may 
be changed.
Collected samples will be stored for a maximum of 20 years (counting from when the last 
subject performed the last study visit), unless local rules, regulations or guidelines require 
different timeframes or different procedures, which will then be in line with the subject 
consent. These extra requirements need to be communicated formally to and discussed 
and agreed with GSK Biologicals.
5.7.1.
Use of specified study materials
When materials are provided by GSK Biologicals, it is MANDATORY that all clinical 
samples (including serum samples) be collected and stored exclusively using those 
materials in the appropriate manner. The use of other materials could result in the 
exclusion of the subject from the ATP analysis (See Section 10.4 for the definition of 
cohorts to be analysed). The investigator must ensure that his/her personnel and the 
laboratory(ies) under his/her supervision comply with this requirement. However, when 
GSK Biologicals does not provide material for collecting and storing clinical samples, 
appropriate materials from the investigator’s site must be used. Refer to the Module on 
Clinical Trial Supplies in the SPM.
5.7.2.
Biological samples
The biological samples are presented in Table 7.
Table 7
Biological samples
Sample type
Quantity*
Unit
Time-point
Blood
5
mL
Day 0 (Pre-Vacc) and Day 30 (Post-Vacc)
Cord Blood
2.5
mL
At Birth
* Approximate quantity
5.7.3.
Laboratory assays
Please refer to APPENDIX A for the address of the clinical laboratories used for sample 
analysis.
 
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At Visits 1, 2 and 3, blood will be collected for measurement of immune response. All 
serology will be determined in GSK Biologicals’ laboratories, or in a laboratory 
designated by GSK, using standardized, validated procedures with adequate controls
(refer to Table 8). 
Table 8
Humoral Immunity (Antibody determination)
System
Component
Method
Kit / Manufacturer
Unit
Cut-
off**
Laboratory†
SER
Corynebacterium 
diphtheriae.Diphtheria 
Toxoid Ab.IgG
ELI
NA
IU/ml
.1
GSK Biologicals*
SER
Clostridium 
tetani.Tetanus Toxoid 
Ab.IgG
ELI
NA
IU/ml
.1
GSK Biologicals*
SER
Bordetella 
pertussis.Pertussis 
Toxin Ab.IgG
ELI
NA
EU/ml
5
GSK Biologicals*
SER
Bordetella 
pertussis.Filamentous 
Hemaglutinin Ab.IgG
ELI
NA
EU/ml
5
GSK Biologicals*
SER
Bordetella 
pertussis.Pertactin 
Ab.IgG
ELI
NA
EU/ml
5
GSK Biologicals*
SER = Serum
ELI = Enzyme-linked immunosorbent assay (ELISA)
NA = Not Applicable
IU/ml = International units/millilitre
EU/ml = ELISA units/millilitre
*GSK Biologicals laboratory refers to the Global Vaccines Clinical Laboratories (GVCL) in Rixensart, Belgium; Wavre, 
Belgium.
** These cut-offs might be subject to change due to assay re-development.
†Refer to APPENDIX A for the laboratory addresses.
The GSK Biologicals’ clinical laboratories have established a Quality System supported 
by procedures. The activities of GSK Biologicals’ clinical laboratories are audited 
regularly for quality assessment by an internal (sponsor-dependent) but laboratory-
independent Quality Department.
 
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5.7.4.
Biological samples evaluation
5.7.4.1.
Immunological read-outs
The immunological read-outs are presented in Table 9.
Table 9
Immunological read-outs
Blood sampling time-point
No. subjects
Component
Components
priority rank
Type of contact 
and time-point
Sampling
time-point
Visit 1 (Day 0)
Pre-Vacc
All
PT, PRN and FHA
D, T
1
2
Visit 2 (Day 30)
Post-Vacc 
All
PT, PRN and FHA
D, T
1
2
Visit 3 (At birth)
At birth
All*
PT, PRN and FHA
1
Pre-vacc: Blood sample to be collected before the dose of the booster vaccination in pregnant women (Visit 1).
Post-vacc: Blood sample to be collected one month after the booster vaccination in pregnant women (Visit 2).
* Cord blood collected from umbilical cord of subjects
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. 
5.7.5.
Immunological correlates of protection
The following cut-offs are accepted as immunological correlates of protection:

Specific antibodies against diphtheria toxoid (anti-diphtheria) and tetanus toxoid 
(anti-tetanus) will be measured by Enzyme-linked immunosorbent assay (ELISA).
The assay cut-off of ELISA is currently set at 0.1 International Units per ml (IU/ml), 
which provides a conservative estimate of the percentage of subjects deemed to be 
protected [Camargo, 1984; Melville-Smith, 1983]. 

No serological correlate of protection against pertussis has been established [Plotkin, 
2010]. Antibodies against the pertussis components pertussis toxoid (PT), 
filamentous haemagglutinin (FHA) and pertactin (PRN) will be measured by ELISA. 
The seropositivity cut-off for all three pertussis antibodies in ELISA is currently 
5 EL.U/ml. Subjects with antibody concentration below the cut-off will be 
considered seronegative.
The immunological assay results will be communicated to the investigator as soon as they 
become available and in any case no later than 12 months after the visit date at which 
sampling allows the assessment of immunogenicity.
The investigator is encouraged to share the immunological assay results for non-
responders with the study subjects.
For the study subjects identified as non-responders, it remains the responsibility of the 
study investigator in charge of the subject’s clinical management to determine the 
medical need for re-vaccination and to re-vaccinate the subjects as per local/regional 
practices.
 
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6.
STUDY VACCINES AND ADMINISTRATION
6.1.
Description of study vaccines
The candidate vaccine 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.
The study vaccines are presented in Table 10.
Table 10
Study vaccines
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+
The vaccine will 
be supplied as 
pre-filled syringes
0.5 ml
1
Placebo for 
dTpa vaccine
NaCl
NaCl=150mM
The placebo will 
be supplied as 
pre-filled syringes
0.5 ml
1
6.2.
Storage and handling of study vaccine
The study vaccines must be stored at the respective label storage temperature conditions 
in a safe and locked place. Access to the storage space should be limited to authorized 
study personnel. The storage conditions will be assessed during pre-study activities under 
the responsibility of the sponsor study contact. The storage temperature should be 
continuously monitored with calibrated (if not validated) temperature monitoring 
device(s) and recorded. Refer to the Module on Clinical Trial Supplies in the SPM for 
more details on storage of the study vaccine.
Temperature excursions must be reported in degree Celsius.
Any temperature excursion outside the range of 0.0 to +8.0C (for +2 to +8°C/+36 to 
+46°F label storage condition) impacting investigational medicinal products (IMPs) must 
be reported in the appropriate (electronic) temperature excursion decision form ([e]TDF). 
The impacted IMPs must not be used and must be stored in quarantine at label 
temperature conditions until usage approval has been obtained from the sponsor.
In case of temperature excursion below +2.0°C down to 0.0°C impacting IMP(s) there is 
no need to report in (e)TDF, but adequate actions must be taken to restore the +2 to 
+8°C/+36 to +46°F label storage temperature conditions. The impacted IMP(s) may still 
be administered, but the site should avoid re-occurrence of such temperature excursion.
Refer to the Module on Clinical Trial Supplies in the SPM for more details on actions to 
take.
 
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Refer to the Module on Clinical Trial Supplies in the SPM for details and instructions on 
the temperature excursion reporting and usage decision process, packaging and 
accountability of the study vaccine.
6.3.
Dosage and administration of study vaccines
The injectable vaccines must be administered intramuscularly, at a 90-degree angle into 
the deltoid muscle of the non-dominant arm [CDC, 2002] on the side stated in Table 11. 
In order to ensure proper intramuscular injection of the vaccines, a needle of at least 
1 inch (2.54 cm) length, 25 gauge will be used [Diggle, 2006; Zuckerman, 2000].
The vaccinees will be observed closely for at least 30 minutes following the 
administration of vaccines, with appropriate medical treatment readily available in case 
of a rare anaphylactic reaction.
The dosage and administration of the study vaccines is presented in Table 11.
Table 11
Dosage and administration (Amended: 15 July 2015)
Type of contact and 
time-point*
volume to be 
administered
Study Group
Treatment name
Route 1
Site 2
Side 3
Visit 1 (Day 0)
0.5 mL
dTpa Group
Boostrix
IM
D
N-D
Control Group
Placebo
Visit 3 (At birth)
0.5 mL
dTpa Group
Placebo
IM
D
N-D
Control Group
Boostrix
1 Intramuscular (IM)
2Deltoid (D) 
3Non-dominant (N-D).
Vaccination can be performed in the opposite side in case of medical indication preventing vaccination in the side 
stated in the table, as judged by the investigator.
*Household contacts in Spain: One dose (0.5mL) of Boostrix vaccine will be administered intramuscularly as 
part of an assessment of cocooning.
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. 
The investigator will use SBIR to obtain the replacement vial number. The replacement 
numbers will be allocated by component. The system will ensure, in a blinded manner, 
that the replacement vial matches the formulation the subject was assigned to by 
randomisation.
6.5.
Contraindications to vaccination
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 
 
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protocol (see Section 5.5), or the subject may be withdrawn at the discretion of the 
investigator (see Section 8.4). 

Acute disease and/or fever at the time of vaccination. 

Fever is defined as temperature 37.5°C/99.5°F for oral, axillary or tympanic 
route, or 38.0°C/100.4°F for rectal route. The preferred route for recording 
temperature in this study will be oral/axillary.

Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory 
infection) without fever can be administered all vaccines.
6.6.
Warnings and precautions
Refer to the approved product label/package insert.
6.7.
Concomitant medications/products and concomitant 
vaccinations
At each study visit, the investigator should question the subject 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 starting at Screening Visit and ending at last study visit (study 
conclusion).

Any concomitant vaccination administered in the period starting at Screening Visit 
and ending at last study visit (study conclusion). Note: Medications/vaccinations
taken during pregnancy are to be recorded as medical/vaccination history.

Prophylactic medication (i.e. medication administered in the absence of ANY 
symptom and in anticipation of a reaction to the vaccination).
E.g. an anti-pyretic is considered to be prophylactic when it is given in the absence 
of fever and any other symptom, to prevent fever from occurring [fever is defined as 
temperature 37.5°C/99.5°F for oral, axillary or tympanic route, or 
38.0°C/100.4°F for rectal route].

Any concomitant medications/products/vaccines listed in Section 6.7.2.

Any concomitant medications/products/vaccines relevant to a SAE to be reported as 
per protocol or administered at any time during the study period for the treatment of 
a SAE. In addition, concomitant medications relevant to SAEs need to be recorded 
on the expedited Adverse Event report.
 
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6.7.2.
Concomitant medications/products/vaccines that may lead to the 
elimination of a subject from ATP analyses
The use of the following concomitant medications/products/vaccines will not require 
withdrawal of the subject from the study but may determine a subject’s evaluability in the 
ATP analysis. See Section 10.4 for cohorts to be analysed.

Any investigational or non-registered product (drug or vaccine) other than the study 
vaccines used during the study period. 

Immunosuppressants or other immune-modifying drugs administered chronically 
(i.e. more than 14 days in total) during the study period. For corticosteroids, this will 
mean prednisone 20 mg/day, or equivalent. Inhaled and topical steroids are 
allowed.

Long-acting immune-modifying drugs administered at any time during the study 
period (e.g. infliximab).

A vaccine not foreseen by the study protocol administered during the period starting 
from 30 days before the dose of vaccine and ending 30 days after*, with the 
exception of seasonal influenza vaccine.
*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 SmPC or Prescribing 
Information and according to the local governmental recommendations and provided 
a written approval of the Sponsor is obtained.

Immunoglobulins and/or any blood products administered during the study period.

Drug and/or alcohol abuse.
6.8.
Intercurrent medical conditions that may lead to elimination 
of a subject from ATP analyses
At each study visit subsequent to the first vaccination visit, it must be verified if the 
subject has experienced or is experiencing any intercurrent medical condition. If it is the 
case, the condition(s) must be recorded in the eCRF.
Subjects may be eliminated from the ATP cohort for immunogenicity if, during the study, 
they incur a condition that has the capability of altering their immune response (i.e.
diphtheria, tetanus or pertussis infection) or are confirmed to have an alteration of their 
initial immune status.
7.
HEALTH ECONOMICS
Not applicable.
 
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8.
SAFETY
The investigator or site staff is/are responsible for the detection, documentation and 
reporting of events meeting the criteria and definition of an adverse event (AE) or serious 
adverse event (SAE) as provided in this protocol. 
Each subject will be instructed to contact the investigator immediately should they
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.

New conditions detected or diagnosed after investigational vaccine administration 
even though they may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either 
investigational vaccine or a concurrent medication (overdose per se should not be 
reported as an AE/SAE).

Signs, symptoms temporally associated with vaccine administration.

Significant failure of expected pharmacological or biological action. 

Pre- or post-treatment events that occur as a result of protocol-mandated procedures 
(i.e. invasive procedures, modification of subject’s previous therapeutic regimen).
AEs to be recorded as endpoints (solicited AEs) are described in Section 8.1.3. All other 
AEs will be recorded as UNSOLICITED AEs.
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.
 
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
Situations where an untoward medical occurrence did not occur (e.g. social and/or 
convenience admission to a hospital, admission for routine examination).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 

Pre-existing conditions or signs and/or symptoms present in a subject prior to the 
study vaccination. These events will be recorded in the medical history section of the 
eCRF.
8.1.2.
Definition of a serious adverse event
A SAE is any untoward medical occurrence that:
a.
Results in death,
b.
Is life-threatening,
Note: The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in 
which the subject was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, had it been more severe.
c.
Requires hospitalisation or prolongation of existing hospitalisation,
Note: In general, hospitalisation signifies that the subject has been admitted at the 
hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician’s office or in an out-patient setting. Complications 
that occur during hospitalisation are also considered AEs. If a complication prolongs 
hospitalisation or fulfils any other serious criteria, the event will also be considered 
serious. When in doubt as to whether ‘hospitalisation’ occurred or was necessary, the 
AE should be considered serious.
Hospitalisation for elective treatment of a pre-existing condition (known or 
diagnosed prior to informed consent signature) that did not worsen from baseline is 
NOT considered an AE.
d.
Results in disability/incapacity, 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.
Adverse pregnancy outcomes specified in Section 8.1.5 and the listed pregnancy-
related events of interest/neonate-related events of interest in Section 8.2.2 should 
always be considered as SAEs (medically important events) and should be reported 
as described in Sections 8.3.1 and 8.3.3.
Medical or scientific judgement should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalisation but may jeopardise the
subject or may require medical or surgical intervention to prevent one of the other 
 
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outcomes listed in the above definition. These should also be considered serious. 
Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalisation.
Note: Any hospitalisation due to either normal or caesarean delivery will not be 
considered as an SAE.
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
Pain at injection site
Redness at injection site
Swelling at injection site
If any study subject reports a large injection site reaction (defined as any local swelling 
with diameter >100 mm and/or any noticeable diffuse injection site swelling (diameter 
not measurable) and/or any noticeable increased circumference of the injected limb), they 
will be asked to contact the study personnel and come for an evaluation by the 
investigator as soon as possible. The investigator will record detailed information 
describing the AE on a specific large swelling reaction sheet in the eCRF.
8.1.3.2.
Solicited general adverse events
The following general AEs will be solicited:
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.
8.1.4.
Clinical laboratory parameters and other abnormal assessments 
qualifying as adverse events or serious adverse events 
In absence of diagnosis, abnormal laboratory findings (e.g. clinical chemistry, 
haematology, urinalysis) or other abnormal assessments (e.g. vital signs etc.) that are 
judged by the investigator to be clinically significant will be recorded as AE or SAE if 
they meet the definition of an AE or SAE (refer to Sections 8.1.1 and 8.1.2). Clinically 
significant abnormal laboratory findings or other abnormal assessments that are present at 
 
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baseline and significantly worsen following the start of the study will also be reported as 
AEs or SAEs. However, clinically significant abnormal laboratory findings or other 
abnormal assessments that are associated with the disease being studied, unless judged by 
the investigator as more severe than expected for the subject’s condition, or that are 
present or detected at the start of the study and do not worsen, will not be reported as AEs 
or SAEs.
The investigator will exercise his or her medical and scientific judgement in deciding 
whether an abnormal laboratory finding or other abnormal assessment is clinically 
significant.
8.1.5.
Pregnancy outcomes
While pregnancy itself is not considered an AE or SAE, any adverse pregnancy outcome
or pregnancy complication or elective termination of a pregnancy for medical reasons 
will be recorded as an AE or a SAE.
The following adverse pregnancy outcomes should always be considered as SAE and will 
be reported as described in Sections 8.3.1 and 8.3.3:

Spontaneous pregnancy loss, including:

spontaneous abortion, (spontaneous pregnancy loss before/at 22 weeks of 
gestation).

ectopic and molar pregnancy.

stillbirth (intrauterine death of foetus after 22 weeks of gestation).
Note: the 22 weeks cut-off in gestational age is based on WHO-ICD 10 noted in the 
EMA Guideline on pregnancy exposure [EMA, 2006]. It is recognized that national 
regulations might be different.

Any early neonatal death (i.e. death of a live born infant occurring within the first 7 
days of life).

Any congenital anomaly or birth defect (as per [CDC MACDP] guidelines) 
identified in the offspring of a study patient (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.
 
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8.2.
Detecting and recording adverse events, serious adverse 
events, pregnancies, pregnancy-related AEs and neonate-
related AEs
8.2.1.
Time period for detecting and recording adverse events, serious 
adverse events, pregnancies, pregnancy-related AEs and
neonate-related AEs (Amended: 15 July 2015)
All AEs starting within 30 days following administration of each dose of study 
vaccine/placebo (Day 0 to Day 30) must be recorded into the appropriate section of the 
eCRF, irrespective of intensity or whether or not they are considered vaccination-related.
The time period for collecting and recording SAEs (including adverse pregnancy 
outcomes, listed pregnancy-related adverse events of interest/neonate-related adverse 
events of interest) will begin at the first receipt of study vaccine/placebo and will end at 
study end (Visit 4) for each subject. See Section 8.3 for instructions on reporting of 
SAEs.
The time period for collecting and recording AEs, SAEs, pregnancies, pregnancy-related 
AEs and neonate-related AEs will begin at the first receipt of study vaccine/placebo and 
will end at study end (Visit 4).
All AEs/SAEs leading to withdrawal from the study will be collected and recorded from 
the time of the first receipt of study vaccine/placebo.
SAEs that are related to the investigational vaccine will be collected and recorded from 
the time of the first receipt of study vaccine/placebo 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 new pregnancies will begin after delivery of 
the baby and will end at Visit 4. See section 8.3 for instructions on reporting of 
pregnancies.
The time period of reporting SAEs for household contacts will begin at the 
administration of Boostrix vaccine (as part of an assessment of cocooning) and end at 
30 days after the vaccination. The SAEs and pregnancies in household contacts will be 
collected till 30 days after vaccination, irrespective of the visit in which Boostrix 
vaccine is administered.
An overview of the protocol-required reporting periods for AEs and SAEs is given in the 
table below Table 13.
 
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Table 13
Reporting periods for adverse events, serious adverse events, 
pregnancies, pregnancy-related adverse events and neonate-related 
adverse events (Amended: 15 July 2015)
Event
Screening 
Visit*
V1
8 d 
(0-7d) 
post V1
31 d 
(0-30d) post V1
V3
8 d 
(0-7d) post 
V3
31 d 
(0-30 d)
post V3
V4
(Study
Conclusion)
D0
V2 (D30)
At birth
Post-
delivery M2
Solicited 
local and 
general AEs
Unsolicited 
AEs
AEs/SAEs 
leading to 
withdrawal 
from the 
study
SAEs
Pregnancy-
related 
adverse 
events and
neonate-
related 
adverse
events
SAEs related to 
study 
participation 
or concurrent 
GSK 
medication/
vaccine
New 
pregnancies
SAEs and 
pregnan-
cies in 
household 
contacts in 
Spain**
 
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Event
Screening 
Visit*
V1
8 d 
(0-7d) 
post V1
31 d 
(0-30d) post V1
V3
8 d 
(0-7d) post 
V3
31 d 
(0-30 d)
post V3
V4
(Study
Conclusion)
D0
V2 (D30)
At birth
Post-
delivery M2
SAEs related 
to study 
participation 
or concurrent 
GSK 
medication/
Vaccine in 
household 
contacts in 
Spain
* i.e. consent obtained; V: Visit; D: Day, M: Month
** The SAEs and pregnancies in household contacts will be reported till 30 days after vaccination, irrespective 
of the visit in which Boostrix vaccine is administered.
8.2.2.
Adverse events of specific interest (adverse pregnancy 
outcomes, listed pregnancy-related adverse events of 
interest/neonate-related events of interest)
All adverse pregnancy outcomes, listed pregnancy-related adverse events of interest and 
neonate-related events of interest occurring at any time during the period starting with the 
first administration of the vaccine till end of the study will be considered as SAEs and 
must be recorded in the appropriate section of the patient’s eCRF, irrespective of 
intensity or whether or not they are considered administration-related.
Adverse pregnancy outcomes include:

Live birth with congenital anomalies, 

Still birth with no congenital anomalies, 

Still birth with congenital anomalies, 

Elective termination with no congenital anomalies  

Elective termination with congenital anomalies
Listed pregnancy-related adverse events of interest/neonate-related events of interest
include:

Gestational diabetes, 

Pregnancy-related hypertension, 

Premature rupture of membranes, 

Preterm premature rupture of membranes,

Premature labour, 

Premature uterine contractions, 
 
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
Intrauterine growth restriction/poor foetal growth, 

Pre-eclampsia and eclampsia, 

Vaginal or intrauterine haemorrhage, 

Maternal death, 

Preterm birth, 

Neonatal death, 

Small for gestational age, 

Neonatal hypoxic ischaemic encephalopathy 

Failure to thrive/growth deficiency
The definitions of the above specified pregnancy outcomes and listed pregnancy-related 
adverse events of interest/neonate-related events of interest are adapted from [Munoz, 
2013] and can be found in the GLOSSARY OF TERMS and in APPENDIX C.
8.2.3.
Post-Study adverse events and serious adverse events
A post-study AE/SAE is defined as any event that occurs outside of the AE/SAE 
reporting period defined in Table 13. Investigators are not obligated to actively seek AEs 
or SAEs in former study participants. However, if the investigator learns of any SAE at 
any time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the investigational vaccine, the investigator will promptly 
notify the Study Contact for Reporting SAEs.
8.2.4.
Evaluation of adverse events and serious adverse events
8.2.4.1.
Active questioning to detect adverse events and serious adverse 
events
As a consistent method of collecting AEs, the subject should be asked a non-leading 
question such as:
‘Have you felt different in any way since receiving the vaccine or since the previous 
visit?’
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g. hospital progress notes, laboratory and diagnostics reports) relative 
to the event. The investigator will then record all relevant information regarding an 
AE/SAE in the eCRF. The investigator is not allowed to send photocopies of the subject’s 
medical records to GSK Biologicals instead of appropriately completing the eCRF. 
However, there may be instances when copies of medical records for certain cases are 
requested by GSK Biologicals. In this instance, all subject identifiers will be blinded on 
the copies of the medical records prior to submission to GSK Biologicals.
 
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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.
8.2.4.2.
Assessment of adverse events
8.2.4.2.1.
Assessment of intensity
The intensity of the following solicited AEs will be assessed as described:
Table 14
Intensity scales for solicited symptoms in adults 
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/°F
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 37.5°C / 99.5°F for oral, axillary or tympanic route, or 38.0°C / 100.4°F for rectal 
route. The preferred route for recording temperature in this study will be oral/axillary.
The maximum intensity of local injection site redness/swelling/fever 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 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 adults, such 
an AE would, for example, prevent attendance at work 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.
8.2.4.2.2.
Assessment of causality
The investigator is obligated to assess the relationship between investigational vaccine 
and the occurrence of each AE/SAE. The investigator will use clinical judgement to 
determine the relationship. Alternative plausible causes, such as natural history of the 
underlying diseases, concomitant therapy, other risk factors, and the temporal relationship 
of the event to the investigational vaccine will be considered and investigated. The 
investigator will also consult the IB to determine his/her assessment.
There may be situations when a SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK Biologicals. However, it is very 
important that the investigator always makes an assessment of causality for every event 
prior to submission of the Expedited Adverse Events Report to GSK Biologicals. The 
investigator may change his/her opinion of causality in light of follow-up information and 
update the SAE information accordingly. The causality assessment is one of the criteria 
used when determining regulatory reporting requirements.
In case of concomitant administration of multiple vaccines, it may not be possible to 
determine the causal relationship of general AEs to the individual vaccine administered. 
The investigator should, therefore, assess whether the AE could be causally related to 
vaccination rather than to the individual vaccines.
 
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All solicited local (injection site) reactions will be considered causally related to 
vaccination. Causality of all other AEs should be assessed by the investigator using the 
following question:
Is there a reasonable possibility that the AE may have been caused by the investigational 
vaccine?
YES
:
There is a reasonable possibility that the vaccine contributed to the 
AE. 
NO
:
There is no reasonable possibility that the AE is causally related to 
the administration of the study vaccine(s). There are other, more 
likely causes and administration of the study vaccine is not 
suspected to have contributed to the AE.
If an event meets the criteria to be determined as ‘serious’ (see Section 8.1.2), additional 
examinations/tests will be performed by the investigator in order to determine ALL
possible contributing factors for each SAE.
Possible contributing factors include:

Medical history.

Other medication.

Protocol required procedure.

Other procedure not required by the protocol.

Lack of efficacy of the vaccine, if applicable.

Erroneous administration.

Other cause (specify).
8.2.4.3.
Assessment of outcomes
The investigator will assess the outcome of all unsolicited AEs (including SAEs) 
recorded during the study as:

Recovered/resolved.

Recovering/resolving.

Not recovered/not resolved.

Recovered with sequelae/resolved with sequelae.

Fatal (SAEs only).
 
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8.2.4.4.
Medically attended visits
For each solicited and unsolicited symptom the subject experiences, the subject will be 
asked if she received medical attention defined as hospitalisation, or an otherwise 
unscheduled visit to or from medical personnel for any reason, including emergency 
room visits. This information will be recorded in the eCRF. 
Note: hospitalisation or an unscheduled visit due to either normal or caesarean delivery 
will not be considered as an SAE and will not be recorded as a medically attended visit in 
the eCRF.
8.3.
Reporting of serious adverse events, pregnancies and other 
events
8.3.1.
Prompt reporting of serious adverse events, pregnancies and 
other events to GSK Biologicals
SAEs that occur in the time period defined in Section 8.2 will be reported promptly to 
GSK within the timeframes described in Table 15, once the investigator determines that 
the event meets the protocol definition of a SAE.
Adverse pregnancy outcomes and listed pregnancy-related adverse events of 
interest/neonate-related adverse events of interest that occur in the time period defined in 
Section 8.2 will be considered as SAE and will be reported promptly to GSK within the 
timeframes described in Table 15, once the investigator becomes aware of them.
Pregnancies that occur in the time period defined in Section 8.2 will be reported promptly 
to GSK within the timeframes described in Table 15, once the investigator becomes 
aware of the pregnancy. 
Table 15
Timeframes for submitting serious adverse event and other events
reports to GSK Biologicals
Type of Event
Initial Reports
Follow-up of Relevant Information on a 
Previous Report
Timeframe
Documents
Timeframe
Documents
SAEs#
24 hours*‡
electronic Expedited 
Adverse Events Report
24 hours*
electronic Expedited Adverse 
Events Report
Pregnancies
1 week*
electronic 
pregnancy report
1 week*
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.
# including adverse pregnancy outcomes and listed pregnancy-related/neonate-related AEs of interest.
 
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8.3.2.
Contact information for reporting serious adverse events, 
pregnancies and other events
Study Contact for Reporting SAEs, pregnancies and other events
Refer to the local study contact information document.
Back-up Study Contact for Reporting SAEs, pregnancies and other events
24/24 hour and 7/7 day availability:
GSK Biologicals Clinical Safety & Pharmacovigilance
Fax: +
 or +
Email address: 
8.3.3.
Completion and transmission of SAE reports to GSK Biologicals
Once an investigator becomes aware that a SAE has occurred in a study subject, the 
investigator (or designate) must complete the information in the electronic Expedited 
Adverse Events Report WITHIN 24 HOURS. The report will always be completed as 
thoroughly as possible with all available details of the event. Even if the investigator does 
not have all information regarding a SAE, the report should still be completed within 24 
hours. Once additional relevant information is received, the report should be updated 
WITHIN 24 HOURS.
The investigator will always provide an assessment of causality at the time of the initial 
report. The investigator will be required to confirm the review of the SAE causality by 
ticking the ‘reviewed’ box in the electronic Expedited Adverse Events Report within 72 
hours of submission of the SAE.
8.3.3.1.
Back-up system in case the electronic reporting system does not work
If the electronic reporting system does not work, the investigator (or designate) must 
complete, then date and sign a paper Expedited Adverse Events Report and fax it to the 
Study Contact for Reporting SAEs (refer to the Sponsor Information) or to GSK 
Biologicals Clinical Safety and Pharmacovigilance department within 24 hours. 
This back-up system should only be used if the electronic reporting system is not working 
and NOT if the system is slow. As soon as the electronic reporting system is working 
again, the investigator (or designate) must complete the electronic Expedited Adverse 
Events Report within 24 hours. The final valid information for regulatory reporting will 
be the information reported through the electronic SAE reporting system. 
8.3.4.
Completion and transmission of pregnancy reports to GSK 
Biologicals
Once the investigator becomes aware that a subject is pregnant after delivery, 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.
8.3.5.
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 15.
8.3.6.
Regulatory reporting requirements for serious adverse events
The investigator will promptly report all SAEs to GSK in accordance with the procedures 
detailed in Section 8.3.1. GSK Biologicals has a legal responsibility to promptly notify, 
as appropriate, both the local regulatory authority and other regulatory agencies about the 
safety of a product under clinical investigation. Prompt notification of SAEs by the 
investigator to the Study Contact for Reporting SAEs is essential so that legal obligations 
and ethical responsibilities towards the safety of other subjects are met.
Investigator safety reports are prepared according to the current GSK policy and are 
forwarded to investigators as necessary. An investigator safety report is prepared for a 
SAE(s) that is both attributable to the investigational vaccine and unexpected. The 
purpose of the report is to fulfil specific regulatory and GCP requirements, regarding the 
product under investigation.
8.4.
Follow-up of adverse events, serious adverse events and 
pregnancies 
8.4.1.
Follow-up of adverse events and serious adverse events 
8.4.1.1.
Follow-up during the study
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject and provide additional relevant information on the subject’s condition to GSK 
Biologicals (within 24 hours for SAEs; refer to Table 15).
All SAEs documented at a previous visit/contact and designated as not recovered/not 
resolved or recovering/resolving will be reviewed at subsequent visits/contacts until the 
end of the study.
 
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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 last vaccination.
8.4.1.2.
Follow-up after the subject is discharged from the study
The investigator will follow subjects:

with SAEs or subjects withdrawn from the study as a result of an AE, until the event 
has resolved, subsided, stabilised, disappeared, or until the event is otherwise 
explained, or the subject is lost to follow-up. 

with other non-serious AEs, until the end of the study period or they are lost to 
follow-up.
If the investigator receives additional relevant information on a previously reported SAE, 
he/she will provide this information to GSK Biologicals using a 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.
8.4.2.
Follow-up of pregnancies
Pregnant subjects will be followed to determine the outcome of the pregnancy. At the end 
of the pregnancy, whether full-term or premature, information on the status of the mother 
and child will be forwarded to GSK Biologicals using the electronic pregnancy report and 
the Expedited Adverse Events Report if applicable. Generally, the follow-up period 
doesn’t need to be longer than six to eight weeks after the estimated date of delivery.
Regardless of the reporting period for SAEs for this study, if the pregnancy outcome is a 
SAE, it should always be reported as SAE.
8.5.
Treatment of adverse events
Treatment of any AE is at the sole discretion of the investigator and according to current 
good medical practice. Any medication administered for the treatment of an AE should 
be recorded in the subject’s eCRF (refer to Section 6.7).
8.6.
Unblinding
GSK Biologicals’ policy (which incorporates ICH E2A guidance, EU Clinical Trial 
Directive and US Federal Regulations) is to unblind the report of any SAE which is 
unexpected and attributable/suspected to be attributable to the investigational vaccines, 
 
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prior to regulatory reporting. The GSK Biologicals’ Central Safety Physician is 
responsible for unblinding the treatment assignment in accordance with the specified 
timeframes for expedited reporting of SAEs (refer to Section 8.3.1).
8.7.
Emergency unblinding
Unblinding of a subject’s individual treatment code should occur only in the case of a 
medical emergency, or in the event of a serious medical condition, when knowledge of 
the treatment is essential for the clinical management or welfare of the subject, as judged 
by the investigator.
The emergency unblinding process consists of the automated system SBIR that allows the 
investigator to have unrestricted, immediate and direct access to the subject’s individual 
study treatment.
The investigator has the option of contacting a GSK Biologicals’ On-call Central Safety 
Physician (or Backup) if he/she needs medical advice or needs the support of GSK to 
perform the unblinding (i.e. he/she cannot access the automated Internet-based system).
Any emergency unblinding must be fully documented by using the Emergency 
Unblinding Documentation Form, which must be appropriately completed by the 
investigator and sent within 24 hours to GSK Biologicals.
GSK Biologicals’ Contact information for Emergency Unblinding
24/24 hour and 7/7 day availability
GSK Biologicals’ Central Safety Physician: 
Outside US/Canada:
+
 (GSK Biologicals Central Safety Physician on-call)
For US/Canada only:
+
 (GSK Biologicals Central Safety Physician on-call)
GSK Biologicals’ Central Safety Physician Back-up:
Outside US/Canada:
+
US/Canada only:
+ 
Emergency Unblinding Documentation Form transmission:
Outside US & Canada:
Fax: +
 or +
US/Canada only:
Fax: +
 
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8.8.
Subject card (Amended: 15 July 2015)
Study subjects and the participating household contacts 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. 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 must be instructed to keep subject cards in their possession at all times.
9.
SUBJECT COMPLETION AND WITHDRAWAL
9.1.
Subject completion
A subject who returns for the concluding visit foreseen in the protocol is considered to 
have completed the study.
9.2.
Subject withdrawal
Withdrawals will not be replaced.
9.2.1.
Subject withdrawal from the study
From an analysis perspective, a ‘withdrawal’ from the study refers to any subject who did 
not come back for the concluding visit foreseen in the protocol. 
All data collected until the date of withdrawal/last contact of the subject will be used for 
the analysis.
A subject is considered a ‘withdrawal’ from the study when no study procedure has 
occurred, no follow-up has been performed and no further information has been collected 
for this subject from the date of withdrawal/last contact.
Investigators will make an attempt to contact those subjects who do not return for 
scheduled visits or follow-up. 
Information relative to the withdrawal will be documented in the eCRF. The investigator 
will document whether the decision to withdraw a subject from the study was made by 
the subject himself/herself, or by the investigator, as well as which of the following 
possible reasons was responsible for withdrawal:

Serious adverse event.

Non-serious adverse event.

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
Consent withdrawal, not due to an adverse event*.

Moved from the study area.

Lost to follow-up.

Other (specify).
*In case a subject is withdrawn from the study because he/she has withdrawn consent, the 
investigator will document the reason for withdrawal of consent, if specified by the 
subject, in the eCRF.
Subjects who are withdrawn from the study because of SAEs/AEs must be clearly 
distinguished from subjects who are withdrawn for other reasons. Investigators will 
follow subjects who are withdrawn from the study as result of a SAE/AE until resolution 
of the event (see Section 8.4.1.2).
9.2.2.
Subject withdrawal from investigational vaccine
A ‘withdrawal’ from the investigational vaccine refers to any subject who does not 
receive the complete treatment, i.e. when no further planned dose is administered from 
the date of withdrawal. A subject withdrawn from the investigational vaccine may not 
necessarily be withdrawn from the study as further study procedures or follow-up may be 
performed (safety or immunogenicity) if planned in the study protocol. 
Information relative to premature discontinuation of the investigational vaccine will be 
documented on the Vaccine Administration screen of the eCRF. The investigator will 
document whether the decision to discontinue further vaccination was made by the 
subject herself or by the investigator, as well as which of the following possible reasons 
was responsible for withdrawal:

Serious adverse event.

Non-serious adverse event.

Other (specify).
9.3.
Extension study
At the end of the study (study conclusion visit), the investigator will ask each subject if 
they are interested to allow their child to participate in the follow-up study. If a subject is 
not interested in allowing their child to participate in the follow-up study, the reason for 
refusal will be documented in the subject’s eCRF.
 
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10.
STATISTICAL METHODS
10.1.
Primary endpoint

Immunogenicity with respect to components of the study vaccine, at delivery (in 
cord blood sample):

Anti-PT, anti-FHA and anti-PRN antibody concentrations.
10.2.
Secondary endpoints (Amended: 15 July 2015)

Outcome of pregnancy in terms of pregnancy outcomes up to study end (Visit 4).

Pregnancy outcomes will include live birth with no congenital anomalies, live 
birth with congenital anomalies, still birth with no congenital anomalies, still 
birth with congenital anomalies, elective termination with no congenital 
anomalies and elective termination with congenital anomalies.

Outcome of pregnancy in terms of listed pregnancy-related adverse events of 
interest/ neonate-related events of interest up to study end (Visit 4).

Listed pregnancy-related adverse events of interest/ neonate-related events of 
interest will include gestational diabetes, pregnancy-related hypertension, 
premature rupture of membranes, preterm premature rupture of membranes, 
premature labour, premature uterine contractions, intrauterine growth 
restriction/poor foetal growth, pre-eclampsia, eclampsia, vaginal or intrauterine 
haemorrhage, maternal death, preterm birth, neonatal death, small for gestational 
age, neonatal hypoxic ischaemic encephalopathy and failure to thrive/growth 
deficiency.

Immunogenicity with respect to components of the study vaccine received during 
pregnancy, one month post vaccination:

Anti-D, anti-T, anti-PT, anti-FHA and anti-PRN seroprotection/seropositivity 
status and antibody concentrations.

Vaccine response to PT, FHA and PRN

Vaccine response to anti-D and anti-T

Immunogenicity with respect to components of the study vaccine, in the cord blood 
sample.

Anti-PT, anti-FHA and anti-PRN seropositivity status.

Solicited local and general symptoms (at Visit 1 and Visit 3).

Occurrence of each solicited local/general symptoms during the 8-day (Day 0-
Day 7) follow-up period after the vaccination.
 
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
Unsolicited adverse events (at Visit 1 and Visit 3).

Occurrence of unsolicited AEs within 31 days (Day 0 – Day 30) after any 
vaccination, according to the Medical Dictionary for Regulatory Activities 
(MedDRA) classification.

Serious adverse events (SAEs).

Occurrence of serious adverse events from Dose 1 up to study end (Visit 4).

Percentage of household contacts of the infants born to pregnant women 
vaccinated in Spain who accepted Boostrix vaccine as part of an assessment of 
cocooning among the eligible household contacts.

Occurrence of SAEs among the vaccinated household contacts of the infants born 
to pregnant women in Spain, as part of an assessment of cocooning, from the day 
of vaccination till 30 days after vaccination.
Refer to GLOSSARY OF TERMS for the definitions of the various pregnancy outcomes 
and listed pregnancy-related adverse events of interest/neonate-related events of interest.
10.3.
Determination of sample size
It is proposed to conduct the study with a sample size of 680 subjects. Assuming a drop-
out rate of approximately 20%, to compensate for subject attrition due to early 
withdrawal, a total of 680 subjects (340 in each group) will be randomised in a 1:1 ratio 
in order to obtain the desired number of 272 evaluable subjects in each group for 
immunogenicity analysis. Availability of 272 evaluable subjects per group (for a total of 
680 subjects) will provide above 96% overall power to reach the primary endpoint for the 
primary maternal phase using Bonferroni adjustment on type II error. This sample size is 
justified by the expected difficulty to enrol pregnant women in the study and on the 
minimum requirement of safety data in pregnant women, as determined by EU guidelines 
[EMA, 2008].
Table 16 presents the Power to rule out the null hypothesis (H0: group GMC ratio < 1.5) 
that dTpa Group is not superior to the Control Group.
Table 16
Power to rule out the null hypothesis (H0: group GMC ratio < 1.5) that 
dTpa Group is not superior to the Control Group (N= 272 evaluable 
subjects per group) 
Endpoint 
Standard deviation*
[Log10 (titre)]
True group 
ratio*
Power**
Anti-PT
0.577
2.3
96%
Anti-FHA
0.564
5
>99%
Anti-PRN
0.564
5
>99%
*anticipated conservative value (References: [Leuridian, 2011; Munoz, 2014])
** PASS2005, one sided test for difference between 2 independent groups, HA: group difference=log10 (true group 
ratio), one-side alpha = 0.025, Assuming common variance between the groups Using Bonferroni adjustment on type II 
error (overall beta=sum of type II error of each endpoint)
 
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Table 17 presents the precision achieved with a sample of 300 subjects in each group for 
the various possible expected adverse pregnancy outcomes and listed pregnancy-related
adverse events of interest/neonate-related events of interest in terms of exact 95% CIs.
Table 17
Precision achieved with a sample of 300 subjects in each group for 
the various possible expected pregnancy outcomes and listed 
pregnancy-related adverse events of interest/ neonate-related events 
of interest in terms of exact 95 percent CI
No. of 
subjects 
expected 
(N)
Pregnancy outcome and listed pregnancy-
related adverse events of interest/neonate-
related events of interest
Subjects with outcome
n
%
Exact 95%CI
LL
UL
300
Stillbirth
1
0.3
0.0
1.8
Stillbirth^
0
0.0
0.0
1.2
Placental Abruption
3
1.0
0.2
2.9
Placenta previa
1
0.3
0.0
1.8
Post-partum haemorrhage
18
6.0
3.6
9.3
Premature rupture of membranes 
24
8.0
5.2
11.7
Premature uterine contractions and premature 
labour
36
12.0
8.5
16.2
Preterm delivery
35
11.7
8.3
15.7
Intrauterine growth restriction / poor foetal 
growth
30
10.0
6.8
14.0
Pregnancy related hypertension, preeclampsia 
and eclampsia
36
12.0
8.5
16.2
Gestational diabetes
15
5.0
2.8
8.1
Congenital anomalies (major anomalies)
9
3.0
1.4
5.6
n = No. of subjects with any pregnancy outcome
% = (n/N)*100; LL = Lower limit; UL = Upper limit
^Even if we observe no events for a specific outcome, the upper limit of the 95% CI will be 1.2%.
Reference paper: Munoz FM, et al. Research on vaccines during pregnancy: Protocol design and assessment of 
safety. Vaccine, 2013
10.4.
Cohorts for Analyses
10.4.1.
Total Vaccinated cohort

The Total Vaccinated cohort (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 
during pregnancy (Visit 1) for whom data concerning at least one immunogenicity 
endpoint measure is available.
 
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10.4.2.
According-To-Protocol cohort for analysis of safety
The ATP cohort for safety will consist of all subjects from the TVC who complied with 
vaccine administration up to the end of the Epoch 001, namely:

Who have received the dose of study vaccine (at Visit 1) according to their random 
assignment,

For whom administration site of study vaccine is known, and is according to 
protocol, 

Who have not received a vaccine not specified or forbidden in the protocol,

For whom the randomisation code is not broken.
10.4.3.
ATP cohort for analysis of immunogenicity
The ATP cohort for analysis of immunogenicity will include all evaluable subjects from 
the ATP cohort for analysis of safety:

Who meet all eligibility criteria.

Who comply with the procedures and intervals defined in the protocol.

Who are within the maximum interval allowed as defined in the protocol.

Who do not meet any of the criteria for elimination from an ATP analysis (refer to 
Section 6.7.2) during the study.

Who did not receive a product leading to exclusion from an ATP analysis as listed 
Section 6.7.2.

Who did not present with a medical condition leading to exclusion from an ATP 
analysis as listed Section 6.8.

Who have the cord blood collection at least 21 days post-vaccination.

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 one month after vaccination i.e. Visit 3 in 
the cord blood sample.
10.4.4.
Total cohort for household contacts in Spain
Total cohort for household contacts will include all eligible household contacts of the 
infants born to pregnant women vaccinated in Spain. For the analysis of safety, all 
vaccinated household contacts will be considered.
10.5.
Derived and transformed data

A seronegative subject is a subject whose antibody concentration is below the assay 
cut-off.
 
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
A seropositive subject is a subject whose antibody concentration is greater than or
equal to the assay cut-off defined (refer to Table 8). The following seropositivity 
thresholds are currently applicable:

Anti-PT, anti-FHA and anti-PRN antibody concentrations 5 EL.U/mL.

A seroprotected subject is a subject whose antibody concentration is greater than or 
equal to the level defining clinical protection (refer to Table 8). The following
seroprotection thresholds are applicable:

Anti-D antibody concentrations 0.1 IU/mL 

Anti-T antibody concentrations 0.1 IU/mL.

Other cut-offs to be considered:

Anti-D antibody concentrations 1.0 IU/mL.

Anti-T antibody concentrations 1.0 IU/mL.

Vaccine response one month post vaccination in pregnant women (at Visit 3) to the 
diphtheria and tetanus antigens is defined as:

For initially seronegative subjects (pre-vaccination concentration below cut-off:
< 0.1 IU/mL): antibody concentrations at least four times the assay cut-off (post-
vaccination concentration ≥ 0.4 IU/mL).

For initially seropositive subjects (pre-vaccination concentration ≥ 0.1 IU/mL):
an increase in antibody concentrations of at least four times the pre-vaccination
concentration.

Vaccine response one month post vaccination in pregnant women (at Visit 3) to the 
PT, FHA and PRN antigens, is defined as:

For initially seronegative subjects with pre-vaccination antibody concentration 
below cut-off, i.e. < 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 antibody concentration 
≥5 EL.U/mL and < 20 EL.U/mL: an increase in antibody concentrations of at 
least four times the pre-booster antibody concentration, one month after 
vaccination.

For initially seropositive subjects with pre-vaccination antibody concentration 
≥20 EL.U/mL: an increase in antibody concentrations of at least two times the 
pre-booster antibody concentration, one month after vaccination.

The GMC calculations will be 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: For a given subject and a given immunogenicity measurement, 
missing or non-evaluable measurements will not be replaced.
Safety/ Reactogenicity

For the analysis of solicited symptoms, missing or non-evaluable measurements will 
not be replaced. Therefore the analysis of the solicited symptoms based on the TVC 
will include only subjects with documented safety data (i.e. symptom screen 
completed).

For the analysis of unsolicited symptoms, SAEs and analyses that combine solicited 
and unsolicited symptoms, subjects with no report of the event will be considered to 
have not had the event. Subjects who do not report being administered concomitant 
medications and vaccinations will be considered to have not received any 
medications and vaccinations.
10.6.
Analysis of demographics (Amended: 15 July 2015)
Demographic characteristics (age at the booster dose in years, race, height [cm], weight 
[kg], body mass index in kg/m2), cohort description and withdrawal status will be 
summarised by group using descriptive statistics:

Frequency tables will be generated for categorical variables such as race;

Mean, median and standard error will be provided for continuous data such as age.
The distribution of subjects enrolled among the study sites and countries will be tabulated 
as a whole and per group.
Summary statistics by height [cm], weight [kg], head circumference [cm], body mass 
index [BMI in kg/m²] and Apgar score of the infant will be tabulated as a whole and per 
group.
10.6.1.
Analysis of eligible household contacts
Analysis of eligible household contacts will be performed on the Total cohort for 
household contacts in Spain.

Demographic characteristics will be summarised for the eligible household 
contacts as a whole and per group using descriptive statistics.

Reasons for refusal of the cocooning vaccination will be summarised for the 
eligible household contacts as a whole and per group.

Percentage of household contacts of the infants born to pregnant women 
vaccinated in Spain who accepted Boostrix vaccine as part of an assessment of 
cocooning among the eligible household contacts will be tabulated as a whole and 
per group.
 
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10.7.
Analysis of immunogenicity
The primary analysis will be based on the ATP cohort for analysis of immunogenicity. If, 
in any vaccine group, the percentage of vaccinated subjects with serological results 
excluded from this ATP cohort is 5% or more, a second analysis based on the TVC will 
be performed to complement the ATP analysis.
10.7.1.
Within group assessment:
For each treatment group, before and one month after vaccination during pregnancy and 
if blood sample result is available:

Seroprotection rates and their exact 95% CIs for antibodies against diphtheria and 
tetanus will be calculated.

Seropositivity rates and their exact 95% CIs for antibodies against PT, FHA, PRN, 
will be tabulated.

GMCs and their 95% CIs for antibodies against all vaccine antigens will be 
calculated. 

The distribution of antibody concentrations one month after booster vaccination for 
each antigen will be displayed using reverse cumulative distribution curves.

Vaccine response to diphtheria, tetanus and pertussis antigens and their exact 95% CI 
will be calculated.
In the cord blood sample, if the blood sample result is available: 

Seropositivity rates and their exact 95% CIs for antibodies against PT, FHA, PRN, 
will be tabulated.

GMCs and their 95% CIs for antibodies against PT, FHA, PRN antigens will be 
calculated. 
10.7.2.
Between group assessment:

The primary objective is to demonstrate that, the immune response in the dTpa 
Group is superior to that in the Control Group for the pertussis antigens, in the cord 
blood sample.

The LL of the 95% CI of the GMC ratio [dTpa Group divided by Control Group] 
for anti-PT, anti-FHA and anti-PRN antibodies are 1.5.
The CI of the group GMC ratios will be computed using a two-sample t test assuming 
heterogeneity of variance.
 
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10.8.
Analysis of safety (Amended: 15 July 2015)
The primary analysis will be performed on the TVC. If in any vaccine group, 5% or more 
of the vaccinated subjects are eliminated from the TVC, a second analysis will be 
performed on the ATP cohort for analysis of safety. Analysis of safety in household 
contacts will be performed on the Total cohort for household contacts in Spain.

The percentage of subjects with each specific pregnancy outcomes and listed 
pregnancy-related adverse events of interest/neonate-related events of interest will be 
tabulated with its exact 95% CI.

The percentage of subjects with at least one local AE (solicited and unsolicited), with 
at least one general AE (solicited and unsolicited) and with any AE during the 8-day 
(Day 0–Day 7) follow-up period after the vaccination will be tabulated after each 
dose and overall with exact 95% CI. The same calculations will be performed for any 
Grade 3 (solicited or unsolicited) symptoms and for any symptoms requiring medical 
attention.

The percentage of doses followed by at least one local AE (solicited and unsolicited), 
with at least one general AE (solicited and unsolicited) and with any AE during the 
8-day (Day 0–Day 7) follow-up period after the vaccination will be tabulated with 
exact 95% CI. The same calculations will be performed for any Grade 3 (solicited or 
unsolicited) symptoms and for any symptoms requiring medical attention.

The percentage of subjects/doses reporting each individual solicited local and general 
AE during the 8-day (Day 0-Day 7) follow-up period after booster vaccination will 
be tabulated with its exact 95% CI for each group.

All computations mentioned above will be done for Grade ≥2 (solicited symptoms 
only) and Grade 3 symptoms, for symptoms considered related to vaccination 
(general symptoms only), for Grade 3 symptoms considered related to vaccination 
(general symptoms only) and for symptoms that resulted in a medically-attended 
visit.

Occurrence of fever and related fever will be reported per 0.5°C cumulative 
temperature increments as well as the occurrence of Grade 3 fever (> 39.0°C axillary 
temperature) with causal relationship to vaccination. 

Any large injection site reaction (defined as any local swelling with diameter 
> 100 mm and/or any noticeable diffuse injection site swelling (diameter not 
measurable) and/or any noticeable increased circumference of the injected limb) 
onset within 8 days (Day 0–Day 7) after each vaccination will be described in detail.

The verbatim reports of unsolicited symptoms will be reviewed by a physician and 
the signs and symptoms will be coded according to MedDRA. Every verbatim term 
will be matched with the appropriate Preferred Term. The percentage of 
subjects/doses with unsolicited symptoms occurring within 31 days (Day 0–Day 30) 
with its exact 95% CI will be tabulated by preferred term. Similar tabulation will be 
done for Grade 3 unsolicited symptoms and for unsolicited symptoms possibly 
related to vaccination. 
 
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
The percentage of subjects/doses who started to receive at least one concomitant 
medication (i.e. any medication, antipyretic medication, prophylactic antipyretics) 
during the 4-day and 31-day follow-up period after vaccination will be tabulated 
after each dose and overall with exact 95% CI.

SAEs and withdrawal due to AEs and SAEs following booster dose up to Visit 4 will 
be described in detail.

All SAEs assessed as being possibly related to study participation occurring 
throughout the study period will be described.

All SAEs assessed as being possibly related to a concurrent GSK medication 
occurring throughout the study period will be described.

For the vaccinated household contacts in Spain, SAEs following Boostrix
vaccination up to 30 days will be described in detail.
10.9.
Interpretation of analyses
For analysis on the primary objective with pre-defined success criteria and an appropriate 
type I error control, appropriate conclusion can be drawn.
The secondary objectives of the study are descriptive and should be interpreted as such.
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
A final analysis including all cleaned data up to Visit 4 (post-delivery Month 2) will be 
conducted. This analysis will include the final analysis of immunogenicity and the final 
analysis of solicited symptoms/unsolicited symptoms and SAEs. A statistical report and a 
clinical report will be written at that time.
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 and publications must be fulfilled. 
 
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11.1.
electronic Case Report Form instructions
A validated GSK defined electronic data collection tool will be used as the method for 
data collection. 
In all cases, subject initials will not be collected nor transmitted to GSK. Subject data 
necessary for analysis and reporting will be entered/transmitted into a validated database 
or data system. Clinical data management will be performed in accordance with 
applicable GSK standards and data cleaning procedures.
While completed eCRFs are reviewed by a GSK Biologicals’ Site Monitor at the study 
site, omissions or inconsistencies detected by subsequent eCRF review may necessitate 
clarification or correction of omissions or inconsistencies with documentation and 
approval by the investigator or appropriately qualified designee. In all cases, the 
investigator remains accountable for the study data. 
The investigator will be provided with a CD-ROM of the final version of the data 
generated at the investigational site once the database is archived and the study report is 
complete and approved by all parties.
11.2.
Study Monitoring by GSK Biologicals
GSK will monitor the study to verify that, amongst others, the: 

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol, any other 
study agreements, GCP and all applicable regulatory requirements. 
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents.
The investigator must ensure provision of reasonable time, space and qualified personnel 
for monitoring visits.
Direct access to all study-site related and source data is mandatory for the purpose of 
monitoring review. The monitor will perform a eCRF review and a Source Document 
Verification (SDV). By SDV we understand verifying eCRF entries by comparing them 
with the source data that will be made available by the investigator for this purpose. 
The Source Documentation Agreement Form describes the source data for the different 
data in the eCRF. This document should be completed and signed by the site monitor and 
investigator and should be filed in the monitor’s and investigator’s study file. Any data 
item for which the eCRF will serve as the source must be identified, agreed and 
documented in the source documentation agreement form. 
For eCRF, the monitor freezes completed and approved screens at each visit.
 
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Upon completion or premature discontinuation of the study, the monitor will conduct site 
closure activities with the investigator or site staff, as appropriate, in accordance with 
applicable regulations, GCP, and GSK procedures.
11.3.
Record retention
Following closure of the study, the investigator must maintain all site study records 
(except for those required by local regulations to be maintained elsewhere) in a safe and 
secure location. The records must be easily accessible, when needed (e.g. audit or 
inspection), and must be available for review in conjunction with assessment of the 
facility, supporting systems, and staff. Where permitted by applicable laws/regulations or 
institutional policy, some or all of these records can be maintained in a validated format 
other than hard copy (e.g. microfiche, scanned, electronic); however, caution needs to be 
exercised before such action is taken. The investigator must ensure that all reproductions 
are legible and are a true and accurate copy of the original and meet accessibility and 
retrieval standards, including re-generating a hard copy, if required. Furthermore, the 
investigator must ensure that an acceptable back-up of the reproductions exists and that 
there is an acceptable quality control procedure in place for making these reproductions.
GSK will inform the investigator/institution of the time period for retaining these records 
to comply with all applicable regulatory requirements. However, the 
investigator/institution should seek the written approval of the sponsor before proceeding 
with the disposal of these records. The minimum retention time will meet the strictest 
standard applicable to a particular site, as dictated by ICH GCP, any institutional 
requirements, applicable laws or regulations, or GSK standards/procedures. 
The investigator/institution must notify GSK of any changes in the archival 
arrangements, including, but not limited to archival at an off-site facility, transfer of 
ownership of the records in the event the investigator leaves the site. 
11.4.
Quality assurance
To ensure compliance with GCP and all applicable regulatory requirements, GSK may 
conduct a quality assurance audit. Regulatory agencies may also conduct a regulatory 
inspection of this study. Such audits/inspections can occur at any time during or after 
completion of the study. If an audit or inspection occurs, the investigator and institution 
agree to allow the auditor/inspector direct access to all relevant documents and to allocate 
his/her time and the time of his/her staff to the auditor/inspector to discuss findings and 
any relevant issues.
11.5.
Posting of information on publicly available clinical trial 
registers and publication policy
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.
 
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Summaries of the results of GSK interventional studies (phase I-IV) are posted on 
publicly available results registers within 12 months of the primary completion date for 
studies of authorised vaccines and 18 months for studies of non-authorised vaccines. 
GSK also aims to publish the results of these studies in the searchable, peer reviewed 
scientific literature. Manuscripts are submitted for publication within 24 months of the 
last subject’s last visit. At the time of publication, this protocol will be fully disclosed.
11.6.
Provision of study results to investigators
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK Biologicals will also provide the investigator with the full summary of the study 
results. The investigator is encouraged to share the summary results with the study 
subjects, as appropriate.
12.
COUNTRY SPECIFIC REQUIREMENTS
Not applicable. 
 
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13.
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Camargo ME, Silveira L, Furuta JA, Oliveira EPT and Germek OA. Immunoenzymatic 
assay of anti-diphtheric toxin antibodies in human serum. J Clin Microbiol 1984; 20(4): 
772-4.
Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Canadian 
Diabetes Association 2013 Clinical Practice Guidelines for the Prevention and 
Management of diabetes in Canada. Canadian J of Diabetes. 2013. 37(suppl 1): S1-212.
Canadian Immunisation Guide (Part 4). Pertussis Vaccine. Public Health Agency of 
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Center for Disease Control and Prevention (CDC), Updated Recommendations for Use of 
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Infant Aged <12 Months- Advisory Committee on Immunization Practices (ACIP), 2011.
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Center for Disease Control and Prevention (CDC), Updated Recommendations for Use of 
Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine (Tdap) in
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Centers for Disease Control and Prevention (CDC). Pertussis Outbreak 
trends.http://www.cdc.gov/pertussis/outbreaks/trends.html. Accessed: 15 July 2015.
Communicable Disease Control Directorate. Ongoing pertussis epidemic in Western 
Australia. 2011; 16 (1).
Conseil Supérieur de la Santé (CSS). Fiches de vaccination éditées par le CSS (CSS 
9110). Vaccination anticoquelucheuse ; vaccination de l’adulte (2013) 
http://health.belgium.be/eportal/Aboutus/relatedinstitutions/SuperiorHealthCouncil/publi
cations/factsheetsvaccination/13038500_FR ?ie2Term=center&ie2section=9130&fodnlan
g=fr ; Accessed : 15 July 2015
Diggle L, Deeks JJ, Pollard AJ. Effect of needle size on immunogenicity and 
reactogenicity of vaccines in infants: randomized controlled trial. BMJ 2006;333 
(7568):571.
Donegan K, King B, Bryan P. Safety of pertussis vaccination in pregnant women in UK: 
observational study. BMJ. 2014; 349:g4219.
EMA Guideline on the exposure to medicinal products during pregnancy: need for post-
authorization data (Doc. Ref. EMEA/CHMP/313666/2005) ‘adopted at Community level 
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uideline/2009/11/WC500011303.pdf. Accessed : 15 July 2015
European Medicines Agency (EMA). Guideline on Risk Assessment of medicinal 
products on human reproduction and lactation: from data to labeling, 2008. Available at 
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WC500003307.pdf. Accessed: 15 July 2015.
Englund JA, Anderson EL, Reed GF et al. The effect of maternal antibody on the 
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toxoids. Pediatrics 1995, 96:580–84.
Frits R Mooi, Sabine C de Greeff. The case for maternal vaccination against pertussis. 
Lancet Infec Dis. 2007; 7: 614-624.
Gall SA, Myers J, Pichichero M. Maternal immunization with tetanus– diphtheria–
pertussis vaccine: effect on maternal and neonatal serum antibody levels. Am J Obstet 
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Hardy-Fairbanks AJ, Pan SJ, Kirkland KB et al. Immune Responses in Infants Whose 
Mothers Received Tdap Vaccine During Pregnancy. Pediatr Infec Dis J. 2013; 32: 1257-
60.Health Protection Report. Confirmed pertussis in England and Wales: data to end-
December 2012. 2013; 7(5).
International Association of Diabetes and Pregnancy Study Groups Recommendations on 
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Association of Diabetes and Pregnancy Study groups Consensus Panel. Diabetes care. 
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Joint Committee on Vaccination and Immunization (JCVI). JVCI meeting on pertussis 
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pregnant women against pertussis. Published 28 September 2012. 
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Leuridian et al. Effect of a pregnancy pertussis booster dose on maternal antibody titers in 
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Melville-Smith ME, Seagroatt VA, Watkins JT. A comparison of enzyme-linked 
immunosorbent assay (ELISA) with the toxin neutralisation test in mice as a method for 
the estimation of tetanus antitoxin in human sera. J Biol Stand 1983; 11: 137-44.
Meyer CU, Habermehl P, Knuf M et al. Immunogenicity and reactogenicity of acellular 
pertussis booster vaccines in children: Standard pediatric versus a reduced-antigen 
content formulation. Hum Vaccin. 2008; 4(3):203-209.
Minh NN, He Q, Ramalho A, et al. Acellular vaccines containing reduced quantities of 
pertussis antigens as a booster in adolescents. Paediatrics 1999; 104:e70.
Munoz FM, Sheffield JS, Beigi RH et al. Research on vaccines during pregnancy: 
Protocol design and assessment of safety. Vaccine. 2013; 31(40): 4274-4279. 
http://dx.doi.org/10.1016/j.vaccine.2013.07.042
Munoz FM, Bond NH, Maccato M, et al. Safety and Immunogenicity of Tetanus 
Diphtheria and Acellular Pertussis (Tdap) Immunization During Pregnancy in Mothers 
and Infants: A Randomized Clinical Trial. JAMA. 2014; 311(17):1760-69. 
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diphtheria, pertussis and tetanus vaccine (Boostrix) listing, 12 December 2012. 
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Plotkin SA. Correlates of protection Induced by Vaccination. Clin Vaccine Immunol. 
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Rüggeberg JU, Gold MS, Bayas JM, et al. Anaphylaxis: case definition and guidelines 
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Spanish Society of Gynecology and Obstetrics (SEGO) and Spanish Association of 
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Technical Advisory Group (TAG) on Vaccine-preventable Diseases. Vaccination: a 
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Turnbull FM et al, A randomized trial of two acellular pertussis vaccines (dTpa and pa) 
and a licensed diphtheria-tetanus vaccine (Td) in adults. Vaccine 2001, 19:628-36.
Van Damme P, Burgess M. Immunogenicity of a combined diphtheria tetanus-acellular 
pertussis vaccine in adults. Vaccine 2004; 22:305-8.
Warshawsky B. NACI update on pertussis vaccination in pregnancy. Can Fam Physician. 
2014; 60(6): 521. 
Zheteyeva YA, Moro PL, Tepper NK, et al. Adverse event reports after tetanus toxoid, 
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Obstet Gynecol 2012; 207:59.e1
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APPENDIX A
CLINICAL LABORATORIES
Table 18
GSK Biologicals’ laboratories
Laboratory
Address
GSK Biologicals Global 
Vaccine Clinical Laboratory, 
Rixensart
Biospecimen Reception – B7/44
Rue de l’Institut, 89 – B-1330 Rixensart –
Belgium
GSK Biologicals Global 
Vaccine Clinical Laboratory, 
Wavre-Nord Noir Epine
Avenue Fleming, 20 – B-1300 Wavre –
Belgium
Table 19
Outsourced laboratories
Laboratory
Address
Quest Diagnostics Clinical Trials 
(UK)
Unit B1, Parkway West Industrial Estate
Cranford Lane – Heston, 
Middlesex TW5 9QA
UK
Quest Diagnostics Nichols Institute
33608 Ortega Highway 
San Juan Capistrano,
CA 92675-2042
USA
CEVAC – University of Gent
De Pintelaan, 185 Gent
Belgium
 
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APPENDIX B
OBSTETRICAL RISK ASSESSMENT FORM
NAME: 
PRIMARY OBSTETRICIAN/FAMILY DOCTOR:
AGE:
DATE OF LAST MENSTRUAL PERIOD (LMP):
MEDICAL HISTORY (EXCLUSIONS FOR A HISTORY OF SERIOUS 
UNDERLYING MEDICAL CONDITIONS WILL BE BASED ON ASSESSMENT 
BY THE STUDY PHYSICIAN ON THE POTENTIAL FOR INCREASED RISK 
TO THE CURRENT PREGNANCY)
YES
NO
DIABETES MELLITUS
YES
NO
HEART DISEASE [requiring medication, previous 
cardiac surgery, cardiac dysfunction including coronary 
disease (congenital VSD surgically corrected is not an 
exclusion)]
YES
NO
AUTOIMMUNE DISORDER (that could affect the 
immune response or put the current pregnancy at risk)
YES
NO
CHRONIC KIDNEY DISEASE (requiring medication, 
elevated creatinine, decreased renal function)
YES
NO
NEUROLOGIC DISEASE (that could put the current 
pregnancy at high risk)
YES
NO
HEPATITIS/LIVER DISEASE
YES
NO
PULMONARY DISEASE (controlled asthma treated as 
needed with inhalers is not excluded)
YES
NO
D (Rh) SENSITIZED OR KELL ANTIBODIES
YES
NO
PREVIOUS STILLBIRTH OR NEONATAL DEATH
The list given above is not exhaustive and contains common examples.
 
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CURRENT PREGNANCY
YES
NO
GESTATIONAL DIABETES OR HYPERTENSION REQUIRING 
DRUG THERAPY
YES
NO
EXPECTED TO DELIVER MULTIPLE INFANTS
YES
NO
EXPECTED TO DELIVER AN INFANT WITH A MAJOR 
CONGENITAL ANOMALY
YES
NO
INCOMPETENT CERVIX
YES
NO
POLYHYDRAMNIOS OR OLIGOHYDRAMNIOS
YES
NO
INTRAUTERINE GROWTH RESTRICTION
YES
NO
PSYCHIATRIC DISORDER (requiring follow up during this pregnancy 
by a mental health specialist)
YES
NO
ASSISTED REPRODUCTIVE TECHNOLOGY [is current pregnancy 
considered high risk at the time of enrolment]
YES
NO
DEEP VEIN THROMBOSIS/PULMONARY 
EMBOLUS/THROMBOPHILIA
YES
NO
UNCORRECTED THYROID DYSFUNCTION AT TIME OF 
ENROLMENT 
YES
NO
CURRENT SUBSTANCE ABUSE (including Methadone maintenance 
treatment)
YES
NO
HYPERTENSION (not controlled by medication)
 
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CURRENT OBSTETRICAL PROCEDURES
YES
NO
CONSIDERED NOT ELIGIBLE BY OSTETRICAL 
PROCEDURE ALGORITHM
SIGNATURE 
DATE
THE ABOVE NAMED PERSON IS AT “HIGH RISK” FOR SERIOUS OBSTETRICAL 
COMPLICATIONS AND IS NOT ELIGIBLE TO BE CONSIDERED FOR STUDY 
ENROLMENT
THE ABOVE NAMED PERSON IS NOT AT “HIGH RISK” FOR SERIOUS OBSTETRICAL 
COMPLICATIONS AND IS ELIGIBLE TO BE CONSIDERED FOR STUDY ENROLMENT
 
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Algorithm: Obstetrical Procedures to Identify Eligible subjects
 
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APPENDIX C Definitions and evaluations of selected terms and adverse events of interest in pregnant women participating in 
clinical trials (adapted from [Munoz, 2013])
Common terms or 
Adverse Events
Definition
Background rates and risk factors, 
if appropriate
Comments
References
PREGNANCY RELATED TERMS
GESTATIONAL AGE 
ESTIMATE
S: Dating of Pregnancy
Dating from:
-first day of last menstrual 
period (LMP), 
OR 
-1st trimester ultrasound if 
no known LMP or the 
ultrasound is not consistent 
with LMP,
OR 
-known date of fertilization
(e.g. by Assisted 
Reproductive Technology or 
Intrauterine Insemination).
[ACOG, 2014]
Test for urine or serum β-HCG
-urine test: positive about 10-12 days 
after conception.
-serum test: positive about 5-7 days 
after conception.
The estimated date of conception or 
pregnancy onset is calculated as the 
last menstrual period plus 14 days. 
Ultrasound (US): Gestational age is 
assessed in the 1st trimester (< 14 
weeks) by measurement of crown-
rump length. In the second trimester 
(14 to 20 weeks), the biparietal 
diameter is used (accuracy is within +/-
10 days up to 34 weeks, then +/- 3 
weeks). At term, abdominal 
circumference and femoral length are 
used.
US limited by: insufficient 
standardization, operator variability 
and expertise, lack of large population 
based reference, assumption that all 
fetuses with the same measurements 
have the same gestational age without 
accounting for true differences in fetal 
growth in early gestation or genetic 
and other familiar factors.
The American College of Obstetricians 
and Gynecologists (ACOG) 
Committee on Obstetric Practice, 
American Institute of Ultrasound in 
Medicine and Society for Maternal-
Fetal. Committee Opinions: Method for 
estimating Due Date. Number 611, 
October 2014 (accessed on-line on 
13/Oct/2014 at: 
http://www.acog.org/Resources-
And-Publications/Committee-
Opinions/Committee-on-Obstetric-
Practice/Method-for-Estimating-Due-
Date).
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Common terms or 
Adverse Events
Definition
Background rates and risk factors, 
if appropriate
Comments
References
TRIMESTER OF 
GESTATION 
Pregnancy is divided in 
three trimesters:
-First trimester: up to and 
including 13 6/7 weeks of 
gestation.
-Second trimester: 14 0/7 
weeks to 27 6/7 weeks of 
gestation.
-Third trimester: 28 0/7 
weeks of gestation and 
beyond.
LENGTH OF 
PREGNANCY
Preterm: up to and including 
36 6/7 weeks of gestation.
Term: 37 0/7 weeks through 
41 6/7 weeks of gestation 
[ACOG, 2013]. 
Early term:  Birth at 37 0/7 
to <39 weeks of gestation.
Post-term (S: post-mature): 
42 0/7 weeks of gestation 
and beyond.
Estimated Date of Delivery (EDD)= 40 
0/7 weeks (280 days) from the first day 
of the last menstrual period or by 
Ultrasound examination.
The American College of Obstetricians 
and Gynecologists (ACOG)
Committee on Obstetric Practice 
Society for Maternal-Fetal Medicine. 
Committee Opinions: Definition of 
Term Pregnancy. Number 579, 
November 2013 (accessed on-line on 
13/Oct/2014 at: 
http://www.acog.org/Resources-
And-Publications/Committee-
Opinions/Committee-on-Obstetric-
Practice/Definition-of-Term-
Pregnancy)
PREGNANCY OUTCOMES
LIVE BIRTH 
S: Live born 
Delivery of a live infant, 
regardless of maturity or 
birth weight, as determined 
by the presence of 
spontaneous respirations, a 
heartbeat, and spontaneous 
movement
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Common terms or 
Adverse Events
Definition
Background rates and risk factors, 
if appropriate
Comments
References
SPONTANEOUS 
ABORTION
S: miscarriage, 
pregnancy loss
Pregnancy ending 
spontaneously before 22 
weeks of gestation (i.e. up 
to and including 21 6/7 
weeks of gestation) [EMEA, 
2005]. Includes death of 
embryo/ fetus in utero 
(missed abortion), or 
blighted ovum /anembryonic 
pregnancy (i.e. fertilized 
ovum whose development 
has ceased at an early 
stage).
Subgroups:
-Early miscarriage if it 
occurs during the first 
trimester.
-Late miscarriage when it 
occurs during the second 
trimester.
Overall rates:  The prevalence of 
spontaneous abortion reported by 
several authors among clinical 
pregnancies (i.e. recognized 
pregnancies following a missed 
menstrual period) for all age groups 
combined is about 12-18% of all 
pregnancies in first or second 
trimester.
-Early miscarriage:  Up to 20%of 
pregnancies.
-Late miscarriage:  Up to 2% of 
pregnancies.
Risk factors:  Studies have shown 
that approximately 50% of 
spontaneous abortions are 
associated with fetal chromosome 
abnormalities [Brown, 2008].  Many 
studies have shown that maternal 
age is one of the strongest and most
consistent risk factor.
Note: case definitions vary between 
countries, as definition of viability is 
varied between resource settings (e.g. 
20-24 weeks versus 28 weeks and 
corresponding fetal weight of 500 mgr. 
vs. 1000 mgr).
Document circumstances of fetal loss, 
physical exam/estimated gestational 
age of the product if feasible and/or 
collect results of available studies 
including pathology report of fetus and 
placenta to establish a possible 
etiology, association/causality. Genetic 
testing if available; a karyotype may or 
may not be performed as part of 
routine clinical care. Of note, it may not 
be possible to perform evaluation if the 
subject does not seek medical 
attention. 
- European Medicines Agency 
(Committee for Medicinal Products for 
Human Use). Guideline on the 
Exposure to Medicinal Products during 
Pregnancy: Need for Post-
authorization Data. London, UK: 
EMEA; 2005.
-  Brown S. Miscarriage and its 
associations. Seminars in 
Reproductive Medicine 2008; 26(5): 
391-400.
- Wilcox AJ, Weinberg CR, O’Connor 
JF, Baird DD, Schlatterer JP, Canfield 
RE,et al. Incidence of early loss of 
pregnancy. New England Journal of 
Medicine1988;319: 189–94.
- Harlap S, Shiono PH. Alcohol, 
smoking, and incidence of 
spontaneous abortions in the first and 
second trimester. Lancet 1980; 2:173–
6.
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Common terms or 
Adverse Events
Definition
Background rates and risk factors, 
if appropriate
Comments
References
STILLBIRTH
S: Stillborn, Fetal 
Demise/Death, 
Deadborn
Delivery of a death fetus 
after 22 0/7 weeks of 
gestation [EMEA, 2005]. 
Categories:
- During pregnancy or 
antepartum.
- Intrapartum. 
Subgroups:
-Early Stillbirth: Delivery 22 
0/7 – <28 weeks and/or 
≥500 -1000 grams.
-Late Stillbirth: Delivery ≥ 
28 0/7 weeks and/or >1,000 
grams
Overall rates [ACOG, 2009]:  
6.2/1,000 births or 1 in 160 deliveries.
-Early stillbirth:  3.2/1,000 births.
-Late stillbirth:  3.1/1,000 births.
Risk factors:  Non-Hispanic black 
race, nulliparity, maternal age >35 
years, hypertension, diabetes, obesity 
BMI >30, multiple gestations, 
smoking, drug and alcohol use, 
infections, growth restriction, and 
placental anomalies.
Includes macroscopic examination for 
fetal anomalies, and if available, 
autopsy and karyotype; cord and 
placental examination and pathology. 
Document antepartum events:  
maternal factors, fetal factors (e.g., 
IUGR), external factors (e.g., trauma), 
and peripartum events such as 
preterm premature rupture of 
membranes (PPROM), infection, 
abruption, cord events.
- European Medicines Agency 
(Committee for Medicinal Products for 
Human Use). Guideline on the 
Exposure to Medicinal Products during 
Pregnancy: Need for Post-
authorization Data. London, UK: 
EMEA; 2005.
- American College of Obstetricians 
and Gynecologists. Management of 
stillbirth. ACOG Practice Bulletin 
Number 102. Obstetrics and 
Gynecology2009; 113: 748–61.
(accessed on-line on 13/Oct/2014 at: 
https://stillbirthmatters.files.wordpr
ess.com/2014/05/acog-management-
of-stillbirth1.pdf)
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Common terms or 
Adverse Events
Definition
Background rates and risk factors, 
if appropriate
Comments
References
CONGENITAL 
ANOMALIES
S: Birth defects, 
Malformations
The collection of congenital 
anomalies is based on the 
Centers for Disease Control 
and Prevention (CDC) 
Metropolitan Atlanta 
Congenital Defects 
Program (MACDP) 
guidelines [CDC,2007] and 
include morphological, 
functional, chromosomal or 
genetic anomalies, 
regardless of whether 
detected at birth or not, the 
fetus is delivered dead or 
alive, or defects are 
identified by prenatal 
ultrasound, amniocentesis 
or examination of the 
products of conception.
Live-born neonates with 
transient (postural) defects, 
infectious conditions or 
certain biochemical 
disorders are classified as 
being without congenital 
anomalies unless there is a 
reasonable possibility that 
the condition reflects an 
unrecognized congenital 
birth defect. 
Minor anomaly:  Rates vary widely 
depending on study. Minor 
malformations and developmental 
variants occur in 14 – 40% of 
otherwise normal newborns [Leppig, 
1987]. 
Major anomaly:  Apparent at birth in 
approximately 3% of population 
[CDC, 2013].
An exact cause or mechanism for a 
major defect can be determined in less 
than 50% of the cases. 
Some agents cause major defects if 
exposure occurs during a specific 
critical period of gestation, but not at 
other times. After organogenesis has 
been completed (about 8 weeks after 
conception or 10 weeks after last 
menstrual period), the observable 
effect may be limited to fetal growth 
restriction or functional rather than 
gross structural defects [Sadler,2009]. 
The primary outcomes relative to stage 
of exposure are as follows:
Pre-implantation: embryonic lethality
Implantation to time of organogenesis: 
morphological defects.
Fetal → neonatal stage: functional 
disorders, growth retardation, 
Carcinogenesis.
A certain pattern of minor 
malformations may have important 
predictive value in identifying more 
serious associated problems, some of 
which may be unrecognizable at an 
early age. Specific patterns of multiple 
minor malformations may be 
presenting signs of a genetic condition 
or malformation syndrome.
Centers for Disease Control (CDC). 
Birth defects and genetic diseases 
branch 6-digit code for reportable 
congenital anomalies; 2007.(accessed 
on-line on 13/Oct/2014 at:
http://www.cdc.gov/ncbddd/birthdefe
cts/documents/macdpcode0807.pdf)
- Rasmussen SA, Olney RS, Holmes 
LB, Lin AE, Keppler-Noreuil KM, 
MooreCA. Guidelines for case 
classification for the National Birth 
Defects Preven-tion Study. Birth 
Defects Research Part A: Clinical and 
Molecular Teratology2003; 67:193–
201.
- Leppig KA, Werler MM, Cann CI, 
Cook CA, Holmes LB. Predictive value 
of minor anomalies. Association with 
major malformations. Journal of
Pediatrics1987; 110: 530–7.
-Sadler TW. Langman’s medical 
embryology. 11th ed. Lippincott 
Williams and Q4Wilkins; 2009.
- Centers for Disease Control and 
Prevention (CDC). Update on overall 
prevalence of major birth defects-
Atlanta, Georgia, 1978–2005. MMWR; 
2013. (accessed on-line on 
13/Oct/2014 at: 
http://www.cdc.gov/mmwr/preview/m
mwrhtml/mm5701a2.htm )
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Common terms or 
Adverse Events
Definition
Background rates and risk factors, 
if appropriate
Comments
References
Morphological anomalies: 
Abnormalities of body 
structure or function that are 
present at birth and are of 
prenatal origin.
Categories:
Minor anomaly:  Anatomic 
variant or defect that do not 
have serious medical, 
functional or cosmetic 
consequences for the child. 
Includes those found in 
association with major 
anomalies.
Major anomaly:  Structural 
or functional defect that 
require surgical/medical 
treatment, have serious 
adverse effects on health or 
development (functional), or 
have significant cosmetic 
impact. [Rasmussen, 2003].
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Common terms or 
Adverse Events
Definition
Background rates and risk factors, 
if appropriate
Comments
References
ELECTIVE OR 
THERAPEUTIC 
TERMINATION OF 
PREGNANCY
S: Induced abortion
Expulsion of products of 
conception with medical or 
surgical assistance. 
The termination of the 
pregnancy can be elective
or therapeutic.
-Elective: performed for 
personal choice/socio-
economic reasons, 
excluding maternal or fetal 
health reasons. 
-Therapeutic: performed to 
preserve the health or save 
the life of a pregnant 
woman. 
ECTOPIC 
PREGNANCY
S: Extra-uterine 
pregnancy  
Condition in which a 
fertilized ovum implants 
outside the uterine cavity, 
most often in the fallopian 
tube (97%).
Affects 1.5% to 2% of all pregnancies 
and poses a significant threat to 
women of reproductive age. It is the 
leading cause of maternal death 
during the first trimester of 
pregnancy.
Risk factors: tubal surgery, genital 
tract infections leading to pelvic 
inflammatory disease, previous 
ectopic pregnancy, and in utero 
exposure to diethylstilbestrol [ACOG, 
2008].
Diagnosis is generally based on: 
clinical symptoms/signs, diagnostic 
transvaginal ultrasonography, 
abnormal serum progesterone level of 
less than 5 ng/mL and/or an 
inappropriate increase in hCG.
- Kurt T. Barnhart. Ectopic pregnancy. 
N Engl J Med 2009; 361:379-87.
- American College of Obstetricians 
and Gynecologists. Medical 
Management of Ectopic Pregnancy. 
ACOG Practice Bulletin Number 94. 
Obstetrics and Gynecology Jun 2008; 
111(6): 1479–85.
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MOLAR PREGNANCY
S:  gestational 
trophoblastic neoplasia, 
gestational trophoblastic 
tumor
Pregnancy marked by a 
neoplasm within the uterus, 
whereby part or all of the 
chorionic villi are converted 
into a mass of clear 
vesicles. Histologically 
distinct disease entities 
encompassed by this 
general terminology include: 
complete and partial 
hydatidiform moles, 
invasive moles, gestational 
choriocarcinomas, and 
placental site trophoblastic 
tumors.
The incidence is estimated at 1-3 per 
1000 pregnancies for partial or 
complete hydatidiform moles. The 
malignant invasive moles 
(choriocarcinoma and placental site 
trophoblastic tumour/epithelioid 
trophoblastic tumour) are very rare, 
0.2% of the gestational trophoblastic 
disease cases [ESMO, 2013; ACOG, 
2004].
Risk factors:  extremes of maternal 
age and prior molar pregnancy. The 
risk of repeat molar pregnancy after 1 
mole is about 1%, or about 10-20 
times the risk for the general 
population.
The disease is most frequently 
diagnosed on the basis of increasing 
or plateauing hCG values. Patients 
should be monitored with serial 
determinations of quantitative hCG 
values. A baseline post-evacuation 
chest X-ray should be considered.
-  American College of Obstetricians 
and Gynecologists.  Diagnosis and 
Treatment of Gestational 
Trophoblastic Disease.  ACOG 
Practice Bulletin Number 53.  
Obstetrics and Gynecology June 
2004; 103 (6):1365-77.
- M. J. Seckl, N. J. Sebire, R. A. 
Fisher, F. Golfier, L. Massuger & C. 
Sessa, on behalf of the ESMO 
Guidelines Working Group. 
Gestational trophoblastic disease: 
ESMO Clinical Practice Guidelines for 
diagnosis, treatment and follow-up.  
Annals of Oncology 2013; 24 
(Supplement 6): vi39–vi50.
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PREGNANCY-RELATED ADVERSE EVENTS OF INTEREST
VAGINAL OR 
INTRAUTERINE 
HEMORRHAGE 
S: Obstetric 
Hemorrhage, Major 
obstetric hemorrhage
Vaginal or intrauterine 
hemorrhage that 
encompasses antepartum 
(i.e. bleeding from the 
genital tract after 24 weeks 
of gestation), intrapartum, 
and postpartum bleeding 
(i.e. within 24 hours post-
delivery).  
A major obstetric 
hemorrhage is defined as 
blood loss from uterus or 
genital tract >1500 mL or a 
decrease in hemoglobin of 
>4 gr/dl or acute loss 
requiring transfusion of >4 
units of blood, or signs or 
symptoms of hypovolemia. 
Common causes of blood 
loss:
- Antepartum hemorrhage: 
placenta previa (presence 
of placental tissue overlying 
or proximate to the internal 
cervical os), placental 
abruption (partial or total 
placental detachment prior 
to delivery of fetus), uterine 
rupture, bleeding from 
vaginal or cervical lesions, 
etc.
Antepartum hemorrhage: has an 
incidence of 2–5% of all pregnancies 
beyond 24 weeks [Walfish, 2009].
Infrequent (14% of cases occur 
before 32 weeks gestation) and up to 
60% between 32-37 weeks gestation 
[Munoz , 2013]. 
Risk factors for placenta previa: prior 
uterine trauma, multiparity, advanced 
maternal age, previous C-section or 
other uterine surgery, and prior 
placenta previa.
Risk factors for placental abruption:   
hypertension, pre-eclampsia, 
advanced maternal age, multiparity, 
maternal/paternal tobacco use, 
cocaine use, trauma, premature 
rupture of membranes, 
chorioamnionitis, and prior abruption.
Risk factors for uterine rupture:  prior 
uterine surgery, trauma, uterine 
anomalies, dystocia, use of uterotonic 
drugs, and abnormal placentation.
Post-partum hemorrhage: Primary 
postpartum hemorrhage, which 
occurs in 4–6% of pregnancies, is 
caused by uterine atony in 80% or 
more of cases [ACOG ,2006].
Risk factors for Postpartum 
Hemorrhage: Prolonged labor, 
Augmented labor, Rapid labor, 
Given the wide range of definitions 
applied to maternal hemorrhage, it is 
important to combine the clinical 
presentation and objective data, while 
keeping in mind the probability of 
concealed bleeding within the uterus, 
peritoneal cavity, and retroperitoneal 
space, and the relative masking of 
haemodynamic signs of haemorrhagic 
shock due to the physiological 
adaptations of pregnancy.
Diagnosis is based on clinical 
presentation; ultrasound and placental 
pathology if available.
- American College of Obstetricians 
and Gynecologists. Cervical 
insufficiency. ACOG Practice Bulletin 
No. 76, Postpartum Haemorrhage   
International Journal of Gynecology 
and Obstetrics Oct 2006: 108 (4): 
1034-47 (accessed on-line on 
13/Oct/2014 at:
https://www.acog.org/~/media/Distri
cts/District%20II/PDFs/Final_Hemorrh
age_Web.pdf
-   Walfish M et al.  Maternal 
haemorrhage. Br. J. Anaesth. (2009) 
103 (suppl 1): i47-i56.
-Munoz et al.  Research on vaccines 
during pregnancy: Protocol design and 
assessment of safety, Vaccine, 
(2013): 31 (40): 4274-4279, 
Appendixes
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References
- Postpartum Hemorrhage: 
uterine atony, retained 
products of conception, 
abnormal placentation 
(abnormal attachment of the 
placenta to the uterine wall 
and includes accreta, 
increta, and percreta, 
depending on the extent of 
uterine invasion), genital 
tract trauma, uterine 
inversion, puerperal sepsis, 
uterine pathology such as 
fibroids, etc.
History of postpartum hemorrhage,  
Episiotomy, especially mediolateral, 
Preeclampsia, Overdistended uterus 
(macrosomia, twins, hydramnios), 
Operative delivery, Asian or Hispanic 
ethnicity, Chorioamnionitis.
Risk factors for abnormal 
placentation: placenta previa with or 
without previous uterine surgery, prior 
myomectomy, prior cesarean 
delivery, Asherman’s syndrome, 
submucous leiomyomata, and 
maternal age older than 35 years.
PREMATURE 
RUPTURE OF 
MEMBRANES (PROM) 
AND 
PRETERM 
PREMATURE 
RUPTURE OF 
MEMBRANES (P-
PROM)
PROM: Spontaneous 
rupture of fetal membranes 
that occurs before the onset 
of labor. 
Preterm PROM (P-PROM):
Spontaneous rupture of 
fetal membranes that 
occurs before the onset of 
labor before 37 weeks 
gestation. 
Term PROM may occur in 8% of 
pregnancies, P-PROM in 
approximately one-third of all preterm 
births or 4% of all births [ACOG, 
2007].
Risk factors:  Numerous maternal and 
fetal factors involved, particularly 
infection, obstetric factors including 
abruption placenta, as well as 
previous P-PROM or premature 
delivery. Recurrence for P-PROM is 
16-32%.
Assessment of gestational age and 
assessment of maternal and fetal 
risks, including intrauterine infection, 
labor, fetal compromise. 
-American College of Obstetricians 
and Gynecologists. Premature rupture 
of membranes. ACOG Practice 
Bulletin Number 80. Obstetrics and 
Gynecology2007;109:1007–20.
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PREMATURE 
UTERINE 
CONTRACTIONS AND 
PREMATURE LABOR
Premature uterine 
contractions:  Uterine
contractions without cervical 
change.
Premature labor:  Cervical 
change in the presence of 
regular uterine contractions 
that occur before 37 weeks 
of gestation. 
Refer to incidence of preterm 
delivery: 12% of all live births [ACOG, 
2012].
Collect any clinical and laboratory 
information that is available. Standard 
work-up may include:  vaginal 
examination, uterine monitoring, and 
fetal monitoring. Work-up to determine 
etiology or association to study product 
may include:  evaluation for infections 
(urine culture, Group B streptococcus, 
Chlamydia, gonococcus, Trichomonas 
vaginalis, bacterial vaginosis), drug 
screen, and ultrasound to rule out 
abruption, cord prolapse, 
oligo/polyhydramnios.
- American College of Obstetricians 
and Gynecologists.  Management of 
preterm labor. ACOG Practice Bulletin 
Number 127. International Journal of 
Gynecology and Obstetrics 2012 Jun; 
19(6):1308-17.
INTRAUTERINE 
GROWTH 
RESTRICTION / POOR 
FETAL GROWTH
S: IUGR 
S: Fetal growth 
retardation 
Estimated or actual birth 
weight below the 10th
percentile for gestational 
age.
10% of live births [ACOG, 2013].
Risk factors:  Numerous, classified as 
maternal, placental, fetal.
May include ultrasound (specific 
biometric parameters and estimated 
fetal weight), umbilical artery Doppler 
velocimetry, amniocentesis, 
chromosomes, and assessment of 
maternal risk factors (infection, 
hypertension, etc.).
NOTE: curves used to determine %iles 
should account for gender and 
race/ethnicity
- American College of Obstetricians 
and Gynecologists. Fetal Growth 
Restriction. ACOG Committee Opinion 
Number 134. Obstetrics and 
Gynecology May 2013;121: 1122–33. 
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GESTATIONAL 
HYPERTENTION, 
PREECLAMPSIA AND 
ECLAMPSIA
S: Pregnancy Related 
Hypertension, 
Pregnancy Induced 
Hypertension (PIH), 
Toxemia 
Gestational hypertension:  
Blood pressure systolic 
>140 and/or diastolic >90 
mmHg, documented in at 
least 2 separate 
measurements after 20 
weeks of gestation, without 
proteinuria or other stigmata 
of preeclampsia, and 
returning to normal post-
partum. Hypertension 
usually resolves by 12 
weeks postpartum
Pre-eclampsia:  
Hypertension (>140 and/or 
>90 mmHg) occurring after 
the 20th week of gestation, 
and up to 6 weeks 
postpartum, combined with 
other abnormalities such as 
proteinuria (>300 mg in a 24 
hr urine specimen).
HELLP syndrome:  Form of 
severe pre-eclampsia with 
associated laboratory 
abnormalities including 
hemolysis (H), elevated 
liver (EL) function tests, and 
low platelets (LP), with or 
without proteinuria.
Eclampsia:
Hypertensive disease occurs in 12-
22% of pregnancies [ACOG, 2001;
ACOG, 2002]. As many as 25% of 
women with gestational hypertension 
will develop preeclampsia. The 
reported incidence of preeclampsia is 
5-8% of pregnancies, usually first 
pregnancies. 
Risk factors:  First pregnancy, 
multiple gestation, preeclampsia in 
previous pregnancy, chronic 
hypertension, pre-gestational 
diabetes, vascular and connective 
tissue disorders, nephropathy, 
antiphospholipid antibody syndrome, 
obesity, age >35 years, non-Hispanic 
black race.
Blood pressure elevation should be 
sustained and documented in two 
independent measurements. 
Additional assessments include a 
random or 24-hour urine protein 
determination of 300 mg/dL, other 
laboratory testing to establish severity 
and collection of available data on fetal 
well-being.
- American College of Obstetricians 
and Gynecologists. Chronic 
hypertension in pregnancy. ACOG 
Practice Bulletin Number 29. 
Obstetrics and Gynecology2001; 
98:177–85.
- American College of Obstetricians 
and Gynecologists. Diagnosis and 
management of preeclampsia and 
eclampsia. ACOG Practice Bulletin 
Number 33.Obstetrics and 
Gynecology 2002; 99:159–67. 
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Common terms or 
Adverse Events
Definition
Background rates and risk factors, 
if appropriate
Comments
References
If the features of pre-
eclampsia are accompanied 
by new onset generalized 
seizures.
Chronic Hypertension with 
superimposed 
preeclampsia: Chronic 
hypertension definition 
PLUS preeclampsia 
definition
GESTATIONAL 
DIABETES MELLITUS
S: Diabetes of 
pregnancy 
Onset or first recognition of 
abnormal glucose tolerance 
during pregnancy (old 
definition still used by 
ACOG).
Diagnosis based on 
administration of glucose 
challenge test at 24-28 
weeks gestation
1% to 14%, with 2-5% being the most 
common figure [ACOG, 2001]. 
Includes urine glucose measurement 
during routine prenatal care visits; a 
fasting plasma glucose ≥126 mg/dL 
[7.0 mmol/L], or A1C ≥6.5 percent 
using a standardized assay, or a 
random plasma glucose ≥200 mg/dL 
[11.1 mmol/L] that is subsequently 
confirmed by elevated fasting plasma 
glucose or A1C, as noted above. 
Glucose tolerance screening is 
universal at 24-28 weeks of gestation.
- American College of Obstetricians 
and Gynecologists. Gestational 
diabetes. ACOG Practice Bulletin 
Number 30. Obstetrics and 
Gynecology2001;98: 525–38.
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Common terms or 
Adverse Events
Definition
Background rates and risk factors, 
if appropriate
Comments
References
MATERNAL DEATH
Death of a woman while 
pregnant or within 42 days 
of termination of pregnancy, 
irrespective of the duration 
and site of the pregnancy, 
from any cause related to or 
aggravated by the 
pregnancy or its 
management, but not from 
accidental or incidental 
causes.
Direct obstetric death: death 
of the mother resulting from 
conditions or complications 
which are unique to 
pregnancy and occur during 
the antepartum, 
intrapartum, or postpartum 
period.
Indirect obstetric death: A 
maternal death that is not 
directly due to obstetric 
cause (such as from 
previously existing disease, 
or disease developing 
during pregnancy, labor, or 
the puerperium but that was 
not unique to pregnancy.)
Late Maternal Death: Death 
of woman from direct or 
indirect causes more than 
42 days but less than one 
year after termination of 
pregnancy.
The global maternal mortality rate is 
estimated to be about 210 maternal 
deaths per 100,000 live births 
[WHO,2013]. Indirect causes and 
obstetric hemorrhage are the largest 
causes of maternal death worldwide. 
Of the direct causes of death, 
hemorrhage is the leading cause of 
maternal death, followed by 
hypertensive disorders and sepsis. 
Regional estimates varied 
substantially [Say, 2014].
- Trends in Maternal Mortality: 1990 to 
2013. Estimates by WHO, UNICEF, 
UNFPA, The World Bank and the 
United Nations Population Division. 
(accessed on-line on 13/Oct/2014 at:
http://apps.who.int/iris/bitstream/106
65/112682/2/9789241507226_eng.pdf
?ua=1)
-Lale Say et al, Global causes of 
maternal death: a WHO systematic 
analysis.  Lancet Glob Health 2014;2: 
e323–33
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Common terms or 
Adverse Events
Definition
Background rates and risk factors, 
if appropriate
Comments
References
NEONATAL RELATED EVENTS OF INTEREST
BIRTH WEIGHT (BW) 
Small for gestational age 
(SGA): Birth weight < 10% 
for newborns of same 
gestational age and gender 
in same population (<2500g 
at term).
Low birth weight: BW <2500 
g (5.5 lb).
Very low birth weight : BW 
<1500 g (3.3 lb)
Extremely low birth weight:  
BW <1000 g (2.2 lb).
Large for gestational age 
(LGA): Birth weight > 90% 
for newborns of same 
gestational age in same 
population (>4000g at 
term).
High Birth Weight 
(Macrosomia): BW >4000 g 
(8.13 lb).
SGA newborns are predisposed to 
complications, including 
hypoglycemia, hyperbilirubinemia, 
hypothermia, intraventricular 
hemorrhage, necrotizing enterocolitis, 
seizures, sepsis, respiratory distress 
syndrome, and neonatal death.
One of the primary risk factors of LGA 
is poorly-controlled maternal diabetes 
(pre-existing diabetes 
mellitus/gestational). Other risk 
factors in decreasing order of 
importance, are as follows: a history 
of macrosomia, maternal weight 
before pregnancy, weight gain during 
pregnancy, multiparity, male fetus, 
gestational age more than 40 weeks, 
ethnicity, maternal birth weight, 
maternal height, maternal age 
younger than 17 years and a positive 
50g glucose screen with a negative 
result on the three-hour glucose 
tolerance test.
Birth weight: Objective is 
measurement of weight on the day of 
delivery (OR first weight obtained). 
Varies with singleton vs. multiple 
gestation, gestational age, gender, 
race, ethnicity, maternal nutritional 
status (BMI), and maternal health 
status.
Birth weight is one of the most 
sensitive – and also one of the most 
important – measures of the well-being 
of children. Weight at birth is directly 
influenced by the general level of 
health status of the mother. 
Assessment of Birth Weight is in 
relation to Gestational Age (BW/GA):
-Gestational age should be based on 
best obstetric estimate, usually 
prenatal ultrasound or first day of last 
menstrual period if ultrasound not 
available; or neonatal physical exam.
-Weight should be based on objective 
measurement on the day of birth.
-Estimate of BW/GA should be based 
on population specific curves
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Common terms or 
Adverse Events
Definition
Background rates and risk factors, 
if appropriate
Comments
References
PRETERM BIRTH
Birth before 37 weeks of 
gestation.
Late Preterm: 34 to <37 
weeks
Moderate Preterm:  32 to 
<34 weeks
Very Preterm: 28 to < 32 
weeks
Extreme Preterm: < 28 
weeks
10-15% of all pregnancies, with most 
recent National Vital Statistics Report 
showing a decline to 11.72% in 
recent years. Extreme preterm birth 
occurs in less than 1% of live births 
[ACOG, 2003]. 
Includes physical examination and 
determination of gestational age, and 
evaluation for maternal or infant 
causes of premature delivery. 
Assessment requires gestational age 
assessment by best available obstetric 
estimate, usually prenatal ultrasound 
or first day of the last menstrual period 
if ultrasound not available.
Also assessed by pediatric estimate 
through physical and neurological 
examination of newborn at birth. This 
is less desirable as this assessment is 
affected by abnormal fetal growth, 
placental anatomic and functional 
anomalies, maternal nutrition, racial 
and ethnic background, population and 
genetic factors, and birth weight for 
GA.
-American College of Obstetricians 
and Gynecologists. Management of 
preterm labor. ACOG Practice Bulletin 
Number 43. International Journal of 
Gynaecology and Obstetrics 2003;82: 
127–35.
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Common terms or 
Adverse Events
Definition
Background rates and risk factors, 
if appropriate
Comments
References
NEONATAL DEATH
Death of newborn at any 
time from birth to 28 days of 
life, regardless of 
gestational age.
Subgroups:
Very early neonatal death: < 
24hrs
Early neonatal death: from 
birth to < 7 days
Late neonatal death: 7 to < 
28 days
Intrapartum-related 
neonatal death (previously 
called: asphyxia deaths): 
neonatal death of term 
babies with neonatal 
encephalopathy or who 
cannot be resuscitated (or 
for whom resuscitation is 
not available). Also includes 
babies who die from birth 
injury without hypoxic brain 
injury)
The early neonatal death rate is 
estimated to be 8.4 per 1000 
liveborns; 67.1% occur by day 3 of 
life [Vogel , 2014].  Prematurity is the 
main cause of early neonatal deaths 
(~62%).
Causes of death and rates may vary 
according to whether the birth setting 
was in a hospital or in the community
- Vogel JP et al, on behalf of the WHO 
Multicountry Survey on Maternal and 
Newborn Health Research Network. 
Maternal complications and perinatal 
mortality: findings of the World Health 
Organization Multicountry Survey on 
Maternal and Newborn Health. BJOG 
2014; 121 (Suppl. 1): 76–88.
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Common terms or 
Adverse Events
Definition
Background rates and risk factors, 
if appropriate
Comments
References
NEONATAL HYPOXIC 
ISCHEMIC 
ENCEPHALOPATHY 
(HIE)
S: HIE, Birth Asphyxia, 
Perinatal Asphyxia, 
Neonatal 
encephalopathy
A disturbance of 
neurological function in the 
earliest days of life in the 
term infant manifested by 
difficulty initiation and 
maintaining respiration, 
depression of tone and 
reflexes, abnormal level of 
consciousness and often 
seizures, which may follow 
an intrapartum hypoxic 
insult or be due to another 
cause.
Rates may vary widely.  The 
incidence of HIE in developed 
countries is estimated to be 1.5 per 
1,000 live births [Kurinczuk, 2010]. 
Estimates in developing countries 
range from 2.3–26.5 per 1,000 live 
births [Horn,2013].
Assessed by clinical and laboratory 
findings: 5 minute Apgar score of 0-3, 
Respiratory distress and Acidosis (pH 
< 7.0), altered tone, depressed level of 
consciousness, seizures, multiorgan 
involvement.
Diagnostic tests:
- MRI is preferred imaging study.
- CT can identify focal lesions, 
hemorrhage, diffuse cortical injury
- EKG (ECG) and continuous EKG 
(ECG)
May result in neonatal death or 
permanent damage to the brain and 
other organs.
May be associated with perinatal 
events, rarely to prenatal events.
- Kurinczuk JJ, White-Koning M, 
Badawi N: Epidemiology of neonatal 
encephalopathy and hypoxic–
ischaemic encephalopathy. Early Hum 
Dev 2010, 86(6):329-338.
- Horn AR, Swingler GH, Myer L, 
Harrison MC, Linley LL, Nelson C, 
Tooke L, Rhoda NR, Robertson NJ: 
Defining hypoxic ischemic 
encephalopathy in newborn infants: 
benchmarking in a South African 
population. J Perinat Med 2013, 
41(2):211-217. 
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Common terms or 
Adverse Events
Definition
Background rates and risk factors, 
if appropriate
Comments
References
FAILURE TO THRIVE 
OR GROWTH 
DEFICIENCY
Inability to maintain 
expected growth rate over 
time, evaluated by plotting 
individual weight gain and 
growth on standard growth 
charts for the population.
Failure to thrive (FTT) is a common 
problem, however precise 
epidemiological data is lacking. The 
population prevalence of FTT has 
been found to range anywhere 
between 1.3% and 20.9% depending 
on the definition of FTT that is used. 
FTT accounts for 1–5% of paediatric 
hospital admissions under 2 year of 
age [Sullivan, 2004]
Normal newborn weight gain includes 
weight loss of up to 10% of birth 
weight in the first 1-2 weeks of life, 
with steady, predictable weight gain 
thereafter. Progress varies by 
gestational and post-natal age, genetic 
and environmental factors.
Definitions vary. Fall of weight below 
5th percentile for age often used. Olsen 
et al have described multiple different 
anthropometric criteria for failure to 
thrive. These criteria include signs of 
failure to gain weight (weight < 75% of 
median weight for chronological age, 
weight for chronological age < 5th
percentile, weight deceleration 
crossing > 2 major percentile lines, 
etc), failure to grow (length for 
chronological age < 5th percentile),
and failure to grow and gain weight 
(weight < 80% of
median weight for length, body mass 
index < 5th percentile) [Olsen, 2007]
- Olsen EM, Petersen J, Skovgaard 
AM, Weile B, Jorgensen T, Wright CM. 
Failure to thrive: the prevalence and 
concurrence of anthropometric criteria 
in a general infant population. Arch Dis 
Child. February2007; 92(2):109-114.
-  Peter B Sullivan. Commentary: The 
epidemiology of failure-to-thrive in 
infants. Int. J. Epidemiol. (2004) 33 
(4): 847-848.
If a reference is not listed, the following references were used as a source for definitions:  
Cunningham F, Gary, et al., editors. Williams obstetrics. 23rd ed. New York: McGraw-Hill; 2010.
Medline Plus; 2013. Available from: http://www.nlm.nih.gov/medlineplus/  
UpToDate. Available from: http://www.uptodate.com/home
American College of Obstetrics and Gynecology, Practice Bulletins, www.acog.org.
the Brighton Collaboration website at http://brightoncollaboration.org/public/resources/standards/case-definitions/pregnancy.html
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APPENDIX D
AMENDMENTS AND ADMINISTRATIVE 
CHANGES TO THE PROTOCOL
GlaxoSmithKline Biologicals
Vaccine Value & Health Science (VVHS)
Protocol Amendment 1
eTrack study number 
and Abbreviated Title
116945 [DTPA (BOOSTRIX)-047]
EudraCT number
2014-001119-38
Amendment number:
Amendment 1
Amendment date:
29 May 2015
Co-ordinating author:
, Scientific Writer
Rationale/background for changes:
The protocol is being amended for the following reasons: 

Based on the feedback from compliance/legal team, the wording related to the 
cocooning has been modified in the protocol. 

For the purpose of clarity and to be in line with the recent changes in the reporting 
timelines for pregnancies, minor modifications have been made to the safety 
sections.

As per feedback from the Australian Ethics Committee,the volume of cord blood 
to be collected from the subjects has been updated.
The list of contributing authors has been updated.
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections:
Contributing authors:

and 
, Global Clinical 
Regulatory Affairs Representatives
Section 2.2 Secondary objectives

To assess the safety of a single dose of Boostrix in pregnant women, administered 
during 27-36 weeks of gestation, in terms of the outcomes of pregnancy and listed 
pregnancy-related adverse events of interest/neonate-related events of interest up 
to two months post-delivery study end(Visit 4).

To assess the safety of a single dose of Boostrix administered during pregnancy 
and post-delivery in terms of unsolicited symptoms during the 31-day (Day 0 –
Day 30) follow-up period after vaccination and serious adverse events (SAEs) 
during the period between vaccination atfrom Visit 1 and two months post delivery
up to Visit 4.
 
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Section 3 Study design overview

Sampling schedule

Cord blood (Visit 3): approximately 5mL2.5 mL of blood sample from the 
umbilical cord will be collected from all subjects.
Section 5.5 Outline of study procedures
Table 4 List of study procedures
Epoch
Epoch 001
Type of contact
Screening Visit 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Time-points
Day -14 to 0
Day 0
Day 30
At birth
Post-delivery 
Month 2
Sampling time-points
Pre-Vacc
Post-Vacc Cord blood
Informed consent†
● 
Collect demographic data 
●
Medical history, including medication 
history and previous 
diphtheria/tetanus/pertussis vaccination 
history*
O 
●
Pregnancy screening**
● 
History directed physical examination 
O 
●
O
Check inclusion/exclusion criteria 
O 
●
Pre-vaccination body temperature 
●
●
Measure/record height and weight 
● 
Check contraindications and warnings 
and precautions 
O 
O 
Study group and treatment number 
allocation 
O 
Recording of administered treatment 
number 
●
●
Treatment number allocation for 
subsequent dose (Cross-over dose) 
O 
Blood sampling for antibody 
determination 
●
●
●
Vaccine administration 
●
●
Distribution of diary cards 
O 
O 
O 
Record any concomitant 
medication/vaccination 
●
●
●
●
Physical examination of newborn, 
including heightlength, weight, head 
circumference and Apgar Score
●
Record breastfeeding status
●
Adverse pregnancy outcome recording 
and follow-up (pregnancy outcomes 
and pregnancy-related adverse events 
of interest/neonate-related) Recording 
and follow up of pregnancy-related 
adverse events and neonate-related 
events
●
●
●
●
Record any intercurrent medical 
conditions 
●
●
●
●
Recording of solicited adverse events 
(Days 0-7) by subjects in diary card 
●
●
Recording of non-serious adverse 
events (Day 0– Day 30), by subjects 
●
●
●
 
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Epoch
Epoch 001
Type of contact
Screening Visit 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Time-points
Day -14 to 0
Day 0
Day 30
At birth
Post-delivery 
Month 2
Sampling time-points
Pre-Vacc
Post-Vacc Cord blood
Recording of serious adverse events 
(SAEs)# and AEs leading to withdrawal 
●
●
●
●
Recording of SAEs related to study 
participation or to a concurrent GSK 
medication/vaccine 
● 
●
●
●
●
Recording of new pregnancies 
●
●
Screening conclusion
● 
Study Conclusion 
●
Note: The procedures to be conducted during screening visit and Visit 1 may be combined. 
In case a woman gives birth to an infant between Visit 1 (Day 0) and Visit 2 (Day 30), the procedures for Visit 2 and 
Visit 3 will be combined. A blood sample from the mother must be taken before the cross-over vaccination is given 
to her.
● is used to indicate a study procedure that requires documentation in the individual eCRF.
○ is used to indicate a study procedure that does not require documentation in the individual eCRF.
Pre-vacc: Blood sample to be collected before the dose of the booster vaccination in pregnant women (Visit 1).
Post-vacc: Blood sample to be collected one month after the booster vaccination in pregnant women (Visit 2).
† Father of the child should also sign the informed consent form, if required by the local laws. 
* History of all medications, excluding the vitamins and supplements taken by the mother during her pregnancy 
before receiving the first dose of study vaccine will be recorded in the eCRF. 
** Pregnancy screening will include checking of records of ultrasound testing, nuchal translucency scan, serum 
testing and any other prenatal tests (if performed). Refer to Section 4.2 for details regarding pregnancy screening.
# including adverse pregnancy outcomes and listed pregnancy-related/neonate-related AEs of interest.
Section 5.6.3.4.1 Blood sampling for immune response assessments
A volume of approximately 5 mL2.5mL of whole blood (to provide approximately
1.7 0.75 mL of serum) from the umbilical cord will be collected from all subjects at 
Visit 3.
Section 5.6.3.5 Study Vaccine administration
Investigators will be encouraged to discuss with the subjects regarding the benefits of 
cocooning i.e. vaccinating anyone that cares for or comes in close contact with 
neonates such as family members and up to-date vaccination of the baby’s siblings with 
DTP vaccines in order to reduce the potential risk of pertussis in neonates. Ideally these 
individuals should be vaccinated two weeks prior to coming in contact with the infant. 
A reimbursement for cocooning vaccination will be done in countries where the 
recommendation for cocooning vaccination is not available. However, this will be done 
outside the scope of this study.The investigators should discuss with the subjects 
about the official recommendations and/or local practice regarding the use of Tdap 
vaccines for individuals in close contact with neonates and up to-date vaccination of 
the neonate’s siblings with DTP vaccines in order to reduce the potential risk of 
pertussis in neonates.
Section 5.6.3.7 Physical examination of the newborn
At Visit 3 or after the birth of the child, physical examination of the newborn will be 
done. The body weight, heightlength, head circumference and Apgar Score will be 
recorded in the eCRF.
 
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Section 5.6.3.9 Recording of AEs, pregnancies, pregnancy outcomes, andpregnancy-
related AEs of interest/and neonate-related eventsAEs

Refer to Section 8.2 for procedures for the investigator to record AEs, SAEs, 
pregnancies, pregnancy outcomes and pregnancy-related AEs of interest/and
neonate-related eventsAEs. Refer to Section 8.3 for guidelines and how to report 
SAE reports and pregnancies to GSK Biologicals.

At each vaccination visit, diary cards will be provided to the subject. The subject 
will record body (oral/axillary) temperature and any solicited local/general AEs 
(i.e. on the day of vaccination and during the next 7 days) or any unsolicited AEs 
(i.e. on the day of vaccination and during the next 30 days occurring after 
vaccination. The subject will record any pregnancy outcomes and pregnancy-
related AEs of interest/ neonate-related events (i.e. on the day of vaccination and 
during the next 30 days occurring after vaccination). The subject will be instructed 
to return the completed diary card to the investigator at the next study visit.

All pregnancy-related AEs & neonatal AEs will captured in the diary card from 
the first receipt of study vaccine/placebo and will end at Visit 4. 

All adverse pregnancy outcomes, listed pregnancy-related and neonate-related 
AEs of interest will be reported as SAEs. Refer to Section 8.2.2 for details 
regarding listed pregnancy-related and neonate-related AEs of interest.
Section 5.7.2 Biological samples
Table 6 Biological samples
Sample type
Quantity*
Unit
Time-point
Blood
5
mL
Day 0 (Pre-Vacc) and Day 30 (Post-Vacc)
Cord Blood
52.5
mL
At Birth
   * Approximate quantity
Section 8.1.2 Definition of a serious adverse event
e. Adverse pregnancy outcomes specified in Section 8.1.5 and the listed pregnancy-
related events of interest/neonate-related events of interest in Section 8.2.2 
should always be considered as SAEs (medically important events) and should 
be reported as described in Sections 8.3.1 and 8.3.3.
 
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Section 8.1.5 Pregnancy outcomes
While pregnancy itself is not considered an AE or SAE, any adverse pregnancy 
outcome or pregnancy complication or elective termination of a pregnancy for medical 
reasons will be recorded as an AE or a SAE.
The following adverse pregnancy outcomes should always be considered as SAE and 
will be reported as described in Sections 8.3.1 and 8.3.3:

Spontaneous pregnancy loss, including:

spontaneous abortion, (spontaneous pregnancy loss before/at 22 weeks of 
gestation).

ectopic and molar pregnancy.

stillbirth (intrauterine death of foetus after 22 weeks of gestation).
Note: the 22 weeks cut-off in gestational age is based on WHO-ICD 10 noted in 
the EMA Guideline on pregnancy exposure [EMA, 2006]. It is recognized that 
national regulations might be different.

Any early neonatal death (i.e. death of a live born infant occurring within the first 
7 days of life).

Any congenital anomaly or birth defect (as per [CDC MACDP] guidelines) 
identified in the offspring of a study patient (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.
When there is enough evidence to make any of the above diagnoses, the AE/SAE must 
be reported as per [CDC MACDP] guidelines. Symptoms, signs or conditions which 
might (or might not) represent the above diagnoses, should be recorded and reported as 
AEs until the final or definitive diagnosis has been determined, and alternative 
diagnoses have been eliminated or shown to be less likely.
In order to facilitate the documentation of AEs of interest in the eCRF, the guidelines
[CDC MACDP] list of preferred terms (PTs) and PT codes corresponding to the above 
diagnoses will be available to investigators at study start.
 
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Section 8.2 Detecting and recording adverse events, serious adverse events, 
pregnancies, pregnancy outcomes and pregnancy-related AEs of interest/and neonate-
related eventsAEs
Section 8.2.1 Time period for detecting and recording adverse events, serious adverse 
events, pregnancies, pregnancy outcomes, and pregnancy-related AEs of interest and
neonate-related eventsAEs
All AEs starting within 30 days following administration of each dose of study 
vaccine/placebo (Day 0 to Day 30) must be recorded into the appropriate section of the 
eCRF, irrespective of intensity or whether or not they are considered vaccination-
related.
The time period for collecting and recording SAEs (including adverse pregnancy 
outcomes, listed pregnancy-related adverse events of interest/neonate-related adverse 
events of interest) will begin at the first receipt of study vaccine/placebo and will end
60 days (two months) following administration of the last dose of study 
vaccine/placeboat study end (Visit 4) for each subject. See Section 8.3 for instructions
on reporting of SAEs.
The time period for collecting and recording AEs, SAEs, pregnancies, pregnancy-
related AEs and neonate-related AEs will begin at the first receipt of study 
vaccine/placebo and will end 60 days study end (Visit 4).
All AEs/SAEs/pregnancy outcomes, andpregnancy-related AEs of interest/and 
neonate-related events leading to withdrawal from the study will be collected and 
recorded from the time of the first receipt of study vaccine/placebo.
SAEs that are related to the investigational vaccine will be collected and recorded from 
the time of the first receipt of study vaccine/placebo 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 new pregnancies will begin after delivery 
of the baby and will end at Visit 4post-delivery (study conclusion). See section 8.3 for 
instructions on reporting of pregnancies.
The timriod for collecting and recording pregnancy outcomes and pregnancy-related 
AEs of interest/neonate-related events will begin at the first receipt of study 
vaccine/placebo and will end 60 days (two months) following administration of the last 
dose of study vaccine/placebo.
 
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Table 12 Reporting periods for adverse events, serious adverse events, pregnancies , 
andpregnancy-related adverse events of interest/and neonate-related adverse events
Event
Screening 
Visit*
V1
8 d 
(0-7d) 
post V1
31 d 
(0-30d) post V1
V3
8 d 
(0-7d) post 
V3
31 d 
(0-30 d)
post V3
V4
(Study
Conclusion)
D0
V2 (D30)
At birth
Post-
delivery M2
Solicited 
local and 
general AEs
Unsolicited 
AEs
AEs/SAEs 
leading to 
withdrawal 
from the 
study
SAEs
Pregnancy-
related 
adverse 
events and
neonate-
related 
adverse
events
SAEs related to 
study 
participation 
or concurrent 
GSK 
medication/
vaccine
New 
pregnancie
s
* i.e. consent obtained; V: Visit; D: Day, M: Month
 
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Section 8.2.2 Adverse events of specific interest (adverse pregnancy outcomes, listed 
pregnancy-related adverse events of interestand/neonate-related events of interest) 
All adverse pregnancy outcomes, listed pregnancy-related adverse events of interest
and neonate-related events of interest occurring at any time during the period starting 
with the first administration of the vaccine till end of the study will be considered as 
SAEs and must be recorded on the Adverse Event screenin the appropriate section of 
the patient’s eCRF, irrespective of intensity or whether or not they are considered 
administration-related.
PregnancyAdverse pregnancy outcomes include:

Live birth with no congenital anomalies,

Live birth with congenital anomalies, 

Still birth with no congenital anomalies, 

Still birth with congenital anomalies, 

Elective termination with no congenital anomalies

Elective termination with congenital anomalies
Listed Pregnancypregnancy-related adverse events of interest/neonate-related events of 
interest include:
Note: this list of pregnancy outcomes and pregnancy-related adverse events of 
interest/neonate-related events is not an exhaustive list.
The definitions and grading of the above specified specificpregnancy outcomes and 
listed pregnancy-related adverse events of interest/ neonate-related events of interest
are adapted from [Munoz, 2013] and can be found in the GLOSSARY OF TERMS and 
in APPENDIX C.
Section 8.3.1 Prompt reporting of serious adverse events, pregnancies and other events 
to GSK Biologicals
SAEs that occur in the time period defined in Section 8.2 will be reported promptly to 
GSK within the timeframes described in Table 14, once the investigator determines that 
the event meets the protocol definition of a SAE.
Adverse pregnancy outcomes and listed pregnancy-related adverse events of 
interest/neonate-related adverse events of interest that occur in the time period 
defined in Section 8.2 will be considered as SAE and reported promptly to GSK 
within the timeframes described in Table 14, once the investigator becomes aware of 
them.
Pregnancies that occur in the time period defined in Section 8.2 will be reported 
promptly to GSK within the timeframes described in Table 14, once the investigator 
becomes aware of the pregnancy. 
 
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Section 8.3.1 Prompt reporting of serious adverse events, pregnancies and other events 
to GSK Biologicals.
Table 14 Timeframes for submitting serious adverse event and other events reports to 
GSK Biologicals
Type of Event
Initial Reports
Follow-up of Relevant Information on a Previous 
Report
Timefram
e
Documents
Timeframe
Documents
SAEs#
24 hours*‡
electronic Expedited 
Adverse Events 
Report
24 hours*
electronic Expedited Adverse Events 
Report
Pregnancy-
related adverse 
events of 
interest/neonate-
related events 
24 hours*
electronic 
Expedited Adverse 
Event Report
24 hours*
electronic
Expedited Adverse Event Report
Pregnancies
2 1week*
electronic 
pregnancy report
21 week*
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.
# including adverse pregnancy outcomes and listed pregnancy-related/neonate-related AEs of interest.
Section 10.2 Secondary endpoints

Outcome of pregnancy in terms of pregnancy outcomes up to two months post 
delivery study end (Visit 4)

Outcome of pregnancy in terms of listed pregnancy-related adverse events of 
interest/ neonate-related events of interest up to two months post-delivery study 
end (Visit 4).
Listed pregnancy-related adverse events of interest/ neonate-related events of interest
will include gestational diabetes, pregnancy-related hypertension, premature rupture of 
membranes, preterm premature rupture of membranes, premature labour, premature 
uterine contractions, intrauterine growth restriction/poor foetal growth, pre-eclampsia, 
eclampsia, vaginal or intrauterine haemorrhage, maternal death, preterm birth, neonatal 
death, small for gestational age, neonatal hypoxic ischaemic encephalopathy and failure 
to thrive/growth deficiency.

Serious adverse events (SAEs).

Occurrence of serious adverse events from Dose 1 up to study end (Visit 4).
Refer to GLOSSARY OF TERMS for the definitions of the various pregnancy 
outcomes and listed pregnancy-related adverse events of interest/neonate-
related events of interest.
 
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Section 10.3 Determination of sample size
Table 16 presents the precision achieved with a sample of 300 subjects in each group 
for the various possible expected adverse pregnancy outcomes and listed pregnancy-
related adverse events of interest/neonate-related events of interest in terms of exact 
95% Cis.
Table 16 Precision achieved with a sample of 300 subjects in each group for the 
various possible expected pregnancy outcomes and listed pregnancy-related adverse 
events of interest/ neonate-related events of interest in terms of exact 95 percent CI
No. Of 
subjects 
expected 
(N)
Pregnancy outcome and listed pregnancy-
related adverse events of interest/neonate-
related events of interest
Subjects with outcome
n
%
Exact 95%CI
LL
UL
300
Stillbirth
1
0.3
0.0
1.8
Stillbirth^
0
0.0
0.0
1.2
Placental Abruption
3
1.0
0.2
2.9
Placenta previa
1
0.3
0.0
1.8
Post-partum haemorrhage
18
6.0
3.6
9.3
Premature rupture of membranes 
24
8.0
5.2
11.7
Premature uterine contractions and 
premature labour
36
12.0
8.5
16.2
Preterm delivery
35
11.7
8.3
15.7
Intrauterine growth restriction / poor foetal 
growth
30
10.0
6.8
14.0
Pregnancy related hypertension, 
preeclampsia and eclampsia
36
12.0
8.5
16.2
Gestational diabetes
15
5.0
2.8
8.1
Congenital anomalies (major anomalies)
9
3.0
1.4
5.6
 
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Section 10.8 Analysis of safety

The percentage of subjects with each specific pregnancy outcomes and listed 
pregnancy-related adverse events of interest/neonate-related events of interest will 
be tabulated with its exact 95% CI.

The percentage of subjects with at least one local AE (solicited and unsolicited), 
with at least one general AE (solicited and unsolicited) and with any AE during the 
8-day (Day 0–Day 7) follow-up period after the vaccination will be tabulated after 
each dose and overall with exact 95% CI. The same calculations will be 
performed for any Grade 3 (solicited or unsolicited) symptoms and for any 
symptoms requiring medical attention.

The percentage of doses followed by at least one local AE (solicited and 
unsolicited), with at least one general AE (solicited and unsolicited) and with 
any AE during the 8-day (Day 0–Day 7) follow-up period after the vaccination 
will be tabulated with exact 95% CI. The same calculations will be performed for 
any Grade 3 (solicited or unsolicited) symptoms and for any symptoms requiring 
medical attention.

The percentage of subjects/doses reporting each individual solicited local and 
general AE during the 8-day (Day 0-Day 7) follow-up period after booster 
vaccination will be tabulated with its exact 95% CI for each group.

Any large injection site reaction (defined as any local swelling with diameter 
> 100 mm and/or any noticeable diffuse injection site swelling (diameter not 
measurable) and/or any noticeable increased circumference of the injected limb) 
onset within 8 days (Day 0–Day 7) after each vaccination will be described in 
detail.

The verbatim reports of unsolicited symptoms will be reviewed by a physician and 
the signs and symptoms will be coded according to MedDRA. Every verbatim 
term will be matched with the appropriate Preferred Term. The percentage of 
subjects/doses with unsolicited symptoms occurring within 31 days (Day 0–Day 
30) with its exact 95% CI will be tabulated by preferred term. Similar tabulation 
will be done for Grade 3 unsolicited symptoms and for unsolicited symptoms 
possibly related to vaccination. 

The percentage of subjects/doses who started to receive at least one concomitant 
medication (i.e. any medication, antipyretic medication, prophylactic antipyretics) 
during the 4-day and 31-day follow-up period after vaccination will be tabulated 
after each dose and overall with exact 95% CI.

SAEs and withdrawal due to AEs and SAEs following booster dose up to two 
months post delivery Visit 4 will be described in detail.
 
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Appendix A Clinical Laboratories
Table 17
GSK Biologicals’ laboratories
Laboratory
Address
GSK Biologicals Global Vaccine 
Clinical Laboratory, Rixensart
Biospecimen Reception – B7/44
Rue de l’Institut, 89 – B-1330 Rixensart – Belgium
GSK Biologicals Global Vaccine 
Clinical Laboratory, North America-
Laval
Biospecimen Reception – Clinical Serology
525 Cartier blvd West – Laval – Quebec – Canada – H7V 3S8
GSK Biologicals Global Vaccine 
Clinical Laboratory, Wavre-Nord 
Noir Epine
Avenue Fleming, 20 – B-1300 Wavre – Belgium
 
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GlaxoSmithKline Biologicals
Vaccine Value & Health Science (VVHS)
Protocol Amendment 2
eTrack study number 
and Abbreviated Title
116945 [DTPA (BOOSTRIX)-047]
EudraCT number
2014-001119-38
Amendment number:
Amendment 2
Amendment date:
15 July 2015
Co-ordinating author:
, Scientific Writer
Rationale/background for changes:
The protocol is being amended to include Spain in the study. The reasons for this 
Spain-specific amendment are listed below:

Based on the feedback from the Spanish Ethics Committee, the evaluation related 
to the acceptance of cocooning has been added in the protocol.

The objectives and endpoints to include cocooning are added in the protocol.

The eligibility criteria for participation of household contacts are defined in the 
protocol.

The study procedures for household contacts are included.

The list of contributing authors has been updated
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections:
Contributing authors:

, Medical 
Director, Vaccines, Spain

, Medical Affairs 
Manager, Vaccines, Spain

 and 
 
, Study Delivery Leads
 
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PPD
PPD
PPD
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Section 1.2.2 Rationale for the study design
The following information is added.
In addition, all the eligible household contacts of the infants born to pregnant women 
in a subset of the study enrolled in Spain will be eligible to receive a single dose of 
Boostrix as part of an assessment of cocooning.
Section 2.2 Secondary objectives
The following objectives are added.

To assess the acceptance rate of a single dose of Boostrix among eligible 
household contacts of the infants born to pregnant women enrolled in Spain, as 
part of an assessment of cocooning.

To assess the safety of a single dose of Boostrix in terms of SAEs among the 
vaccinated household contacts of the infants born to pregnant women in Spain, 
as part of an assessment of cocooning, from the day of vaccination till 30 days 
after the vaccination.
Section 3 Study design overview
The following information is added.

Experimental design: Phase IV, observer-blind, randomised, placebo-controlled, 
multi-centric, multi-country study with two cross-over groups. All eligible 
household contacts of the infants born to pregnant women enrolled in Spain will 
be eligible to receive a single dose of Boostrix as part of an assessment of 
cocooning.
Table 2 Study groups and treatment foreseen in the study
The following footnote is added.
Treatment name
Vaccine name
Study Groups
dTpa Group
Control 
Group
Boostrix *
dTpa 
x
x
Placebo for dTpa vaccine 
Placebo
x
x
*All eligible household contacts of the infants born to pregnant women enrolled in Spain will be eligible to 
receive a single dose of Boostrix as part of an assessment of cocooning.

Vaccination schedule:

All subjects will receive a single dose of Boostrix or placebo at 27-36 weeks 
(i.e. completed 27 weeks until 36 weeks) of gestation (Visit 1). Subjects who 
receive Boostrix at Visit 1 will receive a dose of placebo post-delivery (Visit 
3) while those who receive placebo at Visit 1 will receive Boostrix post-
delivery (Visit 3).

All eligible household contacts of the infants born to pregnant women 
enrolled in Spain will be eligible to receive a single dose of Boostrix as part 
of an assessment of cocooning. Although the vaccine can be administered 
anytime during the study, it is recommended that the vaccine is administered 
preferably 2 weeks before birth of the infant.
 
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Section 4.2 Inclusion criteria for enrolment
The following details are added:
Inclusion criteria for study subjects:
Inclusion criteria for household contacts in Spain:

Household contacts living in the same house as that of the infant.

Household contacts or parent(s)/LAR(s) of the household contacts who, in the 
opinion of the investigator, can and will comply with the requirements of the 
protocol (e.g. reporting of SAEs).

Written informed consent obtained from the household contacts or the 
parent(s)/LAR(s) prior to vaccination, as per local regulations.

Household contacts who are eligible to receive a booster dose of DTP-containing 
vaccine according to the Summary of Product Characteristics (SmPC) of 
Boostrix and according to the local governmental recommendations in Spain.

Female household contacts 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 household contacts of childbearing potential may be enrolled in the 
study , if the household contact

has practiced adequate contraception for 30 days prior to vaccination,

has a negative pregnancy test on the day of vaccination and

has agreed to continue adequate contraception for 2 months after receiving
the vaccine dose.
 
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Section 4.3 Exclusion criteria for enrolment
The following details are added:
Exclusion criteria for study subjects:
Exclusion criteria for household contacts in Spain:

Child in care.
Please refer to the glossary of terms for the definition of child in care.

Concurrently participating in another clinical study, at any time during the study 
period, in which the household contact has been or will be exposed to an 
investigational or a non-investigational product (pharmaceutical product or 
device).

Use of any investigational or non-registered product (drug or vaccine) other than 
the study vaccine within 30 days preceding the dose of study vaccine, or planned 
use during the study period.

History of any reaction or hypersensitivity likely to be exacerbated by any
component of the vaccine.

History of an encephalopathy of unknown aetiology, occurring within 7 days 
following previous vaccination with pertussis-containing vaccine.

Acute disease and/or fever at the time of enrolment.

Fever is defined as temperature 37.5°C /99.5°F for oral, axillary or 
tympanic route, or 38.0°C /100.4°F on rectal route. The preferred route of 
recording temperature will be axillary in household contacts.

Household contacts with a minor illness (such as mild diarrhoea, mild upper 
respiratory infection) without fever may be enrolled at the discretion of the 
investigator.

Anything that would put the household contact at risk, as determined by the 
investigator.

Pregnant or lactating household contacts.

Household contacts planning to become pregnant or planning to discontinue 
contraceptive precautions prior to 2 months post-vaccination.
Section 5.2.2.1.1 Study group and treatment number allocation
The following information is added.
All the eligible household contacts of infants born to pregnant women enrolled in 
Spain will be eligible to receive a single dose of Boostrix as part of an assessment of 
cocooning. For specific instructions with respect to treatment allocation of the 
household contacts in Spain, refer to the SPM.
 
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Section 5.5 Outline of study procedures
The list of study procedures are presented in Table 4 and Table 5.
Table 4 ‘List of study procedures for study subjects’ is updated.
Epoch
Epoch 001
Type of contact
Screening 
Visit 
Visit 
1 
Visit 2 
Visit 
3 
Visit 4 
Time-points
Day -14 to 
0
Day 
0
Day 30
At 
birth
Post-delivery 
Month 2
Sampling time-points
Pre-
Vacc
Post-Vacc
Cord 
blood
Informed consent
● 
Collect demographic data 
●
Medical history, including medication history and previous 
diphtheria/tetanus/pertussis vaccination history*
O 
●
Pregnancy screening**
● 
Data collection on household contacts§
●
History directed physical examination 
O 
●
O
Check inclusion/exclusion criteria 
O 
●
Pre-vaccination body temperature 
●
●
Measure/record height and weight 
● 
Check contraindications and warnings and precautions 
O 
O 
Study group and treatment number allocation 
O 
Recording of administered treatment number 
●
●
Treatment number allocation for subsequent dose (Cross-
over dose) 
O 
Blood sampling for antibody determination 
●
●
●
Vaccine administration 
●
●
Distribution of diary cards 
O 
O 
O 
Record any concomitant medication/vaccination 
●
●
●
●
Physical examination of newborn, including length, weight, 
head circumference and Apgar Score
●
Record breastfeeding status
●
Recording and follow up of pregnancy-related adverse events 
and neonate-related events
●
●
●
●
Record any intercurrent medical conditions 
●
●
●
●
Recording of solicited adverse events (Days 0-7) by subjects 
in diary card 
●
●
Recording of non-serious adverse events (Day 0– Day 30), by 
subjects 
●
●
●
Recording of large injection site reactions
●
●
Return of diary cards 
O 
O 
O 
Diary card transcription by investigator/designee 
●
●
●
Recording of serious adverse events (SAEs) # and AEs 
leading to withdrawal 
●
●
●
●
Recording of SAEs related to study participation or to a 
concurrent GSK medication/vaccine 
● 
●
●
●
●
Recording of new pregnancies 
●
●
Screening conclusion
● 
Study Conclusion 
●
Note: The procedures to be conducted during screening visit and Visit 1 may be combined. 
In case a woman gives birth to an infant between Visit 1 (Day 0) and Visit 2 (Day 30), the procedures for Visit 2 and 
Visit 3 will be combined. A blood sample from the mother must be taken before the cross-over vaccination is given to 
her.
 
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● is used to indicate a study procedure that requires documentation in the individual eCRF.
○ is used to indicate a study procedure that does not require documentation in the individual eCRF.
Pre-vacc: Blood sample to be collected before the dose of the booster vaccination in pregnant women (Visit 1).
Post-vacc: Blood sample to be collected one month after the booster vaccination in pregnant women (Visit 2).
† Father of the child should also sign the informed consent form, if required by the local laws. 
* History of all medications, excluding the vitamins and supplements taken by the mother during her pregnancy before 
receiving the first dose of study vaccine will be recorded in the eCRF. 
** Pregnancy screening will include checking of records of ultrasound testing, nuchal translucency scan, serum testing 
and any other prenatal tests (if performed). Refer to Section 4.2 for details regarding pregnancy screening. 
# Including adverse pregnancy outcomes and listed pregnancy-related/neonate-related AEs of interest.
§Information will be obtained by interviewing the mother after she agrees to participate in the study. These 
details can be collected at any of the study visits.
Table 5 ‘List of study procedures for household contacts’ is added.
Epoch
Epoch 001
Type of contact
Screening 
Visit#
Visit 
1 
Visit 2 
Visit 3 
Visit 4 
Time-points
Day -14 to 
0
Day 
0
Day 30
At birth
Post-delivery 
Month 2
Informed consent 
●#
Check inclusion/exclusion criteria 
●#
Collect demographic data 
●#
Medical history and previous DTP-containing vaccination 
history
●#
Urine pregnancy test in female household contacts of 
child bearing potential 
●#
Pre-vaccination body temperature 
●#
Vaccine administration**
●#
Recording of administered treatment number 
●#
Recording of serious adverse events (SAEs) and 
pregnancies ‡
●
●
●
●
● is used to indicate a study procedure that requires documentation in the individual eCRF.
*Screening visit will not be applicable for household contacts.
**The vaccine for household contacts should be administered only after vaccination of the mother (study 
subject).
#The procedures for household contacts can be performed anytime during the study, it is recommended that 
the vaccine is administered preferably 2 weeks before birth of the infant.
‡The SAEs and pregnancies in household contacts should be reported from the date of vaccination till 30 days 
after vaccination.
Table 6 Intervals between study visits
The following footnote is added.
Interval*
Optimal length of 
interval 1
Allowed interval2
Screening Visit Visit 1 
-14 to 0 days
-28 to 0 days  
Visit 1 Visit 2 
30 days 
21- 48 days 
Visit 3 Visit 4 
60 days 
45 - 75 days 
1. Whenever possible the investigator should arrange study visits within this interval.
2. Subjects will not be eligible for inclusion in the ATP cohort for analysis of immunogenicity if they make the study 
visit outside this interval. In case a mother gives birth to an infant before 21 days post-vaccination, she will be 
excluded from the ATP cohort for analysis of immunogenicity.
*Household contacts can be vaccinated anytime during the study, it is recommended that the vaccine is 
administered preferably 2 weeks before birth of the infant.
 
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Section 5.6 Detailed description of study procedures
The section numbers for procedures in study subjects are updated. The following 
changes are incorporated in Section 5.6.1.3.5-Study Vaccine administration

The investigators should discuss with the subjects about the official 
recommendations and/or local practice regarding the use of Tdap vaccines for 
individuals in close contact with neonates and up to-date vaccination of the 
neonate’s siblings with DTP vaccines in order to reduce the potential risk of 
pertussis in neonates. The investigators will discuss with the subjects regarding 
the benefits of cocooning i.e. up to date vaccination of the baby’s siblings with 
DTP-containing vaccines and vaccinating all the household contacts (people 
living under the same roof) eligible to receive DTP-containing vaccines as per 
Summary of Product Characteristics (SmPC) of Boostrix and local governmental 
recommendations in Spain in order to reduce the potential risk of pertussis in 
neonates. The subjects will be requested to provide the number of household 
contacts. Additionally the subjects will also be requested for the number of 
household contacts who refused the visit to site and the reason for refusal for 
subsequent eligibility determination and vaccination will be documented.
The following subsections are included.
5.6.2 Study procedures for household contacts in Spain
5.6.2.1 Informed Consent
The signed/witnessed/thumb printed informed consent of the household 
contact/parent(s)/LAR(s) must be obtained before study participation. If the 
household contact is below 18 years of age, the parent(s)/LAR(s) should sign the 
informed consent form, if required by the local laws. The subject has to visit the site 
to complete the informed consent process.
Refer to Section 5.1 for the requirements on how to obtain informed consent.
5.6.2.2 Check inclusion and exclusion criteria
Check all inclusion and exclusion criteria for household contacts as described in 
Sections 4.2 and 4.3 before enrolment. 
5.6.2.3 Collect demographic data
Record demographic data such as age, gender, ethnicity and relationship to the 
infant in the household contact’s eCRF.
5.6.2.4 Medical history
Obtain the household contact’s medical history by interview and/or review of the 
medical records and record any pre-existing conditions or signs and/or symptoms 
present in a household contact prior to the vaccination in the household contact’s 
eCRF.
 
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5.6.2.5 Urine pregnancy test
Female household contacts of childbearing potential are to have a urine pregnancy 
test prior to study vaccine administration. The study vaccine may only be 
administered if the pregnancy test is negative. Note: The urine pregnancy test must 
be performed even if the household contact is menstruating at the time of the study 
visit.
5.6.2.6 Assess pre-vaccination body temperature
The axillary, rectal, oral or tympanic body temperature of all household contacts 
needs to be measured prior to any study vaccine administration. The preferred route 
for recording temperature in household contacts will be axillary. If the household 
contact has fever [fever is defined as temperature 37.5°C/99.5°F for axillary route 
on the day of vaccination], the vaccination visit will be rescheduled within the 
allowed interval for this visit.
5.6.2.7 Vaccine administration
After completing all prerequisite procedures prior to vaccination, one dose of 
Boostrix will be administered intramuscularly (IM) in the deltoid of the non-
dominant arm (refer to Section 6.3 for detailed description of the vaccine 
administration procedure). If the investigator or delegate determines that the 
household contact’s health on the day of administration temporarily precludes 
vaccine administration, the visit will be rescheduled within the allowed interval for 
this visit (refer to Table 6). The reason for refusal of vaccination by eligible 
household contacts will be recorded, if applicable.
The household contacts 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.
5.6.2.8 Recording of SAEs and pregnancies
Refer to Section 8.2 for procedures for the investigator to record SAEs and 
pregnancies. Refer to Section 8.3 for guidelines and how to report SAE and 
pregnancy reports to GSK Biologicals.
 
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Section 6.3 Dosage and administration of study vaccines
Table 11 Dosage and administration 
The following footnote is added.
Type of contact and 
time-point*
volume to be 
administered
Study Group Treatment 
name
Route 
1
Site 
2
Side 3
Visit 1 (Day 0)
0.5 mL
dTpa Group
Boostrix
IM
D
N-D
Control Group
Placebo
Visit 3 (At birth)
0.5 mL
dTpa Group
Placebo
IM
D
N-D
Control Group
Boostrix
1 Intramuscular (IM)
2Deltoid (D) 
3Non-dominant (N-D).
Vaccination can be performed in the opposite side in case of medical indication preventing vaccination in the side 
stated in the table, as judged by the investigator.
*Household contacts in Spain: One dose (0.5mL) of Boostrix vaccine will be administered intramuscularly as 
part of an assessment of cocooning.
Section 8.2.1 Time period for detecting and recording adverse events, serious adverse 
events, pregnancies, pregnancy-related AEs and neonate-related AEs- The following 
information is added.
The time period of reporting SAEs for household contacts will begin at the 
administration of Boostrix vaccine (as part of an assessment of cocooning) and end 
at 30 days after the vaccination. The SAEs and pregnancies in household contacts 
will be collected till 30 days after vaccination, irrespective of the visit in which the 
vaccine is administered.
 
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Table 13 Reporting periods for adverse events, serious adverse events, pregnancies, 
pregnancy-related adverse events and neonate-related adverse events-is updated as 
follows.
Event
Screening 
Visit*
V1 8 d 
(0-
7d) 
post
V1
31 d 
(0-30d) post 
V1
V3
8 d 
(0-7d)
post 
V3
31 d 
(0-30 
d)
post 
V3
V4
(Study
Conclusion)
D0
V2 (D30)
At birth
Post-delivery 
M2
Solicited local and general AEs
Unsolicited AEs
AEs/SAEs leading to withdrawal 
from the study
SAEs
Pregnancy-related adverse 
events and
neonate-related adverse events
SAEs related to study 
participation 
or concurrent GSK medication/
vaccine
New pregnancies
SAEs and pregnan-cies in 
household contacts in 
Spain**
SAEs related to study 
participation 
or concurrent GSK medication/
Vaccine in household 
contacts in Spain
* i.e. consent obtained; V: Visit; D: Day, M: Month, 
** The SAEs and pregnancies in household contacts will be reported till 30 days after vaccination, 
irrespective of the visit in which the vaccine is administered.
 
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Section 8.8 Subject card is updated as mentioned below.
Study subjects and participating household contacts must be provided with the address 
and telephone number of the main contact for information about the clinical study.
Section 10.2 Secondary endpoints- The following changes are included.

Serious adverse events (SAEs).

Occurrence of serious adverse events from Dose 1 up to study end (Visit 4).

Percentage of household contacts of the infants born to pregnant women 
vaccinated in Spain who accepted Boostrix vaccine as part of an assessment of 
cocooning among the eligible household contacts.

Occurrence of SAEs among the vaccinated household contacts of the infants 
born to pregnant women in Spain, as part of an assessment of cocooning, from
the day of vaccination till 30 days after vaccination.
Section 10.4.4 Total cohort for household contacts in Spain is added as given below.
Total cohort for household contacts will include all eligible household contacts of the 
infants born to pregnant women vaccinated in Spain. For the analysis of safety, all 
vaccinated household contacts will be considered.
Section 10.6 Analysis of demographics
The following section is added.
10.6.1 Analysis of eligible household contacts
Analysis of eligible household contacts will be performed on the Total cohort for 
household contacts in Spain.

Demographic characteristics will be summarised for the eligible household 
contacts as a whole and per group using descriptive statistics.

Reasons for refusal of the cocooning vaccination will be summarised for the 
eligible household contacts as a whole and per group.

Percentage of household contacts of the infants born to pregnant women 
vaccinated in Spain who accepted Boostrix vaccine as part of an assessment of 
cocooning among the eligible household contacts will be tabulated as a whole 
and per group.
 
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Section 10.8 Analysis of safety
The following changes are included.
The primary analysis will be performed on the TVC. If in any vaccine group, 5% or 
more of the vaccinated subjects are eliminated from the TVC, a second analysis will be 
performed on the ATP cohort for analysis of safety. Analysis of safety in household 
contacts will be performed on the Total cohort for household contacts in Spain.

For the vaccinated household contacts in Spain, SAEs following Boostrix
vaccination up to 30 days will be described in detail.
 
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PPD

SAP_001.pdf: 
C O N FI D E N TI A L
1 1 6 9 4 5 [ D T P A (B O O S T RI X) -0 4 7 ]
St ati sti c al A n al y si s Pl a n Fi n al
2 0- F E B -2 0 1 8
P a g e 1 of 6 1
St ati sti c al A n al y si s Pl a n
Det aile d Title:
A P hase I V, o bser ver -bli n d, ra n d o mise d, cr oss -o ver, 
place b o -c o ntr olle d, m ultice ntre st u d y t o assess t he 
i m m u n o ge nicity a n d safe t y of a si n gle d ose of 
B o ostri x i n pre g na nt w o me n.
e Tr ac k st u d y n u m ber a n d 
A b bre vi ate d Title
1 1 6 9 4 5 [ D T P A ( B O O S T RIX) -0 4 7]
Sc o pe:
All data pertai ni n g t o t he a b o ve st u d y.
D ate of St atistic al A n al ysis 
Pl a n
Fi nal: 2 0 -Fe b -2 0 1 8
C o -or di n ati n g a ut h or:
 ( Statisticia n) 
Re vie we d b y:
 ( Cli nical a n d E pi de mi ol o g y 
R & D Pr oject Lea der)
 ( Cli nical Researc h a n d 
De vel o p me nt Lea d)
( Lea d statisticia n) 
 ( Lea d statistical a nal yst)
Scie ntific writer)
 ( Re g ulat or y Affair) 
 ( S E R M p h ysicia n)
 ( P u blic discl os ure re prese ntati ve)
A p pr o ve d b y:
 ( Cli nical a n d E pi de mi ol o g y 
R & D Pr oject Lea der)
 (Cli nical Researc h a n d 
De vel o p me nt Lea d)
( Lea d Statisticia n) 
 ( Scie ntific writer)
 ( Lea d statistical a nal yst)
A P P 9 0 0 0 0 5 8 1 9 3 St atistic al A n alysis Pl a n Te m pl ate ( Effective d ate: 1 4 A pril 2 0 1 7)
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


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TABLE OF CONTENTS
PAGE
LIST OF ABBREVIATIONS.............................................................................................7
1.
DOCUMENT HISTORY............................................................................................8
2.
STUDY DESIGN ......................................................................................................8
3.
OBJECTIVES.........................................................................................................11
4.
ENDPOINTS ..........................................................................................................12
5.
ANALYSIS SETS ...................................................................................................13
5.1.
Definition.....................................................................................................13
5.1.1.
Total Vaccinated cohort ...............................................................13
5.1.2.
According-To-Protocol cohort for analysis of safety .....................13
5.1.3.
ATP cohort for analysis of immunogenicity ..................................14
5.1.4.
Total cohort for household contacts in Spain ...............................14
5.2.
Criteria for eliminating data from Analysis Sets...........................................14
5.2.1.
Elimination from Total vaccinated cohort (TVC) ...........................14
5.2.1.1.
Elimination from ATP cohort for 
immunogenicity Excluded subjects.............................15
5.3.
Important protocol deviation not leading to elimination from per-
protocol analysis set ...................................................................................16
6.
STATISTICAL ANALYSES.....................................................................................16
6.1.
Demography...............................................................................................16
6.1.1.
Analysis of demographics/baseline characteristics planned 
in the protocol..............................................................................16
6.1.1.1.
Analysis of eligible household contacts.......................16
6.1.2.
Additional considerations.............................................................16
6.2.
Exposure ....................................................................................................17
6.3.
Immunogenicity...........................................................................................17
6.3.1.
Analysis of immunogenicity planned in the protocol.....................17
6.3.1.1.
Within group assessment: ..........................................17
6.3.1.2.
Between group assessment: ......................................18
6.3.2.
Additional considerations.............................................................18
6.4.
Analysis of safety........................................................................................19
6.4.1.
Analysis of safety planned in the protocol ....................................19
6.4.2.
Additional considerations.............................................................20
7.
ANALYSIS INTERPRETATION..............................................................................20
8.
CONDUCT OF ANALYSES....................................................................................21
8.1.
Sequence of analyses.................................................................................21
8.2.
Statistical considerations for interim analyses.............................................21
9.
CHANGES FROM PLANNED ANALYSES.............................................................21
10. LIST OF FINAL REPORT TABLES, LISTINGS AND FIGURES .............................21


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11. ANNEX 1 STANDARD DATA DERIVATION RULE AND STATISTICAL
METHODS .............................................................................................................23
11.1.
Statistical Method References ....................................................................23
11.2.
Standard data derivation.............................................................................23
11.2.1.
Date derivation ............................................................................23
11.2.2.
Dose number...............................................................................24
11.2.3.
Demography................................................................................24
11.2.4.
Immunogenicity............................................................................25
11.2.5.
Safety analysis ............................................................................27
11.2.5.1.
Solicited Adverse Events............................................27
11.2.5.2.
Combined Solicited and Unsolicited Adverse 
Events ........................................................................29
11.2.6.
Management of missing data.......................................................30
11.2.7.
Number of decimals displayed.....................................................30
12. ANNEX 3: STUDY SPECIFIC MOCK TFL..............................................................31


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LIST OF TABLES
Table 1
Study groups and epoch foreseen in the study.........................................9
Table 2
Study groups and treatment foreseen in the study ...................................9
Table 3
Blinding of study epoch ..........................................................................10
Table 4
Humoral Immunity (Antibody determination)...........................................26
Table 5
Intensity scales for solicited symptoms in adults.....................................28
Table 6
Percentage of subjects with grade 3 unsolicited symptoms 
classified by MedDRA SOC and PT from Day 0 to Day 30 after 
any vaccination (Total Vaccinated Cohort) .............................................55
Table 7
Number (%) of subjects with serious adverse events from first 
study vaccination up to Visit 3 including number of events 
reported (Total Vaccinated Cohort) ........................................................57
Table 8
Subjects with Serious Adverse Events reported up to Visit 2 
(Total Vaccinated Cohort) ......................................................................58
Table 9
Number and percentage of subjects who started at least one 
concomitant medication from Day 0 to Day 7 (Total Vaccinated 
Cohort)...................................................................................................60
Table 10
Solicited and Unsolicited symptoms experienced by subjects 
classified by MedDRA Primary System Organ Class and 
Preferred Term within the 31-day (Days 0-30) post-vaccination 
period - SAE excluded (Total vaccinated cohort)....................................60
Table 11
Minimum and maximum activity dates (TVC) .........................................60
Table 12
Number of enrolled subjects by age category (TVC) ..............................61
Table 13
Number of subjects by country...............................................................61
Table 14
Listing of dropouts due to AEs, SAEs and solicited symptoms 
(Total cohort)..........................................................................................61


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LIST OF TEMPLATES
Template 1
Number of subjects enrolled by center (Total Vaccinated Cohort)..........32
Template 2
Number of subjects vaccinated, completed and withdrawn with 
reason for withdrawal at Visit 3 (Total Vaccinated Cohort) .....................32
Template 3
Number of subjects at each visit and list of withdrawn subjects 
(Total Vaccinated Cohort) ......................................................................33
Template 4
Number of subjects enrolled into the study as well as the number 
of subjects excluded from ATP analyses with reasons for 
exclusion................................................................................................34
Template 5
Deviations from specifications for age and intervals between 
study visits (Total Vaccinated Cohort) ....................................................35
Template 6
Summary of demography and baseline characteristics (ATP 
cohort for Immunogenicity).....................................................................36
Template 7
Study population (TVC)..........................................................................38
Template 8
Summary of household contacts in Spain (Total vaccinated 
cohort: (subset of subjects in Spain)) .....................................................38
Template 9
Summary of vaccination of household contacts in Spain (Total 
cohort for household contacts in Spain) .................................................39
Template 10
Seropositivity and seroprotection rates and GMCs for anti-
diphtheria and anti-tetanus antibodies before and one month 
after the booster vaccination and cord blood sample (ATP cohort 
for immunogenicity)................................................................................39
Template 11
GMC ratio between groups [dTpa Group divided by Control 
Group] and their 95% CIs for anti-PT, anti-FHA and anti-PRN 
antigens in cord blood sample (ATP cohort for immunogenicity) ............40
Template 12
Vaccine responses for anti-PT, anti-FHA and anti-PRN antibody 
concentration one month after the booster vaccination (ATP 
cohort for immunogenicity) .....................................................................40
Template 13
Reverse cumulative curve for anti-diphtheria antibody 
concentration one month after the booster vaccination (ATP 
cohort for immunogenicity) .....................................................................41
Template 14
Percentage of subjects by pregnancy outcome (Total vaccinated 
cohort-Mother) .......................................................................................42
Template 15
Percentage of subjects with listed pregnancy/neonate related 
adverse events of interest (Total vaccinated cohort) ..............................43
Template 16
Number and percentage of subjects who received study vaccine 
doses - TVC...........................................................................................44


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Template 17
Compliance in returning symptom information (Total Vaccinated 
Cohort)...................................................................................................44
Template 18
Incidence and nature of grade 3 symptoms (solicited and 
unsolicited) reported during the 4-day (Days 0-3) period after 
vaccination following each dose and overall (Total Vaccinated 
Cohort)...................................................................................................44
Template 19
Incidence of solicited local symptoms reported during the 4-day 
(Days 0-3) period after vaccination following each dose and 
overall (Total Vaccinated Cohort)...........................................................45
Template 20
Incidence of solicited general symptoms reported during the 4-
day (Days 0-3) post-vaccination period (Total Vaccinated Cohort).........46
Template 21
Incidence of any large injection site reaction (defined as a 
swelling with a diameter > 100 mm, noticeable diffuse swelling or 
noticeable increase in limb circumference) with onset within 4 
days (Day 0–3) after booster vaccination (Total Vaccinated 
Cohort at Year 9)....................................................................................47
Template 22
Percentage of doses with grade 3 unsolicited symptoms 
classified by MedDRA SOC and PT from Day 0 to Day 30 after 
vaccination in each HRV vaccine liquid formulation group - TVC ...........48
Template 23
Number (%) of subjects with serious adverse events from first 
study vaccination up to Visit 3 including number of events 
reported (TVC) .......................................................................................49
Template 24
Subjects with Serious Adverse Events reported up to Visit 3 -
TVC........................................................................................................50
Template 25
Number and percentage of doses and of subjects who took at 
least one concomitant medication from Day 0 to Day 7 after 
vaccination by type in each HRV vaccine liquid formulation group 
- TVC .....................................................................................................52
Template 26
Solicited and Unsolicited symptoms experienced by subjects 
classified by MedDRA Primary System Organ Class and 
Preferred Term within the 31-day (Days 0-30) post-vaccination 
period - SAE excluded (Total vaccinated cohort)....................................52
Template 27
Minimum and maximum activity dates (TVC) .........................................53
Template 28
Number of enrolled subjects by age category (TVC) ..............................53
Template 29
Number of subjects by country...............................................................53
Template 30
Listing of dropouts due to AEs, SAEs and solicited symptoms 
(Total cohort)..........................................................................................54
Template 31
Summary of demographic characteristics of household contacts 
in Spain (Total cohort for household contacts in Spain)..........................54


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LIST OF ABBREVIATIONS
AE
Adverse event
ANCOVA
Analysis of Covariance
ANOVA
Analysis of Variance
CI
Confidence Interval
CRF
Case Report Form
CSR
Clinical Study Report
CTRS
Clinical Trial Registry Summary
EL.U/ml
ELISA unit per milliliter
Eli Type
Internal GSK database code for type of elimination code
ELISA
Enzyme-linked immunosorbent assay
ES
TVC
GMC
Geometric mean antibody concentration
GMT
GSK
Geometric mean antibody titer
GlaxoSmithKline
IU/ml
International units per milliliter
LL
Lower Limit of the confidence interval
MedDRA
Medical Dictionary for Regulatory Activities
N.A.
Not Applicable
PD
Protocol Deviation
PPS
Per Protocol Set
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SBIR
GSK Biological’s Internet Randomization System
SD
Standard Deviation
SR
Study Report
TFL
Tables Figures and Listings 
TOC
Table of Content
UL
Upper Limit of the confidence interval


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1.
DOCUMENT HISTORY
Date
Description
Protocol Version
20-FEB-2018
first version
Administrative Change 1 Final: 06-SEP-
2016
2.
STUDY DESIGN
N: Number of subjects planned to be enrolled
Pre-vacc: Blood sample to be collected before the dose of the booster vaccination in pregnant women (Visit 1).
Post-vacc: Blood sample to be collected one month after the booster vaccination in pregnant women (Visit 2).
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the outline of study procedures (Section 5.5 of protocol), are essential and 
required for study conduct. 

Experimental design: Phase IV, observer-blind, randomised, placebo-controlled, 
multi-centric, multi-country study with two cross-over groups. All eligible household 
contacts of the infants born to pregnant women enrolled in Spain will be eligible to 
receive a single dose of Boostrix as part of an assessment of cocooning.

Duration of the study: The intended duration of the study will be approximately 5 
months for each subject.

Epoch 001: Booster vaccination starting at Screening visit (Day -14 to 0) and 
ending at Visit 4 (post-delivery Month 2).


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
Study groups: The study groups are defined as follows: 

dTpa Group: This group will consist of pregnant women who will receive a 
single dose of Boostrix at 27-36 weeks (i.e. completed 27 weeks until 36 weeks) 
of gestation (Visit 1) and will receive a dose of the placebo post-delivery (within 
72 hours).

Control Group: This group will consist of pregnant women who will receive a 
single dose of placebo at 27-36 weeks (i.e. completed 27 weeks until 36 weeks) 
of gestation (Visit 1) and will receive a dose of Boostrix post-delivery (within 72 
hours).
The study groups and epoch foreseen in the study are presented in Table 1
Table 1
Study groups and epoch foreseen in the study
Study groups
Number of 
subjects
Age (Min/Max)
Epoch
Epoch 001
dTpa Group
340
18 years - 45 years
x
Control Group
340
18 years - 45 years
x
The study groups and treatment foreseen in the study are presented in Table 2
Table 2
Study groups and treatment foreseen in the study
Treatment name
Vaccine name
Study Groups
dTpa Group
Control Group
Boostrix *
dTpa
x
x
Placebo for dTpa vaccine
Placebo
x
x
*All eligible household contacts of the infants born to pregnant women enrolled in Spain will be eligible to receive a 
single dose of Boostrix as part of an assessment of cocooning.

Control: placebo control

Vaccination schedule:

All subjects will receive a single dose of Boostrix or placebo at 27-36 weeks (i.e. 
completed 27 weeks until 36 weeks) of gestation (Visit 1). Subjects who receive 
Boostrix at Visit 1 will receive a dose of placebo post-delivery (Visit 3) while 
those who receive placebo at Visit 1 will receive Boostrix post-delivery (Visit 
3).

All eligible household contacts of the infants born to pregnant women enrolled 
in Spain will be eligible to receive a single dose of Boostrix as part of an 
assessment of cocooning. Although the vaccine can be administered anytime 
during the study, it is recommended that the vaccine is administered preferably 2 
weeks before birth of the infant.

Treatment allocation: randomised.

Blinding: Observer-blind. Refer to Section 5.3 of protocol for details of the of 
blinding procedure.
The blinding of study epoch is presented in Table 3


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Table 3
Blinding of study epoch
Study Epoch
Blinding
Epoch 001
observer-blind

Sampling schedule: Blood samples will be collected at the following time-points:

Pre-Vacc (Visit 1): Before the booster vaccination, approximately 5 mL of blood 
sample will be collected from all subjects.

Post-Vacc (Visit 2): One month after the booster vaccination, approximately 5 mL 
of blood sample will be collected from all subjects.

Cord blood (Visit 3): approximately 2.5 mL of blood sample from the umbilical 
cord will be collected from all subjects.

Type of study: self-contained

Data collection: Electronic Case Report Form (eCRF).

Safety monitoring: An independent data monitoring committee (IDMC) (including 
obstetrician, paediatrician, statistician and a neonatologist) will be put in place to 
oversee the safety aspects of Boostrix in the clinical study i.e. each SAE/congenital 
anomaly/foetal malformation case/incidence of grade 3 local and general solicited 
adverse events (AEs) will be reviewed by this committee (See Section5.4.1 of 
protocol for details).


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3.
OBJECTIVES
Primary

To demonstrate that the maternally transferred antibodies against pertussis in the 
dTpa Group is superior to that in the Control Group in terms of geometric mean 
concentrations (GMCs) for the pertussis antibodies, in the cord blood sample.
Criterion:

The lower limit (LL) of the 95% confidence interval (CI) of the GMC ratio 
[dTpa Group divided by Control Group] for anti-pertussis toxoid (anti-PT), 
anti-filamentous hemagglutinin (anti-FHA) and anti-pertactin (anti-PRN) 
antibodies is ≥ 1.5.
Secondary

To assess the safety of a single dose of Boostrix in pregnant women, administered 
during 27-36 weeks of gestation, in terms of the outcomes of pregnancy and 
listed pregnancy-related adverse events of interest/neonate-related events of 
interest up to study end (Visit 4).

To assess the immunogenicity of a single dose of Boostrix administered during 
pregnancy in terms of seropositivity status for antibodies against pertussis, in the 
cord blood sample.

To assess the immunogenicity of a single dose of Boostrix administered during 
pregnancy in terms of seroprotection/seropositivity status, vaccine response and 
GMCs for antibodies against diphtheria, tetanus and pertussis, one month post-
vaccination.

To evaluate the reactogenicity of a single dose of Boostrix administered during 
pregnancy and post-delivery in terms of solicited symptoms during the 8-day 
(Day 0 – Day 7) follow-up period after vaccination.

To assess the safety of a single dose of Boostrix administered during pregnancy 
and post-delivery in terms of unsolicited symptoms during the 31-day (Day 0 –
Day 30) follow-up period after vaccination and serious adverse events (SAEs) 
during the period from Visit 1 up to Visit 4.

To assess the acceptance rate of a single dose of Boostrix among eligible 
household contacts of the infants born to pregnant women enrolled in Spain, as 
part of an assessment of cocooning.

To assess the safety of a single dose of Boostrix in terms of SAEs among the 
vaccinated household contacts of the infants born to pregnant women in Spain, as 
part of an assessment of cocooning, from the day of vaccination till 30 days after 
the vaccination.


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4.
ENDPOINTS
Primary

Immunogenicity with respect to components of the study vaccine, at delivery (in 
cord blood sample):

Anti-PT, anti-FHA and anti-PRN antibody concentrations.
Secondary

Outcome of pregnancy in terms of pregnancy outcomes up to study end (Visit 4).

Pregnancy outcomes will include live birth with no congenital anomalies, live 
birth with congenital anomalies, still birth with no congenital anomalies, still 
birth with congenital anomalies, elective termination with no congenital 
anomalies and elective termination with congenital anomalies.

Outcome of pregnancy in terms of listed pregnancy-related adverse events of 
interest/ neonate-related events of interest up to study end (Visit 4).

Listed pregnancy-related adverse events of interest/ neonate-related events of 
interest will include gestational diabetes, pregnancy-related hypertension, 
premature rupture of membranes, preterm premature rupture of membranes, 
premature labour, premature uterine contractions, intrauterine growth 
restriction/poor foetal growth, pre-eclampsia, eclampsia, vaginal or 
intrauterine haemorrhage, maternal death, preterm birth, neonatal death, small 
for gestational age, neonatal hypoxic ischaemic encephalopathy and failure to 
thrive/growth deficiency.

Immunogenicity with respect to components of the study vaccine received during 
pregnancy, one month post vaccination

Anti-D, anti-T, anti-PT, anti-FHA and anti-PRN seroprotection/seropositivity 
status and antibody concentrations.

Vaccine response to PT, FHA and PRN. Refer to section 11.2.4

Vaccine response to anti-D and anti-T. Refer to section 11.2.4

Immunogenicity with respect to components of the study vaccine, in the cord 
blood sample.

Anti-PT, anti-FHA and anti-PRN seropositivity status.

Solicited local and general symptoms (at Visit 1 and Visit 3).

Occurrence of each solicited local/general symptoms during the 8-day (Day 0-
Day 7) follow-up period after the vaccination.

Unsolicited adverse events (at Visit 1 and Visit 3).

Occurrence of unsolicited AEs within 31 days (Day 0 – Day 30) after any 
vaccination, according to the Medical Dictionary for Regulatory Activities 
(MedDRA) classification.

Serious adverse events (SAEs).


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
Occurrence of serious adverse events from Dose 1 up to study end (Visit 4).

Percentage of household contacts of the infants born to pregnant women 
vaccinated in Spain who accepted Boostrix vaccine as part of an assessment of 
cocooning among the eligible household contacts.

Occurrence of SAEs among the vaccinated household contacts of the infants born 
to pregnant women in Spain, as part of an assessment of cocooning, from the day 
of vaccination till 30 days after vaccination.
5.
ANALYSIS SETS
5.1.
Definition
5.1.1.
Total Vaccinated cohort

The Total Vaccinated cohort (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 
during pregnancy (Visit 1) for whom data concerning at least one immunogenicity 
endpoint measure is available.
5.1.2.
According-To-Protocol cohort for analysis of safety
The ATP cohort for safety will consist of all subjects from the TVC who complied with 
vaccine administration up to the end of the Epoch 001, namely:

Who have received the dose of study vaccine (at Visit 1) according to their random 
assignment,

For whom administration site of study vaccine is known, and is according to 
protocol, 

Who have not received a vaccine not specified or forbidden in the protocol,

For whom the randomisation code is not broken.


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5.1.3.
ATP cohort for analysis of immunogenicity
The ATP cohort for analysis of immunogenicity will include all evaluable subjects from 
the ATP cohort for analysis of safety:

Who meet all eligibility criteria.

Who comply with the procedures and intervals defined in the protocol.

Who are within the maximum interval allowed as defined in the protocol.

Who do not meet any of the criteria for elimination from an ATP analysis (refer to 
Section 6.7.2 from protocol) during the study.

Who did not receive a product leading to exclusion from an ATP analysis as listed in 
Section 6.7.2 from protocol.

Who did not present with a medical condition leading to exclusion from an ATP 
analysis as listed in Section 6.8 from protocol.

Who have the cord blood collection at least 21 days post-vaccination.

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 one month after vaccination i.e. Visit 3 in 
the cord blood sample.
5.1.4.
Total cohort for household contacts in Spain
Total cohort for household contacts will include all eligible household contacts of the 
infants born to pregnant women vaccinated in Spain. For the analysis of safety, all 
vaccinated household contacts will be considered.
5.2.
Criteria for eliminating data from Analysis Sets
Elimination codes are used to identify subjects to be eliminated from analysis.  Detail is 
provided below for each sets. 
5.2.1.
Elimination from Total vaccinated cohort (TVC)
Code 1030 (Study vaccine not administered at all) and code 900 (invalid informed 
consent or fraud data) will be used for identifying subjects eliminated from TVC.


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5.2.1.1.
Elimination from ATP cohort for immunogenicity Excluded subjects
A subject will be excluded from the ATP cohort for immunogenicity under the following 
conditions 
Code
Condition under which the code is used
900
Questionable subject => Invalid informed consent or fraudulent 
data.  In case informed consent is obtained retrospectively the 
subject is not eliminated.
1030
Study vaccine dose not administrated at all but subject number 
allocated => subjects enrolled but not vaccinated
1040
Administration of concomitant vaccine(s) forbidden in the protocol
Previous vaccination containing diphtheria, tetanus or pertussis 
antigens or diphtheria and tetanus toxoids at any time during the 
current pregnancy.
1050
Randomisation failure (subject who received a vaccine not 
compatible with randomization)
1060
Randomisation code broken at the investigator site OR at GSK 
Safety department 
1070
Site or route of study vaccine administration wrong or unknown. 
1080
Vaccine has been administered (effective treatment number) despite 
a temperature deviation qualified by Status QA GMP NON Use.
1090
Vaccine has been administered (effective treatment number) out of 
the expiration date at the time of administration.
2010
Protocol violation linked to the inclusion/exclusion criteria 
including age and excluding codes mentioned below. 
2040
Administration of any medication forbidden by the protocol 
2050
Underlying medical condition forbidden by the protocol 
2060
Concomitant infection related to the vaccine which may influence 
immune response
2070
Concomitant infection not related to the vaccine which may 
influence immune response 
2090
Blood sample taken but non-compliance with blood sampling 
schedule for the cord blood sample (dates of BS not corresponding 
to adapted protocol intervals or unknown BS/vaccination dates) )=> 
Cord blood should be at least 21 days after vaccination
2100
Serological results not available for all antigens from the cord blood 
sample
2120
Obvious incoherence, abnormal serology evolution or error in data
in cord blood sample (incoherence between CRF and results, wrong 
sample labelling.


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5.3.
Important protocol deviation not leading to elimination from 
per-protocol analysis set 
Refer to the protocol deviation management plan for important protocol deviation not 
leading to elimination from ATP cohort for immunogenicity.
6.
STATISTICAL ANALYSES
Note that standard data derivation rule and stat methods are described in section 11 and 
will not be repeated below.
6.1.
Demography
6.1.1.
Analysis of demographics/baseline characteristics planned in the 
protocol
Demographic characteristics (age at the booster dose in years, race, height [cm], weight 
[kg], body mass index in kg/m2), cohort description and withdrawal status will be 
summarised by group using descriptive statistics:

Frequency tables will be generated for categorical variables such as race;

Mean, median and standard error will be provided for continuous data such as age.
The distribution of subjects enrolled among the study sites and countries will be tabulated 
as a whole and per group.
Summary statistics by height [cm], weight [kg], head circumference [cm], body mass 
index [BMI in kg/m²] and Apgar score of the infant will be tabulated as a whole and per 
group.
6.1.1.1.
Analysis of eligible household contacts
Analysis of eligible household contacts will be performed on the Total cohort for 
household contacts in Spain.

Demographic characteristics (age, sex, and race) will be summarised for the eligible 
household contacts as a whole and per group using descriptive statistics.

Reasons for refusal of the cocooning vaccination will be summarised for the eligible 
household contacts as a whole and per group.

Percentage of household contacts of the infants born to pregnant women vaccinated 
in Spain who accepted Boostrix vaccine as part of an assessment of cocooning 
among the eligible household contacts will be tabulated as a whole and per group.
6.1.2.
Additional considerations
Breast feeding status, gestational age at vaccination and the time between vaccination and 
delivery will be summarised as a whole and per group using descriptive statistics.


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The total number of household contacts approached, summary statistics for the number of 
household contacts by vaccinated subject will be generated in the subset of subjects in 
Spain.
Note that for a few of the household contacts, since they were later on classified as 
eligible based on the reasons for refusal, their demographic information is missing.
Apgar score will be summarized at 1 minute and 5 minutes post vaccination.  No 
summary will be provided at 10 minutes as the measurement is optional.
6.2.
Exposure
The number of pregnant mother vaccinated will be provided by study group and refer to 
section 6.1.1.1 for exposure in household contacts.
6.3.
Immunogenicity
6.3.1.
Analysis of immunogenicity planned in the protocol
The primary analysis will be based on the ATP cohort for analysis of immunogenicity. If, 
in any vaccine group, the percentage of vaccinated subjects with serological results 
excluded from this ATP cohort is 5% or more, a second analysis based on the TVC will 
be performed to complement the ATP analysis.
6.3.1.1.
Within group assessment:
For each treatment group, before and one month after vaccination during pregnancy and 
if blood sample result is available:

Seroprotection rates and their exact 95% CIs for antibodies against diphtheria and 
tetanus will be calculated.

Seropositivity rates and their exact 95% CIs for antibodies against PT, FHA, PRN, 
will be tabulated.

GMCs and their 95% CIs for antibodies against all vaccine antigens will be 
calculated. 

The distribution of antibody concentrations pre, one month after booster vaccination 
for each antigen will be displayed using reverse cumulative distribution curves.

Vaccine response to diphtheria, tetanus and pertussis antigens and their exact 95% CI 
will be calculated.
In the cord blood sample, if the blood sample result is available: 

Seropositivity rates and their exact 95% CIs for antibodies against PT, FHA, PRN, 
will be tabulated.

GMCs and their 95% CIs for antibodies against PT, FHA, PRN antigens will be 
calculated. 


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6.3.1.2.
Between group assessment:

The primary objective is to demonstrate that, the immune response in the dTpa 
Group is superior to that in the Control Group for the pertussis antigens, in the cord 
blood sample.

The LL of the 95% CI of the GMC ratio [dTpa Group divided by Control 
Group] for anti-PT, anti-FHA and anti-PRN antibodies are 1.5.
The CI of the group GMC ratios will be computed using a two-sample t test assuming 
heterogeneity of variance.
6.3.2.
Additional considerations
Percentage of subjects with anti-D and anti-T antibody concentrations 1.0 IU/ml will be 
calculated along with its exact 95% CI by vaccine group at each visit.
For the distribution of antibody concentrations displayed using reverse cumulative 
distribution curves, the pre booster will also be included in the same graph as the one 
month after booster vaccination.
The distribution of antibody concentrations measured from the cordon blood will also be 
generated in separated graphs. 
The following descriptive analysis will be performed by sub-group of gestational age (27-
32, 33-36 weeks of gestation of foetus at dose 1) and age of mother (18-24, 25-34, 35-
45). 
For each treatment group, before and one month after vaccination during pregnancy, cord 
blood sample and if blood sample result is available:

Seroprotection rates and percentage of subjects with anti-D and anti-T antibody 
concentrations 1.0 IU/ml will be calculated along with and their exact 95% CIs for 
antibodies against diphtheria and tetanus.

Seropositivity rates and their exact 95% CIs for antibodies against PT, FHA, PRN, 
will be tabulated.

GMCs and their 95% CIs for antibodies against all vaccine antigens will be 
calculated. 


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6.4.
Analysis of safety
6.4.1.
Analysis of safety planned in the protocol
The primary analysis will be performed on the TVC. If in any vaccine group, 5% or more 
of the vaccinated subjects are eliminated from the TVC, a second analysis will be 
performed on the ATP cohort for analysis of safety. Analysis of safety in household 
contacts will be performed on the Total cohort for household contacts in Spain.

The percentage of subjects with each specific pregnancy outcomes and listed 
pregnancy-related adverse events of interest/neonate-related events of interest will be 
tabulated with its exact 95% CI.

The percentage of subjects with at least one local AE (solicited and unsolicited), with 
at least one general AE (solicited and unsolicited) and with any AE during the 8-day 
(Day 0–Day 7) follow-up period after the vaccination will be tabulated after each 
dose with exact 95% CI. The same calculations will be performed for any Grade 3 
(solicited or unsolicited) symptoms, any causal relationship to vaccination and for 
any symptoms requiring medical attention.

The percentage of subjects reporting each individual solicited local and general AE 
during the 8-day (Day 0-Day 7) follow-up period after booster vaccination will be 
tabulated with its exact 95% CI for each group.

All computations mentioned above will be done for Grade ≥2 (solicited symptoms 
only) and Grade 3 symptoms, for symptoms considered related to vaccination 
(general symptoms only), for Grade 3 symptoms considered related to vaccination 
(general symptoms only) and for symptoms that resulted in a medically-attended 
visit.

Occurrence of fever and related fever will be reported per 0.5°C cumulative 
temperature increments as well as the occurrence of Grade 3 fever (> 39.0°C axillary 
temperature) with causal relationship to vaccination. 

Any large injection site reaction (defined as any local swelling with diameter 
> 100 mm and/or any noticeable diffuse injection site swelling (diameter not 
measurable) and/or any noticeable increased circumference of the injected limb) 
onset within 8 days (Day 0–Day 7) after each vaccination will be described in detail.

The verbatim reports of unsolicited symptoms will be reviewed by a physician and 
the signs and symptoms will be coded according to MedDRA. Every verbatim term 
will be matched with the appropriate Preferred Term. The percentage of subjects 
with unsolicited symptoms occurring within 31 days (Day 0–Day 30) with its exact 
95% CI will be tabulated by preferred term. Similar tabulation will be done for 
Grade 3 unsolicited symptoms and for unsolicited symptoms possibly 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 and 31-day follow-up period after vaccination will be tabulated 
after each dose with exact 95% CI.


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
SAEs and withdrawal due to AEs and SAEs following booster dose up to Visit 4 will 
be described in detail.

All SAEs assessed as being possibly related to study participation occurring 
throughout the study period will be described.

All SAEs assessed as being possibly related to a concurrent GSK medication 
occurring throughout the study period will be described.

For the vaccinated household contacts in Spain, SAEs following Boostrix
vaccination up to 30 days will be described in detail.
6.4.2.
Additional considerations

The safety analysis will be performed for each vaccination dose separately ie 
pregnancy dose and post-delivery dose.

The percentage of infants with unsolicited symptoms occurring from delivery until 2 
months with its exact 95% CI will be tabulated by preferred term. Similar tabulation 
will be done for Grade 3 unsolicited symptoms and for unsolicited symptoms 
possibly related to vaccination. 

The summary on concomitant medication (i.e. any medication, antipyretic 
medication, prophylactic antipyretics) will be performed over the 8 day period 
instead of 4 days. 

All SAEs will be summarized without distinction of SAEs possibly related to GSK 
concurrent medication.

The analysis of safety in the household contacts will be performed on the vaccinated 
household contacts instead of the Total cohort for household contacts in Spain.
7.
ANALYSIS INTERPRETATION
For analysis on the primary objective with pre-defined success criteria and an appropriate 
type I error control, appropriate conclusion can be drawn.
The secondary objectives of the study are descriptive and should be interpreted as such.


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8.
CONDUCT OF ANALYSES
8.1.
Sequence of analyses
Description
Analysis 
ID 
Disclosure 
Purpose
(IN=internal,
CTRS=public
posting, 
SR=study report
and public 
posting)
Dry run 
review 
needed (Y/N)
Study Headline 
Summary 
(SHS)requiring 
expedited 
communication 
to upper 
management 
(Yes/No)
Reference for 
TFL 
Final
E1_01
SR
Yes
Yes
TFL TOC 
8.2.
Statistical considerations for interim analyses
No statistical interim analysis will be performed.
9.
CHANGES FROM PLANNED ANALYSES

During the course of the study, the assays used to measure the anti-D, anti-T, anti-
PT, anti-FHA and anti-PRN IgG concentrations were re-developed and re-validated 
and both assay units and assay cut-offs were adapted. The new ELISA’s for PT, 
FHA and PRN were calibrated against the WHO International Standard (NIBSC 
06/140). This allowed the expression of concentrations measured with the new 
ELISA’s in international units per milliliter (IU/mL) instead of the formerly used 
ELISA units per milliliter (ELU/mL). The newly validated DTPa ELISA’s used in 
the study have a lower assay cut-off as compared to the one described in the 
protocol. The current assay cut-off is 0.057 IU/mL for anti-D, 0.043 IU/mL for anti-
T, 2.693 IU/mL for anti-PT, 2.046 IU/mL for anti-FHA and 2.187 IU/mL for anti-
PRN. An agreement between the old and new ELISAs was shown with regards to the 
two thresholds of clinical relevance for the DI/TE response (0.1 IU/mL and 1.0 
IU/mL) and therefore the clinical endpoints and anti-D and anti-T are unchanged. In 
the absence of a correlate of protection for the B. pertussis antigens, the pertussis 
endpoints were redefined based on the assay cut-off.

Refer to section 6.1.2, 6.3.2 and 6.4.2 for other changes.
10.
LIST OF FINAL REPORT TABLES, LISTINGS AND 
FIGURES
The TFL TOC provides the list of tables/listings and figures needed for the study report. 
It also identifies the tables eligible for each analyses and their role (synopsis, in-text, 
post-text, SHS, CTRS,…).  Note that all TFL aimed to be included as post-text are noted 
as post-text even if these are tabulation of individual data such as listing of SAE.  The 
post-text material contains all source material for the study report and accordingly a post-
text table may be redundant with an in-text table.


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Add the text below as applicable 
The mock tables referred under column named ‘layout’ can be found in legacy-NV/GSK 
SDD dedicated folder for standard tables and in section 12 for study specific mock 
table/figure/listing. The latter table/figure/listing are identified by the prefix SS_ in the 
TFL Toc.
The following group names will be used in the TFL TOC:
Group order in 
tables
Group label in 
tables
Group definition for 
footnote
Pooled Groups 
label in tables
Pooled 
definition for 
footnote
1
dTpa Group
Mothers received dTpa during 
pregnancy
NA
NA
2
Control Group
Mothers received placebo 
during pregnancy
NA
NA
If sub-groups are defined in the protocol, you can use the following example to describe 
these.
The following sub-group names will be used in the TFLs
Sub-group order in 
tables
Sub-group label in tables 
Sub-group definition for footnote
1
18-24Y
18-24 years old subjects
2
25-34Y
25-34 years old subjects
3
35-45Y
35-45 years old subjects
4
27-32W
27-32 weeks of gestation of foetus at dose 1
5
33-36W
33-36 weeks of gestation of foetus at dose 1


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11.
ANNEX 1 STANDARD DATA DERIVATION RULE AND 
STATISTICAL METHODS
11.1.
Statistical Method References
The exact two-sided 95% CIs for a proportion within a group will be the Clopper-Pearson 
exact CI [Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in 
the case of binomial. Biometrika. 1934;26:404-413].
The 95% CIs of the group GMC ratios will be computed using an ANOVA model on the 
logarithm10 transformation of the concentrations. The ANOVA model will include the
vaccine group as fixed effects. The CI of the group GMC ratios will be computed using a 
two-sample Welch’s t test assuming heterogeneity of variance.
The 95% CI for GMTs/GMCs will be obtained within each group separately. The 95% CI 
for the mean of log-transformed titre/concentration will be first obtained assuming that 
log-transformed values were normally distributed with unknown variance. The 95% CI 
for the GMTs/GMCs will then be obtained by exponential-transformation of the 95% CI 
for the mean of log-transformed titre/concentration.
11.2.
Standard data derivation 
11.2.1.
Date derivation

SAS date derived from a character date:  In case day is missing, 15 is used. In case 
day & month are missing, 30 June is used.

Onset day for an event for the mother (AE, medication, vaccination, …): The onset 
day is the number of days between the last study vaccination & the onset/start date of 
the event.   This is 0 for an event starting on the same day as a vaccination.    See 
SAS date derived in case the start date of the event is incomplete.

Onset day for an event for the infant (AE, medication, vaccination, …): The onset 
day is the number of days from date of birth of infant & the onset/start date of the 
event.   This is 0 for an event starting on the same day of birth. There could also be 
events reported in the infant before delivery (anomalies diagnosed during pregnancy 
at ultrasound investigation), for these cases onset day will be negative ‘-‘ days.  See 
SAS date derived in case the start date of the event is incomplete.

Duration: Duration of an event is expressed in days.   It is the number of days 
between the start & the stop dates + 1.  Therefore duration is 1 day for an event 
starting & ending on the same day.


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11.2.2.
Dose number

The study dose number is defined in reference to the number of study visits at which 
injection occurred.  More specifically dose 1 refers to all injections administered at 
the first vaccination visit (Visit 1) while dose 2 corresponds to all injections 
administered at the second vaccination visit (Visit 3) even if this is the first time a 
product is administered to the subject. 

Relative dose: the relative dose for an event (AE, medication, vaccination) is the 
most recent study dose given before an event. In case the event takes place on the 
day a study dose is given, the related dose will be that of the study dose, even if the 
event actually took place before vaccination. For instance, if an adverse event begins 
on the day of the study vaccination but prior to administration of the vaccine, it will 
be assigned to this dose.

Relative dose for infant :  Since the infants are not receiving any vaccine in this 
study, relative dose will be ‘0’.

The number of doses for a product is the number of time the product is administered 
to a subject. 

The incidence per dose is the number of vaccination visits at which an event was 
reported among all vaccination visits. 
11.2.3.
Demography

Age of mother: Age at the reference activity, computed as the number of units 
between the date of birth and the reference activity.  Note that due to incomplete 
date, the derived age may be incorrect by 1 month when month is missing from the 
birthdate.  This may lead to apparent inconsistency between the derived age and the 
eligibility criteria/the age category used for randomization. Gestational age at 
delivery : The gestational age at delivery is calculated by adding the number of 
weeks between screening and delivery to the gestational age recorded at the 
ultrasound screening. 

Gestational age at dose 1: The gestational age at dose 1 is calculated by adding the 
number of weeks between screening and dose1 to the gestational age recorded at the 
ultrasound screening. 

Age of infant: Age at the reference activity, computed as the number of complete 
weeks between the date of birth and the reference activity.

Conversion of weight to kg: the following conversion rule is used: 
Weight in Kilogram= weight in Pounds / 2.2 + weight in ounces / 35.2
The result is rounded to 2 decimals.


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
Conversion of height to cm: the following conversion rule is used:  
Height in Centimetres = Height in Feet * 30.48+
Height in Inch * 2.54
The result is rounded to the unit (ie no decimal).

Conversion of temperature to °C: the following conversion rule is used:  
Temperature in °Celsius  = ((Temperature in °Fahrenheit -32) *5)/9
The result is rounded to 1 decimal.
11.2.4.
Immunogenicity

For a given subject and given immunogenicity measurement, missing or non-
evaluable measurements will not be replaced.

The Geometric Mean Concentrations (GMCs) calculations are performed by taking 
the anti-log of the mean of the log titre transformations. Antibody concentrations
below the cut-off of the assay will be given an arbitrary value of half the cut-off of 
the assay for the purpose of GMC calculation. 

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.
Vaccine response definition:

Vaccine response to D and T antigens was defined as: 

for subjects with pre-vaccination concentration < 0.1 IU/mL antibody (ie below 
the seroprotection cut-off), antibody concentrations at least 0.4 IU/mL, one 
month after vaccination, and 

for subjects with pre-vaccination concentration 0.1 IU/mL (ie 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.

Vaccine response to PT, FHA and PRN antigens was defined as: 

for subjects with pre-vaccination antibody concentration below the assay cut-off, 
post-vaccination antibody concentration ≥4 times the assay cut-off,

for subjects with pre-vaccination antibody concentration between the assay cut-
off and below 4 times the assay cut-off, post-vaccination antibody concentration 
≥4 times the pre-vaccination antibody concentration, and

for subjects with pre-vaccination antibody concentration ≥4 times the assay cut-
off, post-vaccination antibody concentration ≥ 2 times the pre-vaccination 
antibody concentration.


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The thresholds defining seropositivity are provided below as per new re-validated assay 
are the following.
Table 4
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
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
†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.

In general, the assay cut-off is the value under which there is no quantifiable result 
available. For an assay with a specific ‘assay cut_off’ , numerical immuno result is 
derived from a character field (rawres):

If rawres is ‘NEG’ or ‘-’ or ‘(-)’, numeric result= assay cut_off/2,

if rawres is ‘POS’ or ‘+’ or ‘(+)’, numeric result = assay cut_off,

if rawres is ‘< value’ and value<=assay cut_off, numeric result =assay cut_off/2,

if rawres is ‘< value’ and value>assay cut_off, numeric result =value,

if rawres is ‘> value’ and value<assay cut_off, numeric result =assay cut_off/2,

if rawres is ‘> value’ and value>=assay cut_off, numeric result =value,

if rawres is ‘<= value’ or ‘>= value’ and value<assay cut_off, numeric result 
=assay cut_off/2,

if rawres is ‘<= value’ or ‘>= value’ and value>=assay cut_off, numeric result 
=value,

if rawres is a value < assay cut_off, numeric result = assay cut_off/2,

if rawres is a value >= assay cut_off, numeric result = rawres,

else numeric result is left blank.


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11.2.5.
Safety analysis
11.2.5.1.
Solicited Adverse Events
For analysis of solicited, unsolicited adverse events (such as serious adverse events or 
adverse events by primary MedDRA term) and for the analysis of concomitant 
medications, all vaccinated subjects will be considered. Subjects who did not report the 
event or the concomitant medication will be considered as subjects without the event or 
the concomitant medication respectively.
The following rules will be used for the analysis of solicited symptoms: 

Subject who didn’t document the presence or absence of a solicited symptom after 
one dose will be considered not having that symptom after that dose in the 
analysis done on “administered dose”

Subjects who documented the absence of a solicited symptom after one dose will 
be considered not having that symptom after that dose.

Subjects who documented the presence of a solicited symptom and fully or 
partially recorded daily measurement over the solicited period will be included in 
the summaries at that dose and classified according to their maximum observed 
daily recording over the solicited period.

Subjects who documented the presence of a solicited symptom after one dose 
without having recorded any daily measurement will be considered as having that 
symptom after that dose (at the lowest intensity).

Intensity of the following solicited AEs will be assessed as described below.


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Table 5
Intensity scales for solicited symptoms in adults 
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/°F
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 37.5°C / 99.5°F for oral, axillary or tympanic route, or 38.0°C / 100.4°F for rectal 
route. The preferred route for recording temperature in this study will be oral/axillary.
The maximum intensity of local injection site redness/swelling/fever will be scored at 
GSK Biologicals as follows:
0
:
Absent
1
:
20 mm
2
:
> 20 mm and 50 mm
3
:
> 50 mm 
Event
N used for deriving % per subject for 
Vaccination phase
N used for deriving % per dose for 
Vaccination phase
Concomitant 
vaccination
All subjects with study vaccine 
administered
All study visits with study vaccine administered
Solicited general 
symptom
Primary analysis: all subjects with study 
vaccine administered
Sensitivity analysis: all subjects with at 
least one solicited general symptom 
documented as either present or absent 
(i.e., symptom screen completed)
Primary analysis: all study visits with study 
vaccine administered
Sensitivity analysis: all study visits with study 
vaccine administered and with at least one 
solicited general symptom documented as 
either present or absent (i.e., symptom screen 
completed)
Unsolicited 
symptom
All subjects with study vaccine 
administered 
All study visits with study vaccine administered
Concomitant 
medication
All subjects with study vaccine 
administered 
All study visits with study vaccine administered


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Body temperature will be broken down by route of measurement according to the 
recommendations of the Brighton collaboration and will be summarized according to the 
2 schemes described below:

by 0.5 °C increments: 

>=37.5

>=38.0

>38.5

>39.0

>39.5

>40.0
Fever, defined as a body temperature of ≥37.5°C irrespective of route of measurement, 
will be integrated to the summaries as a systemic adverse event.
11.2.5.2.
Combined Solicited and Unsolicited Adverse Events
A summary of subjects with all combined solicited (regardless of their duration) and 
unsolicited adverse events will be provided. Solicited adverse events will be coded by 
MedDRA as per the following codes. 
Solicited 
symptom
Lower level term 
code
Corresponding Lower level term decode 
Fever
10016558
Fever
Headache
10019211
Headache
Fatigue
10016256
Fatigue
Gastrointestinal 
symptoms 
(nausea, 
vomiting, 
diarrhoea and/or 
abdominal pain)
10017944
Gastrointestinal disorder
Pain at injection 
site
10022086
Injection site pain
Redness at 
injection site
10022098
Redness at injection site
Swelling at 
injection site
10053425
Swelling at injection site
For clintrial.gov and EudraCT posting purposes, a summary of combined solicited and 
unsolicited non-serious adverse events will be produced by System Organ Class and 
preferred terms and according to occurrence of each event. 


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11.2.6.
Management of missing data
Demography:

For a given subject and a given demographic variable, missing measurements will
not be replaced.
Immunogenicity:

For a given subject and a given immunogenicity measurement time point, missing or 
non-evaluable measurements will not be replaced.
Reactogenicity and safety:

Subjects who missed reporting symptoms (solicited/unsolicited or concomitant
medications) will be treated as subjects without symptoms (solicited/unsolicited or
concomitant medications, respectively).
11.2.7.
Number of decimals displayed
The following decimal description from the decision rules will be used for the 
demography, immunogenicity and safety/reactogenicity.
Display Table
Parameters
Number of decimal digits
All summaries
% of count, including LL & UL of CI
1
All summaries
% of difference, including LL & UL of CI
2
Demographic 
characteristics
Mean, median age, SD (age) 
1
Reactogenicity
Mean, Min, Q1, Median, Q3, Max for 
duration
1
Immunogenicity
Ratio of GMT/GMC
2
Immunogenicity
GMC
2 ( D and T)
1 (PT, FHA and PRN)


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12.
ANNEX 3: STUDY SPECIFIC MOCK TFL
The following draft study specific mock TFLs will be used.  
The data display, title and footnote are for illustration purpose and will be adapted to the 
study specificity such as one group and one dose for the study.  
These templates were copied from recent studies. Note that there may be few changes 
between the study specific SAP mock TFL and the final TFLs.  These editorial/minor 
changes will not lead to a SAP amendment.


C O N FI D E N TI A L
1 1 6 9 4 5 [ D T P A (B O O S T RI X) -0 4 7 ]
St ati sti c al A n al y si s Pl a n Fi n al
2 0- F E B -2 0 1 8
P a g e 3 2 of 6 1
T e m pl at e 1
N u m b er of s u bj e ct s e nr oll e d b y  c e nt er ( T ot al V a c ci n at e d C o h ort)
C o m b o gr o u p
C o ntr ol gr o u p
T ot al
C e nt er
n
n
n
%
2 0
2 1
4 1
9. 1
2 7
2 8
5 5
1 2. 2
7
7
1 4
3. 1
1 6
1 6
3 2
7. 1
2 7
2 6
5 3
1 1. 8
2 6
2 6
5 2
1 1. 5
2 5
2 5
5 0
1 1. 1
2 3
2 4
4 7
1 0. 4
2 2
2 2
4 4
9. 8
2 4
2 5
4 9
1 0. 9
7
7
1 4
3. 1
All
2 2 4
2 2 7
4 5 1
1 0 0
< gr o u p d escri pti o n >
n = n u m b er of s u bj ects i ncl u d e d i n e ac h gr o u p or i n t ot al f or a giv e n c e nt er or f or all c e nt ers
All = s u m of all s u bj ects i n e ac h gr o u p or i n t ot al (s u m of all gr o u ps)
% = n/ All x 1 0 0
T e m pl at e 2
N u m b er of s u bj e ct s v a c ci n at e d, c o m pl et e d a n d wit h dr a w n wit h 
r e a s o n f or wit h dr aw a l at Vi sit 3 ( T ot al V a c ci n at e d C o h ort)
d T p a 
Gr o u p
C o ntr ol 
Gr o u p
N u m b er of s u bj e ct s v a c ci n at e d
3 0 0
3 0 0
N u m b er of s u bj e ct s c o m pl et e d
2 9 8
2 9 7
N u m b er of s u bj e ct s wit h dr a w n
2
3
R e a s o n s f or wit h dr a w al :
S eri o us A dv ers e Ev e nt
0
1
N o n -s eri o us a dv ers e ev e nt
0
0
Pr ot oc ol vi ol ati o n
0
0
C o ns e nt wit h dr a w al ( n ot d u e t o a n a dv ers e ev e nt)
1
2
Mi gr at e d/ m ov e d fr o m st u dy ar e a
1
0
L ost t o f oll o w -u p (s u bj ects wit h i nc o m pl et e v acci n ati o n c o urs e)
0
0
L ost t o f oll o w -u p (s u bj ects wit h c o m pl et e v acci n ati o n c o urs e)
0
0
Ot h ers
0
0
P P D
H R V LI Q = H R V v acci n e li q ui d f or m ul ati o n
H R V L Y O = H R V v acci n e H R V Ly o p hilis e d f or m ul ati o n
V acci n at e d = n u m b er of s u bj ects w h o w er e v acci n at e d i n t h e st u dy
C o m pl et e d = n u m b er of s u bj ects w h o c o m pl et e d st u dy visit 3
Wit h dr a w n = n u m b er of s u bj ects w h o di d n ot c o m e f or st u dy visit 3
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


C O N FI D E N TI A L
1 1 6 9 4 5 [ D T P A (B O O S T RI X) -0 4 7 ]
St ati sti c al A n al y si s Pl a n Fi n al
2 0- F E B -2 0 1 8
P a g e 3 3 of 6 1
T e m pl at e 3
N u m b er of s u bj e ct s at e a c h vi sit a n d li st of wit h dr a w n s u bj e ct s 
( T ot al V a c ci n at e d C o h ort)
Gr o u p
VI SI T
N
Wit h dr a w n
S u bj e ct n u m b er s
R e a s o n f or wit h dr a w al
H R V Li q
VI SI T 1
5 0 8
n o. 
C O N S E N T WI T H D R A W A L
n o. 
C O N S E N T WI T H D R A W A L
n o. 
C O N S E N T WI T H D R A W A L
n o. 
C O N S E N T WI T H D R A W A L
VI SI T 2
5 0 4
n o. 
C O N S E N T WI T H D R A W A L
n o. 
C O N S E N T WI T H D R A W A L
n o. 
S E RI O U S A D V E R S E E X P E RI E N C E
VI SI T 3
5 0 1
n o. 
MI G R A TI O N F R O M S T U D Y A R E A
n o. 
C O N S E N T WI T H D R A W A L
n o. 
MI G R A TI O N F R O M S T U D Y A R E A
n o. 
C O N S E N T WI T H D R A W A L
n o. 
MI G R A TI O N F R O M S T U D Y A R E A
n o. 
MI G R A TI O N F R O M S T U D Y A R E A
n o. 
C O N S E N T WI T H D R A W A L
n o. 
MI G R A TI O N F R O M S T U D Y A R E A
n o. 
MI G R A TI O N F R O M S T U D Y A R E A
VI SI T 4
4 9 2
H R V L y o
VI SI T 1
2 5 7
n o. 
P R O T O C O L VI O L A TI O N
n o.
C O N S E N T WI T H D R A W A L
VI SI T 2
2 5 5
n o.
C O N S E N T WI T H D R A W A L
VI SI T 3
2 5 4
n o.
MI G R A TI O N F R O M S T U D Y A R E A
n o.
L O S T T O F O L L O W -U P
n o. 
L O S T T O F O L L O W -U P
n o. 
C O N S E N T WI T H D R A W A L
n o. 
MI G R A TI O N F R O M S T U D Y A R E A
n o. 
L O S T T O F O L L O W -U P
n o. 
A D V E R S E E X P E RI E N C E
VI SI T 4
2 4 7
P P
DP P
DP P D
P P D
P P D
P P D
P P D
P
P
D
P P
DP P
DP P
DP P
DP P
DP P D
P P D
P P D
P P
DP P D
P P D
P P D
P P D
P P
DP P
DP P
DP P D
P P D


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Template 4
Number of subjects enrolled into the study as well as the number of 
subjects excluded from ATP analyses with reasons for exclusion
Total
HRV LIQ
HRV LYO
Title
N
n
s
%
N
n
s
N
n
s
Total enrolled cohort
1200
300
300
TVC
1200
100 300
300
Administration of vaccine(s) 
forbidden in the protocol 
(code 1040)
2
2
0
0
0
0
Study vaccine dose not 
administered according to 
protocol (code 1070)
73
73
23
23
16
16
Initially seropositive or unknown 
anti-rotavirus IgA antibody on 
day of dose 1 (code 1500)
10
11
3
3
1
1
Protocol violation 
(inclusion/exclusion criteria)
(code 2010)
1
1
1
1
0
0
Administration of any 
medication forbidden by the 
protocol (code 2040)
1
1
0
0
1
1
Underlying medical condition 
forbidden by the protocol 
(code 2050)
1
1
0
0
0
0
Concomitant infection not 
related to the vaccine which 
may influence immune 
response (code 2070)
0
1
0
0
0
1
Non compliance with 
vaccination schedule (including 
wrong and unknown dates ) 
(code 2080)
14
16
6
7
3
4
Non compliance with blood 
sampling schedule (including 
wrong and unknown dates) 
(code 2090)
12
16
3
5
4
5
Essential serological data 
missing (code 2100)
87
95
20
22
23
26
Subjects with incomplete study 
vaccination schedule but with 
post serological result (code 
2500)
1
1
0
0
0
0
ATP
998
83.2 244
252
HRV LIQ = HRV vaccine liquid formulation Lot C HRV LYO = HRV vaccine HRV Lyophilised formulation
Note: Subjects may have more than one elimination code assigned
n = number of subjects with the elimination code assigned excluding subjects who have been assigned a lower 
elimination code number
s = number of subjects with the elimination code assigned
% = percentage of subjects in the per protocol set (ATP) relative to the TVC (ES)


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Template 5
Deviations from specifications for age and intervals between study 
visits (Total Vaccinated Cohort)
Age
VAC_1-SER_2
Group
Protocol
Protocol
Adapted
from 10 to 15 year
from 30 to 48 days
from 21 to 48 days
dTpaNew Group
N
335
329
329
n
0
11
8
%
0.0
3.3
2.4
range
10 to 15
28 to 74
28 to 74
dTpaPre Group
N
336
329
329
n
0
10
8
%
0.0
3.0
2.4
range
10 to 15
29 to 95
29 to 95
HRV LIQ = HRV vaccine liquid formulation Lot A
HRV LIQ = HRV vaccine liquid formulation Lot B
HRV LIQ = HRV vaccine liquid formulation Lot C
HRV LYO = HRV vaccine HRV Lyophilised formulation
dTpaNew Group = Subjects who received Boostrix in new syringe presentation
dTpaPre Group = Subjects who received Boostrix in previous syringe presentation
Adapted = interval used for defining the ATP cohorts for immunogenicity
N = total number of subjects with available results
n(%) = number(percentage) of subjects with results outside of the interval
range = minimum-maximum for age and intervals
VAC = vaccination
SER = Blood Sampling


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Template 6
Summary of demography and baseline characteristics (ATP cohort 
for Immunogenicity)
dTpaNew 
Group
N = 335
dTpaPre 
Group
N = 336
Total
N = 671
Characteristics
Parameters or
Categories
Value or n %
Value or 
n
%
Value or 
n
%
Age (years) at vaccination 
dose: 1
Mean
SD
Median
Minimum
Maximum
Gender
Female
Male
Geographic Ancestry
African Heritage / African American
American Indian or Alaskan Native
White - Arabic / North African 
Heritage
White - Caucasian / European 
Heritage
Other (Hispanic)
Height (km)
Mean
SD
Median
Minimum
Maximum
Weight (kg)
Mean
SD
Median
Minimum
Maximum
BMI (kg/m²)
Mean
SD
Median
Minimum
Maximum
Gestational week at dose 1
Below 27
27 to 32
33 to 36
Above 36
Mean
SD
Median
Minimum
Maximum
Gestational week at delivery
Mean
SD
Median
Minimum
Maximum


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dTpaNew 
Group
N = 335
dTpaPre 
Group
N = 336
Total
N = 671
Characteristics
Parameters or
Categories
Value or n %
Value or 
n
%
Value or 
n
%
Number of days between 
vaccination (dose 1) and 
delivery
Mean
SD
Median
Minimum
Maximum
Breast feeding
Yes 
No
Never
Breast feeding (number of 
times in a day)
Mean
SD
Median
1st Quartile
3rd Quartile
Duration of breast feeding
Mean
SD
Median
Formula feeding
Yes 
No
Apgar score (1min)
Mean
SD
Median
Minimum
Maximum
Unknown
Apgar score (5min)
Mean
SD
Median
Minimum
Maximum
Unknown
dTpaNew Group = Subjects who received Boostrix in new syringe presentation
dTpaPre Group = Subjects who received Boostrix in previous syringe presentation
N = total number of subjects
n(%) = Number(percentage) of subjects in a given category
Value = value of the considered parameter
SD = standard deviation
Height (cm) = Height expressed in centimeters
Weight (kg) = Weight expressed in kilograms
BMI (kg/m2) = Body Mass Index expressed in kilograms per meter square


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Template 7
Study population (TVC)
Study population (Total vaccinated cohort)
Number of subjects
Combo group
Control group
Planned, N
225
225
Randomised, N (Total Vaccinated Cohort)
224
227
Completed, n (%)
224 (100)
227 (100)
Demographics
Combo group
Control group
N (Total Vaccinated Cohort)
224
227
Females :Males
97:127
115:112
Mean Age, weeks (SD)
8.8 (1.1)
8.8 (1.1)
Median Age, weeks (minimum, maximum)
9 (7, 11)
9 (7, 11)
Most frequent race: Asian - East Asian Heritage, n (%)
224 (100)
226 (99.6)
Combo group = Subjects received DTPa-IPV/Hib vaccine as a single injection at 2, 4 and 6 months of age
Control group = Subjects received DTPa-IPV and Hib vaccines at different injection sites at 2, 4 and 6 months of age
N = Total number of subjects enrolled in the study
n/% = Number/percentage of subjects in a given category
SD = Standard Deviation
MeaAge = Age calculated from Date of birth to first study vaccination
Template 8
Summary of household contacts in Spain (Total vaccinated cohort:
(subset of subjects in Spain))
Household group
N = 
Characteristics
Parameters 
or categories
n or value
%
Household 
contacts 
approached
Yes
No
 
Number of 
household 
contacts by 
vaccinated subject
Mean
SD
Median
1st Quartile
3rd Quartile
Household contact 
approached
Total
Eligible Household 
contact
Total
N = Total number of subjects vaccinated in Spain
n(%) = Number(percentage) of subjects in a given category
value = value of the considered parameter


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Statistical Analysis Plan Final
20-FEB-2018
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Template 9
Summary of vaccination of household contacts in Spain (Total 
cohort for household contacts in Spain)
Household Group
N = 
95% CI
Parameters or Categories
Value or n
Per 
LL
UL
Household contacts who accepted 
vaccination
Household contacts who refused 
vaccination
Reasons for refusal
Reason 1
Reason 2
dTpa group = Mothers received dTpa during pregnancy
Control group = Mothers received placebo during pregnancy 
N = Total number of eligible household contacts
n/Per  = number/percentage of subjects reporting 
95% CI= exact 95% confidence interval; LL = Lower Limit, UL = Upper Limit
Template 10 Seropositivity and seroprotection rates and GMCs for anti-diphtheria 
and anti-tetanus antibodies before and one month after the booster 
vaccination and cord blood sample (ATP cohort for immunogenicity)
≥ assay cut-off*
≥ 0.1 IU/mL
GMC
95% CI
95% CI
95% CI
Antibody
Group
Timing N
n
%
LL
UL
n
%
LL
UL
value
LL
UL
anti-diphtheria
dTpaNew Group
PRE
321 284 88.5 84.5 91.8 83
25.9 21.2 31.0 0.472
0.403
0.553
POST
321 320 99.7 98.3 100 315 98.1 96.0 99.3 6.784
6.178
7.450
CORD 
dTpaPre Group
PRE
319 286 89.7 85.8 92.8 89
27.9 23.0 33.2 0.456
0.392
0.530
POST
319 319 100 98.9 100 310 97.2 94.7 98.7 6.493
5.915
7.128
CORD
anti-tetanus
dTpaNew Group
PRE
321 311 96.9 94.3 98.5 151 47.0 41.5 52.7 0.956
0.835
1.095
POST
321 321 100 98.9 100 321 100 98.9 100 18.937 17.313 20.713
CORD
dTpaPre Group
PRE
319 314 98.4 96.4 99.5 143 44.8 39.3 50.5 0.899
0.789
1.026
POST
319 319 100 98.9 100 319 100 98.9 100 18.515 16.851 20.342
CORD
dTpaNew Group = Subjects who received Boostrix in new syringe presentation
dTpaPre Group = Subjects who received Boostrix in previous syringe presentation
Seroprotection=anti-diphtheria and anti-tetanus antibody concentration ≥0.1 IU/mL
*Assay cut-off is 0.057 IU/mL and 0.043 IU/mL for anti-diphtheria and anti-tetanus respectively
GMC = geometric mean antibody concentration calculated on all subjects
N = number of subjects with available results
n(%)=number(percentage) of subjects with antibody concentrations above the specified cut-off
95% CI = 95% confidence interval; LL = Lower Limit, UL = Upper Limit
PRE=Pre-booster blood sampling time point
POST=Post-booster blood sampling time point


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20-FEB-2018
Page 40 of 61
Template 11 GMC ratio between groups [dTpa Group divided by Control Group] 
and their 95% CIs for anti-PT, anti-FHA and anti-PRN antigens in 
cord blood sample (ATP cohort for immunogenicity)
dTpa group
Control group
GMC Ratio
(dTpa / Control)
Antibody
N
GMC
N
GMC
GMC ratio
95% CI
LL
UL
anti-PT
anti-FHA 
anti-PRN 
Tdap = Subjects receiving a second dose of Tdap vaccine
N= Number of subjects with available results
95% CI = 95% confidence interval for the adjusted GMC ratio LL = lower limit, UL = upper limit. The associated CI was 
will be computed using a two-sample t test assuming heterogeneity of variance.
GMC = geometric mean antibody concentration calculated on all subjects
Template 12 Vaccine responses for anti-PT, anti-FHA and anti-PRN antibody 
concentration one month after the booster vaccination (ATP cohort 
for immunogenicity)
Booster response
95% CI
Antibody
Group
Pre-vaccination
status
N
n
%
LL
UL
anti-PT
dTpaNew Group
S-
142
135
95.1
90.1
98.0
S+ (< 4*assay cut-off)
104
103
99.0
94.8
100
S+ (≥4*assay cut-off)
71
60
84.5
74.0
92.0
Total
317
298
94.0
90.8
96.4
dTpaPre Group
S-
143
131
91.6
85.8
95.6
S+ (<4*assay cut-off)
114
112
98.2
93.8
99.8
S+ (≥4*assay cut-off)
61
52
85.2
73.8
93.0
Total
318
295
92.8
89.3
95.4
anti-FHA
dTpaNew Group
S-
6
6
100
54.1
100
S+ (<4*assay cut-off)
57
57
100
93.7
100
S+ (≥4*assay cut-off)
251
242
96.4
93.3
98.3
Total
314
305
97.1
94.6
98.7
dTpaPre Group
S-
5
5
100
47.8
100
S+ (<4*assay cut-off)
55
55
100
93.5
100
S+ (≥4*assay cut-off)
255
244
95.7
92.4
97.8
Total
315
304
96.5
93.8
98.2
anti-PRN
dTpaNew Group
S-
52
50
96.2
86.8
99.5
S+ (<4*assay cut-off)
152
151
99.3
96.4
100
S+ (≥4*assay cut-off)
117
114
97.4
92.7
99.5
Total
321
315
98.1
96.0
99.3
dTpaPre Group
S-
47
47
100
92.5
100
S+ (<4*assay cut-off)
159
159
100
97.7
100
S+ (≥4*assay cut-off)
112
111
99.1
95.1
100
Total
318
317
99.7
98.3
100
dTpaNew Group = Subjects who received Boostrix in new syringe presentation
dTpaPre Group = Subjects who received Boostrix in previous syringe presentation
S- = Initially seronegative subjects prior to vaccination
S+ = Initially seropositive subjects  prior to vaccination
Total = subjects either seropositive or seronegative at pre-vaccination
S- = seronegative subjects (antibody concentration below assay cut off for anti-PT, anti-FHA, anti-PRN)
S+ = seropositive (antibody concentration below assay cut off for anti-PT, anti-FHA, anti-PRN)


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Statistical Analysis Plan Final
20-FEB-2018
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Booster response to PT, FHA and PRN antigens is defined as: 

initially seronegative subjects (pre-booster antibody concentration below the assay cut-off) with an increase of at 
least four times the assay cut-off one month after vaccination,

initially seropositive subjects with anti-body concentration < four times the assay cut-off with an increase of at 
least four times the pre-booster antibody concentration one month after vaccination

initially seropositive subjects with anti-body concentration ≥ four times the assay cut-off with an increase of at 
least two times the pre-booster antibody concentration one month after vaccination
Assay cut-off is 2.693 IU/mL, 2.046 IU/mL and 2.187 IU/mL for anti-PT, FHA and PRN respectively
N = number of subjects with both pre- and post-vaccination results available
n(%) = number(percentage) of subjects with a booster response
95% CI = exact 95% confidence interval, LL = Lower Limit, UL = Upper Limit
Template 13 Reverse cumulative curve for anti-diphtheria antibody concentration 
one month after the booster vaccination (ATP cohort for 
immunogenicity)
dTpaNew Group = Subjects who received Boostrix in new syringe presentation
dTpaPre Group = Subjects who received Boostrix in previous syringe presentation
PRE = Pre-vaccination at Day 0
POST = Post-vaccination 1 at Day 28 for primed subject or post-vaccination 2 at Day 56 for unprimed subjects


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20-FEB-2018
Page 42 of 61
Template 14 Percentage of subjects by pregnancy outcome (Total vaccinated 
cohort-Mother) 
dTpa Group
Control Group
N = 
N = 
95% CI
95% CI
Pregnancy outcome
n
Per 
LL
UL
n
Per 
LL
UL
Live infant NO apparent congenital anomaly
Live infant congenital anomaly
Elective termination NO apparent congenital anomaly
Elective termination congenital anomaly
Spontaneous abortion NO apparent congenital anomaly
Spontaneous abortion congenital anomaly
Stillbirth NO apparent congenital anomaly
Stillbirth congenital anomaly
Ectopic pregnancy
Molar pregnancy
Lost to follow-up
Pregnancy ongoing
dTpa group = Mothers received dTpa during pregnancy
Control group = Mothers received placebo during pregnancy 
N = number of subjects with at least one administered dose
n/Per  = number/percentage of subjects reporting a specific pregnancy outcome
95% CI= exact 95% confidence interval; LL = Lower Limit, UL = Upper Limit


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20-FEB-2018
Page 43 of 61
Template 15 Percentage of subjects with listed pregnancy/neonate related 
adverse events of interest (Total vaccinated cohort)
Pregnancy-related adverse 
events of interest/neonate-
related events of interest
dTpa Group
N = 
Control Group
N =
n
%
Exact 95%CI
n
%
Exact 95%CI
LL
UL
LL
UL
Gestational diabetes 
Pregnancy-related hypertension 
Premature rupture of 
membranes 
Preterm premature rupture of 
membranes 
Premature labour 
Premature uterine contractions 
Intrauterine growth 
restriction/poor foetal growth 
Pre-eclampsia 
Eclampsia
Vaginal or intrauterine 
haemorrhage 
Maternal death 
Preterm birth 
Neonatal death 
Small for gestational age 
Neonatal hypoxic ischaemic 
encephalopathy 
Failure to thrive/growth 
deficiency 
dTpa group = Mothers received dTpa during pregnancy
Control group = Mothers received placebo during pregnancy 
N = number of subjects with at least one administered dose
n/Per = number/percentage of pregnancies/neonate with a specific adverse event
95% CI= exact 95% confidence interval; LL = Lower Limit, UL = Upper Limit


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20-FEB-2018
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Template 16 Number and percentage of subjects who received study vaccine 
doses - TVC
HRV LIQ 
N = 300
HRV LYO 
N = 300
Total 
N = 1200
VACCINE
Total number of
doses received
n
%
n
%
n
%
Pediarix
1
0
0.0
1
0.3
3
0.3
2
300
100
299
99.7
1197
99.8
3
Any
Any
300
100
300
100
1200
100
Hiberix
1
0
0.0
1
0.3
3
0.3
2
300
100
299
99.7
1197
99.8
3
Any
Any
300
100
300
100
1200
100
Prevnar
1
0
0.0
1
0.3
3
0.3
2
300
100
299
99.7
1197
99.8
3
Any ON COAD
Any
300
100
300
100
1200
100
HRV LIQ = HRV vaccine Liquid formulation lot A HRV LIQ = HRV vaccine Liquid formulation lot B
HRV LIQ = HRV vaccine Liquid formulation lot C HRV LYO = HRV vaccine HRV Lyophilised formulation
N = number of subjects in each group or in total included in the considered cohort
n (%) = number/percentage of subjects receiving the specified total number of doses
Any = number and percentage of subjects receiving at least one dose
Template 17 Compliance in returning symptom information (Total Vaccinated 
Cohort)
Group
Number
of
doses
Doses
NOT
according to
protocol
Number
of
general SS
Compliance
%
general SS
Number
of
local SS
Compliance
%
local SS
dTpaNew Group
335
0
330
98.5
330
98.5
dTpaPre Group
336
1
329
97.9
329
97.9
dTpaNew Group = Subjects who received Boostrix in new syringe presentation
dTpaPre Group = Subjects who received Boostrix in previous syringe presentation
SS = Symptom screens/sheets used for the collection of local and general solicited AEs
Compliance % = (number of doses with symptom screen/sheet return / number of administered doses) X 100
Template 18 Incidence and nature of grade 3 symptoms (solicited and 
unsolicited) reported during the 4-day (Days 0-3) period after 
vaccination following each dose and overall (Total Vaccinated 
Cohort)
Any symptom
General symptoms
Local symptoms
95% CI
95% CI
95% CI
Group
N
n
%
LL
UL
N
n
%
LL
UL
N
n
%
LL
UL
dTpaNew Group
335 264 78.8
74.0
83.1
335 134 40.0
34.7
45.5
335 250 74.6
69.6
79.2
dTpaPre Group
336 279 83.0
78.6
86.9
336 151 44.9
39.5
50.4
336 264 78.6
73.8
82.8
dTpaNew Group = Subjects who received Boostrix in new syringe presentation
dTpaPre Group = Subjects who received Boostrix in previous syringe presentation
N = number of subjects with the administered dose
n(%)= number(percentage) of subjects presenting at least one type of symptom whatever the study vaccine 
administered
95% CI = exact 95% confidence interval, LL = Lower Limit, UL = Upper Limit


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20-FEB-2018
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Template 19 Incidence of solicited local symptoms reported during the 4-day 
(Days 0-3) period after vaccination following each dose and overall 
(Total Vaccinated Cohort)
dTpaNew Group
dTpaPre Group
95 % CI
95 % CI
Symptom
Type
N
n
%
LL
UL
N
n
%
LL
UL
Pain
All
330
237
71.8
66.6
76.6
329
248
75.4
70.4
79.9
Grade 3
330
24
7.3
4.7
10.6
329
20
6.1
3.8
9.2
Medical advice
330
0
0.0
0.0
1.1
329
0
0.0
0.0
1.1
Redness (mm)
All
330
113
34.2
29.1
39.6
329
94
28.6
23.8
33.8
Grade 3
330
4
1.2
0.3
3.1
329
1
0.3
0.0
1.7
Medical advice
330
0
0.0
0.0
1.1
329
0
0.0
0.0
1.1
Swelling (mm)
All
330
98
29.7
24.8
34.9
329
90
27.4
22.6
32.5
Grade 3
330
6
1.8
0.7
3.9
329
5
1.5
0.5
3.5
Medical advice
330
0
0.0
0.0
1.1
329
0
0.0
0.0
1.1
dTpaNew Group = Subjects who received Boostrix in new syringe presentation
dTpaPre Group = Subjects who received Boostrix in previous syringe presentation
N = number of subjects with the documented dose
n(%)= number(percentage) of subjects reporting the symptom at least once
95%CI = Exact 95% confidence interval; LL = lower limit, UL = upper limit


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20-FEB-2018
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Template 20 Incidence of solicited general symptoms reported during the 4-day 
(Days 0-3) post-vaccination period (Total Vaccinated Cohort)
Boostrix
Adacel
Control
95 % CI
95 % CI
95 % CI
Symptom
Type
N
n %
LL
UL N
n %
LL
UL N
n %
LL
UL
Fatigue
All
306 71 23.2 18.6 28.3 137 23 16.8 11.0 24.1 358 51 14.2 10.8 18.3
Grade 2 or 3
306 23 7.5 4.8 11.1 137 10 7.3 3.6 13.0 358 9 2.5 1.2 4.7
Grade 3
306 3 1.0 0.2 2.8 137 1 0.7 0.0 4.0 358 0 0.0 0.0 1.0
Related
306 57 18.6 14.4 23.4 137 21 15.3 9.7 22.5 358 34 9.5 6.7 13.0
Grade 3 Related 306 3 1.0 0.2 2.8 137 1 0.7 0.0 4.0 358 0 0.0 0.0 1.0
Medical advice
306 0 0.0 0.0 1.2 137 0 0.0 0.0 2.7 358 0 0.0 0.0 1.0
Gastrointestinal symptoms All
306 27 8.8 5.9 12.6 137 4 2.9 0.8 7.3 358 29 8.1 5.5 11.4
Grade 2 or 3
306 6 2.0 0.7 4.2 137 0 0.0 0.0 2.7 358 9 2.5 1.2 4.7
Grade 3
306 0 0.0 0.0 1.2 137 0 0.0 0.0 2.7 358 0 0.0 0.0 1.0
Related
306 18 5.9 3.5 9.1 137 4 2.9 0.8 7.3 358 17 4.7 2.8 7.5
Grade 3 Related 306 0 0.0 0.0 1.2 137 0 0.0 0.0 2.7 358 0 0.0 0.0 1.0
Medical advice
306 0 0.0 0.0 1.2 137 0 0.0 0.0 2.7 358 0 0.0 0.0 1.0
Headache
All
306 52 17.0 13.0 21.7 137 25 18.2 12.2 25.7 358 53 14.8 11.3 18.9
Grade 2 or 3
306 12 3.9 2.0 6.7 137 6 4.4 1.6 9.3 358 8 2.2 1.0 4.4
Grade 3
306 0 0.0 0.0 1.2 137 1 0.7 0.0 4.0 358 1 0.3 0.0 1.5
Related
306 37 12.1 8.7 16.3 137 19 13.9 8.6 20.8 358 28 7.8 5.3 11.1
Grade 3 Related 306 0 0.0 0.0 1.2 137 0 0.0 0.0 2.7 358 0 0.0 0.0 1.0
Medical advice
306 1 0.3 0.0 1.8 137 0 0.0 0.0 2.7 358 0 0.0 0.0 1.0
Temperature (°C)
All
306 2 0.7 0.1 2.3 137 0 0.0 0.0 2.7 358 2 0.6 0.1 2.0
>38.5
306 1 0.3 0.0 1.8 137 0 0.0 0.0 2.7 358 0 0.0 0.0 1.0
>39.0
306 1 0.3 0.0 1.8 137 0 0.0 0.0 2.7 358 0 0.0 0.0 1.0
>39.5
306 0 0.0 0.0 1.2 137 0 0.0 0.0 2.7 358 0 0.0 0.0 1.0
>40.0
306 0 0.0 0.0 1.2 137 0 0.0 0.0 2.7 358 0 0.0 0.0 1.0
Related
306 2 0.7 0.1 2.3 137 0 0.0 0.0 2.7 358 2 0.6 0.1 2.0
>40.0 Related
306 0 0.0 0.0 1.2 137 0 0.0 0.0 2.7 358 0 0.0 0.0 1.0
Medical advice
306 0 0.0 0.0 1.2 137 0 0.0 0.0 2.7 358 0 0.0 0.0 1.0
dTpaNew Group = Subjects who received Boostrix in new syringe presentation
dTpaPre Group = Subjects who received Boostrix in previous syringe presentation
N = number of subjects with the documented dose
n(%)= number(percentage) of subjects reporting the symptom at least once
95%CI = Exact 95% confidence interval; LL = lower limit, UL = upper limit
Related = Symptoms which is assessed by the investigator as related to vaccination
Grade3*Related = Grade 3 symptom which is assessed by the investigator as related to vaccination
Grade 3 For Headache: Headache that prevented normal activity
For Fatigue: Fatigue that prevented normal activity
For Gastrointestinal symptoms: Gastrointestinal symptoms that prevented normal activity
For Fever: >39.0 °C


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20-FEB-2018
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Template 21 Incidence of any large injection site reaction (defined as a swelling 
with a diameter > 100 mm, noticeable diffuse swelling or noticeable 
increase in limb circumference) with onset within 4 days (Day 0–3) 
after booster vaccination (Total Vaccinated Cohort at Year 9)
Type of Swelling
(Each group)
N=
Total
N=
n
%
95%CI
n
%
95% CI
LL
UL
LL
UL
Any
Local Swelling
Diffuse Swelling
Involving at least one adjacent 
joint
Boostrix group= Subjects who had received GSK Biologicals’ Tdap vaccine (Boostrix) in study 106316 and a second 
dose of Tdap vaccine (Boostrix) at Year 9 Visit 6
Adacel group= Subjects who had received Sanofi Pasteurs’ Tdap vaccine (Adacel) in study 106316 and a second dose 
of Tdap vaccine (Boostrix) at Year 9 Visit 6
Control group= Subjects who will receive the first dose of Tdap vaccine (Boostrix) at Year 9 Visit 6
N = Number of subjects with documented dose
n/% = number/percentage of subjects reporting a specified symptom
95% CI = Exact 95% confidence interval, LL = Lower Limit, UL = Upper Limit


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20-FEB-2018
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Template 22 Percentage of doses with grade 3 unsolicited symptoms classified 
by MedDRA SOC and PT from Day 0 to Day 30 after vaccination in 
each HRV vaccine liquid formulation group - TVC
HRV LIQ
N = 603
HRV LIQ
N = 600
95% CI
95% CI
Primary System Organ 
Class (CODE)
Preferred Term (CODE)
n
%
LL
UL
n
%
LL
UL
At least one symptom
30
5.0
3.4
7.0
38
6.3
4.5
8.6
Ear and labyrinth 
disorders (10013993)
Ear pain (10014020)
1
0.2
0.0
0.9
0
0.0
0.0
0.6
Eye disorders (10015919)
Conjunctivitis (10010741)
1
0.2
0.0
0.9
1
0.2
0.0
0.9
Gastrointestinal disorders 
(10017947)
Diarrhoea (10012735)
2
0.3
0.0
1.2
1
0.2
0.0
0.9
Flatulence (10016766)
1
0.2
0.0
0.9
2
0.3
0.0
1.2
General disorders and 
administration site 
conditions (10018065)
Injection site erythema 
(10022061)
0
0.0
0.0
0.6
1
0.2
0.0
0.9
Injection site pain (10022086)
0
0.0
0.0
0.6
1
0.2
0.0
0.9
Injection site swelling 
(10053425)
0
0.0
0.0
0.6
1
0.2
0.0
0.9
Irritability (10022998)
1
0.2
0.0
0.9
1
0.2
0.0
0.9
Pyrexia (10037660)
3
0.5
0.1
1.4
4
0.7
0.2
1.7
Immune system disorders 
(10021428)
Hypersensitivity (10020751)
1
0.2
0.0
0.9
0
0.0
0.0
0.6
Infections and 
infestations (10021881)
Bronchitis (10006451)
0
0.0
0.0
0.6
1
0.2
0.0
0.9
Ear infection (10014011)
3
0.5
0.1
1.4
2
0.3
0.0
1.2
Exanthema subitum 
(10015586)
1
0.2
0.0
0.9
0
0.0
0.0
0.6
Eye infection (10015929)
0
0.0
0.0
0.6
0
0.0
0.0
0.6
Gastroenteritis (10017888)
0
0.0
0.0
0.6
1
0.2
0.0
0.9
Impetigo (10021531)
0
0.0
0.0
0.6
0
0.0
0.0
0.6
Influenza (10022000)
1
0.2
0.0
0.9
0
0.0
0.0
0.6
Laryngitis (10023874)
0
0.0
0.0
0.6
0
0.0
0.0
0.6
Otitis media (10033078)
7
1.2
0.5
2.4
12
2.0
1.0
3.5
Perianal abscess (10034447)
0
0.0
0.0
0.6
0
0.0
0.0
0.6
Pneumonia (10035664)
1
0.2
0.0
0.9
0
0.0
0.0
0.6
Respiratory tract infection 
(10062352)
2
0.3
0.0
1.2
0
0.0
0.0
0.6
Respiratory tract infection viral 
(10062106)
0
0.0
0.0
0.6
1
0.2
0.0
0.9
Rhinitis (10039083)
1
0.2
0.0
0.9
3
0.5
0.1
1.5
Upper respiratory tract 
infection (10046306)
6
1.0
0.4
2.2
8
1.3
0.6
2.6
Varicella (10046980)
1
0.2
0.0
0.9
2
0.3
0.0
1.2
Psychiatric disorders 
(10037175)
Crying (10011469)
0
0.0
0.0
0.6
1
0.2
0.0
0.9
Respiratory, thoracic and 
mediastinal disorders 
Cough (10011224)
1
0.2
0.0
0.9
6
1.0
0.4
2.2
(10038738)
Nasal congestion (10028735)
0
0.0
0.0
0.6
0
0.0
0.0
0.6
Rales (10037833)
0
0.0
0.0
0.6
1
0.2
0.0
0.9
Skin and subcutaneous 
tissue disorders 
Dermatitis allergic (10012434)
1
0.2
0.0
0.9
0
0.0
0.0
0.6


CONFIDENTIAL
116945 [DTPA (BOOSTRIX)-047]
Statistical Analysis Plan Final
20-FEB-2018
Page 49 of 61
HRV LIQ
N = 603
HRV LIQ
N = 600
95% CI
95% CI
Primary System Organ 
Class (CODE)
Preferred Term (CODE)
n
%
LL
UL
n
%
LL
UL
(10040785)
Eczema (10014184)
0
0.0
0.0
0.6
1
0.2
0.0
0.9
Rash (10037844)
0
0.0
0.0
0.6
0
0.0
0.0
0.6
HRV LIQ = HRV vaccine liquid formulation Lot A
HRV LIQ = HRV vaccine liquid formulation Lot B
HRV LIQ = HRV vaccine liquid formulation Lot C
N = Total number of doses administered
n/% = number/percentage of doses followed by at least one report of the specified unsolicited symptom
At least one symptom = number of doses followed by at least one report of an unsolicited symptom whatever the 
MedDRA PT
95% CI = Exact 95% Confidence Interval; LL = Lower Limit, UL = Upper Limit
Template 23 Number (%) of subjects with serious adverse events from first study 
vaccination up to Visit 3 including number of events reported (TVC)
Gr 1
N =
Gr2
N =
Type of Event
Primary System Organ 
Class
Preferred Term 
(CODE)
n*
n
%
n*
n
%
SAE
At least one symptom
<each SOC>
<each PT term>
Related SAE
At least one symptom
<each SOC>
<each PT term>
Fatal SAE
At least one symptom
<each SOC>
<each PT term>
Related fatal SAE
At least one symptom
<each SOC>
<each PT term>
Gr 1 = Group 1 description
Gr 2 = Group 2 description
N = number of subjects with the administered dose
n* = number of events reported
n/% = number/percentage of subjects reporting the symptom at least once


C O N FI D E N TI A L
1 1 6 9 4 5 [ D T P A (B O O S T RI X) -0 4 7 ]
St ati sti c al A n al y si s Pl a n Fi n al
2 0- F E B -2 0 1 8
P a g e 5 0 of 6 1
T e m pl at e 2 4
S u bj e ct s wit h S eri o u s A d v er s e E v e nt s r e p ort e d u p t o V i sit 3 - T V C
S u b.
N o.
C a s e I d
A g e at
o n s et
( W e e k)
S e x
V er b ati m
Pr ef err e d t er m
S y st e m Or g a n 
Cl a s s
M A 
t y p e
D o s e
D a y of
o n s et
D ur ati o n
C a u s alit y
O ut c o m e
1 2
M
K a w as aki’s 
dis e as e
K a w as aki’s 
dis e as e
I nf ecti o ns a n d 
i nf est ati o ns
H O
1
1 2
2 9
N
R ec ov er e d/r es olv e d
1 8
M
I nfl u e nz a-b
I nfl u e nz a
I nf ecti o ns a n d 
i nf est ati o ns
H O
2
2
5
N
R ec ov er e d/r es olv e d
1 7
M
Ac ut e 
g astr o e nt eritis
G astr o e nt eritis
I nf ecti o ns a n d 
i nf est ati o ns
H O
2
9
5
N
R ec ov er e d/r es olv e d
1 7
F
I nf a ntil e s p as ms I nf a ntil e s p as ms
N erv o us syst e m 
dis or d ers
H O
2
2
5 1
N
R ec ov er e d/r es olv e d wit h 
s e q u el a e
2 1
M
Rs -vir us 
br o nc hi olitis
R es pir at ory 
sy ncyti al vir us 
br o nc hi olitis
I nf ecti o ns a n d 
i nf est ati o ns
H O
2
3 0
1 6
N
R ec ov er e d/r es olv e d
1 3
M
G astr o e nt eritis
G astr o e nt eritis
I nf ecti o ns a n d 
i nf est ati o ns
H O
1
2 5
6
N
R ec ov er e d/r es olv e d
2 2
M
P n e u m o ni a
P n e u m o ni a
I nf ecti o ns a n d 
i nf est ati o ns
H O
2
3 2
1 3
N
R ec ov er e d/r es olv e d
2 3
Mi d dl e e ar 
i nf ecti o n
Otitis m e di a
I nf ecti o ns a n d 
i nf est ati o ns
H O
2
3 7
8
N
R ec ov er e d/r es olv e d
1 4
F
S ecr et ory otitis 
m e di a
Otitis m e di a
I nf ecti o ns a n d 
i nf est ati o ns
H O
1
7
2 5
N
R ec ov er e d/r es olv e d
2 0
M
Vir al p n e u m o ni a
P n e u m o ni a vir al
I nf ecti o ns a n d 
i nf est ati o ns
H O
2
1 3
2 3
N
R ec ov er e d/r es olv e d
1 4
M
Mi d dl e e ar 
i nf ecti o n, l eft
Otitis m e di a
I nf ecti o ns a n d 
i nf est ati o ns
H O
1
1 9
8
N
R ec ov er e d/r es olv e d
1 4
P n e u m o ni a
P n e u m o ni a
I nf ecti o ns a n d 
i nf est ati o ns
H O
1
1 9
8
N
R ec ov er e d/r es olv e d
1 3
M
Ac ut e 
ly m p h a d e nitis
Ly m p h a d e nitis
Bl o o d a n d ly m p h atic 
syst e m dis or d ers
H O
1
1 3
2 2
N
R ec ov er e d/r es olv e d
1 0
F
Py el o n e p hritis 
ac ut e
Py el o n e p hritis 
ac ut e
I nf ecti o ns a n d 
i nf est ati o ns
H O
1
6
1 2
N
R ec ov er e d/r es olv e d
1 9
M
L ary n gitis
L ary n gitis
I nf ecti o ns a n d 
i nf est ati o ns
H O
2
1 1
7
N
R ec ov er e d/r es olv e d
P
P
DP P
D
P P D
P P D
P P
D
P P D
P P D
P P D
P P D
P P
D
P P
D
P P
D
P P
D
P P
D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


C O N FI D E N TI A L
1 1 6 9 4 5 [ D T P A (B O O S T RI X) -0 4 7 ]
St ati sti c al A n al y si s Pl a n Fi n al
2 0- F E B -2 0 1 8
P a g e 5 1 of 6 1
S u b.
N o.
C a s e I d
A g e at
o n s et
( W e e k)
S e x
V er b ati m
Pr ef err e d t er m
S y st e m Or g a n 
Cl a s s
M A 
t y p e
D o s e
D a y of
o n s et
D ur ati o n
C a u s alit y
O ut c o m e
1 4
M
Br o nc hitis ac ut a
Br o nc hitis
I nf ecti o ns a n d 
i nf est ati o ns
H O
1
2 3
1 2
N
R ec ov er e d/r es olv e d
1 9
M
Br o nc hi olitis 
ac ut a
Br o nc hi olitis
I nf ecti o ns a n d 
i nf est ati o ns
H O
2
2 6
7
N
R ec ov er e d/r es olv e d
1 9
F
L ary n gitis ac ut a
L ary n gitis
I nf ecti o ns a n d 
i nf est ati o ns
H O
2
7
4
N
R ec ov er e d/r es olv e d
1 8
F
L ary n gitis
L ary n gitis
I nf ecti o ns a n d 
i nf est ati o ns
H O
2
7
4
N
R ec ov er e d/r es olv e d
1 4
F
G astr o e nt eritis
G astr o e nt eritis
I nf ecti o ns a n d 
i nf est ati o ns
H O
1
2 2
7
N
R ec ov er e d/r es olv e d
P P D
M A = m e dic al att e nti o n
H O = h os pit alis ati o n
D os e = d os e giv e n pri or t o t h e st art of t h e S A E
D ay of o ns et = n u m b er of d ays si nc e l ast st u dy v acci n e d os e
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


CONFIDENTIAL
116945 [DTPA (BOOSTRIX)-047]
Statistical Analysis Plan Final
20-FEB-2018
Page 52 of 61
Template 25 Number and percentage of doses and of subjects who took at least 
one concomitant medication from Day 0 to Day 7 after vaccination 
by type in each HRV vaccine liquid formulation group - TVC
HRV LIQ
HRV LIQ
HRV LIQ
95% CI
95% CI
95% CI
N
n
%
LL
UL
N
n
%
LL
UL
N
n
%
LL
UL
Dose 1
Any
298
173 58.1
52.2
63.7 302 175 57.9
52.2
63.6
300
157 52.3
46.5
58.1
Any antipyretic
298
97
32.6
27.3
38.2 302 94
31.1
25.9
36.7
300
71
23.7
19.0
28.9
Prophylactic 
antipyretic
298
8
2.7
1.2
5.2
302
6
2.0
0.7
4.3
300
9
3.0
1.4
5.6
Dose 2
Any
297
105 35.4
29.9
41.1 301 117 38.9
33.3
44.6
300
89
29.7
24.6
35.2
Any antipyretic
297
98
33.0
27.7
38.7 301 109 36.2
30.8
41.9
300
86
28.7
23.6
34.1
Prophylactic 
antipyretic
297
7
2.4
1.0
4.8
301
8
2.7
1.2
5.2
300
6
2.0
0.7
4.3
Overall/dose
Any
595
278 46.7
42.7
50.8 603 292 48.4
44.4
52.5
600
246 41.0
37.0
45.1
Any antipyretic
595
195 32.8
29.0
36.7 603 203 33.7
29.9
37.6
600
157 26.2
22.7
29.9
Prophylactic 
antipyretic
595
15
2.5
1.4
4.1
603 14
2.3
1.3
3.9
600
15
2.5
1.4
4.1
Overall/subject
Any
298
194 65.1
59.4
70.5 302 205 67.9
62.3
73.1
300
182 60.7
54.9
66.2
Any antipyretic
298
130 43.6
37.9
49.5 302 141 46.7
41.0
52.5
300
111 37.0
31.5
42.7
Prophylactic 
antipyretic
298
11
3.7
1.9
6.5
302 12
4.0
2.1
6.8
300
13
4.3
2.3
7.3
HRV LIQ = HRV vaccine liquid formulation Lot A
HRV LIQ = HRV vaccine liquid formulation Lot B
HRV LIQ = HRV vaccine liquid formulation Lot C
For each dose and overall/subject:
N = number of subjects with at least one administered dose
n/% = number/percentage of subjects who started to take the specified concomitant medication at least once during the 
mentioned period
For overall/dose:
N = number of administered doses
n/% = number/percentage of doses after which the specified concomitant medication was started at least once during 
the mentioned period
95% CI = exact 95% Confidence Interval, LL = Lower Limit, UL = Upper Limit
Template 26 Solicited and Unsolicited symptoms experienced by subjects 
classified by MedDRA Primary System Organ Class and Preferred 
Term within the 31-day (Days 0-30) post-vaccination period - SAE 
excluded (Total vaccinated cohort) 
HPV_2D
N =
MMR_DTPa
N =
Primary System Organ Class (CODE)
Preferred Term (CODE)
n*
n
%
n*
n
%
At least one symptom
<each SOC>
<each PT term>
HPV_2D = females aged 4-6 years who received two doses of HPV-16/18 L1 VLP AS04 vaccine at Day 0 and Month 6
MMR_DTPa = females aged 4-6 years who received MMR vaccine at Day 0 and DTPa vaccine at Month 6
At least one symptom = at least one symptom experienced (regardless of the MedDRA Preferred Term)
N = number of subjects with the administered dose
n* = number of events reported 
n/% = number/percentage of subjects reporting the symptom at least once
95% CI = exact 95% confidence interval; LL = Lower Limit, UL = Upper Limit


CONFIDENTIAL
116945 [DTPA (BOOSTRIX)-047]
Statistical Analysis Plan Final
20-FEB-2018
Page 53 of 61
Template 27 Minimum and maximum activity dates (TVC)
Visit
Minimum date
Maximum date
1
19JUN2007
29DEC2007
2
24JUL2007
08FEB2008
3
24AUG2007
18MAR2008
4
25MAR2008
22NOV2008
5
24MAR2009
31MAR2009*
*Database Lock Date = 31MAR2009
Template 28 Number of enrolled subjects by age category (TVC)
dTpa 
group-
Mother
N =
Control 
group -
Mother
dTpa 
group-
Infant
N =
Control 
group -
Infant
Household 
group
Characteristics
Categories
n
n
n
n
n
Age category
In utero
Preterm newborn infants 
(gestational age < 37 wks)
Newborns (0-27 days)
Infants and toddlers (28 days-
23 months)
Children (2-11 years)
Adolescents (12-17 years)
Adults (18-64 years)
From 65-84 years
85 years and over
Missing
Gr 1 = Group 1 description
Gr 2 = Group 2 description
Gr 3 = Group 3 description
N = Number of enrolled subjects
n= number of enrolled subjects included in each group or in total for a given age category or for all age categories
Missing = <describe missing>
Template 29 Number of subjects by country
ACWY-TT 
N = 259
ACWYHPV 
N = 259
HPV 
N = 261
Co-ad 
N = 260
Tdap 
N = 261
Total 
N = 1300
Country
n
n
N
n
n
n
Dominican Republic
86
87
88
87
87
435
Estonia
87
86
87
87
88
435
Thailand
86
86
86
86
86
430
ACWY-TT = Subjects who received MenACWY-TT at Month 0 and Cervarix at Month 1, 2 and 7
ACWYHPV = Subjects who received MenACWY-TT and Cervarix at Month 0 and Cervarix at Month 1 and 6
HPV = Subjects who received Cervarix at Month 0, 1 and 6
Co-ad = Subjects who received MenACWY-TT, Cervarix and Boostrix at Month 0 and Cervarix at Month 1 and 6
Tdap = Subjects who received Boostrix and Cervarix at Month 0 and Cervarix at Month 1 and 6
N = number of subjects
n= number of enrolled subjects included in each group or in total for a given age category or for all age categories


C O N FI D E N TI A L
1 1 6 9 4 5 [ D T P A (B O O S T RI X) -0 4 7 ]
St ati sti c al A n al y si s Pl a n Fi n al
2 0- F E B -2 0 1 8
P a g e 5 4 of 6 1
T e m pl at e 3 0
Li sti n g of dr o p o ut s d u e t o A E s, S A E s a n d s oli cit e d s y m pt o m s ( T ot al 
c o h ort)
St u d y -
S u bj e ct 
N o.
C o u ntr y
G e n d er
A E D e s cri pti o n S A E
C a u s alit y
O ut c o m e
T y p e of di s c o nti n u ati o n
G er m a ny
F
S U BJ E C T DI E D Y
F at al
St u dy at visit/c o nt act: VI SI T 1 1 
( Y 5)
G er m a ny
F
S U BJ E C T DI E D Y
F at al
St u dy at visit/c o nt act: VI SI T 1 1 
( Y 5)
T e m pl at e 3 1
S u m m ar y  of d e m o gr a p hi c c h ar a ct eri sti c s of h o u s e h ol d c o nt a ct s i n 
S p ai n ( T ot al c o h ort f or h o u s e h ol d c o nt a ct s i n S p ai n)
H o u s e h ol d Gr o u p
N = 
9 5 % CI
P ar a m et er s or C at e g ori e s
V al u e or 
n
P er 
L L
U L
A g e at v acci n ati o n
M e a n
S D
M e di a n
Mi ni m u m
M axi m u m
G e n d er
F e m al e
M al e
G e o gr a p hic a nc estry
Afric a n H erit a g e / Afric a n 
A m eric a n
A m eric a n I n di a n or Al ask a n 
N ativ e
W hit e - Ar a bic / N ort h Afric a n 
H erit a g e
W hit e - C a uc asi a n / E ur o p e a n 
H erit a g e
Ot h er ( His p a nic)
P P
D
d T p a gr o u p = M ot h ers r ec eiv e d d T p a d uri n g pr e g n a ncy
C o ntr ol gr o u p = M ot h ers r ec eiv e d pl ac e b o d uri n g pr e g n a ncy 
N = T ot al n u m b er of eli gi bl e h o us e h ol d c o nt acts
n/ P er  = n u m b er/ p erc e nt a g e of s u bj ects r e p orti n g 
9 5 % CI = ex act 9 5% c o nfi d e nc e i nt erv al; L L = L o w er Li mit, U L = U p p er Li mit
P P
D


CONFIDENTIAL
116945 [DTPA (BOOSTRIX)-047]
Statistical Analysis Plan Final
20-FEB-2018
Page 55 of 61
Table 6
Percentage of subjects with grade 3 unsolicited symptoms classified 
by MedDRA SOC and PT from Day 0 to Day 30 after any vaccination 
(Total Vaccinated Cohort) 
HRV LIQ
N = 298
HRV LIQ
N = 302
HRV LIQ
N = 300
95% CI
95% CI
95% CI
Primary System Organ 
Class (CODE)
Preferred 
Term (CODE)
n
%
LL
UL
n
%
LL
UL
n
%
LL
UL
At least one symptom
24
8.1
5.2
11.7
26
8.6
5.7 12.4
33
11.0 7.7 15.1
Ear and labyrinth 
disorders (10013993)
Ear pain 
(10014020)
0
0.0
0.0
1.2
1
0.3
0.0
1.8
0
0.0
0.0
1.2
Eye disorders (10015919) Conjunctivitis 
(10010741)
1
0.3
0.0
1.9
1
0.3
0.0
1.8
1
0.3
0.0
1.8
Gastrointestinal 
disorders (10017947)
Diarrhoea 
(10012735)
0
0.0
0.0
1.2
2
0.7
0.1
2.4
1
0.3
0.0
1.8
Flatulence 
(10016766)
1
0.3
0.0
1.9
1
0.3
0.0
1.8
2
0.7
0.1
2.4
General disorders and 
administration site 
conditions (10018065)
Injection site 
erythema 
(10022061)
0
0.0
0.0
1.2
0
0.0
0.0
1.2
1
0.3
0.0
1.8
Injection site 
pain 
(10022086)
0
0.0
0.0
1.2
0
0.0
0.0
1.2
1
0.3
0.0
1.8
Injection site 
swelling 
(10053425)
0
0.0
0.0
1.2
0
0.0
0.0
1.2
1
0.3
0.0
1.8
Irritability 
(10022998)
0
0.0
0.0
1.2
1
0.3
0.0
1.8
1
0.3
0.0
1.8
Pyrexia 
(10037660)
4
1.3
0.4
3.4
3
1.0
0.2
2.9
4
1.3
0.4
3.4
Immune system 
disorders (10021428)
Hypersensitivit
y (10020751)
0
0.0
0.0
1.2
1
0.3
0.0
1.8
0
0.0
0.0
1.2
Infections and 
infestations (10021881)
Bronchitis 
(10006451)
2
0.7
0.1
2.4
0
0.0
0.0
1.2
1
0.3
0.0
1.8
Ear infection 
(10014011)
1
0.3
0.0
1.9
3
1.0
0.2
2.9
2
0.7
0.1
2.4
Exanthema 
subitum 
(10015586)
1
0.3
0.0
1.9
1
0.3
0.0
1.8
0
0.0
0.0
1.2
Eye infection 
(10015929)
1
0.3
0.0
1.9
0
0.0
0.0
1.2
0
0.0
0.0
1.2
Gastroenteritis 
(10017888)
0
0.0
0.0
1.2
0
0.0
0.0
1.2
1
0.3
0.0
1.8
Impetigo 
(10021531)
1
0.3
0.0
1.9
0
0.0
0.0
1.2
0
0.0
0.0
1.2
Influenza 
(10022000)
0
0.0
0.0
1.2
1
0.3
0.0
1.8
0
0.0
0.0
1.2
Laryngitis 
(10023874)
1
0.3
0.0
1.9
0
0.0
0.0
1.2
0
0.0
0.0
1.2
Otitis media 
(10033078)
5
1.7
0.5
3.9
6
2.0
0.7
4.3
11
3.7
1.8
6.5
Perianal 
abscess 
(10034447)
1
0.3
0.0
1.9
0
0.0
0.0
1.2
0
0.0
0.0
1.2


CONFIDENTIAL
116945 [DTPA (BOOSTRIX)-047]
Statistical Analysis Plan Final
20-FEB-2018
Page 56 of 61
HRV LIQ
N = 298
HRV LIQ
N = 302
HRV LIQ
N = 300
95% CI
95% CI
95% CI
Primary System Organ 
Class (CODE)
Preferred 
Term (CODE)
n
%
LL
UL
n
%
LL
UL
n
%
LL
UL
Pneumonia 
(10035664)
0
0.0
0.0
1.2
1
0.3
0.0
1.8
0
0.0
0.0
1.2
Respiratory 
tract infection 
(10062352)
3
1.0
0.2
2.9
2
0.7
0.1
2.4
0
0.0
0.0
1.2
Respiratory 
tract infection 
viral 
(10062106)
0
0.0
0.0
1.2
0
0.0
0.0
1.2
1
0.3
0.0
1.8
Rhinitis 
(10039083)
2
0.7
0.1
2.4
1
0.3
0.0
1.8
3
1.0
0.2
2.9
Upper 
respiratory tract 
infection 
(10046306)
2
0.7
0.1
2.4
5
1.7
0.5
3.8
7
2.3
0.9
4.7
Varicella 
(10046980)
0
0.0
0.0
1.2
1
0.3
0.0
1.8
2
0.7
0.1
2.4
Psychiatric disorders 
(10037175)
Crying 
(10011469)
0
0.0
0.0
1.2
0
0.0
0.0
1.2
1
0.3
0.0
1.8
Respiratory, thoracic and 
mediastinal disorders 
(10038738)
Cough 
(10011224)
1
0.3
0.0
1.9
1
0.3
0.0
1.8
6
2.0
0.7
4.3
Nasal 
congestion 
(10028735)
1
0.3
0.0
1.9
0
0.0
0.0
1.2
0
0.0
0.0
1.2
Rales 
(10037833)
0
0.0
0.0
1.2
0
0.0
0.0
1.2
1
0.3
0.0
1.8
Skin and subcutaneous 
tissue disorders 
(10040785)
Dermatitis 
allergic 
(10012434)
1
0.3
0.0
1.9
1
0.3
0.0
1.8
0
0.0
0.0
1.2
Eczema 
(10014184)
0
0.0
0.0
1.2
0
0.0
0.0
1.2
1
0.3
0.0
1.8
Rash 
(10037844)
2
0.7
0.1
2.4
0
0.0
0.0
1.2
0
0.0
0.0
1.2
HRV LIQ = HRV vaccine liquid formulation Lot A
HRV LIQ = HRV vaccine liquid formulation Lot B
HRV LIQ = HRV vaccine liquid formulation Lot C
N = number of subjects with at least one administered dose
n/% = number/percentage of subjects reporting at least once a specified unsolicited symptom
At least one symptom = number of subjects reporting at least one unsolicited symptom, whatever the MedDRA PT
95% CI = exact 95% Confidence Interval, LL = Lower Limit, UL = Upper Limit


CONFIDENTIAL
116945 [DTPA (BOOSTRIX)-047]
Statistical Analysis Plan Final
20-FEB-2018
Page 57 of 61
Table 7
Number (%) of subjects with serious adverse events from first study 
vaccination up to Visit 3 including number of events reported (Total 
Vaccinated Cohort)
Gr 1
N =
Gr2
N =
Type of Event
Primary System Organ 
Class
Preferred Term 
(CODE)
n*
n
%
n*
n
%
SAE
At least one symptom
<each SOC>
<each PT term>
Related SAE
At least one symptom
<each SOC>
<each PT term>
Fatal SAE
At least one symptom
<each SOC>
<each PT term>
Related fatal SAE
At least one symptom
<each SOC>
<each PT term>
Gr 1 = Group 1 description
Gr 2 = Group 2 description
N = number of subjects with the administered dose
n* = number of events reported
n/% = number/percentage of subjects reporting the symptom at least once


C O N FI D E N TI A L
1 1 6 9 4 5 [ D T P A (B O O S T RI X) -0 4 7 ]
St ati sti c al A n al y si s Pl a n Fi n al
2 0- F E B -2 0 1 8
P a g e 5 8 of 6 1
T a bl e 8
S u bj e ct s wit h S eri o u s A d v er s e E v e nt s r e p ort e d u p t o Vi sit 2 ( T ot al V a c ci n at e d C o h ort)
S u b.
N o.
C a s e I d
A g e at
o n s et
( W e e k)
S e x
V er b ati m
Pr ef err e d t er m
S y st e m Or g a n 
Cl a s s
M A 
t y p e
D o s e
D a y of
o n s et
D ur ati o n
C a u s alit y
O ut c o m e
1 2
M
K a w as aki’s
dis e as e
K a w as aki’s 
dis e as e
I nf ecti o ns a n d 
i nf est ati o ns
H O
1
1 2
2 9
N
R ec ov er e d/r es olv e d
1 8
M
I nfl u e nz a-b
I nfl u e nz a
I nf ecti o ns a n d 
i nf est ati o ns
H O
2
2
5
N
R ec ov er e d/r es olv e d
1 7
M
Ac ut e 
g astr o e nt eritis
G astr o e nt eritis
I nf ecti o ns a n d 
i nf est ati o ns
H O
2
9
5
N
R ec ov er e d/r es olv e d
1 7
F
I nf a ntil e 
s p as ms
I nf a ntil e s p as ms N erv o us syst e m 
dis or d ers
H O
2
2
5 1
N
R ec ov er e d/r es olv e d wit h 
s e q u el a e
2 1
M
Rs -vir us 
br o nc hi olitis
R es pir at ory 
sy ncyti al vir us 
br o nc hi olitis
I nf ecti o ns a n d 
i nf est ati o ns
H O
2
3 0
1 6
N
R ec ov er e d/r es olv e d
1 3
M
G astr o e nt eritis
G astr o e nt eritis
I nf ecti o ns a n d 
i nf est ati o ns
H O
1
2 5
6
N
R ec ov er e d/r es olv e d
2 2
M
P n e u m o ni a
P n e u m o ni a
I nf ecti o ns a n d 
i nf est ati o ns
H O
2
3 2
1 3
N
R ec ov er e d/r es olv e d
2 3
Mi d dl e e ar 
i nf ecti o n
Otitis m e di a
I nf ecti o ns a n d 
i nf est ati o ns
H O
2
3 7
8
N
R ec ov er e d/r es olv e d
1 4
F
S ecr et ory otitis 
m e di a
Otitis m e di a
I nf ecti o ns a n d 
i nf est ati o ns
H O
1
7
2 5
N
R ec ov er e d/r es olv e d
2 0
M
Vir al 
p n e u m o ni a
P n e u m o ni a vir al
I nf ecti o ns a n d 
i nf est ati o ns
H O
2
1 3
2 3
N
R ec ov er e d/r es olv e d
1 4
M
Mi d dl e e ar 
i nf ecti o n, l eft
Otitis m e di a
I nf ecti o ns a n d 
i nf est ati o ns
H O
1
1 9
8
N
R ec ov er e d/r es olv e d
1 4
P n e u m o ni a
P n e u m o ni a
I nf ecti o ns a n d 
i nf est ati o ns
H O
1
1 9
8
N
R ec ov er e d/r es olv e d
1 3
M
Ac ut e 
ly m p h a d e nitis
Ly m p h a d e nitis
Bl o o d a n d 
ly m p h atic syst e m 
dis or d ers
H O
1
1 3
2 2
N
R ec ov er e d/r es olv e d
1 0
F
Py el o n e p hritis 
ac ut e
Py el o n e p hritis 
ac ut e
I nf ecti o ns a n d 
i nf est ati o ns
H O
1
6
1 2
N
R ec ov er e d/r es olv e d
1 9
M
L ary n gitis
L ary n gitis
I nf ecti o ns a n d 
i nf est ati o ns
H O
2
1 1
7
N
R ec ov er e d/r es olv e d
P
P
D
P P D
P P D
P P
D
P P
D
P P D
P P D
P P D
P P D
P P D
P P
D
P P
D
P P
D
P P
D
P P D
P P D
P P D
P P D
P P
D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


C O N FI D E N TI A L
1 1 6 9 4 5 [ D T P A (B O O S T RI X) -0 4 7 ]
St ati sti c al A n al y si s Pl a n Fi n al
2 0- F E B -2 0 1 8
P a g e 5 9 of 6 1
S u b.
N o.
C a s e I d
A g e at
o n s et
( W e e k)
S e x
V er b ati m
Pr ef err e d t er m
S y st e m Or g a n 
Cl a s s
M A 
t y p e
D o s e
D a y of
o n s et
D ur ati o n
C a u s alit y
O ut c o m e
1 4
M
Br o nc hitis 
ac ut a
Br o nc hitis
I nf ecti o ns a n d 
i nf est ati o ns
H O
1
2 3
1 2
N
R ec ov er e d/r es olv e d
1 9
M
Br o nc hi olitis 
ac ut a
Br o nc hi olitis
I nf ecti o ns a n d 
i nf est ati o ns
H O
2
2 6
7
N
R ec ov er e d/r es olv e d
1 9
F
L ary n gitis 
ac ut a
L ary n gitis
I nf ecti o ns a n d 
i nf est ati o ns
H O
2
7
4
N
R ec ov er e d/r es olv e d
1 8
F
L ary n gitis
L ary n gitis
I nf ecti o ns a n d 
i nf est ati o ns
H O
2
7
4
N
R ec ov er e d/r es olv e d
1 4
F
G astr o e nt eritis
G astr o e nt eritis
I nf ecti o ns a n d 
i nf est ati o ns
H O
1
2 2
7
N
R ec ov er e d/r es olv e d
P P D
M A = m e dic al att e nti o n
H O = h os pit alis ati o n
D os e = d os e giv e n pri or t o t h e st art of t h e S A E
D ay of o ns et = n u m b er of d ays si nc e l ast st u dy v acci n e d os e
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


CONFIDENTIAL
116945 [DTPA (BOOSTRIX)-047]
Statistical Analysis Plan Final
20-FEB-2018
Page 60 of 61
Table 9
Number and percentage of subjects who started at least one 
concomitant medication from Day 0 to Day 7 (Total Vaccinated 
Cohort)
dTpaNew Group
dTpaPre Group
95% CI
95% CI
N
n
%
LL
UL
N
n
%
LL
UL
Any
335
41
12.2
8.9
16.2
336
43
12.8
9.4
16.8
Any antipyretic
335
37
11.0
7.9
14.9
336
41
12.2
8.9
16.2
Prophylactic antipyretic
335
2
0.6
0.1
2.1
336
2
0.6
0.1
2.1
dTpaNew Group = Subjects who received Boostrix in new syringe presentation
dTpaPre Group = Subjects who received Boostrix in previous syringe presentation
N = number of subjects with the administered dose
n(%)= number(percentage) of subjects who started to take the specified concomitant medication at least once during 
the mentioned period
95% CI = exact 95% confidence interval, LL = Lower Limit, UL = Upper Limit
Table 10
Solicited and Unsolicited symptoms experienced by subjects 
classified by MedDRA Primary System Organ Class and Preferred 
Term within the 31-day (Days 0-30) post-vaccination period - SAE 
excluded (Total vaccinated cohort) 
HPV_2D
N =
MMR_DTPa
N =
Primary System Organ Class (CODE) Preferred Term (CODE) n*
n
%
n*
n
%
At least one symptom
<each SOC>
<each PT term>
HPV_2D = females aged 4-6 years who received two doses of HPV-16/18 L1 VLP AS04 vaccine at Day 0 and Month 6
MMR_DTPa = females aged 4-6 years who received MMR vaccine at Day 0 and DTPa vaccine at Month 6
At least one symptom = at least one symptom experienced (regardless of the MedDRA Preferred Term)
N = number of subjects with the administered dose
n* = number of events reported 
n/% = number/percentage of subjects reporting the symptom at least once
95% CI = exact 95% confidence interval; LL = Lower Limit, UL = Upper Limit
Table 11
Minimum and maximum activity dates (TVC) 
Visit
Minimum date
Maximum date
1
19JUN2007
29DEC2007
2
24JUL2007
08FEB2008
3
24AUG2007
18MAR2008
4
25MAR2008
22NOV2008
5
24MAR2009
31MAR2009*
*Database Lock Date = 31MAR2009


C O N FI D E N TI A L
1 1 6 9 4 5 [ D T P A (B O O S T RI X) -0 4 7 ]
St ati sti c al A n al y si s Pl a n Fi n al
2 0- F E B -2 0 1 8
P a g e 6 1 of 6 1
T a bl e 1 2
N u m b er of e nr oll e d s u bj e ct s b y  a g e c at e g or y (T V C )
Gr 1
N =
Gr 2
N =
Gr 3
N =
T ot al
N =
C h ar a ct eri sti c s
C at e g ori e s
n
n
n
n
A g e c at e g ory
I n ut er o
Pr et er m n e w b or n i nf a nts 
( g est ati o n al a g e < 3 7 wks)
N e w b or ns ( 0 -2 7 d ays)
I nf a nts a n d t o d dl ers ( 2 8 d ays-
2 3 m o nt hs)
C hil dr e n ( 2 -1 1 y e ars)
A d ol esc e nts ( 1 2 -1 7 y e ars)
A d ults ( 1 8 -6 4 y e ars)
Fr o m 6 5 -8 4 y e ars
8 5 y e ars a n d ov er
Missi n g
Gr 1 = Gr o u p 1 d escri pti o n
Gr 2 = Gr o u p 2 d escri pti o n
Gr 3 = Gr o u p 3 d escri pti o n
N = N u m b er of e nr oll e d s u bj ects
n = n u m b er of e nr oll e d s u bj ects i ncl u d e d i n e ac h gr o u p or i n t ot al f or a giv e n a g e c at e g ory or f or all a g e c at e g ori es
Missi n g = < d escri b e missi n g >
T a bl e 1 3
N u m b er of s u bj e ct s b y  c o u ntr y
A C W Y -T T 
N = 2 5 9
A C W Y H P V 
N = 2 5 9
H P V 
N = 2 6 1
C o -a d 
N = 2 6 0
T d a p 
N = 2 6 1
T ot al 
N = 1 3 0 0
C o u ntr y
n
n
N
n
n
n
D o mi nic a n R e p u blic
8 6
8 7
8 8
8 7
8 7
4 3 5
Est o ni a
8 7
8 6
8 7
8 7
8 8
4 3 5
T h ail a n d
8 6
8 6
8 6
8 6
8 6
4 3 0
A C W Y -T T = S u bj ects w h o r ec eiv e d M e n A C W Y -T T at M o nt h 0 a n d C erv arix at M o nt h 1, 2 a n d 7
A C W Y H P V = S u bj ects w h o r ec eiv e d M e n A C W Y -T T a n d C erv arix at M o nt h 0 a n d C erv arix at M o nt h 1 a n d 6
H P V = S u bj ects w h o r ec eiv e d C erv arix at M o nt h 0, 1 a n d 6
C o -a d = S u bj ects w h o r ec eiv e d M e n A C W Y -T T, C erv arix a n d B o ostrix at M o nt h 0 a n d C erv arix at M o nt h 1 a n d 6
T d a p = S u bj ects w h o r ec eiv e d B o ostrix a n d C erv arix at M o nt h 0 a n d C erv arix at M o nt h 1 a n d 6
N = n u m b er of s u bj ects
n = n u m b er of e nr oll e d s u bj ects i ncl u d e d i n e ac h gr o u p or i n t ot al f or a giv e n a g e c at e g ory or f or all a g e c at e g ori es
T a bl e 1 4
Li sti n g of dr o p o ut s d u e t o A E s, S A E s a n d s oli cit e d s y m pt o m s ( T ot al 
c o h ort)
St u d y -
S u bj e ct 
N o.
C o u ntr y
G e n d er
A E D e s cri pti o n
S A E
C a u s alit y
O ut c o m e
T y p e of di s c o nti n u ati o n
G er m a ny
F
S U BJ E C T DI E D Y
F at al
St u dy at visit/c o nt act: VI SI T 1 1 
( Y 5)
G er m a ny
F
S U BJ E C T DI E D Y
F at al
St u dy at visit/c o nt act: VI SI T 1 1 
( Y 5)
P P
D
P P
D