An Observer-blind Study to Evaluate the Safety, Reactogenicity and Immunogenicity of the Investigational GSK Biologicals' GSK3277511A Vaccine in Adults.
Phase: PHASE1
Conditions: Respiratory Disorders
Sponsor: GlaxoSmithKline

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Clinical Study Protocol
Sponsor:
GlaxoSmithKline Biologicals
Rue de l’Institut 89, 1330 Rixensart, Belgium
Primary Study vaccines and 
numbers
GlaxoSmithKline (GSK) Biologicals non-typeable 
Haemophilus influenzae (NTHi) and Moraxella 
catarrhalis (Mcat) multi-antigen vaccine consisting of 
three conserved surface proteins (PD, PE and PilA) 
from Haemophilus influenzae and one conserved 
surface protein (UspA2) from Mcat (GSK3277511A):
!
GSK3277513A (10 μg of PD, 10 μg of PE-PilA 
and 10 μg of UspA2/ plain or AS01E)
!
GSK3339036A (10∀g of PD, 10 μg of PE-PilA, 
and 3.3∀g of UspA2/ AS01E)
Other Study vaccine
!
Control: saline Placebo
eTrack study number and 
Abbreviated Title
201281 (NTHI MCAT-001)
Investigational New Drug 
(IND) number
16531
EudraCT number
2015-000378-36
Date of protocol
Final Version 1: 09 March 2015
Final Version 2: 30 March 2015
Final Version 3: 22 April 2015
Date of protocol 
amendment
Amendment 1 Final: 30 July 2015
Amendment 2 Final 16 March 2016
Title
An observer-blind study to evaluate the safety, 
reactogenicity and immunogenicity of the 
investigational GSK Biologicals’ GSK3277511A 
vaccine in adults.
Detailed Title
A Phase I, randomised, observer-blind, 
placebo-controlled, multi-centre study to evaluate the 
safety, reactogenicity and immunogenicity of GSK 
Biologicals' GSK3277511A investigational vaccine 
when administered intramuscularly according to a 0, 2 
months schedule in adults.
Co-ordinating author
 (XPE Pharma & Science for 
GSK Biologicals)
Contributing authors
!
, Director, 
Clinical Research & Translational Science
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PPD
PPD

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eTrack study number and 
Abbreviated Title
201281 (NTHI MCAT-001)
Investigational New Drug 
(IND) number
16531
EudraCT number
2015-000378-36
Detailed Title
A Phase I, randomised, observer-blind, 
placebo-controlled, multi-centre study to evaluate the 
safety, reactogenicity and immunogenicity of GSK 
Biologicals' GSK3277511A investigational vaccine 
when administered intramuscularly according to a 0, 2 
months schedule in adults.
Contributing authors
(continued) (Amended 16
March 2016)
!
, Clinical Research and 
Development Lead
!
,
, Lead 
Biostatistician
!
, Project Biostatistician
!
, Project Delivery Lead
!
, Study Delivery Lead
!
 (Novellas Healthcare 
for GSK Biologicals)/
, Study 
Delivery Manager
!
, CLS Clinical Readout Team 
Leader
!
, CLS Laboratory Study Manager 
!
/
, Clinical Safety 
Representatives
!
 (Aixial Pharma for 
GSK Biologicals), Study Data Manager
!
, Global Regulatory Lead
!
 (CVO-Europe for 
GSK Biologicals), Vaccine Supply Coordinator
GSK Biologicals’ Protocol DS v 14.1.1
Copyright 2015 - 2016 the GlaxoSmithKline group of companies. All rights reserved. 
Unauthorised copying or use of this information is prohibited.
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PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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Protocol Amendment 2 Sponsor Signatory Approval
eTrack study number and 
Abbreviated Title
201281 (NTHI MCAT-001)
IND number
16531
EudraCT number
2015-000378-36
Date of protocol amendment
Amendment 2 Final 16 March 2016
Detailed Title 
A Phase I, randomised, observer-blind, 
placebo-controlled, multi-centre study to evaluate the 
safety, reactogenicity and immunogenicity of GSK 
Biologicals' GSK3277511A investigational vaccine 
when administered intramuscularly according to a 
0, 2 months schedule in adults.
Sponsor signatory
(Amended 16 March 2016)
Ashwani Kumar Arora, Clinical and Epidemiology 
Project Lead
Signature
Date
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Protocol Amendment 2 Rationale
Amendment number:
Amendment 2
Rationale/background for changes: 
!
The spirometry test must be of good quality. If this is not the case, a re-test 
should be done. This re-test is covered by the current Informed Consent Form.
!
In compliance with ICH requirements, the protocol mentions that all results will 
be presented in an integrated report at the end of the study.
!
A description of how subjects will be included in the CMI sub-cohort and a 
description of how the sub-cohort will represent the fully randomized study 
groups has been added.
!
Following re-development and re-validation of the anti-PD ELISA, a new cut-off 
was defined. 
!
Additional administrative changes have been performed:
#
The IND number has been added.
#
The list of contributing authors as well as Sponsor signatory has been 
updated.
#
GSK Biologicals’ “Global Vaccines Clinical Laboratories (GVCL)” has 
been renamed as “Clinical Laboratory Sciences (CLS)”
#
Name “Quest Diagnostic Limited” has been replaced by “Q² Solutions” due 
to its merge with QLab.
#
Reference to the GSK Biologicals’ Laval laboratory was removed, as this
laboratory will not be used in the study. In addition, this laboratory is no 
longer part of GSK Biologicals’ laboratories.
#
In addition, minor edits in other sections were made for clarification.
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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 vaccines and other study-related duties and 
functions as described in the protocol.
!
To acquire the reference ranges for laboratory tests performed locally and, if required 
by local regulations, obtain the laboratory’s current certification or Quality 
Assurance procedure manual.
!
To ensure that no clinical samples (including serum samples) are retained onsite or 
elsewhere without the approval of GSK Biologicals and the express written informed 
consent of the subject and/or the subject’s legally acceptable representative. 
!
To perform no other biological assays on the clinical samples except those described 
in the protocol or its amendment(s). 
!
To co-operate with a representative of GSK Biologicals in the monitoring process of 
the study and in resolution of queries about the data.
!
That I have been informed that certain regulatory authorities require the sponsor to 
obtain and supply, as necessary, details about the investigator’s ownership interest in 
the sponsor or the investigational vaccines, and more generally about his/her 
financial ties with the sponsor. GSK Biologicals 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
201281 (NTHI MCAT-001)
IND number
16531
EudraCT number
2015-000378-36
Date of protocol amendment
Amendment 2 Final: 16 March 2016
Detailed Title
A Phase I, randomised, observer-blind, 
placebo-controlled, multi-centre study to evaluate the 
safety, reactogenicity and immunogenicity of GSK 
Biologicals' GSK3277511A investigational vaccine 
when administered intramuscularly according to a 
0, 2 months schedule in adults.
Investigator name
Signature
Date
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Sponsor Information
1.
Sponsor
GlaxoSmithKline Biologicals
GlaxoSmithKline Biologicals
Rue de l’Institut 89, 1330 Rixensart, Belgium
2.
Sponsor Medical Expert for the Study
Refer to the local study contact information document.
3.
Sponsor Study Monitor
Refer to the local study contact information document.
4.
Sponsor Study Contact for Reporting of a Serious Adverse Event
GSK Biologicals Central Back-up Study Contact for Reporting SAEs: refer to protocol 
Section 8.4.2.
5.
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 8.8.
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SYNOPSIS
Detailed Title
A Phase I, randomised, observer-blind, placebo-controlled, 
multi-centre study to evaluate the safety, reactogenicity and 
immunogenicity of GSK Biologicals' GSK3277511A 
investigational vaccine when administered intramuscularly 
according to a 0, 2 months schedule in adults.
Indication
Immunisation against non-typeable Haemophilus influenzae
(NTHi) and Moraxella catarrhalis (Mcat) in adults.
Rationale for the 
study and study 
design
!
Rationale for the study
GSK Biologicals is developing a new NTHi-Mcat 
investigational vaccine against diseases caused by NTHi and 
Mcat, such as respiratory tract infections in COPD (chronic 
obstructive pulmonary disease) patients, which can lead to 
acute exacerbations of COPD (AECOPD). The investigational 
vaccine that will be evaluated in the present study is a 
multi-component vaccine based on conserved surface proteins 
of NTHi and Mcat. Three NTHi proteins have been selected: 
Protein D (PD), as a free recombinant protein and Protein E 
(PE) and PilA protein, as a recombinant fusion protein named 
PE-PilA. The selected Mcat antigen is UspA2.
The purpose of this new Phase I study is to evaluate the 
safety, reactogenicity and immunogenicity of the NTHi-Mcat 
investigational vaccines, first in healthy young adults 
(18-40 years old) with a non-adjuvanted formulation and 
secondly in adults 50–70 years old having a significant 
smoking history (≥10 pack-years) with two adjuvanted 
formulations. The investigational vaccines will be 
administered according to a 0, 2 months schedule. Saline 
placebo will be used as control.
!
Rationale for the study design
As the UspA2 antigen has never been administered to human, 
healthy young adults will be enrolled and vaccinated with a 
non-adjuvanted vaccine in the study prior to vaccinate adults 
of 50-70 years old with the adjuvanted formulations. The 
study will hence follow a staggered design with two steps. 
Step 1 will include healthy adults 18–40 years old either 
receiving a non-adjuvanted (plain) vaccine containing 10 μg 
of PD, 10 μg of PE-PilA and 10 μg of UspA2, or a placebo 
control. Step 2 will include adults 50–70 years old with a 
smoking history of at least 10 pack years either receiving 
placebo control, or one of two AS01E-adjuvanted 
formulations, i.e. 10 μg of PD, 10 μg of PE-PilA and 10 μg of 
UspA2 or 10 μg of PD, 10 μg of PE-PilA and 3.3 μg of
UspA2.
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Moving to Step 2 or administration of vaccine Dose 2 within a 
step will be conditional on the favourable outcome of an 
evaluation of safety data obtained up to 7 days after 
administration of (a) previous vaccine dose(s) by an internal 
Safety Review Committee (iSRC).
!
Rationale for the use of placebo
The placebo group (saline solution) is included in the 
NTHI MCAT-001 study as a control for both the safety and 
immunogenicity assessments.
Objectives
Primary
!
To evaluate the safety and reactogenicity profile of the 
NTHi-Mcat investigational vaccines.
Secondary
!
To evaluate the humoral and cellular immune response of 
the NTHi-Mcat investigational vaccines.
Tertiary
!
To collect blood samples for assay 
development/validation and/or for 
evaluation/characterisation of the humoral and cellular
immune responses to components of either the
NTHi-Mcat investigational vaccines and/or of other 
respiratory pathogens.
Study design
!
Experimental design: Phase I, observer-blind, 
randomised, placebo-controlled, multi-centric study with 
two steps.
!
Duration of the study: For each subject, the study will 
last approximately 15 months, from screening to study 
end.
#
Epoch 001: Primary starting at Screening Visit and 
ending at, and including Visit 6 (Day 90).
#
Epoch 002: Follow-up starting at Visit 7 (Day 210) 
and ending at Visit 8 (Day 420).
!
Study groups:
#
10-10-10: Approximately 15 subjects receiving two 
doses of the non-adjuvanted GSK Biologicals' 
NTHi-Mcat investigational vaccine containing 10 μg 
of PD, PE-PilA and UspA2 during Step 1 of the 
study.
#
PLACE1: Approximately 15 subjects receiving two 
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doses of placebo (saline solution) during Step 1 of 
the study.
#
10-10-10-AS: Approximately 30 subjects receiving 
two doses of the AS01E-adjuvanted 
GSK Biologicals' NTHi-Mcat investigational vaccine 
containing 10 μg of PD, PE-PilA and UspA2 during 
Step 2 of the study.
#
10-10-3-AS: Approximately 30 subjects receiving 
two doses of the AS01E-adjuvanted GSK Biologicals' 
NTHi-Mcat investigational vaccine containing 10 μg 
of PD, 10 ∀g of PE-PilA, and 3.3 μg of UspA2 
during Step 2 of the study.
#
PLACE2: Approximately 30 subjects receiving two 
doses of placebo (saline solution) during Step 2 of 
the study.
Synopsis Table 1
Study groups and epochs foreseen in the study
Study groups
Number of 
subjects
Age (Min/Max)
Epochs
Step
Epoch 001
Epoch 002
10-10-10
15
18 - 40 years
x
x
1
PLACE1
15
18 - 40 years
x
x
1
10-10-10-AS
30
50 - 70 years 
x
x
2
10-10-3-AS
30
50 - 70 years 
x
x
2
PLACE2
30
50 - 70 years 
x
x
2
Synopsis Table 2
Study groups and treatment foreseen in the study
Treatment 
name
Vaccine/
product name
Study Groups
10-10-10
10-10-10-AS
10-10-3-AS
PLACE1
PLACE2
10-10-10/Plain
NTHi-Mcat 10-10-10
X
NaCl
10-10-10/AS01E
NTHi-Mcat 10-10-10
X
AS01E
10-10-3/AS01E
NTHi-Mcat 30-30-10 *
X
AS01E
Placebo
NaCl
X
X
* Vials containing 37.5 ∀g, 37.5 ∀g and 12.5 ∀g of freeze-dried PD, PE-PilA and UspA2, respectively, will be diluted in
three volumes of AS01E (total of ∃1875 ∀L). 0.5 mL will be administered.
!
Control: placebo control (saline solution).
!
Vaccination schedule: 0, 2 months (i.e. at Visit 1 
[Day 0] and Visit 4 [Day 60]).
!
Treatment allocation: Subjects will be allocated to a 
study group using a centralised randomisation system on 
internet (SBIR). SBIR will also be used for treatment 
allocation at second dose. The randomisation algorithm 
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will use a minimisation procedure accounting for centre 
at Step 1 and accounting for age (50-59 years or 60-70 
years), for smoking status (current or former smokers), 
for centre and for forced expiratory volume in 1 second 
(FEV1) / forced vital capacity (FVC) (% 0.7 or < 0.7) at 
Step 2.
!
Blinding: Observer-blind.
Synopsis Table 3
Blinding of study epochs
Study Epochs
Blinding
Epoch 001
observer-blind
Epoch 002
observer-blind
!
Sampling schedule:
#
Blood samples for safety (haematology/ biochemistry) 
will be collected from all subjects at Screening Visit 
(pre-Day 0), at Visit 1 (Day 0), Visit 2 (Day 7), Visit 4 
(Day 60), Visit 5 (Day 67), Visit 7 (Day 210) and at 
Visit 8 (Day 420).
#
Blood samples for immunogenicity will be collected 
from all subjects for humoral immunity at Visit 1 
(Day 0), Visit 3 (Day 30), Visit 4 (Day 60), Visit 6 
(Day 90), Visit 7 (Day 210) and at Visit 8 (Day 420), 
and from a sub-cohort of subjects for cell-mediated 
immunity (CMI) at Visit 1 (Day 0), Visit 4 (Day 60), 
Visit 6 (Day 90), Visit 7 (Day 210) and at Visit 8 
(Day 420).
!
Type of study: self-contained
!
Data collection: Electronic Case Report Form (eCRF)
!
Safety monitoring during vaccination period: Safety 
evaluations by the Safety Review Team (SRT) and iSRC.
Moving to Step 2 or administration of vaccine Dose 2 
within a step will depend on the favourable outcome of a 
safety evaluation based on the safety data collected up to 
7 days after administration of the previous dose(s). In order 
to move to Step 2, safety data will be needed from all 
subjects. In order to move from Dose 1 to Dose 2 within a 
step, safety data from about 50% of the vaccinated subjects
will be needed.
Number of subjects
The target is to enrol ∃30 eligible subjects 18–40 years old in 
Step 1 (∃15/group) and ∃90 eligible subjects 50–70 years old in 
Step 2 (∃30/group). The total target number of subjects is ∃120.
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Endpoints
Primary
!
Occurrence of each solicited local and general adverse 
event (AE), during a 7-day follow-up period (i.e. day of 
vaccination and 6 subsequent days) post-Dose 1 and 
post-Dose 2, in all subjects, in all vaccine groups.
!
Occurrence of any unsolicited AEs, during a 30-day 
follow-up period (i.e. day of vaccination and 29 subsequent 
days) post-Dose 1 and post-Dose 2, in all subjects, in all
vaccine groups.
!
Occurrence of haematological and biochemical laboratory 
abnormalities, after vaccination, in all subjects, in all 
vaccine groups: 
#
Any haematological (RBC, WBC and differential 
count, platelets count and haemoglobin level) or 
biochemical (alanine aminotransferase [ALT], 
aspartate aminotransferase [AST] and creatinine) 
laboratory abnormality on Day 7, Day 60, Day 67, 
Day 210 and Day 420.
!
Occurrence of any serious AE (SAE), occurring from first 
vaccination to study conclusion in all subjects, in all 
vaccine groups. 
!
Occurrence of any potential immune-mediated disease 
(pIMD) occurring from first vaccination to study 
conclusion in all subjects, in all vaccine groups.
Secondary
!
Humoral immune response to the components of the 
NTHi-Mcat investigational vaccine formulations, on Day 0, 
Day 30, Day 60, Day 90, Day 210 and Day 420, in all 
subjects, in all vaccine groups: 
#
Anti-PD, anti-PE, anti-PilA and anti-UspA2 antibody 
concentrations.
!
Cell-mediated immune response to components of the 
NTHi-Mcat investigational vaccine formulations, on Day 0, 
Day 60, Day 90, Day 210 and Day 420, in a sub-cohort of 
subjects, in all vaccine groups: 
#
Frequency of specific CD4+/CD8+ T-cells measured on 
cryopreserved peripheral blood mononuclear cells 
(PBMCs) and identified by flow cytometry 
intracellular cytokine staining (ICS) expressing two or 
more markers (such as IL-2, IL-13, IL-17, IFN-γ, 
TNF-α and CD40L).
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TABLE OF CONTENTS
PAGE
SPONSOR INFORMATION ............................................................................................7
SYNOPSIS......................................................................................................................8
LIST OF ABBREVIATIONS...........................................................................................22
GLOSSARY OF TERMS ...............................................................................................25
1.
INTRODUCTION....................................................................................................30
1.1.
Background ................................................................................................30
1.1.1.
COPD: an introduction.................................................................30
1.1.2.
Current management of AECOPD ...............................................30
1.1.3.
GSK Biologicals’ NTHi-Mcat investigational vaccine ....................31
1.2.
Rationale for the study and study design ....................................................32
1.2.1.
Rationale for the study.................................................................32
1.2.2.
Rationale for the study design......................................................33
1.2.3.
Rationale for the use of placebo ..................................................33
1.3.
Benefit/Risk Assessment ............................................................................34
1.3.1.
Risk Assessment .........................................................................34
1.3.2.
Benefit Assessment .....................................................................34
1.3.3.
Overall Benefit/Risk Conclusion...................................................34
2.
OBJECTIVES.........................................................................................................35
2.1.
Primary objective ........................................................................................35
2.2.
Secondary objective ...................................................................................35
2.3.
Tertiary objective ........................................................................................35
3.
STUDY DESIGN OVERVIEW ................................................................................36
3.1.
Study design...............................................................................................36
3.2.
Safety precautions......................................................................................38
3.2.1.
Details of the staggered design of the study ................................38
3.2.2.
Vaccination..................................................................................39
4.
STUDY COHORT...................................................................................................39
4.1.
Number of subjects/centres ........................................................................39
4.2.
Inclusion criteria for enrolment....................................................................40
4.2.1.
Healthy adults 18-40 years old (Step 1) .......................................40
4.2.2.
Current and former smokers 50-70 years old (Step 2) .................41
4.3.
Exclusion criteria for enrolment...................................................................41
4.3.1.
Healthy adults 18-40 years old (Step 1) .......................................41
4.3.2.
Current or former smokers 50-70 years old (Step 2) ....................43
5.
CONDUCT OF THE STUDY ..................................................................................44
5.1.
Regulatory and ethical considerations, including the informed 
consent process..........................................................................................44
5.2.
Subject identification and randomisation of treatment .................................45
5.2.1.
Subject identification....................................................................45
5.2.2.
Randomisation of treatment.........................................................45
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5.2.2.1.
Randomisation of supplies..........................................45
5.2.2.2.
Treatment allocation to the subject.............................45
5.2.2.2.1.
Study group and treatment 
number allocation ...................................46
5.2.2.2.2.
Treatment number allocation for 
subsequent doses ..................................46
5.3.
Method of blinding ......................................................................................46
5.4.
General study aspects ................................................................................47
5.5.
Outline of study procedures ........................................................................48
5.6.
Detailed description of study procedures ....................................................50
5.6.1.
Informed consent.........................................................................50
5.6.2.
Check inclusion and exclusion criteria .........................................50
5.6.3.
Collect demographic data ............................................................50
5.6.4.
Medical history.............................................................................51
5.6.5.
Smoking status ............................................................................51
5.6.6.
Smoking exposure history............................................................51
5.6.7.
Measure/record height and weight...............................................51
5.6.8.
Spirometry ...................................................................................52
5.6.9.
Physical examination ...................................................................52
5.6.10.
Urine pregnancy test....................................................................53
5.6.11.
Check contraindications...............................................................53
5.6.12.
Assess pre-vaccination body temperature ...................................53
5.6.13.
Study group and treatment number allocation..............................53
5.6.14.
Blood sampling ............................................................................53
5.6.14.1.
Blood sampling for safety assessment........................53
5.6.14.2.
Blood sampling for antibody determination and 
assay development.....................................................54
5.6.14.3.
Blood sampling for CMI ..............................................54
5.6.15.
Vaccination..................................................................................54
5.6.16.
Recording of AEs, SAEs, pregnancies and pIMDs.......................54
5.6.17.
Check and record concomitant medication/vaccination and 
intercurrent medical conditions requiring medical attention ..........55
5.6.18.
Study conclusion..........................................................................55
5.7.
Biological sample handling and analysis.....................................................55
5.7.1.
Use of specified study materials ..................................................56
5.7.2.
Biological samples.......................................................................57
5.7.3.
Laboratory assays .......................................................................57
5.7.4.
Biological samples evaluation......................................................60
5.7.4.1.
Immunological read-outs ............................................60
5.7.4.2.
Haematology and biochemistry...................................60
5.7.5.
Immunological correlates of protection.........................................60
6.
STUDY VACCINES AND ADMINISTRATION ........................................................61
6.1.
Description of study vaccines......................................................................61
6.2.
Storage and handling of study vaccines......................................................61
6.3.
Dosage and administration of study vaccines .............................................62
6.3.1.
Instructions for study vaccine preparation and 
administration ..............................................................................62
6.3.1.1.
Instructions for reconstitution and 
administration of investigational 10-10-10/Plain 
or 10-10-10/AS01E vaccines.......................................62
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6.3.1.2.
Instructions for reconstitution and 
administration of investigational 10-10-3/AS01E
vaccine.......................................................................63
6.3.1.3.
Instructions for preparation and administration 
of saline placebo ........................................................63
6.4.
Replacement of unusable vaccine doses....................................................63
6.5.
Contraindications to subsequent vaccination ..............................................64
6.6.
Concomitant medications/products and concomitant vaccinations..............65
6.6.1.
Recording of concomitant medications/products and 
concomitant vaccinations.............................................................65
6.6.2.
Concomitant medications/products/vaccines that may lead 
to the elimination of a subject from ATP analyses........................65
6.7.
Intercurrent medical conditions that may lead to elimination of a 
subject from ATP analyses .........................................................................66
7.
HEALTH ECONOMICS ..........................................................................................66
8.
SAFETY.................................................................................................................66
8.1.
Safety definitions ........................................................................................66
8.1.1.
Definition of an adverse event......................................................66
8.1.2.
Definition of a serious adverse event ...........................................67
8.1.3.
Solicited adverse events..............................................................68
8.1.3.1.
Solicited local (injection-site) adverse events..............68
8.1.3.2.
Solicited general adverse events................................69
8.1.4.
Clinical laboratory parameters and other abnormal 
assessments qualifying as adverse events or serious 
adverse events ............................................................................69
8.1.5.
Adverse events of specific interest (potential immune-
mediated diseases)......................................................................69
8.2.
Events or outcomes not qualifying as adverse events or serious 
adverse events ...........................................................................................71
8.3.
Detecting and recording adverse events, serious adverse events 
and pregnancies .........................................................................................72
8.3.1.
Time period for detecting and recording adverse events, 
serious adverse events and pregnancies.....................................72
8.3.2.
Post-study adverse events and serious adverse events...............73
8.3.3.
Evaluation of adverse events and serious adverse events...........74
8.3.3.1.
Active questioning to detect adverse events 
and serious adverse events........................................74
8.3.3.2.
Assessment of adverse events...................................75
8.3.3.2.1.
Assessment of intensity..........................75
8.3.3.2.2.
Assessment of causality .........................76
8.3.3.3.
Assessment of outcomes............................................77
8.3.3.4.
Medically attended visits.............................................78
8.4.
Reporting of serious adverse events, pregnancies, and other events .........78
8.4.1.
Prompt reporting of serious adverse events, pregnancies, 
and other events to GSK Biologicals............................................78
8.4.2.
Contact information for reporting serious adverse events, 
pregnancies and pIMDs...............................................................79
8.4.3.
Completion and transmission of SAE reports to GSK 
Biologicals ...................................................................................79
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8.4.3.1.
Back-up system in case the electronic reporting 
system does not work.................................................79
8.4.4.
Reporting of pIMDs to GSK Biologicals........................................79
8.4.5.
Completion and transmission of pregnancy reports to GSK 
Biologicals ...................................................................................80
8.4.6.
Updating of SAE, pregnancy, and pIMD information after 
removal of write access to the subject’s eCRF.............................80
8.4.7.
Regulatory reporting requirements for serious adverse 
events..........................................................................................80
8.5.
Follow-up of adverse events, serious adverse events, and 
pregnancies................................................................................................81
8.5.1.
Follow-up of adverse events and serious adverse events ............81
8.5.1.1.
Follow-up during the study..........................................81
8.5.1.2.
Follow-up after the subject is discharged from 
the study.....................................................................81
8.5.2.
Follow-up of pregnancies.............................................................81
8.6.
Treatment of adverse events ......................................................................82
8.7.
Unblinding...................................................................................................82
8.8.
Emergency unblinding ................................................................................82
8.9.
Subject card................................................................................................83
8.10.
Holding rules and safety monitoring............................................................83
8.10.1.
Safety Review Team....................................................................84
8.10.2.
Internal Safety Review Committee...............................................84
8.10.2.1.
Outcome of safety evaluation .....................................85
8.10.2.2.
Process for the suspension of vaccination 
and/or study modification............................................85
8.10.3.
Study holding rules ......................................................................85
8.10.4.
Risk assessments........................................................................86
9.
SUBJECT COMPLETION AND WITHDRAWAL.....................................................88
9.1.
Subject completion .....................................................................................88
9.2.
Subject withdrawal......................................................................................88
9.2.1.
Subject withdrawal from the study................................................88
9.2.2.
Subject withdrawal from investigational vaccine...........................89
9.3.
Screening failures.......................................................................................89
10. STATISTICAL METHODS......................................................................................89
10.1.
Primary endpoints.......................................................................................89
10.2.
Secondary endpoints ..................................................................................90
10.3.
Determination of sample size......................................................................90
10.4.
Cohorts for analyses...................................................................................92
10.4.1.
Total vaccinated cohort................................................................92
10.4.2.
According-to-protocol cohort........................................................92
10.4.2.1.
According-to-protocol cohort for analysis of 
immunogenicity (Epoch 001) ......................................92
10.4.2.2.
According-to-protocol cohort for analysis of 
persistence of immunogenicity (Epoch 002) ...............93
10.5.
Derived and transformed data.....................................................................93
10.6.
Statistical analysis ......................................................................................94
10.6.1.
Analysis of demographics ............................................................94
10.6.2.
Analysis of safety.........................................................................94
10.6.3.
Analysis of immunogenicity..........................................................96
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10.6.3.1.
Humoral immune response.........................................96
10.6.3.2.
CMI response.............................................................96
10.6.3.3.
Summary score to support dose selection ..................97
10.7.
Interpretation of analyses............................................................................97
10.8.
Conduct of analyses ...................................................................................97
10.8.1.
Sequence of analyses..................................................................97
10.8.2.
Statistical considerations for interim analyses..............................98
11. ADMINISTRATIVE MATTERS ...............................................................................98
11.1.
Electronic Case Report Form instructions...................................................98
11.2.
Study monitoring by GSK Biologicals..........................................................99
11.3.
Record retention .........................................................................................99
11.4.
Quality assurance.....................................................................................100
11.5.
Posting of information on publicly available clinical trial registers and 
publication policy ......................................................................................100
11.6.
Provision of study results to investigators .................................................100
12. COUNTRY SPECIFIC REQUIREMENTS.............................................................101
13. REFERENCES.....................................................................................................101
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LIST OF TABLES
PAGE
Table 1
Study groups and epochs foreseen in the study.....................................37
Table 2
Study groups and treatment foreseen in the study .................................37
Table 3
Blinding of study epochs ........................................................................38
Table 4
Sub-cohorts for CMI ...............................................................................40
Table 5
List of study procedures for healthy adults 18-40 years old 
(Step 1) ..................................................................................................48
Table 6
List of study procedures for current or former smokers 50-70 
years old (Step 2) (Amended 16 March 2016)........................................49
Table 7
Intervals between study visits.................................................................50
Table 8
Biological samples .................................................................................57
Table 9
Haematology and biochemistry tests......................................................58
Table 10
Humoral Immunity (antibody determination) (Amended 16 March 
2016)......................................................................................................59
Table 11
Cell-Mediated Immunity (CMI) (Amended 16 March 2016).....................59
Table 12
Immunological read-outs........................................................................60
Table 13
Haematology/ biochemistry ....................................................................60
Table 14
Study vaccines.......................................................................................61
Table 15
Dosage and administration.....................................................................62
Table 16
Solicited local adverse events ................................................................68
Table 17
Solicited general adverse events............................................................69
Table 18
List of potential immune-mediated diseases...........................................70
Table 19
Reporting periods for collecting safety information .................................73
Table 20
Intensity scales for solicited symptoms...................................................75
Table 21
Timeframes for submitting serious adverse event, pregnancy and 
other events reports to GSK Biologicals .................................................78
Table 22
List of holding rules ................................................................................86
Table 23
Exact confidence interval for one proportion with 15 subjects.................91
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Table 24
GSK Biologicals’ laboratories ...............................................................105
Table 25
Outsourced laboratories.......................................................................105
Table 26
FDA toxicity grading scales for haematology/ biochemistry 
parameters...........................................................................................109
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LIST OF FIGURES
PAGE
Figure 1
Study design overview ...........................................................................36
Figure 2
Overview of iSRC evaluations................................................................84
Figure 3
Risk assessment curve for safety holding rules 1 and 2 for 
treatment arms of 15 subjects (no adjustment for multiplicity) ................87
Figure 4
Risk assessment curve for safety holding rules 1 and 2 for 
treatment arms of 30 subjects (no adjustment for multiplicity) ................87
Figure 5
Probability of not detecting an AE with a true occurrence rate of 
0-10% ....................................................................................................91
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LIST OF APPENDICES
PAGE
APPENDIX A LABORATORY ASSAYS .....................................................................104
APPENDIX B CLINICAL LABORATORIES (Amended 16 March  2016) ....................105
APPENDIX C FDA’s Guidance for Industry: Toxicity Grading Scale for Healthy 
Adult and Adolescent Volunteers Enrolled in Preventive Vaccine 
Clinical Trials (September 2007) ..........................................................106
APPENDIX D AMENDMENTS AND ADMINISTRATIVE CHANGES TO THE 
PROTOCOL.........................................................................................111
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LIST OF ABBREVIATIONS
ANCOVA
analysis of covariance
AE
adverse event
AECOPD
acute exacerbation of COPD
Al
aluminium
ALT
alanine aminotransferase
AS
adjuvant system
AST
aspartate aminotransferase
ATP
according-to-protocol
ATS 
American Thoracic Society
CI
confidence interval
CLS (Amended 16
March 2016)
Clinical Laboratory Sciences
CMI
cell-mediated immunity
COPD
chronic obstructive pulmonary disease
CRDL
Clinical Research & Development Lead
CSR
clinical study report
eCRF
electronic Case Report Form
ELISA
enzyme-linked immunosorbent assay
EL.U/mL
ELISA unit per millilitre
EMA
European Medicines Agency
ERS
European Respiratory Society
(e)TDF
(electronic) temperature excursion decision form
FDA
Food and Drug Administration, United States
FEV1
forced expiratory volume in 1 second
FTIH
first time in human
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FVC
forced vital capacity
GCP
Good Clinical Practice
GMC
geometric mean concentration 
GOLD
Global Initiative for Chronic Obstructive Lung Disease
GSK
GlaxoSmithKline
IB
Investigator Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
ICS
intracellular cytokine staining
IEC
Independent Ethics Committee
IFN-γ
interferon gamma
Ig
immunoglobulin
IL
interleukin
IM
intramuscular
IMP
investigational medicinal product
IRB
Institutional Review Board
iSRC
internal Safety Review Committee
Mcat
Moraxella catarrhalis
MedDRA
medical dictionary for regulatory activities
NaCl
sodium chloride (saline solution)
NTHi
non-typeable Haemophilus influenzae
PBMC
peripheral blood mononuclear cell
PD
protein D of Haemophilus influenzae
PE
protein E of Haemophilus influenzae
PilA
type IV pili subunit of non-typeable Haemophilus 
influenzae
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pIMD
potential immune-mediated disease
PT
preferred term
RBC
red blood cells
SAE
serious adverse event
SBIR
randomisation system on internet
SDV
source document verification
SPM
Study Procedures Manual
SRT
Safety Review Team
TNF-α
tumour necrosis factor alpha
TVC
total vaccinated cohort
UspA2
ubiquitous surface protein A2 of Moraxella catarrhalis
VSMB
Vaccine Safety Monitoring Board
WBC
white blood cells
WHO
World Health Organisation
∀L
microliter
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GLOSSARY OF TERMS
Adequate contraception
Adequate contraception is defined as:
1.
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,
!
current tubal ligation,
!
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.
2.
a contraceptive method with failure rate of more than 
1% per year but still considered as acceptable birth 
control method:
!
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. 
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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.
Alcoholism
Alcoholism, also known as dependency on alcohol or 
alcohol addiction, is a chronic disease. The signs and 
symptoms of alcoholism include:
!
A strong craving for alcohol.
!
Continued use despite repeated physical, 
psychological, or interpersonal problems.
The inability to limit drinking.
Blinding
A procedure in which one or more parties to the trial are 
kept unaware of the treatment assignment in order to 
reduce the risk of biased study outcomes. The level of 
blinding is maintained throughout the conduct of the trial, 
and only when the data are cleaned to an acceptable level 
of quality will appropriate personnel be unblinded or 
when required in case of a serious adverse event (SAE). 
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).
Current smoker
A person who is currently smoking or who has stopped 
smoking within the past 6 months.
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 
timepoints or a single timepoint from a single protocol. 
Self-contained means that data collected for all subjects 
at all timepoints within that epoch allows to draw a 
complete conclusion to define or precise the targeted 
label of the product. Typical examples of epochs are 
primary vaccinations, boosters, yearly immunogenicity 
follow-ups, and surveillance periods for efficacy or 
safety.
eTrack
GSK’s tracking tool for clinical trials.
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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 6.6.2 and 10.4 for details on criteria for 
evaluability).
Former smoker
A person who stopped smoking for at least 6 months.
Immunological correlate 
of protection
The defined immune response above which there is a high 
likelihood of protection in the absence of any host factors 
that might increase susceptibility to the infectious agent.
Investigational vaccine
(Synonym of 
Investigational Medicinal 
Product)
A pharmaceutical form of an active ingredient or placebo 
being tested or used as a reference in a clinical trial, 
including a product with a marketing authorisation when 
used in a way different from the approved form, or when 
used for an unapproved indication, or when used to gain 
further information about an approved use. 
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.
Pack-years of smoking
Pack-years is a quantification of cigarette smoking, a way 
to measure the total amount a person has smoked in the 
course of his/ her lifetime. The number of pack-years is 
calculated as follows:
(average number of cigarettes smoked per day x number 
of years smoked)/ 20
E.g. a smoking history of 10 pack-years means having 
smoked 20 cigarettes per day for 10 years, or having 
smoked 10 cigarettes per day for 20 years.
Note: For the purpose of this study, pipe and/or cigar use 
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should not be used to calculate pack-year history.
Potential immune-
mediated disease
Potential immune-mediated diseases (pIMDs) are a subset 
of AEs that include autoimmune diseases and other 
inflammatory and/or neurologic disorders of interest 
which may or may not have an autoimmune aetiology.
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 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.
Protocol administrative 
change
A protocol administrative change addresses changes to 
only logistical or administrative aspects 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.
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.
Sub-cohort
A group of subjects for whom specific study procedures 
are planned as compared to other subjects.
Subject
Term used throughout the protocol to denote an 
individual who has been contacted in order to participate 
or participates in the clinical study, either as a recipient of 
the vaccines or as a control.
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Subject number
A unique number identifying a subject, assigned to each 
subject consenting to participate in the study.
Treatment
Term used throughout the clinical study to denote a set of 
investigational products or marketed product(s) or 
placebo intended to be administered to a subject, 
identified by a unique number, according to the study 
randomisation or treatment allocation.
Treatment number
A number identifying a treatment to a subject, according 
to the study randomisation or treatment allocation.
Unsolicited adverse event
Any AE reported in addition to those solicited during the 
clinical study. Also any ‘solicited’ symptom with onset 
outside the specified period of follow-up for solicited 
symptoms will be reported as an unsolicited adverse 
event.
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1.
INTRODUCTION
1.1.
Background
1.1.1.
COPD: an introduction
Chronic Obstructive Pulmonary Disease (COPD), a common preventable disease, is 
characterised by persistent airflow limitation that is usually progressive and associated 
with an enhanced chronic inflammatory response in the airways and lungs to noxious 
particles of gases. The most important environmental risk factor for COPD is tobacco 
smoking, even though other factors, such as occupational exposure, may also contribute 
to the development of the disease [GOLD, 2014]. It is a multi-component disease with 
several contributory mechanisms, including airway inflammation, airway obstruction, 
mucociliary dysfunction and structural changes to the airways [American Thoracic 
Society and European Respiratory Society, 2004; GOLD, 2014]. Together, these
mechanisms manifest as an accelerated decline in lung function, with symptoms such as 
breathlessness on physical exertion, deteriorating health status and exacerbations.
The prevalence of COPD is increasing. Worldwide, COPD (GOLD grade II and above) 
affects 10.1±4.8% of the population ≥40 years of age [Buist, 2007]. COPD is most 
prevalent in adults/elderly with a history of smoking [Mannino, 2002]. It is the fourth
leading cause of chronic morbidity and mortality in the United States and the first in 
terms of disease burden in China. According to the World Health Organisation (WHO), 
COPD is expected to be the third cause of death worldwide by 2020 [Rabe, 2007].
Acute exacerbations and comorbidities contribute to the overall disease severity in 
individual COPD patients. An acute exacerbation of COPD (AECOPD) is defined as an 
acute event characterised by a worsening of the patient’s respiratory symptoms that is 
beyond normal day-to-day variations and leads to a change in medication [GOLD, 2014].
The rate at which AECOPD occur varies greatly between patients, with severe patients 
exacerbating more often. AECOPD additionally increase morbidity and mortality, lead to 
faster decline in lung function, poorer functional status, and have a significant impact on 
healthcare systems worldwide [Sapey, 2006]. Between 40-60% of medical expenditure 
for COPD is a direct consequence of AECOPD &Cazzola, 2008∋.
The lungs are known to be colonised with different strains of bacteria [Erb-
Downward, 2011]. In COPD patients, acquisition of new bacterial strains is believed to 
be an important cause of AECOPD [Sethi, 2002]. Although estimates vary widely, 
non-typeable Haemophilus influenzae (NTHi) appears to be the main bacterial pathogen 
associated with AECOPD (11-38%), followed by Moraxella catarrhalis (Mcat) (3-25%) 
and Streptococcus pneumoniae (4-9%) [Alamoudi, 2007; Bandi, 2003; Hutchinson, 2007; 
Ko, 2007; Larsen, 2009; Murphy, 2005; Papi, 2006; Rosell, 2005; Sethi, 2002; 
Sethi, 2008; Wilkinson, 2006].
1.1.2.
Current management of AECOPD
A wide range of pharmacologic (such as inhaled corticosteroids, bronchodilators, 
phosphodiesterase inhibitors, theophyllines, long-term antibiotics and mucolytics) and 
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non-pharmacologic (such as lung volume reduction surgery, home oxygen, ventilatory 
support and pulmonary rehabilitation) interventions exist to manage or treat COPD, some 
with a positive impact on the AECOPD rate. However, a need for further novel 
interventions remains because current approaches are not completely effective, even 
when targeted and used optimally.
Prevention of AECOPD is an insufficiently addressed medical need today, despite 
existing preventative therapies (bronchodilators such as long-acting muscarinic 
antagonists, long-acting beta agonists, methylxanthines, corticosteroids, 
phosphodiesterase-4 inhibitors and combination drugs), and is thought to remain so in the 
10 years horizon. 
The use of antibiotics is recommended by several guidelines [American Thoracic Society 
and European Respiratory Society, 2004] as a standard treatment for COPD patients with 
AECOPD showing purulent sputum. However, as not all patients have confirmed 
bacterial-related exacerbations, there is an inappropriate use of antibiotics, leading to the 
spread of antibiotic-resistant bacteria [Daubin, 2008]. Infections with multidrug-resistant 
bacteria have been linked to increases in morbidity, length of hospitalisation, health care 
cost and mortality [Nseir, 2008].
There is currently no vaccine indicated for prevention of AECOPD, even though 
influenza and pneumococcal vaccines are routinely recommended to COPD patients. The 
availability of a vaccine for the prevention of bacterial AECOPD could contribute 
significantly to the current management of COPD, in terms of reducing the risk of 
bacterial exacerbations as well as the inappropriate use of antibiotics.
1.1.3.
GSK Biologicals’ NTHi-Mcat investigational vaccine
GlaxoSmithKline (GSK) Biologicals is developing a new NTHi-Mcat investigational 
vaccine against diseases caused by NTHi and Mcat. The investigational vaccine that will 
be evaluated in the present study is an adjuvanted multi-component vaccine consisting of 
conserved surface proteins from NTHi and Mcat. Three NTHi proteins have been 
selected: Protein D (PD), as a free recombinant protein and Protein E (PE) and PilA 
protein, as a recombinant fusion protein named PE-PilA. The selected Mcat antigen is the 
UspA2.
PD acts as a glycerophosphodiesterase and is involved in the adhesion and invasion via 
phosphorylcholine decoration of bacterial membrane’s components. Passive transfer of 
anti-PD sera induces protection in the NTHi chinchilla otitis media model [Novotny, 
2006], as well as vaccination with PD induces protection in the mouse nasopharyngeal 
colonisation model [Forsgren, 2008].
During the infection process, PE is involved in the adhesion of the bacteria to human 
respiratory and mucosal cells and in the resistance to human complement, a key 
component of the innate immune system. PilA is involved in bacterial biofilm formation 
and in the adhesion to human cells mechanism. Anti-PilA antibodies were shown to 
strongly reduce biofilm formation, in vitro and in vivo in preclinical animal models 
[Jurcisek, 2007]. It was demonstrated that antibodies against PE and PilA strongly 
reduces nasopharyngeal colonisation in mice and/or otitis media in a chinchilla model 
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&Ronander, 2009; Jurcisek, 2007; Novotny, 2009; GSK unpublished data∋. Preclinical 
experiments demonstrated that even if PE and PilA are expressed as a fusion protein 
(PE-PilA), the biological activities of elicited antibodies against PE and PilA are kept 
[GSK unpublished data].
UspA2 is a putative autotransporter macromolecule and is a vitronectin-binding protein. 
UspA2 seems to be involved in the ability of Mcat to resist to the bactericidal activity of 
normal human serum [Attia, 2005]. UspA2 has been shown to induce cross-bactericidal 
antibodies production and cross-protection in a mouse lung colonisation model 
[Chen, 1996].
The target population of GSK NTHi-Mcat vaccine are COPD patients, which are often 
elderly, who are known to have a weakened immune response due to functional defects 
and altered frequencies of innate and adaptive immune cells, with impaired generation of 
long-term immune memory (immunosenescence) &Weinberger, 2008∋. Moreover, the 
immune response of COPD patients has been suggested to be disturbed both locally and 
systemically. Using an adjuvant is thought to help to induce a higher and longer-lasting 
immune response. 
Several formulations of a vaccine containing the NTHi antigens (10 or 30 μg) either 
non-adjuvanted or combined with different adjuvants (aluminium [Al], adjuvant system 
[AS]01E and AS04C) were already evaluated in two previous Phase I clinical trials 
(NTHI-002 in healthy adults 18-40 years old and NTHI-003 in current and former healthy 
smokers 50-70 years old). The investigational vaccines were well-tolerated, with an 
acceptable safety and reactogenicity profile. These studies allowed the dose selection of 
the NTHi antigens (i.e. 10 μg) and the adjuvant system (i.e. AS01E) to be used in the 
current study.
Refer to the current Investigator Brochure (IB) for information regarding the completed
pre-clinical and clinical (NTHi) studies of the NTHi-Mcat investigational vaccine.
1.2.
Rationale for the study and study design
1.2.1.
Rationale for the study
The purpose of this new Phase I study is to evaluate the safety, reactogenicity and 
immunogenicity of the NTHi-Mcat investigational vaccine, first in healthy young adults 
(18-40 years old) with a non-adjuvanted formulation and secondly in adults 50–70 years 
old having a significant smoking history (% 10 pack-years) with two adjuvanted
formulations. The investigational vaccines will be administered according to a 
0, 2 months schedule. Saline placebo will be used as control.
As the prevalence of COPD increases with age and as age has an influence on both the 
immunogenicity and reactogenicity of a vaccine, subjects 50–70 years old will be 
enrolled in Step 2 of this study. As cigarette smoking is the most commonly encountered 
risk factor for COPD, adults with a smoking history of at least 10 pack-years have been 
selected in order to immunologically match the COPD population as much as possible. 
Literature data indeed suggest that alterations of the immune system start early on in 
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smokers, before the COPD disease is recognised &Barcelo, 2008; Droemann, 2005; 
Takanashi, 1999∋.
1.2.2.
Rationale for the study design
As the UspA2 antigen has never been administered to human, healthy young adults will 
be enrolled and vaccinated with a non-adjuvanted vaccine prior to vaccinate adults 50-70 
years old with adjuvanted formulations. The study will hence follow a staggered design 
with two steps:
!
Step 1 will include 30 healthy adults 18–40 years old either receiving a 
non-adjuvanted (plain) vaccine containing 10 μg of PD, 10∀g of PE-PilA and 10∀g 
of UspA2, or a placebo control (15/group).
!
Step 2 will include 90 healthy adults 50–70 years old with a smoking history of at 
least 10 pack-years, either receiving placebo control, or one of two 
AS01E-adjuvanted formulations, i.e. 10 μg of PD, 10 μg of PE-PilA and 10 μg of 
UspA2 (Group 10-10-10-AS) or 10 μg of PD, 10 μg of PE-PilA and 3.3 μg of 
UspA2 (Group 10-10-3-AS) (30/group).
Moving to Step 2 or administration of vaccine Dose 2 within a step will be conditional on 
the favourable outcome of an evaluation of safety data obtained up to 7 days after 
administration of (a) previous vaccine dose(s) by an internal Safety Review Committee
(iSRC).
1.2.3.
Rationale for the use of placebo
The placebo group (saline solution) is included in the NTHI MCAT-001 study as a 
control for both safety and immunogenicity assessments.
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1.3.
Benefit/Risk Assessment
Please refer to the current IB for the summary of potential risks and benefits of the 
NTHi-Mcat investigational vaccine.
The following section outlines the risk assessment and mitigation strategy for this study 
protocol:
1.3.1.
Risk Assessment
Important 
Potential/Identified Risk
Data/Rationale for Risk
Mitigation Strategy
NTHi-Mcat investigational vaccine
Theoretical risk of acquiring 
a vaccine-induced 
autoimmune disease after 
vaccination
No confirmed signals related to 
this potential risk have been 
identified during the preclinical 
and clinical programs so far 
(data from two studies using 
NTHi vaccines: NTHI-002 (non-
adjuvanted formulations) and 
NTHI-003 (adjuvanted and 
non-adjuvanted formulations).
Close monitoring of potential 
immune-mediated diseases in 
clinical development programs 
using adjuvants systems. The 
potential risk of events of 
possible autoimmune aetiology 
to occur is mentioned in the 
Informed Consent Form (ICF).
1.3.2.
Benefit Assessment
Benefits considerations include:
!
Contribution to the process of developing of a vaccine against AECOPD.
!
Medical evaluations/assessments associated with this study (i.e. physical 
examination, blood testing [haematology and biochemistry data], spirometry [only in 
Step 2]).
!
Early detection of COPD in heavy smokers or elderly.
!
Subjects with mild COPD/pulmonary obstruction may benefit from the vaccine (i.e. 
possible prevention of AECOPD caused by NTHi and/or Mcat).
1.3.3.
Overall Benefit/Risk Conclusion
Taking into account the measures taken to minimise risks to subjects participating in this 
study, the potential and/or known risks identified in association with the candidate 
NTHi-Mcat vaccines are justified by the anticipated benefits that may be afforded to 
patients for the prevention of AECOPD.
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2.
OBJECTIVES
2.1.
Primary objective
!
To evaluate the safety and reactogenicity profile of the NTHi-Mcat investigational 
vaccines.
Refer to Section 10.1 for the definition of the primary endpoints.
2.2.
Secondary objective
!
To evaluate the humoral and cellular immune response of the NTHi-Mcat 
investigational vaccines.
Refer to Section 10.2 for the definition of the secondary endpoints.
2.3.
Tertiary objective
!
To collect blood samples for assay development/validation and/or for 
evaluation/characterisation of the humoral and cellular immune responses to 
components of either the NTHi-Mcat investigational vaccines and/or of other 
respiratory pathogens.
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3.
STUDY DESIGN OVERVIEW
3.1.
Study design
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.
Figure 1
Study design overview
!
Experimental design: Phase I, observer-blind, randomised, placebo-controlled, 
multi-centre study with two steps.
!
Duration of the study: For each subject, the study will last approximately 
15 months, from screening to study end.
#
Epoch 001: Primary starting at Screening Visit and ending at, and including 
Visit 6 (Day 90).
#
Epoch 002: Follow-up starting at Visit 7 (Day 210) and ending at Visit 8 
(Day 420).
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!
Study groups:
#
10-10-10: Approximately 15 subjects receiving two doses of the non-adjuvanted 
GSK Biologicals' NTHi-Mcat investigational vaccine containing 10 μg of PD, 
PE-PilA and UspA2 during Step 1 of the study.
#
PLACE1: Approximately 15 subjects receiving two doses of placebo 
(saline solution) during Step 1 of the study.
#
10-10-10-AS: Approximately 30 subjects receiving two doses of the 
AS01E-adjuvanted GSK Biologicals' NTHi-Mcat investigational vaccine 
containing 10 μg of PD, PE-PilA and UspA2 during Step 2 of the study.
#
10-10-3-AS: Approximately 30 subjects receiving two doses of the 
AS01E-adjuvanted GSK Biologicals' NTHi-Mcat investigational vaccine 
containing 10 μg of PD, 10∀g of PE-PilA, and 3.3 μg of UspA2 during Step 2 of 
the study.
#
PLACE2: Approximately 30 subjects receiving two doses of placebo 
(saline solution) during Step 2 of the study.
Table 1
Study groups and epochs foreseen in the study
Study groups
Number of 
subjects
Age (Min/Max)
Epochs
Step
Epoch 001
Epoch 002
10-10-10
15
18 - 40 years
x
x
1
PLACE1
15
18 - 40 years
x
x
1
10-10-10-AS
30
50 - 70 years
x
x
2
10-10-3-AS
30
50 - 70 years
x
x
2
PLACE2
30
50 - 70 years
x
x
2
Table 2
Study groups and treatment foreseen in the study
Treatment 
name
Vaccine/
product name
Study Groups
10-10-10
10-10-10-AS
10-10-3-AS
PLACE1
PLACE2
10-10-10/Plain
NTHi-Mcat 10-10-10
X
NaCl
10-10-10/AS01E
NTHi-Mcat 10-10-10
X
AS01E
10-10-3/AS01E
NTHi-Mcat 30-30-10 *
X
AS01E
Placebo
NaCl
X
X
* Vials containing 37.5 ∀g, 37.5 ∀g and 12.5 ∀g of freeze-dried PD, PE-PilA and UspA2, respectively, will be diluted in 
three volumes of AS01E (total of ∃1875 ∀L). 0.5 mL will be administered.
!
Control: Placebo control.
!
Vaccination schedules: 0, 2 months (i.e. at Visit 1 [Day 0] and Visit 4 [Day 60]).
!
Treatment allocation: Subjects will be allocated to a study group using a centralised 
randomisation system on internet (SBIR). SBIR will also be used for treatment 
allocation of the second dose. The randomisation algorithm will use a minimisation 
procedure accounting for centre at Step 1 and accounting for age (50-59 years or 
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60-70 years), for smoking status (current or former smokers), for centre and for 
forced expiratory volume in 1 second (FEV1) / forced vital capacity (FVC) (% 0.7 or 
< 0.7) at Step 2.
!
Blinding: Observer-blind.
Table 3
Blinding of study epochs
Study Epochs
Blinding
Epoch 001
observer-blind
Epoch 002
observer-blind
!
Sampling schedule:
#
Blood samples for safety (haematology/ biochemistry) will be collected from all 
subjects at Screening Visit (pre-Day 0), at Visit 1 (Day 0), Visit 2 (Day 7), Visit 
4 (Day 60), Visit 5 (Day 67), Visit 7 (Day 210) and at Visit 8 (Day 420).
#
Blood samples for immunogenicity will be collected from all subjects for 
humoral immunity at Visit 1 (Day 0), Visit 3 (Day 30), Visit 4 (Day 60), Visit 6 
(Day 90), Visit 7 (Day 210) and at Visit 8 (Day 420), and from a sub-cohort of 
subjects for cell-mediated immunity (CMI) at Visit 1 (Day 0), Visit 4 (Day 60),
Visit 6 (Day 90), Visit 7 (Day 210) and at Visit 8 (Day 420).
!
Type of study: Self-contained.
!
Data collection: Electronic Case Report Form (eCRF).
!
Safety monitoring during vaccination period: Safety evaluations by the Safety 
Review Team (SRT) (blinded) and by an iSRC (unblinded) will be performed. Refer 
to Section 8.10 for detailed description of holding rules and safety monitoring.
3.2.
Safety precautions
3.2.1.
Details of the staggered design of the study
This study will be conducted following a staggered design with two steps:
!
Step 1: Vaccination of ~30 subjects randomised into the groups 10-10-10 and 
PLACE1 (1:1).
!
Step 2: Vaccination of ~90 subjects randomised into the groups 10-10-10-AS, 
10-10-3-AS and PLACE2 (1:1:1).
Please refer to Section 8.10 for detailed information about safety evaluations in this 
study.
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3.2.2.
Vaccination
In Step 1, for each of the vaccine doses (Dose 1 and Dose 2), all subjects will preferably 
be vaccinated within 2 weeks.
Limited vaccination
For Step 1, vaccination will be limited to 6 subjects/ day during the first three days for 
each vaccine dose. These subjects are to be vaccinated sequentially, leaving sufficient 
time for close observation for a minimum of 60 minutes prior to proceeding to the 
vaccination of the next subject. As soon as three days have passed and at least 12 subjects 
have been vaccinated, the remaining subjects from Step 1 can be vaccinated without 
further limitation.
Vaccination without limitation
After vaccination day 3 in Step 1 (see limited vaccination), and for all subjects in Step 2, 
there won’t be a limitation in the number of vaccinees per day nor in the timing between 
vaccinations of each subject. All subjects will be closely observed for a minimum of 60 
minutes after vaccination (Figure 2).
4.
STUDY COHORT
4.1.
Number of subjects/centres
This will be a multi-centre study.
There will be five study groups, three of which will receive an investigational 
NTHi-Mcat vaccine formulation and two placebo groups. The target is to enrol 
approximately 30 eligible subjects 18–40 years old in Step 1 (~15/group) and 
approximately 90 eligible subjects 50–70 years old in Step 2 (~30/group).The total target 
number of subjects is approximately 120 (see also Table 1).
Please refer to Section 10.3 for a detailed description of the criteria used in the 
determination of sample size.
Approximately 50% of the subjects in each group of Step 2 will be part of a sub-cohort 
for CMI analysis. Subjects will be selected based on the enrolment order, i.e. the first 
50% of the participants (approximately the first 15 subjects/group) will be enrolled in 
the sub-cohort for CMI. An additional blood sample for CMI analysis will be taken from 
those subjects at each of the CMI blood sampling time points (i.e. Day 0, Day 60, 
Day 90, Day 210 and Day 420). (Amended 16 March 2016)
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Table 4
Sub-cohorts for CMI
Sub-cohort name
Description
Estimated number of subjects
in Step 2
CMI
An additional blood sample will be taken from about 
50% of subjects in each group of Step 2 for CMI 
analysis
~15/ group 
~45 in total
CMI: cell-mediated immunity
4.2.
Inclusion criteria for enrolment
Deviations from inclusion criteria are not allowed because they can potentially jeopardise 
the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential.
4.2.1.
Healthy adults 18-40 years old (Step 1)
All subjects must satisfy ALL the following criteria at study entry:
!
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).
!
A male or female between, and including, 18 and 40 years of age at the time of the 
Screening Visit.
!
Written informed consent obtained from the subject.
!
Healthy subjects without acute or chronic, clinically significant pulmonary, 
cardiovascular, hepatic or renal functional abnormality, as determined by physical 
examination or laboratory screening tests.
!
Female subjects of non-childbearing potential may be enrolled in the study.
#
Non-childbearing potential is defined as pre-menarche, hysterectomy, 
ovariectomy or post-menopause.
Please refer to the glossary of terms for the definition of menarche and menopause.
!
Female subjects of childbearing potential may be enrolled in the study, if the subject:
#
has practiced adequate contraception for 30 days prior to vaccination, and
#
has a negative pregnancy test on the day of vaccination, and
#
has agreed to continue adequate contraception during the entire treatment period 
and for 2 months after completion of the vaccination series.
Please refer to the glossary of terms for the definition of adequate contraception.
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4.2.2.
Current and former smokers 50-70 years old (Step 2)
All subjects must satisfy ALL the following criteria at study entry:
!
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).
!
A male or female between, and including, 50 and 70 years of age at the time of the 
Screening Visit.
!
Written informed consent obtained from the subject.
!
Subjects without medical history, clinical finding or laboratory finding which in the 
opinion of the investigator could pose a safety concern or interfere with the protocol.
!
Current or former smoker with a cigarette smoking history ≥ 10 pack-years.
Please refer to the glossary of terms for the definitions of pack-years and of current 
and former smoker.
!
Female subjects of non-childbearing potential may be enrolled in the study.
#
Non-childbearing potential is defined as pre-menarche, hysterectomy, 
ovariectomy or post-menopause. 
Please refer to the glossary of terms for the definition of menarche and menopause.
!
Female subjects of childbearing potential may be enrolled in the study, if the subject:
#
has practiced adequate contraception for 30 days prior to vaccination, and
#
has a negative pregnancy test on the day of vaccination, and
#
has agreed to continue adequate contraception during the entire treatment period 
and for 2 months after completion of the vaccination series. 
Please refer to the glossary of terms for the definition of adequate contraception.
4.3.
Exclusion criteria for enrolment
Deviations from exclusion criteria are not allowed because they can potentially jeopardise 
the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential.
4.3.1.
Healthy adults 18-40 years old (Step 1)
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:
!
Use of any investigational or non-registered product (drug or vaccine) other than the 
study vaccines within 30 days preceding the first dose of study vaccine, or planned 
use during the study period.
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!
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).
!
Planned administration/ administration of a vaccine not foreseen by the study 
protocol in the period starting 30 days before the first dose and ending 30 days after 
the last dose of vaccine, with the exception of any influenza vaccine which may be 
administered ≥ 15 days preceding or following any study vaccine dose.
!
Previous vaccination with any vaccine containing NTHi and/or Mcat antigens.
!
Chronic administration (defined as more than 14 days in total) of 
immunosuppressants or other immune-modifying drugs within 6 months prior to the 
first vaccine dose. For corticosteroids, this will mean prednisone ≥20 mg/day, or 
equivalent. Only topical steroids are allowed.
!
Administration of long-acting immune-modifying drugs at any time during the study 
period (e.g. infliximab).
!
Administration of immunoglobulins and/or any blood products within the 3 months 
preceding the first dose of study vaccine or planned administration during the study 
period.
!
Any confirmed or suspected immunosuppressive or immunodeficient condition, 
based on medical history and physical examination (no laboratory testing required).
!
History of or current autoimmune disease.
!
Laboratory evidence of clinically significant haematological (complete blood cell 
count [RBC, WBC], WBC differential count [lymphocytes, neutrophils and 
eosinophils], platelets count or haemoglobin level) and biochemical (alanine 
aminotransferase [ALT], aspartate aminotransferase [AST] or creatinine) 
abnormalities as per the opinion of the investigator.
!
Acute disease and/or fever at the time of enrolment.
#
Fever is defined as temperature % 37.5°C for oral or axillary route. The preferred 
route for recording temperature in this study will be oral.
#
Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory 
infection) without fever may, be enrolled at the discretion of the investigator.
!
Current alcoholism and/or drug abuse.
Please refer to the glossary of terms for the definition of alcoholism.
!
History of or current condition preventing intramuscular injection as bleeding or 
coagulation disorder.
!
Malignancies within previous 5 years (excluding non-melanoma skin cancer) or 
lymphoproliferative disorders.
!
Pregnant or lactating female.
!
Female planning to become pregnant or planning to discontinue contraceptive 
precautions.
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!
Any other condition that the investigator judges may interfere with study findings.
4.3.2.
Current or former smokers 50-70 years old (Step 2)
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:
!
Use of any investigational or non-registered product (drug or vaccine) other than the 
study vaccines within 30 days preceding the first dose of study vaccine, or planned 
use 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).
!
Planned administration/ administration of a vaccine not foreseen by the study 
protocol in the period starting 30 days before the first dose and ending 30 days after 
the last dose of vaccine, with the exception of any influenza or pneumococcal 
licensed vaccine which may be administered ≥ 15 days preceding or following any 
study vaccine dose.
!
Previous vaccination with any vaccine containing NTHi and/or Mcat antigens.
!
Chronic administration (defined as more than 14 days in total) of 
immunosuppressants or other immune-modifying drugs within 6 months prior to the 
first vaccine dose. For corticosteroids, this will mean prednisone ≥20 mg/day, or 
equivalent. Only topical steroids are allowed.
!
Administration of long-acting immune-modifying drugs at any time during the study 
period (e.g. infliximab).
!
Administration of immunoglobulins and/or any blood products within the 3 months 
preceding the first dose of study vaccine or planned administration during the study 
period.
!
Any confirmed or suspected immunosuppressive or immunodeficient condition, 
based on medical history and physical examination (no laboratory testing required).
!
History of or current autoimmune disease.
!
Post-bronchodilator FEV1 < 80% of predicted normal value.
!
Diagnosed with a respiratory disorder (e.g. asthma, COPD, sarcoidosis, tuberculosis, 
bronchiectasis, lung fibrosis, pulmonary embolism, pneumothorax, or 
physician-confirmed lung cancer). Please note that subjects with mild pulmonary 
obstruction (i.e. FEV1/ FVC ratio < 0.7 with FEV1 ≥ 80% of normal predicted values 
[GOLD grade 1]) can be enrolled.
!
Has contraindication for spirometry testing (such as recent eye surgery, recent 
thoracic or abdominal surgery procedures, unstable cardiovascular status, recent 
myocardial infection or pulmonary embolism).
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!
Laboratory evidence of clinically significant* haematological (complete blood cell 
count [RBC, WBC], WBC differential count [lymphocytes, neutrophils and 
eosinophils], platelets count or haemoglobin level) and biochemical (ALT, AST or 
creatinine) abnormalities.
* As the subjects are adult or elderly, current or former smokers, various pre-existing 
laboratory abnormalities might be detected. The investigator should use his clinical 
judgement to decide which ones are clinically significant.
!
Acute disease and/or fever at the time of enrolment.
#
Fever is defined as temperature % 37.5°C for oral or axillary route. The preferred 
route for recording temperature will be oral.
#
Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory 
infection) without fever may be enrolled at the discretion of the investigator.
!
Current alcoholism and/or drug abuse.
Please refer to the glossary of terms for the definition of alcoholism.
!
Has significant disease (including significant neurological or psychological 
disorders), in the opinion of the investigator, likely to interfere with the study and/or 
likely to cause death within the study duration.
!
History of or current condition preventing intramuscular injection as bleeding or 
coagulation disorder.
!
Malignancies within previous 5 years (excluding non-melanoma skin cancer) or 
lymphoproliferative disorders.
!
Pregnant or lactating female.
!
Female planning to become pregnant or planning to discontinue contraceptive 
precautions.
!
Any other condition that the investigator judges may interfere with study findings.
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:
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!
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 informed consent must be obtained from each subject prior to 
participation in the study.
GSK Biologicals will prepare a model ICF which will embody the ICH GCP and GSK 
Biologicals required elements. While it is strongly recommended that this model ICF is to 
be followed as closely as possible, the informed consent requirements given in this 
document are not intended to pre-empt any local regulations which require additional 
information to be disclosed for informed consent to be legally effective. Clinical 
judgement, local regulations and requirements should guide the final structure and 
content of the local version of the ICF.
The investigator has the final responsibility for the final presentation of the ICF, 
respecting the mandatory requirements of local regulations. The ICF generated by the 
investigator with the assistance of the sponsor’s representative must be acceptable to 
GSK Biologicals and be approved (along with the protocol, and any other necessary 
documentation) by the IRB/IEC.
5.2.
Subject identification and randomisation of treatment
5.2.1.
Subject identification
Subject identification numbers will be assigned sequentially to the subjects who have 
consented to participate in the study, according to the range of subject identification 
numbers allocated to each study centre.
5.2.2.
Randomisation of treatment
5.2.2.1.
Randomisation of supplies
Two randomisation lists corresponding to each step of the study will be generated at 
GSK Biologicals using MATerial Excellence (MATEX), a SAS® (Statistical Analysis 
System) programme developed by GSK Biologicals and will be used to number the 
vaccines. A block randomisation scheme will be used.
5.2.2.2.
Treatment allocation to the subject
The treatment numbers will be allocated by dose.
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5.2.2.2.1.
Study group and treatment number allocation
The target will be to enrol approximately 120 eligible subjects who will be randomly 
assigned per step:
!
Step 1: two study groups in a (1:1) ratio (approximately 15 subjects per group).
!
Step 2: three study groups in a (1:1:1) ratio (approximately 30 subjects per group).
Allocation of the subject to a study group at the investigator site will be performed using 
SBIR.
Subjects will be minimised for centre at Step 1. At Step 2, subjects will be minimised for 
age (50-59 years or 60-70 years), for smoking status (current or former smokers), for 
centre and for forced expiratory volume in 1 second (FEV1) / forced vital capacity (FVC) 
(% 0.7 or < 0.7). Minimisation factors will have equal weight in the minimisation 
algorithm.
As several minimisation factors have been defined for the treatment allocation at 
Step 2, it was decided at the design phase not to minimise for the CMI group allocation. 
This wouldn’t be feasible from an implementation point of view. (Amended 16 March 
2016)
After obtaining the signed and dated ICF from the subject (at Screening Visit) and after 
having checked the eligibility of the subject, the dedicated study staff will access SBIR 
(at Visit 1). Upon providing the information for each minimisation factor and the subject 
identification number, the randomisation system will determine the study group and will 
provide the treatment number to be used for the first dose. This treatment number will be 
used by the dedicated staff member for administration of the vaccine.
The number of each administered treatment must be recorded in the eCRF on the Vaccine 
Administration screen.
When SBIR is not available, please refer to the SBIR user guide or the Study Procedures 
Manual (SPM) for specific instructions.
5.2.2.2.2.
Treatment number allocation for subsequent doses
For the second dose, the dedicated study staff 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, and immunogenicity) will 
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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.
An analysis of Epoch 001 will be done on as cleaned as possible data up to Visit 6 
(Day 90) (please refer to Section 10.8.1 for more information). At this point, the GSK 
statistician will be unblinded (i.e. will have access to the individual subject treatment 
assignment). The remaining GSK study personnel (excluding the iSRC members) will 
stay blinded (i.e. will not have access to the individual subject treatment assignment) until 
study end. It is possible however, due to the limited sample size, that unblinding occurs 
for a few subjects having a specific adverse event (AE) or serious AE (SAE) (e.g. an 
AE/SAE occurring only in a single group). Therefore anyone having access to the 
analysis of Epoch 001 could become unblinded regarding those specific cases.
The site staff will work in an observer-blind manner during the entire study. As the 
vaccines in this study are of different appearance (see also Table 14), two teams of study 
personnel will be set up:
!
A team of unblinded personnel (responsible for the reception, preparation and 
administration of the vaccines).
!
A team of blinded personnel (responsible for the clinical safety evaluation of the 
subjects).
Please refer to the SPM for more information on vaccine preparation and administration 
while maintaining the blind.
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.
The laboratory personnel in charge of CMI testing may be unblinded for treatment (active 
treatment versus placebo) due to the observed response in the CMI samples of certain 
subjects.
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.
Refer to Section 8.10 for more information on safety holding rules and safety evaluation 
by iSRC.
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5.5.
Outline of study procedures
Table 5
List of study procedures for healthy adults 18-40 years old (Step 1)
Epoch
Epoch 001
Epoch 002
Type of contact
Screening 
Visit
Visit 
1
Visit 
2
Visit 
3
Visit 
4
Visit 
5
Visit 
6
Visit 
7
Visit 
8
Time points
pre-Day 0 Day 0 Day 7 Day 
30
Day 
60
Day 
67
Day 
90
Day 
210
Day 
420
Sampling time points
Screening
Pre
Post-Vacc I 
Post-Vacc II
Informed consent
●
Check inclusion/exclusion criteria
●(d)
O
Collect demographic data
●
Medical history
O(d)
●
Measure/record height and weight
●
●
Physical examination
●(d, e)
O
O
O
O
O
O
O
O
Urine pregnancy test (a)
●
●
●
Check contraindications
O
O
Pre-vaccination body temperature
●
●
Treatment number allocation (b)
●
●
Blood sampling for safety assessment 
(∃5.5 mL)
●(d)
●
●
●
●
●
●
Blood sampling for antibody determination and 
assay development (∃20 mL)
●
●
●
●
●
●
Vaccine administration
●
●
Distribution of Diary Cards (c)
O
O
O
O
Return of Diary Cards
O
O
O
O
Diary Card transcription by investigator
●
●
●
●
Recording of AEs
●
●
●
●
●
●
Recording of SAEs
●(f)
●
●
●
●
●
●
●
●
Recording of pIMDs
●
●
●
●
●
●
●
●
Recording of pregnancies
●
●
●
●
●
●
●
●
Record concomitant medication/vaccination (g)
●
●
●
●
●
●
●
●
Record intercurrent medical conditions requiring 
medical attention
●
●
●
●
●
●
●
●
Screening conclusion
●
Study conclusion
●
Note: The double-line borders following Day 90 and Day 420 indicates the statistical analyses which will be performed 
on all data (i.e. data that are as clean as possible) obtained up to Day 90 and Day 420, respectively.
Vacc: Vaccination; AEs: Adverse events; SAEs: Serious adverse events; pIMDs: potential immune-mediated disease.
● is used to indicate a study procedure that requires documentation in the individual eCRF.
O is used to indicate a study procedure that does not require documentation in the individual eCRF.
(a) A urine pregnancy test will be performed only for women of childbearing potential.
(b)Treatment number allocation with randomisation at Visit 1 (Day 0); treatment number allocation without 
randomisation at Visit 4 (Day 60).
(c) Distribution of 2 Diary Cards after each vaccination:
–
a 1st one distributed on the day of vaccination for recording of solicited and unsolicited AEs and concomitant 
medications/ products and vaccinations from Day 0 to Day 6 after each vaccination.
–
a 2nd one distributed on the 7 day post-vaccination visit for recording of unsolicited AEs and concomitant 
medications/ products and vaccinations from Day 7 to Day 29 after each vaccination.
(d) Screening evaluations may be completed 1 to 28 days before Day 0. Site staff should allow sufficient time between 
the Screening and Visit 1 to receive and review screening safety laboratory test results. If a delay occurs such that the 
interval between Screening and the Visit 1 vaccination exceeds 28 days, a re-screening visit should be scheduled 
before Visit 1 during which blood sample collection for safety laboratory assessment must be repeated; an interim 
medical history and physical examination must be obtained and inclusion / exclusion criteria must be re-reviewed.
(e) Complete physical examination including vital signs.
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(f) From Screening to Visit 1, only those SAEs that are considered related to study participation or to concomitant use of 
GSK products or any fatal events need to be recorded. GSK products or any fatal event need to be recorded.
(g) Concomitant medication products/vaccination as indicated in Section 6.6.1 need to be recorded.
Table 6
List of study procedures for current or former smokers 50-70 years 
old (Step 2) (Amended 16 March 2016)
Epoch
Epoch 001
Epoch 002
Visit 6
Screening 
Visit
Visit 
1
Visit 
2
Visit 
3
Visit 
4
Visit 
5
Visit 
6
Visit 
7
Visit 
8
Time points
pre-Day 0 Day 
0
Day 
7
Day 
30
Day 
60
Day 
67
Day 
90
Day 
210 
Day 
420 
Sampling time points
Screening Pre
Post-Vacc I
Post-Vacc II
Informed consent
●
Check inclusion/exclusion criteria
●(e)
O
Collect demographic data
●
Medical history
O(e)
●
Smoking status
●
●
●
Smoking exposure history
●
Measure/record height and weight
●
●
Spirometry (i)
●
●
Physical examination
●(e, f)
O
O
O
O
O
O
O
O
Urine pregnancy test (a)
●
●
●
Check contraindications
O
O
Pre-vaccination body temperature
●
●
Treatment number allocation(b)
●
●
Blood sampling for safety assessment 
(∃5.5 mL)
●(e)
●
●
●
●
●
●
Blood sampling for antibody determination and assay 
development (∃20 mL)
●
●
●
●
●
●
Blood sampling for CMI response (∃20 mL)(c)
●
●
●
●
●
Vaccine administration
●
●
Distribution of Diary Cards(d)
O
O
O
O
Return of Diary Cards
O
O
O
O
Diary Card transcription by investigator
●
●
●
●
Recording of AEs
●
●
●
●
●
●
Recording of SAEs
●(g)
●
●
●
●
●
●
●
●
Recording of pIMDs
●
●
●
●
●
●
●
●
Recording of pregnancies
●
●
●
●
●
●
●
●
Record concomitant medication/vaccination(h)
●
●
●
●
●
●
●
●
Record intercurrent medical conditions requiring 
medical attention
●
●
●
●
●
●
●
●
Screening conclusion
●
Study conclusion
●
Note: The double-line borders following Day 90 and Day 420 indicates the statistical analyses which will be performed 
on all data (i.e. data that are as clean as possible) obtained up to Day 90 and Day 420, respectively.
Vacc: Vaccination; CMI: Cell-mediated immunity; AEs: Adverse events; SAEs: Serious adverse events; pIMDs:
potential immune-mediated disease.
● is used to indicate a study procedure that requires documentation in the individual eCRF.
O is used to indicate a study procedure that does not require documentation in the individual eCRF.
(a) A urine pregnancy test will be performed only for women of childbearing potential.
(b) Treatment number allocation with randomisation at Visit 1 (Day 0); treatment number allocation without 
randomisation at Visit 4 (Day 60).
(c) Only for subjects belonging to the CMI sub-cohort. 
(d)Distribution of 2 Diary Cards after each vaccination:
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–
a 1st one distributed on the day of vaccination for recording of solicited and unsolicited AEs and concomitant 
medications/ products and vaccinations from Day 0 to Day 6 after each vaccination.
–
a 2nd one distributed on the 7 day post-vaccination visit for recording of unsolicited AEs and concomitant 
medications/ products and vaccinations from Day 7 to Day 29 after each vaccination.
(e) Screening evaluations may be completed 1 to 28 days before Day 0. Site staff should allow sufficient time between 
the Screening and Visit 1 to receive and review screening safety laboratory test results. If a delay occurs such that the 
interval between Screening and the Visit 1 vaccination exceeds 28 days, a re-screening visit should be scheduled 
before Visit 1 during which blood sample collection for safety laboratory assessment must be repeated; an interim 
medical history and physical examination must be obtained and inclusion / exclusion criteria must be re-reviewed.
(f) Complete physical examination including vital signs.
(g) From Screening to Visit 1, only those SAEs that are considered related to study participation or to concomitant use 
of GSK products or any fatal events need to be recorded. GSK products or any fatal event need to be recorded.
(h) Concomitant medication products/vaccination as indicated in Section 6.6.1 need to be recorded.
(i) This test should be repeated on another day if the first attempt doesn’t meet quality requirements as 
described by ATS/ERS standards (Miller, 2005).
Table 7
Intervals between study visits
Interval
Optimal length of interval (a)
Allowed interval
Screening (Pre-Day 0) 
(
Visit 1 (Day 0)
5 days
1 – 28 days (b)
Visit 1 (Day 0) 
(
Visit 2 (Day 7)
7 days
7 - 9 days
Visit 1 (Day 0)
(
Visit 3 (Day 30)
30 days
30 - 40 days
Visit 1 (Day 0)
(
Visit 4 (Day 60)
60 days
60 - 70 days
Visit 4 (Day 60)
(
Visit 5 (Day 67)
7 days
7 - 9 days
Visit 4 (Day 60)
(
Visit 6 (Day 90)
30 days
30 - 40 days
Visit 1 (Day 0)
(
Visit 7 (Day 210)
210 days
210 - 230 days
Visit 1 (Day 0)
(
Visit 8 (Day 420)
420 days
420 - 440 days
Note: visits out of range can lead to elimination from ATP analyses.
(a) Whenever possible the investigator should arrange study visits within this interval.
(b)Screening evaluations may be completed 1 to 28 days before Day 0. Site staff should allow sufficient time between 
the Screening and Day 0 visits to receive and review screening safety laboratory test results. If a delay occurs such 
that the interval between Screening and the Day 0 vaccination exceeds 28 days, a re-screening visit should be 
scheduled before Visit 1 during which blood sample collection for safety laboratory assessment must be repeated; an 
interim medical history and physical examination must be obtained and inclusion / exclusion criteria must be 
re-reviewed.
5.6.
Detailed description of study procedures
5.6.1.
Informed consent
The signed informed consent of the subject must be obtained before study participation. 
Refer to Section 5.1 for the requirements on how to obtain informed consent.
5.6.2.
Check inclusion and exclusion criteria
Check all inclusion and exclusion criteria as described in Sections 4.2 and 4.3 before 
enrolment.
5.6.3.
Collect demographic data
Record demographic data such as year of birth, gender and race (ethnicity and geographic 
ancestry) in the subject’s eCRF.
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5.6.4.
Medical history
Obtain the subject’s medical history by interview and/or review of the subject’s medical 
records and record any pre-existing conditions or signs and/or symptoms present in a 
subject prior to the first study vaccination in the eCRF.
5.6.5.
Smoking status
For all subjects in Step 2, record smoking status (current or former smoker) in the 
subject’s eCRF.
Please refer to the glossary of terms for the definitions of current and former smoker.
5.6.6.
Smoking exposure history
For all subjects in Step 2, smoking history will be obtained by means of a 
self-administered questionnaire (which will be part of the ATS-DLD-78A questionnaire)
provided to the subjects, in which they will give answers about their smoking history,
including duration (number of years) and number of cigarettes smoked.
Please refer to the SPM for more details on questionnaire.
From the information obtained via the questionnaire, calculate the pack-years using the 
following calculation (also refer to the glossary of terms for the definitions of pack-years) 
Please note that pipe and/or cigar use should not be used to calculate pack-year history:
Total pack-years = Average no. cigarettes smoked / day x no. years of smoking
20
All data will be recorded in the subject’s eCRF.
5.6.7.
Measure/record height and weight
Measure height and weight of the subject and record the data in the ‘physical 
examination’ section of the eCRF.
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5.6.8.
Spirometry
For all subjects in Step 2, spirometry to assess FEV1 and FVC will be performed using 
techniques that meet American Thoracic Society (ATS)/European Respiratory Society 
(ERS) published standards [Miller, 2005].
Only certified study staff can perform spirometry assessment.
The spirometry test must be of good quality. If this is not the case, a re-test should be 
done. (Amended 16 March 2016)
The following measurements (best efforts)/ values will be used:
!
FVC, which is the total volume of air that a person exhales in a forced expiratory 
manoeuvre (the act of exhaling as hard and fast as possible after maximal 
inspiration), measured in litres. 
!
FEV1, which is the amount of air that a person breathes out during the first second of 
a forced expiratory manoeuvre, measured in litres. 
!
FVC predicted normal value.
!
FEV1 predicted normal value.
!
FEV1 % of predicted normal value.
!
The ratio of FEV1 to the FVC (FEV1/FVC).
If FEV1 < 80% of predicted normal values and/ or FEV1/ FVC ratio < 0.7 without 
bronchodilator, post-bronchodilator spirometry should also be performed.
The data will be directly transferred from the provider to GSK Biologicals.
Treatment of any abnormality observed during spirometry has to be performed according 
to local medical practice outside of this study or by referral to an appropriate health care 
provider.
5.6.9.
Physical examination
Perform a complete physical examination of the subject at the Screening Visit, including 
resting vital signs (systolic/diastolic blood pressure, heart rate and respiratory rate after at 
least 10 minutes of rest). Collected information needs to be recorded in the eCRF.
Physical examination at each study visit subsequent to the Screening Visit will be 
performed only if the subject indicates that there might be some underlying 
pathology(ies) or if deemed necessary by the investigator or delegate.
Treatment of any abnormality observed during physical examination has to be performed 
according to local medical practice outside this study or by referral to an appropriate 
health care provider.
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5.6.10.
Urine pregnancy test
Female subjects of childbearing potential are to have a urine pregnancy test prior to any 
study vaccine administration. The study vaccines may only be administered if the 
pregnancy test is negative.
Note: The urine pregnancy test must be performed even if the subject is menstruating at 
the time of the study visit.
5.6.11.
Check contraindications
Contraindications, warnings and precautions to vaccination must be checked at the 
beginning of each vaccination visit. Refer to Sections 6.5 for more details.
5.6.12.
Assess pre-vaccination body temperature
The oral or axillary 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.
If the subject has fever (fever is defined as a temperature % 37.5°C for oral or axillary 
route) on the day of vaccination, the vaccination visit will be rescheduled within the 
allowed interval for this visit (see Table 7).
5.6.13.
Study group and treatment number allocation
Study group and treatment number allocation will be performed as described in 
Section 5.2.2. The number of each administered treatment must be recorded in the eCRF.
5.6.14.
Blood sampling
Refer to the Module on Biospecimen Management in the SPM and to the Central 
Laboratory Manual for detailed instructions for the collection, handling and processing of 
blood samples.
5.6.14.1.
Blood sampling for safety assessment
Blood samples for safety assessment will be taken from all subjects during certain study 
visits as specified in Table 5 and Table 6 ‘List of study procedures’.
A volume of approximately 5.5 mL of whole blood should be drawn at each pre-defined 
time point.
When borderline abnormalities in haematology or biochemistry parameters (i.e. 
considered not clinically significant) are reported at Screening Visit, at least one re-test 
(at least one week after the first result) has to be done before Visit 1 to ensure that the 
abnormality is not due to an evolving medical condition.
Blood samples for safety assessment may be repeated during the course of the study at 
discretion of the investigator if medically indicated.
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5.6.14.2.
Blood sampling for antibody determination and assay development
Blood samples for antibody determination and assay development will be taken from all 
subjects during specific study visits as specified in Table 5 and Table 6.
A volume of approximately 20 mL of whole blood would be drawn at each pre-defined 
time point. After centrifugation, the serum should be stored at -20°C or colder until 
shipment. Refer to the SPM and to the central laboratory manual for more details on 
sample storage conditions.
5.6.14.3.
Blood sampling for CMI
Blood samples for CMI will be taken from the subjects in the sub-cohort for CMI
analysis, and for development of read-outs during certain study visits as specified in 
Table 6.
A volume of approximately 20 mL of whole blood should be drawn from all subjects 
included in the immunogenicity sub-cohort for CMI at each pre-defined time point. The 
blood should be stored at the investigator’s site at room temperature and it must not be 
centrifuged. Samples will be shipped at room temperature (20 to 25°C) to the designated 
laboratory for cell and plasma separation to be performed within 24 hours of collection.
5.6.15.
Vaccination
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 5 and Table 6).
The subjects will be observed closely for at least 60 minutes following the administration 
of the vaccine, with appropriate medical treatment readily available in case of 
anaphylaxis.
5.6.16.
Recording of AEs, SAEs, pregnancies and pIMDs
Refer to Section 8.3 for procedures for the investigator to record AEs, SAEs, pregnancies 
and pIMDs. Refer to Section 8.4 for guidelines on how to submit SAE, pregnancy and 
pIMD reports to GSK Biologicals.
The subjects will be instructed to contact the investigator immediately should they 
manifest any signs or symptoms they perceive as serious.
Diary Cards
!
After each vaccination, two Diary Cards will be provided to the subjects:
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#
The first Diary Card will be provided at the vaccination visit. On this Diary 
Card, the subject will record any solicited local/general AEs, any unsolicited 
AEs and all concomitant medications/ products and vaccinations during a 7-day 
follow-up period (i.e. on the day of vaccination and during the next 6 days). The 
subject will be instructed to return the completed diary card to the investigator at 
the next study visit (7 days post-vaccination).
#
The second Diary Card will be provided at the next study visit 
(7 days post-vaccination). On this Diary Card, the subject will record any 
unsolicited AEs and all concomitant medications/ products and vaccinations
from Day 7 to Day 29 after each vaccination (for 30-day follow-up period). The 
subject will be instructed to return the completed diary card to the investigator at 
the next study visit (30 days post-vaccination).
!
Collect and verify completed Diary Cards during discussion with the subject during 
each 7-days post-vaccination visit and during each 30-day post-vaccination visit.
!
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.
Refer to the SPM for more details on Diary Card completion guidelines.
5.6.17.
Check and record concomitant medication/vaccination and 
intercurrent medical conditions requiring medical attention
Concomitant medication/vaccination must be checked and recorded in the eCRF as 
described in Section 6.6.
Intercurrent medical conditions must be checked and recorded in the eCRF as described 
in Section 6.7.
5.6.18.
Study conclusion
The investigator will:
!
review data collected to ensure accuracy and completeness.
!
complete study conclusion screen in the eCRF.
5.7.
Biological sample handling and analysis
Please refer to the SPM and Central Laboratory Manual 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 
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tests, the maintenance or improvement of these tests, the development of new test 
methods, as well as making sure that new tests are comparable to previous methods 
and work reliably.
!
It is also possible that future findings may make it desirable to use the samples 
acquired in this study for future research, not described in this protocol. Therefore, 
all subjects in countries where this is allowed, will be asked to give a specific 
consent to allow GSK or a contracted partner to use the samples for future research. 
Future research will be subject to the laws and regulations in the respective countries 
and will only be performed once an independent Ethics Committee or Review Board 
has approved this research.
Information on further investigations and their rationale can be obtained from GSK 
Biologicals.
Any sample testing will be done in line with the consent of the individual subject.
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). 
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 or by the Central laboratory, 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. (Amended 16 March 
2016)
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5.7.2.
Biological samples
Table 8
Biological samples
Sample type
Quantity
Unit
Time point
Sub-cohort
Blood for safety assessment
∃5.5
mL
Screening Visit 
(pre-Day 0)
All screened subjects
Visit 1 (Day 0)
All enrolled subjects
Visit 2 (Day 7)
Visit 4 (Day 60)
Visit 5 (Day 67)
Visit 7 (Day 210)
Visit 8 (Day 420)
Blood for antibody determination and assay 
development
∃20
mL
Visit 1 (Day 0))
All enrolled subjects
Visit 3 (Day 30)
Visit 4 (Day 60)
Visit 6 (Day 90)
Visit 7 (Day 210)
Visit 8 (Day 420)
Blood for CMI response
∃20
mL
Visit 1 (Day 0))
Sub-cohort for CMI*
Visit 4 (Day 60)
Visit 6 (Day 90)
Visit 7 (Day 210)
Visit 8 (Day 420)
* Refer to Section 4.1 for sub-cohort description.
5.7.3.
Laboratory assays
Please refer to APPENDIX A for a detailed description of the assays performed in the 
study. Please refer to APPENDIX B for the address of the clinical laboratories used for 
sample analysis.
Haematology and biochemistry
Haematology and biochemistry assays for safety assessment will be performed in a 
central laboratory (refer to Table 9).
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Table 9
Haematology and biochemistry tests
System
Discipline
Component
Method
Scale
Laboratory**
Whole 
blood
Haematology
Leukocytes (White 
Blood Cells)
Per contract laboratory’s 
procedures
Quantitative
Central 
laboratory
Neutrophils*
Per contract laboratory’s 
procedures
Quantitative
Lymphocytes*
Per contract laboratory’s 
procedures
Quantitative
Basophils*
Per contract laboratory’s 
procedures
Quantitative
Monocytes*
Per contract laboratory’s 
procedures
Quantitative
Eosinophils*
Per contract laboratory’s 
procedures
Quantitative
Haemoglobin
Per contract laboratory’s 
procedures
Quantitative
Platelets
Per contract laboratory’s 
procedures
Quantitative
Erythrocytes (Red 
Blood Cells)
Per contract laboratory’s 
procedures
Quantitative
Serum
Biochemistry
Alanine 
Aminotransferase (ALT)
Per contract laboratory’s 
procedures
Quantitative
Central 
laboratory
Aspartate 
Aminotransferase (AST)
Per contract laboratory’s 
procedures
Quantitative
Creatinine
Per contract laboratory’s 
procedures
Quantitative
* For White Blood Cell (WBC) differential count.
** Refer to Table 25 for the laboratory address.
Humoral immune responses
Serological assays for the quantification of antibodies will be performed by ELISA at 
GSK Biologicals’ laboratory or in a laboratory designated by GSK Biologicals using 
standardised procedures (refer to Table 10).
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Table 10
Humoral Immunity (antibody determination) (Amended 16 March 
2016)
System
Component
Method
Kit / 
Manufacturer
Unit
Cut-off
Laboratory*
Serum
Anti-PD
ELISA
In house
EL.U/mL
153
GSK Biologicals**
Serum
Anti-PE
ELISA
In house
EL.U/mL 
8
GSK Biologicals**
Serum
Anti-PilA
ELISA
In house
EL.U/mL
7
GSK Biologicals**
Serum
Anti-UspA2
ELISA
In house
EL.U/mL
18
GSK Biologicals**
ELISA: Enzyme-Linked Immunosorbent Assay; EL.U/mL = ELISA unit per millilitre; 
* Refer to APPENDIX B for the laboratory addresses.
** GSK Biologicals laboratory refers to the Clinical Laboratory Sciences (CLS) Laboratories in Rixensart, Belgium; 
Wavre, Belgium or a designated laboratory.
Serum samples might also be used for development and validation of other assays to 
measure the immune response to components of either the NTHi-Mcat investigational 
vaccines and/or of other respiratory pathogens such as, but not limited to, serum 
bactericidal activity assay, anti-PD, -PE, -PilA, -UspA2 functional assays, 
immunochemistry assays for other immunoglobulin classes and/or for anti-IgG 
subclasses, and anti-AS01E assays. Hence, additional use and/or testing of serum samples 
may occur during the course of the study or after study completion in case these data 
should be required for accurate interpretation of the study results and/or for further 
research related to the vaccine and/ or the disease and/ or should such test(s) become 
available at GSK Biologicals’ laboratory or a laboratory designated by GSK Biologicals.
Cell-mediated immune responses
CMI assays will be performed at GSK Biologicals’ laboratory using standardised 
procedures (refer to Table 11). Plasma collected during the processing of peripheral blood 
mononuclear cells (PBMCs) will be stored for potential future analyses and/or for assay 
development purposes.
Table 11
Cell-Mediated Immunity (CMI) (Amended 16 March 2016)
System
Component
Scale
Method
Unit
Laboratory*
PBMC
Specific CD4+/CD8+ T-cells Quantitative
Flow cytometry
Number of specific 
CD4+/CD8+ T cells /106
GSK 
Biologicals**
PBMC = peripheral blood mononuclear cell.
* Refer to APPENDIX B for the laboratory addresses.
** GSK Biologicals laboratory refers to the Clinical Laboratory Sciences (CLS) Laboratories in Rixensart, Belgium; 
Wavre, Belgium or a designated laboratory.
Additional testing on PBMCs, such as, but not limited to, evaluation of NTHi- and 
Mcat-specific memory B-cells and intracellular cytokine staining (ICS) using other 
microbial antigens, may be done during the study or after study completion, should these 
data be required for accurate interpretation of the data and/ or for further research related 
to the investigational vaccine and/ or the disease and/ or should such test(s) become 
available at GSK Biologicals’ laboratory or a laboratory designated by GSK Biologicals.
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The GSK Biologicals’ clinical laboratories have established a Quality System supported 
by procedures. The activities of GSK Biologicals’ clinical laboratories are audited 
regularly for quality assessment by an internal (sponsor-dependent) but laboratory-
independent Quality Department.
5.7.4.
Biological samples evaluation
5.7.4.1.
Immunological read-outs
Table 12
Immunological read-outs
Blood sampling time point
Sub-cohort 
Name
No. subjects
Component
Type of contact 
and time point
Sampling 
time point
Visit 1 (Day 0)
Pre-Vacc
All subjects
~120
Anti-PD, Anti-PE, Anti-PilA and Anti-UspA2
CMI sub-cohort*
~45
Specific CD4+/CD8+ T-cells
Visit 3 (Day 30)
Post-Vacc I
All subjects
~120
Anti-PD, Anti-PE, Anti-PilA and Anti-UspA2
Visit 4 (Day 60)
Post-Vacc I
All subjects
~120
Anti-PD, Anti-PE, Anti-PilA and Anti-UspA2
CMI sub-cohort*
~45
Specific CD4+/CD8+ T-cells
Visit 6 (Day 90)
Post-Vacc II
All subjects
~120
Anti-PD, Anti-PE, Anti-PilA and Anti-UspA2
CMI sub-cohort*
~45
Specific CD4+/CD8+ T-cells
Visit 7 (Day 210)
Post-Vacc II
All subjects
~120
Anti-PD, Anti-PE, Anti-PilA and Anti-UspA2
CMI sub-cohort*
~45
Specific CD4+/CD8+ T-cells
Visit 8 (Day 420)
Post-Vacc II
All subjects
~120
Anti-PD, Anti-PE, Anti-PilA and Anti-UspA2
CMI sub-cohort*
~45
Specific CD4+/CD8+ T-cells
* Approximately 50% of the subjects in each group of the Step 2 will be part of a sub-cohort for CMI analysis.
5.7.4.2.
Haematology and biochemistry
Table 13
Haematology/ biochemistry
Blood sampling time point
Sub-cohort 
Name
No. 
subjects
Component
Type of contact and 
time point
Sampling 
time point
Screening* (Pre-Day 0)
Screening
All subjects
~120
Haematology (leukocytes [white blood cells], 
white blood cell differential count [neutrophils, 
lymphocytes, eosinophils, basophils, 
monocytes], erythrocytes [red blood cells], 
haemoglobin, platelets
Biochemistry (ALT, AST, creatinine)
Visit 1 (Day 0)
Pre-Vacc I
All subjects
~120
Visit 2 (Day 7)
Post-Vacc I
All subjects
~120
Visit 4 (Day 60)
Post-Vacc I
All subjects
~120
Visit 5 (Day 67)
Post-Vacc II
All subjects
~120
Visit 7 (Day 210)
Post-Vacc II
All subjects
~120
Visit 8 (Day 420)
Post-Vacc II
All subjects
~120
ALT: Alanine aminotransferase; AST: Aspartate aminotransferase
Screening evaluations may be completed 1 to 28 days before Day 0. Site staff should allow sufficient time between the 
Screening and Day 0 visits to receive and review screening safety laboratory test results. If a delay occurs such that 
the interval between Screening and the Day 0 vaccination exceeds 28 days, a re-screening visit should be scheduled 
before Visit 1 during which blood sample collection for safety laboratory assessment should be repeated.
5.7.5.
Immunological correlates of protection
No generally accepted immunological correlate of protection has been demonstrated so 
far for the antigens used in the investigational vaccines.
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6.
STUDY VACCINES AND ADMINISTRATION
6.1.
Description of study vaccines
All candidate vaccines to be used have been developed and manufactured by GSK 
Biologicals.
The Quality Control Standards and Requirements for each candidate vaccine are 
described in separate Quality Assurance documents (e.g. release protocols, certificate of 
analysis) and the required approvals have been obtained.
The vaccines are labelled and packed according to applicable regulatory requirements.
Table 14
Study vaccines
Treatment 
name
Vaccine/
product name
Formulation
Presentation
Volume to be 
administered
No 
doses
10-10-10/ 
Plain
NTHi-Mcat 10-10-10
PD=10 μg; PE-PilA=10 μg; 
UspA2=10 μg
Freeze-dried 
antigens in 
monodose vial
0.5 ml
2
NaCl
NaCl=150mM
Liquid in 
monodose vial
10-10-
10/AS01E
NTHi-Mcat 10-10-10
PD=10 μg; PE-PilA=10 μg; 
UspA2=10 μg
Freeze-dried 
antigens in 
monodose vial
0.5 ml
2
AS01E
MPL=25 μg; QS21=25 μg; 
Liposomes
Liquid in 
monodose vial
10-10-
3/AS01E
NTHi-Mcat 30-30-10
* PD=30 μg; PE-PilA=30
μg; UspA2=10 μg 
Freeze-dried 
antigens in 
monodose vial
0.5 ml
2
AS01E
MPL=25 μg; QS21=25 μg; 
Liposomes
Liquid in 
monodose vial
Placebo
NaCl 
NaCl=150mM 
Liquid in 
monodose vial
0.5 ml
2
*Vials containing 37.5 ∀g, 37.5 ∀g and 12.5 ∀g of freeze-dried PD, PE-PilA and UspA2, respectively, will be diluted in 
three volumes of AS01E (total of ∃1875 ∀L). 0.5 mL will be administered.
6.2.
Storage and handling of study vaccines
The study vaccines must be stored at the respective label storage temperature conditions 
in a safe and locked place. Access to the storage space should be limited to authorized 
study personnel. The storage conditions will be assessed during pre-study activities under 
the responsibility of the sponsor study contact. The storage temperature should be 
continuously monitored with calibrated (if not validated) temperature monitoring 
device(s) and recorded. Refer to the Module on Clinical Trial Supplies in the SPM for 
more details on storage of the study vaccines.
Temperature excursions must be reported in degree Celsius.
Any temperature excursion outside the range of 0.0 to +8.0)C (for +2 to +8°C label 
storage condition) impacting investigational medicinal products (IMPs) must be reported 
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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 
label storage temperature conditions. The impacted IMP(s) may still be administered, but 
the site should avoid re-occurrence of such temperature excursion. Refer to the Module 
on Clinical Trial Supplies in the SPM for more details on actions to take.
Refer to the Module on Clinical Trial Supplies in the SPM for details and instructions on 
the temperature excursion reporting and usage decision process, packaging and 
accountability of the study vaccines.
6.3.
Dosage and administration of study vaccines
Table 15
Dosage and administration
Type of contact and 
time point
Volume to 
be 
administered
Study Group
Treatment name
Route 1
Site
Side 2
Visit 1 (Day 0)
0.5mL
10-10-10
10-10-10/Plain
IM 
Deltoid 
Non-
dominant 
10-10-10-AS
10-10-10/AS01E
10-10-3-AS
10-10-3/AS01E*
PLACE1
Placebo
PLACE2
Visit 4 (Day 60)
0.5mL
10-10-10
10-10-10/Plain
IM 
Deltoid 
Non-
dominant 
10-10-10-AS
10-10-10/AS01E
10-10-3-AS
10-10-3/AS01E*
PLACE1
Placebo
PLACE2
1Intramuscular (IM)
2 The deltoid of the non-dominant arm is the preferred side of injection. In case it is not possible to inject in the 
non-dominant arm, an injection in the dominant arm may be performed.
* Vials containing 37.5 ∀g, 37.5 ∀g and 12.5 ∀g of freeze-dried PD, PE-PilA and UspA2, respectively, will be diluted in 
three volumes of AS01E (∃1875 ∀L). 0.5mL will be administered.
6.3.1.
Instructions for study vaccine preparation and administration
GSK Biologicals’ NTHi-Mcat investigational vaccines should be prepared maximum two
hours prior to injection.
6.3.1.1.
Instructions for reconstitution and administration of investigational 
10-10-10/Plain or 10-10-10/AS01E vaccines
The vaccine formulations 10-10-10/Plain and 10-10-10/AS01E will be delivered as two 
separate monodose vials, one containing the freeze-dried cake (NTHi-Mcat 10-10-10) 
and the other one containing the diluent (saline or AS01E adjuvant). The entire content of 
the liquid-containing vial (diluent) will be injected into the vial of the freeze-dried cake. 
Following complete reconstitution of the cake by gentle rotations, the entire volume of 
this final reconstituted formulation will be withdrawn into a syringe. The excess volume 
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together with any remaining air bubbles will be expelled, so that a volume of 0.5 mL is 
finally administered to the subject. The content of the syringe will be masked with an 
opaque injection label to ensure blinding of the subjects. A small gap at the top of the 
syringe should be left in order to allow the administrator of the vaccine to check the 
liquid before injection. Finally, intramuscular injection of 0.5 mL should be done into the 
deltoid of the non-dominant arm. In case it is not possible to inject in the non-dominant 
arm, an injection in the dominant arm may be performed.
6.3.1.2.
Instructions for reconstitution and administration of investigational 
10-10-3/AS01E vaccine
The vaccine formulation 10-10-3/AS01E will be delivered as four separate monodose 
vials, one containing the freeze-dried cake (NTHi-Mcat 30-30-10 ) and three vials 
containing the AS01E adjuvant. The whole content of each of the three vials of AS01E
must be used to reconstitute one vial of NTHi-Mcat 30-30-10 freeze-dried cake. 
Complete reconstitution of the cake by gentle rotations needs to be achieved before 
vaccine can be retrieved for injection. A suitable volume of this final reconstituted 
formulation will be withdrawn in a new calibrated syringe. The excess volume together 
with any remaining air bubbles will be expelled, so that a volume of 0.5 mL is 
administered to the subject. The content of the syringe should be masked with an opaque 
injection label to ensure blinding of the subjects. A small gap at the top of the syringe 
should be left in order to allow the administrator of the vaccine to check the liquid before 
injection. Finally, intramuscular injection of 0.5 mL should be done into the deltoid of the 
non-dominant arm. In case it is not possible to inject in the non-dominant arm, an 
injection in the dominant arm may be performed.
Please refer to the SPM for more detailed instructions on study vaccines preparation 
(e.g. needles and syringes used for reconstitution).
6.3.1.3.
Instructions for preparation and administration of saline placebo
The saline solution will be delivered in a monodose vial, ready to use. The saline solution 
is transparent. If turbid or a precipitation is observed, the vial should not be used. Air 
bubbles and any excess volume have to be expelled. The content of the syringe will be 
masked with an opaque injection label to ensure blinding of the subjects. A small gap at 
the top of the syringe should be left in order to allow the administer to check the liquid 
before injection. Finally, intramuscular injection of 0.5 mL should be done into the 
deltoid of the non-dominant arm. In case it is not possible to inject in the non-dominant 
arm, an injection in the dominant arm may be performed.
Please refer to the SPM for more detailed instructions on study vaccines administration.
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 20% additional vaccine doses will be 
supplied to replace those that are unusable.
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The investigator will use SBIR to obtain the replacement vial number. The replacement 
numbers will be allocated by dose. 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 subsequent vaccination
The following events constitute absolute contraindications to further administration of the 
NTHi-Mcat investigational vaccines. If any of these events occur during the study, the 
subject must not receive vaccine Dose 2 but may continue other study procedures at the 
discretion of the investigator (see Section 8.5).
!
Anaphylaxis following the administration of vaccine.
!
Pregnancy.
!
Any confirmed or suspected immunosuppressive or immunodeficient condition, 
including HIV infection.
!
Current auto-immune disease.
The following events constitute contraindications to administration of the NTHi-Mcat 
investigational vaccines at that point in time; if any of these events occur at the time 
scheduled for vaccination, the subject may be vaccinated at a later date, within the time 
window specified in the protocol (see Table 7), or the subject may be withdrawn at the 
discretion of the investigator (see Section 8.5).
!
Acute disease and/or fever at the time of vaccination. 
#
Fever is defined as a temperature % 37.5°C for oral or axillary route. The 
preferred route for recording temperature in this study will be oral.
#
Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory 
infection) without fever can be administered all vaccines.
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6.6.
Concomitant medications/products and concomitant 
vaccinations
At each study visit/contact, the investigator should question the subject about any 
medication/product taken and vaccination received by the subject.
6.6.1.
Recording of concomitant medications/products and 
concomitant vaccinations
The following concomitant medications/products/vaccines must be recorded in the 
eCRF if administered during the indicated recording period:
!
All concomitant medications/products, except vitamins and dietary supplements, 
administered 30 days following each dose of study vaccine.
!
Any concomitant vaccination administered in the period starting 30 days before the 
first dose of study vaccine and ending at the last study visit.
!
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 
an oral or axillary temperature % 37.5°C for oral or axillary route).
!
Any concomitant medications/products/vaccines listed in Section 6.6.2 during the 
entire study period.
!
Any concomitant medication/product/vaccine relevant to a SAE* or administered at 
any time during the study period for the treatment of a SAE*.
* SAEs that are required to be reported per protocol.
6.6.2.
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 Section10.4 for study cohorts/ data sets 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) during the study period. For corticosteroids, this will mean 
prednisone % 20 mg/day, or equivalent. 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 first dose and ending 30 days after the last dose of vaccine 
with the exception of any influenza vaccine or pneumococcal vaccine (Step 2 only) 
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which may be administered ≥15 days preceding or following any study vaccine 
dose.*
* In case an emergency mass vaccination for an unforeseen public health threat (e.g.
a pandemic) is organised by the public health authorities, outside the routine 
immunisation programme, the time period described above can be reduced if 
necessary for that vaccine provided it is licensed and used according to its summary 
of product characteristics or prescribing information and according to the local 
governmental recommendations and provided a written approval of the Sponsor is 
obtained.
!
Immunoglobulins and/or any blood products administered during the study period.
6.7.
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(s) requiring 
medical attention. If it is the case, the condition(s) must be recorded in the eCRF.
Subjects may be eliminated from the ATP cohort for immunogenicity if, during the study, 
they incur a condition that has the capability of altering their immune response (e.g.
confirmed immunosuppressive or immunodeficient condition, including HIV).
7.
HEALTH ECONOMICS
Not applicable.
8.
SAFETY
The investigator or site staff is/are responsible for the detection, documentation and 
reporting of events meeting the criteria and definition of an AE or SAE as provided in 
this protocol.
Each subject will be instructed to contact the investigator immediately should he/she 
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. 
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Examples of an AE include:
!
Worsening of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
!
New conditions detected or diagnosed after investigational vaccines 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.
!
Pre- or post-treatment events that occur as a result of protocol-mandated procedures 
(i.e. invasive procedures, modification of subject’s previous therapeutic regimen).
AEs to be recorded as endpoints (solicited AEs) are described in Section 8.1.3. All other 
AEs will be recorded as UNSOLICITED AEs.
Examples of an AE DO NOT include:
!
Medical or surgical procedures (e.g. endoscopy, appendectomy); the condition that 
leads to the procedure is an AE/SAE.
!
Situations where an untoward medical occurrence did not occur (e.g. social and/or 
convenience admission to a hospital, admission for routine examination).
!
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 
!
Pre-existing conditions or signs and/or symptoms present in a subject prior to the 
first study vaccination. These events will be recorded in the medical history section 
of the eCRF.
8.1.2.
Definition of a serious adverse event 
A SAE is any untoward medical occurrence that:
a.
Results in death,
b.
Is life-threatening,
Note: The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in 
which the subject was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, had it been more severe.
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c.
Requires hospitalisation or prolongation of existing hospitalisation,
Note: In general, hospitalisation signifies that the subject has been admitted at the 
hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician’s office or in an out-patient setting. Complications 
that occur during hospitalisation are also considered AEs. If a complication prolongs 
hospitalisation or fulfils any other serious criteria, the event will also be considered 
serious. When in doubt as to whether ‘hospitalisation’ occurred or was necessary, the 
AE should be considered serious.
Hospitalisation for elective treatment of a pre-existing condition (known or 
diagnosed prior to informed consent signature) that did not worsen from baseline is 
NOT considered an AE.
d.
Results in disability/incapacity, OR
Note: The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhoea, influenza like illness, and accidental trauma (e.g. sprained 
ankle) which may interfere or prevent everyday life functions but do not constitute a 
substantial disruption.
e.
Is a congenital anomaly/birth defect in the offspring of a study subject.
Medical or scientific judgement should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalisation but may jeopardise the 
subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These should also be considered serious. 
Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalisation.
8.1.3.
Solicited adverse events
Solicited local and general AEs occurring during a 7-day follow-up period after each 
vaccination (i.e. the day of vaccination and the 6 subsequent days), as well as unsolicited 
AEs occurring during a 30-day follow-up period after each vaccination (i.e. the day of 
vaccination an the 29 subsequent days), will be reported via paper Diary Cards for 
vaccine reactogenicity and recorded via the appropriate section of the eCRF.
8.1.3.1.
Solicited local (injection-site) adverse events
The following local (injection-site) AEs will be solicited:
Table 16
Solicited local adverse events
Pain at injection site
Redness at injection site
Swelling at injection site
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8.1.3.2.
Solicited general adverse events
The following general AEs will be solicited:
Table 17
Solicited general adverse events
Fever
Headache
Fatigue
Myalgia
Gastrointestinal symptoms a
a 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 that are judged by the 
investigator to be clinically significant will be recorded as AE or SAE if they meet the 
definition of an AE or SAE (refer to Sections 8.1.1 and 8.1.2). Clinically significant 
abnormal laboratory findings or other abnormal assessments that are present at baseline 
and significantly worsen following the start of the study will also be reported as AEs or 
SAEs.
The investigator will exercise his or her medical and scientific judgement in deciding 
whether an abnormal laboratory finding or other abnormal assessment is clinically 
significant.
8.1.5.
Adverse events of specific interest (potential immune-mediated 
diseases)
Potential immune-mediated diseases (pIMDs) are a subset of AEs that include 
autoimmune diseases and other inflammatory and/or neurologic disorders of interest 
which may or may not have an autoimmune aetiology. AEs that need to be recorded and 
reported as pIMDs include those listed in Table 18.
However, the investigator will exercise his/her medical and scientific judgement in 
deciding whether other diseases have an autoimmune origin (i.e. pathophysiology 
involving systemic or organ-specific pathogenic autoantibodies) and should also be 
recorded as a pIMD.
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Table 18
List of potential immune-mediated diseases
Neuroinflammatory disorders
Musculoskeletal disorders
Skin disorders
!
Cranial nerve disorders, 
including paralyses/paresis 
(e.g. Bell’s palsy) 
!
Optic neuritis
!
Multiple sclerosis
!
Transverse myelitis
!
Guillain-Barré syndrome, 
including Miller Fisher 
syndrome and other variants
!
Acute disseminated 
encephalomyelitis, including 
site specific variants: e.g. non-
infectious encephalitis, 
encephalomyelitis, myelitis, 
myeloradiculoneuritis
!
Myasthenia gravis, including 
Lambert-Eaton myasthenic 
syndrome 
!
Immune-mediated peripheral 
neuropathies and plexopathies, 
(including chronic inflammatory 
demyelinating polyneuropathy, 
multifocal motor neuropathy 
and polyneuropathies 
associated with monoclonal 
gammopathy).
!
Narcolepsy
!
Systemic lupus erythematosus 
and associated conditions
!
Systemic scleroderma (Systemic 
sclerosis), including diffuse 
systemic form and CREST 
syndrome
Idiopathic inflammatory 
myopathies, including 
dermatomyositis 
!
Polymyositis 
!
Antisynthetase syndrome
!
Rheumatoid arthritis, and 
associated conditions including 
juvenile chronic arthritis and Still’s 
disease
!
Polymyalgia rheumatica
!
Spondyloarthritis, including 
ankylosing spondylitis, reactive 
arthritis (Reiter's Syndrome) and 
undifferentiated spondyloarthritis 
!
Psoriatic arthropathy
!
Relapsing polychondritis
!
Mixed connective tissue disorder
!
Psoriasis
!
Vitiligo
!
Erythema nodosum
!
Autoimmune bullous 
skin diseases (including 
pemphigus, pemphigoid 
and dermatitis 
herpetiformis)
!
Alopecia areata
!
Lichen planus
!
Sweet’s syndrome
!
Localised Scleroderma 
(Morphoea)
Vasculitides
Blood disorders
Others
!
Large vessels vasculitis 
including: giant cell arteritis 
such as Takayasu's arteritis 
and temporal arteritis. 
!
Medium sized and/or small 
vessels vasculitis including: 
polyarteritis nodosa, Kawasaki's 
disease, microscopic 
polyangiitis, Wegener's 
granulomatosis, Churg–Strauss 
syndrome (allergic 
granulomatous angiitis), 
Buerger’s disease 
(thromboangiitis obliterans), 
necrotizing vasculitis and anti-
neutrophil cytoplasmic antibody 
(ANCA) positive vasculitis (type 
unspecified), Henoch-Schonlein 
purpura, Behcet's syndrome, 
leukocytoclastic vasculitis.
!
Autoimmune hemolytic 
anemia
!
Autoimmune 
thrombocytopenia
!
Antiphospholipid 
syndrome
!
Pernicious anemia
!
Autoimmune aplastic 
anaemia
!
Autoimmune 
neutropenia 
!
Autoimmune 
pancytopenia
!
Autoimmune glomerulonephritis 
(including IgA nephropathy, 
glomerulonephritis rapidly 
progressive, membranous 
glomerulonephritis, 
membranoproliferative 
glomerulonephritis, and 
mesangioproliferative 
glomerulonephritis)
!
Ocular autoimmune diseases 
(including autoimmune uveitis and 
autoimmune retinopathy)
!
Autoimmune 
myocarditis/cardiomyopathySarco
idosis
!
Stevens-Johnson syndrome
!
Sjögren’s syndrome
!
Idiopathic pulmonary fibrosis
!
Goodpasture syndrome
!
Raynaud’s phenomenon
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Liver disorders
Gastrointestinal disorders
Endocrine disorders
!
Autoimmune hepatitis
!
Primary biliary cirrhosis
!
Primary sclerosing 
cholangitis
!
Autoimmune cholangitis
!
Inflammatory Bowel disease, 
including Crohn’s disease, 
ulcerative colitis, microscopic 
colitis, ulcerative proctitis 
!
Celiac disease
!
Autoimmune pancreatitis
!
Autoimmune thyroiditis (including 
Hashimoto thyroiditis)
!
Grave's or Basedow’s disease
!
Diabetes mellitus type I
!
Addison’s disease
!
Polyglandular autoimmune 
syndrome
!
Autoimmune hypophysitis
When there is enough evidence to make any of the above diagnoses, the AE must be 
reported as a pIMD. Symptoms, signs or conditions which might (or might not) represent 
the above diagnoses, should be recorded and reported as AEs but not as pIMDs 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 pIMDs in the eCRF, a pIMD standard 
questionnaire and a list of preferred terms (PTs) and PT codes corresponding to the above 
diagnoses will be available to investigators at study start.
8.2.
Events or outcomes not qualifying as adverse events or 
serious adverse events
Pregnancy
Female subjects who are pregnant or lactating at the time of vaccination must not receive 
additional doses of study vaccines but may continue other study procedures at the 
discretion of the investigator.
While pregnancy itself is not considered an AE or SAE, any adverse pregnancy outcome 
or complication or elective termination of a pregnancy for medical reasons will be 
recorded and reported as an AE or a SAE.
Note: The pregnancy itself should always be recorded on an electronic pregnancy report.
The following should always be considered as SAE and will be reported as described in 
Sections 8.4.1 and 8.4.3:
!
Spontaneous pregnancy loss, including:
#
spontaneous abortion, (spontaneous pregnancy loss before/at 22 weeks of 
gestation)
#
ectopic and molar pregnancy
#
stillbirth (intrauterine death of foetus after 22 weeks of gestation).
Note: the 22 weeks cut-off in gestational age is based on WHO-ICD 10 noted in the 
EMA Guideline on pregnancy exposure [EMA, 2006]. It is recognized that national 
regulations might be different.
!
Any early neonatal death (i.e. death of a live born infant occurring within the first 7 
days of life).
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!
Any congenital anomaly or birth defect (as per [CDC MACDP] guidelines) 
identified in the offspring of a study subject (either during pregnancy, at birth or 
later) regardless of whether the foetus is delivered dead or alive. This includes 
anomalies identified by prenatal ultrasound, amniocentesis or examination of the 
products of conception after elective or spontaneous abortion.
Furthermore, any SAE occurring as a result of a post-study pregnancy AND considered 
by the investigator to be reasonably related to the investigational vaccines will be 
reported to GSK Biologicals as described in Section 8.4.3. While the investigator is not 
obligated to actively seek this information from former study participants, he/she may 
learn of a pregnancy through spontaneous reporting.
8.3.
Detecting and recording adverse events, serious adverse 
events and pregnancies
8.3.1.
Time period for detecting and recording adverse events, serious 
adverse events and pregnancies
All AEs starting within 30 days following administration of each dose/ of study vaccines
(Day 0 to Day 30) must be recorded into the appropriate section of the eCRF, irrespective 
of intensity or whether or not they are considered vaccination-related.
The time period for collecting and recording SAEs will begin at the first receipt of study 
vaccines and will end at study conclusion. See Section 8.4 for instructions on reporting of 
SAEs.
All AEs/SAEs leading to withdrawal from the study will be collected and recorded from 
the time of the first receipt of study vaccines until study conclusion.
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 of pIMDs will begin at the first receipt of 
study vaccine and will end at study conclusion. See Section 8.4 for instructions on 
reporting of pIMDs.
The time period for collecting and recording pregnancies will begin at the first receipt of 
study vaccine and will end at study conclusion. See Section 8.4 for instructions on 
reporting of pregnancies.
The time period for collecting and recording of intercurrent medical conditions requiring 
medical attention will begin at the first receipt of study vaccine and will end at study 
conclusion.
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Table 19
Reporting periods for collecting safety information
Event
Screening
Visit*
Visit 1
Dose 1
7 d post 
Dose 1
30 d post 
Dose 1
Visit 4
Dose 2
7 d post 
Dose 2
30 d post 
Dose 2
Study 
Conclusion
Day 0
Day 6
Day 29
Day 60
Day 66
Day 89
Day 
210
Day 420
Solicited local 
and general AEs
Unsolicited AEs
AEs/SAEs 
leading to 
withdrawal from 
the study
SAEs 
SAEs related to 
study participation 
or concurrent GSK 
medication/vaccine 
Pregnancies
pIMDs 
Intercurrent 
medical 
condictions 
requiring medical 
attention
d = day follow-up period.
* i.e. consent obtained. 
The double-bordered lines indicate timings of vaccination.
8.3.2.
Post-study adverse events and serious adverse events
A post-study AE/SAE is defined as any event that occurs outside of the AE/SAE 
reporting period defined in Table 19. Investigators are not obligated to actively seek AEs 
or SAEs in former study participants. However, if the investigator learns of any SAE at 
any time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the investigational vaccines, the investigator will promptly 
notify the Study Contact for Reporting SAEs.
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8.3.3.
Evaluation of adverse events and serious adverse events
8.3.3.1.
Active questioning to detect adverse events and serious adverse 
events
As a consistent method of collecting AEs, the subject 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.
The investigator will attempt to establish a diagnosis pertaining to the event based on 
signs, symptoms, and/or other clinical information. In such cases, the diagnosis should be 
documented as the AE/SAE and not the individual signs/symptoms.
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8.3.3.2.
Assessment of adverse events
8.3.3.2.1.
Assessment of intensity
The intensity of the following solicited AEs will be assessed as described:
Table 20
Intensity scales for solicited symptoms
Adverse Event
Intensity grade
Parameter
Pain at injection site
0
None
1
Mild: Any pain neither interfering with nor preventing 
normal every day activities.
2
Moderate: Painful when limb is moved and interferes with 
every day activities.
3
Severe: Significant pain at rest. Prevents normal every 
day activities.
Redness at injection site
Record greatest surface diameter in mm
Swelling at injection site
Record greatest surface diameter in mm
Fevera
Record temperature in °C
Headache
0
Normal
1
Mild: Headache that is easily tolerated
2
Moderate: Headache that interferes with normal activity
3
Severe: Headache that prevents normal activity
Fatigue
0
Normal
1
Mild: Fatigue that is easily tolerated
2
Moderate: Fatigue that interferes with normal activity
3
Severe: Fatigue that prevents normal activity
Myalgiab
0
None
1
Mild: Myalgia that is easily tolerated
2
Moderate: Myalgia that interferes with normal activity
3
Severe: Myalgia that prevents normal activity
Gastrointestinal symptoms
0
Gastrointestinal symptoms 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
a Fever is defined as a temperature % 37.5°C for oral or axillary route. The preferred route for recording temperature in 
this study will be oral.
b Myalgia is defined as generalised muscle pain with an intensity judged by the subject and confirmed by the 
investigator as more severe than expected for the subject’s condition or higher than pre-vaccination.
The maximum intensity of local injection site redness/swelling will be scored at GSK 
Biologicals as follows:
0
:
≤ 20 mm
1
:
> 20 mm to ≤ 50 mm
2
:
> 50 mm to ≤ 100 mm
3
:
> 100 mm
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The maximum intensity of fever will be scored at GSK Biologicals as follows: 
0
:
< 37.5 °C
1
:
≥37.5 °C to ≤ 38.5 °C
2
:
> 38.5 °C to ≤ 39.5°C
3
:
> 39.5°C
The investigator will assess the maximum intensity that occurred over the duration of the 
event for all unsolicited AEs (including SAEs) recorded during the study. The assessment 
will be based on the investigator’s clinical judgement.
The intensity should be assigned to one of the following categories:
1 (mild)
=
An AE which is easily tolerated by the subject, causing minimal 
discomfort and not interfering with everyday activities.
2 (moderate)
=
An AE which is sufficiently discomforting to interfere with 
normal everyday activities.
3 (severe)
=
An AE which prevents normal, everyday activities. Such an AE 
would, for example, prevent attendance at work/school and would 
necessitate the administration of corrective therapy.
An AE that is assessed as Grade 3 (severe) should not be confused with a SAE. 
Grade 3 is a category used for rating the intensity of an event; and both AEs and SAEs 
can be assessed as Grade 3. An event is defined as ‘serious’ when it meets one of the 
pre-defined outcomes as described in Section 8.1.2.
8.3.3.2.2.
Assessment of causality
The investigator is obligated to assess the relationship between investigational vaccines
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 vaccines will be considered and investigated. The 
investigator will also consult the IB to determine his/her assessment.
There may be situations when a SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK Biologicals. However, it is very 
important that the investigator always makes an assessment of causality for every event 
prior to submission of the Expedited Adverse Events Report to GSK Biologicals. The 
investigator may change his/her opinion of causality in light of follow-up information and 
update the SAE information accordingly. The causality assessment is one of the criteria 
used when determining regulatory reporting requirements.
In case of concomitant administration of multiple vaccines/products, it may not be 
possible to determine the causal relationship of general AEs to the individual vaccine. 
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The investigator should, therefore, assess whether the AE could be causally related to 
vaccination rather than to the individual vaccines.
All solicited local (injection site) reactions will be considered causally related to 
vaccination. Causality of all other AEs should be assessed by the investigator using the 
following question:
Is there a reasonable possibility that the AE may have been caused by the investigational 
vaccine?
YES
:
There is a reasonable possibility that the vaccines contributed to the 
AE. 
NO
:
There is no reasonable possibility that the AE is causally related to 
the administration of the study vaccines. There are other, more 
likely causes and administration of the study vaccines is not 
suspected to have contributed to the AE.
If an event meets the criteria to be determined as ‘serious’ (see Section 8.1.2), additional 
examinations/tests will be performed by the investigator in order to determine ALL 
possible contributing factors for each SAE.
Possible contributing factors include:
!
Medical history.
!
Other medication.
!
Protocol required procedure.
!
Other procedure not required by the protocol.
!
Lack of efficacy of the vaccines, if applicable.
!
Erroneous administration.
!
Other cause (specify).
8.3.3.3.
Assessment of outcomes
The investigator will assess the outcome of all unsolicited AEs (including SAEs) 
recorded during the study as:
!
Recovered/resolved.
!
Recovering/resolving.
!
Not recovered/not resolved.
!
Recovered with sequelae/resolved with sequelae.
!
Fatal (SAEs only).
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8.3.3.4.
Medically attended visits
For each solicited and unsolicited symptom the subject experiences, the subject will be 
asked if he/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.
8.4.
Reporting of serious adverse events, pregnancies, and 
other events
8.4.1.
Prompt reporting of serious adverse events, pregnancies, and 
other events to GSK Biologicals
SAEs that occur in the time period defined in Section 8.3 will be reported promptly to 
GSK within the timeframes described in Table 21, once the investigator determines that 
the event meets the protocol definition of a SAE.
pIMDs that occur in the time period defined in Section 8.3 will be reported promptly to 
GSK within the timeframes described in Table 21, once the investigator determines that 
the event meets the protocol definition of a pIMD.
Pregnancies that occur in the time period defined in Section 8.3 will be reported promptly 
to GSK within the timeframes described in Table 21, once the investigator becomes 
aware of the pregnancy. 
Table 21
Timeframes for submitting serious adverse event, pregnancy 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
pIMDs 
24 hours**‡
electronic Expedited 
Adverse Events Report
24 hours*
electronic Expedited Adverse 
Events Report
Pregnancies 
2 weeks*
electronic pregnancy report
2 weeks*
electronic pregnancy report
* Timeframe allowed after receipt or awareness of the information.
**Timeframe allowed once the investigator determines that the event meets the protocol definition of a pIMD.
‡ The investigator will be required to confirm review of the SAE/pIMD causality by ticking the ‘reviewed’ box in the 
electronic Expedited Adverse Events Report within 72 hours of submission of the SAE/pIMD.
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8.4.2.
Contact information for reporting serious adverse events,
pregnancies and pIMDs
Study Contact for Reporting SAEs, pIMDs and pregnancies
Refer to the local study contact information document.
Back-up Study Contact for Reporting SAEs, pIMDs and pregnancies 
24/24 hour and 7/7 day availability:
GSK Biologicals Clinical Safety & Pharmacovigilance
Fax: 
 or 
Email address: Rix.CT-safety-vac@gsk.com
8.4.3.
Completion and transmission of SAE reports to GSK Biologicals
Once an investigator becomes aware that a SAE has occurred in a study subject, the 
investigator (or designate) must complete the information in the electronic Expedited 
Adverse Events Report WITHIN 24 HOURS. The report will always be completed as 
thoroughly as possible with all available details of the event. Even if the investigator does 
not have all information regarding a SAE, the report should still be completed within 24 
hours. Once additional relevant information is received, the report should be updated 
WITHIN 24 HOURS.
The investigator will always provide an assessment of causality at the time of the initial 
report. The investigator will be required to confirm the review of the SAE causality by 
ticking the ‘reviewed’ box in the electronic Expedited Adverse Events Report within 
72 hours of submission of the SAE.
8.4.3.1.
Back-up system in case the electronic reporting system does not work
If the electronic reporting system does not work, the investigator (or designate) must 
complete, then date and sign a paper Expedited Adverse Events Report and fax it to the 
Study Contact for Reporting SAEs (refer to the Sponsor Information) or to GSK 
Biologicals Clinical Safety and Pharmacovigilance department within 24 hours. 
This back-up system should only be used if the electronic reporting system is not working 
and NOT if the system is slow. As soon as the electronic reporting system is working 
again, the investigator (or designate) must complete the electronic Expedited Adverse 
Events Report within 24 hours. The final valid information for regulatory reporting will 
be the information reported through the electronic SAE reporting system. 
8.4.4.
Reporting of pIMDs to GSK Biologicals
Once a pIMD is diagnosed (serious or non-serious) in a study subject, the investigator (or 
designate) must complete the information in the electronic Expedited Adverse Events 
Report WITHIN 24 HOURS after he/she becomes aware of the diagnosis. The report 
allows to specify that the event is a pIMD and whether it is serious or non-serious. The 
report will always be completed as thoroughly as possible with all available details of the 
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event, in accordance with the pIMD standard questionnaire provided. Even if the 
investigator does not have all information regarding a pIMD, 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 pIMD causality by 
ticking the ‘reviewed’ box in the electronic Expedited Adverse Events Report within 
72 hours of submission of the pIMD.
Refer to Section 8.4.3.1 for back-up system in case the electronic reporting system does 
not work.
8.4.5.
Completion and transmission of pregnancy reports to GSK 
Biologicals
Once the investigator becomes aware that a subject is pregnant, the investigator (or 
designate) must complete the required information onto the electronic pregnancy report 
WITHIN 2 WEEKS.
Note: Conventionally, the estimated gestational age (EGA) of a pregnancy is dated from 
the first day of the last menstrual period (LMP) of the cycle in which a woman conceives. 
If the LMP is uncertain or unknown, dating of EGA and the estimated date of delivery
(EDD) should be estimated by ultrasound examination and recorded in the pregnancy 
report.
8.4.6.
Updating of SAE, pregnancy, and pIMD information after removal 
of write access to the subject’s eCRF
When additional SAE, pIMD, or pregnancyinformation is received after removal of the 
write access to the subject’s eCRF, new or updated information should be recorded on the 
appropriate paper report, with all changes signed and dated by the investigator. The 
updated report should be faxed to the Study Contact for Reporting SAEs (refer to the 
Sponsor Information) or to GSK Biologicals Clinical Safety and Pharmacovigilance 
department within the designated reporting time frames specified in Table 21.
8.4.7.
Regulatory reporting requirements for serious adverse events
The investigator will promptly report all SAEs to GSK in accordance with the procedures 
detailed in Section 8.4.1. GSK Biologicals has a legal responsibility to promptly notify, 
as appropriate, both the local regulatory authority and other regulatory agencies about the 
safety of a product under clinical investigation. Prompt notification of SAEs by the 
investigator to the Study Contact for Reporting SAEs is essential so that legal obligations 
and ethical responsibilities towards the safety of other subjects are met.
Investigator safety reports are prepared according to the current GSK policy and are 
forwarded to investigators as necessary. An investigator safety report is prepared for a 
SAE(s) that is both attributable to the investigational vaccines and unexpected. The 
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purpose of the report is to fulfil specific regulatory and GCP requirements, regarding the 
product under investigation.
8.5.
Follow-up of adverse events, serious adverse events, and
pregnancies
8.5.1.
Follow-up of adverse events and serious adverse events 
8.5.1.1.
Follow-up during the study
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject and provide additional relevant information on the subject’s condition to GSK 
Biologicals (within 24 hours for SAEs; refer to Table 21).
All SAEs and pIMDs (serious or non-serious) documented at a previous visit/contact and 
designated as not recovered/not resolved or recovering/resolving will be reviewed at 
subsequent visits/contacts until the end of the study.
All AEs documented at a previous visit/contact and designated as not recovered/not 
resolved or recovering/resolving will be reviewed at subsequent visits/contacts until 30 
days after the last vaccination.
8.5.1.2.
Follow-up after the subject is discharged from the study
The investigator will follow subjects with SAEs, pIMDs (serious or non-serious), or 
subjects withdrawn from the study as a result of an AE, until the event has resolved, 
subsided, stabilised, disappeared, or until the event is otherwise explained, or the subject 
is lost to follow-up. 
If the investigator receives additional relevant information on a previously reported SAE, 
he/she will provide this information to GSK Biologicals using a paper/ electronic 
Expedited Adverse Events Report and/or pregnancy report as applicable.
GSK Biologicals may request that the investigator performs or arranges the conduct of 
additional clinical examinations/tests and/or evaluations to elucidate as fully as possible 
the nature and/or causality of the AE or SAE. The investigator is obliged to assist. If a 
subject dies during participation in the study or during a recognised follow-up period, 
GSK Biologicals will be provided with any available post-mortem findings, including 
histopathology.
8.5.2.
Follow-up of pregnancies
Pregnant subjects will be followed to determine the outcome of the pregnancy. At the end 
of the pregnancy, whether full-term or premature, information on the status of the mother 
and child will be forwarded to GSK Biologicals using the 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.
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Regardless of the reporting period for SAEs for this study, if the pregnancy outcome is a 
SAE, it should always be reported as SAE.
8.6.
Treatment of adverse events
Treatment of any AE is at the sole discretion of the investigator and according to current 
good medical practice. Any medication administered for the treatment of an AE should 
be recorded in the subject’s eCRF (refer to Section 6.6).
8.7.
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, 
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 8.4.1).
8.8.
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 study 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).
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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: 
 (GSK Biologicals Central Safety Physician on-call)
GSK Biologicals’ Central Safety Physician Back-up:
Emergency Unblinding Documentation Form transmission:
Fax: 
 or 
8.9.
Subject card
Study subjects 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.
8.10.
Holding rules and safety monitoring
The investigator is not permitted to start the administration of the next dose (Dose2) or 
next step (Step 2) until receipt of the favourable outcome of the safety evaluation, based 
on the safety data collected up to seven days after administration of the previous dose(s)
(Figure 2).
In order to move to the next step, safety data will be needed from all subjects. In order to 
move from Dose 1 to Dose 2 within a step, safety data from about 50% of the vaccinated 
subjects will be needed (Figure 2).
Moreover, if the investigator becomes aware of a holding rule being met, he/she will 
suspend vaccination and will inform GSK Biologicals Central Safety immediately (within 
24 hours) (e.g. in case of SAEs).
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Figure 2
Overview of iSRC evaluations
8.10.1.
Safety Review Team
The project’s SRT includes as core members the GSK Biologicals’ Central Safety 
Leader, the Clinical Research & Development Lead (CRDL), Epidemiologist, Global
Regulatory Lead and a Biostatistician of the project. The SRT is responsible for on-going 
safety monitoring of the entire project and meets on a regular basis. The SRT will inform 
the iSRC about any potential safety concern relevant to the study.
Before each iSRC safety evaluation in this study (see below), the SRT will review the 
same safety data, but in a blinded manner in order to keep all people involved in the 
conduct, cleaning and final analysis of the study blinded.
8.10.2.
Internal Safety Review Committee
As the investigational vaccine formulation will be administered for first time to human, 
an iSRC will be appointed in addition to the existing project’s SRT and safety holding 
rules have been defined.
The iSRC, authorised by the GSK Biologicals’ Vaccine Safety Monitoring Board
(VSMB) will include as core members a GSK Biologicals’ Safety Leader, a CRDL and a 
Biostatistician, who are not otherwise involved in the conduct of the project, in order to 
maintain the observer-blind to the treatment codes amongst project-related personnel 
until the final analysis of data.
The iSRC will conduct unblinded reviews of all available safety data from the present 
study, while taking into account any other findings that could have an impact on the 
safety of the subjects, and will determine whether there is a safety signal that needs to be 
escalated to GSK Biologicals’ VSMB. In the event that a safety signal is observed, GSK 
Biologicals’ VSMB might decide to suspend, modify or continue the conduct of the study 
in all groups or in selected groups. 
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To facilitate the safety evaluation, the investigator or his/her designee will need to 
transcribe the information of the Diary Cards returned at the 7 day post-vaccination visits
into the eCRF promptly (preferably within two working days of data availability).
8.10.2.1.
Outcome of safety evaluation
If no safety signal is observed, the favourable outcome of the safety evaluation will be 
documented and provided in writing (scanned and emailed) authorising the investigator to 
proceed to the next dose and/or step of the trial.
If a safety signal is observed during the safety evaluation or if any of the holding rules 
1a, 1b, 1c is reported by the investigator at any time, the SRT and iSRC leader is 
responsible for the urgent communication and escalation of the concern to the GSK 
Biologicals VSMB who will decide during an ad hoc meeting whether to suspend, 
modify or continue the conduct of the study on all groups or on selected groups. The 
decision of the GSK Biologicals VSMB will be documented and provided in writing 
(scanned and emailed) to the investigator regarding the further conduct of the study.
In the event that a safety signal has prompted a GSK Biologicals’ VSMB review, further 
vaccination may resume following, and dependent upon, a decision provided in writing to 
the investigator (scanned and emailed) authorising the resumption of vaccinations.
8.10.2.2.
Process for the suspension of vaccination and/or study modification
In the event that a safety signal is observed, GSK Biologicals’ VSMB might decide to 
suspend further vaccinations in all groups or in selected groups.
In case the vaccination is suspended:
!
Subjects who signed an informed consent but have not received any study vaccine 
will be informed that their study participation will be stopped.
!
For all other subjects, all visits will continue as planned for evaluation of the safety 
and immunogenicity of the vaccine except that Visit 5 on Day 67 will be cancelled if 
no vaccine dose is administered at Visit 4 on Day 60.
8.10.3.
Study holding rules
The safety holding rules which will be checked by the iSRC during each safety 
evaluation are defined below (Table 22). Please refer to APPENDIX C for the definition 
of the Food and Drug Administration (FDA) Toxicology Grading Scale for laboratory 
abnormalities in healthy subjects.
These holding rules have been written under the assumption that the safety data will be 
available from all subjects. If the data from all subjects are not available (i.e. in case a 
subject is lost to follow-up), then the holding rules will be assessed on a pro-rata basis.
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Table 22
List of holding rules
Holding 
rule N°
Event
Number of subjects
Step 1
Step 2
1a
Death or any life-threatening SAE 
≥1
≥ 1
1b
Any withdrawal from the study (by investigator or subject request) 
following a Grade 3 AE that cannot reasonably be attributed to a 
cause other than vaccination
% 1
% 1
1c
Any local or general solicited AE leading to hospitalisation, or 
fever >40°C (104°F) that cannot reasonably be attributed to a 
cause other than vaccination, or necrosis at the injection site, 
within the 7-day (Day 0-Day 6) post-vaccination period
% 1
% 1
2a
Any Grade 3 solicited local AE lasting 48h or more in an 
investigational group, within the 7-day (Day 0-Day 6) post-
vaccination period
% 5/15 and 
% 2 
subjects/group
% 8/30 and 
% 2 
subjects/group
2b
Any Grade 3 solicited general AE lasting 48h or morein an 
investigational group, that cannot reasonably be attributed to a 
cause other than vaccination, within the 7-day (Day 0-Day 6) post-
vaccination period
% 5/15 and 
% 2 
subjects/group
% 8/30 and 
% 2 
subjects/group
2c
Any Grade 3 unsolicited AE in an investigational group, that 
cannot reasonably be attributed to a cause other than vaccination, 
within the 7-day (Day 0-Day 6) post-vaccination period or
Any Grade 3 abnormality in pre-specified haematological or 
biochemical laboratory parameters* in an investigational group 
within the 7-day (Day 0-Day 6) post-vaccination period
% 5/15 and 
% 2 
subjects/group
% 8/30 and 
% 2 
subjects/group
* i.e. haemoglobin, WBC, platelets, creatinine, ALT and AST
8.10.4.
Risk assessments
Figure 3 gives the probability of not meeting each holding rule 1 and 2 for the 15 subjects 
in a candidate vaccine group (as in Step 1 of this study). The figure illustrates that 
holding rule 1 has more than 86% chance of not being met for an event with a true 
incidence rate below 1.0% and has less than 3.5% of chance of not being met for an event
with a true incidence rate above 20%.
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Figure 3
Risk assessment curve for safety holding rules 1 and 2 for treatment 
arms of 15 subjects (no adjustment for multiplicity)
Figure 4 gives the probability of not meeting holding rules 1 and 2 for the 30 subjects in a 
candidate vaccine group (as in Step 2 of this study). The figure illustrates that holding 
rule 1 has more than 74% chance of not being met for an event with a true incidence rate 
below 1% and has less than 4.2% of not being met for an event with a true incidence rate 
above 10%.
Figure 4
Risk assessment curve for safety holding rules 1 and 2 for treatment 
arms of 30 subjects (no adjustment for multiplicity)
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9.
SUBJECT COMPLETION AND WITHDRAWAL
9.1.
Subject completion
A subject who returns for the concluding visit/is available for the concluding contact 
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/was not available for the concluding contact 
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:
!
SAE.
!
Non-serious AE.
!
Protocol violation (specify).
!
Consent withdrawal, not due to an AE*.
!
Moved from the study area.
!
Lost to follow-up.
!
Other (specify).
* In case a subject is withdrawn from the study because he/she 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 
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follow subjects who are withdrawn from the study as result of a SAE/AE until resolution 
of the event (see Section 8.5.1.2).
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 page/screen of the eCRF. The investigator 
will document whether the decision to discontinue further vaccination/treatment was 
made by the subject himself/herself, or by the investigator, as well as which of the 
following possible reasons was responsible for withdrawal:
!
SAE.
!
Non-SAE.
!
Other (specify).
9.3.
Screening failures
Screening failures are defined as subjects who are withdrawn from the study after giving 
informed consent, but who do not meet the inclusion and exclusion criteria.
The following information will be collected for screening failures:
!
Informed consent.
!
Inclusion/exclusion criteria.
!
Demographic data.
!
SAEs related to study participation, to concomitant use of GSK products or any fatal 
SAEs.
!
Screening conclusion.
10.
STATISTICAL METHODS
10.1.
Primary endpoints
!
Occurrence of each solicited local and general AE, during a 7-day follow-up period 
(i.e. day of vaccination and 6 subsequent days) post-Dose 1 and post-Dose 2, in all 
subjects, in all vaccine groups.
!
Occurrence of any unsolicited AEs, during a 30-day follow-up period (i.e. day of 
vaccination and 29 subsequent days) post-Dose 1 and post-Dose 2, in all subjects, in 
all vaccine groups.
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!
Occurrence of haematological and biochemical laboratory abnormalities, after 
vaccination, in all subjects, in all vaccine groups:
#
Any haematological (RBC, WBC and differential count, platelets count and 
haemoglobin level) or biochemical (ALT, AST and creatinine) laboratory 
abnormality on Day 7, Day 60, Day 67, Day 210 and Day 420.
!
Occurrence of any SAE, occurring from first vaccination (Day 0) to study conclusion 
(Day 420) in all subjects, in all vaccine groups.
!
Occurrence of any pIMD occurring from first vaccination (Day 0) to study 
conclusion (Day 420) in all subjects, in all vaccine groups.
10.2.
Secondary endpoints
!
Humoral immune response to the components of the NTHi-Mcat vaccine 
formulations, on Day 0, Day 30, Day 60, Day 90, Day 210 and Day 420, in all 
subjects, in all vaccine groups:
#
Anti-PD, anti-PE, anti-PilA and anti-UspA2 antibody concentrations.
!
Cell-mediated immune response to components of the NTHi-Mcat vaccine 
formulations, on Day 0, Day 60, Day 90, Day 210 and Day 420, in a sub-cohort of 
subjects, in all vaccine groups: 
#
Frequency of specific CD4+/CD8+ T-cells measured on cryopreserved peripheral 
blood mononuclear cells (PBMCs) and identified by flow cytometry intracellular 
cytokine staining (ICS) expressing two or more markers (such as IL-2, IL-13, 
IL-17, IFN-γ, TNF-α and CD40L).
10.3.
Determination of sample size
This study is a Phase I safety study to get a preliminary safety assessment of the vaccine 
formulations in healthy adults.
Considering the sample size of 15 in each study group in Step 1, Table 23 illustrates the 
precision one can get on the percentage of subjects with symptoms following vaccination.
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Table 23
Exact confidence interval for one proportion with 15 subjects
Number(%) of subjects
with a symptom
Exact 95% Confidence Interval (CI)
Lower Limit
Upper limit
0 (0.0)
0.0
21.8
1 (6.7)
0.2
31.9
2 (13.3)
1.7
40.5
3 (20.0)
4.3
48.1
4 (26.7)
7.8
55.1
5 (33.3)
11.8
61.6
6 (40.0)
16.3
67.7
7 (46.7)
21.3
73.4
8 (53.3)
26.6
78.7
9 (60.0)
32.3
83.7
10 (66.7)
38.4
88.2
11 (73.3)
44.9
92.2
12 (80.0)
51.9
95.7
13 (86.7)
59.5
98.3
14 (93.3)
68.1
99.8
15 (100.0)
78.2
100
Considering the sample size of 30 or less in each study group in Step 2, Figure 5
illustrates the probability of detecting an AE with a true occurrence rate of 0 - 10%.
Figure 5
Probability of not detecting an AE with a true occurrence rate of 
0-10%
The probability of detecting an AE with a true incidence of 5% is around 78.5% with 
30 subjects per group.
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10.4.
Cohorts for analyses
The following subject cohorts will be evaluated.
10.4.1.
Total vaccinated cohort
The total vaccinated cohort (TVC) will include all subjects with at least one vaccine 
administration documented:
!
A safety analysis based on the TVC will include all vaccinated subjects.
!
An immunogenicity analysis based on the TVC will include all vaccinated subjects 
for whom immunogenicity data are available.
The TVC analysis will be performed per treatment actually administered at Dose 1.
10.4.2.
According-to-protocol cohort
The ATP cohorts will be defined by epoch and will consist of all subjects from the TVC 
who will comply with eligibility criteria, study procedures up to the end of the epoch and 
had immunogenicity results in the epoch.
10.4.2.1.
According-to-protocol cohort for analysis of immunogenicity
(Epoch 001)
The ATP cohort for immunogenicity will include all subjects in the TVC:
!
Who met all eligibility criteria.
!
For whom the administration route and site of the vaccines was according to 
protocol.
!
Who complied with the vaccination schedule, as specified in Table 7.
!
Who did not receive a concomitant medication/ product/vaccine leading to the 
elimination from the ATP analysis (see Section 6.6.2) up the one month post-Dose 2 
visit (Visit 6, Day 90).
!
Who did not present with an intercurrent medical condition leading to elimination 
from the ATP analysis (see Section 6.7) up to the one month post-Dose 2 visit 
(Visit 6, Day 90).
!
Who complied with the immunogenicity blood sample timings as specified in 
Table 7 at 1 month post-Dose 2 visit (Visit 6, Day 90).
!
For whom post-Dose 2 immunogenicity results are available for at least one assay.
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10.4.2.2.
According-to-protocol cohort for analysis of persistence of 
immunogenicity (Epoch 002)
The ATP cohort for persistence of immunogenicity will include all evaluable subjects, 
i.e., those who were included in the ATP cohort for immunogenicity, or were excluded 
from this cohort solely because they had no blood samples taken or because of 
non-compliance with blood sample timings up to the one month post-Dose 2 visit 
(Visit 6, Day 90), and:
!
Who did not receive a concomitant medication/ product/vaccine leading to 
elimination from the ATP analysis for immunogenicity (see Section 6.6.2).
!
Who did not present with an intercurrent medical condition leading to elimination 
from the ATP analysis for immunogenicity (see Section 6.7).
!
Who complied with at least one of the blood sample timings after the one month 
post-last vaccination visit (Visit 6, Day 90) as specified in Table 7.
!
For whom persistence immunogenicity results are available for at least one assay in 
at least one of the two persistence time points (Visit 7, Day 210 and Visit 8, 
Day 420).
10.5.
Derived and transformed data
The study groups will be defined by treatment actually administered at Dose 1.
Demography
!
For a given subject and a given demographic variable, missing measurement will not 
be replaced.
Immunogenicity
!
For a given subject and the analysis of a given immunogenicity measurement, 
missing or un-evaluable measurements will not be replaced.
!
A seronegative subject is defined as a subject whose antibody concentration is below 
the assay cut-off value.
!
A seropositive subject is defined as a subject whose antibody concentration is greater 
than or equal to the assay cut-off value.
!
Antibody concentrations below the assay cut-off will be given an arbitrary value of 
half the assay cut-off for the purpose of geometric mean concentration (GMC) 
calculation.
!
Calculation of the GMCs will be performed by taking the anti-logarithm in base 10 
(anti-log10) of the mean of the log10 concentration/titre transformations.
!
All confidence intervals (CIs) computed will be two-sided 95% CIs.
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Safety/reactogenicity
!
For solicited symptoms, the analysis will exclude subjects with missing or un-
evaluable measurements (e.g. total analysis of solicited symptoms will include all 
vaccinated subjects with documented solicited symptom sheets).
!
For the unsolicited symptoms and concomitant medications/ products/ 
vaccinations, subjects who did not report unsolicited symptoms/concomitant 
medications/ products/ vaccinations will be treated as subjects without unsolicited 
symptoms or concomitant medications/ products/ vaccinations, respectively.
10.6.
Statistical analysis
The final analyses will be descriptive and will be presented by study group.
10.6.1.
Analysis of demographics
!
Demographic characteristics (age at the first dose in years, gender and race), cohort 
description, withdrawal status will be summarised by group using descriptive 
statistics:
#
Frequency tables will be generated for categorical variables such as race;
#
Mean, median and standard error will be provided for continuous data such as 
age.
!
The distribution of subjects enrolled among the study sites will be tabulated as a 
whole and per group.
!
Withdrawal status will be summarised by group using descriptive statistics:
#
The numbers of withdrawn subjects will be tabulated according to the reason for 
withdrawal.
!
The number of subjects enrolled into the study as well as the number of subjects 
excluded from ATP analyses will be tabulated.
10.6.2.
Analysis of safety
The primary analysis will be performed on the TVC and, if in any vaccine group and at 
any time point the percentage of vaccinated subjects excluded from the ATP cohort is at 
least 10%, a second analysis will be performed on the ATP cohort to complement the 
TVC.
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 7-day or 
30-day follow-up period will be tabulated after Dose 1 and Dose 2 and overall with exact 
95% CI. The same computations will be done for Grade 3 AEs, any AEs causally related 
to vaccination and any Grade 3 AEs causally related to vaccination. 
The percentage of subjects/doses reporting each individual solicited local (any grade, 
Grade 3) and general (any grade, Grade 3, any causally related to vaccination and any 
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Grade 3 causally related to vaccination) AE during the 7-days (Day 0 to Day 6) follow-up 
period will be tabulated for each group as follows:
!
Overall, the percentage of subjects with the symptom and its exact 95% CI.
!
Overall, the percentage of doses with the symptom and its exact 95% CI.
!
At each study dose (visit), the percentage of subjects with the symptom and its exact 
95% CI.
The exact 95% CIs will be calculated assuming independence between doses. For fever, 
additional analyses will be performed by 0.5°C increments.
The verbatim reports of unsolicited symptoms will be reviewed by a physician and the 
signs and symptoms will be coded according to the MedDRA Dictionary for Adverse 
Reaction Terminology. Every verbatim term will be matched with the appropriate 
preferred term (PT). The percentage of subjects with unsolicited symptoms within 30 
days after any doses with its exact 95% CI will be tabulated by group and by MedDRA 
PT. Similar tabulation will be done for Grade 3 unsolicited symptoms, for unsolicited 
symptoms that resulted in a medically attended visit, for unsolicited symptoms causally 
related to vaccination and for Grade 3 symptoms causally related to the vaccination.
For each group and for each haematology and biochemistry parameter:
!
The percentage of subjects having haematology and biochemistry results below or 
above the normal laboratory ranges will be tabulated by time point.
!
The maximum grading from Screening up to Visit 8 (Day 420) will be tabulated 
(grades will be based on local laboratory normal ranges and derived from FDA 
Guidance to Industry “Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials”, see APPENDIX C.
Those laboratory parameters not included in the FDA grading scale will not be 
graded).
The number of subjects who experienced at least one SAE or any pIMDs during the 
entire study period will be reported.
The percentage of subjects/dose using concomitant medication/ product (any 
medication/ product, any antipyretic and any antipyretic taken prophylactically, 
respectively) during the 30-day follow-up period (Day 0 – Day 29) will be summarised 
per group for each dose and overall per dose.
The number of subjects who experienced any AE leading to study withdrawal, from 
first vaccination up to study conclusion, or any SAE related to study participation of 
concurrent GSK medication/ vaccination, during the entire study period, will be 
reported.
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iSRC safety evaluations
At each iSRC time point, a blinded review will be done by the GSK SRT followed by an 
unblinded review of safety data by the iSRC (refer to Section 8.10 for more information). 
No individual clinical study report (CSR) will be written as a result of these safety 
evaluations.
10.6.3.
Analysis of immunogenicity
The primary analysis will be performed on the ATP cohort for immunogenicity and if, in 
any study group, the percentage of vaccinated subjects with serological results excluded 
from the ATP cohort is at least 10%, a second analysis will be performed on the TVC. 
10.6.3.1.
Humoral immune response
Within group evaluation
For each group, at each time point during which blood samples are collected for humoral 
immune response and for each assay:
!
Seropositivity rate and their exact 95% CI will be tabulated.
!
GMCs and their 95% CI will be calculated.
!
Antibody concentrations distribution will be investigated using Reverse Cumulative 
Curves.
These analyses will also be performed for each level of the following minimisation 
factors: age (50-59 years vs. 60-70 years), smoking status (current vs. former smoker), 
FEV1/FCV ratio (≥0.7 vs. <0.7).
Between groups evaluation (only for Step 2)
Comparative analyses will be exploratory with the aim to characterise the difference 
between the 10-10-10-AS and 10-10-3-AS groups in humoral immune response.
The difference in terms of GMCs will be evaluated, one month post-Dose 2, by 
computing the 95% CIs of the GMC ratio between groups for Step 2 by using a one-way 
ANCOVA model on the logarithm10 transformation of the concentrations/ titres. The 
ANCOVA model will include the group category, the age category, the smoking status 
and FEV1/FVC (% 0.7 or < 0.7) and the pre-Dose 1 concentration (as covariate) as fixed 
effects. The groups will be considered significantly different if the 95% CI for the GMC 
ratio between the two groups does not contain the value 1. (Amended 16 March 2016)
However, these differences should be interpreted with caution considering that there will 
be no adjustment for multiplicity of endpoints.
10.6.3.2.
CMI response
The frequency of specific CD4+/CD8+ T-cells will be summarised (descriptive statistics) 
by group in Step 2 at each time point during which blood samples are collected for CMI.
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10.6.3.3.
Summary score to support dose selection
For each group in Step 2, a summary score at one month post-Dose 2 (Day 90) will 
summarise how well the group is performing in terms of immunogenicity and CMI 
results. The calculation of a summary score for both active groups (i.e. 10-10-10-AS and 
10-10-3-AS) will be proposed in order to help the formulation selection as a higher 
summary score indicates a higher global immunogenicity and CMI response.
The summary scores will be calculated based on the subjects from the ATP cohort.
The calculation of these summary scores from immunogenicity data for the interim, and 
from immunogenicity data and CMI data for the final analyses, and the strategy for their 
use in the dose selection will be presented more in detail in the Statistical Analysis Plan.
10.7.
Interpretation of analyses
Comparative analyses with the aim to characterise the difference in reactogenicity/ 
immunogenicity between groups will be descriptive. These descriptive analyses should be 
interpreted with caution as neither the power or type I error are controlled for.
10.8.
Conduct of analyses
Any deviation(s) or change(s) from the original statistical plan outlined in this protocol 
will be described and justified in the final study report.
10.8.1.
Sequence of analyses
!
The analysis of data up to Visit 6 (Day 90, end of Epoch 001) will be performed in a 
first step. This analysis will include:
#
The final analysis of all immunogenicity results (including CMI), solicited AEs 
post-Dose 1 and post-Dose 2,
#
The assessment of unsolicited AEs up to 30 days post-Dose 1 and post-Dose 2, 
and of SAEs and pIMDs up to 30 days post-Dose 2 on as cleaned as possible 
data. No individual listings will be written at this stage.
This analysis will be documented in a statistical report. At this point, the GSK 
statistician will be unblinded (i.e. will have access to the individual subject treatment 
assignments).
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!
The analysis of Epoch 002 (from Visit 7 [Day 210] up to Visit 8 [Day 420]) will be 
performed in a second step, once those data will be available and cleaned. This 
analysis will include:
#
The final analysis of all immunogenicity results (including CMI) up to Visit 8 
(Day 420).
#
SAEs and pIMDs up to Visit 8 (Day 420) on cleaned data.
In addition, all previous analyses will be re-produced based on cleaned data at this 
point.
Individual listings will only be provided at this stage.
All study results will be presented in an integrated study report at the end of the study.
(Amended 16 March 2016)
10.8.2.
Statistical considerations for interim analyses
No adjustment for multiplicity will be performed for the comparative analyses since they 
are all descriptive and will all be performed on final data.
11.
ADMINISTRATIVE MATTERS
To comply with ICH GCP administrative obligations relating to data collection, 
monitoring, archiving data, audits, confidentiality and publications must be fulfilled. 
11.1.
Electronic Case Report Form instructions
A validated GSK defined electronic data collection tool will be used as the method for 
data collection. 
In all cases, subject initials will not be collected nor transmitted to GSK. Subject data 
necessary for analysis and reporting will be entered/transmitted into a validated database 
or data system. Clinical data management will be performed in accordance with 
applicable GSK standards and data cleaning procedures.
While completed eCRFs are reviewed by a GSK Biologicals’ Site Monitor at the study 
site, omissions or inconsistencies detected by subsequent eCRF review may necessitate 
clarification or correction of omissions or inconsistencies with documentation and 
approval by the investigator or appropriately qualified designee. In all cases, the 
investigator remains accountable for the study data. 
The investigator will be provided with a CD-ROM of the final version of the data 
generated at the investigational site once the database is archived and the study report is 
complete and approved by all parties.
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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 an 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.
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.
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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 enrolment of subjects begins.
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.
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12.
COUNTRY SPECIFIC REQUIREMENTS
Not applicable.
13.
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Immuno 2011; 31: 443-54.
Murphy TF, Brauer AL, Grant BJ, et al. Moraxella catarrhalis in chronic obstructive 
pulmonary disease: burden of disease and immune response. Am J Respir Crit Care Med
2005;172:195-9.
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Novotny LA, Jurcisek JA, Godfroid F, et al. Passive immunization with human 
anti-protein D antibodies induced by polysaccharide protein D conjugates protects 
chinchillas against otitis media after intranasal challenge with Haemophilus influenzae.
Vaccine 2006;24:4804-11.
Novotny LA, Adams LD, Kang RD, et al. Epitope mapping immunodominant regions of 
the PilA protein of non-typeable Haemophilus influenzae (NTHi) to facilitate the design 
of two novel chimeric vaccine candidates. Vaccine 2009;28:279-289.
Nseir S, Ader F. Prevalence and outcome of severe chronic obstructive pulmonary 
disease exacerbations caused by multidrug-resistant bacteria. Curr Opin Pulm Med
2008;14:95-100.
Papi A, Bellettato CM, Braccioni F, et al. Infections and airway inflammation in chronic 
obstructive pulmonary disease severe exacerbations. Am J Respir Crit Care Med
2006;173:1114-21.
Rabe KF, Hurd S, Anzueto, et al. Global Strategy for the Diagnosis, Management, and 
Prevention of Chronic Obstructive Pulmonary Disease. GOLD Executive Summary. Am J 
Respir Crit Care Med 2007;176:532-555.
Ronander E, Brant M, Eriksson E, et al. non-typeable Haemophilus influenzae Adhesin 
Protein E: Characterization and Biological Activity. J Infect Dis 2009;199:522-31.
Rosell A, Monsó E, Soler N, et al. Microbiologic determinants of exacerbation in chronic 
obstructive pulmonary disease. Arch Intern Med 2005;165: 891-7.
Sapey E, Stockley RA. COPD exacerbations 2: aetiology. Thorax 2006;61:250-8.
Sethi S, Evans N, Grant BJ, et al. New strains of bacteria and exacerbations of chronic 
obstructive pulmonary disease. N Engl J Med 2002;347:465-71.
Sethi S, Murphy TF. Infection in the pathogenesis and course of chronic obstructive 
pulmonary disease. N Engl J Med 2008;359:2355-65.
Takanashi S, Hasegawa Y, Kanehira Y, et al. Interleukin-10 level in sputum is reduced in 
bronchial asthma, COPD and in smokers. Eur Respir J 1999;14:309-314.
Weinberger B, Herndler-Brandstetter D, Schwanninger A, et al. Biology of Immune 
Responses to Vaccines in Elderly Persons. Clin Infect Dis 2008;46:1078-84.
Wilkinson TM, Hurst JR, Perera WR, et al. Effect of interactions between lower airway 
bacterial and rhinoviral infection in exacerbations of COPD. Chest 2006;129:317-24.
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APPENDIX A
LABORATORY ASSAYS
Humoral immunity
Serological assays will be performed at GSK Biologicals’ laboratory or in a GSK 
designated laboratory using assays as described in Table 10.
Anti-PD antibodies
Anti-PD antibodies will be determined using an ELISA assay developed by GSK 
Biologicals. Concentration of specific anti-PD antibodies will be determined, using 
in-house made reference serum. The current cut-off of the assay is 153 EL.U/mL.
(Amended 16 March 2016)
Anti-PE antibodies
Anti-PE antibodies will be determined using an ELISA assay developed by GSK 
Biologicals. Concentration of specific anti-PE antibodies will be determined, using in-
house made reference serum. The cut-off of the assay is 8 EL.U/mL.
Anti-PilA antibodies
Anti-PilA antibodies will be determined using an ELISA assay developed by GSK 
Biologicals. Concentration of specific anti-PilA antibodies will be determined, using an 
in-house made reference serum. The cut-off of the assay is 7 EL.U/mL.
Anti-UspA2 antibodies
Anti-UspA2 antibodies will be determined using an ELISA assay developed by GSK 
Biologicals. Concentration of specific anti-UspA2 antibodies will be determined, using 
an in-house made reference serum. The cut-off of the assay is 18 EL.U/mL.
Cell-mediated immunity
CMI assays will be performed at GSK Biologicals' laboratory or in a GSK designated 
laboratory using assays as described in Table 11.
The ICS staining assay will be used to assess CMI responses, using an adaptation of 
previously described methods [Moris, 2011]. After PBMC stimulation with the relevant 
antigens, the frequency of CD4+ and/or CD8+ T-cells expressing selected set of cytokines 
(such as IL-2, IL-13, IL-17, IFN-γ, TNF-α and CD40L) or selected combination of 
cytokines will be evaluated by flow cytometry.
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APPENDIX B
CLINICAL LABORATORIES (Amended 16 March 
2016)
Table 24
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 25
Outsourced laboratories
Laboratory
Address
Q² Solutions
Unit B1, Parkway West Industrial Estate 
Cranford Lane – Heston, 
Middlesex TW5 9QA 
United Kingdom
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APPENDIX C
FDA’s Guidance for Industry: Toxicity Grading 
Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials 
(September 2007)
This guidance represents the Food and Drug Administration’s (FDA’s) current thinking 
on this topic. It does not create or confer any rights for or on any person and does not 
operate to bind FDA or the public. You can use an alternative approach if the approach 
satisfies the requirements of the applicable statutes and regulations. If you want to 
discuss an alternative approach, contact the appropriate FDA staff. If you cannot identify 
the appropriate FDA staff, call the appropriate number listed on the title page of this 
guidance.
i.
INTRODUCTION
Preventive vaccines are usually developed to prevent disease in a healthy population. The 
Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, 
regulates preventive vaccines under authority of section 351 of the Public Health Service 
Act (42 U.S.C. 262), as well as specific sections of the Federal Food, Drug, and Cosmetic 
Act, and reviews investigational new drug applications (INDs) and biologics license 
applications (BLAs). (See, for example, Title 21 Code of Federal Regulations (CFR) 
Parts 312, 600, and 601). Most of the clinical trials of preventive vaccines conducted to 
support INDs and BLAs enroll healthy volunteers in all phases of vaccine testing. The 
enrollment of healthy volunteers warrants a very low tolerance for risk in those clinical 
trials.
This guidance provides you, sponsors, monitors, and investigators of vaccine trials, with 
recommendations on assessing the severity of clinical and laboratory abnormalities in 
healthy adult and adolescent volunteers enrolled in clinical trials. The grading system 
described in the table can also be useful in defining a particular study’s stopping rules 
(e.g. a certain number of adverse events, as defined in the table, may call for stopping the 
study). Less extreme observations (e.g. mild) may not require discontinuing the study 
vaccine but can still contribute to evaluating safety by identifying parameters to focus 
upon in subsequent product development. Uniform criteria for categorizing toxicities in 
healthy volunteers can improve comparisons of safety data among groups within the 
same study and also between different studies. We, FDA, recommend using toxicity 
grading scale tables, provided below, as a guideline for selecting the assessment criteria 
to be used in a clinical trial of a preventive vaccine. We recommend incorporation of 
such appropriate, uniform, criteria into the investigational plan, case report forms, and 
CSRs and correspondence with FDA, sponsors, monitors, investigators, and Institutional 
Review Boards (IRBs).
This guidance finalizes the draft guidance of the same title dated April 2005 
(70 FR 22664, May 2, 2005).
FDA’s guidance documents, including this guidance, do not establish legally enforceable 
responsibilities. Instead, guidances describe FDA’s current thinking on a topic and should 
be viewed only as recommendations, unless specific regulatory or statutory requirements 
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are cited. The use of the word should in FDA’s guidances means that something is 
suggested or recommended, but not required.
ii.
BACKGROUND
Standardised toxicity assessment scales have been widely used to evaluate products 
treating specific diseases. For example, the National Cancer Institute’s Common Toxicity 
Criteria Scale and the Division of AIDS’ Toxicity Grading Scale standardize the 
evaluation of adverse events among patients with cancer and HIV/AIDS, respectively 
(Refs. 1, 2). The defined toxicity parameters in those scales are designed for patients who 
may already experience mild, moderate, or severe adverse clinical or laboratory events 
due to the disease process, and may not be appropriate for healthy volunteers.
In the development of the toxicity grading scales for healthy volunteers, we chose 
parameter limit values based on published information, when such values were available 
(Refs. 1-6). For example, the Brighton Collaboration has developed case definitions and 
guidelines to evaluate some adverse events associated with administering vaccines 
(Ref. 3). In some cases, parameter limit values were based on clinical experience and 
experience reviewing vaccine clinical trials that enrol normal healthy subjects.
Toxicity grading scales for laboratory abnormalities should consider the local laboratory 
reference values when the parameter limit values are defined. The characterization of 
laboratory parameters among some populations of healthy adults and adolescents may 
require the exercise of clinical judgment, for example, consideration of the potential for 
ethnic differences in white blood cell (WBC) counts or gender differences in creatine 
phosphokinase (CPK) values.
iii. TOXICITY GRADING SCALE TABLES
Adverse events in a clinical trial of an investigational vaccine must be recorded and 
monitored and, when appropriate, reported to FDA and others involved in an
investigation (sponsors, IRBs, and investigators). (See, for example, 21 CFR 312.32, 
312.33, 312.50, 312.55, 312.56, 312.60, 312.62, 312.64, and 312.66). Although the use of 
a toxicity grading scale for adverse events would not replace these regulatory 
requirements, using a scale to categories adverse events observed during a clinical trial 
may assist you in monitoring safety and making required reports. Nonetheless, we believe 
that categorization or grading of data as outlined in this document is supplementary to 
and should not replace full and complete data analysis.
These guidelines for toxicity grading scales are primarily intended for healthy adult and 
adolescent volunteers. The parameters in the tables below are not necessarily applicable 
to every clinical trial of healthy volunteers. The parameters monitored should be 
appropriate for the specific study vaccine. For some preventive vaccines under 
development, it may be appropriate to include additional parameters to be monitored 
during a clinical trial or to alter the choice of values in the toxicity table. For example, 
additional parameters might be added based on one or more of the following: safety 
signals observed in pre-clinical toxicology studies, the biological plausibility of the 
occurrence of certain adverse events, or previous experience with a similar licensed 
product.
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As discussed above, the tables do not represent a recommendation to monitor all the 
listed parameters in all clinical trials of healthy volunteers, nor do the tables represent all 
possible parameters to be monitored. In addition, these tables do not represent study 
inclusion or exclusion criteria. We recommend that the parameters monitored be 
appropriate for the study vaccine administered to healthy volunteers participating in the 
clinical trial.
Tables for Clinical Abnormalities
Note from the sponsor: The tables in this section of the guidance will not be used in this 
particular study. Instead, the parameters as provided in the study protocol are to be used.
Tables for Laboratory Abnormalities
The laboratory values provided in the tables below serve as guidelines and are dependent 
upon institutional normal parameters. Institutional normal reference ranges should be 
provided to demonstrate that they are appropriate.
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C O N FI D E N TI A L
2 0 1 2 8 1 ( N T HI M C A T- 0 0 1)
Pr ot o c ol A m e n d m e nt 2 Fi n al
1 6- M A R- 2 0 1 6
1 0 9
T a bl e 2 6 
F D A t o xi cit y gr a di n g s c al e s f or h a e m at ol o g y/ bi o c h e mi str y 
p ar a m et er s
S er u m *
Mil d
( Gr a d e 1)
M o d er at e
( Gr a d e 2)
S e v er e
( Gr a d e 3)
P ot e nti all y Lif e
T hr e at e ni n g
( Gr a d e 4)**
S o di u m – H y p o n atr e mi a m E q/ L 
1 3 2 – 1 3 4
 1 3 0
 
– 1 3 1
 1 2 5
 
– 1 2 9
 <
 
1 2 5
 
S o di u m – H y p er n atr e mi a m E q/ L 
1 4 4 – 1 4 5
 1 4 6
 
– 1 4 7
 1 4 8
 
– 1 5 0
 >
 
1 5 0
 
P ot a s si u m – H y p er k al e mi a 
m E q/ L 
5. 1 – 5. 2
 5. 3
 
– 5. 4
 5. 5
 
– 5. 6
 >
 
5. 6
 
P ot a s si u m – H y p o k al e mi a m E q/ L 
3. 5 – 3. 6
 3. 3
 
– 3. 4
 3. 1
 
– 3. 2
 <
 
3. 1
 
Gl u c o s e – H y p o gl y c e mi a m g/ d L 
6 5 – 6 9
 5 5
 
– 6 4
 4 5
 
– 5 4
 <
 
4 5
 
Gl u c o s e – H y p er gl y c e mi a 
F a sti n g –  m g/ d L 
R a n d o m –  m g/ d L 
1 0 0 – 1 1 0 
1 1 0 – 1 2 5 
1 1 1 – 1 2 5 
1 2 6 – 2 0 0 
> 1 2 5 
> 2 0 0 
I ns uli n r e q uir e m e nts 
or hy p er os m ol ar 
c o m a 
Bl o o d Ur e a Nitr o g e n 
B U N m g/ d L 
2 3 – 2 6
 2 7
 
– 3 1
 >
 
3 1
  
R e q uir es
 
di alysis
 
Cr e ati ni n e – m g/ d L 
1. 5 – 1. 7
 1. 8
 
– 2. 0
 2. 1
 
– 2. 5  
> 2. 5 or r e q uir es 
di alysis 
C al ci u m – h y p o c al c e mi a m g/ d L 
8. 0 – 8. 4
 7. 5
 
– 7. 9
 7. 0
 
– 7. 4
 <
 
7. 0
 
C al ci u m – h y p er c al c e mi a m g/ d L 
1 0. 5 – 1 1. 0
 1 1. 1
 
– 1 1. 5
 1 1. 6
 
– 1 2. 0
 >
 
1 2. 0
 
M a g n e si u m – h y p o m a g n e s e mi a 
m g/ d L 
1. 3 – 1. 5
 1. 1
 
– 1. 2
 0. 9
 
– 1. 0
 <
 
0. 9
 
P h o s p h or o u s –
h y p o p h o s p h at e mi a m g/ d L 
2. 3 – 2. 5
 2. 0
 
– 2. 2
 1. 6
 
– 1. 9
 <
 
1. 6
 
C P K – m g/ d L 
1. 2 5 – 1. 5 x 
U L N
1. 6 – 3. 0 x 
U L N 
3. 1 – 1 0 x U L N  
> 1 0 x U L N 
Al b u mi n – H y p o al b u mi n e mi a 
g/ d L 
2. 8 – 3. 1
 2. 5
 
– 2. 7
 <
 
2. 5
  
--
T ot al Pr ot ei n – H y p o pr ot ei n e mi a 
g/ d L 
5. 5 – 6. 0
 5. 0
 
– 5. 4
 <
 
5. 0
  
--
Al k ali n e p h o s p h at e –
i n cr e a s e b y f a ct or 
1. 1 – 2. 0 x 
U L N 
2. 1 – 3. 0 x 
U L N 
3. 1 – 1 0 x 
U L N 
> 1 0 x U L N 
Li v er F u n cti o n T e st s – A L T, A S T 
i n cr e a s e b y f a ct or 
1. 1 – 2. 5 x 
U L N 
2. 6 – 5. 0 x 
U L N 
5. 1 – 1 0 x U L N  > 1 0 x U L N 
Bilir u bi n – w h e n a c c o m p a ni e d 
b y a n y i n cr e a s e i n Li v er 
F u n cti o n T e st 
i n cr e a s e b y f a ct or 
1. 1 – 1. 2 5 x 
U L N 
1. 2 6 – 1. 5 x 
U L N 
1. 5 1 – 1. 7 5 x 
U L N 
> 1. 7 5 x U L N 
Bilir u bi n – w h e n Li v er F u n cti o n 
T e st i s n or m al; i n cr e a s e b y 
f a ct or 
1. 1 – 1. 5 x 
U L N 
1. 6 – 2. 0 x 
U L N 
2. 0 – 3. 0 x 
U L N 
> 3. 0 x U L N 
C h ol e st er ol 
2 0 1 – 2 1 0
 2 1 1
 
– 2 2 5
 >
 
2 2 6
  
---
P a n cr e ati c e nz y m e s – a m yl a s e, 
li p a s e 
1. 1 – 1. 5 x 
U L N 
1. 6 – 2. 0 x 
U L N 
2. 1 – 5. 0 x 
U L N 
> 5. 0 x U L N 
* T h e l a b or at ory v al u es pr ovi d e d i n t h e t a bl es s erv e as g ui d eli n es a n d ar e d e p e n d e nt u p o n i nstit uti o n al n or m al 
p ar a m et ers. I nstit uti o n al n or m al r ef er e nc e r a n g es s h o ul d b e pr ovi d e d t o d e m o nstr at e t h at t h ey ar e a p pr o pri at e.
** T h e cli nic al si g ns or sy m pt o ms ass oci at e d wit h l a b or at ory a b n or m aliti es mi g ht r es ult i n c h ar act eris ati o n of t h e 
l a b or at ory a b n or m aliti es as P ot e nti ally Lif e T hr e at e ni n g ( Gr a d e 4). F or ex a m pl e, a l o w s o di u m v al u e t h at f alls wit hi n a 
gr a d e 3 p ar a m et er ( 1 2 5- 1 2 9 m E/ L) s h o ul d b e r ec or d e d as a gr a d e 4 hy p o n atr e mi a ev e nt if t h e s u bj ect h a d a n e w 
s eiz ur e ass oci at e d wit h t h e l o w s o di u m v al u e.
U L N is t h e u p p er li mit of t h e n or m al r a n g e.
C O N FI D E N TI A L
2 0 1 2 8 1 ( N T HI M C A T- 0 0 1)
Pr ot o c ol A m e n d m e nt 2 Fi n al
1 4 5 c 1 6f 3 3 d c 4 7 bf a 4 6 d d 1 a 0 6f 0 3 4 4f d c 2 4 8 8 7 9 4 1
1 0 9
1 6- M A R- 2 0 1 6

C O N FI D E N TI A L
2 0 1 2 8 1 ( N T HI M C A T- 0 0 1)
Pr ot o c ol A m e n d m e nt 2 Fi n al
1 6- M A R- 2 0 1 6
1 1 0
H a e m at ol o g y *
Mil d
( Gr a d e 1)
M o d er at e
( Gr a d e 2)
S e v er e
( Gr a d e 3)
P ot e nti all y Lif e T hr e at e ni n g
( Gr a d e 4)
H a e m o gl o bi n ( F e m al e) -
g m/ d L 
1 1. 0 – 1 2. 0
 9. 5
 
– 1 0. 9
 8. 0
 
– 9. 4
 <
 
8. 0
 
H a e m o gl o bi n ( F e m al e) 
c h a n g e fr o m b a s eli n e v al u e 
- g m/ d L 
A ny d ecr e as e 
– 1. 5 
1. 6 – 2. 0
 2. 1
 
– 5. 0
 >
 
5. 0
 
H a e m o gl o bi n ( M al e) - g m/ d L 
1 2. 5 – 1 3. 5
 1 0. 5
 
– 1 2. 4
 8. 5
 
– 1 0. 4
 <
 
8. 5
 
H a e m o gl o bi n ( M al e) 
c h a n g e fr o m b a s eli n e v al u e 
– g m/ d L 
A ny d ecr e as e 
– 1. 5 
1. 6 – 2. 0
 2. 1
 
– 5. 0
 >
 
5. 0
 
W B C I n cr e a s e - c ell/ m m
3
1 0, 8 0 0 –
1 5, 0 0 0 
1 5, 0 0 1 –
2 0, 0 0 0 
2 0, 0 0 1 –
2 5, 0 0 0 
> 2 5, 0 0 0 
W B C D e cr e a s e - c ell/ m m
3
2, 5 0 0 – 3, 5 0 0
 1, 5 0 0
 
– 2, 4 9 9
 1, 0 0 0
 
–
1, 4 9 9 
< 1, 0 0 0 
L y m p h o c yt e s D e cr e a s e -
c ell/ m m
3
7 5 0 – 1, 0 0 0
 5 0 0
 
– 7 4 9
 2 5 0
 
– 4 9 9
 <
 
2 5 0
 
N e utr o p hil s D e cr e a s e -
c ell/ m m
3
1, 5 0 0 – 2, 0 0 0
 1, 0 0 0
 
– 1, 4 9 9
 5 0 0
 
– 9 9 9
 <
 
5 0 0
 
E o si n o p hil s - c ell/ m m
3
6 5 0 – 1 5 0 0
 1 5 0 1
 
- 5 0 0 0
 >
 
5 0 0 0
  Hy p er e osi n o p hilic
 
Pl at el et s D e cr e a s e d -
c ell/ m m
3
1 2 5, 0 0 0 –
1 4 0, 0 0 0 
1 0 0, 0 0 0 –
1 2 4, 0 0 0 
2 5, 0 0 0 –
9 9, 0 0 0 
< 2 5, 0 0 0 
P T – i n cr e a s e b y f a ct or 
( pr ot hr o m bi n ti m e) 
1. 0 – 1. 1 0 x 
U L N
1. 1 1 – 1. 2 0 
x U L N 
1. 2 1 – 1. 2 5 
x U L N 
> 1. 2 5 U L N 
P T T – i n cr e a s e b y f a ct or 
( p arti al t hr o m b o pl a sti n 
ti m e) 
1. 0 – 1. 2 x 
U L N 
1. 2 1 – 1. 4 x 
U L N 
1. 4 1 – 1. 5 x 
U L N 
> 1. 5 x U L N 
Fi bri n o g e n i n cr e a s e -  m g/ d L 
4 0 0 – 5 0 0
 5 0 1
 
– 6 0 0
 >
 
6 0 0
  --
Fi bri n o g e n d e cr e a s e -
m g/ d L 
1 5 0 – 2 0 0
 1 2 5
 
– 1 4 9
 1 0 0
 
– 1 2 4  
< 1 0 0 or ass oci at e d wit h gr oss 
bl e e di n g or diss e mi n at e d 
i ntr av asc ul ar c o a g ul ati o n ( DI C) 
* T h e l a b or at ory v al u es pr ovi d e d i n t h e t a bl es s erv e as g ui d eli n es a n d ar e d e p e n d e nt u p o n i nstit uti o n al n or m al 
p ar a m et ers. I nstit uti o n al n or m al r ef er e nc e r a n g es s h o ul d b e pr ovi d e d t o d e m o nstr at e t h at t h ey ar e a p pr o pri at e.
U L N is t h e u p p er li mit of t h e n or m al r a n g e.
i v.  R E F E R E N C E S f or t he A p pe n di x C
1.  
Nati o nal Ca ncer I nstit ute C o m m o n T o xicit y Criteria, A pril 3 0, 1 9 9 9. 
(htt p://cte p.c a ncer. g ov/re p orti n g/ C T C- 3. ht ml ).
2.  
Di visi o n of AI D S Ta ble f or Gra di n g Se verit y of A d ult A d verse E x perie nces; 
A u g ust 1 9 9 2. ( htt p://rcc.tec h-res-i ntl.c o m/t ox _t a bles. ht m ).
3. 
T he Bri g ht o n C olla b orati o n. Fi nalize d Case Defi niti o ns a n d G ui deli nes. 
(htt p:// bri g ht o nc oll a b or ati o n. or g/i nter net/e n/i n dex/ defi niti o n _ g ui deli nes. ht ml ).
4.  
HI V Vacci ne Trials Net w or k Ta ble f or Gra di n g Se verit y of A d verse E x perie nces; 
Se pte m ber 1 8, 2 0 0 2. ( htt p://rcc.tec h-res-i ntl.c o m/t ox _t a bles. ht m ).
5.  
Di visi o n of AI D S Ta ble f or Gra di n g t he Se verit y of A d ult a n d Pe diatric A d verse 
E ve nts, Dece m ber 2 0 0 4. 
(htt p:// w w w 3. ni ai d. ni h. g ov/rese arc h/res o urces/ D AI D S Cli n Rsrc h/ P D F/ S afety/ D AI D S
A E Gr a di n g T a ble. p df ).
6.  
Kratz A, Ferrar o M, Sl uss P M, Le wa n dr o ws ki K B. La b orat or y Refere nce 
Val ues. E n gl J Me d 2 0 0 4; 3 5 1: 1 5 4 8- 1 5 6 3.
C O N FI D E N TI A L
2 0 1 2 8 1 ( N T HI M C A T- 0 0 1)
Pr ot o c ol A m e n d m e nt 2 Fi n al
1 4 5 c 1 6f 3 3 d c 4 7 bf a 4 6 d d 1 a 0 6f 0 3 4 4f d c 2 4 8 8 7 9 4 1
1 1 0
1 6- M A R- 2 0 1 6

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APPENDIX D
AMENDMENTS AND ADMINISTRATIVE 
CHANGES TO THE PROTOCOL
GlaxoSmithKline Biologicals
Clinical Research & Development
Protocol Amendment 1
eTrack study number 
and Abbreviated Title(s)
201281 (NTHI MCAT-001)
Amendment number:
Amendment 1
Amendment date:
30 July 2015
Co-ordinating author:
, Scientific Writer, XPE Pharma for GSK 
Biologicals
Rationale/background for changes: 
!
The definition of adequate contraception has been aligned with the Heads of 
Medicines Agencies (HMA) Clinical Trial Facilitation Group (CTFG) guidance
‘Recommendations related to contraception and pregnancy testing in clinical trials’ 
(2014).
!
The blood sample volume has been adapted as follows:
#
Safety samples: ~5.5 mL per visit instead of ~10 mL.
#
CMI sample: ~20 mL per visit instead of ~30 mL.
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections:
LIST OF ABBREVIATIONS
ATS
American Thoracic Society
ERS
European Respiratory Society
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GLOSSARY OF TERMS
Adequate contraception
Adequate contraception is defined as:
1.
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,
!
current tubal ligation,
!
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.
2.
a contraceptive method with failure rate of more 
than 1% per year but still considered as acceptable 
birth control method:
!
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.
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Section 4.2.1 Healthy adults 18-40 years old (Step 1)
!
Female subjects of non-childbearing potential may be enrolled in the study. 
#
Non-childbearing potential is defined as pre-menarche, current tubal ligation,
hysterectomy, ovariectomy or post-menopause.
Section 4.2.2 Current and former smokers 50-70 years old (Step 2)
!
Female subjects of non-childbearing potential may be enrolled in the study.
#
Non-childbearing potential is defined as pre-menarche, hysterectomy, current 
tubal ligation, ovariectomy or post-menopause.
Section 5.5 Outline of study procedures
Table 5
List of study procedures for healthy adults 18-40 years old (Step 1)
Epoch
Epoch 001
Epoch 002
Type of contact
Screening 
Visit
Visit 
1
Visit 
2
Visit 
3
Visit 
4
Visit 
5
Visit 
6
Visit 
7
Visit 
8
Time points
pre-Day 0 Day 0 Day 7 Day 
30
Day 
60
Day 
67
Day 
90
Day 
210
Day 
420
Sampling time points
Screening
Pre
Post-Vacc I 
Post-Vacc II
Informed consent
●
Check inclusion/exclusion criteria
●(d)
O
Collect demographic data
●
Medical history
O(d)
●
Measure/record height and weight
●
●
Physical examination
●(d, e)
O
O
O
O
O
O
O
O
Urine pregnancy test (a)
●
●
●
Check contraindications
O
O
Pre-vaccination body temperature
●
●
Treatment number allocation (b)
●
●
Blood sampling for safety assessment 
(∃105.5 mL)
●(d)
●
●
●
●
●
●
Blood sampling for antibody determination and 
assay development (∃20 mL)
●
●
●
●
●
●
Vaccine administration
●
●
Distribution of Diary Cards (c)
O
O
O
O
Return of Diary Cards
O
O
O
O
Diary Card transcription by investigator
●
●
●
●
Recording of AEs
●
●
●
●
●
●
Recording of SAEs
●(f)
●
●
●
●
●
●
●
●
Recording of pIMDs
●
●
●
●
●
●
●
●
Recording of pregnancies
●
●
●
●
●
●
●
●
Record concomitant medication/vaccination (g)
●
●
●
●
●
●
●
●
Record intercurrent medical conditions requiring 
medical attention
●
●
●
●
●
●
●
●
Screening conclusion
●
Study conclusion
●
Note: The double-line borders following Day 90 and Day 420 indicates the statistical analyses which will be performed 
on all data (i.e. data that are as clean as possible) obtained up to Day 90 and Day 420, respectively.
Vacc: Vaccination; AEs: Adverse events; SAEs: Serious adverse events; pIMDs: potential immune-mediated disease.
● is used to indicate a study procedure that requires documentation in the individual eCRF.
O is used to indicate a study procedure that does not require documentation in the individual eCRF.
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(a) A urine pregnancy test will be performed only for women of childbearing potential.
(b)Treatment number allocation with randomisation at Visit 1 (Day 0); treatment number allocation without 
randomisation at Visit 4 (Day 60).
(c) Distribution of 2 Diary Cards after each vaccination:
–
a 1st one distributed on the day of vaccination for recording of solicited and unsolicited AEs and concomitant 
medications/ products and vaccinations from Day 0 to Day 6 after each vaccination.
–
a 2nd one distributed on the 7 day post-vaccination visit for recording of unsolicited AEs and concomitant 
medications/ products and vaccinations from Day 7 to Day 29 after each vaccination.
(d) Screening evaluations may be completed 1 to 28 days before Day 0. Site staff should allow sufficient time between 
the Screening and Visit 1 to receive and review screening safety laboratory test results. If a delay occurs such that the 
interval between Screening and the Visit 1 vaccination exceeds 28 days, a re-screening visit should be scheduled 
before Visit 1 during which blood sample collection for safety laboratory assessment must be repeated; an interim 
medical history and physical examination must be obtained and inclusion / exclusion criteria must be re-reviewed.
(e) Complete physical examination including vital signs.
(f) From Screening to Visit 1, only those SAEs that are considered related to study participation or to concomitant use of 
GSK products or any fatal events need to be recorded. GSK products or any fatal event need to be recorded.
(g) Concomitant medication products/vaccination as indicated in Section 6.6.1 need to be recorded.
Table 6
List of study procedures for current or former smokers 50-70 years 
old (Step 2)
Epoch
Epoch 001
Epoch 002
Visit 6
Screening 
Visit
Visit 
1
Visit 
2
Visit 
3
Visit 
4
Visit 
5
Visit 
6
Visit 
7
Visit 
8
Time points
pre-Day 0 Day 
0
Day 
7
Day 
30
Day 
60
Day 
67
Day 
90
Day 
210 
Day 
420 
Sampling time points
Screening Pre
Post-Vacc I
Post-Vacc II
Informed consent
●
Check inclusion/exclusion criteria
●(e)
O
Collect demographic data
●
Medical history
O(e)
●
Smoking status
●
●
●
Smoking exposure history
●
Measure/record height and weight
●
●
Spirometry
●
●
Physical examination
●(e, f)
O
O
O
O
O
O
O
O
Urine pregnancy test (a)
●
●
●
Check contraindications
O
O
Pre-vaccination body temperature
●
●
Treatment number allocation(b)
● 
● 
Blood sampling for safety assessment 
(∃105.5 mL)
●(e)
●
●
●
●
●
●
Blood sampling for antibody determination and assay 
development (∃20 mL)
●
●
●
●
●
●
Blood sampling for CMI response (∃3020 mL)(c)
●
●
●
●
●
Vaccine administration
●
●
Distribution of Diary Cards(d)
O
O
O 
O
Return of Diary Cards
O
O
O
O
Diary Card transcription by investigator
●
●
●
●
Recording of AEs
●
●
●
●
●
●
Recording of SAEs
●(g)
●
●
●
●
●
●
●
●
Recording of pIMDs
●
●
●
●
●
●
●
●
Recording of pregnancies
●
●
●
●
●
●
●
●
Record concomitant medication/vaccination(h)
●
●
●
●
●
●
●
●
Record intercurrent medical conditions requiring 
medical attention
●
●
●
●
●
●
●
●
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Epoch
Epoch 001
Epoch 002
Visit 6
Screening 
Visit
Visit 
1
Visit 
2
Visit 
3
Visit 
4
Visit 
5
Visit 
6
Visit 
7
Visit 
8
Time points
pre-Day 0 Day 
0
Day 
7
Day 
30
Day 
60
Day 
67
Day 
90
Day 
210 
Day 
420 
Sampling time points
Screening Pre
Post-Vacc I
Post-Vacc II
Screening conclusion
●
Study conclusion
●
Note: The double-line borders following Day 90 and Day 420 indicates the statistical analyses which will be performed 
on all data (i.e. data that are as clean as possible) obtained up to Day 90 and Day 420, respectively.
Vacc: Vaccination; CMI: Cell-mediated immunity; AEs: Adverse events; SAEs: Serious adverse events; pIMDs:
potential immune-mediated disease.
● is used to indicate a study procedure that requires documentation in the individual eCRF.
O is used to indicate a study procedure that does not require documentation in the individual eCRF.
(a) A urine pregnancy test will be performed only for women of childbearing potential.
(b) Treatment number allocation with randomisation at Visit 1 (Day 0); treatment number allocation without 
randomisation at Visit 4 (Day 60).
(c) Only for subjects belonging to the CMI sub-cohort. 
(d)Distribution of 2 Diary Cards after each vaccination:
–
a 1st one distributed on the day of vaccination for recording of solicited and unsolicited AEs and concomitant 
medications/ products and vaccinations from Day 0 to Day 6 after each vaccination.
–
a 2nd one distributed on the 7 day post-vaccination visit for recording of unsolicited AEs and concomitant 
medications/ products and vaccinations from Day 7 to Day 29 after each vaccination.
(e) Screening evaluations may be completed 1 to 28 days before Day 0. Site staff should allow sufficient time between 
the Screening and Visit 1 to receive and review screening safety laboratory test results. If a delay occurs such that the 
interval between Screening and the Visit 1 vaccination exceeds 28 days, a re-screening visit should be scheduled 
before Visit 1 during which blood sample collection for safety laboratory assessment must be repeated; an interim 
medical history and physical examination must be obtained and inclusion / exclusion criteria must be re-reviewed.
(f) Complete physical examination including vital signs.
(g) From Screening to Visit 1, only those SAEs that are considered related to study participation or to concomitant use 
of GSK products or any fatal events need to be recorded. GSK products or any fatal event need to be recorded.
(h) Concomitant medication products/vaccination as indicated in Section 6.6.1 need to be recorded.
Section 5.6.8 Spirometry
For all subjects in Step 2, spirometry to assess FEV1 and FVC will be performed using 
techniques that meet American Thoracic Society (ATS)/European Respiratory Society 
(ERS) published standards [Miller, 2005].
Section 5.6.14.1 Blood sampling for safety assessment
A volume of approximately 5.510 mL of whole blood should be drawn at each pre-
defined time point.
5.6.14.3 Blood sampling for CMI
A volume of approximately 2030 mL of whole blood should be drawn from all subjects 
included in the immunogenicity sub-cohort for CMI at each pre-defined time point. The 
blood should be stored at the investigator’s site at room temperature and it must not be 
centrifuged. Samples will be shipped at room temperature (20 to 25°C) to the designated 
laboratory for cell and plasma separation to be performed within 24 hours of collection.
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Section 5.7.2 Biological samples
Table 8
Biological samples
Sample type
Quantity
Unit
Time point
Sub-cohort
Blood for safety assessment
∃5.510
mL
Screening Visit
(pre-Day 0)
All screened subjects
Visit 1 (Day 0)
All enrolled subjects
Visit 2 (Day 7)
Visit 4 (Day 60)
Visit 5 (Day 67)
Visit 7 (Day 210)
Visit 8 (Day 420)
Blood for antibody determination and assay 
development
∃20
mL
Visit 1 (Day 0))
All enrolled subjects
Visit 3 (Day 30)
Visit 4 (Day 60)
Visit 6 (Day 90)
Visit 7 (Day 210)
Visit 8 (Day 420)
Blood for CMI response
∃2030
mL
Visit 1 (Day 0))
Sub-cohort for CMI*
Visit 4 (Day 60)
Visit 6 (Day 90)
Visit 7 (Day 210)
Visit 8 (Day 420)
* Refer to Section 4.1 for sub-cohort description.
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GlaxoSmithKline Biologicals
Clinical Research & Development
Protocol Amendment 2
eTrack study number 
and Abbreviated Title(s)
201281 (NTHI MCAT-001)
Amendment number:
Amendment 2
Amendment date:
16 March 2016
Co-ordinating author:
, Scientific Writer, XPE Pharma for GSK 
Biologicals
Rationale/background for changes: 
!
The spirometry test must be of good quality. If this is not the case, a re-test should 
be done. This re-test is covered by the current Informed Consent Form.
!
In compliance with ICH requirements, the protocol mentions that all results will be 
presented in an integrated report at the end of the study.
!
A description of how subjects will be included in the CMI sub-cohort and a 
description of how the sub-cohort will represent the fully randomized study groups
has been added.
!
Following re-development and re-validation of the anti-PD ELISA, a new cut-off 
was defined. 
!
Additional administrative changes have been performed:
#
The IND number has been added
#
The list of contributing authors as well as Sponsor signatory has been updated
#
GSK Biologicals’ “Global Vaccines Clinical Laboratories (GVCL)” has been 
renamed as “Clinical Laboratory Sciences (CLS)”
#
Name “Quest Diagnostic Limited” has been replaced by “Q² Solutions” due to 
its merge with QLab
#
Reference to the GSK Biologicals’ Laval laboratory was removed, as this 
laboratory will not be used in the study. In addition, this laboratory is no 
longer part of GSK Biologicals’ laboratories.
In addition, minor edits in other sections were made for clarification.
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections:
Cover Page, Protocol Amendment 2 Sponsor Signatory Approval and Protocol 
Amendment 2 Investigator Agreement
Investigational New Drug 
(IND) number
16531
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Contributing authors
Contributing authors
(continued)
!
, Director
Clinical Research & Translational Science
!
, Clinical Research and 
Development Lead
!
, 
,
 
, Lead Biostatistician
!
, Project Biostatistician
!
, Project Delivery Lead
!
, Study Delivery Lead
!
 (Novellas Healthcare 
for GSK Biologicals)/
, Study 
Delivery Manager
!
, GVCL CLS Clinical 
Readout Team Leader Project Manager
!
, GVCL CLS Laboratory Study 
Manager 
Protocol Amendment 2 Sponsor Signatory Approval
Sponsor signatory
Jeanne-Marie Devaster, Director Clinical Research 
and Translational Science
Ashwani Kumar Arora, Clinical and Epidemiology 
Project Lead
List of Abbreviations
CLS
Clinical Laboratory Sciences
GVCL
Global Vaccine Clinical Laboratories
Section 4.1 Number of subjects/centres
Approximately 50% of the subjects in each group of Step 2 will be part of a sub-cohort 
for CMI analysis. Subjects will be selected based on the enrolment order, i.e. the first 
50% of the participants (approximately the first 15 subjects/group) will be enrolled in 
the sub-cohort for CMI. An additional blood sample for CMI analysis will be taken from 
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those subjects at each of the CMI blood sampling time points (i.e. Day 0, Day 60, 
Day 90, Day 210 and Day 420).
Section 5.2.2.2.1 Study group and treatment number allocation
As several minimisation factors have been defined for the treatment allocation at 
Step 2, it was decided at the design phase not to minimise for the CMI group allocation. 
This wouldn’t be feasible from an implementation point of view. 
Section 5.5
Outline of study procedures
Table 6
List of study procedures for current or former smokers 50-70 years 
old (Step 2)
Epoch
Epoch 001
Epoch 002
Visit 6
Screening 
Visit
Visit 
1
Visit 
2
Visit 
3
Visit 
4
Visit 
5
Visit 
6
Visit 
7
Visit 
8
Time points
pre-Day 0 Day 
0
Day 
7
Day 
30
Day 
60
Day 
67
Day 
90
Day 
210 
Day 
420 
Sampling time points
Screening Pre
Post-Vacc I
Post-Vacc II
Informed consent
●
Check inclusion/exclusion criteria
●(e)
O
Collect demographic data
●
Medical history
O(e)
●
Smoking status
●
●
●
Smoking exposure history
●
Measure/record height and weight
●
●
Spirometry (i)
●
●
(i) This test should be repeated on another day if the first attempt doesn’t meet quality requirements as 
described by ATS/ERS standards (Miller, 2005).
Section 5.6.8 Spirometry
The spirometry test must be of good quality. If this is not the case, a re-test should be 
done.
Section 5.7.1 Use of specific study materials
When materials are provided by GSK Biologicals or by the Central laboratory, it is 
MANDATORY that all clinical samples (including serum samples) be collected and 
stored exclusively using those materials in the appropriate manner.
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Section 5.7.3 Laboratory assays
Table 10
Humoral Immunity (antibody determination) 
System
Component
Method
Kit / 
Manufacturer
Unit
Cut-off
Laboratory*
Serum
Anti-PD
ELISA
In house
EL.U/mL
153 100***
GSK Biologicals**
Serum
Anti-PE
ELISA
In house
EL.U/mL 
8
GSK Biologicals**
Serum
Anti-PilA
ELISA
In house
EL.U/mL
7
GSK Biologicals**
Serum
Anti-UspA2
ELISA
In house
EL.U/mL
18
GSK Biologicals**
ELISA: Enzyme-Linked Immunosorbent Assay; EL.U/mL = ELISA unit per millilitre; 
* Refer to APPENDIX B for the laboratory addresses.
** GSK Biologicals laboratory refers to the Clinical Laboratory Sciences (CLS) Laboratories Global Vaccines 
Clinical Laboratories (GVCL) in Rixensart, Belgium; Wavre, Belgium.; Laval, Canada or a designated laboratory.
*** A new cut-off may be defined after anti-PD-ELISA assay re-development.
Table 11
Cell-Mediated Immunity (CMI)
System
Component
Scale
Method
Unit
Laboratory*
PBMC
Specific CD4+/CD8+ T-cells Quantitative
Flow cytometry
Number of specific 
CD4+/CD8+ T cells /106
GSK 
Biologicals**
PBMC = peripheral blood mononuclear cell.
* Refer to APPENDIX B for the laboratory addresses.
** GSK Biologicals laboratory refers to the Clinical Laboratory Sciences (CLS) Laboratories Global Vaccines 
Clinical Laboratories (GVCL) in Rixensart, Belgium; Wavre, Belgium; Laval, Canada or a designated laboratory.
Section 10.6.3.1  Humoral immune response
The difference in terms of GMCs will be evaluated, one month post-Dose 2, by 
computing the 95% CIs of the GMC ratio between groups for Step 2 by using a one-way 
ANCOVA model on the logarithm10 transformation of the concentrations/ titres. The 
ANCOVA model will include the group category, the age category, the smoking status 
and FEV1/FVC (% 0.7 or < 0.7) and the pre-Dose 1 concentration (as covariate) as fixed 
effects and the pre-Dose 1 concentration as regressor. The groups will be considered 
significantly different if the 95% CI for the GMC ratio between the two groups does not 
contain the value 1.
Section 10.8.1 Sequence of analysis
All study results will be presented in an integrated study report at the end of the study.
Appendix A
Laboratory Assays
Humoral immunity 
Anti-PD antibodies
Anti-PD antibodies will be determined using an ELISA assay developed by GSK 
Biologicals. Concentration of specific anti-PD antibodies will be determined, using 
in-house made reference serum. The current cut-off of the assay is 153 100 EL.U/mL. 
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This assay will however be re-worked according to the latest validation standards and a 
new cut-off might be defined based on a precise and accurate limit of quantification.
Appendix B Clinical laboratories
Table 24
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
Table 25
Outsourced laboratories
Laboratory
Address
Quest Diagnostic Limited Q² 
Solutions
Unit B1, Parkway West Industrial Estate 
Cranford Lane – Heston, 
Middlesex TW5 9QA 
United Kingdom
References
Heads of Medicines Agencies (HMA) Clinical Trial Facilitation Group (CTFG) guidance 
- Recommendations related to contraception and pregnancy testing in clinical trials. 
(2014). http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf
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Protocol Amendment 2 Sponsor Signatory Approval
eTrack study number and 
Abbreviated Title
201281 (NTHI MCAT-001)
IND number
16531
EudraCT number
2015-000378-36
Date of protocol amendment
Amendment 2 Final 16 March 2016
Detailed Title 
A Phase I, randomised, observer-blind, 
placebo-controlled, multi-centre study to evaluate the 
safety, reactogenicity and immunogenicity of GSK 
Biologicals' GSK3277511A investigational vaccine 
when administered intramuscularly according to a 
0, 2 months schedule in adults.
Sponsor signatory
(Amended 16 March 2016)
Ashwani Kumar Arora, Clinical and Epidemiology 
Project Lead
Signature
Date
 
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