An Observer-blind Study to Evaluate the Efficacy, Safety, Reactogenicity and Immunogenicity of the GSK Biologicals' Investigational Vaccine GSK3277511A When Administered to COPD Patients
Phase: PHASE2
Conditions: Respiratory Disorders
Sponsor: GlaxoSmithKline

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Clinical Study Protocol
Sponsor:
GlaxoSmithKline Biologicals SA
Rue de l’institut 89, 
1330 Rixensart
Primary Study vaccine 
and number
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)
Other Study vaccine
!
Control: Placebo
eTrack study number and 
Abbreviated Title
207489 (NTHI MCAT-002)
Investigational New Drug 
(IND) number
16531
EudraCT number
2017-000880-34
Date of protocol
Final Version 2: 07 June 2017
Date of protocol 
amendment/administrative 
change
Amendment 1 Final: 30 November 2017
Administrative Change 1 Final: 15 December 2017
Amendment 2 Final: 27 March 2019
Title
An observer-blind study to evaluate the efficacy, safety, 
reactogenicity and immunogenicity of the GSK 
Biologicals’ investigational vaccine GSK3277511A 
when administered to COPD patients.
Detailed Title
A Phase IIB, randomised, observer-blind, placebo-
controlled, multi-centre study to evaluate the efficacy, 
safety, reactogenicity and immunogenicity of the GSK 
Biologicals’ investigational vaccine GSK3277511A 
when administered intramuscularly according to a 0, 2 
month schedule in COPD patients aged 40 to 80 years 
with a previous history of acute exacerbation 
(AECOPD).
Co-ordinating author
(Amended 27 March 2019)
(Amendment 2 
onward) (XPE Pharma & Science for GSK Biologicals)
Contributing authors
!
(Clinical & Epidemiology 
Project Lead)

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eTrack study number and 
Abbreviated Title
207489 (NTHI MCAT-002)
Investigational New Drug 
(IND) number
16531
EudraCT number
2017-000880-34
Detailed Title
A Phase IIB, randomised, observer-blind, placebo-
controlled, multi-centre study to evaluate the efficacy, 
safety, reactogenicity and immunogenicity of the GSK 
Biologicals’ investigational vaccine GSK3277511A 
when administered intramuscularly according to a 0, 2 
month schedule in COPD patients aged 40 to 80 years 
with a previous history of acute exacerbation 
(AECOPD).
Contributing authors
(continued) (Amended 27 
March 2019)
!
(Senior Clinical Research & 
Development Lead)
(Amendment 2 
onward) (Clinical Research & Development Lead)
!
(Lead Statistician)
!
(Director Clinical Statistics)
!
(Amendment 2 onward) (Study 
Statistician)
!
(Amendment 2 onward) (Study Delivery Leads) 
!
(CLS Clinical Read-out Team 
Leader)
!
(CLS Study manager)
!
(Amendment 2 
onward) (Clinical Trials Supply Manager)
!
(Clinical Safety Representative)
!
(Oversight Data Manager)
!
(Study Data Manager)
!
(Amendment 2 onward) (Regulatory Affairs 
Representatives)
!
(Global Patents Representative)
!
(Vaccine Development Lead)
GSK Biologicals’ Protocol DS v 15.0
©2017-2019 GSK group of companies or its licensor. (Amended 27 March 2019)

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Protocol Amendment 2 Sponsor Signatory Approval
eTrack study number and 
Abbreviated Title
207489 (NTHI MCAT-002)
IND number
16531
EudraCT number
2017-000880-34
Date of protocol amendment
Amendment 2 Final: 27 March 2019
Detailed Title 
A Phase IIB, randomised, observer-blind, placebo-
controlled, multi-centre study to evaluate the efficacy, 
safety, reactogenicity and immunogenicity of the 
GSK Biologicals’ investigational vaccine 
GSK3277511A when administered intramuscularly 
according to a 0, 2 month schedule in COPD patients 
aged 40 to 80 years with a previous history of acute 
exacerbation (AECOPD).
Sponsor signatory
Ashwani Kumar Arora
Clinical & Epidemiology Project Lead
Signature
Date
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Protocol Amendment 2 Rationale
Amendment number:
Amendment 2
Rationale/background for changes:

The coordinating and contributing authors on (pages 1& 2) were updated to reflect
the current team in this Amendment.

Copyright statement (page 2), date updated in this Amendment.

Glossary (pages 32 and 33), definitions were added for acquisition and apparition
in this Amendment.

The text in Section 1.4.1 (page 42) related to spirometry was aligned with the
wording used in the informed consent form (ICF) in this Amendment.

The text in Section 4.1.1 (page 50) was aligned with the wording used in the
inclusion criteria in this Amendment.

The text in footnote c of Table 6 (page 61) was amended to clarify that pregnancy
tests will be performed in on all females of childbearing potential in this
Amendment.

The text in Section 6.9.14 (page 67) was aligned with the changes made to
Footnote c for Table 6 in this Amendment.

Clarification was provided in Section 6.9.21, Recording of AEs, SAEs,
pregnancies and pIMDs (page 70) in this amendment (minor change to wording)

Table 10 (page 75) the new ELISA cut-offs were added in this Amendment as
there are now qualified assays.

In Section 9.4.1 (page 100) text was added to clarify that AECOPD classified as
SAE occurring within a defined time period should also be recorded in the eCRF
as “AECOPD visit” or as “Missed AECOPD visit”

Synopsis (page 11) referring to Section 2.3 Tertiary objectives (page 44), and
Synopsis (page 17) referring to Section 11.3 Tertiary endpoints (page 110) has
been updated to include the analyses of acquisition and apparition of bacteria in
culture and PCR.

Clarification of the correct process to report pIMDs during the study was included
in Section 9.4.5 Reporting of pIMDs to GSK Biologicals (page 102) in this
Amendment.

Clarification was provided in Section 10.2.2 Subject (page 108) regarding the
withdrawal procedure in this Amendment.

In Section 11.3 (Tertiary Endpoints, page 110), “acquisition and apparition” was
added to the endpoints.

In Section 11.8, Analysis of Efficacy, Efficacy – Clinical (page 118) the text was
modified to correct an inconsistency within the section, clarifying that all efficacy
clinical endpoints will be computed with 95% confidence intervals with the
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exception of the primary clinical efficacy endpoint that will also be computed with 
87% confidence interval. There will be no change in the interpretation of the 
analysis compared to the previous version of the Protocol.

In Section 11.8, Analysis of Efficacy, Efficacy – Bacteriological Endpoint (PCR),
(pages 119-120) text was added to clarify the timepoints for the analysis.

In Section 11.8, Analysis of Efficacy, Efficacy – Bacteriological Endpoint
(culture), (page 120) text was added to clarify the timepoints for the analysis.

In Section 11.8 Analysis of Efficacy (page 120) a section was added regarding the
definitions of acquisition and apparition and information regarding the analysis
was added in this Amendment

Appendix A Laboratory Assays (page 136), the new ELISA cut-offs were added in
this Amendment as there are now qualified assays.

Appendix B Clinical Laboratories, Table 26 (page 137) CEVAC and DDL added
to the table of outsourced laboratories in this Amendment.

Minor corrections; e.g. correction of minor typographical and formatting errors
were made for clarity in Section 4.1.1 (from eDiaries to eDiary), Section 6.7 (from
SP to SPM), Section 9.1.3 (from eDiaries to eDiary), Section 11.4 (Table 23 and
Table 24 [et al removed from footnote Keen et al. (2007) to Keen, 2007]),
Sections 11.5.4 (Per protocol to per protocol), and 11.9.3 (from A descriptive
statistics to Descriptive statistics).
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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’ study vaccine/product and other study-related duties and
functions as described in the protocol.

To acquire the reference ranges for laboratory tests performed locally and, if required
by local regulations, obtain the laboratory’s current certification or Quality
Assurance procedure manual.

To ensure that no clinical samples (including serum samples) are retained onsite or
elsewhere without the approval of GSK Biologicals and the express written informed
consent of the subject and/or the subject’s legally acceptable representative.

To perform no other biological assays on the clinical samples except those described
in the protocol or its amendment(s).

To co-operate with a representative of GSK Biologicals in the monitoring process of
the study and in resolution of queries about the data.

That I have been informed that certain regulatory authorities require the sponsor to
obtain and supply, as necessary, details about the investigator’s ownership interest in
the sponsor or the investigational vaccine/product, 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
207489 (NTHI MCAT-002)
IND number
16531
EudraCT number
2017-000880-34
Date of protocol amendment
Amendment 2 Final: 27 March 2019
Detailed Title
A Phase IIB, randomised, observer-blind, placebo-
controlled, multi-centre study to evaluate the 
efficacy, safety, reactogenicity and immunogenicity 
of the GSK Biologicals’ investigational vaccine 
GSK3277511A when administered intramuscularly 
according to a 0, 2 month schedule in COPD patients 
aged 40 to 80 years with a previous history of acute 
exacerbation (AECOPD).
Investigator name
Signature
Date
 
name, function and 
title
Signature
Date
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Sponsor Information
1.
Sponsor
GlaxoSmithKline Biologicals
Rue de l’Institut 89, 1330 Rixensart, Belgium
2.
Sponsor Medical Expert for the Study
Refer to the local study contact information document.
3.
Sponsor Study Monitor
Refer to the local study contact information document.
4.
Sponsor Study Contact for Reporting of a Serious Adverse Event
GSK Biologicals Central Back-up Study Contact for Reporting SAEs: refer to protocol 
Section 9.4.2.
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 9.8.
 
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SYNOPSIS
Detailed Title
A Phase IIB, randomised, observer-blind, placebo-controlled, 
multi-centre study to evaluate the efficacy, safety, reactogenicity 
and immunogenicity of the GSK Biologicals’ investigational 
vaccine GSK3277511A when administered intramuscularly 
according to a 0, 2 month schedule in COPD patients aged 40 to 
80 years with a previous history of acute exacerbation 
(AECOPD).
Indication
Active immunisation for the reduction of frequency of moderate 
and severe acute exacerbations of COPD in patients with a 
previous history of AECOPD.
Rationale for the 
study and study 
design

Rationale for the study
The purpose of this Phase IIB proof-of-concept (POC) study in 
moderate to very severe COPD patients (i.e. GOLD grade 2, 3 
and 4) aged 40 to 80 years with a history of moderate or severe
AECOPD in the previous 12 months is to evaluate whether the 
NTHi-Mcat vaccine can reduce the frequency of AECOPD in 
this population and to assess the vaccine’s safety, reactogenicity 
and immunogenicity.
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 aged 18 - 40 years and NTHI-
003 in current and former healthy smokers of 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 (10 µg) and the 
adjuvant system (AS01E) currently evaluated for the first time in 
moderate and severe COPD patients aged 45 - 81 years in the
Phase II study NTHI-004.
The safety, reactogenicity and immunogenicity of different 
formulations of the NTHi-Mcat investigational vaccine have 
been evaluated in the Phase I study in healthy adults aged 19 -
40 years and in current and former smokers aged 50 - 70 years 
(study NTHI MCAT-001). Based on results obtained up to 30 
days post-Dose 2 from this study, the AS01E-adjuvanted 
formulation containing 10 µg of NTHi proteins PD and PE-PilA 
and 3.3 µg of UspA2 has been selected for evaluation in the 
current NTHI MCAT-002 study. Placebo will be used as a 
control. The NTHi-Mcat investigational vaccine and placebo
will be given on top of standard of care to subjects in the
respective study groups.
 
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
Rationale for the study design
In the current study, moderate, severe and very severe COPD 
patients (i.e. GOLD grade 2, 3 and 4) with a history of AECOPD 
will receive 2 doses of the NTHi-Mcat investigational vaccine or 
placebo intramuscularly (IM) according to a 0, 2 month 
vaccination schedule, in addition to standard care.
Scheduled study visits, during which the effect of immunisation 
against NTHi and Mcat will be evaluated, will take place at pre-
defined timepoints. 
In addition to the scheduled study visits, ad hoc AECOPD-
driven study visit(s) and/ or phone contact(s) will take place for 
each AECOPD occurring from first vaccination up to study 
conclusion:

An AECOPD visit will be scheduled as soon as 
possible after the onset of the AECOPD symptoms 
(maximum 96 hours after the onset of the symptoms). 

Follow-up visit(s) and/or phone call(s) will take place 
to determine the end of the AECOPD.

Rationale for the use of placebo
There is currently no established vaccine with recognised 
efficacy in reducing the frequency of AECOPD. Placebo (PBS) 
will therefore be used as a control.
Objectives
Primary

To assess efficacy of the investigational vaccine as 
compared to the placebo control with respect to the rate of 
moderate and severe AECOPDs.
Secondary

To describe the safety and reactogenicity of the 
investigational vaccine.

To assess efficacy of the investigational vaccine as 
compared to the placebo control with respect to the rate of 
all AECOPDs and by severity (i.e. mild, moderate or 
severe).
 
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
To assess efficacy of the investigational vaccine as 
compared to the placebo control with respect to the rate of 
all AECOPDs and by severity (i.e. mild, moderate or 
severe) associated with NTHi and/or Mcat detected by PCR.

To evaluate the humoral immunogenicity of the 
investigational vaccine.

To evaluate the cellular immunogenicity of the 
investigational vaccine.
Tertiary

To evaluate the effect of the investigational vaccine on the 
presence, acquisition/apparition and load of NTHi and/or 
Mcat at stable visits and AECOPD by PCR. (Amended 27 
March 2019)

To evaluate the effect of the investigational vaccine on the 
presence, acquisition/apparition and load of NTHi and/or 
Mcat at stable visits and AECOPD in a subset of sputum 
samples by culture. (Amended 27 March 2019)

To explore the efficacy of the investigational vaccine as 
compared to placebo with respect to the rate of all 
AECOPDs and by severity (i.e. mild, moderate or severe) 
associated with NTHi and/or Mcat detected in a subset of 
sputum samples by culture.

To explore the impact of the investigational vaccine on 
health-related quality of life (HRQOL).

To explore the impact of the investigational vaccine on use 
of medication for COPD and Healthcare Resource 
Utilisation.

To explore the impact of the investigational vaccine on lung 
function.

To describe selected biomarkers in stable COPD and during 
AECOPD.

To explore the T helper profile of the PD-, PE-, PilA-, 
UspA2-specific CD4+/ CD8+ T cell responses.

To collect blood and sputum samples for assay 
development, for lung microbiome analysis, to explore the 
level of inflammation (into the lung) and/ or for additional 
evaluation of the immune responses to the investigational 
vaccine and to other potential pathogens involved in 
AECOPD.

To explore the data for an immune correlate of protection.
 
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Study design

Experimental design: Phase IIB, randomised, observer-blind, 
placebo-controlled, multi-centric study with two parallel 
groups.

Duration of the study: for each subject enrolled, the study 
will last approximately 15 months from Visit 1 up to study 
completion (Visit 8).

Epoch 001: Screening Visit.

Epoch 002: Primary starting at Visit 1 (Day 1) and 
ending at Visit 8 (Day 451).

Primary completion Date (PCD): Last Subject Last Visit 
(LSLV) at Visit 8 (Day 451) or last visit/ contact of Epoch 
002.

End of Study (EoS): Last testing results released of samples 
collected up to Visit 8 (Day 451).

Study groups:

10-10-3-AS: Approximately 300 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.

CONTROL: Approximately 300 subjects receiving 
two doses of placebo (PBS).
Synopsis Table 1
Study groups and epochs foreseen in the study
Study groups
Number of subjects
Age (Min/Max)
Epochs
Epoch 001
Epoch 002
10-10-3-AS
~300
40 – 80 years
x
x
CONTROL
~300
40 – 80 years
x
x
Synopsis Table 2
Study groups and treatment foreseen in the study
Treatment name
Vaccine name
Study Groups
10-10-3-AS
CONTROL
10-10-3/AS01E
NTHi-Mcat 10-10-3
x
AS01E
Placebo
Formulation buffer S9b
x

Control: Placebo control (PBS)

Vaccination schedule: at Visit 1 (Day 1) and Visit 3 (Day 
61).
 
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
Treatment allocation: subjects will be minimised by:

Age (40 - 59 years or 60 - 80 years).

Number of moderate/ severe AECOPD in the 
previous year (< 2 or 2).

GOLD grade (GOLD 2, GOLD 3 or GOLD 4).

Country
All factors will have equal weight in the minimisation 
algorithm.
Subjects will be randomised using a centralised 
randomisation system on internet (SBIR) at first dose. 
Treatment number allocation (without randomisation) will 
also occur at Dose 2 using SBIR.

Blinding: observer-blind.
Synopsis Table 3
Blinding of study epochs
Study Epochs
Study Groups
Blinding
Epoch 001
10-10-3-AS / CONTROL
observer-blind
Epoch 002
10-10-3-AS /  CONTROL
observer-blind

Sampling schedule:

Blood samples for assessment of humoral 
immunogenicity will be collected from all subjects at 
Visit 1 (Day 1), Visit 2 (Day 31), Visit 3 (Day 61), 
Visit 4 (Day 91), Visit 6 (Day 271), Visit 8 (Day 451) 
and at each AECOPD visit from first vaccination to 
study conclusion.

Blood samples for assessment of cell-mediated 
immunogenicity (CMI) will be collected from all 
subjects in the CMI sub-cohort at Visit 1 (Day 1), Visit 
4 (Day 91), Visit 6 (Day 271) and at Visit 8 (Day 451).

Blood samples for biomarkers will be collected from 
all subjects at Visit 1 (Day 1), Visit 8 (Day 451) and at 
each AECOPD visit from first vaccination to study 
conclusion.

Sputum samples will be collected from all subjects at 
Visit 1 (Day 1), Visit 4 (Day 91), Visit 5 (Day 181), 
Visit 6 (Day 271), Visit 7 (Day 361), Visit 8 (Day 451) 
and at each AECOPD visit from first vaccination to 
study conclusion.
 
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
COPD symptoms: All subjects will be asked to record 
COPD symptoms in their electronic Diary Card:

Daily in the morning throughout the study (including 
during AECOPD): morning symptoms 
questionnaire. 

Daily in the evening throughout the study (including 
during AECOPD): EXACT-PRO questionnaire. 

HRQOL assessments:

All subjects will be asked to complete the COPD 
assessment test (CAT) at the Screening Visit (pre-
Day 1), Visit 6 (Day 271), Visit 8 (Day 451) and at 
each AECOPD visit from first vaccination to study 
conclusion.

All subjects will be asked to complete St. George's 
Respiratory Questionnaire for COPD patients 
(SGRQ-C) at the Screening Visit (pre-Day 1), Visit 6 
(Day 271), at Visit 8 (Day 451) and at each AECOPD 
visit from first vaccination to study conclusion.

Pre- and post-bronchodilator spirometry assessments 
will be done for all subjects at the Screening Visit 
(pre-Day 1), Visit 6 (Day 271) and at Visit 8 (Day 451).
Type of study: self-contained

Data collection: Electronic Case Report Form (eCRF) and 
Electronic Diary Cards (eDiary) and Phone Contacts.

Safety monitoring
Safety evaluations by the safety review team (SRT) (blinded) 
and by an internal Safety Review Committee (iSRC) 
(unblinded) will be performed. Refer to Section 9.10 for more 
detailed information on safety monitoring.
Number of subjects
Approximately 300 subjects receiving two doses of the AS01E-
adjuvanted GSK Biologicals NTHi-Mcat investigational 
vaccine containing 10 µg of PD, 10 µg of PE-PilA, and 3.3 µg 
of UspA2 and approximately 300 subjects receiving two doses 
of placebo (PBS).
Endpoints
Primary

Rate of moderate and severe AECOPD (any cause), 
occurring within a period starting 1 month post-Dose 2 
and lasting for 1 year.
 
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Secondary
Safety:

Occurrence of each solicited local AE, during the 7-day 
follow-up period (Day 1 - Day 7) following each 
vaccination.

Occurrence of each solicited general AE, during the 7-day 
follow-up period (Day 1 - Day 7) following each 
vaccination.

Occurrence of any unsolicited AE, during the 30-day 
follow-up period (Day 1 - Day 30) following each 
vaccination.

Occurrence of any pIMD from first vaccination up to 
study conclusion.

Occurrence of any SAE from first vaccination up to study 
conclusion.
Efficacy: All AECOPD

Yearly rate of all AECOPD (any cause, any severity) 
starting 1 month post-Dose 2, in vaccinated and control 
subjects.

Rate of moderate and severe AECOPD cases in 
vaccinated and control subjects, during 3, 6 and 9 
months observation starting 1 month post-Dose 2.

Rate of all AECOPD cases in vaccinated and control 
subjects, during 3, 6, 9 and 12 months observation 
starting 1 month post-Dose 2.

Rate of all AECOPD cases in vaccinated and control 
subjects, during 3, 6, 9 and 12 months observation 
starting 1 month post-Dose 2, by severity.

Time to first moderate or severe AECOPD.

Time to first AECOPD of any severity.

Time to first AECOPD, by severity.

Duration of moderate and severe AECOPDs.

Duration of AECOPDs of any severity.

Duration of AECOPDs, by severity.
 
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Efficacy: AECOPD associated to bacteriological pathogens 
(PCR)

Rate of NTHi-associated and/ or Mcat-associated 
moderate and severe AECOPD, over a period starting 1 
month post-Dose 2 and lasting for 1 year.

Rate of NTHi-associated and/ or Mcat-associated any 
severity AECOPD, over a period starting 1 month post-
Dose 2 and lasting for 1 year.

Rate of NTHi-associated and/ or Mcat-associated 
AECOPD, over a period starting 1 month post-Dose 2 and 
lasting for 1 year, by severity.

Time to first moderate or severe NTHi-associated and/ or
Mcat-associated AECOPD.

Time to first NTHi-associated and/or Mcat-associated 
AECOPD of any severity.

Time to first NTHi-associated and/or Mcat-associated 
AECOPD, by severity.

Duration of moderate and severe NTHi-associated and 
Mcat-associated AECOPD.

Duration of NTHi-associated and/or Mcat-associated 
AECOPDs of any severity.

Duration of NTHi-associated and/or Mcat-associated 
AECOPD, by severity.
Immunogenicity and CMI:

Anti-PD, anti-PE, anti-PilA and anti-UspA2 total IgG 
antibody concentrations as measured by ELISA at Day 1, 
Day 31, Day 61, Day 91, Day 271 and at Day 451, in all 
subjects.

NTHi-specific and Mcat-specific cell-mediated immune 
responses as measured by flow cytometry ICS (frequency 
of specific CD4+ T-cells expressing two or more markers, 
such as interleukin (IL)-2, IL-13, IL-17, interferon gamma 
(IFN-γ), tumour necrosis factor alpha (TNF-α), and CD40 
ligand (CD40L) at Day 1, Day 91, Day 271 and at Day 
451, in a sub-cohort of subjects.
 
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Tertiary
Sputum sample PCR:

Occurrence (presence and absence), acquisition, 
apparition, and bacterial load measured by PCR of NTHi 
and/or Mcat in sputum before first vaccination and at Day 
91, Day 181, Day 271, Day 361 and Day 451 and at each 
AECOPD visit. (Amended 27 March 2019)
Sputum sample culture:

Occurrence (presence and absence), acquisition, 
apparition, and semi-quantitative bacterial load measured 
in a subset of sputum sample by culture of NTHi and/or 
Mcat in sputum before first vaccination and at Day 91, 
Day 181, Day 271, Day 361 and Day 451 and at each 
AECOPD visit. (Amended 27 March 2019)

Rate of NTHi-associated and Mcat-associated, moderate 
and severe AECOPD.

Rate of NTHi-associated and Mcat-associated any severity 
AECOPD.

Rate of NTHi-associated and Mcat-associated AECOPD, 
by severity.

Time to first moderate or severe NTHi-associated and/or 
Mcat-associated AECOPD.

Time to first any NTHi-associated and rate Mcat-
associated AECOPD.

Time to first NTHi-associated and rate Mcat-associated 
AECOPD, by severity.

Duration of each moderate and severe NTHi-associated 
and Mcat-associated AECOPD.

Duration of NTHi-associated and/or Mcat-associated 
AECOPDs of any severity.

Duration of NTHi-associated and/or Mcat-associated 
AECOPD, by severity.
 
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QOL:

Assessment of EXACT-PRO score, daily in the evening 
throughout the study, in all subjects.

Assessment of CAT score at Screening, Day 271 and Day 
451, and from first vaccination to study conclusion for 
each AECOPD visit, in all subjects.

Assessment of SGRQ-C score at Screening, Day 271 and 
Day 451, and from first vaccination to study conclusion 
for each AECOPD visit, in all subjects.

Assessment of use of medication to treat (AE)COPD and 
healthcare utilization in all subjects throughout the study 
period.
Lung function:

Assessment of FEV1% of predicted normal value at 
Screening, Day 271 and Day 451, in all subjects.
Biomarkers:

Concentration of selected biomarkers (fibrinogen, hsCRP 
and IP-10), at Day 1 and Day 451, and for each AECOPD 
visit from first vaccination to study conclusion.
CMI:

T helper profile of the specific CD4+ (CD8+) T cell 
response based on the expression of T helper 1, T helper 2 
and T helper 17 specific markers at Day 1, Day 91, Day 
271 and Day 451.
Assay development, microbiome analysis and lung 
inflammation:

Presence of respiratory viral pathogens in sputum 
(including respiratory syncytial virus, parainfluenza virus, 
enterovirus/ rhinovirus, metapneumovirus, influenza virus, 
adenovirus, bocavirus and coronavirus) at Day 1, Day 91, 
Day 181, Day 271, Day 361, Day 451 and at each 
AECOPD visit from first vaccination to study conclusion.

Presence and/or concentration of inflammatory cytokines 
in sputum at Day 1, Day 91, Day 181, Day 271, Day 361, 
Day 451 and at each AECOPD visit from first vaccination 
to study conclusion on a subset of samples.
 
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TABLE OF CONTENTS
PAGE
SPONSOR INFORMATION ............................................................................................8
SYNOPSIS......................................................................................................................9
LIST OF ABBREVIATIONS...........................................................................................28
GLOSSARY OF TERMS ...............................................................................................32
1.
INTRODUCTION....................................................................................................37
1.1.
Background ................................................................................................37
1.1.1.
Chronic obstructive pulmonary disease and acute 
exacerbations ..............................................................................37
1.1.2.
Current management of AECOPD ...............................................39
1.1.3.
GSK Biologicals’ NTHi-Mcat investigational vaccine ....................40
1.2.
Rationale for the study and study design ....................................................40
1.2.1.
Rationale for the study.................................................................40
1.2.2.
Rationale for the study design......................................................41
1.2.2.1.
Scheduled study visits and AECOPD-driven 
study contacts ............................................................41
1.3.
Rationale for the use of placebo .................................................................41
1.4.
Benefit: Risk Assessment ...........................................................................41
1.4.1.
Risk Assessment .........................................................................42
1.4.2.
Benefit Assessment.....................................................................42
1.4.3.
Overall Benefit: Risk Conclusion..................................................43
2.
OBJECTIVES.........................................................................................................43
2.1.
Primary objective ........................................................................................43
2.2.
Secondary objectives..................................................................................43
2.3.
Tertiary objectives.......................................................................................44
3.
STUDY DESIGN OVERVIEW ................................................................................45
4.
AECOPD................................................................................................................48
4.1.
Detection of AECOPD.................................................................................48
4.1.1.
Date of onset and end date of AECOPD......................................50
4.1.2.
Guideline for assessing AECOPD that increase in severity..........50
4.2.
Treatment of AECOPD ...............................................................................50
5.
STUDY COHORT...................................................................................................51
5.1.
Number of subjects.....................................................................................51
5.2.
Inclusion criteria for enrolment....................................................................51
5.3.
Exclusion criteria for enrolment...................................................................52
6.
CONDUCT OF THE STUDY ..................................................................................55
6.1.
Regulatory and ethical considerations, including the informed 
consent process..........................................................................................55
6.2.
Subject identification and randomisation.....................................................56
6.2.1.
Subject identification....................................................................56
6.2.2.
Randomisation of treatment.........................................................56
 
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6.2.2.1.
Randomisation of supplies..........................................56
6.2.2.2.
Treatment allocation to the subject.............................56
6.2.2.2.1.
Study group and treatment 
number allocation ...................................56
6.2.2.2.2.
Treatment number allocation for 
subsequent doses ..................................57
6.2.3.
Allocation of subjects to assay subsets........................................57
6.3.
Method of blinding ......................................................................................57
6.4.
General study aspects ................................................................................58
6.5.
Outline of study procedures ........................................................................59
6.6.
List of study procedures during AECOPD-driven study visits and 
phone contacts ...........................................................................................62
6.7.
Concurrence of AECOPD-driven study visits and scheduled study 
visits ...........................................................................................................63
6.8.
Intervals between study visits .....................................................................64
6.9.
Detailed description of study procedures ....................................................64
6.9.1.
Informed consent.........................................................................64
6.9.2.
Check inclusion and exclusion criteria .........................................64
6.9.3.
Record history of moderate and severe AECOPD within 
the previous year .........................................................................65
6.9.4.
Check subject’s COPD status......................................................65
6.9.5.
Collect demographic data ............................................................65
6.9.6.
Record medical history, including significant co-morbidities.........65
6.9.7.
Vaccination history.......................................................................66
6.9.8.
Smoking exposure history............................................................66
6.9.9.
Smoking status ............................................................................66
6.9.10.
Physical examination ...................................................................66
6.9.11.
Measure/ record height and weight..............................................66
6.9.12.
Pre- and post-bronchodilator spirometry ......................................67
6.9.13.
Chest X-ray..................................................................................67
6.9.14.
Pregnancy test.............................................................................67
6.9.15.
Sampling......................................................................................68
6.9.15.1.
Blood samples............................................................68
6.9.15.2.
Sputum samples.........................................................69
6.9.16.
Check contraindications to vaccination ........................................69
6.9.17.
Assess pre-vaccination body temperature ...................................69
6.9.18.
Study group and treatment number allocation with 
randomisation ..............................................................................70
6.9.19.
Vaccination..................................................................................70
6.9.20.
Check and record concomitant medication/vaccination and 
intercurrent medical conditions ....................................................70
6.9.21.
Recording of AEs, SAEs, pregnancies and pIMDs.......................70
6.9.22.
Train subjects on the use of electronic Diary Card and 
assign electronic Diary Card to subject........................................71
6.9.23.
Distribution of Subject Card .........................................................71
6.9.24.
Healthcare Resource Utilisation...................................................71
6.9.25.
HRQOL questionnaires................................................................71
6.9.26.
Confirm AECOPD and record its start date..................................72
6.9.27.
Document AECOPD severity and end date..................................72
6.9.28.
Screening conclusion...................................................................72
6.9.29.
Study conclusion..........................................................................72
6.10.
Biological sample handling and analysis.....................................................72
 
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6.10.1.
Use of specified study materials ..................................................73
6.10.2.
Biological samples.......................................................................74
6.10.3.
Laboratory assays .......................................................................74
6.10.4.
Biological samples evaluation......................................................81
6.10.4.1.
Immunological read-outs ............................................81
6.10.5.
Immunological correlates of protection.........................................81
7.
STUDY VACCINES AND ADMINISTRATION ........................................................82
7.1.
Description of study vaccines......................................................................82
7.2.
Storage and handling of study vaccines......................................................82
7.3.
Dosage and administration of study vaccines .............................................83
7.4.
Replacement of unusable vaccine doses....................................................83
7.5.
Contraindications to subsequent vaccination ..............................................84
7.6.
Concomitant medications/products and concomitant vaccinations..............84
7.6.1.
Recording of concomitant medications/products and 
concomitant vaccinations.............................................................85
7.6.2.
Concomitant medications/products/vaccines that may lead 
to the elimination of a subject from per-protocol analyses 
for immunogenicity.......................................................................85
7.6.3.
Concomitant medications/ products/ intervention that may 
lead to the elimination of a subject from the per-protocol 
analysis for efficacy .....................................................................86
7.7.
Intercurrent medical conditions that may lead to elimination of a 
subject from per-protocol analyses .............................................................86
8.
HEALTH ECONOMICS ..........................................................................................86
9.
SAFETY.................................................................................................................86
9.1.
Safety definitions ........................................................................................87
9.1.1.
Definition of an adverse event......................................................87
9.1.2.
Definition of a serious adverse event ...........................................88
9.1.3.
Solicited adverse events..............................................................89
9.1.3.1.
Solicited local (injection-site) adverse events..............89
9.1.3.2.
Solicited general adverse events................................89
9.1.4.
Clinical laboratory parameters and other abnormal 
assessments qualifying as adverse events or serious 
adverse events ............................................................................89
9.1.5.
Adverse events of specific interest...............................................90
9.1.5.1.
Potential immune-mediated diseases .........................90
9.2.
Events or outcomes not qualifying as adverse events or serious 
adverse events ...........................................................................................93
9.2.1.
AECOPD .....................................................................................93
9.2.2.
Pregnancy ...................................................................................93
9.3.
Detecting and recording adverse events, serious adverse events 
and pregnancies .........................................................................................94
9.3.1.
Time period for detecting and recording adverse events, 
serious adverse events and pregnancies.....................................94
9.3.2.
Post-Study adverse events and serious adverse events..............96
9.3.3.
Evaluation of adverse events and serious adverse events...........96
9.3.3.1.
Active questioning to detect adverse events 
and serious adverse events........................................96
9.3.3.2.
Assessment of adverse events...................................97
 
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9.3.3.2.1.
Assessment of intensity..........................97
9.3.3.2.2.
Assessment of causality .........................98
9.3.3.3.
Assessment of outcomes..........................................100
9.4.
Reporting of serious adverse events, pregnancies, and other events .......100
9.4.1.
Prompt reporting of serious adverse events, pregnancies, 
and other events to GSK Biologicals..........................................100
9.4.2.
Contact information for reporting serious adverse events, 
pregnancies and pIMDs.............................................................101
9.4.3.
Completion and transmission of SAE reports to GSK 
Biologicals .................................................................................101
9.4.3.1.
Back-up system in case the electronic 
reporting system does not work................................101
9.4.4.
Completion and transmission of pregnancy reports to GSK 
Biologicals .................................................................................102
9.4.5.
Reporting of pIMDs to GSK Biologicals......................................102
9.4.6.
Updating of SAE, pregnancy, and pIMD information after 
removal of write access to the subject’s eCRF...........................102
9.4.7.
Regulatory reporting requirements for serious adverse 
events........................................................................................103
9.5.
Follow-up of adverse events, serious adverse events, and 
pregnancies..............................................................................................103
9.5.1.
Follow-up of adverse events and serious adverse events..........103
9.5.1.1.
Follow-up during the study........................................103
9.5.1.2.
Follow-up after the subject is discharged from 
the study...................................................................103
9.5.2.
Follow-up of pregnancies...........................................................104
9.6.
Treatment of adverse events ....................................................................104
9.7.
Unblinding.................................................................................................104
9.8.
Emergency unblinding ..............................................................................104
9.9.
Subject card..............................................................................................105
9.10.
Safety monitoring......................................................................................106
9.10.1.
Safety Review Team..................................................................106
9.10.2.
Internal Safety Review Committee.............................................106
10. SUBJECT COMPLETION AND WITHDRAWAL...................................................107
10.1.
Subject completion ...................................................................................107
10.2.
Subject withdrawal....................................................................................107
10.2.1.
Subject withdrawal from the study .............................................107
10.2.2.
Subject withdrawal from study vaccines.....................................108
10.3.
Extension study ........................................................................................108
10.4.
Screening failures.....................................................................................108
11. STATISTICAL METHODS....................................................................................109
11.1.
Primary endpoint.......................................................................................109
11.2.
Secondary endpoints ................................................................................109
11.3.
Tertiary endpoints.....................................................................................110
11.4.
Determination of sample size....................................................................112
11.5.
Cohorts for analyses.................................................................................113
11.5.1.
All enrolled set ...........................................................................113
11.5.2.
Total vaccinated cohort..............................................................113
11.5.3.
Modified total vaccinated cohort.................................................114
11.5.4.
Per-protocol set for analysis of immunogenicity .........................114
 
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11.5.5.
Per-protocol set for analysis of efficacy......................................114
11.5.6.
Full Analysis set (FAS)...............................................................115
11.6.
Derived and transformed data...................................................................115
11.7.
Analysis of demographics.........................................................................117
11.8.
Analysis of efficacy ...................................................................................118
11.9.
Analysis of immunogenicity.......................................................................121
11.9.1.
Within groups assessment.........................................................121
11.9.2.
Between groups assessment.....................................................121
11.9.3.
Cell-mediated immune response ...............................................122
11.9.4.
Analysis of selected biomarkers.................................................122
11.9.5.
Correlate of protection ...............................................................122
11.10. Analysis of safety......................................................................................122
11.10.1. Analysis of HRQOL, lung capacity .............................................123
11.11. Interpretation of analyses..........................................................................124
11.12. Conduct of analyses .................................................................................124
11.12.1. Sequence of analyses................................................................124
12. ADMINISTRATIVE MATTERS .............................................................................124
12.1.
Case Report Form/electronic Case Report Form instructions ...................124
12.2.
Study Monitoring by GSK Biologicals........................................................125
12.3.
Record retention .......................................................................................125
12.4.
Quality assurance.....................................................................................126
12.5.
Posting of information on publicly available clinical trial registers and 
publication policy ......................................................................................126
12.6.
Provision of study results to investigators .................................................127
12.7.
Data Sharing.............................................................................................127
13. COUNTRY SPECIFIC REQUIREMENTS.............................................................127
13.1.
Requirements for Germany.......................................................................127
13.2.
Requirements for France ..........................................................................128
14. REFERENCES.....................................................................................................133
 
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LIST OF TABLES
PAGE
Table 1
Classification of severity of AECOPD.....................................................39
Table 2
Study groups and epochs foreseen in the study.....................................46
Table 3
Study groups and treatment foreseen in the study .................................46
Table 4
Blinding of study epochs ........................................................................47
Table 5
Sub-cohorts............................................................................................51
Table 6
List of study procedures .........................................................................59
Table 7
List of study procedures during AECOPD-driven study visits and 
phone contacts.......................................................................................62
Table 8
Intervals between study visits.................................................................64
Table 9
Biological samples .................................................................................74
Table 10
Humoral Immunity (Antibody determination) (Amended 27 March 
2019)......................................................................................................75
Table 11
Cell-Mediated Immunity (CMI)................................................................75
Table 12
Sputum assessments.............................................................................77
Table 13
Biomarkers.............................................................................................80
Table 14
Immunological read-outs........................................................................81
Table 15
Study vaccines.......................................................................................82
Table 16
Dosage and administration.....................................................................83
Table 17
Solicited local adverse events ................................................................89
Table 18
Solicited general adverse events............................................................89
Table 19
List of potential immune-mediated diseases...........................................91
Table 20
Reporting periods for collecting safety information .................................95
Table 21
Intensity scales for solicited symptoms...................................................97
Table 22
Timeframes for submitting serious adverse event, pregnancy and 
other events reports to GSK Biologicals ...............................................100
Table 23
Total number of subjects for primary endpoint......................................112
 
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Table 24
Sample size for secondary bacteriological endpoint.............................113
Table 25
GSK Biologicals’ laboratories ...............................................................137
Table 26
Outsourced laboratories (Amended 27 March 2019)............................137
Table 27
MedDRA preferred terms for potential immune mediated 
diseases...............................................................................................138
 
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LIST OF FIGURES
PAGE
Figure 1
The refined ABCD assessment tool........................................................37
Figure 2
Study design overview ...........................................................................45
Figure 3
Overview of iSRC evaluation................................................................106
 
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LIST OF APPENDICES
PAGE
APPENDIX A LABORATORY ASSAYS .....................................................................136
APPENDIX B CLINICAL LABORATORIES ................................................................137
APPENDIX C MEDDRA PREFERRED TERMS FOR POTENTIAL IMMUNE 
MEDIATED DISEASES........................................................................138
APPENDIX D AMENDMENTS AND ADMINISTRATIVE CHANGES TO THE 
PROTOCOL.........................................................................................145
 
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LIST OF ABBREVIATIONS
L:
Microliter
AE:
Adverse event
AECOPD:
Acute Exacerbation of Chronic Obstructive Pulmonary 
Disease
ANCOVA:
Analysis of co-variance
AS:
Adjuvant system
ATS DLD 78A:
American Thoracic Society and the Division of Lung 
Diseases 78A
CAT:
COPD assessment test
CD40L:
CD40 ligand
CI:
Confidence interval
CLS:
Clinical Laboratory Sciences
CMI:
Cell-mediated immunogenicity
COPD:
Chronic Obstructive Pulmonary Disease
CXCL10:
C-X-C motif chemokine 10 (= IP-10)
eCOA: 
Electronic Clinical Outcome Assessment
eCRF:
Electronic Case Report Form
EGA:
Estimated gestational age
ELISA:
Enzyme-linked immunosorbent assay
EoS:
End of Study
EU/ml:
ELISA unit per millilitre
EXACT-PRO:
EXAcerbations of Chronic Pulmonary Disease Tool -
Patient Reported Outcome
FAS: 
Full-Analysis Set
FCV:
forced capacity vital
FDA:
Food and Drug Administration, United States
 
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FEV1:
Forced expiratory volume in 1 second 
GCP:
Good Clinical Practice
GMC:
Geometric mean concentration
GOLD:
Global initiative for Chronic Obstructive Lung Disease
GSK:
GlaxoSmithKline
HCU:
Healthcare utilisation
HRQOL:
Health-related quality of life
hsCRP:
High-sensitivity C-reactive protein
IB:
Investigator Brochure
ICF:
Informed Consent Form
ICH:
International Conference on Harmonization
ICS:
Intracellular cytokine staining
IDMC:
Independent Data Monitoring Committee
IFN-γ
Interferon gamma
IgG:
Immunoglobulin G
IL:
Interleukin
IM:
Intramuscular
IND:
Investigational new drug
IP-10:
Interferon gamma-induced protein 10 (= CXCL10)
iSRC:
Internal Safety Review Committee
LLOQ:
Lower limit of quantification
LMP:
Last menstrual period
LSLV:
Last Subject Last Visit
LTOT:
Long-term oxygen therapy
Mcat:
Moraxella catarrhalis
 
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mMRC:
Modified Medical Research Council Dyspnoea
NTHi:
Non-Typeable Haemophilus influenzae
PBMC:
Peripheral blood mononuclear cell
PBS:
Phosphate buffered saline
PC:
Phone call
PCD:
Primary completion date
PCR: 
Polymerase chain reaction
PD:
Protein D
PE:
Protein E
PilA:
Type IV pilus assembly protein 
pIMD:
Potential immune-mediated disease
PPS: 
Per-protocol set
RNA:
Ribonucleic acid
SAE:
Serious adverse event
SBIR:
Randomisation system on internet
SGRQ-C:
St. George’s Respiratory Questionnaire for COPD 
patients
SPM: 
Study Procedures Manual
SRT: 
Safety review team
TNF-:
Tumour necrosis factor alpha
TVC:
Total vaccinated cohort
US:
United States
UspA2:
Ubiquitous surface protein A2
VE:
Vaccine efficacy
 
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VSMB: 
Vaccine Safety Monitoring Board
WHO:
World Health Organisation
 
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GLOSSARY OF TERMS
Acquisition:
The first time a bacterium is detected in the sputum of a 
patient over the course of the study visits (a positive 
status at the visit considered as baseline excludes a
subject from this analysis). (Amended 27 March 2019)
Adequate contraception:
Adequate contraception is defined as a contraceptive 
method with failure rate of less than 1% per year when 
used consistently and correctly and when applicable, in 
accordance with the product label for example:

abstinence from penile-vaginal intercourse, when this 
is their preferred and usual lifestyle, 

Combined estrogen and progesterone oral 
contraceptives,

injectable progestogen, 

implants of etenogestrel or levonorgestrel, 

Contraceptive vaginal ring, 

percutaneous contraceptive patches, 

intrauterine device or intrauterine system, 

male partner sterilisation prior to the female subject’s 
entry into the study, and this male is the sole partner 
for that subject,
The information on the male sterility can come from 
the site personnel’s review of the subject’s medical 
records; or interview with the subject on her medical 
history.

male condom combined with a vaginal spermicide 
(foam, gel, film, cream or suppository), and/or 
progesterone alone oral contraceptive
Adequate contraception does not apply to subjects of 
child bearing potential with same sex partners or for 
subjects who are and will continue to be abstinent from 
penile-vaginal intercourse on a long term and persistent 
basis, when this is their preferred and usual lifestyle.
Adverse event:
Any untoward medical occurrence in a patient or clinical 
investigation subject, temporally associated with the use 
of a medicinal product, whether or not considered related 
to the medicinal product.
An adverse event (AE) can therefore be any unfavourable 
and unintended sign (including an abnormal laboratory 
 
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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.
Apparition:
Detection of a bacterium in the sputum of a patient 
taken during a study visit which was not detected in the 
sputum taken during the previous visit. (Amended 27 
March 2019)
Blinding:
A procedure in which one or more parties to the trial are 
kept unaware of the treatment assignment in order to 
reduce the risk of biased study outcomes. The level of
blinding is maintained throughout the conduct of the trial, 
and only when the data are cleaned to an acceptable level 
of quality will appropriate personnel be unblinded or 
when required in case of a serious adverse event. In an 
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.
Current smoker:
A person who is currently smoking or who stopped 
smoking within the past 6 months before study start.
Eligible:
Qualified for enrolment into the study based upon strict 
adherence to inclusion/exclusion criteria.
End of Study:
(Synonym of End of 
Trial)
For studies without collection of human biologicals 
samples or imaging data EoS is the Last Subject Last 
Visit (LSLV). 
For studies with collection of Human Biologicals 
Samples or imaging data, EoS is defined as the date of the 
last testing/reading released of the Human Biological 
Samples or imaging data, related to primary and 
secondary endpoints. EoS must be achieved no later than 
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Epoch:
An epoch is a set of consecutive timepoints or a single 
timepoint from a single protocol. Epochs are defined to 
support a main purpose which either to draw conclusions 
on subject participation or to draw a complete conclusion 
to define or precise the targeted label of the product. 
Supporting means that data collected at the timepoints 
included in an epoch must be sufficient to fulfil the 
purpose of the epoch.
Typical examples of epochs are screening, primary 
vaccinations, boosters, yearly immunogenicity follow-
ups, and surveillance periods for efficacy or safety.
eTrack:
GSK’s tracking tool for clinical trials.
Evaluable:
Meeting all eligibility criteria, complying with the 
procedures defined in the protocol, and, therefore, 
included in the per-protocol analysis.
Former smoker:
A person who stopped smoking for at least 6 months at 
the time of study start.
Immunological correlate 
of protection:
The defined immune response above which there is a high 
likelihood of protection in the absence of any host factors 
that might increase susceptibility to the infectious agent.
Investigational vaccine:
(Synonym of 
Investigational Medicinal 
Product)
A pharmaceutical form of an active ingredient being 
tested in a clinical trial, including a product with a 
marketing authorisation when used in a way different 
from the approved form, or when used for an unapproved 
indication, or when used to gain further information about 
an approved use. 
Menarche:
Menarche is the onset of menses for the first time in a 
young female and is preceded by several changes 
associated with puberty including breast development and 
pubic hair growth. Menarche usually occurs within 1-2 
years of breast development, thelarche. However, a young 
female can become pregnant before her first menses. 
Thus, a conservative definition of non-childbearing 
potential in a pre-menarcheal female is a young female 
who has not yet entered puberty as evidenced by lack of 
breast development (palpable glandular breast tissue).
 
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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 
should not be used to calculate pack-year history.
Potential Immune-
Mediated Disease:
Potential immune-mediated diseases (pIMDs) are a subset 
of diseases 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 all primary outcomes, whether the clinical trial was 
concluded according to the pre-specified protocol or was 
terminated.
Protocol amendment:
The International Conference on Harmonisation (ICH) 
defines a protocol amendment as: ‘A written description 
of a change(s) to or formal clarification of a protocol.’ 
GSK Biologicals further details this to include a change 
to an approved protocol that affects the safety of subjects, 
scope of the investigation, study design, or scientific 
integrity of the study.
Randomisation:
Process of random attribution of treatment to subjects in 
order to reduce bias of selection.
Self-contained study:
Study with objectives not linked to the data of another 
study.
 
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Solicited adverse event:
Adverse events to be recorded as endpoints in the clinical 
study. The presence/occurrence/intensity of these events 
is actively solicited from the subject or an observer during 
a specified post-vaccination follow-up period.
Study vaccine:
Any investigational vaccine being tested and/or any 
authorized use of a vaccine/placebo as a reference or 
administered concomitantly, in a clinical trial that 
evaluates the use of an investigational vaccine.
Study Works:
Secure electronic Clinical Outcome Assessment (eCOA)
Web-Portal where reports are displayed to investigator 
staff showing data entered on the eCOA devices used by 
subjects (eDiary) and allowing the investigator staff to 
make decisions such as changing the eligibility status of 
the patient on the study.
Sub-cohort:
A group of subjects for whom specific study procedures 
are planned as compared to other subjects or a group of 
subjects who share a common characteristic (e.g. ages, 
vaccination schedule,…) at the time of enrolment.
Subject:
Term used throughout the protocol to denote an 
individual who has been contacted in order to participate 
or participates in the clinical study, either as a recipient of 
the vaccine(s)/product(s) or as a control.
Treatment:
Term used throughout the clinical study to denote a set of 
investigational product(s) or marketed product(s) or 
placebo intended to be administered to a subject.
Treatment number:
A number identifying a treatment to a subject, according 
to the 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.
Chronic obstructive pulmonary disease and acute exacerbations
Chronic Obstructive Pulmonary Disease (COPD), a common preventable and treatable 
disease, is characterised by persistent airflow limitation that is usually progressive in the 
long term. The classification of COPD severity is done based on the patient’s spirometric 
classification according to [GOLD, 2013]. The airflow limitation in COPD patients can 
be classified into Global Initiative for Chronic Obstructive Lung Disease (GOLD) grades 
as shown in Figure 1 [GOLD, 2017]. 
Additional parameters can be collected in order to allow for a combined assessment that 
could be used for future evaluation (Figure 1) [GOLD, 2017].
Figure 1
The refined ABCD assessment tool
COPD = Chronic Obstructive Pulmonary Disease; GOLD = Global Initiative for Chronic Obstructive Lung Disease; 
CAT = COPD assessment test; mMRC = Modified Medical Research Council Dyspnoea; FEV1 = Forced 
expiratory volume of air expired in 1 second; FVC = forced expiratory vital capacity.
Number of exacerbations per year, number of hospitalizations per year and CAT score 
will be collected at the enrollment in order to allow for the classification according to the 
[GOLD, 2017]:

Patient Group A – Low Risk, Less Symptoms; and/or 0-1 exacerbation per year and 
no hospitalization for exacerbation; and CAT score < 10 or Modified Medical 
Research Council Dyspnoea (mMRC) grade 0-1*

Patient Group B – Low Risk, More Symptoms; and/or 0-1 exacerbation per year and 
no hospitalization for exacerbation; and CAT score ≥ 10 or mMRC grade ≥ 2*
 
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
Patient Group C – High Risk, Less Symptoms; and/or ≥ 2 exacerbations per year or
≥ 1 with hospitalization for exacerbation; and CAT score < 10 or mMRC grade 0-1*

Patient Group D – High Risk, More Symptoms; and/or ≥ 2 exacerbations per year or 
≥ 1 with hospitalization for exacerbation; and CAT score ≥ 10 or mMRC grade ≥ 2*.
* Note: in this study, the mMRC scaling will not be used to classify patients in different 
COPD categories. 
The airflow limitation is 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, 2017]. 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, 
2017]. Together, these mechanisms manifest as an accelerated decline in lung function, 
with symptoms such as breathlessness on physical exertion, deteriorating health status 
and exacerbations.
In 2015, COPD ranked third among the global age-standardised death rates for both 
sexes, with about 3.2 million patients dying of the disease [Wang, 2016]. The morbidity 
and mortality of COPD is substantially contributed to acute exacerbation of COPD 
(AECOPD), which are events during which the patient’s respiratory symptoms acutely 
worsen beyond normal day-to-day variations and which require a change in maintenance 
treatment. Higher exacerbation rates have been related to a faster decline in lung function 
and are known to have a negative effect on the patient’s quality of life. Moreover, 
frequent exacerbations are associated with significant mortality, particularly if they 
require hospitalization. Between 40 - 60% of medical expenditure for COPD is a direct 
consequence of AECOPD Cazzola, 2008. 
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 characterized 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, 2017]. 
The rate at which acute exacerbations occur varies greatly between patients, with severe 
patients exacerbating more often. AECOPD additionally increase morbidity and 
mortality, leading to faster decline in lung function, poorer functional status, and have a 
significant impact on healthcare systems worldwide [Sapey, 2006].
The lungs are known to be colonised with different strains of bacteria [Erb-Downward, 
2011; Wilkinson, 2017]. 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].
 
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Reducing the frequency and severity of AECOPD is one of the main goals of COPD 
maintenance treatment. The severity of AECOPD can be graded according to the 
intensity of medical intervention required (see Table 1) [Wedzicha, 2007. 
Table 1
Classification of severity of AECOPD
Grade
Intensity of medical intervention
Mild
Can be controlled with an increase in dosage of regular medications
Moderate
Requires treatment with systemic corticosteroids and/ or antibiotics
Severe
Requires hospitalisation*
* In general, hospitalisation signifies that the subject has been admitted at the hospital or emergency ward for 
observation and/or treatment for AECOPD that would not have been appropriate in the physician’s office or in an out-
patient setting. 
1.1.2.
Current management of AECOPD
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 increase in morbidity, length of hospitalisation, health care 
cost and mortality [Nseir, 2008].
A wide range of pharmacologic (such as inhaled corticosteroids, bronchodilators, 
phosphodiesterase inhibitors, theophyllines, long-term antibiotics and mucolytics) and 
non-pharmacologic (such as lung volume reduction surgery, home oxygen, ventilatory 
support and pulmonary rehabilitation) interventions also exist to reduce AECOPD and 
hospitalisation rates. 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 [LAMA], long-acting beta agonists [LABA], methylxanthines, 
corticosteroids, phosphodiesterase-4 inhibitors and combination drugs), and is thought to 
remain so in the 10-years horizon.
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.
 
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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 
surface proteins from NTHi and Mcat. The selected NTHi antigens are three conserved 
surface proteins presented as a free recombinant Protein D (PD) and a recombinant fusion 
protein combining Protein E (PE) and protein PilA, named PE-PilA. The selected Mcat 
antigen is UspA2, a surface protein from Mcat that is expressed in more than 95% of the 
Mcat strains. The vaccine is being developed for active immunisation to reduce the 
frequency of moderate and severe acute exacerbations of COPD in patients with a 
previous history of AECOPD.
The target population of the GSK NTHi-Mcat investigational vaccine are COPD patients, 
who 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 may help to induce a higher 
and longer-lasting immune response.
Please refer to the current Investigator Brochure for information regarding the pre-
clinical and clinical studies and the epidemiological information 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 Phase IIB proof-of-concept (POC) study in moderate to very severe 
COPD patients (i.e. GOLD grade 2, 3 and 4) aged 40 to 80 years with a history of 
moderate or severe AECOPD in the previous 12 months is to evaluate whether the NTHi-
Mcat vaccine can reduce the frequency of AECOPD in this population and to assess the 
vaccine’s safety, reactogenicity and immunogenicity.
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 aged 18 - 40 years and NTHI-003 in current and former 
healthy smokers of 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 (10 µg) and the adjuvant system (AS01E) currently 
evaluated for the first time in moderate and severe COPD patients aged 45 - 81 years in 
the Phase II study NTHI-004.
 
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The safety, reactogenicity and immunogenicity of different formulations of the NTHi-
Mcat investigational vaccine have been evaluated in the Phase I study in healthy adults 
aged 18 - 40 years and in current and former smokers aged 50 - 70 years (study NTHI 
MCAT-001). Based on results obtained up to 30 days post-Dose 2 from this study, the 
AS01E-adjuvanted formulation containing 10 µg of NTHi proteins PD and PE-PilA and 
3.3 µg of UspA2 has been selected for evaluation in the current NTHI MCAT-002 study. 
Placebo will be used as a control. The NTHi-Mcat investigational vaccine and placebo
will be given on top of standard of care to subjects in the respective study groups.
1.2.2.
Rationale for the study design
In the current study, moderate, severe and very severe COPD patients (i.e. GOLD grade 
2, 3 and 4) with a history of AECOPD will receive 2 doses of the NTHi-Mcat 
investigational vaccine or placebo intramuscularly (IM) according to a 0, 2 month
vaccination schedule, in addition to standard care.
1.2.2.1.
Scheduled study visits and AECOPD-driven study contacts
Scheduled study visits, during which the effect of immunisation against NTHi and Mcat 
will be evaluated, will take place at pre-defined timepoints (see Figure 2). 
In addition to the scheduled study visits, ad hoc AECOPD-driven study visit(s) and/ or 
phone contact(s) will take place for each AECOPD occurring from first vaccination up 
to study conclusion:

An AECOPD visit will be scheduled as soon as possible after the onset of the 
AECOPD symptoms (maximum 96 hours after the onset of the symptoms). 

Follow-up visit(s) and/or phone call(s) will take place to determine the end of the 
AECOPD. 
1.3.
Rationale for the use of placebo
There is currently no established vaccine with recognised efficacy in reducing the 
frequency of AECOPD. Placebo will therefore be used as a control.
1.4.
Benefit: Risk Assessment
Please refer to the current Investigator Brochure for the summary of potential risks and 
benefits of the NTHi-Mcat investigational vaccine.
 
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The following section outlines the risk assessment and mitigation strategy for this study 
protocol:
1.4.1.
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
Close monitoring of potential immune-
mediated diseases in clinical 
development programs using adjuvants 
systems. The potential risk for events of 
possible autoimmune aetiology to occur 
is mentioned in the Informed Consent 
Form (ICF).
Study Procedures
Risk of blood sampling
Blood sampling associated risk of 
syncope, dizziness, infection at the 
site after or during venepuncture.
Blood samples will be obtained by a 
trained professional and medical 
assistance will be available.
The potential risk of feeling faint, or 
experiencing mild local pain, bruising, 
irritation or redness at the site where 
blood was taken, is mentioned in the 
ICF. The amount of blood to be taken
for sampling will not be harmful to the 
subject’s health.
Risk of induced sputum sampling
Small risk of bronchoconstriction as 
a reaction to the inhalation of the 
saline solution used to induce the 
sputum
Sputum induction is generally 
considered safe. The potential risk of 
bronchoconstriction is mentioned in the 
ICF. 
Spirometry
In a few cases spirometry has 
been associated with dizziness. 
Strong exhalation can cause 
increased pressure in chest, eyes 
or stomach. Occasionally after 
receiving the 
albuterol/salmeterol inhaler, a 
temporary sensation of “heart 
racing” and shakiness may be 
felt. (Amended 27 March 2019)
Screening of patients with a 
contraindication for spirometry testing 
(such as recent eye surgery, recent 
thoracic or abdominal surgery 
procedures, unstable cardiovascular 
status, recent myocardial infection or 
pulmonary embolism). Risks associated 
with spirometry are mentioned in the 
ICF.
1.4.2.
Benefit Assessment
Benefits considerations include:

Contribution to the process of developing a vaccine which may help in reducing 
AECOPD frequency.

Medical evaluations/assessments associated with this study (e.g. physical 
examination, spirometry).

Close follow-up of COPD patients during the study.
 
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1.4.3.
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 vaccine are justified by the anticipated benefits that may be afforded to patients for 
the prevention of AECOPD.
2.
OBJECTIVES
2.1.
Primary objective

To assess efficacy of the investigational vaccine as compared to the placebo control 
with respect to the rate of moderate and severe AECOPDs.
Refer to Section 11.1 for the definition of the primary endpoint.
2.2.
Secondary objectives

To describe the safety and reactogenicity of the investigational vaccine.

To assess efficacy of the investigational vaccine as compared to the placebo control 
with respect to the rate of all AECOPDs and by severity (i.e. mild, moderate or 
severe).

To assess efficacy of the investigational vaccine as compared to the placebo control 
with respect to the rate of all AECOPDs and by severity (i.e. mild, moderate or 
severe) associated with NTHi and/or Mcat detected by PCR.

To evaluate the humoral immunogenicity of the investigational vaccine.

To evaluate the cellular immunogenicity of the investigational vaccine.
Refer to Section 11.2 for the definition of the secondary endpoints.
 
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2.3.
Tertiary objectives

To evaluate the effect of the investigational vaccine on the presence, 
acquisition/apparition and load of NTHi and/or Mcat at stable visits and AECOPD 
by PCR. (Amended 27 March 2019)

To evaluate the effect of the investigational vaccine on the presence, 
acquisition/apparition and load of NTHi and/or Mcat at stable visits and AECOPD 
in a subset of sputum samples by culture. (Amended 27 March 2019)

To explore the efficacy of the investigational vaccine as compared to placebo with 
respect to the rate of all AECOPDs and by severity (i.e. mild, moderate or severe) 
associated with NTHi and/or Mcat detected in a subset of sputum samples by culture.

To explore the impact of the investigational vaccine on health-related quality of life 
(HRQOL).

To explore the impact of the investigational vaccine on use of medication for COPD
and Healthcare Resource Utilisation.

To explore the impact of the investigational vaccine on lung function.

To describe selected biomarkers in stable COPD and during AECOPD.

To explore the T helper profile of the PD-, PE-, PilA-, UspA2-specific CD4+/ CD8+
T cell responses.

To collect blood and sputum samples for assay development, for lung microbiome 
analysis, to explore the level of inflammation (into the lung) and/ or for additional 
evaluation of the immune responses to the investigational vaccine and to other 
potential pathogens involved in AECOPD.

To explore the data for an immune correlate of protection.
Refer to Section 11.3 for the definition of the tertiary endpoints and to section 11.12.1 for 
the reporting of tertiary endpoint results. 
 
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3.
STUDY DESIGN OVERVIEW
Figure 2
Study design overview
S = Screening Visit; V = Visit; PC = Phone contact; D = Day; FU = Follow-up; BS (1) = blood sample for humoral 
immunogenicity; BS (2) = blood sample for cell-mediated immunogenicity (CMI), this blood sample will only be 
collected from a sub-cohort of subjects; BS (3) blood sample for biomarkers; SP = sputum sample
The allowed maximum interval between Screening Visit and Visit 1 is 29 days. If a delay occurs for an eligible subject 
so that the interval exceeds 29 days, some study procedures performed during the Screening Visit need to be 
repeated within 7 days (see Table 6 for more details).
* An AECOPD visit should be scheduled as soon as possible after the onset of AECOPD symptoms (max 96 hours 
after and, if applicable, preferably before starting treatment with antibiotics). During this visit blood and sputum 
samples will be collected. In addition, follow-up phone call(s) and/or visit(s) will take place to determine the end of 
the AECOPD. These contacts will take place at least every 2 weeks until the AECOPD is resolved.
Protocol waivers or exemptions are not allowed unless necessary for the management of 
immediate safety concerns. Therefore, adherence to the study design requirements, 
including those specified in the outline of study procedures (Section 6.5), are essential 
and required for study conduct. 
Investigational vaccine and placebo will be administered in addition to standard of care.

Experimental design: Phase IIB, randomised, observer-blind, placebo-controlled, 
multi-centric study with two parallel groups.

Duration of the study: for each subject enrolled, the study will last approximately 
15 months from Visit 1 up to study completion (Visit 8).

Epoch 001: Screening Visit.

Epoch 002: Primary starting at Visit 1 (Day 1) and ending at Visit 8 (Day 451).

Primary completion Date (PCD): Last Subject Last Visit (LSLV) at Visit 8 (Day 
451) or last visit/contact of Epoch 002.
 
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Refer to glossary of terms for the definition of PCD.

End of Study (EoS): Last testing results released of samples collected up to Visit 8 
(Day 451).
Refer to glossary of terms for the definition of EoS.

Study groups:

10-10-3-AS: Approximately 300 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.

CONTROL: Approximately 300 subjects receiving two doses of placebo 
(PBS).
Table 2
Study groups and epochs foreseen in the study
Study groups
Number of subjects
Age (Min/Max)
Epochs
Epoch 001
Epoch 002
10-10-3-AS
~300
40 – 80 years
x
x
CONTROL
~300
40 – 80 years
x
x
Table 3
Study groups and treatment foreseen in the study
Treatment name
Vaccine name
Study Groups
10-10-3-AS
CONTROL
10-10-3/AS01E
NTHi-Mcat 10-10-3
x
AS01E
Placebo
Formulation buffer S9b
x

Control: placebo control (PBS).

Vaccination schedule: at Visit 1 (Day 1) and Visit 3 (Day 61).

Treatment allocation: subjects will be minimised by:

Age (40 - 59 years or 60 - 80 years).

Number of moderate/ severe AECOPD in the previous year (< 2 or 2).

GOLD grade (GOLD 2, GOLD 3 or GOLD 4).

Country
All factors will have equal weight in the minimisation algorithm.
Subjects will be randomised using a centralised randomisation system on internet (SBIR) 
at first dose. Treatment number allocation (without randomisation) will also occur at 
Dose 2 using SBIR.

Blinding: observer-blind. 
 
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Table 4
Blinding of study epochs
Study Epochs
Study Groups
Blinding
Epoch 001
10-10-3-AS / CONTROL
observer-blind
Epoch 002
10-10-3-AS/ CONTROL
observer-blind

Sampling schedule:

Blood samples for assessment of humoral immunogenicity will be collected 
from all subjects at Visit 1 (Day 1), Visit 2 (Day 31), Visit 3 (Day 61), Visit 4 
(Day 91), Visit 6 (Day 271), Visit 8 (Day 451) and at each AECOPD visit from 
first vaccination to study conclusion.

Blood samples for assessment of cell-mediated immunogenicity (CMI) will 
be collected from all subjects in the CMI sub-cohort at Visit 1 (Day 1), Visit 4 
(Day 91), Visit 6 (Day 271) and at Visit 8 (Day 451).

Blood samples for biomarkers will be collected from all subjects at Visit 1 
(Day 1), Visit 8 (Day 451) and at each AECOPD visit from first vaccination to 
study conclusion.

Sputum samples will be collected from all subjects at Visit 1 (Day 1), Visit 4 
(Day 91), Visit 5 (Day 181), Visit 6 (Day 271), Visit 7 (Day 361), Visit 8 (Day 
451) and at each AECOPD visit from first vaccination to study conclusion.

COPD symptoms: All subjects will be asked to record COPD symptoms in their 
electronic Diary Card:

Daily in the morning throughout the study (including during AECOPD): 
morning symptoms questionnaire.

Daily in the evening throughout the study (including during AECOPD): 
EXACT-PRO questionnaire.

HRQOL assessments:

All subjects will be asked to complete the COPD assessment test (CAT) at the 
Screening Visit (pre-Day 1), Visit 6 (Day 271), Visit 8 (Day 451) and at each 
AECOPD visit from first vaccination to study conclusion.

All subjects will be asked to complete St. George's Respiratory Questionnaire 
for COPD patients (SGRQ-C) at the Screening Visit (pre-Day 1), Visit 6 (Day 
271), at Visit 8 (Day 451) and at each AECOPD visit from first vaccination to 
study conclusion.

Pre- and post-bronchodilator spirometry assessments will be done for all subjects 
at the Screening Visit (pre-Day 1), Visit 6 (Day 271) and at Visit 8 (Day 451).

Type of study: self-contained

Data collection: Electronic Case Report Form (eCRF), electronic Diary Cards
(eDiary) and Phone Contacts.

Safety monitoring: Safety evaluations by the safety review team (SRT) (blinded) and 
by an internal Safety Review Committee (iSRC) (unblinded) will be performed. 
Refer to section 9.10 for detailed description of safety monitoring.
 
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4.
AECOPD
4.1.
Detection of AECOPD
Occurrence of potential AECOPD will be monitored by means of electronic Diary Cards 
which the subject will use to record his/ her morning symptoms on a daily basis. The 
electronic Diary Cards will be programmed as to detect potential AECOPD as follows 
(based on the Anthonisen criteria [Anthonisen, 1987]):

Worsening of two or more of the following major symptoms for at least two 
consecutive days: dyspnoea, sputum volume, sputum purulence (colour), OR

Worsening of any major symptom together with any of the following minor 
symptoms for at least two consecutive days: sore throat, cold (nasal discharge and/or 
nasal congestion), fever (oral temperature 37.5°C/99.5°F) without other cause, 
increased cough, increased wheeze.
Note: The same two symptoms do not have to be present on both days as long as at least 
one major symptom is present on both days.
Each time a potential AECOPD is detected via the electronic Diary Card, the device will 
alert the subject to contact the study site, and at the same time an alert will be sent to the 
site so that the investigator contacts the subject to determine if the alert is an AECOPD or 
not, and if an AECOPD visit is warranted. Delegation of this responsibility from the 
investigator to study staff should be agreed with the Sponsor. In addition, the site should 
proactively follow-up all data received via the electronic Diary Card and contact the 
subject whenever deemed necessary.
During the contact with the subject, the investigator will determine whether the subject 
might actually be experiencing an AECOPD (e.g. notifications that can be explained 
solely by increased physical activity will not be considered):

If the investigator concludes that the subject is not experiencing an AECOPD, this 
should be documented/ reported in the Study Works (Web portal). Please refer to 
study procedures manual (SPM) for more details on how to perform this.

If the investigator concludes that the subject is experiencing an AECOPD, an 
occurrence of AECOPD will be entered in the eCRF and an AECOPD visit will be 
scheduled as soon as possible after the onset of AECOPD symptoms as recorded in 
the electronic Diary Card or confirmed by the subject (maximum 96 hours after onset 
of symptoms and, if applicable, preferably before starting treatment with antibiotics). 
The AECOPD onset date will be captured in the eCRF and additional information 
about severity will be also collected.

In case the AECOPD is confirmed but no AECOPD visit can take place, the site 
should record the information in the medical records subject files, and in the 
eCRF in medical records section and obtain all relevant information regarding 
the AECOPD (hospital record, medical record etc) and record this in the eCRF.
 
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
If the investigator concludes the subject is experiencing/continuing with the same 
event for which a visit has been performed already, an AECOPD visit should not 
take place. Medical treatment should be foreseen according to standard medical 
practice outside of the study.
During the AECOPD visit, the investigator will again confirm the occurrence of the 
AECOPD based on clinical and medical judgement and based on the Anthonisen criteria 
and will record its date of onset. The end date of the AECOPD and its severity will be 
determined/ confirmed by the investigator during (a) follow up phone call(s), which will 
take place at least every 2 weeks until the AECOPD has resolved.
If an AECOPD occurs at the time when one of the scheduled stablestudy visits is 
planned, it should be handled and recorded as an AECOPD visit, with all relevant 
AECOPD visit study procedures performed and, if possible, the stable study visit should 
be re-scheduled to a later date, when the subject is stable again and within the time 
window specified in the protocol.
The site must engage their best efforts to reach the patients, however, if the site does not 
succeed in contacting the patient, the reason should be recorded and an explanation given 
about what occurred. For example, the subject could be hospitalized or could visit a 
different physician (and in that case medical records should be obtained), or the subject is 
on holidays or not able to go to the site.
For the analysis of the primary endpoint, the AECOPD must be confirmed by the 
investigator:

Via a phone call following the eDiary alert, and/or 

At a spontaneous site visit with or without eDiary alert and/or 

At the AECOPD visit and/or 

Via medical records
If an AECOPD occurs at the time of a scheduled study visit, it should be handled and 
recorded as an AECOPD visit, with all relevant study procedures done during AECOPD-
driven study visits performed and, if possible, the scheduled visit should be re-scheduled 
to a later date within the time window specified in the protocol. 
Some subjects may have been supplied with a prescription for antibiotics and/or steroids 
for treatment of AECOPD to use according to instructions provided by their physician in 
the event of an AECOPD occurring at a future date. During the course of this study, 
following an eDiary alert for potential AECOPD or other contact for potential AECOPD,
the investigator should make all possible efforts to ensure contact with the patient prior to 
the patient self-administering any antibiotics or steroids for their potential AECOPD. To 
manage situations where this prior contact cannot occur the investigator should use their 
clinical judgement. 
Please refer to the SPM for more details on detection and recording of AECOPDs.
 
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4.1.1.
Date of onset and end date of AECOPD
Per inclusion criteria, the subject should be a stable COPD patient (i.e. a subject for 
whom the last episode of AECOPD is resolved for at least 30 days at the time of first 
vaccination). (Amended 27 March 2019) This effectively sets the baseline for 
evaluating the symptoms stated within the Anthonisen criteria (see Section 4.1). The date 
of onset of AECOPD is the first day (of at least 2 consecutive days) of worsening 
symptoms of COPD as determined by the investigator according to the Anthonisen 
criteria. For example, worsening of dyspnoea, sputum volume and sputum purulence is 
evaluated daily by the patient relative to this baseline. For an AECOPD confirmed by the 
investigator following an eDiary alert the onset date is considered to be the first day of 2 
consecutive days that the patient enters symptoms meeting the Anthonisen criteria. Each 
day that there is no new symptom effectively becomes the new baseline. Once the 
Anthonisen criteria are met, an eDiary alert is triggered. (Amended 27 March 2019) If 
the investigator determines this to be an AECOPD, that event is recorded via the eCRF. 
Subsequently, the investigator will follow the patient via phone contact (or clinic visit) at 
least every 2 weeks until resolution of this event.
The end date should be based on when the investigator and/or subject determines that the 
AECOPD symptoms have returned to pre-exacerbation levels or to a new baseline. In 
determining this end date, consideration should be given to symptoms recorded in the 
electronic Diary Card and during the phone calls and/or study subject evaluation.
The patient continues to daily monitor the symptoms within the Anthonisen criteria 
relative to the symptom state at the time of determined resolution.
Both start and end date of each confirmed AECOPD occurring from Visit 1 to study 
conclusion will be recorded in the eCRF.
4.1.2.
Guideline for assessing AECOPD that increase in severity
If an exacerbation starts off as mild, but becomes moderate or severe, or starts off as 
moderate and becomes severe, the exacerbation should be captured as one exacerbation 
and classified by its highest level of severity.
4.2.
Treatment of AECOPD
AECOPD should be treated according to standard of care.
 
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5.
STUDY COHORT
5.1.
Number of subjects
The target is to enrol approximately 300 eligible COPD patients aged 40 to 80 years per 
study group (i.e. ~600 subjects in total). Refer to Section 11.4 for a detailed description 
of the criteria used in the estimation of the sample size.
Approximately 20% of the subjects (~120 subjects in total) will be part of a sub-cohort 
for CMI analysis. An additional blood sample will be taken from these subjects at 
specified timepoints (Visit 1, 4, 6 and 8). The CMI sub-cohort will be selected from sites 
able to process the blood samples according to GSK procedures for peripheral blood 
mononuclear cell (PBMC) preparation.
Table 5
Sub-cohorts
Sub-cohort name
Description
Estimated number of subjects
Sub-cohort for CMI
At specific timepoints (Visit 1, 4, 6 and 8), an 
additional blood sample will be taken from these 
subjects for evaluation of the vaccine component-
specific CMI responses.
120 subjects (60 subjects in 
each group)
5.2.
Inclusion criteria for enrolment
Deviations from inclusion criteria are not allowed because they can potentially jeopardize 
the scientific integrity, regulatory acceptability of the study or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential.
All subjects must satisfy ALL the following criteria at study entry:

Subjects who, in the opinion of the investigator, can and will comply with the 
requirements of the protocol (e.g. electronic Diary Card completion, number of 
blood draws, sputum sampling, pre- and post-bronchodilator spirometry, return for 
follow-up visits).

Written informed consent obtained from the subject prior to performing any study 
specific procedure.

A male or female between, and including, 40 and 80 years of age at the time of the 
first vaccination.

Confirmed diagnosis of COPD (based on post-bronchodilator spirometry) with 
forced expiratory volume in 1 second (FEV1) over forced vital capacity (FVC) ratio 
(FEV1/FVC) < 0.7, AND FEV1 < 80% predicted (GOLD 2, 3 and 4).

Current or former smoker with a cigarette smoking history of ≥ 10 pack-years.
Refer to the glossary of terms for the definitions of pack-years and of current and 
former smoker.
 
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
Stable COPD patient* with documented history** (e.g. medical record verification) 
of at least 1 moderate or severe AECOPD within the 12 months before Screening.
* Patient for whom the last episode of AECOPD is resolved for at least 30 days at 
the time of first vaccination.
** A documented history of a COPD exacerbation (e.g. medical record verification) 
is a medical record of worsening COPD symptoms that required systemic/oral 
corticosteroids and/or antibiotics (for a moderate exacerbation) or hospitalization (for 
a severe exacerbation). Prior use of antibiotics alone does not qualify as an
exacerbation history unless the use was associated with treatment of worsening 
symptoms of COPD, such as increased dyspnea, sputum volume, or sputum 
purulence (color). Subject verbal reports are not acceptable.
Refer to the Study Procedures Manual (SPM) for additional details on what is 
accepted as documented history of AECOPD. Refer to Table 1 for the definitions of 
moderate and severe AECOPD.

Capable of complying with the daily electronic Diary Card completion throughout 
the study period, according to investigator’s judgement at Visit 1.
Refer to the SPM for recommendations on what is considered adequate compliance 
by Visit 1. 

Female subjects of non-childbearing potential may be enrolled in the study.

Non-childbearing potential is defined as pre-menarche, current bilateral tubal 
ligation or occlusion, hysterectomy, bilateral 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.
5.3.
Exclusion criteria for enrolment
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity, regulatory acceptability of the study or subject safety. 
Therefore, adherence to the criteria as specified in the protocol is essential.
The following criteria should be checked at the time of study entry. If ANY exclusion 
criterion applies, the subject must not be included in the study:

Use of any investigational or non-registered product (drug or vaccine) other than the 
study vaccine during the period starting 30 days before the first dose of study 
vaccine (Day -29 to Day 1), or planned use during the study period.
 
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
Any medical condition that in the judgment of the investigator would make 
intramuscular injection unsafe.

Administration of immunoglobulins 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).

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 
vaccine which may be administered ≥15 days preceding or following any study 
vaccine dose.

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).

Chronic administration (defined as more than 14 days in total) of 
immunosuppressants or other immune-modifying drugs during the period starting six 
months prior to the first vaccine dose (e.g. methotrexate).

Administration of systemic corticosteroids (prednisone ≥10 mg/day, or equivalent) 
within the 30 days before first vaccination.

Subjects who received systemic corticosteroids within this period may be 
enrolled at a later date if enrolment is still open.

Inhaled and topical steroids are allowed.

Administration of systemic antibiotics within the 30 days before first vaccination.

Subjects who received systemic antibiotics within this period may be enrolled at 
a later date if enrolment is still open.

Chronic use of antibiotics for prevention of AECOPD (e.g. azithromycin).

Acute disease and/or fever at the time of first vaccination.

Fever is defined as temperature 37.5°C/99.5°F. The preferred location for 
measuring temperature in this study will be the oral cavity or the axilla.

Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory 
infection) without fever may be enrolled at the discretion of the investigator. 

Oxygen therapy: Use of long-term oxygen therapy (LTOT) described as resting 
oxygen therapy >3L/min (Oxygen use ≤3L/min flow is not exclusionary).

Planned lung transplantation.

Lung resection: Subjects with planned lung volume reduction surgery during the 
study or within the 12 months prior to first vaccination.

Diagnosis of α-1 antitrypsin deficiency as the underlying cause of COPD.
 
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
Diagnosed with a respiratory disorder other than COPD at time of enrolment (such as 
sarcoidosis, active tuberculosis, clinically significant bronchiectasis, clinically 
significant lung fibrosis, clinically significant pulmonary embolism, clinically 
significant pneumothorax, current diagnosis of asthma in the opinion of the 
investigator), or chest X-ray/ CT scan revealing evidence of clinically significant 
abnormalities not believed to be due to the presence of COPD. Subjects with allergic 
rhinitis do not need to be excluded and may be enrolled at the discretion of the 
investigator.

History of immune-mediated disease other than COPD.
Please refer to Table 19 for a non-exhaustive List of potential immune-mediated 
diseases. If the subject has any condition on this list, they must be excluded unless 
the aetiology is clearly documented to be non-immune mediated.
The investigator will exercise his/her medical and scientific judgement in deciding 
whether other diseases have an autoimmune origin and thus meet the exclusion 
criteria.

Previous vaccination with any vaccine containing NTHi and/ or Mcat antigens.

History of any reaction or hypersensitivity likely to be exacerbated by any 
component of the vaccines and/ or the bronchodilator used for spirometry assessment 
during the study.

Contraindication for spirometry testing (such as recent eye surgery, recent thoracic 
or abdominal surgery procedures, unstable cardiovascular status, recent myocardial 
infarction or pulmonary embolism).

Unstable or life threatening cardiac disease: subjects with any of the following at 
Screening (Visit 1) would be excluded:  

Myocardial infarction or unstable angina in the last 6 months.

Unstable or life threatening cardiac arrhythmia requiring intervention in the last 
3 months

NYHA Class IV Heart failure

Malignancies within the previous 5 years (excluding non-melanotic skin cancer and 
carcinoma in situ of the cervix, if considered cured) or lymphoproliferative disorder.

Any known disease or condition likely to cause death during the study period.

Pregnant or lactating female.

Current alcoholism and/or drug abuse.
Refer to the glossary of terms for the definition of alcoholism.

Other condition which the investigator judges may put the safety of the subject at 
risk through study participation or which may interfere with the study findings (e.g. 
anaemia, patient on dialysis).

Planned move to a location that will complicate participation in the trial through 
study end.
 
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6.
CONDUCT OF THE STUDY
6.1.
Regulatory and ethical considerations, including the 
informed consent process
The study will be conducted in accordance with all applicable regulatory requirements.
The study will be conducted in accordance with the ICH Guideline for GCP, all 
applicable subject privacy requirements and the guiding principles of the Declaration of 
Helsinki. 
GSK will obtain favourable opinion/approval to conduct the study from the appropriate 
regulatory agency, in accordance with applicable regulatory requirements, prior to a site 
initiating the study in that country.
Conduct of the study includes, but is not limited to, the following:

Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and 
favourable opinion/approval of study protocol and any subsequent amendments.

Subject informed consent.

Investigator reporting requirements as stated in the protocol.
GSK will provide full details of the above procedures to the investigator, either verbally, 
in writing, or both.
Freely given and written or witnessed/ thumb printed informed consent must be obtained 
from each subject, as appropriate, prior to participation in the study.
GSK Biologicals will prepare a model Informed Consent Form (ICF) which will embody 
the ICH GCP and GSK Biologicals required elements. While it is strongly recommended 
that this model ICF is to be followed as closely as possible, the informed consent 
requirements given in this document are not intended to pre-empt any local regulations 
which require additional information to be disclosed for informed consent to be legally 
effective. Clinical judgement, local regulations and requirements should guide the final 
structure and content of the local version of the ICF. 
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.
 
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6.2.
Subject identification and randomisation
6.2.1.
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.
6.2.2.
Randomisation of treatment
6.2.2.1.
Randomisation of supplies
The randomisation of supplies within blocks will be performed at GSK Biologicals, using 
MATerial EXcellence (MATEX), a program developed for use in Statistical Analysis 
System (SAS) (Cary, NC, USA) by GSK Biologicals. Entire blocks will be shipped to the 
study centres /warehouse(s).
6.2.2.2.
Treatment allocation to the subject
The treatment numbers will be allocated by dose.
6.2.2.2.1.
Study group and treatment number allocation
The target will be to enrol approximately 600 eligible subjects who will be randomly 
assigned to two study groups in a (1:1) ratio (approximately 300 subjects in each group).
Allocation of the subject to a study group at the investigator site will be performed using 
a randomisation system on internet (SBIR). The randomisation algorithm will use a 
minimisation procedure accounting for age (40 - 59 years or 60 - 80 years), number of 
moderate/ severe AECOPD in the previous year (< 2 or ≥2), GOLD grade (GOLD 2, 
GOLD 3 or GOLD 4) and country. Minimisation factors will have equal weight in the 
minimisation algorithm.
Details on the minimisation algorithm are reported in the statistical analysis plan. 
At Visit 1, before administration of vaccine Dose 1 to eligible subjects who signed and 
dated the ICF at the Screening Visit, the study staff in charge of the vaccine 
administration will access SBIR. Upon providing the subject’s age category (40 - 59 
years or 60 - 80 years), number of moderate/ severe AECOPD in the previous year, his/ 
her GOLD grade and subject identification number, the randomisation system will 
determine the study group and will provide the treatment number to be used for the first 
dose.
The number of each administered treatment must be recorded in the eCRF on the Vaccine 
Administration screen.
 
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When SBIR is not available, please refer to the SBIR user guide or the Study Procedures 
Manual (SPM) for specific instructions.
6.2.2.2.2.
Treatment number allocation for subsequent doses 
For each dose subsequent to the first dose, the study staff in charge of the vaccine 
administration will access SBIR, provide the subject identification number, and the 
system will provide a treatment number consistent with the allocated study group.
The number of each administered treatment must be recorded in the eCRF on the Vaccine 
Administration form/screen.
When SBIR is not available, refer to the SBIR user guide or the SPM for specific 
instructions.
6.2.3.
Allocation of subjects to assay subsets 
Approximately 50% of the subjects (~150 subjects per group) will have their sputum 
samples analysed for microbiology in investigator institutions or GSK designated lab. 
The sub-set will be selected for sites that have microbiology accredited local/hospital 
laboratories able to process and test the sputum samples according to GSK agreed 
procedures.
Sputum samples (or a subset of them), not tested for microbiology at investigator 
institutions or GSK designated labs, will also be used for cytokine measurement (see also
Table 12).
6.3.
Method of blinding 
As the investigational NTHi-Mcat vaccine in this study is of different appearance than 
the placebo and the investigational NTHi-Mcat vaccine will have to be reconstituted 
whereas the placebo does not, double-blinding is not feasible.
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 efficacy) will all be 
unaware of whether vaccine or placebo was administered. 
Study site
Each study site is responsible for having a blinding plan. To work in an observer-blind 
manner, vaccine preparation and administration will be done by authorised medical 
personnel who will not participate in any of the study clinical evaluation assays. Two 
teams of study personnel will hence be set up:

A team of unblinded personnel (responsible for the preparation and the 
administration of the vaccines)

A team of blinded personnel (responsible for the clinical evaluation of the subjects).
 
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Refer to the SPM for guidance on vaccine preparation and administration while 
maintaining the blind.
Laboratory testing
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.
6.4.
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.
Subjects will continue to receive their COPD standard of care during the entire study 
duration.
 
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6.5.
Outline of study procedures
Table 6
List of study procedures
Epoch
Epoch 001
Epoch 002
Type of contact
Screening
Visit (a)
Visit 1
Phone 
contac
t 1 (k)
Visit 2
Visit 3
Phone 
contact 
2 (k)
Visit 4 Visit 5 Visit 6
Visit 7
Visit 8
Timepoint
pre-Day 1
Day 1
Day 8
Day 
31
Day 61
Day 68
Day 
91
Day 
181
Day 
271
Day 361
Day
451
Sampling timepoint
Screening Pre-Vacc 1
Post-Vacc 1
Pre-Vacc 2
Post-Vacc 2
Informed consent
●
Check inclusion/exclusion criteria
●
O
Record of moderate and severe AECOPD within the previous year
O
●
Check subject's COPD status
●
●
●
●
●
●
●
●
●
●
Record demographic data
●
Record medical history, including significant comorbidities
O
●
Vaccination history
O
●
Smoking exposure history (ATS-DLD-78A questionnaire)
x
Smoking status
●
●
●
Physical examination
●
O
O
O
O
O
O
O
O
Measure/record height and weight
●
O
●
Pre- and post-bronchodilator spirometry (l)
x (b)
x
x
Chest X-ray (d)
●(b)
Pregnancy test   (c)
●(b)
●
●
Blood sampling:
 For humoral immunogenicity (~20 ml of blood)
●
●
●
●
●
●
  For CMI (~40 ml of blood) (e)
●
●
●
●
  For biomarkers, serum and plasma (~13 ml of blood)  
●
●
  For biomarker, haematology profile (~2 ml of blood)
●
Sputum sampling (f)
●
●
●
●
●
●
Check contraindications to vaccination
O
O (g)
Record pre-vaccination body temperature
●
●
Study group and Treatment number allocation with randomisation
●
●
Vaccination
●
●
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Epoch
Epoch 001
Epoch 002
Type of contact
Screening
Visit (a)
Visit 1
Phone 
contac
t 1 (k)
Visit 2
Visit 3
Phone 
contact 
2 (k)
Visit 4 Visit 5 Visit 6
Visit 7
Visit 8
Timepoint
pre-Day 1
Day 1
Day 8
Day 
31
Day 61
Day 68
Day 
91
Day 
181
Day 
271
Day 361
Day
451
Sampling timepoint
Screening Pre-Vacc 1
Post-Vacc 1
Pre-Vacc 2
Post-Vacc 2
Train subject on the use of electronic Diary Card and assign electronic 
Diary Card to subject
O
Distribute electronic Diary Card for recording of local and general AEs, 
medication and vaccination, morning and evening COPD symptoms
O
Collection of electronic Diary Card data (h)
x
x
x
x
x
x
x
x
x
x
Distribution of Subject Card
O
Record AEs (i)
●
●
●
●
●
●
●
●
●
●
Record SAEs (i)
●(b)
●
●
●
●
●
●
●
●
●
●
Record pregnancies (i)
●
●
●
●
●
●
●
●
●
●
Record pIMDs (i)
●
●
●
●
●
●
●
●
●
●
Record concomitant medication/products and vaccination
O
●
●
●
●
●
●
●
●
●
●
Record intercurrent medical conditions
●
●
●
●
●
●
●
●
●
Return electronic Diary Card
O (j)
O (j)
O
HRQOL questionnaires:
  CAT
x
x
x
  SGRQ-C
x
x
x
Healthcare Resource Utilisation
●
●
●
●
●
●
●
●
●
●
Screening conclusion
●
Study Conclusion
●
D = Day; Vacc = vaccination. PC = Phone contact; CAT = COPD assessment test; SGRQ-C = St. George’s Respiratory Questionnaire for COPD patients; AECOPD = Acute 
exacerbation of chronic obstructive pulmonary disease; COPD = chronic obstructive pulmonary disease; CMI = cell-mediated immunity; AE = adverse event; SAE = serious 
adverse event; pIMDs = potential immune mediated diseases; HRQOL = health-related quality of life.
● 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; x is used to indicate a study procedure that does not require documentation in the individual eCRF as the data will be directly transferred from the provider to 
GSK.
a If needed, the Screening Visit(s) can be done in more than 1 day. All screening procedures with exception of eDiary training should be performed within 7 days from 1st screening 
visit. The allowed maximum interval between 1st Screening Visit and Visit 1 is 29 days. If a delay occurs for an eligible subject so that interval exceeds 29 days, some study 
procedures performed during Screening Visit(s) need to be repeated (see footnote b). In case of AECOPD occurring before Visit 1, subjects should be treated outside the study 
according to standard practice. These subjects are considered screening failures. They will need to sign a new ICF, will receive a new subject number and will need to repeat the 
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entire Screening Visit after they are stable for at least 30 days. The entire Screening Visit can only be repeated once. Once subject is determined as eligible, the eDiary for 
completion will be given to the subject for a training period of maximum 14 days before Visit 1 (see Section 6.9.22.)
b Procedures indicated by this footnote need to be repeated if the subject has any medical condition (e.g. fever) that prevents his/her participation in the study within 29 days of 
Screening Visit. In that case, a re-Screening Visit must be scheduled as soon as possible and no more than 7 days from Day 29 (Day 30 - Day 36) during which the procedures 
indicated by this footnote need to be repeated. Same as for the initial screening, the chest X-ray only has to be redone if no chest X-ray/ CT scan is available within the last 3 
months. Data obtained during re-screening procedures should be entered in the eCRF.
c Pregnancy tests will be performed on all females of childbearing potential at screening and prior to vaccination (Visit 1 and Visit 3 [(including those female subjects of 
childbearing potential who did not have a pregnancy test at screening because an X-ray/ CT scan was available within the last 3 months]). In case a chest X-ray will be 
performed (i.e. in subjects who do not have an X-ray / CT scan) the pregnancy test should be carried out prior to the chest X-ray and if a subject has a positive pregnancy test the 
chest X-ray should not be performed and the subject will be deemed not eligible for the study. Please also refer to Section 10.2.2. (Amended 27 March 2019)
d Only if no chest X-ray/ CT scan available within the last 3 months.
e Only for subjects in the sub-cohort for CMI.
f Only if, in the opinion of the investigator, it is safe for the subject. Sputum samples can be either spontaneous or induced, as per investigator judgement.
g Refer to Section 7.5 for more details on study procedures for subjects meeting contraindications to subsequent vaccination before administration of vaccine Dose 2.
h The following information will be collected with the electronic Diary Card: COPD morning and evening symptoms (including EXACT-PRO questionnaire), smoking exposure history, 
local and general solicited AEs and Healthcare utilisation.
i Please refer to Table 20 for recording periods of local and general solicited AEs, AEs/SAEs leading to study withdrawal, SAEs, pregnancies and pIMDs. Solicited AEs will be collected 
up to Day 7 post- vaccination. Solicited AEs ongoing at Day 7 will be followed up until resolution (for a maximum of 30 Days). Unsolicited AEs will be collected for 30 days after 
each vaccination and thereafter only AEs leading to Withdrawal.
j Only for Screening failures.
k The safety phone call at Day 8 and Day 68 can be performed by the (sub)-investigator or a medically trained delegate.
l If a good quality spirometry was not obtained, the spirometry can be repeated within 7 days, as per investigator medical judgement.
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6.6.
List of study procedures during AECOPD-driven study visits 
and phone contacts
In addition to the scheduled study visits, ad hoc AECOPD-driven study contacts will take 
place for each AECOPD occurring from first vaccination up to study conclusion. The 
procedures to be performed during these contacts are listed in Table 7. 
In case of AECOPD occurring before Visit 1, subjects should be treated outside the study 
according to standard practice. These subjects are considered screening failures. They 
will need to sign a new ICF, will receive a new subject number and will need to repeat 
the entire Screening Visit after they are stable for at least 30 days.
Table 7
List of study procedures during AECOPD-driven study visits and 
phone contacts
Type of contact
AECOPD visit
End of AECOPD contact(s)
(phone call[s7 and/ or visit[s)
Timepoint
within 96 hours of 
onset symptoms
at least every 2 weeks from the 
AECOPD visit until AECOPD 
has resolved 1
Sampling timepoint
AECOPD
Record date of visit
●
Physical examination
O
O 2
Chest X-ray 3
●
Pregnancy test 4
●
Confirm AECOPD and record its start date
●
Blood sampling:
  For humoral immunogenicity (~5 ml of blood)
●
  For biomarkers, serum and plasma (~13 ml of blood)
●
Sputum sampling 5
●
HRQOL questionnaire:
  CAT
x
  SGRQ-C
x
Healthcare Resource Utilisation 8
●
●
Record AEs 6
●
●
Record SAEs 6
●
●
Record pregnancies 6
●
●
Record pIMDs 6
●
●
Record concomitant medication/products and vaccination
●
●
Record intercurrent medical conditions
●
●
Record AECOPD severity
O
●
Record AECOPD end date
●
● 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.
x is used to indicate a study procedure that does not require documentation in the individual eCRF as the data will be 
directly transferred from the provider to GSK.
AECOPD = Acute exacerbation of chronic obstructive pulmonary disease; HRQOL = health-related quality of life; CAT
= COPD assessment test; SGRQ-C = St. George’s Respiratory Questionnaire for COPD patients; AEs = adverse 
events; SAEs = serious adverse events; pIMDs = potential immune mediated diseases.
1 End of AECOPD phone calls/ visits should be scheduled at least every 2 weeks, until the AECOPD has resolved. 
Only the contact during which the end date of the AECOPD can be determined will be recorded in the eCRF as 
the end of the AECOPD contact. All intermediate contacts should be recorded on source documentation.
2Only applicable if the contact is a visit (not for phone calls).
 
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3 Only if clinically indicated to exclude another cause of worsening of symptoms (e.g. pneumonia).
4Pregnancy test will be performed on females of childbearing potential at each visit where a chest X-ray is performed. 
The pregnancy test should be carried out prior to the chest X-ray and if a subject has a positive pregnancy test 
the chest X-ray should not be performed and the subject must not receive further study vaccinations. Please also 
refer to Section 10.2.2.
5 Only if, in the opinion of the investigator, it is safe for the subject. Sputum samples can be either spontaneous or 
induced, as per investigator judgement. Self-collection of the sputum sample will be allowed in specific cases, 
where the first dose of antibiotics absolutely needs to be taken before an AECOPD visit can take place. As much 
as possible, the sputum sample collection should happen during the visit at investigator site. Self-collection is not 
allowed at scheduled visits when the subject should be in stable condition. See Section 6.9.15.2.
6Please refer to Table 20 for recording periods of local and general solicited AEs, unsolicited AEs, AEs/SAEs leading
to study withdrawal, SAEs, pregnancies and pIMDs.
7 The phone call to determine the end of AECOPD contact should be performed by the (sub)-investigator. Delegation 
to study staff should be agreed with the Sponsor.
8 The AECOPD visit does not need to be recorded as a Healthcare Resource Utilisation.
6.7.
Concurrence of AECOPD-driven study visits and scheduled 
study visits
If an AECOPD occurs at the time of a scheduled study visit, it should be handled and 
recorded as an AECOPD visit, with all relevant study procedures done during 
AECOPD-driven study visits performed and, if possible, the scheduled visit should be re-
scheduled to a later date within the time window specified in the protocol.
If the end of AECOPD contact occurs around the same time of a scheduled study visit, 
they can be combined into a single visit with the study procedures relevant to both visit 
types performed. In this case, both visit types will need to be recorded in the eCRF 
separately. 
Please refer to SPM for specific instructions. (Amended 27 March 2019)
 
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6.8.
Intervals between study visits
Whenever possible, the investigator should arrange study visits within the interval 
described in Table 8.
Table 8
Intervals between study visits
Interval
Optimal length of interval
Allowed interval
Scheduled study visits
Screening Visit* Visit 1
14 days
6 - 29 days
Visit 1  Phone contact 1
7 days
7 - 9 days
Visit 1  Visit 2
30 days
30 - 45 days
Visit 1 Visit 3
60 days
60 - 75 days 1
Visit 3 Phone contact 2
7 days
7 - 9 days
Visit 3 Visit 4
30 days
30 - 45 days 1
Visit 4   Visit 5
90 days
90 - 120 days
Visit 4 Visit 6
180 days
180- 210 days
Visit 4 Visit 7
270 days
270 - 300 days
Visit 4   Visit 8
360 days
360 - 390 days
AECOPD-driven study visit(s) and/ or phone contacts
Onset of AECOPD symptoms as recorded in the electronic 
Diary Card or confirmed by the subject AECOPD Visit
NA
max 96 hours 2
Interval between AECOPD Visit and scheduled study visit
AECOPD visit scheduled study visit
NA
min 7 days 3
PC = phone contact; AECOPD = Acute exacerbation of chronic obstructive pulmonary disease; NA = Not applicable
1 Subjects will not be eligible for inclusion in the Per Protocol Set for analysis of immunogenicity if they make the study 
visit outside this interval.
2 AECOPD visits will be scheduled as soon as possible after the onset of AECOPD symptoms as recorded in the 
electronic Diary Card or confirmed by the subject (maximum 96 hours after and, if applicable, preferably before 
starting treatment with antibiotics).
3 If an AECOPD occurs at the time of a scheduled study visit, it should be handled and recorded as an AECOPD visit, 
with all relevant study procedures done during AECOPD-driven study visits performed and, if possible, the 
scheduled visit should be re-scheduled to a later date within the time window specified in the protocol.
* In case of a re-Screening Visit, the visit must be scheduled as soon as possible and no more than 7 days from Day 
29 (Day 30 - Day 36).
6.9.
Detailed description of study procedures
6.9.1.
Informed consent
The signed/witnessed/thumb printed informed consent of the subject must be obtained 
before study participation. Refer to Section 6.1 for the requirements on how to obtain 
informed consent, as appropriate.
6.9.2.
Check inclusion and exclusion criteria
Check all inclusion and exclusion criteria as described in Sections 5.2 and 5.3 before 
enrolment. 
 
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6.9.3.
Record history of moderate and severe AECOPD within the 
previous year
Obtain the subject’s history of moderate and severe AECOPD within the previous year. 
At Screening, subjects need documentation for at least 1 moderate or severe AECOPD 
within the previous year to be eligible for study participation. 
At Visit 1, both documented (by medical record review) and self-reported, 
non-documented moderate and severe AECOPD within the year before Visit 1 should be 
recorded in the eCRF. The total number of moderate and severe AECOPD (including 
self-reported, non-documented AECOPD) will be entered in SBIR for randomisation.
Refer to the SPM for details on recording of moderate and severe AECOPD within the 
previous year. 
6.9.4.
Check subject’s COPD status
Record the subject’s COPD status (stable/ recovered or not recovered) in the eCRF.
6.9.5.
Collect demographic data
Record demographic data such as year of birth, sex, race and ethnicity in the subjects’
eCRF.
Differences in the safety and efficacy of certain medical products, including vaccines 
[Haralambieva, 2013; Pérez-Losada, 2009; Kollmann, 2013], have been observed in 
racially and ethnically distinct subgroups. These differences may be attributable to 
intrinsic factors (e.g. genetics, metabolism, elimination), extrinsic factors (e.g. diet, 
environmental exposure, sociocultural issues), or interactions between these factors. 
Therefore, both race and ethnicity will be collected for all subjects participating in the 
NTHI MCAT-002 study.
6.9.6.
Record medical history, including significant co-morbidities
Obtain the subject’s medical history by interview and/ or review of the subject’s medical 
records and record any pre-existing conditions, signs and/ or symptoms present in a
subject and significant COPD co-morbidities prior to the first study vaccination in the 
eCRF.
Significant comorbidities include weight loss, cardiovascular disease, hypertension, 
gastro-oesophageal reflux disease, osteoporosis/ osteopenia, skeletal muscle wasting and 
dysfunction, anxiety/ depression and diabetes.
 
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6.9.7.
Vaccination history
Record in the eCRF whether the subject received any influenza vaccination within the 
previous 12 months or has ever received any pneumococcal vaccination (including date 
of vaccination [as detailed as possible). 
6.9.8.
Smoking exposure history
The subject should self-complete the smoking history questionnaire (a shortened version 
of the ATS-DLD-78A questionnaire), which will be provided electronically via the
eDiary. The subject will have to provide information about his/ her smoking history, 
including duration (number of years) and number of cigarettes smoked. 
From the information obtained via the questionnaire, calculation of the pack-years will be 
done.
The data will be directly transferred from the provider to GSK Biologicals.
Refer to the SPM for details and guidance on the smoking exposure history questionnaire.
6.9.9.
Smoking status
Record the subject’s smoking status (current or former smoker) in the eCRF. Refer to the 
glossary of terms for the definitions of current and former smoker.
6.9.10.
Physical examination
At Screening, perform a complete physical examination of the subject, including vital 
signs after at least 10 minutes of rest (systolic/ diastolic blood pressure, heart rate, 
respiratory rate). Record collected information in the eCRF.
Physical examination at each study visit subsequent to the Screening Visit will be 
performed only if deemed necessary by the investigator or delegate.
If the investigator determines that the subject’s health on the day of vaccination 
temporarily precludes vaccination, the visit will be rescheduled.
Treatment of any abnormality observed during a physical examination has to be 
performed according to local medical practice outside this study or by referral to an 
appropriate health care provider. 
6.9.11.
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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6.9.12.
Pre- and post-bronchodilator spirometry
Pre- and post-bronchodilator spirometry should be performed during specified study 
visits as detailed in Table 6.
Only certified study staff can perform spirometry assessment. 
Spirometry will be performed following the eResearchTechnology (ERT) instructions for 
use FlowScreen manual and following all safety requirements.
A good quality spirometry should be obtained and will be confirmed by the spirometry 
provider. If a good quality spirometry was not obtained, the spirometry can be repeated 
within 7 days, as per investigator medical judgement. 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 this study or by referral to an appropriate health care 
provider.
6.9.13.
Chest X-ray
Screening
A posterior to anterior (PA) chest X-ray must be performed at Screening if no chest 
X-ray/ CT scan is available within the last 3 months. 
Subjects with evidence of clinically significant abnormalities not believed to be due to 
the presence of COPD will not be eligible for study participation.
The pregnancy test should be carried out prior to the chest X-ray and if a subject has a 
positive test, the chest X-ray should not be performed and the subject will be deemed not 
eligible for the study.  Please also refer to section 10.2.2. 
AECOPD visit
A chest X-ray should be performed at the AECOPD visit if it is clinically indicated to 
exclude another cause of worsening of symptoms (e.g. pneumonia).
All cases of pneumonia (including all signs and symptoms assessed to confirm 
pneumonia) should be documented in the eCRF.
The pregnancy test should be carried out prior to the chest X-ray and if a subject has a 
positive test, the chest X-ray should not be performed and the subject must not receive 
further study vaccinations. Please also refer to section 10.2.2.
6.9.14.
Pregnancy test 
Female subjects of childbearing potential are to have a pregnancy test at Screening and 
prior to vaccination (Visit 1 and Visit 3). The study vaccine may only be administered if 
the pregnancy test is negative. (Amended 27 March 2019)
 
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Note: the pregnancy test must be performed even if the subject is menstruating at the time 
of the study visit.
The pregnancy test should be carried out prior to the chest X-ray and if a subject has a 
positive test at time of Screening, the chest X-ray should not be performed and the 
subject will be deemed not eligible for the study.  If the positive test occurs during the 
study, the subject must not receive further study vaccinations. Please also refer to section 
10.2.2. 
6.9.15.
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 
the samples.
6.9.15.1.
Blood samples
Blood samples will be taken during specified study visits (scheduled visits and AECOPD
visits) as detailed in Table 6 and Table 7.
Blood samples for humoral immunogenicity
A volume of approximately 20 mL of whole blood should be drawn from all subjects at 
Visit 1, Visit 2, Visit 3, Visit 4, Visit 6 and Visit 8. A volume of approximately 5 mL of 
whole blood should be drawn from all subjects at each AECOPD visit from first 
vaccination to study conclusion. After whole blood processing into serum, serum samples 
should be kept at ≤-20°C/-4°F or any temperature below until shipment.
Blood samples for CMI
A volume of approximately 40 mL of whole blood should be drawn from the subjects 
included in the sub-cohort for CMI at Visit 1, Visit 4, Visit 6 and Visit 8. The samples 
should be kept at room temperature and should be shipped as soon as possible (maximum 
8 hours after whole blood collection), so that samples can be processed at the CMI 
laboratory within 24 hours of collection. Refer to the SPM and Central Laboratory 
manual for more details on sample storage conditions.
Blood samples for biomarkers
At Visit 1, Visit 8 and at each AECOPD visit from first vaccination to study conclusion: 
a volume of approximately 13 mL of whole blood should be drawn from all subjects and 
will be split and processed as follows:

Specific biomarkers will include serum hsCRP, CXCL10 (IP-10) and plasma 
fibrinogen, may include other biomarkers based on results of ongoing disease 
understanding research.

Approximately 8.5 mL of whole blood will be collected and processed to serum 
for hsCRP & CXCL10 (IP-10) assessment. After processing, these samples 
should be kept at -70/-80°C until shipment.
 
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
Approximately 4.5 mL of whole blood (Na Citrate) will be collected and 
processed to plasma for fibrinogen assessment. After processing, these samples 
should be kept at -70/-80°C until shipment.
In addition to the above, the following will be collected at Visit 1:

Haematology profile, including differential cell counts.

Approximately 2.0 mL of whole blood will be collected for haematology 
assessment. These samples should be kept at room temperature and shipped for 
testing on the day of collection, ambient.
Refer to the SPM and Central Laboratory manual for details on blood sample handling.
6.9.15.2.
Sputum samples
Sputum samples will be collected during specified study visits (scheduled visits and 
AECOPD visits) as detailed in Table 6 and Table 7, if, in the opinion of the investigator, 
it is safe for the subject.

Sputum samples can be either spontaneous or induced, as per investigator judgement. 
Internal standard operating procedures should be put in place to ensure proper 
sputum collection, sample tracking and subject safety at study collection site.

Sputum sample collected at subject’s home (spontaneous): Self-collection of the 
sputum sample will be allowed in specific cases, where the first dose of antibiotics 
absolutely needs to be taken before an AECOPD visit can take place. As much as 
possible, the sputum sample collection should happen during the visit at investigator
site. Self-collection is not allowed at scheduled visits when the subject should be in 
stable condition.
Note: The sputum samples collected during AECOPD should preferably be obtained 
before administration of the first dose of antibiotics to treat the AECOPD (if applicable).
Refer to the SPM and to the central laboratory manual for more details and guidance on 
collection and handling of sputum samples.
6.9.16.
Check contraindications to vaccination
Contraindications to vaccination must be checked at the beginning of each vaccination 
visit. Refer to Section 7.5 for more details on contraindication and on study procedures 
for subjects meeting contraindications to subsequent vaccination before administration of 
vaccine Dose 2.
6.9.17.
Assess pre-vaccination body temperature
The oral or axillary body temperature of all subjects needs to be measured prior to any 
study vaccine administration. If the subject has fever (fever is defined as temperature 
37.5°C/99.5°F) on the day of vaccination, the vaccination visit will be rescheduled 
within the allowed interval for this visit (see Table 8).
 
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6.9.18.
Study group and treatment number allocation with randomisation
Study group and treatment number allocation will be performed as described in Section 
6.2.2.2. The number of each administered treatment must be recorded in the eCRF.
6.9.19.
Vaccination
After completing all prerequisite procedures prior to vaccination, one dose of study 
vaccine will be administered intramuscularly in the deltoid of the non-dominant arm 
(refer to Section 7.3 for a detailed description of the vaccines’ administration procedure). 
If the investigator or delegate determines that the subject’s health on the day of 
administration temporarily precludes vaccine administration, the visit will be rescheduled 
within the allowed interval for this visit (see Table 8).
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.
6.9.20.
Check and record concomitant medication/vaccination and 
intercurrent medical conditions 
Concomitant medication/vaccination must be checked and recorded in the eCRF as 
described in Section 7.6.
Intercurrent medical conditions must be checked and recorded in the eCRF as described 
in Section 7.7.
6.9.21.
Recording of AEs, SAEs, pregnancies and pIMDs

Refer to Section 9.3 for procedures for the investigator to record AEs, SAEs, 
pregnancies and pIMDs. Refer to Section 9.4 for guidelines and how to report SAE, 
pregnancy and pIMD reports to GSK Biologicals.

The subjects will be instructed to contact the investigator immediately should 
they/the subjects manifest any signs or symptoms they perceive as serious.

At Screening visit, electronic Diary Cards will be distributed to the subject. The 
subject will be instructed to measure and record the oral or axillary body 
temperature, and any solicited local/general AEs (i.e. on the day of vaccination and 
during the next 6 days). Any solicited AE ongoing after Day 7 will be followed in the 
eDiary until resolution (for a maximum of 30 days). (Amended 27 March 2019)

Any unsolicited AEs (i.e. on the day of vaccination and during the next 29 days 
occurring after vaccination) will be collected during discussion with the subject at 
subsequent study visit(s) and Phone Call(s). 

The investigator will transcribe the collected unsolicited AEs into the eCRF in 
English.
 
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6.9.22.
Train subjects on the use of electronic Diary Card and assign
electronic Diary Card to subject
During the Screening Visit, subjects will be trained on how to use their electronic Diary 
Card. 
At Visit 1, the investigator should evaluate whether or not the subject will be able to 
comply with the daily completion of the electronic Diary Card throughout the study 
(based on electronic Diary Card completion between Screening and Visit 1). 
Compliance with electronic Diary Card completion implies that subject learns how to 
translate his/ her respiratory symptoms in answers to the questions as well as acquiring 
the technical expertise to use the device. Refer to the SPM for recommendations on what 
is considered adequate compliance by Visit 1.
Subjects for whom the investigator thinks they will not comply will be considered 
Screening failures.
During the learning period in-between Screening and Visit 1, the site staff will follow 
electronic Diary Card completion closely and should provide timely input/guidance to 
ensure that the subject reaches the targeted learning curve.
In addition, site staff will pro-actively monitor electronic Diary Card compliance 
throughout the study and provide the necessary input to maintain compliance.
6.9.23.
Distribution of Subject Card
For information regarding the Subject Card, please refer to Section 9.9.
6.9.24.
Healthcare Resource Utilisation
Healthcare use for each COPD patient will be obtained through review of the subject’s 
medical record (aided by subject self-reporting). Healthcare Resource Utilisation includes 
all unscheduled visits to a physician office, visits to urgent care, visits to emergency
department, and hospitalizations. Healthcare use should be recorded in eDiary and 
reported in the eCRF at study visit. Refer to the SPM for more details and guidance on 
recording of Healthcare Resource Utilisation.
6.9.25.
HRQOL questionnaires
The subject should self-complete the questionnaires on HRQOL (CAT and SGRQ-C), 
which will be provided electronically via the eDiary, during specified study visits as 
detailed in Table 6 and Table 7.
All data from the HRQOL questionnaires will be transferred directly from the eDiary to 
GSK Biologicals.
Refer to the SPM for more details and guidance on the HRQOL questionnaires.
 
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6.9.26.
Confirm AECOPD and record its start date
Indicate the start date of each confirmed AECOPD in the eCRF. 
6.9.27.
Document AECOPD severity and end date
Indicate the severity and end date of each confirmed AECOPD in the eCRF. Refer to 
Table 1 for severity grading of AECOPD and to Section 4.1.1 for determination of end 
date.
6.9.28.
Screening conclusion
The investigator will: 

Review data collected to ensure accuracy and completeness.

Complete the Screening conclusion screen in the eCRF.
For Screening failures, only informed consent, demographic data, inclusion/ exclusion 
criteria, SAEs related to study participation that occurred after signing the informed 
consent and the Screening conclusion pages need to be completed in the eCRF. For other 
activities, ‘not done’ can be indicated. 
For subjects who are Screening failures only for reasons that are expected to be 
temporary (e.g. fever), a re-Screening may be organised during which a limited number 
of Screening procedures need to be repeated (see also Table 6). 
6.9.29.
Study conclusion
The investigator will:

Review data collected to ensure accuracy and completeness

Complete the Study Conclusion screen in the eCRF.
6.10.
Biological sample handling and analysis
Please refer to the SPM and Central Laboratory investigator 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 
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.
 
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
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.
6.10.1.
Use of specified study materials
When materials are provided by GSK Biologicals and/or a 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 per-protocol analysis (See 
Section 11.5 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 and/or a central laboratory 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 and to the Central Laboratory investigator manual.
 
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6.10.2.
Biological samples
Table 9
Biological samples
Sample type
Quantity
Unit
Timepoints
Sub-Cohort
Blood for humoral 
immunogenicity
20
ml

Visit 1 (Day 1)

Visit 2 (Day 31)

Visit 3 (Day 61)

Visit 4 (Day 91)

Visit 6 (Day 271)

Visit 8 (Day 451)
All enrolled subjects
Blood for humoral 
immunogenicity
~5
ml

During each AECOPD
All enrolled subjects
Blood for CMI
40
ml

Visit 1 (Day 1)

Visit 4 (Day 91)

Visit 6 (Day 271)

Visit 8 (Day 451)
Sub-cohort for CMI *
Blood for 
biomarker, serum 
and plasma
13
ml

Visit 1 (Day 1)

Visit 8 (Day 451)
All enrolled subjects

During each AECOPD 
Blood for 
biomarkers; 
haematology 
parameters
~2.0
ml

Visit 1
All enrolled subjects
Sputum
1
Sample

Visit 1 (Day 1)

Visit 4 (Day 91)

Visit 5 (Day 181)

Visit 6 (Day 271)

Visit 7 (Day 361)

Visit 8 (Day 451)
All enrolled subjects

During each AECOPD
* Refer to Section 5.1 for sub-cohort description.
6.10.3.
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.
Humoral antibody responses
Total IgG concentrations will be measured by ELISA at GSK Biologicals’ laboratory or a 
GSK designated laboratory using qualified procedures.
 
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Table 10
Humoral Immunity (Antibody determination) (Amended 27 March
2019)
System
Component
Method
Kit / 
Manufacturer
Unit*
Cut-off*
Laboratory
SERUM
anti-PD 
antibody
ELISA
In house
EU/ml
153
GSK Biologicals** 
or GSK designated 
laboratory
anti-PE 
antibody
16
anti-PilA 
antibody
8
anti-UspA2 
IgG antibody
28
EU/ml = ELISA unit per millilitre
* Assay cut-off and unit might be subject to change during the course of the study (e.g. in case of assay re-
optimization, qualification, (re)validation or standardization). In this case, this will be documented in the clinical 
study report.
** GSK Biologicals laboratory refers to the Clinical Laboratory Sciences (CLS) in Rixensart, Belgium; Wavre, Belgium; 
Marburg, Germany.
Other assays may be developed and/or validated on blood samples with the aim to 
measure the immune response to any component of either the NTHi-Mcat investigational 
vaccines and/or to other respiratory pathogens. The research may include, but is not 
limited to, functional assays such as serum bactericidal activity assays against NTHi 
and/or Mcat.
Cell-mediated immune responses
CMI assays will be performed at GSK Biologicals or GSK designated laboratory using 
qualified procedures. 
Table 11
Cell-Mediated Immunity (CMI)
System
Component
Scale
Method
Unit
Laboratory
PBMCs
Specific CD4+ T-cells
Quantitative
Flow 
cytometry ICS
Number of specific 
CD4+ T-cells /106
GSK 
Biologicals* or 
GSK 
designated 
laboratory
PBMC = peripheral blood mononuclear cell; ICS = intracellular cytokine staining
* GSK Biologicals laboratory refers to the Clinical Laboratory Sciences (CLS) in Rixensart, Belgium; Wavre, Belgium;
Marburg, Germany. 
Additional vaccine antigen-specific CD8+ T-cells data will be generated on peripheral 
blood mononuclear cells (PBMCs) in context of the specific CD4+ T cell data generation 
by ICS. 
Additional testing on peripheral blood mononuclear cells (PBMCs), such as, but not 
limited to, evaluation of NTHi and/or Mcat-specific memory B-cells, intracellular 
cytokine staining (ICS) testing using other bacterial 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 
 
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disease, should such test(s) become available at GSK Biologicals’ laboratory or a 
laboratory designated by GSK Biologicals.
Plasma of the CMI sub-cohort will be obtained during the processing of whole blood to 
obtain PBMCs and will be stored for potential future analyses and/ or assay development 
purposes.
Microbiological assessments
The quality of sputum samples will be assessed at the investigator’s institution and/ or at 
a laboratory designated by GSK Biologicals by Gram staining.
Identification and semi-quantitative assessment of potential bacterial pathogens will be 
performed on fresh sputum samples using conventional bacteriological methods at the 
investigator’s institution and/ or at a laboratory designated by GSK Biologicals on a 
subset of subjects (50% of subjects) according to local laboratory procedures and agreed 
identification methods (potential pathogens including, but not necessarily limited to 
identification of H. influenzae, S. pneumoniae, M. catarrhalis, S. aureus and 
P. aeruginosa).
Identification of potential bacterial pathogens (including, but not necessarily limited 
to, H. influenzae, S. pneumoniae, M. catarrhalis, S. aureus, P. aeruginosa and 
Streptococcus pyogenes [S. pyogenes) and quantification (for H. influenzae, 
S. pneumoniae, M. catarrhalis) on frozen sputum samples will be performed at GSK 
Biologicals’ laboratory or a laboratory designated by GSK Biologicals using qualified 
molecular methods such as multiplex real time PCR and/ or quantitative PCR (qPCR).
Further bacterial characterisation on frozen isolates of H. influenzae and/or M. 
catarrhalis will be done at GSK Biologicals' laboratory or at a laboratory designated by 
GSK Biologicals using either standard agglutination techniques or molecular tools, such
as PCR, microarray serotyping and/or sequencing.
Viral pathogen identification (including, but not necessarily limited to, respiratory 
syncytial virus, parainfluenza virus, enterovirus/ rhinovirus, metapneumovirus, influenza 
virus, adenovirus, bocavirus and coronavirus) on frozen sputum samples will be 
performed using multiplex PCR at GSK Biologicals' laboratory or at a laboratory 
designated by GSK Biologicals using standardised and optimised procedures. 
In addition, viral pathogens (such as enterovirus/rhinovirus) in frozen sputum samples
will be quantified on all samples or a subset of samples (i.e. enterovirus/rhinovirus-
positive sputum samples) using qPCR at GSK Biologicals' laboratory or at a laboratory 
designated by GSK Biologicals using standardised and optimised procedures.
 
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Table 12
Sputum assessments
Number of subjects
Group Visit no.
Pathogen to identify
Type of sample
Method
Testing Laboratory
Quality assessment
~600
Both
1
4
5
6
7
8
AECOPD 
visits
Please refer to SPM 
and/or Central Laboratory 
Manual for components 
tested
Fresh sputum
Gram staining
Investigator institution or GSK 
designated laboratory
Bacterial pathogen identification
~300*
Both
1
4
5
6
7
8
AECOPD 
visits
H. influenzae 
Fresh sputum
Standard bacteriological identification methods and 
semi-quantitative assessment.
Investigator institution or GSK 
designated laboratory
Isolate
H. influenzae species confirmation and when 
possible Hi/NTHi differentiation by PCR
GSK Biologicals’ ** or designated 
laboratory
M. catarrhalis
Fresh sputum
Standard bacteriological identification methods and 
semi-quantitative assessment.
Investigator institution or GSK 
designated laboratory
S. pneumoniae, 
P. aeruginosa, S. aureus, 
other potential pathogen
Fresh sputum
Standard bacteriological identification methods and 
semi-quantitative assessment.
Investigator institution or GSK 
designated laboratory
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Number of subjects
Group Visit no.
Pathogen to identify
Type of sample
Method
Testing Laboratory
~600
Both
1
4
5
6
7
8
AECOPD 
visits
H. influenzae***, 
M. catarrhalis, 
S. pneumoniae
Frozen sputum
Multiplex bacterial pathogen quantitative PCR assay GSK Biologicals’ ** or designated 
laboratory
S. aureus, Group A 
streptococci, 
P. aeruginosa
Multiplex bacterial pathogen qualitative PCR assay
Viral pathogen identification
~600
Both
1
4
5
6
7
8
AECOPD 
visits
Respiratory viral 
pathogens 
(including respiratory 
syncytial virus, 
parainfluenza virus, 
enterovirus, rhinovirus, 
metapneumovirus, 
influenza virus, 
adenovirus, bocavirus 
and coronavirus)
Frozen sputum
Multiplex viral pathogen qualitative PCR assay
GSK Biologicals** or designated 
laboratory
~600 or Subset 
(enterovirus/rhinovirus
positive samples)
Both
Rhinovirus
Frozen sputum quantitative PCR assay
GSK Biologicals** or designated 
laboratory
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Number of subjects
Group Visit no.
Pathogen to identify
Type of sample
Method
Testing Laboratory
Biomarker identification and quantification
Patients not in culture 
subset*
Both
1
4
5
6
7
8
AECOPD 
visits
Inflammatory cytokines 
(such as TNF-α, IL-1, IL-
8, IL-6)
Frozen sputum
Quantitative ELISA, multiplex CBA, ECL or PCR 
assays
GSK Biologicals** or designated 
laboratory
AECOPD = Acute exacerbation of chronic obstructive pulmonary syndrome; SPM = Study Procedures Manual; H. influenzae and Hi = Haemophilus influenzae; M. catarrhalis = 
Moraxella catarrhalis; PCR = Polymerase Chain Reaction; S. pneumoniae = Streptococcus pneumoniae; S. aureus = Staphylococcus aureus; TNF = Tumor Necrosis Factor; IL = 
Interleukin; ELISA = Enzyme Linked Immunosorbant Assay; CBA = Cytometric bead assay; ECL = Electrochemiluminescence.
*Testing will only be performed on a subset of 50% of the subjects.
**GSK Biologicals laboratory refers to the pre-clinical team or the Clinical Laboratory Sciences (CLS) in Rixensart, Belgium; Wavre, Belgium; Marburg, Germany.
***The PCR assay can detect and quantify H. influenzae in sputum samples. It can be assumed that more than 99% of H. influenzae isolates in sputum (derived from lung) are non-
typeable (NTHi) [Wilkinson, 2017] and thus the presence of Hi bacteria in sputum during exacerbation will be used to determine AECOPD associated to NTHi.  
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Sputum samples might also be used for assay development, such as assays for diagnostic 
purposes or for microbiome analysis.
Additional testing on frozen sputum samples (such as, but not limited to, qPCR for other 
bacterial and/or viral pathogens, quantitative serotype-specific PCR, microarray typing, 
sequencing, 16S RNA for microbiome analysis, presence (and/or concentration) of 
inflammatory cytokines) may be done during the study or after study completion, should 
these data be required for accurate interpretation of the study data and/ or for further 
research related to the investigational vaccine and/ or to respiratory diseases, should such 
test(s) become available at GSK Biologicals’ laboratory or a laboratory designated by 
GSK Biologicals.
Biomarkers
Table 13
Biomarkers
System
Component
Method
Scale
Laboratory
Plasma
Fibrinogen
Per contract 
laboratory’s procedures Quantitative
GSK Biologicals** or 
GSK designated lab
Serum
hsC-reactive protein (hsCRP)
Serum
CXCL10 (IP-10)
Whole blood
Leukocytes (White Blood Cells) 
Neutrophils *
Lymphocytes *
Eosinophils *
Basophils *
Monocytes *
Erythrocytes (Red Blood Cells) 
Hemoglobin 
Platelets
CXCL10 (IP-10) = C-X-C motif chemokine 10 (interferon gamma-induced protein 10)
*For white blood cell differential counts
**GSK Biologicals laboratory refers to the Clinical Laboratory Sciences (CLS) in Rixensart, Belgium; Wavre, Belgium; 
Marburg, Germany. 
The presence of other selected biomarkers might be evaluated.
Additional exploratory testing on the vaccine and/or on the disease under study may be 
performed within the framework of the study if deemed necessary for accurate 
interpretation of the data or should such assay(s) become available at GSK. These assays 
may not be represented in the objectives/endpoints of the study protocol.
The GSK Biologicals' clinical laboratories have established a Quality System supported 
by procedures. The activities of GSK Biologicals' clinical laboratories are audited 
regularly for quality assessment by an internal (sponsor-dependent) but laboratory-
independent Quality Department.
 
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6.10.4.
Biological samples evaluation
6.10.4.1.
Immunological read-outs
Table 14
Immunological read-outs
Blood sampling timepoint
Sub-cohort 
Name
No. subjects
Component
Type of contact and 
timepoint
Sampling 
timepoint
Visit 1 (Day 1)
Pre-Vacc 1
All enrolled 
subjects
~600
Anti-PD, Anti-PE, Anti-PilA and Anti-
UspA2
Fibrinogen, hsCRP, IP-10 and 
haematology profile*
Sub-cohort for 
CMI 
~120
Specific CD4+ T-cell
Visit 2 (Day 31)
Post-Vacc 1
All enrolled 
subjects
~600
Anti-PD, Anti-PE, Anti-PilA and Anti-
UspA2
Visit 3 (Day 61)
Pre-Vacc 2
All enrolled 
subjects
~600
Anti-PD, Anti-PE, Anti-PilA and Anti-
UspA2
Visit 4 (Day 91)
Post-Vacc 2
All enrolled 
subjects
~600
Anti-PD, Anti-PE, Anti-PilA and Anti-
UspA2
Sub-cohort for 
CMI
~120
Specific CD4+ T-cell
Visit 6 (Day 271)
Post-Vacc 2
All enrolled 
subjects
~600
Anti-PD, Anti-PE, Anti-PilA and Anti-
UspA2
Sub-cohort for 
CMI
~120
Specific CD4+ T-cell
Visit 8 (Day 451)
Post-Vacc 2
All enrolled
subjects
~600
Anti-PD, Anti-PE, Anti-PilA and Anti-
UspA2
Fibrinogen, hsCRP and IP-10
Sub-cohort for 
CMI 
~120
Specific CD4+ T-cell
During each AECOPD visit from first 
vaccination to study conclusion
All enrolled 
subjects
-
Anti-PD, Anti-PE, Anti-PilA and Anti-
UspA2
Fibrinogen, hsCRP and IP-10
hsCRP = high-sensitivity C-reactive protein, CMI = cell-mediated immunogenicity, IP-10 = interferon gamma-induced 
protein 10.
*Including: WBC, neutrophils, eosinophils, lymphocytes, basophils, monocytes, RBC, haemoglobin and platelets.
6.10.5.
Immunological correlates of protection
No generally accepted immunological correlate of protection has been demonstrated so 
far for the antigen(s) used in the candidate vaccine or licensed vaccine.
 
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7.
STUDY VACCINES AND ADMINISTRATION
7.1.
Description of study vaccines
The candidate vaccine to be used has been developed and manufactured by GSK 
Biologicals. 
The Quality Control Standards and Requirements for the candidate are described in 
separate Quality Assurance documents (e.g. release protocols, certificate of analysis) and 
the required approvals have been obtained. 
The study vaccines are labelled and packed according to applicable regulatory 
requirements.
Table 15
Study vaccines
Treatment 
name
Vaccine/
product name
Formulation
Presentation
Volume to 
be 
administered
Number 
of doses
10-10-
3/AS01E
NTHi-Mcat 10-10-3
PD=10µg; PE-PilA=10µg; 
UspA2=3.3µg
Freeze-dried 
antigens in 
monodose 
vial
0.5 ml
2
AS01E
MPL=25µg; QS21=25µg; 
Liposomes
Liquid in 
monodose 
vial
Placebo
Formulation buffer 
S9b
Na₂HPO₄=0.4mg; 
KH₂PO₄=56µg; 
NaCl=1,16mg; KCl=30µg; 
MgCl₂=15µg
Liquid in 
monodose 
vial
0.5 ml
2
MPL = 3-O-desacyl-4′-monophosphoryl lipid A; QS-21 =  Quillaja saponaria Molina, fraction 21 (Licensed by GSK from 
Antigenics Inc, a wholly owned subsidiary of Agenus Inc., a Delaware, USA corporation).
7.2.
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/+36 to 
+46°F label storage condition) impacting investigational medicinal products (IMPs) must 
be reported in the appropriate (electronic) temperature excursion decision form ([e]TDF). 
The impacted IMPs must not be used and must be stored in quarantine at label 
temperature conditions until usage approval has been obtained from the sponsor.
 
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In case of temperature excursion below +2.0°C down to 0.0°C impacting IMP(s) there is 
no need to report in (e)TDF, but adequate actions must be taken to restore the +2 to 
+8°C/+36 to +46°F label storage temperature conditions. The impacted IMP(s) may still 
be administered, but the site should avoid re-occurrence of such temperature excursion.
Refer to the Module on Clinical Trial Supplies in the SPM for more details on actions to 
take.
Refer to the Module on Clinical Trial Supplies in the SPM for details and instructions on 
the temperature excursion reporting and usage decision process, packaging and 
accountability of the study vaccines.
7.3.
Dosage and administration of study vaccines
Table 16
Dosage and administration
Type of contact 
and timepoint
Study 
group
Treatment 
name
Volume to 
be 
administered
Route 1
Site
Location
Directionality2
Laterality3
Visit 1  (Day 1)
10-10-3-AS 10-10-3/AS01E
0.5 ml
IM
Deltoid
Upper
Non-
dominant
CONTROL
Placebo
Visit 3  (Day 61)
10-10-3-AS 10-10-3/AS01E 0.5 ml
IM
Deltoid
Upper
Non-
dominant
CONTROL
Placebo
1Intramuscular (IM)
2Directionality is a qualifier for further detailing the location of the vaccine administration (e.g. Upper, Lower)
3The non-dominant arm is the preferred arm of injection. In case it is not possible to administer the vaccine in the non-
dominant arm, an injection in the dominant arm may be performed.
The investigational NTHi-Mcat vaccine needs to be reconstituted. Please refer to the 
SPM for more detailed instructions on study vaccines preparation. 
7.4.
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 30% additional vaccine doses will be 
supplied to replace those that are unusable. 
The investigator will use SBIR to obtain the replacement vial number. The replacement 
numbers will be allocated by dose. The system will ensure, in a blinded manner, that the 
replacement vial matches the formulation the subject was assigned to by randomisation.
 
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7.5.
Contraindications to subsequent vaccination
The following events constitute absolute contraindications to further administration of the 
investigational NTHi-Mcat vaccine. If any of these events occur during the study, the 
subject must not receive additional doses but may continue other study procedures (see 
Section 6.5).

Anaphylaxis following the administration of vaccine.

Pregnancy.

Any confirmed or suspected immunosuppressive or immunodeficient condition, 
based on medical history and physical examination (no laboratory testing required).

Any condition that in the judgment of the investigator would make intramuscular 
injection unsafe.

Current immune-mediated disease other than COPD.

Malignancy (excluding non-melanotic skin cancer and carcinoma in situ of the 
cervix, if considered cured) or lymphoproliferative disorder.

Occurrence of a new pIMD or the exacerbation of an existing pIMD that, in the 
opinion of the investigator, expose the subject to unacceptable risk from subsequent 
vaccination. In such cases, the investigator should use his/her clinical judgement 
prior to administering the next dose of the vaccine. Refer to Section 9.1.5.1 for the 
definition of pIMDs.
The following events constitute contraindications to administration of the investigational 
NTHi-Mcat vaccine at that point in time; if any of these events occur at the time 
scheduled for vaccination, the subject may be vaccinated at a later date, within the time 
window specified in the protocol (see Section 6.5), or withdrawn at the discretion of the 
investigator (see Section 9.5). 

Moderate or severe AECOPD that is on-going or that has not been resolved for at 
least 7 days at the time of vaccination.

Acute disease and/or fever at the time of vaccination. 

Fever is defined as temperature 37.5°C/99.5°F. The preferred location for 
measuring temperature in this study will be the oral cavity or the axilla.

Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory 
infection) without fever can be administered all vaccines at discretion of the 
investigator.
7.6.
Concomitant medications/products and concomitant 
vaccinations
At each study visit/contact, the investigator or delegate should question the subject about 
any medications/products taken and vaccinations received by the subject (including 
standard medication taken before vaccination collected at Screening and/or at Visit 1).
This includes the subject’s COPD medication.
 
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7.6.1.
Recording of concomitant medications/products and 
concomitant vaccinations
The following concomitant medication(s)/product(s)/vaccine(s) must be recorded in 
the eCRF.

All concomitant vaccines/medications/products, except vitamins and dietary 
supplements, administered during the entire study period following the first dose of 
study vaccine (Day 1 to Day 451).

Prophylactic medication (i.e. medication administered in the absence of ANY 
symptom and in anticipation of a reaction to the vaccination).
E.g. an anti-pyretic is considered to be prophylactic when it is given in the absence 
of fever and any other symptom, to prevent fever from occurring [fever is defined as 
temperature 37.5°C/99.5°F]. The preferred location for measuring temperature in 
this study will be the oral cavity or the axilla.

Any concomitant medications/products/vaccines listed in Section 7.6.2.

Any concomitant medications/products/vaccines relevant to a SAE/pIMD to be 
reported as per protocol or administered during the study period for the treatment of 
a SAE /pIMD. In addition, concomitant medications relevant to SAEs and pIMD 
need to be recorded on the expedited Adverse Event report.

Any receipt of influenza vaccine up to 1 year before the first dose of study vaccine.

Any receipt of pneumococcal vaccine at any time before the first dose of study 
vaccine. Approximate timing of receipt should be recorded.
7.6.2.
Concomitant medications/products/vaccines that may lead to the 
elimination of a subject from per-protocol analyses for 
immunogenicity
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 
per-protocol analysis for immunogenicity. See Section 11.5 for cohorts to be analysed.

Any investigational or non-registered product (drug or vaccine) other than the study 
vaccine used during the study period. 

A vaccine not foreseen by the study protocol administered during the period starting 
30 days before and ending 30 days after each dose of vaccine*, with the exception of 
any influenza, pneumococcal vaccines or other routinely recommended vaccine
which may be administered 15 days preceding or following any dose of study 
vaccine.
* In case an emergency mass vaccination for an unforeseen public health threat (e.g.: 
a pandemic) is organised by the public health authorities, outside the routine 
immunisation program, the time period described above can be reduced if necessary 
for that vaccine provided it is licensed and used according to its Prescribing 
Information and according to the local governmental recommendations and provided 
a written approval of the Sponsor is obtained.
 
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
Immunoglobulins or any blood products administered at any time during the study 
period.

Immunosuppressants or other immune-modifying drugs administered chronically 
(i.e. more than 14 days) at any time during the study period (e.g. methotrexate). Use 
of corticosteroids is allowed as per local treatment recommendations.
7.6.3.
Concomitant medications/ products/ intervention that may lead 
to the elimination of a subject from the per-protocol analysis for 
efficacy
In addition to the concomitant medications/ products/ vaccines described in the Section
7.6.2, the use of the following medications/ products/ intervention will not require 
withdrawal of the subject from the study but may determine a subject’s evaluability in the 
per-protocol analysis for efficacy.

Underwent lung transplantation/ lung resection surgery at any time during the entire 
study period.

Chronic use of antibiotics at any time during the entire study period.
7.7.
Intercurrent medical conditions that may lead to elimination 
of a subject from per-protocol analyses
At each study visit subsequent to the first vaccination, it must be verified if the subject 
has experienced or is experiencing any intercurrent medical condition. If it is the case, the 
condition(s) must be recorded in the eCRF.
Subjects may be eliminated from the per-protocol cohort for immunogenicity and 
efficacy if, during the study, they incur a condition that has the capability of altering their 
immune response or are confirmed to have an alteration of their initial immune status.
8.
HEALTH ECONOMICS
Not applicable. 
9.
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 they/the 
subject manifest any signs or symptoms they perceive as serious.
 
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9.1.
Safety definitions
9.1.1.
Definition of an adverse event
An AE is any untoward medical occurrence in a clinical investigation subject, temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with 
the use of a medicinal product. For marketed medicinal products, this also includes 
failure to produce expected benefits (i.e. lack of efficacy), abuse or misuse. 
Examples of an AE include:

Significant or unexpected worsening of the condition under study.

Exacerbation of a chronic or intermittent pre-existing condition, apart from the 
condition under study, including either an increase in frequency and/or intensity of 
the condition.

New conditions detected or diagnosed after investigational vaccine administration 
even though they may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms 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 9.1.3. 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. 

The disease being studied, or expected progression, signs, or symptoms of the 
disease being studied, unless more severe than expected for the subject’s condition.

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.
 
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9.1.2.
Definition of a serious adverse event 
A SAE is any untoward medical occurrence that:
a.
Results in death,
b.
Is life-threatening,
Note: The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in 
which the subject was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, had it been more severe.
c.
Requires hospitalisation or prolongation of existing hospitalisation,
Note: In general, hospitalisation signifies that the subject has been admitted at the 
hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician’s office or in an out-patient setting. Complications 
that occur during hospitalisation are also considered AEs. If a complication prolongs 
hospitalisation or fulfils any other serious criteria, the event will also be considered 
serious. When in doubt as to whether ‘hospitalisation’ occurred or was necessary, the 
AE should be considered serious.
Hospitalisation for elective treatment of a pre-existing condition (known or 
diagnosed prior to informed consent signature) that did not worsen from baseline is 
NOT considered an AE.
d.
Results in disability/incapacity, OR
Note: The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhoea, influenza like illness, and accidental trauma (e.g. sprained 
ankle) which may interfere or prevent everyday life functions but do not constitute a 
substantial disruption.
e.
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.
 
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9.1.3.
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), will be reported via 
eDiary for vaccine reactogenicity. (Amended 27 March 2019) Unsolicited AEs 
occurring during a 30-day follow-up period after each vaccination (i.e. the day of 
vaccination and the 29 subsequent days), will be reported at Phone Contacts and Clinical 
Visits, and recorded via the appropriate section of the eCRF.
9.1.3.1.
Solicited local (injection-site) adverse events
The following local (injection-site) AEs will be solicited:
Table 17
Solicited local adverse events
Pain at injection site
Redness  at injection site
Swelling at injection site
9.1.3.2.
Solicited general adverse events
The following general AEs will be solicited:
Table 18
Solicited general adverse events
Fatigue
Fever
Gastrointestinal symptoms †
Headache
Myalgia
Chills
†Gastrointestinal symptoms include nausea, vomiting, diarrhoea and/or abdominal pain.
Note: Subjects will be instructed to measure and record the oral or axillary body 
temperature in the evening. Should additional temperature measurements be performed at 
other times of day, subjects will be instructed to record the highest temperature in the 
eDiary.
9.1.4.
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 9.1.1 and 9.1.2). 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.
 
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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.
9.1.5.
Adverse events of specific interest
9.1.5.1.
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 19.
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 19
List of potential immune-mediated diseases
Neuroinflammatory disorders
Musculoskeletal disorders
Skin disorders

Cranial nerve neuropathy, 
including paralysis and 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.

Demyelinating peripheral 
neuropathies including:
-
Chronic inflammatory 
demyelinating 
polyneuropathy, 
-
Multifocal motor 
neuropathy 
-
Polyneuropathies 
associated with 
monoclonal gammopathy.

Narcolepsy.

Systemic lupus 
erythematosus and 
associated conditions

Systemic scleroderma 
(Systemic sclerosis), 
including:
-
Diffuse Scleroderma
-
CREST syndrome

Idiopathic inflammatory 
myopathies, including:
-
Dermatomyositis 
-
Polymyositis 

Anti-synthetase 
syndrome.

Rheumatoid Arthritis and 
associated conditions 
including: 
-
Juvenile Idiopathic 
Arthritis
-
Still’s disease.

Polymyalgia rheumatica.

Spondyloarthropathies, 
including: 
-
Ankylosing 
Spondylitis, 
-
Reactive Arthritis 
(Reiter's 
Syndrome),
-
Undifferentiated 
Spondyloarthritis,
-
Psoriatic Arthritis,
-
Enteropathic 
arthritis.

Relapsing Polychondritis.

Mixed Connective Tissue 
disorder.

Gout.

Psoriasis.

Vitiligo.

Erythema nodosum.

Autoimmune bullous skin diseases 
(including pemphigus, pemphigoid 
and dermatitis herpetiformis).

Lichen planus.

Sweet’s syndrome.

Localised Scleroderma (Morphoea).
 
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Vasculitis
Blood disorders
Others

Large vessels vasculitis 
including: 
-
Giant Cell Arteritis 
(Temporal Arteritis),
-
Takayasu's Arteritis. 

Medium sized and/or small 
vessels vasculitis including: 
-
Polyarteritis nodosa,
-
Kawasaki's disease, 
-
Microscopic Polyangiitis, 
-
Wegener's 
Granulomatosis 
(granulomatosis with 
polyangiitis), 
-
Churg–Strauss syndrome 
(allergic granulomatous 
angiitis or eosinophilic 
granulomatosis with 
polyangiitis), 
-
Buerger’s disease 
(thromboangiitis 
obliterans), 
-
Necrotizing vasculitis 
(cutaneous or systemic), 
-
anti-neutrophil 
cytoplasmic antibody 
(ANCA) positive vasculitis 
(type unspecified),
-
Henoch-Schonlein 
purpura (IgA vasculitis), 
-
Behcet's syndrome,
-
Leukocytoclastic 
vasculitis.

Autoimmune hemolytic 
anemia.

Autoimmune 
thrombocytopenia.

Antiphospholipid 
syndrome.

Pernicious anemia.

Autoimmune aplastic 
anemia.

Autoimmune 
neutropenia.

Autoimmune 
pancytopenia.

Autoimmune glomerulonephritis 
including:
-
IgA nephropathy, 
-
Glomerulonephritis rapidly 
progressive, 
-
Membranous 
glomerulonephritis, 
-
Membranoproliferative 
glomerulonephritis, 
-
Mesangioproliferative 
glomerulonephritis. 
-
Tubulointerstitial nephritis and 
uveitis syndrome.

Ocular autoimmune diseases 
including:
-
Autoimmune uveitis 
-
Autoimmune retinitis.

Autoimmune myocarditis.

Sarcoidosis.

Stevens-Johnson syndrome.

Sjögren’s syndrome.

Alopecia areata.

Idiopathic pulmonary fibrosis.

Goodpasture syndrome.

Raynaud’s phenomenon.
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 (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) corresponding to the above diagnoses
will be available to investigators at study start as presented in APPENDIX C. The list of 
PTs was created using MedDRA version 20.1.
 
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9.2.
Events or outcomes not qualifying as adverse events or 
serious adverse events
9.2.1.
AECOPD
AECOPD are common in subjects with COPD. Because they are typically associated 
with the disease under study, only AECOPD meeting the definition of an SAE and 
occurring in the time period defined in Section 9.3.1 will be reported to GSK Biologicals 
as described in Sections 9.4.1 and 9.4.3.
9.2.2.
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.
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 9.4.1 and 9.4.3:

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). 

Any congenital anomaly or birth defect (as per [CDC MACDP] guidelines) 
identified in the offspring of a study subject (either during pregnancy, at birth or 
later) regardless of whether the foetus is delivered dead or alive. This includes 
anomalies identified by prenatal ultrasound, amniocentesis or examination of the 
products of conception after elective or spontaneous abortion.
Furthermore, any SAE occurring as a result of a post-study pregnancy AND considered 
by the investigator to be reasonably related to the study vaccines will be reported to GSK 
Biologicals as described in Section 9.4.3. 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.
 
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9.3.
Detecting and recording adverse events, serious adverse 
events and pregnancies
9.3.1.
Time period for detecting and recording adverse events, serious 
adverse events and pregnancies
All AEs starting within 29 days following administration of each dose of study vaccines
(Day 1 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 last study visit for each subject. See Section 9.4 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.
In addition to the above-mentioned reporting requirements and in order to fulfil 
international reporting obligations, SAEs that are related to study participation (i.e. 
protocol-mandated procedures, invasive tests, a change from existing therapy) or are 
related to a concurrent GSK medication/vaccine will be collected and recorded from the 
time the subject consents to participate in the study until she/he is discharged from the 
study.
The time period for collecting and recording pregnancies will begin at the first receipt of 
study vaccines and will end at last study visit. See section 9.4 for instructions on 
reporting of pregnancies.
The time period for collecting and recording of pIMDs will begin at the first receipt of 
study vaccines and will end at last study visit. See section 9.4 for instructions on 
reporting of pIMDs.
An overview of the protocol-required reporting periods for AEs, SAEs, and pregnancies 
is given in Table 20.
 
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Table 20
Reporting periods for collecting safety information
Event
Screening
Visit*
Visit 1
Dose 1
6 d post 
Dose 1
29 d post 
Dose 1
Visit 3
Dose 2
6 d post 
Dose 2
29 d post 
Dose 2
6 months post
Dose 2
Study 
Conclusion
Timepoint
Day 1
Day 7
Day 30
Day 61
Day 67
Day 90
Day 241
Day 451
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 conditions
* i.e. consent obtained. 
The double-bordered lines indicate timings of vaccination.
AE = adverse event; SAE = Severe adverse event; GSK = GlaxoSmithKline; pIMD = potential immune mediated diseases. 
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9.3.2.
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 20. 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 study vaccines, the investigator will promptly notify the 
Study Contact for Reporting SAEs.
9.3.3.
Evaluation of adverse events and serious adverse events
9.3.3.1.
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 vaccines 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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9.3.3.2.
Assessment of adverse events
9.3.3.2.1.
Assessment of intensity
The intensity of the following solicited AEs will be assessed as described:
Table 21
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
Fever*
Record temperature in °C/°F
Headache
0
Normal
1
Mild: Headache that is easily tolerated
2
Moderate: Headache that interferes with normal activity
3
Severe: Headache that prevents normal activity
Fatigue
0
Normal
1
Mild: Fatigue that is easily tolerated
2
Moderate: Fatigue that interferes with normal activity
3
Severe: Fatigue that prevents normal activity
Gastrointestinal symptoms
0
Normal
(nausea, vomiting, diarrhoea and/or 
abdominal pain)
1
Mild: Gastrointestinal symptoms that are easily tolerated
2
Moderate: Gastrointestinal symptoms that interfere with 
normal activity
3
Severe: Gastrointestinal symptoms that prevent normal 
activity
Myalgia
0
Normal 
1
Mild: Myalgia that is easily tolerated
2
Moderate: Myalgia that interferes with normal activity
3
Severe: Myalgia that prevents normal activity
Chills
0
None
1
Chills that are easily tolerated
2
Chills that interfere with normal activity
3
Chills that prevent normal activity
*Fever is defined as temperature 37.5°C/99.5°F. The preferred location for measuring temperature in this study will 
be the oral cavity or the axilla.
The investigator will assess the maximum intensity that occurred over the duration of the 
event for all unsolicited AEs (including SAEs) recorded during the study. The assessment 
will be based on the investigator’s clinical judgement.
 
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The maximum intensity of local injection site redness/swelling will be scored at GSK
Biologicals using the following grading scale:
0 : < 20 mm diameter
1 : 20 mm to 50 mm diameter
2 : > 50 mm to 100 mm diameter
3 : > 100 mm diameter
Temperature (in this study preferred location to measure the temperature is oral cavity or 
axilla) will be scored as follows:
0 : < 37.5°C
1 : 37.5°C to 37.9°C
2 : 38.0°C to 38.9°C
3 : ≥39.0°C
The intensity of each AE and SAE 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 9.1.2.
9.3.3.2.2.
Assessment of causality
The investigator is obligated to assess the relationship between study vaccines and the 
occurrence of each unsolicited AE/SAE using clinical judgement. In case of concomitant 
administration of multiple vaccines/products, if possible, the investigator should specify 
if the AE could be causally related to a specific vaccine/product administered (i.e. 
investigational, control/placebo or co-administered vaccine). When causal relationship to 
a specific vaccine(s)/product(s) cannot be determined the investigator should indicate the 
AE to be related to all products.
 
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Alternative plausible causes, such as natural history of the underlying diseases, 
concomitant therapy, other risk factors, and the temporal relationship of the event to the 
study 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.
All solicited local (injection site) and general 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 study vaccine?
YES
:
There is a reasonable possibility that the study 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 9.1.2), 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).
 
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9.3.3.3.
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).
9.4.
Reporting of serious adverse events, pregnancies, and 
other events
9.4.1.
Prompt reporting of serious adverse events, pregnancies, and 
other events to GSK Biologicals
SAEs that occur in the time period defined in Section 9.3 will be reported promptly to 
GSK within the timeframes described in Table 22, once the investigator determines that 
the event meets the protocol definition of a SAE.
Pregnancies that occur in the time period defined in Section 9.3 will be reported promptly 
to GSK within the timeframes described in Table 22, once the investigator becomes 
aware of the pregnancy. 
pIMDs that occur in the time period defined in Section 9.3 will be reported promptly to 
GSK within the timeframes described in Table 22, once the investigator determines that 
the event meets the protocol definition of a pIMD.
AECOPD (Section 4) that meet the criteria of a SAE (Section 9.1.3) that occur in the 
time period defined in Section 9.3 should also be recorded in eCRF as “AECOPD visit” 
or as “Missed AECOPD visit”. (Amended 27 March 2019)
Table 22
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
Pregnancies 
2 weeks*
electronic pregnancy report
2 weeks*
electronic pregnancy report
pIMDs 
24 hours** ‡
electronic Expedited 
Adverse Events Report
24 hours*
electronic Expedited Adverse 
Events 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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9.4.2.
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
Outside US & Canada sites:
Fax: 
or 
Email address:
US sites only:
Fax: 
Canadian sites only:
Fax: 
9.4.3.
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.
9.4.3.1.
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. 
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PPD
PPD
PPD
PPD
PPD

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9.4.4.
Completion and transmission of pregnancy reports to GSK 
Biologicals
Once the investigator becomes aware that a subject is pregnant, the investigator (or 
designate) must complete the required information onto the electronic pregnancy report 
WITHIN 2 WEEKS.
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.
9.4.5.
Reporting of pIMDs to GSK Biologicals
Once a new onset of a pIMD or exacerbation of a pre-existing 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. (Amended 27 March 2019) 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 
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 9.4.3.1 for back-up system in case the electronic reporting system does 
not work.
9.4.6.
Updating of SAE, pregnancy, and pIMD information after removal 
of write access to the subject’s eCRF
When additional SAE, pregnancy, or pIMD information is received after removal of the 
write access to the subject’s eCRF, new or updated information should be recorded on the 
appropriate paper report, with all changes signed and dated by the investigator. The 
updated report should be faxed to the Study Contact for Reporting SAEs (refer to the 
Sponsor Information) or to GSK Biologicals Clinical Safety and Pharmacovigilance 
department within the designated reporting time frames specified in Table 22.
 
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9.4.7.
Regulatory reporting requirements for serious adverse events
The investigator will promptly report all SAEs to GSK in accordance with the procedures 
detailed in Section 9.4.1. GSK Biologicals has a legal responsibility to promptly notify, 
as appropriate, both the local regulatory authority and other regulatory agencies about the 
safety of a product under clinical investigation. Prompt notification of SAEs by the 
investigator to the Study Contact for Reporting SAEs is essential so that legal obligations 
and ethical responsibilities towards the safety of other subjects are met.
Investigator safety reports are prepared according to the current GSK policy and are 
forwarded to investigators as necessary. An investigator safety report is prepared for a 
SAE(s) that is both attributable to the study vaccines and unexpected. The purpose of the 
report is to fulfil specific regulatory and GCP requirements, regarding the product under 
investigation.
9.5.
Follow-up of adverse events, serious adverse events, and 
pregnancies
9.5.1.
Follow-up of adverse events and serious adverse events 
9.5.1.1.
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 22).
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.
All pIMDs (serious or non-serious) and SAEs documented at a previous visit/contact and 
designated as not recovered/not resolved or recovering/resolving will be reviewed at 
subsequent visits/contacts until the end of the study.
9.5.1.2.
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.
 
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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.
9.5.2.
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.
Regardless of the reporting period for SAEs for this study, if the pregnancy outcome is a 
SAE, it should always be reported as SAE.
9.6.
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 SAEs / pIMDs
should be recorded in Expedited Adverse Event Report of the subject’s eCRF (refer to 
Section 7.6).
9.7.
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 study 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 9.4.1).
9.8.
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 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 
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The investigator has the option of contacting a GSK Biologicals’ On-call Central Safety 
Physician (or Backup) if he/she needs medical advice or needs the support of GSK to 
perform the unblinding (i.e. he/she cannot access the automated Internet-based system).
Any emergency unblinding must be fully documented by using the Emergency 
Unblinding Documentation Form, which must be appropriately completed by the 
investigator and sent within 24 hours to GSK Biologicals.
GSK Biologicals’ Contact information for Emergency Unblinding
24/24 hour and 7/7 day availability
GSK Biologicals’ Central Safety Physician: 
Outside US/Canada:
(GSK Biologicals Central Safety Physician on-call)
For US/Canada only:
(GSK Biologicals Central Safety Physician on-call)
GSK Biologicals’ Central Safety Physician Back-up:
Outside US/Canada:
US/Canada only:
Emergency Unblinding Documentation Form transmission:
Outside US & Canada:
Fax: 
or 
US/Canada only:
Fax: 
9.9.
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 during 
the study duration.

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PPD
PPD
PPD
PPD
PPD
PPD
PPD

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9.10.
Safety monitoring
9.10.1.
Safety Review Team
The project’s SRT includes as core members the GSK Biologicals’ Central Safety 
Physician, the Clinical Research & Development Lead (CRDL), Epidemiologist, Clinical 
Regulatory Affairs representative and the Biostatistician of the project. The SRT is 
responsible for on-going safety monitoring of the entire project and SRT meets if there is 
a need to perform a data review, or if there is a safety problem (at least once per year). 
The SRT will inform the iSRC about any potential safety concern relevant to the study. 
Before each iSRC safety evaluation in this study, 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.
9.10.2.
Internal Safety Review Committee
The iSRC will be authorised by GSK Biologicals’ Vaccine Safety Monitoring Board 
(VSMB) and its core members will include a GSK Biologicals’ Safety Physician, a 
CRDL, and a Biostatistician who are not otherwise involved in the conduct of the project. 
If none of the core members listed above is a respiratory expert, such an expert will be 
included.
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.
Planned iSRC reviews will be done when approximately 60 and 300 subjects have 
completed one month after first vaccination and when approximately 60 and 300 subjects
have completed one month after second vaccination (Figure 3).
In addition to the planned iSRC evaluations, ad hoc safety evaluations can take place if a 
safety concern is identified by an investigator or by the SRT. 
Details about the working of the iSRC will be documented in an iSRC Charter.
Figure 3
Overview of iSRC evaluation
 
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10.
SUBJECT COMPLETION AND WITHDRAWAL
10.1.
Subject completion
A subject who returns for the concluding visit foreseen in the protocol is considered to 
have completed the study.
10.2.
Subject withdrawal
Withdrawals will not be replaced.
10.2.1.
Subject withdrawal from the study
From an analysis perspective, a ‘withdrawal’ from the study refers to any subject who did 
not come back for the concluding visit foreseen in the protocol. 
All data collected until the date of withdrawal/last contact of the subject will be used for 
the analysis.
A subject is considered a ‘withdrawal’ from the study when no study procedure has 
occurred, no follow-up has been performed and no further information has been collected 
for this subject from the date of withdrawal/last contact.
Investigators will make an attempt (e.g. 3 telephone calls and a certified letter to the last 
known address) to contact those subjects who do not return for scheduled visits or follow-
up. 
Information relative to the withdrawal will be documented in the eCRF. The investigator 
will document whether the decision to withdraw a subject from the study was made by 
the subject himself/herself or by the investigator, as well as which of the following 
possible reasons was responsible for withdrawal:

Serious adverse event.

Unsolicited non-serious adverse event.

Solicited adverse event.

Protocol violation (specify).

Consent withdrawal, not due to an adverse event*.

Moved from the study area.

Lost to follow-up.

Other (specify).
*In case a subject is withdrawn from the study because he/she has withdrawn consent, the 
investigator will document the reason for withdrawal of consent, if specified by the 
subject in the eCRF.
 
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Subjects who are withdrawn from the study because of SAEs/AEs must be clearly 
distinguished from subjects who are withdrawn for other reasons. Investigators will 
follow subjects who are withdrawn from the study as result of a SAE/AE until resolution 
of the event (see Section 9.5.1.2).
10.2.2.
Subject withdrawal from study vaccines
A ‘withdrawal’ from the study vaccines 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 study vaccines may not necessarily be 
withdrawn from the study as further study procedures or follow-up may be performed
(safety or immunogenicity according to protocol procedure. (Amended 27 March 2019)
Information relative to premature discontinuation of the study vaccines will be 
documented on the Vaccine Administration 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:

Serious adverse event.

Unsolicited non-serious adverse event.

Solicited adverse event

Not willing to be vaccinated

Other (specify).
10.3.
Extension study
During the study conclusion visit, the investigator will ask each subject if they are 
interested to participate in an extension study, if planned. If a subject is not interested in 
participating in an extension study the reason for refusal will be documented in the 
subject’s eCRF.
10.4.
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.

Demographic data.

Inclusion/exclusion criteria.

SAEs related to study participation that occurred after signing informed consent.

Screening conclusion.
 
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11.
STATISTICAL METHODS
11.1.
Primary endpoint

Rate of moderate and severe AECOPD (any cause), occurring within a period 
starting 1 month post-Dose 2 and lasting for 1 year.
11.2.
Secondary endpoints
Safety:

Occurrence of each solicited local AE, during the 7-day follow-up period (Day 1 -
Day 7) following each vaccination.

Occurrence of each solicited general AE, during the 7-day follow-up period (Day 1 -
Day 7) following each vaccination.

Occurrence of any unsolicited AE, during the 30-day follow-up period (Day 1 - Day 
30) following each vaccination.

Occurrence of any pIMD from first vaccination up to study conclusion.

Occurrence of any SAE from first vaccination up to study conclusion.
Efficacy: All AECOPD

Yearly rate of all AECOPD (any cause, any severity) starting 1 month post-Dose 2, 
in vaccinated and control subjects.

Rate of moderate and severe AECOPD cases in vaccinated and control subjects, 
during 3, 6 and 9 months observation starting 1 month post-Dose 2.

Rate of all AECOPD cases in vaccinated and control subjects, during 3, 6, 9 and 
12 months observation starting 1 month post-Dose 2.

Rate of all AECOPD cases in vaccinated and control subjects, during 3, 6, 9 and 
12 months observation starting 1 month post-Dose 2, by severity.

Time to first moderate or severe AECOPD.

Time to first AECOPD of any severity.

Time to first AECOPD, by severity.

Duration of moderate and severe AECOPDs.

Duration of AECOPDs of any severity.

Duration of AECOPDs, by severity.
 
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Efficacy: AECOPD associated to bacteriological pathogens (PCR)

Rate of NTHi-associated and/ or Mcat-associated moderate and severe AECOPD, 
over a period starting 1 month post-Dose 2 and lasting for 1 year.

Rate of NTHi-associated and/ or Mcat-associated any severity AECOPD, over a 
period starting 1 month post-Dose 2 and lasting for 1 year.

Rate of NTHi-associated and/ or Mcat-associated AECOPD, over a period starting 1 
month post-Dose 2 and lasting for 1 year, by severity.

Time to first moderate or severe NTHi-associated and/ or Mcat-associated AECOPD.

Time to first NTHi-associated and/or Mcat-associated AECOPD of any severity.

Time to first NTHi-associated and/or Mcat-associated AECOPD, by severity.

Duration of moderate and severe NTHi-associated and Mcat-associated AECOPD.

Duration of NTHi-associated and/or Mcat-associated AECOPDs of any severity.

Duration of NTHi-associated and/or Mcat-associated AECOPD, by severity.
Immunogenicity and CMI:

Anti-PD, anti-PE, anti-PilA and anti-UspA2 total IgG antibody concentrations as 
measured by ELISA at Day 1, Day 31, Day 61, Day 91, Day 271 and at Day 451, in 
all subjects.

NTHi-specific and Mcat- specific cell-mediated immune responses as measured by 
flow cytometry ICS (frequency of specific CD4+ T-cells expressing two or more 
markers, such as interleukin (IL)-2, IL-13, IL-17, interferon gamma (IFN-γ), tumour 
necrosis factor alpha (TNF-α), and CD40 ligand (CD40L) at Day 1, Day 91, Day 271 
and at Day 451, in a sub-cohort of subjects.
11.3.
Tertiary endpoints
Sputum sample PCR:

Occurrence (presence and absence), acquisition, apparition, and bacterial load 
measured by PCR of NTHi and/or Mcat in sputum before first vaccination and at 
Day 91, Day 181, Day 271, Day 361 and Day 451 and at each AECOPD visit.
(Amended 27 March 2019)
Sputum sample culture:

Occurrence (presence and absence), acquisition, apparition, and semi-quantitative 
bacterial load measured in a subset of sputum sample by culture of NTHi and/or 
Mcat in sputum before first vaccination and at Day 91, Day 181, Day 271, Day 361 
and Day 451 and at each AECOPD visit. (Amended 27 March 2019)

Rate of NTHi-associated and Mcat-associated, moderate and severe AECOPD.

Rate of NTHi-associated and Mcat-associated any severity AECOPD.
 
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
Rate of NTHi-associated and Mcat-associated AECOPD, by severity.

Time to first moderate or severe NTHi-associated and/or Mcat-associated AECOPD.

Time to first any NTHi-associated and rate Mcat-associated AECOPD.

Time to first NTHi-associated and rate Mcat-associated AECOPD, by severity.

Duration of each moderate and severe NTHi-associated and Mcat-associated 
AECOPD.

Duration of NTHi-associated and/or Mcat-associated AECOPDs of any severity.

Duration of NTHi-associated and/or Mcat-associated AECOPD, by severity.
QOL:

Assessment of EXACT-PRO score, daily in the evening throughout the study, in all 
subjects.

Assessment of CAT score at Screening, Day 271 and Day 451, and from first 
vaccination to study conclusion for each AECOPD visit, in all subjects.

Assessment of SGRQ-C score at Screening, Day 271 and Day 451, and from first 
vaccination to study conclusion for each AECOPD visit, in all subjects.

Assessment of use of medication to treat (AE)COPD and healthcare utilization in all 
subjects throughout the study period.
Lung function:

Assessment of FEV1% of predicted normal value at Screening, Day 271 and Day 
451, in all subjects.
Biomarkers:

Concentration of selected biomarkers (fibrinogen, hsCRP and IP-10), at Day 1 and 
Day 451, and for each AECOPD visit from first vaccination to study conclusion.
CMI:

T helper profile of the specific CD4+ (CD8+) T cell response based on the expression 
of T helper 1, T helper 2 and T helper 17 specific markers at Day 1, Day 91, Day 271 
and Day 451.
Assay development, microbiome analysis and lung inflammation:

Presence of respiratory viral pathogens in sputum (including respiratory syncytial 
virus, parainfluenza virus, enterovirus/ rhinovirus, metapneumovirus, influenza 
virus, adenovirus, bocavirus and coronavirus) at Day 1, Day 91, Day 181, Day 271, 
Day 361, Day 451 and at each AECOPD visit from first vaccination to study 
conclusion.

Presence and/or concentration of inflammatory cytokines in sputum at Day 1, Day 
91, Day 181, Day 271, Day 361, Day 451 and at each AECOPD visit from first 
vaccination to study conclusion on a subset of samples.
 
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11.4.
Determination of sample size
Primary objective - Efficacy: All (causes) of moderate and severe AECOPD
The primary objective of this study is to assess the efficacy of the investigational vaccine 
as compared to placebo control, as measured by the rate of moderate and severe 
AECOPD from 1 month after second dose of vaccination till 1 year after. Sample size is 
computed based on the probability to detect a clinically relevant effect. Sample size is 
estimated using a formula from [Keen, 2007]. Assuming a yearly incidence rate of 
moderate and severe AECOPD in the placebo arm equal to 0.8 per subject [Mackay, 
2012; Dransfield, 2013] and an over-dispersion parameter of 1.8, ~300 subjects per group 
will provide 80% power to detect at least a 28% reduction in the rate of AECOPDs in the 
vaccinated group compared to the placebo group, with a 1-sided 6.5% significance level 
and a dropout rate of 15%.
Table 23 presents sample size under different assumption for over-dispersion parameter 
and AECOPD incidence rate in placebo arm, assuming a VE=28%, a drop-out of 15% 
(85% of enrolled subjects are expected to complete one year follow up) and 1:1 
randomization ratio.
Table 23
Total number of subjects for primary endpoint
Overdispersion factor*: 1.8
2-side α-level
Rate in Placebo
Rate in Treatment
N per group
Total Sample size**
13%
0.9
0.648
228
536
10%
0.9
0.648
254
596
13%
0.8
0.576
257
604
10%
0.8
0.576
286
672
13%
0.7
0.504
293
690
10%
0.7
0.504
327
768
13%
0.6
0.432
342
804
10%
0.6
0.432
381
896
Overdispersion factor*: 2
13%
0.9
0.648
251
590
10%
0.9
0.648
280
658
13%
0.8
0.576
282
664
10%
0.8
0.576
314
740
13%
0.7
0.504
323
760
10%
0.7
0.504
360
846
13%
0.6
0.432
376
886
10%
0.6
0.432
419
986
Sample size calculated from a formula from Keen, 2007 implemented on SAS.
* Overdispersion factor for a Poisson distribution.
**Total sample size takes in to account 15% drop-out rate.
Secondary objective - Efficacy: mild and moderate AECOPD associated to 
bacteriological pathogens (PCR).
One of the secondary objectives is to assess efficacy of the investigational vaccine 
compared to placebo, as measured by the rate of moderate and severe AECOPD 
associated to NTHi and/or Mcat (detected by PCR), starting from 1 month after second 
dose of vaccination till 1 year after. 
 
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Assuming an incidence rate of AECOPD (all causes) equal to 0.8 per subject per year, a 
vaccine efficacy of 70% against AECOPD associated with NTHi and/or Mcat and 
assuming that 25% of AECOPDs are associated with NTHi and 15% with Mcat [Wang,
2015; Garcha, 2012], Table 24 shows the sample size requested for the bacteriological 
endpoint, assuming a rate of loss sputum samples equal to 20%.
Table 24
Sample size for secondary bacteriological endpoint
All  AECOPD Rate
NTHi 
Mcat 
2-side
α-level
Beta
N per group
Sample** size
0.8
20%
10%
13%
0.2
308
908
0.8
25%
15%
13%
0.2
218
642
0.8
20%
10%
10%
0.2
339
998
0.8
25%
15%
10%
0.2
237
694
0.8
20%
10%
13%
0.3
248
730
0.8
25%
15%
13%
0.3
175
514
0.8
20%
10%
10%
0.3
276
810
0.8
25%
15%
10%
0.3
196
578
Sample size calculated from a formula from Keen, 2007 implemented on SAS.
**Total sample size takes in to account for 15% of subject drop-out and 20% of samples lost.
Study is planned to enrol approximately 600 subjects (~300 in each arm), assuming a 
subject drop-out rate of 15% and a loss of sputum samples of 20%, we have a power of 
77.5% to detect a reduction in AECOPDs associated with NTHi and/or Mcat of at least 
70% of vaccine efficacy with a 1-sided 6.5% significance level.
11.5.
Cohorts for analyses
The following study cohorts will be evaluated.
11.5.1.
All enrolled set 
All subjects who will sign the inform consent and for whom a subject number is assigned.
11.5.2.
Total vaccinated cohort
The total vaccinated cohort (TVC) will include all subjects with at least 1 documented 
study vaccine administration, with respect to the vaccine actually administered:

A safety analysis based on the TVC will include all subjects with at least one 
vaccine dose administered and who provided safety data.

An immunogenicity/efficacy analysis based on the TVC will include all vaccinated 
subjects for whom immunogenicity/ efficacy data are available.

An efficacy analysis based on the TVC will include all subjects for whom at least 
one dose was administered.  
 
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In subjects receiving only one dose the efficacy endpoint is the number of moderate or 
severe AECOPD (any cause), occurring within a period starting from Day 90 and lasting 
for 1 year (until study conclusion).
The TVC analysis will be performed per treatment actually administered at Dose 1.
11.5.3.
Modified total vaccinated cohort
The modified total vaccinated cohort (mTVC) will include all subjects with 2 
documented study vaccine administrations with respect to the vaccine actually 
administered.
The primary efficacy analysis will be performed on the mTVC. 
11.5.4.
Per-protocol set for analysis of immunogenicity
The per-protocol set (PPS) for immunogenicity will include all subjects in the TVC:

Who met all eligibility criteria.

For whom the administration of the vaccines was according to protocol.

Who complied with the vaccination schedule, as specified in Table 8.

Who received the study vaccines according to protocol procedures.

Who did not receive a concomitant medication/ product leading to elimination from 
the PPS (per-protocol) analysis for immunogenicity (see Section 7.6.2) up to the 1 
month post--Dose 2 visit (Day 91).

Who did not present an intercurrent medical condition leading to elimination from 
the PPS analysis for immunogenicity (see Section 7.7), up to the 1 month 
post--Dose 2 visit (Day 91).

Who complied with the blood sample timings as specified in Table 8, at the 1 month 
post-Dose 2 visit (Day 91).

For whom post-vaccination immunogenicity results are available for at least 1 assay.
11.5.5.
Per-protocol set for analysis of efficacy
The PPS for analysis of efficacy will include all subjects in the TVC:

Who met all eligibility criteria.

For whom the administration of the vaccines was according to protocol.

Who complied with the vaccination schedule, as specified in Table 8.

Who received the study vaccine according to protocol procedures.

Not having received a medication/ product/ vaccine that may lead to elimination 
from the PPS (per-protocol) analysis for efficacy (see Section 7.6.3).
 
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In addition, for the Bacteriological efficacy endpoints:

For whom the sputum sample results are available.
11.5.6.
Full Analysis set (FAS)
The FAS will include all randomized subjects who will receive at least 1 vaccine 
administration. As per intention-to-treat principle, a subject in the FAS will be analysed 
“as randomized” (i.e. according to the vaccine a subject was planned to receive 
irrespectively of his/her real exposure).
11.6.
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.
Efficacy – Clinical Endpoint

For a given subject and a given efficacy measurement, missing or unevaluable 
measurements will not be imputed. The missing endpoint and censoring are 
supposed to occur independently, and the pattern of the missing is assumed to be 
Missing Completely at Random (MCAR) or Missing At Random (MAR) only.

The number of AECOPD occurring during the 1 year follow-up period starting 1 
month post-Dose 2 will be used to describe vaccine efficacy (VE). Exacerbation rate 
reported during this period will be calculated for each subject. The number of 
exacerbations during the 1-year follow-up period will be imputed for subjects 
withdrawing from the study to provide an estimate of the number of exacerbations 
over the follow-up period. This calculation will only be performed for purposes of 
reporting summary statistics since the modelling of exacerbations takes into account 
the number of exacerbations and the time of follow-up for each subject. 

The number of AECOPD occurring from enrolment up to 1 month post-Dose 2 will 
be used as ‘baseline’ value.  No difference between vaccine and placebo is expected 
in this period.

The calculation of exacerbation rate will be based on follow-up period intervals to 
avoid obtaining high imputed rates if a subject withdrew very early in the follow-up 
period after experiencing an exacerbation. Since treatment courses for 
moderate/severe exacerbations are 2 - 4 weeks when appropriate, calculated 
numbers of exacerbations for subjects withdrawing from the study will be based on 
4-week intervals of the follow-up period. For subjects followed for less than 1 year, 
the number of exacerbations during the 1-year follow-up period will be calculated by 
multiplying the number of exacerbations experienced by the subject by 13 and 
dividing by the number of 4-week periods the subject was followed up [Stockley, 
2006]: 
Number of exacerbations per year = Number of exacerbations * 13 /Number of 
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Safety

For solicited symptoms, missing or unevaluable measurements will not be replaced. 
Therefore the analysis of the solicited symptoms based on the TVC will include only 
subjects/doses with documented safety data (i.e., symptom screen/sheet completed).

For the unsolicited symptoms and concomitant medications/ products/ vaccinations,
all vaccinated subjects will be considered and subjects who miss reporting 
symptoms/concomitant medications/ products/ vaccinations will be treated as 
subjects without unsolicited symptoms or concomitant medications/ products/ 
vaccinations, respectively.
Efficacy – Bacteriological Endpoint

For a given subject and a given bacteriological measurement, missing or unevaluable 
measurements will not be imputed.

Subjects who did not have any sputum collected or have missing measurements at all 
AECOPD (if at least 1 AECOPD occurred) will not be taken into account for the 
NTHi and/or Mcat-associated AECOPD analyses.
Immunogenicity

Calculation of the GMCs will be performed by taking the anti-logarithm in base 10 
(anti-log10) of the mean of the log10 concentration transformations.

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.

A seronegative subject is defined as a subject whose antibody concentration is below 
the assay cut-off value (i.e. the ELISA lower limit of quantification).

A seropositive subject is defined as a subject whose antibody concentration is greater 
than or equal to the assay cut-off value (i.e. the ELISA lower limit of quantification). 

For a given subject and the analysis of a given immunogenicity measurement, 
missing or unevaluable measurements will not be replaced.
CMI

The frequency of CD4+ T-cells producing two or more markers (such as CD40 
Ligand (CD40L), interleukin (IL)-2, IL-13, IL-17, interferon gamma (IFN-γ), tumour 
necrosis factor alpha (TNF-α), upon in vitro stimulation with the antigen (induction 
condition) is presented per million of CD4+ T cells for the analysis and in percent for 
the graphical representation.
 
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
The frequency of antigen-specific CD4+ T-cells for each individual subject is 
calculated as the difference between the frequency of CD4+ T-cells producing at least 
2 cytokines among IFN-, IL-2, IL-13, IL-17, TNF-and/or CD40L, upon in vitro 
stimulation with the antigen (induction condition) minus the frequency of CD4+ T-
cells producing at least 2 cytokines upon in vitro stimulation in medium only 
(background condition). 
= Number of antigen-specific CD4+ T-cells expressing two or more cytokines.

The frequency of CD4+ T-cells expressing a marker (such as interleukin (IL)-2, IL-
13, IL-17, interferon gamma (IFN-γ), tumour necrosis factor alpha (TNF-α) upon in 
vitro stimulation with the antigen (induction condition) is presented per million of 
cells for the analysis and per hundred cells for the graphical representation.

Values less or equal to zero will be set to 1 for the purpose of the analysis. 

The Geometric Mean (GM) frequency calculations are performed by taking the anti-
log of the mean of the log frequency transformations.
HRQOL

The CAT index will be derived as the sum of the ratings recorded for each of the 
eight individual items. Each of these items has 6 possible scores (0, 1, 2, 3, 4 or 5), 
leading to a range of 0 to 40 for CAT score.

The SGRQ-C score will be grouped in total scores and by three component scores: 
Symptoms, Activity, Impacts. Score are assigned following the SGRQ-C Manual.
11.7.
Analysis of demographics
Demographic characteristics (age at the first dose in years, gender, geographical ancestry, 
smoking status) and cohort description will be summarised by group using descriptive 
statistics:

Frequency tables will be generated for categorical variable such as gender;
geographical ancestry, age category, smoking status;

Mean, median and standard deviation will be provided for continuous data such as 
age.
The distribution of subjects enrolled among the study sites will be tabulated as a whole 
and per group.
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.
No inferential analyses of demographic data are planned.
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11.8.
Analysis of efficacy
The primary analysis will be performed on the mTVC and repeated on the TVC and the 
FAS. The primary analysis will also be repeated on the efficacy ATP (per-protocol) 
cohort if the percentage of vaccinated subjects excluded from the ATP cohort for efficacy 
is more than 5%.
Efficacy – Clinical Endpoint
The following incidence rates of AECOPD (any type) occurring from enrolment up to 1 
month post-Dose 2 will be computed together with 95% CI, and incidence rates together 
with VE in the prevention of AECOPD (any type) will be computed over a period 
starting 1 month post-Dose 2 and lasting for 1 year, with 95% CI: 

All-cause moderate and severe AECOPD (primary endpoint).

All-cause, all-severity AECOPD.

All-cause AECOPD, by severity.
For the primary endpoint, the 87% CI will also be reported in order to evaluate the null 
hypothesis at 13% alpha level (2-side). This objective will be considered a success if the 
lower limit of the 87% CI will be above 0%. (Amended 27 March 2019)
The CIs of the incidence rate will be computed using a model which accounts for 
repeated events. The primary outcome will be analysed using the Negative Binomial 
regression model with number of AECOPD as dependent variable; treatment (vaccine or 
placebo), age group (40–59 years or 60–80 years ), GOLD grade (2, 3 or 4), history of 
exacerbations (<2 or ≥ 2) and country as independent variables, with logarithm as link 
function, and the logarithm of time for follow-up (in years) as an offset variable. If the 
model does not converge, the Poisson distribution will be used instead of the Negative 
Binomial one.
VE for AECOPD events is defined as:
VE (AECOPD) = 1 - Rvacc / Rcon
with:

Rvacc = average yearly incidence rate of AECOPD events per subject in the group 10-
10-3-AS.

Rcon = average yearly incidence rate of AECOPD events per subject in the Control
group.
 
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Incidence rates of AECOPD (any type) and VE, together with 95% CI, will be computed 
for the following time periods:

At Month 3, 6, 9, 12, 15 from Day 1 (cumulative)

By 6 Months follow up period (from 1 month post-Dose 2)

By 3 Months follow up period (from 1 month post-Dose 2) 
The model usd will be the same as for the primary analysis. 
A sensitivity analysis using a permutation test will be performed for the primary efficacy 
endpoint. 
Efficacy – Bacteriological Endpoint (PCR)
Similarly, VE in prevention of NTHi and/or Mcat associated AECOPD, over a period 
starting 1 month post-Dose 2 and lasting for 1 year and its 95% CI will be computed, 
with the following incidence rate:

NTHi-associated moderate and severe AECOPD.

NTHi-associated all-severity AECOPD.

NTHi-associated AECOPD, by severity.

Mcat-associated moderate and severe AECOPD.

Mcat-associated all-severity AECOPD.

Mcat-associated AECOPD, by severity.

NTHi and/or Mcat-associated moderate and severe AECOPD.

NTHi and/or Mcat-associated all-severity AECOPD.

NTHi and/or Mcat-associated AECOPD, by severity.

The time until first moderate and severe AECOPD.

The time until first AECOPD (any severity).

The time until first AECOPD by severity.
The proportion of sputum samples with exact 95% CI obtained at each visit (scheduled 
visits and AECOPD-driven visits) and positive for bacterial pathogens (overall and by 
bacterial pathogen) will be computed by group and overall. The exact CIs will be 
estimated assuming independence of bacterial results across sputum samples.
Incidence rates of AECOPD associated to NTHi and/or Mcat, and VE, together with 95% 
CI will be evaluated for the following time periods:

At Month 3, 6, 9, 12, 15 from day 1 (cumulative)

At 6 months follow up period (from 1 month post-Dose 2)

At 3 months follow up period (from 1 month post-Dose 2) 
 
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The model used will be the same as for the primary analysis. All above analyses will be 
performed in sputum samples using PCR. (Amended 27 March 2019)
Efficacy – Bacteriological Endpoint (culture)
Same set of analyses, as in the bacteriological efficacy endpoints, will be performed in 
the subset of culture sputum data. 
Incidence rates of AECOPD associated to NTHi and/or Mcat, and VE, together with 95% 
CI will be evaluated for the following time periods:

At Month 3, 6, 9, 12, 15 from day 1 (cumulative)

At 6 months follow up period (from 1 month post-Dose 2)

At 3 months follow up period (from 1 month post-Dose 2) 
The model used will be the same as for the primary analysis. All above analyses will be 
performed in sputum samples using PCR. (Amended 27 March 2019)
Bacteriological load
The following will be performed in PCR and culture samples:

Percentage of subjects with H. influenzae and M. catarrhalis in sputum before first 
vaccination and at Day 91, Day 181, Day 271, Day 361 and Day 451, per group. 

Relative abundance of H. influenzae and M. catarralis in sputum as measured by 
culture before first vaccination and at Day 91, Day 181, Day 271, Day 361 and Day 
451 and at each AECOPD visit, per group.

Descriptive summaries of the presence and quantity of NTHi and/or Mcat and/or 
other bacteria at each planned visit will be provided for both culture (semi-
quantitative estimation) and PCR analysis (copies/mL).
Acquisition and apparition
The following definitions will be used:

Acquisition: The first time a bacterium is detected in the sputum of a patient over 
the course of the study visits (a positive status at the visit considered as baseline 
excludes a subject from this analysis).

Apparition: Detection of a bacterium in the sputum of a patient taken during a 
study visit which was not detected in the sputum taken during the previous visit.
The following analyses will be performed for (NT)Hi (alone or with other bacteria), 
MCAT (alone or with other bacteria) and either Hi or MCAT:

Percentages of subjects with acquisition for each treatment group and risk ratio 
between groups, considering both Day 1 and Day 91 as baseline.

Percentages of subjects with apparition for each treatment group and risk ratio 
between groups, considering Day 1 as baseline.
 
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
Percentages of subjects with acquisition at AECOPD visit for each treatment 
group and risk ratio between groups, considering both Day 1 and Day 91 as 
baseline.

Percentages of subjects with apparition at AECOPD visit (when negative at 
previous stable visit) for each treatment group and risk ratio between groups, 
considering Day 1 as baseline

Frequency table for apparition (number of apparition for each subject from Day 
1), by treatment groups. (Amended 27 March 2019)
11.9.
Analysis of immunogenicity
The analysis will be performed on the immunogenicity ATP (per-protocol) cohort. If the 
percentage of vaccinated subjects with serological results excluded from the ATP cohort 
for analysis of immunogenicity is more than 10%, a second analysis will be performed on 
the TVC.
11.9.1.
Within groups assessment
Humoral immune response
For each group and at each timepoint during which blood samples are collected for 
humoral immune response (at Day 1, Day 31, Day 61, Day 91, Day 271 and at Day 451), 
and for each component (PD, PE, PilA and UspA2), the following will be computed:

Seropositivity rate (i.e, percentage of seropositive subject) and the associated exact 
95% CI

GMCs and the associated 95% CI
The distribution of antibody concentrations will be investigated using Reverse 
Cumulative Curves.
A seropositive subject is a subject whose antibody concentration is greater than or equal 
to the assay cut-off value, as specified in Table 10.
11.9.2.
Between groups assessment
Comparative analyses will be exploratory with the aim to characterise the difference 
between the 2 groups in humoral immune response.
The difference in terms of GMCs will be evaluated at 1 month post-Dose 2 by computing 
the 95% CIs of the GMC ratio between groups by using an ANCOVA model on the 
logarithm base10 transformation of the concentrations. This model will include the group
(vaccine or control), age category (40 - 59 years or 60 - 80 years), GOLD grade (GOLD 
2, GOLD 3 or GOLD 4) and country as fixed effects and pre-Dose 1 concentration (as 
covariate). 
 
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11.9.3.
Cell-mediated immune response
Cell-mediated immune response as part of secondary endpoints
CMI induced by the NTHi-Mcat candidate vaccine will be evaluated, presenting the 
frequencies of antigen-specific CD4+ T cells per 106 cells. The specific CD4+ T cells 
being identified as the CD4+ T cells expressing at least 2 different cytokines/activation 
markers among CD40L, IL-2, TNF-, IFN- γ, IL-13 and IL-17 upon in vitro stimulation. 
Descriptive statistics (Min, Q1, Median, Q3 & Max) will be reported for each group at 
Day 1, Day 91, Day 271 and Day 451. (Amended 27 March 2019)
Cell-mediated immune response as part of tertiary endpoints
CMI response as the frequencies of specific CD4+ T cells per 106 cells expressing any 
combination of cytokines/activation markers will be determined. In addition, the T 
helper profile of the specific T cell response in T helper 1, T helper 2 and T helper 17 
based on the specific expression of respectively IFN-, IL-13 and IL-17 will be 
characterized. Descriptive statistics (Min, Q1, Median, Q3 & Max) will be reported for 
each group at Day 1, Day 91, Day 271 and Day 451. (Amended 27 March 2019)
11.9.4.
Analysis of selected biomarkers
Descriptive statistics (median, mean, range, standard deviation, first and third quartiles) 
will be tabulated for each selected biomarker at study start (Day 1) and end of the study 
(Day 451) and for each AECOPD from first vaccination to study conclusion.
11.9.5.
Correlate of protection
An exploratory analysis will be implemented in an attempt to correlate immune responses 
to vaccination. A specific analysis plan will describe the methodologies to be used for 
that purpose. 
11.10.
Analysis of safety
The analysis will be performed on 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 (Day 
1 – Day 7) or the 30-day (Day 1 – Day 30) follow-up period will be tabulated after each 
vaccination and overall with exact 95% confidence interval (CI). The same computations 
will be done for Grade 3 AEs, for related AEs and for Grade 3 related AEs. 
The percentage of subjects/doses reporting each individual solicited local (any grade, 
Grade 3) and general (any grade, Grade 3, related, Grade 3 related) AE during the 7-day 
(Day 1 to Day 7) 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.
 
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
Per study vaccine dose, 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 during the 
30-day follow-up period after any study vaccine dose with its exact 95% CI will be 
tabulated by group and by MedDRA PT. Similar tabulation will be done for the 
percentage of doses, for Grade 3 unsolicited symptoms, for unsolicited symptoms that 
resulted in a medically attended visit, for Grade 3 and causally related unsolicited 
symptoms and for unsolicited symptoms causally related to vaccination.
The number of subjects who experienced any pIMD or any SAE from first vaccination 
up to 12 months post-Dose 2 will be reported.
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.
Pregnancy from first vaccination up to study end for each female subject and pregnancy 
outcomes will be described in detail.
The percentage of subjects/ dose using concomitant medication/ product (any 
medication/ product, any antipyretic and any antipyretic taken prophylactically, 
respectively) during the 7-day follow-up period (Day 1 – Day 7) and during the 30-day 
follow-up period (Day 1 – Day 30) will be summarised per group for each dose and 
overall per dose.

iSRC safety evaluations
For safety, 4 interim analysis evaluations are planned. iSRC reviews will be done once 60 
and 300 subjects complete one month after first vaccination and once 60 and 300 subjects 
complete one month after second vaccination (see Figure 3). 
Unblinded review of safety data will be done during iSRC evaluations. No individual 
clinical study report will be written as a result of these safety evaluations.
11.10.1.
Analysis of HRQOL, lung capacity
The analysis will be performed on the TVC.
Descriptive statistics (median, mean, range, standard deviation, first and third quartiles) 
on the EXACT-PRO, CAT, SGRQ-C scores, on FEV1% of predicted normal value
will be tabulated by specified visit.
 
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11.11.
Interpretation of analyses
The primary objective of this POC will be evaluated at alpha error of 13% (two-sided 
test) which is the measurement of the accuracy of our estimation. 
Comparative analyses related to the secondary and tertiary objectives, with the aim to 
characterise the difference in reactogenicity/ immunogenicity/ efficacy between groups 
will be descriptive and should be interpreted with caution.
11.12.
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.
11.12.1.
Sequence of analyses
The analyses of the primary, secondary and tertiary endpoints will be completed once 
data are released. They will be finalized at the end of the trial, when all data up to and 
including Visit 8 (Day 451) will be available and cleaned.
An integrated clinical study report containing all data will be written and made available 
to the investigators.
If the data for tertiary endpoints become available at a later stage, (an) additional 
analysis/ analyses will be performed. These data will be documented in annex(es) to the 
study report and will be made available to the investigators at that time.
12.
ADMINISTRATIVE MATTERS
To comply with ICH GCP administrative obligations relating to data collection, 
monitoring, archiving data, audits, confidentiality, public disclosure requirements and 
publications must be fulfilled. 
12.1.
Case Report Form/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 by the investigator or appropriately qualified designee. In all 
cases, the investigator remains accountable for the study data. 
 
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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.
12.2.
Study Monitoring by GSK Biologicals
GSK will monitor the study to verify that, amongst other items, the: 

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol, any other 
study agreements, GCP and all applicable regulatory requirements. 
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents.
The investigator must ensure provision of reasonable time, space and qualified personnel 
for monitoring visits.
Direct access to all study-site related and source data is mandatory for the purpose of 
monitoring review. The monitor will perform 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 investigator’s study file. Any data item for which 
the eCRF will serve as the source must be identified, agreed and documented in the 
source documentation agreement form. 
Upon completion or premature discontinuation of the study, the monitor will conduct site 
closure activities with the investigator or site staff, as appropriate, in accordance with 
applicable regulations, GCP, and GSK procedures.
12.3.
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 
 
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investigator must ensure that an acceptable back-up of the reproductions exists and that 
there is an acceptable quality control procedure in place for making these reproductions.
GSK will inform the investigator/institution of the time period for retaining these records 
to comply with all applicable regulatory requirements. The minimum retention time will 
meet the strictest standard applicable to a particular site, as dictated by ICH GCP, any 
institutional requirements, applicable laws or regulations, or GSK standards/procedures, 
otherwise, the minimum retention period will default to 25 years after completion of the 
study report.
The investigator/institution must notify GSK of any changes in the archival 
arrangements, including, but not limited to archival at an off-site facility, transfer of 
ownership of the records in the event the investigator leaves the site. 
12.4.
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.
12.5.
Posting of information on publicly available clinical trial 
registers and publication policy
GSK assures that the key design elements of this protocol will be posted on the GSK 
website and in publicly accessible database(s) such as clinicaltrials.gov, in compliance 
with the current regulations.
GSK also assures that results of this study will be posted on the GSK website and in 
publicly accessible regulatory registry(ies) within the required time-frame, in compliance 
with the current regulations. The minimal requirement is to have primary endpoint 
summary results disclosed at latest 12 months post primary completion date (PCD) and to 
have secondary endpoint disclosed at latest 12 months after the last subject last visit 
(LSLV) as described in the protocol.
As per EU regulation, summaries of the results of GSK interventional studies (phase I-
IV) in adult population conducted in at least one EU member state will be posted on 
publicly available EMA registers within 12 months of EoS (as defined in the protocol) in 
the concerned EU member state. However, where, for scientific reasons detailed in the 
protocol, it is not possible to submit a summary of the results within one year in the 
concerned EU member state, the summary of results shall be submitted as soon as it is 
available. In this case, the protocol shall specify when the results are going to be 
submitted, together with a justification. 
 
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GSK also aims to publish the results of these studies in searchable, peer reviewed 
scientific literature and follows the guidance from the International Committee of 
Medical Journal Editors.
12.6.
Provision of study results to investigators
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK Biologicals will also provide the investigator with the full summary of the study 
results. The investigator is encouraged to share the summary results with the study 
subjects, as appropriate.
12.7.
Data Sharing
Under the framework of the SHARE initiative, results of GSK studies may be combined 
with non- GSK studies, to investigate further about the study product(s) and other 
product(s), and /or the disease/condition under investigation and related diseases and 
conditions.
13.
COUNTRY SPECIFIC REQUIREMENTS
13.1.
Requirements for Germany
Explanatory statement concerning Gender Distribution (Article 7, paragraph 2 (12) 
of the German GCP ORDER)
For this NTHI MCAT-002 study, there is no intention to conduct specific analyses 
investigating the relationship between gender and the safety and efficacy of the 
investigational NTHi-Mcat vaccine. Recruitment will include males and females. To not 
expose pregnant women and their foetuses/children to an early-phase investigational 
vaccine, females enrolled in this trial will either be of non-childbearing potential (i.e.,
have a current tubal ligation or occlusion, hysterectomy, bilateral ovariectomy or be
premenarchal or postmenopausal), or if she is of childbearing potential, she must practice 
adequate contraception for 30 days prior to the beginning of the administration of study 
treatment, have a negative pregnancy test and continue such precautions during the entire 
study treatment period and for 2 months after completion of the injection series (Refer to
the study protocol, Section 5.2 “Inclusion criteria” and Section 5.3 “Exclusion criteria”). 
The recruitment will be closed to females who are pregnant or lactating. Similarly,
patients becoming or deciding to become pregnant during the study must stop the study 
treatment administrations.
Historically, COPD was considered a disease of males. The past few decades have seen a 
shift in this paradigm. In the United States, between the periods of the First National 
 
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Health and Nutrition Examination Survey (NHANES I) and NHANES III, the prevalence 
of spirometrically determined moderate COPD increased in women from 50.8 per 1000 
to 58.2 per 1000, whereas the prevalence decreased in men from 108.1 per 1000 to 74.3 
per 1000.3 Data from the National Health Interview Survey show that the self-reported 
prevalence of COPD in the United States was stable from 1998 through 2009 and has 
remained higher in women than in men. A similar trend is seen in other developed 
countries such as Canada, the Netherlands, and Australia [Aryal, 2013]. There are no
reports of gender differences in the efficacy or safety outcomes for patients receiving the 
investigational NTHi-Mcat vaccine. 
13.2.
Requirements for France
This section includes all the requirements of the French law (n2004-806 of 9th August 
2004), and identifies, item per item, the mandatory modifications or additional 
information to the study protocol and includes specifics GSK requirements.
1.
Concerning the «STUDY POPULATION»

In line with the local regulatory requirements, the following text about «PAYMENT 
TO SUBJECTS» is added:
Subjects will be paid for the inconvenience of participating in the study. The amount 
of payment is stated in the informed consent form. Subjects not completing the study 
for whatever reason could be paid at the discretion of the Investigator, generally on a 
pro rata basis.

In line with the local regulatory requirements, the following text about «NATIONAL 
FILE» is added:
All subjects who will be paid, will be recorded into the “National File” by the 
investigator. They could be identified and monitored under the «Fichier national».
The following details will be described:

Reference of the study

Surname and first name

Date and place of birth

Sex

Dates of beginning and termination of the study

Exclusion period

The total amount of allowance.

In line with the local regulatory requirements, the following text in section «OTHER 
STUDY ELIGIBILITY CRITERIA CONSIDERATIONS» is added:
A subject will be eligible for inclusion in this study if he/she is either affiliated to or 
beneficiary of a social security category.
 
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It is the investigator’s responsibility to ensure and to document (in source document -
patient notes) that the patient is either affiliated to or beneficiary of a social security 
category.
2.
Concerning the “DATA ANALYSIS AND STATISTICAL 
CONSIDERATIONS” and specially in the “SAMPLE SIZE ASSUMPTION”
The expected number of patients to be recruited in France is declared to the French 
regulatory authority.
3.
Concerning the “STUDY CONDUCT CONSIDERATIONS”

In section “REGULATORY AND ETHICAL CONSIDERATIONS, INCLUDING 
THE INFORMED CONSENT PROCESS”

Concerning the process for informing the patient or his/her legally authorized 
representative, the following text is added:
French Patient Informed Consent form is a document which summarizes the 
main features of the study and allows collection of the patient's written consent 
in triplicate. It also contains a reference to the authorisation of ANSM and the 
approval from the French Ethic committee and the maintenance of 
confidentiality of the returned consent form by GSK France.

Concerning the management of the Patient Informed Consent forms, the 
following text is added:
The first copy of the Patient Informed Consent form is kept by the investigator. 
The second copy is kept by the Medical Direction of GSK France and the last 
copy is given to the patient or his/her legally authorized representative.
The second copy of all the consent forms will be collected by the investigator 
under the Clinical Research Assistant’s (CRAs) control, and placed in a sealed 
envelope bearing only:

the study number, 

the identification of the Centre: name of the principal investigator and 
centre number,

the number of informed consents,

the date,

and the principal investigator’s signature.
Then, the CRA hands the sealed envelope over to the Medical Direction, for 
confidential recording, under the responsibility of the Medical Director.

In section concerning the “NOTIFICATION TO THE HOSPITAL DIRECTOR” the 
following text is added:
In accordance with Article L1123-13 of the Public Health Code, the Hospital 
Director is informed of the commitment to the trial in his establishment. The 
Hospital Director is supplied with the protocol and any information needed for the 
 
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financial disposition, the name of the investigator(s), the number of sites involved in 
his establishment and the estimated time schedule of the trial (R.1123-63).

In section concerning the “INFORMATION TO THE HOSPITAL PHARMACIST” 
the following text is added:
In accordance with Article R.1123-64 of the Public Health Code, the Hospital
Pharmacist is informed of the commitment to the trial in his establishment. The 
Pharmacist is supplied with a copy of the protocol (which allows him to dispense the 
drug(s) of the trial according to the trial methodology), all information concerning 
the product(s) of the trial (e.g. included in the CIB), the name of the investigator(s), 
the number of sites involved in his establishment and the estimated time schedule of 
the trial.

In section “DATA MANAGEMENT” the following text is added:
Within the framework of this clinical trial, data regarding the identity of the 
investigators and/or co-investigators and/or the pharmacist if applicable, involved in 
this clinical trial, and data regarding the patients recruited in this clinical trial (patient 
number, treatment number, patient status with respect to the clinical trial, dates of 
visit, medical data) will be collected and computerized in GSK data bases by GSK 
Laboratory or on its behalf, for reasons of follow up, clinical trial management and 
using the results of said clinical trial. According to the Act n° 78-17 of 6th January 
1978 further modified, each of these people aforesaid has a right of access, 
correction and opposition on their own data through GSK Laboratory (Clinical 
Operations Department).

In the section concerning “DEMOGRAPHIC DATA”, the following text is added:
In accordance with the data processing and freedom French law dated on 6th of 
January 1978 modified on the 6th of August 2004 - article 8, the ethnic origin can 
only be collected if the collection of this data is justified within the framework of this 
study.

In the section concerning “TESTING OF BIOLOGICAL SAMPLES” the following 
text is added:
In accordance with the Article L1211-2 of the French Public Health Code, a 
biological sample without identified purpose at the time of the sample and subject’s 
preliminary information is not authorized.
 
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4.
Concerning the «SAE»
!
In section “TRANSMISSION OF THE SAE REPORTS”:
In case of paper CRF, the SAE Reports have to be transmitted to the GSK France 
Drug Safety Department, which name, address and phone number are:
Département de Pharmacovigilance
Laboratoire GlaxoSmithKline
23 rue François Jacob
92500 RUEIL MALMAISON
Tel : 
Fax : 
5.
Monitoring visits
The Health Institution and the Investigator agree to receive on a regular basis a 
Clinical Research Assistant (CRA) of GSK or of a service provider designated by 
GSK. The Health Institution and the Investigator agree to be available for any phone 
call and to systematically answer to all correspondence regarding the Study from 
GSK or from a service provider designated by GSK. In addition, the Health 
Institution and the Investigator agree that the CRA or the service provider designated 
by GSK have direct access to all the data concerning the Study (test results, medical 
record, etc. …). This consultation of the information by GSK is required to validate 
the data registered in the electronic Case Report Form (eCRF), in particular by 
comparing them directly to the source data. In accordance with the legal and 
regulatory requirements, the strictest confidentiality will be respected.
6.
Data entry into the eCRF
The Health Institution and the Investigator agree to meet deadlines, terms and 
conditions of the Study’s eCRF use here below:
The Health Institution and the Investigator undertake:
!
That the Investigator and the staff of the investigator center make themselves 
available to attend the training concerning the computer system dedicated to the 
eCRF of the Study provided by GSK or by a company designated by GSK.
!
That the Investigator and the staff of the investigator center use the IT Equipment 
loaned and/or the access codes only for the purpose of which they are intended and 
for which they have been entrusted to them, namely for the Study achievement, to 
the exclusion of any other use.
!
That the Investigator and the staff of the investigator center use the IT Equipment 
loaned according to the specifications and manufacturer’s recommendations which 
will have been provided by GSK.
!
To keep the IT Equipment and/or access codes in a safe and secure place and to only 
authorize the use of this IT Equipment by investigator center staff designated by the 
principal investigator to enter the data of the Study.
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
That the Investigator and the staff of the investigator center enter the data of the 
eCRF related to a patient visit in the 3 days following the date of the patient visit or, 
for the patient test results, in the 3 days following the reception of the results of such 
tests.

That the Investigator resolves and returns to GSK the data queries issued by GSK or 
a service provider designated by GSK within 7 days after the reception of the request 
of clarification or in a period of one (1) day during the final stage of clarification of 
the data base or in such other period as provided by GSK and/or a company 
designated by GSK.

To be responsible for the installation and payment of the required Internet 
connections needed for the use of the IT Equipment, Computer systems and/or 
access codes.

To return at the end of the Study the IT Equipment and/or access codes to GSK or to 
any company designated by GSK and any training material and documentation. The 
IT Equipment cannot under any circumstances be kept by the Health Institution or 
the Investigator for any reason whatsoever.
7.
CTR publication
It is expressly specified that GSK and/or the Sponsor can make available to the 
public the results of the Study by the posting of the said results on a website of the 
GSK GROUP named Clinical Trial Register (CTR) including the registration of all 
the clinical trials conduct by the GSK Group and this before or after the publication 
of such results by any other process.
8.
Data Protection French Law of 6 January 1978 (CNIL)
In accordance with the Data Protection French Law of 6 January 1978 as modified, 
computer files used by GSK to monitor and follow the implementation and the 
progress of the Study are declared with the CNIL by GSK. The Investigator has 
regarding the processing data related to him a right of access, of rectification and of 
opposition with GSK in accordance with the legal provisions. This information can 
be transferred or be accessed to other entities of GSK Group in France, Britain or 
United States, what the Investigator agrees by the signature of the present Protocol.
 
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14.
REFERENCES
Alamoudi OS. Bacterial infection and risk factors in outpatients with acute exacerbation 
of chronic obstructive pulmonary disease: a 2-year prospective study. Respirology. 2007; 
12: 283-7.
American Thoracic Society and European Respiratory Society. Standards for the 
diagnosis and management of patients with COPD. 2004. New York, USA; Lausanne, 
Switzerland. Ref Type: Conference.
Anthonisen NR, Manfreda J, Warren CP, et al. Antibiotic therapy in exacerbations of 
chronic obstructive pulmonary disease. Ann Intern Med. 1987; 106: 196-204.
Aryal S, Diaz-GuzmanN E, Mannino DM. COPD and gender differences: an update. 
Transl Res. 2013; 162(4): 208-18.
Bandi V, Jakubowycz M, Kinyon C, et al. Infectious exacerbations of chronic obstructive 
pulmonary disease associated with respiratory viruses and non-typeable Haemophilus 
influenzae. FEMS Immunol Med Microbiol. 2003; 37: 69-75.
Cazzola M, MacNee W, Martinez FJ, et al. Outcomes for COPD pharmacological trials: 
from lung function to biomarkers. Eur Respir J 2008; 31: 416-69.
Centers for Disease Control and Prevention Metropolitan Atlanta Congenital Defects 
Program (CDC MACDP) guidelines. Birth defects and genetic diseases branch 6-digit 
code for reportable congenital anomalies; 
http://www.cdc.gov/ncbddd/birthdefects/documents/MACDPcode0807.pdf
Daubin C, Parienti JJ, Vabret A, et al. Procalcitonin levels in acute exacerbation of 
COPD admitted in ICU: a prospective cohort study. BMC Infect Dis. 2008; 8: 145.
Dransfield MT, Bourbeau J, Jones PW, et al. Once-daily inhaled fluticasone furoate and 
vilanterol versus vilanterol only for prevention of exacerbations of COPD: two replicate 
double-blind, parallel-group, a randomised controlled trials. The Lancet Respir Med.
2013; 1: 210-223.
EMA Guideline on the exposure to medicinal products during pregnancy: need for post-
authorization data (Doc. Ref. EMEA/CHMP/313666/2005 ) ‘adopted at Community level 
in May 2006);
http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_g
uideline/2009/11/WC500011303.pdf
Erb-Downward JR, Thompson DL, Han MK, et al. Analysis of the lung microbiome in 
the "healthy" smoker and in COPD. PLoS One. 2011; 6:e16384.
Garcha DS, Thurston SJ, Patel AR, et al. Changes in prevalence and load of airway 
bacteria using quantitative PCR in stable and exacerbated COPD. Thorax. 2012; 67(12):
1075-80.
 
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Global Initiative for Chronic Obstructive Lung Disease (GOLD). From the Global 
Strategy for the diagnosis, management, and prevention of Chronic Obstructive 
Pulmonary Disease, updated 2017; http://www.goldcopd.org/. Last accessed: 17-JAN-
2017.
Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the 
diagnosis, management, and prevention of Chronic Obstructive Pulmonary Disease, 
updated 2013. Available from: 
http://www.goldcopd.org/uploads/users/files/GOLD_Report_2013_Feb20.pdf
Haralambieva IA, Ovsyannikova IG, Kennedy RB, et al. Race and Sex-Based 
Differences in Cytokine Immune Responses to Smallpox Vaccine in Healthy Individuals. 
Hum Immunol. 2013; 74(10): 1263–1266. 
Hutchinson AF, Ghimire AK, Thompson MA, et al. A community-based, time-matched, 
case-control study of respiratory viruses and exacerbations of COPD. Respir Med. 2007;
101: 2472-81.
Keen ON, Jones MR, Lane PW, Anderson J. Analysis of exacerbation rates in asthma and 
chronic obstructive pulmonary disease: example from the TRISTAN study. Pharm. Stat. 
2007; 6(2): 89–97.
Ko FW, Ip M, Chan PK, et al. A 1-year prospective study of the infectious etiology in 
patients hospitalized with acute exacerbations of COPD. Chest 2007; 131: 44-52.
Kollmann TR. Variation between Populations in the Innate Immune Response to Vaccine 
Adjuvants. Front Immunol. 2013; 4: 81. 
Larsen MV, Janner JH, Nielsen SD, et al. Bacteriology in acute exacerbation of chronic 
obstructive pulmonary disease in patients admitted to hospital. Scand J Infect Dis. 2009;
41: 26-32.
Mackay AJ, Hurst JR. COPD exacerbations: causes, prevention, and treatment. Med Clin 
North Am. 2012; 96(4): 789-809.
Moris P, van der Most R, Leroux-Roels I, et al. H5N1 influenza vaccine formulated with 
AS03 A induces strong cross-reactive and polyfunctional CD4 T-cell responses. J Clin 
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.
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.
 
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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.
Pérez-Losada M, Posada D, Arenas M, et al. Ethnic differences in the adaptation rate of 
HIV gp120 from a vaccine trial. Retrovirology. 2009; 6: 67.
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.
Stockley RA, Chopra N and Rice L. Addition of salmeterol to existing treatment in 
patients with COPD: a 12 month study. Thorax .2006; 61: 122-8.
Wang H, Gu X, Weng Y, et al. Quantitative analysis of pathogens in the lower 
respiratory tract of patients with chronic obstructive pulmonary disease. BMC Pulm Med. 
2015; 15: 94.
Wang H, Naghavi M, Allen C, et al. Global, regional, and national life expectancy, all-
cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: a 
systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;
388(10053): 1459-1544.
Wedzicha JA and Seemungal TA. COPD exacerbations: defining their cause and 
prevention. Lancet. 2007; 370: 786-96.
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.
Wilkinson TMA, Aris E, Bourne S, et al. A prospective, observational cohort study of the 
seasonal dynamics of airway pathogens in the aetiology of exacerbations in COPD. 
Thorax. 2017, 72(10): 919-927.
 
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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 below and in Table 10. The cut-off and 
unit of these assays might be subject to change during the course of the study (e.g. in case 
of assay re-optimization, qualification or standardization). In this case, this will be 
documented in the clinical study report.
Anti-PD antibodies
Anti-PD antibodies will be determined using a validated ELISA assay developed by GSK 
Biologicals. Concentration of specific anti-PD antibodies will be determined, using 
in-house made reference serum. The technical cut-off of the assay is 153 EU/mL.
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 technical cut-off of the assay is 16 EU/mL. (Amended 
27 March 2019)
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 technical cut-off of the assay is 8 EU/mL.
(Amended 27 March 2019)
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 technical cut-off of the assay is 28 EU/mL. 
(Amended 27 March 2019)
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
Table 25
GSK Biologicals’ laboratories
Laboratory
Address
GSK Biological’s Clinical Laboratory Sciences, 
Rixensart 
Biospecimen Reception - B7/44
Rue de l'Institut, 89 - B-1330 Rixensart – Belgium 
GSK Biological’s Pre-clinical Laboratory, 
Rixensart
Rue de l'Institut, 89 - B-1330 Rixensart – Belgium
GSK Biological’s Clinical Laboratory Sciences, 
Wavre-Nord Noir Epine
Avenue Fleming, 20 - B-1300 Wavre - Belgium
GSK Biological’s Pre-clinical Laboratory, Siena
Via Fiorentina, 1, 53100 Siena SI, Italy
GSK Vaccines GmbH
Klinische Serologie, Clinical Laboratory 
Sciences
Gebaeude Z26
Emil-von-Behring Str. 76, Marburg 35041 - Germany
Table 26
Outsourced laboratories (Amended 27 March 2019)
Laboratory
Address
CEVAC - University of Gent
De Pintelaan, 185 Gent, Belgium
DDL Diagnostic Laboratory B.V.
Visseringlaan 25, 2288 ER Rijswijk, The Netherlands
Q2 Solutions Clinical Trials (US)
27027 Tourney Road, Suite 2E
Valencia, CA 91355
USA
Q2 Solutions Clinical Trials (UK)
The Alba Campus Rosebank 
Livingston West Lothian, EH54 7EG Scotland, 
UK 
 
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APPENDIX C
MEDDRA PREFERRED TERMS FOR POTENTIAL 
IMMUNE MEDIATED DISEASES
Table 27
MedDRA preferred terms for potential immune mediated diseases 
Event Category
Immune-Mediated Disorder
MedDRA PT
Neuroinflammatory 
disorders
Cranial nerve disorders
Anosmia
IIIrd nerve paralysis
IIIrd nerve paresis
IVth nerve paralysis
IVth nerve paresis
Trigeminal palsy
Trigeminal nerve paresis
VIth nerve paralysis
VIth nerve paresis
Facial paralysis
Facial paresis
Acoustic neuritis
Glossopharyngeal nerve paralysis
Tongue paralysis
Vagus nerve paralysis
Vocal cord paralysis
Vocal cord paresis
XIth nerve paralysis
Hypoglossal nerve paralysis
Hypoglossal nerve paresis
Bulbar palsy
Oculofacial paralysis
Neuritis cranial
Cranial nerve disorder
Paresis cranial nerve
Cranial nerve paralysis
Cranial nerve palsies multiple
Optic neuritis
Optic neuritis
Multiple sclerosis
Multiple sclerosis
Radiologically isolated syndrome
Primary progressive multiple 
sclerosis
Progressive multiple sclerosis
Marburg's variant multiple sclerosis
Secondary progressive multiple 
sclerosis
Multiple sclerosis relapse
Multiple sclerosis relapse 
prophylaxis
Progressive relapsing multiple 
sclerosis
Relapsing-remitting multiple 
sclerosis
Tumefactive multiple sclerosis
 
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Event Category
Immune-Mediated Disorder
MedDRA PT
Transverse myelitis
Myelitis transverse
Myelitis
Noninfectious myelitis
Guillain-Barré syndrome
Guillain-Barré syndrome
Miller Fisher syndrome
Acute disseminated 
encephalomyelitis/demyelination 
(including site specific variants)
Demyelination
Autoimmune demyelinating disease
Clinically isolated syndrome
Leukoencephalomyelitis
Leukoencephalopathy
Acute disseminated 
encephalomyelitis
Acute haemorrhagic 
leukoencephalitis
Concentric sclerosis
Encephalitis periaxialis diffusa
Neuromyelitis optica spectrum 
disorder
Autoimmune encephalopathy
Bickerstaff's encephalitis
Noninfective encephalitis
Encephalitis autoimmune
Rasmussen encephalitis
Encephalitis allergic
Encephalitis brain stem
Encephalitis haemorrhagic
Encephalomyelitis
Noninfective encephalomyelitis
Encephalitis post immunisation
Panencephalitis
Encephalitis toxic
Myasthenia gravis
Myasthenia gravis
Myasthenia gravis crisis
Ocular myasthenia
Myasthenic Syndrome
Immune-mediated peripheral 
neuropathies and plexopathies
Autoimmune neuropathy
Neuritis
Anti-myelin-associated glycoprotein 
associated polyneuropathy
Chronic inflammatory demyelinating 
polyradiculoneuropathy
Lewis-Sumner syndrome
Demyelinating polyneuropathy
Polyneuropathy idiopathic 
progressive
Multifocal motor neuropathy
Acute motor-sensory axonal 
neuropathy
Acute motor axonal neuropathy
Cervical neuritis
Mononeuritis
Mononeuropathy multiplex
Brachial plexopathy
Radiculitis brachial
 
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Event Category
Immune-Mediated Disorder
MedDRA PT
Narcolepsy
Narcolepsy
Musculoskeletal 
disorders
Systemic lupus erythematosus
Systemic lupus erythematosus
SLE arthritis
Cutaneous lupus erythematosus
Acute cutaneous lupus 
erythematosus
Chronic cutaneous lupus 
erythematosus
Subacute cutaneous lupus 
erythematosus
Lupus cystitis
Lupus encephalitis
Lupus endocarditis
Lupus enteritis
Lupus hepatitis
Lupus myocarditis
Lupus myositis
Lupus nephritis
Lupus pancreatitis
Lupus pleurisy
Lupus pneumonitis
Lupus-like syndrome
Neuropsychiatric lupus
Central nervous system lupus
Pericarditis lupus
Peritonitis lupus
Systemic lupus erythematosus rash
Systemic Scleroderma 
Scleroderma
Scleroderma renal crisis
Scleroderma associated digital ulcer
Reynold’s syndrome
Systemic sclerosis pulmonary
Systemic scleroderma
CREST syndrome
Muscular autoimmune disorders
Polymyalgia rheumatica
Dermatomyositis
Polymyositis
Juvenile polymyositis
Immune-mediated necrotising 
myopathy
Antisynthetase syndrome
Rheumatoid arthritis and 
associated conditions
Rheumatoid arthritis
Autoimmune arthritis
Laryngeal rheumatoid arthritis
Rheumatoid lung
Rheumatoid scleritis
Rheumatic brain disease
Rheumatoid neutrophilic dermatosis
Rheumatoid nodule
Juvenile idiopathic arthritis
Cogan's syndrome
Palindromic rheumatism
Still's disease
Spondyloarthropathies
Arthritis reactive
 
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Event Category
Immune-Mediated Disorder
MedDRA PT
Reiter's syndrome
Ankylosing spondylitis
Spondylitis
Spondyloarthropathy
Juvenile spondyloarthritis
Enteropathic spondylitis
Psoriatic arthropathy
Psoriatic arthropathy
Juvenile psoriatic arthritis
Relapsing polychondritis
Polychondritis
Mixed connective tissue disease
Overlap syndrome
Mixed connective tissue disease
Gout
Gout
Gouty arthritis
Gouty tophus
Gastrointestinal 
disorders
Inflammatory Bowel disease
Crohn's disease
Colitis ulcerative
Colitis microscopic
Autoimmune colitis
Inflammatory bowel disease
Arthritis enteropathic
Proctitis ulcerative
Autoimmune pancreatitis
Autoimmune pancreatitis
Celiac disease
Coeliac disease
Liver disorders
Autoimmune hepatitis
Autoimmune hepatitis
Primary biliary cirrhosis
Biliary cirrhosis primary
Autoimmune cholangitis
Cholangitis sclerosing
Endocrine and 
Metabolic disorders
Autoimmune thyroid diseases
Autoimmune hypothyroidism
Atrophic thyroiditis
Autoimmune thyroiditis
Silent thyroiditis
Hashimoto's encephalopathy
Hashitoxicosis
Basedow's disease
Marine Lenhart syndrome
Autoimmune thyroid disorder
Autoimmune endocrine disorder 
(NOS)
Autoimmune endocrine disorder
Diabetes mellitus type I
Type 1 diabetes mellitus
Fulminant type 1 diabetes mellitus
Polyglandular autoimmune 
syndrome
Polyglandular autoimmune
syndrome type I
Polyglandular autoimmune 
syndrome type II
Polyglandular autoimmune 
syndrome type III
Autoimmune hypophysitis
Lymphocytic hypophysitis
Addison's disease
Addison's disease
 
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Event Category
Immune-Mediated Disorder
MedDRA PT
Skin disorders
Psoriasis
Psoriasis
Vitiligo
Vitiligo
Erythema nodosum
Erythema nodosum
Alopecia areata
Alopecia areata
lichen planus
Lichen planus
Sweet’s syndrome
Acute febrile neutrophilic dermatosis
Autoimmune bullous skin diseases
Pemphigus
Pemphigoid
Dermatitis herpetiformis
Autoimmune dermatitis
Localised Scleroderma
Morphoea
Vasculitides
Vasculitis and vasculitides
Acute haemorrhagic oedema of 
infancy
Administration site vasculitis
Anti-neutrophil cytoplasmic antibody 
positive vasculitis
Aortitis
Application site vasculitis
Arteritis
Arteritis coronary
Behcet's syndrome
Capillaritis
Cerebral arteritis
Chronic pigmented purpura
Cutaneous vasculitis
Diffuse vasculitis
Eosinophilic granulomatosis with 
polyangiitis
Erythema induratum
Granulomatosis with polyangiitis
Haemorrhagic vasculitis
Henoch-Schonlein purpura
Henoch-Schonlein purpura nephritis
Hypersensitivity vasculitis 
Injection site vasculitis
Kawasaki's disease
Langerhans' cell histiocytosis
Lupus vasculitis
MAGIC syndrome
Microscopic polyangiitis
Nodular vasculitis
Ocular vasculitis
Optic ischaemic neuropathy
Optic neuropathy
Polyarteritis nodosa
Pulmonary vasculitis
Renal arteritis
Renal vasculitis
Retinal vasculitis
Rheumatoid vasculitis
Segmented hyalinising vasculitis
Takayasu's arteritis
Temporal arteritis
Thromboangiitis obliterans
 
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Event Category
Immune-Mediated Disorder
MedDRA PT
Urticarial vasculitis
Vaccination site vasculitis
Vascular purpura
Vasculitic rash
Vasculitic ulcer
Vasculitis
Vasculitis cerebral
Vasculitis gastrointestinal
Vasculitis necrotising
Other
Stevens-Johnson syndrome
Stevens-Johnson syndrome
Erythema multiforme
Toxic epidermal necrolysis
Blood autoimmune disoders
Autoimmune anaemia
Autoimmune haemolytic anaemia
Warm type haemolytic anaemia
Cold type haemolytic anaemia
Coombs positive haemolytic 
anaemia
Evans syndrome
Immune thrombocytopenic purpura 
Thrombocytopenic purpura
Thrombotic thrombocytopenic 
purpura
Autoimmune aplastic anaemia
Autoimmune neutropenia
Autoimmune pancytopenia
Antiphospholipid syndrome
Pernicious anaemia
Autoimmune glomerulonephritis
Glomerulonephritis rapidly 
progressive
IgA nephropathy
IgM nephropathy
Glomerulonephritis membranous
Glomerulonephritis 
membranoproliferative
Mesangioproliferative 
glomerulonephritis
Autoimmune nephritis
Chronic autoimmune 
glomerulonephritis
Tubulointerstitial nephritis and uveitis 
syndrome
Ocular autoimmune diseases
Uveitis
Ocular pemphigoid
Autoimmune retinopathy
Acute macular outer retinopathy
Autoimmune uveitis
Autoimmune heart disease
Autoimmune myocarditis
Autoimmune pericarditis
Sarcoidosis
Sarcoidosis
Pulmonary sarcoidosis
Neurosarcoidosis
Cutaneous sarcoidosis
Liver sarcoidosis
 
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Event Category
Immune-Mediated Disorder
MedDRA PT
Muscular sarcoidosis
Ocular sarcoidosis
Sjögren’s syndrome
Sjogren's syndrome
Idiopathic pulmonary fibrosis
Idiopathic pulmonary fibrosis
Idiopathic interstitial pneumonia
Interstitial lung disease
Pulmonary fibrosis
Goodpasture’s syndrome
Goodpasture’s syndrome
Raynaud's phenomenon
Raynaud's phenomenon
 
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APPENDIX D
AMENDMENTS AND ADMINISTRATIVE 
CHANGES TO THE PROTOCOL
GlaxoSmithKline Biologicals SA
Vaccines R &D
Protocol Amendment 1
eTrack study number and 
Abbreviated Title
207489 (NTHI MCAT-002)
IND number
16531
EudraCT number
2017-000880-34
Amendment number:
Amendment 1
Amendment date:
30 November 2017
Co-ordinating author:
, XPE Pharma & Science for GSK 
Biologicals
Rationale/background for changes: 
!
Removal of the ® and ™ symbols in the document and simplification of the 
copyright statement as per GSK Legal Global Trade Marks (LGTM) department’s 
recommendation.
!
The tertiary endpoint regarding ‘biomarkers’ has been adjusted as haematology is 
measured at baseline only and not throughout the study and thus cannot be 
considered a study endpoint.
!
CD8+ T cell component was removed from the secondary endpoint, but kept in the 
exploratory/tertiary endpoint. Previous clinical studies have shown that the 
investigational NTHi and NTHi-Mcat vaccines do not induce CD8+ T cell 
responses. This was observed in all studies performed with the NTHi vaccine and 
seen in the interim analysis of NTHi Mcat-001 study. 
!
The definition of ‘current smoker’ has been updated to better clarify the time 
frame during which a subject who stopped smoking is still considered as ‘current 
smoker’. A definition for ‘Study Works’ was also added to the glossary of terms. 
!
An exclusion criterion was updated to clarify that only subjects with clinically 
significant respiratory diseases other than COPD (e.g. clinically significant lung 
fibrosis, clinically significant pulmonary embolism) need to be excluded from 
study participation.
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
Footnote a and b of the Study Procedures Table were rewritten to clarify when 
some study procedures of the Screening Visit needs to be repeated (i.e. in case 
Visit 1 was done more than 29 days after the Screening Visit and  if the subject has 
any medical condition [e.g. fever] that prevents his/her participation in the study 
within 29 days of Screening Visit) and when the entire Screening Visit needs to be 
repeated (i.e. in case the subject had AECOPD before Visit 1 and only after 
subject was stable for 30 days). The footnote to the study design overview figure 
was adjusted in a similar way.

A footnote was added to the study procedures table to explain that solicited 
(general/local) AEs will be collected up to Day 7 post-vaccination, but solicited 
AEs ongoing at Day 7 will be followed until resolution (for a maximum of 30 
days). This was also added to Section 6.9.21. 

A scientific rationale for collecting race/ethnicity was added per country specific 
requirement for France (Section 6.9.5).

Cut-off values for anti-PE, anti-PilA and anti-UspA2 antibody ELISAs were 
updated following the re-set up of the assays.

The PCR assay for sputum samples was not designed to discriminate amongst 
Haemophilus influenzae (Hi) serotypes. Results from AERIS epidemiological 
study [Wilkinson, 2017] showed that more than 99% of these bacteria would be 
Non-Typeable Haemophilus influenzae (NTHi). Therefore, the protocol was 
updated to clarify that the presence of Hi bacteria in sputum during exacerbation 
will be used to determine AECOPD associated to NTHi.

The list of potential immune mediated diseases (Table 19) was updated (effective 
June 30th 2017). A list of MedDRA preferred terms for potential immune mediated 
diseases was added as Appendix C.

The FDA reference was removed from the intensity scale for redness/swelling and 
temperature as the reference did not reflect the correct cut-off values for the 
different intensities that will be used in this study. 

A definition for ‘All enrolled set’ was missing in the original protocol. Table and 
listings referring to this cohort will be prepared.

The 87% confidence interval (CI) was removed from all secondary analyses. This 
confidence interval will only be maintained for the primary analysis because the 
95% CIs are underpowered for this study.  All other sensitivity analyses on 
different cohorts will be described using 95% CIs. As the primary objective will 
have both 87% and 95%, the sensitivity analyses can be interpreted with 95% CIs.

‘According-to-Protocol’ was replaced by ‘Per-Protocol Set’ as per current CDISC 
standard for cohorts for analysis. 

A Full-Analysis Set (FAS) that corresponds to an intent-to-treat analysis was 
added. The FAS will include all randomized subjects who will receive at least 1 
vaccine administration and, as per intention-to-treat principle, a subject in the FAS 
will be analysed “as randomized” (i.e. according to the vaccine a subject was 
planned to receive irrespectively of his/her real exposure).
 
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!
Additional minor updates were based on the scientific and operational experience 
gained from current COPD studies. 
!
Correction of some typographical errors. Some sentences were also reworded or 
additions were made for clarity.
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections:
Contributing authors
!
(Oversight Statistician Director Clinical Statistics)
!
(Aixial for GSK Biologicals) (Clinical Trials Supply 
Manager)
Copyright statement
Copyright 2017 the GlaxoSmithKline group of companies. All rights reserved. 
Unauthorised copying or use of this information is prohibited. ©2017 GSK group of 
companies or its licensor.
LIST OF ABBREVIATIONS
ATP:
According-to-protocol
eCOA:
Electronic Clinical Outcome Assessment
FAS:
Full-Analysis Set
PPS:
Per-protocol set
GLOSSARY OF TERMS
Current smoker:
A person who is currently smoking or who stopped 
smoking within the past 6 months before study start.
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.
Study Works:
Secure electronic Clinical Outcome Assessment (eCOA) 
Web-Portal where reports are displayed to investigator 
staff showing data entered on the eCOA devices used by 
subjects (eDiary) and allowing the investigator staff to 
make decisions such as changing the eligibility status of 
the patient on the study.
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Section 1.1.1 Chronic obstructive pulmonary disease and acute exacerbations
Table 1 Classification of severity of AECOPD
Grade
Intensity of medical intervention
Mild
Can be controlled with an increase in dosage of regular medications
Moderate
Requires treatment with systemic corticosteroids and/ or antibiotics
Severe
Requires hospitalisation*
*In general, hospitalisation signifies that the subject has been admitted at the hospital or emergency ward for 
observation and/or treatment for AECOPD that would not have been appropriate in the physician’s office 
or in an out-patient setting.
Section 3 Study design overview
Figure 2
Study design overview
S = Screening Visit; V = Visit; PC = Phone contact; D = Day; FU = Follow-up; BS (1) = blood sample for humoral 
immunogenicity; BS (2) = blood sample for cell-mediated immunogenicity (CMI), this blood sample will only be 
collected from a sub-cohort of subjects; BS (3) blood sample for biomarkers; SP = sputum sample
The allowed maximum interval between Screening Visit and Visit 1 is 29 days. If a delay occurs for an eligible subject 
so that the interval exceeds 29 days, some study procedures performed during the entire Screening Visit 
needs to be repeated within 7 days (see Table 6 for more details).
* An AECOPD visit should be scheduled as soon as possible after the onset of AECOPD symptoms (max 96 hours 
after and, if applicable, preferably before starting treatment with antibiotics). During this visit blood and sputum 
samples will be collected. In addition, follow-up phone call(s) and/or visit(s) will take place to determine the end of 
the AECOPD. These contacts will take place at least every 2 weeks until the AECOPD is resolved.
 
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
COPD symptoms: All subjects will be asked to record COPD symptoms in their 
electronic Diary Card:

Daily in the morning throughout the study (including during AECOPD): 
morning symptoms questionnaire. 

Daily in the evening throughout the study (including during AECOPD): 
EXACT-PRO questionnaire. 
Section 4.1 Detection of AECOPD

If the investigator concludes that the subject is not experiencing an AECOPD, this 
should be documented/ reported in the eCRF Study Works (Web portal). Please refer 
to study procedures manual (SPM) for more details on how to perform this.
The site must engage their best efforts to reach the patients, however, if the site does not 
succeed in contacting the patient, the reason should be recorded and an explanation given 
about what occurred. For example, the subject could be hospitalized or could visit a 
different physician (and in that case medical records should be obtained), or the subject is 
on holidays or not able to go to the site.
If an AECOPD occurs at the time of a scheduled study visit and if the minimum 7 day 
interval between AECOPD visit and the scheduled study visit will result in a scheduled 
study visit falling outside of the allowed interval, the AECOPD visit can be scheduled 
within 7 days before the scheduled study visit., it should be handled and recorded as an 
AECOPD visit, with all relevant study procedures done during AECOPD-driven study 
visits performed and, if possible, the scheduled visit should be re-scheduled to a later 
date within the time window specified in the protocol.
Some subjects may have been supplied with a prescription for antibiotics and/or 
steroids for treatment of AECOPD to use according to instructions provided by their 
physician in the event of an AECOPD occurring at a future date. During the course of 
this study, following an eDiary alert for potential AECOPD or other contact for 
potential AECOP, the investigator should make all possible efforts to ensure contact 
with the patient prior to the patient self-administering any antibiotics or steroids for 
their potential AECOPD. To manage situations where this prior contact cannot occur 
the investigator should use their clinical judgement.
Section 4.1.1. Date of onset and end date of AECOPD
Per inclusion criteria, the subject should be a stable COPD patient (i.e. a subject for 
whom the last episode of AECOPD is resolved for at least 30 days at the time of 
Screening). This effectively sets the baseline for evaluating the symptoms stated within 
the Anthonisen criteria (see Section 4.1). The date of onset of AECOPD is the first day 
(of at least 2 consecutive days) of worsening symptoms of COPD as determined by the 
investigator according to the Anthonisen criteria. For example, worsening of dyspnoea, 
sputum volume and sputum purulence is evaluated daily by the patient relative to this 
baseline. For an AECOPD confirmed by the investigator following an eDiary alert the 
onset date is considered to be the first day of 2 consecutive days that the patient enters 
symptoms meeting the Anthonisen criteria. Each day that there is no new symptom 
 
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effectively becomes the new baseline. Once the Anthonisen criteria are met, an eDairy 
alert is triggered. If the investigator determines this to be an AECOPD, that event is 
recorded via the eCRF. Subsequently, the investigator will follow the patient via phone 
contact (or clinic visit) at least every 2 weeks until resolution of this event.
Section 5.3 Exclusion criteria

Diagnosed with a respiratory disorder other than COPD at time of enrolment (such as 
sarcoidosis, active tuberculosis, clinically significant bronchiectasis, clinically 
significant lung fibrosis, clinically significant pulmonary embolism, clinically 
significant pneumothorax, current diagnosis of asthma in the opinion of the 
investigator), or chest X-ray/ CT scan revealing evidence of clinically significant 
abnormalities not believed to be due to the presence of COPD. Subjects with allergic 
rhinitis do not need to be excluded and may be enrolled at the discretion of the 
investigator. 

Contraindication for spirometry testing (such as recent eye surgery, recent thoracic 
or abdominal surgery procedures, unstable cardiovascular status, recent myocardial 
infection infarction or pulmonary embolism).
Section 6.2.2.1 Randomisation of supplies
The randomisation of supplies within blocks will be performed at GSK Biologicals, using 
MATerial EXcellence (MATEX), a program developed for use in Statistical Analysis 
System (SAS®) (Cary, NC, USA) by GSK Biologicals. Entire blocks will be shipped to 
the study centres /warehouse(s). 
Section 6.2.2.2.1 Study group and treatment number allocation
The target will be to enrol approximately 600 eligible subjects who will be randomly 
assigned to two study groups in a (1: 1) ratio (approximately 300 subjects in each group).
Allocation of the subject to a study group at the investigator site will be performed using 
a randomisation system on internet (SBIR). The randomisation algorithm will use a 
minimisation procedure accounting for age (40 - 59 years or 60 - 80 years), number of 
moderate/ severe AECOPD in the previous year (< 2 or ≥2), GOLD grade (GOLD 2, 
GOLD 3 or GOLD 4) and country. Minimisation factors will have equal weight in the 
minimisation algorithm.
Details on the minimisation algorithm are reported in the statistical analysis plan.
 
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Section 6.5 outline of study procedures
Table 6
List of study procedures
Epoch
Epoch 001
Epoch 002
Type of contact
Screening 
Visit (a)
Visit 1
Phone 
contac
t 1 (k)
Visit 2
Visit 3
Phone 
contact 
2 (k)
Visit 4 Visit 5 Visit 6
Visit 7
Visit 
8
Timepoint
pre-Day 1
Day 1
Day 8
Day 
31
Day 61
Day 68
Day 
91
Day 
181
Day 
271
Day 361 Day 
451
Sampling timepoint
Screening Pre-Vacc 1
Post-Vacc 1
Pre-Vacc 2
Post-Vacc 2
Informed consent 
●
Check inclusion/exclusion criteria 
●
O
Record of moderate and severe AECOPD within the previous year 
O
●
Check subject's COPD status 
●
●
●
●
●
●
●
●
●
●
Record demographic data 
●
Record medical history, including significant comorbidities 
O
●
Vaccination history 
O
●
Smoking exposure history (ATS-DLD-78A questionnaire) 
x
Smoking status 
●
●
●
Physical examination 
●
O
O
O
O
O
O
O
O
Measure/record height and weight 
●
O
●
Pre- and post-bronchodilator spirometry (l)
x (b)
x
x
Chest X-ray (d)
● (b)
Pregnancy test   (c)
● (b)
●
●
Blood sampling:
  For humoral immunogenicity (~20 ml of blood) 
●
●
●
●
●
●
  For CMI (~40 ml of blood)  (e)
●
●
●
●
  For biomarkers, serum and plasma (~13 ml of blood)  
●
●
  For biomarker, haematology profile (~2 ml of blood)
●
Sputum sampling (f)
●
●
●
●
●
●
Check contraindications to vaccination 
O
O (g)
Record pre-vaccination body temperature 
●
●
Study group and Treatment number allocation with randomisation 
●
●
Vaccination 
●
●
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Epoch
Epoch 001
Epoch 002
Type of contact
Screening 
Visit (a)
Visit 1
Phone 
contac
t 1 (k)
Visit 2
Visit 3
Phone 
contact 
2 (k)
Visit 4 Visit 5 Visit 6
Visit 7
Visit 
8
Timepoint
pre-Day 1
Day 1
Day 8
Day 
31
Day 61
Day 68
Day 
91
Day 
181
Day 
271
Day 361 Day 
451
Sampling timepoint
Screening Pre-Vacc 1
Post-Vacc 1
Pre-Vacc 2
Post-Vacc 2
Train subject on the use of electronic Diary Card and assign electronic 
Diary Card to subject 
O
Distribute electronic Diary Card for recording of local and general AEs, 
medication and vaccination, morning and evening COPD symptoms 
O
Collection of electronic Diary Card data (h)
x
x
x
x
x
x
x
x
x
x
Distribution of Subject Card 
O
Record AEs (i)
●
●
●
●
●
●
●
●
●
●
Record SAEs (i)
●(b)
●
●
●
●
●
●
●
●
●
●
Record pregnancies (i)
●
●
●
●
●
●
●
●
●
●
Record pIMDs (i)
●
●
●
●
●
●
●
●
●
●
Record concomitant medication/products and vaccination 
O
●
●
●
●
●
●
●
●
●
●
Record intercurrent medical conditions 
●
●
●
●
●
●
●
●
●
Return electronic Diary Card 
O (j)
O (j)
O
HRQOL questionnaires:
  CAT 
x
x
x
  SGRQ-C 
x
x
x
Healthcare Resource Utilisation 
●
●
●
●
●
●
●
●
●
●
Screening conclusion 
●
Study Conclusion 
●
D = Day; Vacc = vaccination. PC = Phone contact; CAT = COPD assessment test; SGRQ-C = St. George’s Respiratory Questionnaire for COPD patients; AECOPD = Acute 
exacerbation of chronic obstructive pulmonary disease; COPD = chronic obstructive pulmonary disease; CMI = cell-mediated immunity; AE = adverse event; SAE = serious 
adverse event; pIMDs = potential immune mediated diseases; HRQOL = health-related quality of life.
● 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; x is used to indicate a study procedure that does not require documentation in the individual eCRF as the data will be directly transferred from the provider to 
GSK.
a If needed, the Screening Visit(s) can be done in more than one 1 day. All screening procedures with the exception of eDiary training should be performed within 7 days from 
1st screening visit. The allowed maximum interval between 1st Screening Visit and Visit 1 is 29 days. If a delay occurs for an eligible subject so that the interval exceeds 29 days, 
the entire some study procedures performed during Screening Visit(s) needs to be repeated (see footnote b). In case of AECOPD occurring before Visit 1, subjects 
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should be treated outside the study according to standard practice. These subjects are considered screening failures. They will need to sign a new ICF, will receive a 
new subject number and will need to repeat the entire Screening Visit after they are stable for at least 30 days. The entire Screening Visit can only be repeated once. 
Once subject is determined as eligible, the eDiary for completion from Day -14 to Day -1 will be given to the subject for a training period of maximum 14 days before Visit 1 
(see Section 6.9.22).
b Screening failures could be due to the following reasons: 1) Visit 1 done more than 29 days after the Screening Visit. 2) In case of AECOPD occurring before Visit 1, subjects should 
be treated outside the study according to standard practice. These subjects can only continue in the study if the entire Screening Visit is repeated after they are stable for at least 
30 days. 3) Procedures indicated by this footnote need to be repeated If the subject has any medical condition (e.g. fever) that prevents his/her participation in the study within 
29 days of Screening Visit. In that case of screening failure, a re-Screening Visit may must be scheduled as soon as possible and no more than 7 days from Day 29 (Day 30 -
Day 36) during which the procedures indicated by this footnote need to be repeated. Same as for the initial screening, the chest X-ray only has to be redone if no chest X-
ray/ CT scan is available within the last 3 months. Data obtained during re-screening procedures should be entered in the eCRF. 
c Pregnancy tests will be performed on all females of childbearing potential in case a chest X-ray will be performed. The pregnancy test should be carried out prior to the chest X-ray 
and if a subject has a positive pregnancy test the chest X-ray should not be performed and the subject will be deemed not eligible for the study. Please also refer to Section
10.2.2. This pregnancy test should be repeated before vaccination at Visit 1 and Visit 3 (including those female subjects of childbearing potential who did not have a pregnancy 
test at screening because an X-ray/ CT scan was available within the last 3 months).
d Only if no chest X-ray/ CT scan available within the last 3 months.
e Only for subjects in the sub-cohort for CMI.
f Only if, in the opinion of the investigator, it is safe for the subject. Sputum samples can be either spontaneous or induced, as per investigator judgement. 
g Refer to Section 7.5 for more details on study procedures for subjects meeting contraindications to subsequent vaccination before administration of vaccine Dose 2.
h  The following information will be collected with the electronic Diary Card: COPD morning and evening symptoms (including EXACT-PRO questionnaire), smoking exposure history, 
local and general solicited AEs and Healthcare utilisation.
i Please refer to Table 20 for recording periods of local and general solicited AEs, AEs/SAEs leading to study withdrawal, SAEs, pregnancies and pIMDs. Solicited AEs will be 
collected up to Day 7 post- vaccination. Solicited AEs ongoing at Day 7 will be followed up until resolution (for a maximum of 30 Days). Unsolicited AEs will be 
collected for 30 days after each vaccination and thereafter only AEs leading to Withdrawal.
j Only for Screening failures.
k The safety phone call at Day 8 and Day 68 can be performed by the (sub)-investigator or a medically trained delegate. 
lIf a good quality spirometry was not obtained, the spirometry can be repeated within 7 days, as per investigator medical judgement.
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Section 6.6 List of study procedures during AECOPD-driven study visits and phone 
contacts
In addition to the scheduled study visits, ad hoc AECOPD-driven study contacts will take 
place for each AECOPD occurring from first vaccination up to study conclusion. The 
procedures to be performed during these contacts are listed in Table 7. 
In case of AECOPD occurring before Visit 1, subjects should be treated outside the study 
according to standard practice. These subjects can only continue in the study if are 
considered screening failures. They will need to sign a new ICF, will receive a new 
subject number and will need to repeat the entire Screening Visit is repeated after they 
are stable for at least 30 days.
Table 7 List of study procedures during AECOPD-driven study visits and phone 
contacts
Type of contact
AECOPD visit
End of AECOPD contact(s)
(phone call[s7 and/ or visit[s)
Timepoint
within 96 hours of 
onset symptoms
at least every 2 weeks from the 
AECOPD visit until AECOPD 
has resolved 1
Sampling timepoint
AECOPD
Record date of visit 
●
Physical examination 
O
O 2
Chest X-ray 3
●
Pregnancy test 4
●
Confirm AECOPD and record its start date 
●
Blood sampling:
  For humoral immunogenicity (~5 ml of blood) 
●
  For biomarkers, serum and plasma (~13 ml of blood) 
●
Sputum sampling 5
●
HRQOL questionnaire:
  CAT 
x
  SGRQ-C 
x
Healthcare Resource Utilisation 8
●
●
Record AEs 6
●
●
Record SAEs 6
●
●
Record pregnancies 6
●
●
Record pIMDs 6
●
●
Record concomitant medication/products and vaccination 
●
●
Record intercurrent medical conditions 
●
●
Record AECOPD severity 
O
●
Record AECOPD end date 
●
● 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.
x is used to indicate a study procedure that does not require documentation in the individual eCRF as the data will be 
directly transferred from the provider to GSK.
AECOPD = Acute exacerbation of chronic obstructive pulmonary disease; HRQOL = health-related quality of life; CAT
= COPD assessment test; SGRQ-C = St. George’s Respiratory Questionnaire for COPD patients; AEs = adverse 
events; SAEs = serious adverse events; pIMDs = potential immune mediated diseases.
1 End of AECOPD phone calls/ visits should be scheduled at least every 2 weeks, until the AECOPD has resolved. 
Only the contact during which the end date of the AECOPD can be determined will be recorded in the eCRF as 
the end of the AECOPD contact. All intermediate contacts should be recorded on source documentation. 
2 Only applicable if the contact is a visit (not for phone calls). 
 
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3 Only if clinically indicated to exclude another cause of worsening of symptoms (e.g. pneumonia). 
4 Pregnancy test will be performed on females of childbearing potential at each visit where a chest X-ray is performed. 
The pregnancy test should be carried out prior to the chest X-ray and if a subject has a positive pregnancy test 
the chest X-ray should not be performed and the subject must not receive further study vaccinations. Please also 
refer to Section 10.2.2. 
5 Only if, in the opinion of the investigator, it is safe for the subject. Sputum samples can be either spontaneous or 
induced, as per investigator judgement. Self-collection of the sputum sample will be allowed in specific cases, 
where the first dose of antibiotics absolutely needs to be taken before an AECOPD visit can take place. As much 
as possible, the sputum sample collection should happen during the visit at investigator site. Self-collection is not 
allowed at scheduled visits when the subject should be in stable condition. See Section 6.9.15.2.  
6 Please refer to Table 20 for recording periods of local and general solicited AEs, unsolicited AEs, AEs/SAEs leading 
to study withdrawal, SAEs, pregnancies and pIMDs.
7 The phone call to determine the end of AECOPD contact should be performed by the (sub)-investigator. Delegation to 
study staff should be agreed with the Sponsor. 
8 The AECOPD visit does not need to be recorded as a Healthcare Resource Utilisation.
Section 6.7 Concurrence of AECOPD-driven study visits and scheduled study visits 
If an AECOPD occurs at the time of a scheduled study visit, it should be handled and 
recorded as an AECOPD visit, with all relevant study procedures done during AECOPD-
driven study visits performed and, if possible, the scheduled visit should be re-scheduled 
to a later date within the time window specified in the protocol.
Section 6.8 Intervals between study visits
Whenever possible, the investigator should arrange study visits within the interval 
described in Table 8.
 
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Table 8 
Intervals between study visits
Interval
Optimal length of interval
Allowed interval
Scheduled study visits
Screening Visit* Visit 1 
NA 14 days
14 6 - 29 days
Visit 1  Phone contact 1 
7 days
7 - 9 days
Visit 1  Visit 2 
30 days
30 - 45 days
Visit 1 Visit 3 
60 days
60 - 75 days 1
Visit 3 Phone contact 2 
7 days
7 - 9 days
Visit 3 Visit 4 
30 days
30 - 45 days 1
Visit 4    Visit 5 
90 days
90 - 120 days
Visit 4  Visit 6 
180 days
180- 210 days
Visit 4 Visit 7 
270 days
270 - 300 days
Visit 4   Visit 8 
360 days
360 - 390 days
AECOPD-driven study visit(s) and/ or phone contacts
Onset of AECOPD symptoms as recorded in the electronic 
Diary Card or confirmed by the subject AECOPD Visit
NA
max 96 hours 2
Interval between AECOPD Visit and scheduled study visit
AECOPD visit scheduled study visit
NA
min 7 days 3
PC = phone contact; AECOPD = Acute exacerbation of chronic obstructive pulmonary disease; NA = Not applicable
1 Subjects will not be eligible for inclusion in the according-to-protocol (ATP) cohort Per Protocol Set for analysis of 
immunogenicity if they make the study visit outside this interval.
2 AECOPD visits will be scheduled as soon as possible after the onset of AECOPD symptoms as recorded in the 
electronic Diary Card or confirmed by the subject (maximum 96 hours after and, if applicable, preferably before 
starting treatment with antibiotics).
3If an AECOPD occurs at the time of a scheduled study visit, and if the minimum 7 day interval between AECOPD visit 
and the scheduled study visit will result in a scheduled study visit falling outside of the allowed interval, the 
AECOPD visit can be scheduled within 7 days before the scheduled study visit. it should be handled and 
recorded as an AECOPD visit, with all relevant study procedures done during AECOPD-driven study visits 
performed and, if possible, the scheduled visit should be re-scheduled to a later date within the time 
window specified in the protocol.
* In case of a re-Screening Visit, the visit must be scheduled as soon as possible and no more than 7 days 
from Day 29 (Day 30 - Day 36).
Section 6.9.5 Collect demographic data
Record demographic data such as year of birth, sex, race and ethnicity in the subjects’ 
eCRF.
Differences in the safety and efficacy of certain medical products, including vaccines 
[Haralambieva, 2013; Pérez-Losada, 2009; Kollmann, 2013], have been observed in 
racially and ethnically distinct subgroups. These differences may be attributable to 
intrinsic factors (e.g. genetics, metabolism, elimination), extrinsic factors (e.g. diet, 
environmental exposure, sociocultural issues), or interactions between these factors. 
Therefore, both race and ethnicity will be collected for all subjects participating in the 
NTHI MCAT-002 study.
Section 6.9.12 Pre- and post-bronchodilator spirometry
Spirometry will be performed using techniques that meet published standards [NICE, 
2010] following the eResearchTechnology (ERT) instructions for use FlowScreen
manual and following all safety requirements.
 
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A good quality spirometry should be obtained, and will be confirmed by the spirometry 
provider. If a good quality spirometry was not obtained, the spirometry can be repeated 
within 7 days, as per investigator medical judgement. The data will be directly 
transferred from the provider to GSK Biologicals.
Section 6.9.15.1. Blood samples
Blood samples for humoral immunogenicity
A volume of approximately 20 mL of whole blood should be drawn from all subjects at 
Visit 1, Visit 2, Visit 3, Visit 4, Visit 6 and Visit 8. A volume of approximately 5 mL of 
whole blood should be drawn from all subjects at each AECOPD visit from first 
vaccination to study conclusion. After whole blood processing into serum, serum samples 
should be kept at ≤-20°C/-4°F or any temperature below until shipment.
Section 6.9.21. Recording of AEs, SAEs, pregnancies and pIMDs

At Screening visit, electronic Diary Cards will be distributed to the subject. The 
subject will be instructed to measure and record the oral or axillary body 
temperature, and any solicited local/general AEs (i.e. on the day of vaccination and 
during the next 6 days). Any solicited AE ongoing after Day 7 will be collected in 
the eDiary until resolution (for a maximum of 30 days).
Section 6.9.24 Healthcare Resource Utilisation
Healthcare use for each COPD patient will be obtained through review of the subject’s 
medical record (aided by subject self-reporting). Healthcare Resource Utilisation includes 
all unscheduled visits to a physician office, visits to urgent care, visits to emergency
department, and hospitalizations. Healthcare use should be entered recorded in eDiary
and reported in the eCRF at study visit. Refer to the SPM for more details and guidance 
on recording of Healthcare Resource Utilisation.
Section 6.10.3. Laboratory assays
Table 10
Humoral Immunity (Antibody determination)
System
Component
Method
Kit / 
Manufacturer
Unit*
Cut-off*
Laboratory
SERUM
anti-PD 
antibody 
ELISA
In house
EU/ml 
153 
GSK Biologicals** or 
GSK designated 
laboratory
anti-PE 
antibody 
8 25
anti-PilA 
antibody 
7 16
anti-UspA2 
IgG antibody 
18 38
EU/ml = ELISA unit per millilitre
* Assay cut-off and unit might be subject to change during the course of the study (e.g. in case of assay re-
optimization, qualification, (re)validation or standardization). In this case, this will be documented in the clinical 
study report.
** GSK Biologicals laboratory refers to the Clinical Laboratory Sciences (CLS) in Rixensart, Belgium; Wavre, Belgium; 
Marburg, Germany.
 
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Table 11
Cell-Mediated Immunity (CMI)
System
Component
Scale
Method
Unit
Laboratory
PBMCs
Specific CD4+/CD8+ T-
cells
Quantitative
Flow 
cytometry ICS
Number of specific 
CD4+/CD8+ T-cells /106
GSK 
Biologicals* or 
GSK 
designated 
laboratory
PBMC = peripheral blood mononuclear cell; ICS = intracellular cytokine staining
* GSK Biologicals laboratory refers to the Clinical Laboratory Sciences (CLS) in Rixensart, Belgium; Wavre, Belgium;
Marburg, Germany. 
Additional vaccine antigen-specific CD8+ T-cells data will be generated on peripheral 
blood mononuclear cells (PBMCs) in context of the specific CD4+ T cell data 
generation by ICS. 
The quality of sputum samples will be assessed at the investigator’s institution and/ or at 
a laboratory designated by GSK Biologicals by Gram staining.
Identification and semi-quantitative assessment of potential bacterial pathogens will be 
performed on fresh sputum samples using conventional bacteriological methods at the 
investigator’s institution and/ or at a laboratory designated by GSK Biologicals on a 
subset of subjects (50% of subjects) according to local laboratory procedures and agreed 
identification methods (potential pathogens including, but not necessarily limited to 
identification of H. influenzae, S. pneumoniae, M. catarrhalis, S. aureus and 
P. aeruginosa).
Identification of potential bacterial pathogens (including, but not necessarily limited 
to, H. influenzae, S. pneumoniae, M. catarrhalis, S. aureus, P. aeruginosa and 
Streptococcus pyogenes [S. pyogenes) and quantification (for H. influenzae, 
S. pneumoniae, M. catarrhalis) on frozen sputum samples will be performed at GSK 
Biologicals’ laboratory or a laboratory designated by GSK Biologicals using qualified 
molecular methods such as multiplex RT real time PCR and/ or quantitative PCR 
(qPCR).
Further bacterial characterisation on frozen isolates of H. influenzae and/or M. 
catarrhalis will be done at GSK Biologicals' laboratory or at a laboratory designated by 
GSK Biologicals using either standard agglutination techniques or molecular tools, such
as PCR, microarray serotyping and/or sequencing.
Viral pathogen identification (including, but not necessarily limited to, respiratory 
syncytial virus, parainfluenza virus, enterovirus/ rhinovirus, metapneumovirus, influenza 
virus, adenovirus, bocavirus and coronavirus) on frozen sputum samples will be 
performed using multiplex PCR at GSK Biologicals' laboratory or at a laboratory 
designated by GSK Biologicals using qualified standardised and optimized procedures. 
In addition, viral pathogens (such as enterovirus/rhinovirus) in frozen sputum samples
will be quantified on all samples or a subset of samples (i.e. enterovirus/rhinovirus-
positive sputum samples) using qPCR at GSK Biologicals' laboratory or at a laboratory 
designated by GSK Biologicals using qualified standardised and optimised procedures.
 
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Table 12
Sputum assessments
Number of subjects
Group Visit no.
Pathogen to identify
Type of sample
Method
Testing Laboratory
Quality assessment
~600
Both
1
4
5
6
7
8
AECOPD 
visits
Please refer to SPM 
and/or Central Laboratory 
Manual for components 
tested
Fresh sputum
Gram staining
Investigator institution or GSK 
designated laboratory
Bacterial pathogen identification
~300*
Both
1
4
5
6
7
8
AECOPD 
visits
H. influenzae 
Fresh sputum
Standard bacteriological identification methods and 
semi-quantitative counts assessment.
Investigator institution or GSK 
designated laboratory
Isolate
Sequencing
GSK Biologicals’ ** or designated 
laboratory
Hi vs H. haemolyticus discriminationH. influenzae 
species confirmation and when possible Hi/NTHi 
differentiation by PCR
GSK Biologicals’ ** or designated 
laboratory
M. catarrhalis
Fresh sputum
Standard bacteriological identification methods and 
semi-quantitative counts assessment.
Investigator institution or GSK 
designated laboratory
Isolate 
Sequencing
GSK Biologicals’ laboratory** or 
designated laboratory
S. pneumoniae, 
P. aeruginosa, S. aureus, 
other potential pathogen
Fresh sputum
Standard bacteriological identification methods and 
semi-quantitative counts assessment.
Investigator institution or GSK 
designated laboratory
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Number of subjects
Group Visit no.
Pathogen to identify
Type of sample
Method
Testing Laboratory
~600
Both
1
4
5
6
7
8
AECOPD 
visits
H. influenzae***, 
M. catarrhalis, 
S. pneumoniae
Frozen sputum
Multiplex bacterial pathogen quantitative PCR assay GSK Biologicals’ ** or designated 
laboratory
S. aureus, Group A 
streptococci, 
P. aeruginosa
Multiplex bacterial pathogen qualitative PCR assay
Viral pathogen identification
~600
Both
1
4
5
6
7
8
AECOPD 
visits
Respiratory viral 
pathogens 
(including respiratory 
syncytial virus, 
parainfluenza virus, 
enterovirus/, rhinovirus, 
metapneumovirus, 
influenza virus, 
adenovirus, bocavirus 
and coronavirus)
Frozen sputum
Multiplex viral pathogen qualitative PCR assay
GSK Biologicals** or designated 
laboratory
~600 or Subset 
(enterovirus/rhinovirus
positive samples)
Both
Rhinovirus
Frozen sputum
quantitative PCR assay
GSK Biologicals** or designated 
laboratory
Biomarker identification and quantification
Patients not in culture 
subset*
Both
1
4
5
6
7
8
AECOPD 
visits
Inflammatory cytokines 
(such as TNF-α, IL-1, IL-
8, IL-6)
Frozen sputum
Quantitative ELISA, multiplex CBA, ECL or PCR 
assays
GSK Biologicals** or designated 
laboratory
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AECOPD = Acute exacerbation of chronic obstructive pulmonary syndrome; SPM = Study Procedures Manual; H. influenzae and Hi = Haemophilus influenzae; M. catarrhalis = 
Moraxella catarrhalis; H. haemolyticus = Haemophilus haemolyticus; PCR = Polymerase Chain Reaction; S. pneumoniae = Streptococcus pneumoniae; S. aureus = 
Staphylococcus aureus; TNF = Tumor Necrosis Factor; IL = Interleukin; ELISA = Enzyme Linked Immunosorbant Assay; CBA = Cytometric bead assay; ECL = 
Electrochemiluminescence.
*Testing will only be performed on a subset of 50% of the subjects.
**GSK Biologicals laboratory refers to the pre-clinical team or the Clinical Laboratory Sciences (CLS) in Rixensart, Belgium; Wavre, Belgium; Marburg, Germany.
***The PCR assay can detect and quantify Hi in sputum samples. It can be assumed that more than 99% of H. influenzae isolates in sputum (derived from lung) are non-
typeable (NTHi) [Wilkinson, 2017] and thus the presence of Hi bacteria in sputum during exacerbation will be used to determine AECOPD associated to NTHi.
Sputum samples might also be used for assay development, such as assays for diagnostic purposes or for microbiome analysis.
Additional testing on frozen sputum samples (such as, but not limited to, qPCR for other bacterial and/or viral pathogens, quantitative 
serotype-specific PCR, microarray typing, sequencing, 16S RNA for microbiome analysis, presence (and/or concentration) of 
inflammatory cytokines) may be done during the study or after study completion, should these data be required for accurate interpretation 
of the study data and/ or for further research related to the investigational vaccine and/ or to respiratory diseases, should such test(s) 
become available at GSK Biologicals’ laboratory or a laboratory designated by GSK Biologicals.
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Section 6.10.4.1 Immunological read-outs
Table 14
Immunological read-outs
Blood sampling timepoint
Sub-cohort 
Name
No. subjects
Component
Type of contact and 
timepoint
Sampling 
timepoint
Visit 1 (Day 1)
Pre-Vacc 1
All enrolled 
subjects
~600
Anti-PD, Anti-PE, Anti-PilA and Anti-
UspA2
Fibrinogen, hsCRP, IP-10 and 
haematology profile*
Sub-cohort for 
CMI 
~120
Specific CD4+/CD8+ T-cell
Visit 2 (Day 31)
Post-Vacc 1
All enrolled 
subjects
~600
Anti-PD, Anti-PE, Anti-PilA and Anti-
UspA2
Visit 3 (Day 61)
Pre-Vacc 2
All enrolled 
subjects
~600
Anti-PD, Anti-PE, Anti-PilA and Anti-
UspA2
Visit 4 (Day 91)
Post-Vacc 2
All enrolled 
subjects
~600
Anti-PD, Anti-PE, Anti-PilA and Anti-
UspA2
Sub-cohort for 
CMI
~120
Specific CD4+/CD8+ T-cell
Visit 6 (Day 271)
Post-Vacc 2
All enrolled 
subjects
~600
Anti-PD, Anti-PE, Anti-PilA and Anti-
UspA2
Sub-cohort for 
CMI
~120
Specific CD4+/CD8+ T-cell
Visit 8 (Day 451)
Post-Vacc 2
All enrolled 
subjects
~600
Anti-PD, Anti-PE, Anti-PilA and Anti-
UspA2
Fibrinogen, hsCRP and IP-10
Sub-cohort for 
CMI 
~120
Specific CD4+/CD8+ T-cell
During each AECOPD visit from first 
vaccination to study conclusion
All enrolled 
subjects
-
Anti-PD, Anti-PE, Anti-PilA and Anti-
UspA2
Fibrinogen, hsCRP and IP-10
hsCRP = high-sensitivity C-reactive protein, CMI = cell-mediated immunogenicity, IP-10 = interferon gamma-induced 
protein 10.
*Including: WBC, neutrophils, eosinophils, lymphocytes, basophils, monocytes, RBC, haemoglobin and platelets.
Section 7.6 Concomitant medications/products and concomitant vaccination
At each study visit/contact, the investigator or delegate should question the subject about 
any medications/products taken and vaccinations received by the subject (including 
standard medication taken before first vaccination collected at Screening and/or at 
Visit 1). This includes the subject’s COPD medication.
 
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Section 9.1.5.1. Potential immune-mediated diseases
Table 19
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/cardiomyopathySarcoidosis

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
Neuroinflammatory disorders
Musculoskeletal disorders
Skin disorders

Cranial nerve neuropathy, 
including paralysis and 
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.

Demyelinating peripheral 
neuropathies including:
-
Chronic inflammatory 
demyelinating 
polyneuropathy, 
-
Multifocal motor 
neuropathy 
-
Polyneuropathies 
associated with 
monoclonal 
gammopathy.

Narcolepsy.

Systemic lupus 
erythematosus and 
associated conditions

Systemic scleroderma 
(Systemic sclerosis), 
including:
-
Diffuse Scleroderma
-
CREST syndrome

Idiopathic inflammatory 
myopathies, including:
-
Dermatomyositis 
-
Polymyositis 

Anti-synthetase syndrome.

Rheumatoid Arthritis and 
associated conditions 
including: 
-
Juvenile Idiopathic 
Arthritis
-
Still’s disease.

Polymyalgia rheumatica.

Spondyloarthropathies,
including: 
-
Ankylosing 
Spondylitis, 
-
Reactive Arthritis 
(Reiter's Syndrome),
-
Undifferentiated 
Spondyloarthritis,
-
Psoriatic Arthritis,
-
Enteropathic arthritis.

Relapsing Polychondritis.

Mixed Connective Tissue 
disorder.

Gout.

Psoriasis.

Vitiligo.

Erythema nodosum.

Autoimmune bullous skin 
diseases (including 
pemphigus, pemphigoid and 
dermatitis herpetiformis).

Lichen planus.

Sweet’s syndrome.

Localised Scleroderma 
(Morphoea).
 
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Vasculitis
Blood disorders
Others

Large vessels vasculitis 
including: 
-
Giant Cell Arteritis 
(Temporal Arteritis),
-
Takayasu's Arteritis. 

Medium sized and/or small 
vessels vasculitis including: 
-
Polyarteritis nodosa,
-
Kawasaki's disease, 
-
Microscopic 
Polyangiitis, 
-
Wegener's 
Granulomatosis 
(granulomatosis with 
polyangiitis), 
-
Churg–Strauss 
syndrome (allergic 
granulomatous angiitis
or eosinophilic 
granulomatosis with 
polyangiitis), 
-
Buerger’s disease 
(thromboangiitis 
obliterans), 
-
Necrotizing vasculitis 
(cutaneous or 
systemic), 
-
anti-neutrophil 
cytoplasmic antibody 
(ANCA) positive 
vasculitis (type 
unspecified),
-
Henoch-Schonlein 
purpura (IgA vasculitis), 
-
Behcet's syndrome,
-
Leukocytoclastic 
vasculitis.

Autoimmune hemolytic 
anemia.

Autoimmune 
thrombocytopenia.

Antiphospholipid 
syndrome.

Pernicious anemia.

Autoimmune aplastic 
anemia.

Autoimmune neutropenia.

Autoimmune pancytopenia.

Autoimmune 
glomerulonephritis including:
-
IgA nephropathy, 
-
Glomerulonephritis 
rapidly progressive, 
-
Membranous 
glomerulonephritis, 
-
Membranoproliferative 
glomerulonephritis, 
-
Mesangioproliferative 
glomerulonephritis. 
-
Tubulointerstitial 
nephritis and uveitis 
syndrome.

Ocular autoimmune diseases 
including:
-
Autoimmune uveitis 
-
Autoimmune retinitis.

Autoimmune myocarditis.

Sarcoidosis.

Stevens-Johnson syndrome.

Sjögren’s syndrome.

Alopecia areata.

Idiopathic pulmonary fibrosis.

Goodpasture syndrome.

Raynaud’s phenomenon.
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 
(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.
 
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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 as presented in Appendix C.
The list of PTs was created using MedDRA version 20.1.
Section 9.3.3.2.1. Assessment of intensity
The maximum intensity of local injection site redness/swelling will be scored at GSK 
Biologicals using GSK Biologicals’ standard the following grading scale: based on the 
US Food and Drug Administration (FDA) guidelines for Toxicity Grading Scale for 
Healthy Adult and Adolescent Volunteers enrolled in Preventive Vaccine Clinical Trials” 
[FDA, 2007].
0 : < 20 mm diameter
1 : 20 mm to 50 mm diameter
2 : > 50 mm to 100 mm diameter
3 : > 100 mm diameter
Temperature (in this study preferred location to measure the temperature is oral cavity or 
axilla) will be scored as follows:
0 : < 37.5°C
1 : 37.5°C to 38.07.9°C
2 : 38.10°C to 39.08.9°C
3: ˃≥39.0°C
Section 11.2 Secondary endpoints 
Immunogenicity and CMI:
NTHi-specific and Mcat- specific cell-mediated immune responses as measured by flow 
cytometry ICS (frequency of specific CD4+/CD8+ T-cells expressing two or more 
markers, such as interleukin (IL)-2, IL-13, IL-17, interferon gamma (IFN-γ), tumour 
necrosis factor alpha (TNF-α), and CD40 ligand (CD40L) at Day 1, Day 91, Day 271 and 
at Day 451, in a sub-cohort of subjects.
Section 11.3 Tertiary endpoint
Biomarkers:

Concentration of selected biomarkers (fibrinogen, hsCRP and IP-10), at Day 1 and 
Day 451, and for each AECOPD visit from first vaccination to study conclusion and 
haematology profile at Visit 1. 
 
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Section 11.5.1 All enrolled set 
All subjects who will sign the inform consent and for whom a subject number is 
assigned.
Section 11.5.4 Per-protocol set for analysis of immunogenicity
The according-to-protocol (ATP) Per-protocol set (PPS) cohort for immunogenicity will 
include all subjects in the TVC:

Who met all eligibility criteria.

For whom the administration of the vaccines was according to protocol.

Who complied with the vaccination schedule, as specified in Table 8.

Who received the study vaccines according to protocol procedures.

Who did not receive a concomitant medication/ product leading to elimination from 
the ATP PPS (per-protocol) analysis for immunogenicity (see Section 7.6.2) up to
the 1 month post-Dose 2 visit (Day 91).

Who did not present an intercurrent medical condition leading to elimination from 
the ATP PPS analysis for immunogenicity (see Section 7.7), up to the 1 month 
post-Dose 2 visit (Day 91).

Who complied with the blood sample timings as specified in Table 8, at the 1 month 
post-Dose 2 visit (Day 91).

For whom post-vaccination immunogenicity results are available for at least 1 assay.
Section 11.5.5 Per-protocol set for analysis of efficacy
The ATP PPS cohort for analysis of efficacy will include all subjects in the TVC:

Who met all eligibility criteria.

For whom the administration of the vaccines was according to protocol.

Who complied with the vaccination schedule, as specified in Table 8.

Who received the study vaccine according to protocol procedures.

Not having received a medication/ product/ vaccine that may lead to elimination 
from the ATP PPS (per-protocol) analysis for efficacy (see Section 7.6.3).
In addition for the Bacteriological efficacy endpoints:

For whom the sputum sample results are available.
Section 11.5.6. Full Analysis set (FAS)
The FAS will include all randomized subjects who will receive at least 1 vaccine 
administration. As per intention-to-treat principle, a subject in the FAS will be 
analysed “as randomized” (i.e. according to the vaccine a subject was planned to 
receive irrespectively of his/her real exposure).
 
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Section 11.6 Derived and transformed data
CMI

The frequency of CD4+ or CD8+ T-cells producing two or more markers (such as 
CD40 Ligand (CD40L), interleukin (IL)-2, IL-13, IL-17, interferon gamma (IFN-γ), 
tumour necrosis factor alpha (TNF-α), upon in vitro stimulation with the antigen 
(induction condition) is presented per million of CD4+ T (CD8+T) cells for the 
analysis and in percent for the graphical representation.

The frequency of antigen-specific CD4+ or CD8+ T-cells for each individual subject 
is calculated as the difference between the frequency of CD4+ or CD8+ T-cells 
producing at least 2 cytokines among IFN-, IL-2, IL-13, IL-17, TNF-and/or 
CD40L, upon in vitro stimulation with the antigen (induction condition) minus the 
frequency of CD4+ or CD8+ T-cells producing at least 2 cytokines upon in vitro 
stimulation in medium only (background condition). 
= Number of antigen-specific CD4+/CD8+ T-cells expressing two or more 
cytokines.

The frequency of CD4+ or CD8+ T-cells expressing a marker (such as interleukin 
(IL)-2, IL-13, IL-17, interferon gamma (IFN-γ), tumour necrosis factor alpha (TNF-
α) upon in vitro stimulation with the antigen (induction condition) is presented per 
million of cells for the analysis and per hundred cells for the graphical 
representation.
Section 11.8 Analysis of efficacy
The primary analysis will be performed on the mTVC and repeated on the TVC and the 
FAS. The primary analysis will also be repeated on the efficacy ATP (per-protocol) 
cohort if the percentage of vaccinated subjects excluded from the ATP cohort for efficacy 
is more than 5%.
Efficacy – Clinical Endpoint
The following incidence rates of AECOPD (any type) occurring from enrolment up to 1 
month post-Dose 2 will be computed together with 87% and 95% CIs, and  incidence 
rates together with VE in the prevention of AECOPD (any type) will be computed over a 
period starting 1 month post-Dose 2 and lasting for 1 year, with 87% and 95% CIs:

All-cause moderate and severe AECOPD (primary endpoint).

All-cause, all-severity AECOPD.

All-cause AECOPD, by severity.
For the primary analysis, the 95% CI will also be reported in order to evaluate the null 
hypothesis at 5% alpha level (2-side).
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Incidence rates of AECOPD (any type)  and VE, together with 87% and 95% CIs, will be 
computed for all study period (starting from day 1 until study termination) and at 3, 6, 9 
and 12 months post-Dose 2, using the same model as for the primary.
As sensitivity analysis using a permutation test will be performed for the primary 
efficacy endpoint. Subjects will be grouped in to homogenous strata (based on the 
covariates and using a clustering procedure or similar methods). Treatment group will be 
permutated within each stratum. Then the negative binomial regression model for the 
number of AECOPD will be applied, for each permutation performed, without covariates 
(only treatment).
Efficacy – Bacteriological Endpoint (PCR)
Similarly, VE in prevention of NTHi and/or Mcat associated AECOPD, over a period 
starting 1 month post-Dose 2 and lasting for 1 year and their 87% and its 95% CIs will be 
computed, with the following incidence rate:

NTHi-associated moderate and severe AECOPD.

NTHi-associated all-severity AECOPD.

NTHi-associated AECOPD, by severity.

Mcat-associated moderate and severe AECOPD.

Mcat-associated all-severity AECOPD.

Mcat-associated AECOPD, by severity.

NTHi and/or Mcat-associated moderate and severe AECOPD.

NTHi and/or Mcat-associated all-severity AECOPD.

NTHi and/or Mcat-associated AECOPD, by severity.

The time until first moderate and severe AECOPD.

The time until first AECOPD (any severity).

The time until first AECOPD by severity.
The proportion of sputum samples with exact 87% and 95% CIs obtained at each visit 
(scheduled visits and AECOPD-driven visits) and positive for bacterial pathogens 
(overall and by bacterial pathogen) will be computed by group and overall. The exact CIs 
will be estimated assuming independence of bacterial results across sputum samples.
Incidence rates of AECOPD associated to NTHi and/or Mcat, and VE, together with 87% 
and 95% CIs will be evaluated for all study period (starting from Day 1 until study 
completion) and at 3, 6, 9 and 12 months post-Dose 2.
 
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Efficacy – Bacteriological Endpoint (culture)
Same set of analyses, as in the bacteriological efficacy endpoint, will be performed in the 
subset of culture sputum data.
Incidence rates of AECOPD associated to NTHi and/or Mcat, and VE, together with 87% 
and 95% CIs will be evaluated for all study period (starting from Day 1 until study 
completion) and at 3, 6, 9 and 12 months post-Dose 2.
Bacteriological load
The following will be performed in PCR and culture samples:

Percentage of subjects with H. influenzae and M. catarrhalis in sputum before first 
vaccination and at Day 91, Day 181, Day 271, Day 361 and Day 451, per group. 

Relative abundance of H. influenzae and M. catarralis in sputum as measured by 
culture before first vaccination and at Day 91, Day 181, Day 271, Day 361 and Day 
451 and at each AECOPD visit, per group.
Section 11.9.3 Cell-mediated immune response
Cell-mediated immune response as part of secondary endpoints
CMI induced by the NTHi-Mcat candidate vaccine will be evaluated, presenting the 
frequencies of antigen-specific CD4+ /CD8+T cells per 106 cells. The specific CD4+/ 
CD8+T cells being identified as the CD4+/ CD8+ T cells expressing at least 2 different 
cytokines/activation markers among CD40L, IL-2, TNF-, IFN- γ, IL-13 and IL-17 upon 
in vitro stimulation. A descriptive statistics (Min, Q1, Median, Q3 & Max) will be 
reported for each group at Day 1, Day 91, Day 271 and Day 451.
Cell-mediated immune response as part of tertiary endpoints
CMI response as the frequencies of specific CD4+/ CD8+T cells per 106 cells expressing 
any combination of cytokines/activation markers will be determined. In addition, the T 
helper profile of the specific T cell response in T helper 1, T helper 2 and T helper 17 
based on the specific expression of respectively IFN-, IL-13 and IL-17 will be 
characterized. A descriptive statistics (Min, Q1, Median, Q3 & Max) will be reported for 
each group at Day 1, Day 91, Day 271 and Day 451.
 
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Section 14 References
FDA, U.S. Department of Health and Human Services, Center for Biologics Evaluation 
and Research. Guidance for Industry: Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials. Version of 
September 2007.
Haralambieva IA, Ovsyannikova IG, Kennedy RB, et al. Race and Sex-Based 
Differences in Cytokine Immune Responses to Smallpox Vaccine in Healthy 
Individuals. Hum Immunol. 2013; 74(10): 1263–1266.
Kollmann TR. Variation between Populations in the Innate Immune Response to 
Vaccine Adjuvants. Front Immunol. 2013; 4: 81.
National Clinical Guideline Centre. (NICE 2010) Chronic obstructive pulmonary disease: 
management of chronic obstructive pulmonary disease in adults in primary and secondary 
care. London: National Clinical Guideline Centre. Available from: 
http://guidance.nice.org.uk/CG101/Guidance/pdf/English
Pérez-Losada M, Posada D, Arenas M, et al. Ethnic differences in the adaptation rate 
of HIV gp120 from a vaccine trial. Retrovirology. 2009; 6: 67.
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 below and in Table 10. The cut-off and 
unit of these assays might be subject to change during the course of the study (e.g. in case 
of assay re-optimization, qualification, (re)validation or standardization). In this case, this 
will be documented in the clinical study report.
APPENDIX C
MEDDRA PREFERRED TERMS FOR POTENTIAL 
IMMUNE MEDIATED DISEASES
Table 27
MedDRA preferred terms for potential immune mediated diseases
Event Category
Immune-Mediated Disorder
MedDRA PT
Neuroinflammatory 
disorders
Cranial nerve disorders
Anosmia
IIIrd nerve paralysis
IIIrd nerve paresis
IVth nerve paralysis
IVth nerve paresis
Trigeminal palsy
Trigeminal nerve paresis
VIth nerve paralysis
VIth nerve paresis
Facial paralysis
Facial paresis
Acoustic neuritis
Glossopharyngeal nerve paralysis
Tongue paralysis
Vagus nerve paralysis
 
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Event Category
Immune-Mediated Disorder
MedDRA PT
Vocal cord paralysis
Vocal cord paresis
XIth nerve paralysis
Hypoglossal nerve paralysis
Hypoglossal nerve paresis
Bulbar palsy
Oculofacial paralysis
Neuritis cranial
Cranial nerve disorder
Paresis cranial nerve
Cranial nerve paralysis
Cranial nerve palsies multiple
Optic neuritis
Optic neuritis
Multiple sclerosis
Multiple sclerosis
Radiologically isolated syndrome
Primary progressive multiple sclerosis
Progressive multiple sclerosis
Marburg's variant multiple sclerosis
Secondary progressive multiple sclerosis
Multiple sclerosis relapse
Multiple sclerosis relapse prophylaxis
Progressive relapsing multiple sclerosis
Relapsing-remitting multiple sclerosis
Tumefactive multiple sclerosis
Transverse myelitis
Myelitis transverse
Myelitis
Noninfectious myelitis
Guillain-Barré syndrome
Guillain-Barré syndrome
Miller Fisher syndrome
Acute disseminated 
encephalomyelitis/demyelination 
(including site specific variants)
Demyelination
Autoimmune demyelinating disease
Clinically isolated syndrome
Leukoencephalomyelitis
Leukoencephalopathy
Acute disseminated encephalomyelitis
Acute haemorrhagic leukoencephalitis
Concentric sclerosis
Encephalitis periaxialis diffusa
Neuromyelitis optica spectrum disorder
Autoimmune encephalopathy
Bickerstaff's encephalitis
Noninfective encephalitis
Encephalitis autoimmune
Rasmussen encephalitis
Encephalitis allergic
Encephalitis brain stem
Encephalitis haemorrhagic
Encephalomyelitis
Noninfective encephalomyelitis
Encephalitis post immunisation
Panencephalitis
Encephalitis toxic
Myasthenia gravis
Myasthenia gravis
Myasthenia gravis crisis
 
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Event Category
Immune-Mediated Disorder
MedDRA PT
Ocular myasthenia
Myasthenic Syndrome
Immune-mediated peripheral 
neuropathies and plexopathies
Autoimmune neuropathy
Neuritis
Anti-myelin-associated glycoprotein 
associated polyneuropathy
Chronic inflammatory demyelinating 
polyradiculoneuropathy
Lewis-Sumner syndrome
Demyelinating polyneuropathy
Polyneuropathy idiopathic progressive
Multifocal motor neuropathy
Acute motor-sensory axonal neuropathy
Acute motor axonal neuropathy
Cervical neuritis
Mononeuritis
Mononeuropathy multiplex
Brachial plexopathy
Radiculitis brachial
Narcolepsy
Narcolepsy
Musculoskeletal 
disorders
Systemic lupus erythematosus
Systemic lupus erythematosus
SLE arthritis
Cutaneous lupus erythematosus
Acute cutaneous lupus erythematosus
Chronic cutaneous lupus erythematosus
Subacute cutaneous lupus erythematosus
Lupus cystitis
Lupus encephalitis
Lupus endocarditis
Lupus enteritis
Lupus hepatitis
Lupus myocarditis
Lupus myositis
Lupus nephritis
Lupus pancreatitis
Lupus pleurisy
Lupus pneumonitis
Lupus-like syndrome
Neuropsychiatric lupus
Central nervous system lupus
Pericarditis lupus
Peritonitis lupus
Systemic lupus erythematosus rash
Systemic Scleroderma 
Scleroderma
Scleroderma renal crisis
Scleroderma associated digital ulcer
Reynold’s syndrome
Systemic sclerosis pulmonary
Systemic scleroderma
CREST syndrome
Muscular autoimmune disorders
Polymyalgia rheumatica
Dermatomyositis
Polymyositis
 
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Event Category
Immune-Mediated Disorder
MedDRA PT
Juvenile polymyositis
Immune-mediated necrotising myopathy
Antisynthetase syndrome
Rheumatoid arthritis and associated 
conditions
Rheumatoid arthritis
Autoimmune arthritis
Laryngeal rheumatoid arthritis
Rheumatoid lung
Rheumatoid scleritis
Rheumatic brain disease
Rheumatoid neutrophilic dermatosis
Rheumatoid nodule
Juvenile idiopathic arthritis
Cogan's syndrome
Palindromic rheumatism
Still's disease
Spondyloarthropathies
Arthritis reactive
Reiter's syndrome
Ankylosing spondylitis
Spondylitis
Spondyloarthropathy
Juvenile spondyloarthritis
Enteropathic spondylitis
Psoriatic arthropathy
Psoriatic arthropathy
Juvenile psoriatic arthritis
Relapsing polychondritis
Polychondritis
Mixed connective tissue disease
Overlap syndrome
Mixed connective tissue disease
Gout
Gout
Gouty arthritis
Gouty tophus
Gastrointestinal 
disorders
Inflammatory Bowel disease
Crohn's disease
Colitis ulcerative
Colitis microscopic
Autoimmune colitis
Inflammatory bowel disease
Arthritis enteropathic
Proctitis ulcerative
Autoimmune pancreatitis
Autoimmune pancreatitis
Celiac disease
Coeliac disease
Liver disorders
Autoimmune hepatitis
Autoimmune hepatitis
Primary biliary cirrhosis
Biliary cirrhosis primary
Autoimmune cholangitis
Cholangitis sclerosing
Endocrine and 
Metabolic disorders
Autoimmune thyroid diseases
Autoimmune hypothyroidism
Atrophic thyroiditis
Autoimmune thyroiditis
Silent thyroiditis
Hashimoto's encephalopathy
Hashitoxicosis
Basedow's disease
Marine Lenhart syndrome
Autoimmune thyroid disorder
Autoimmune endocrine disorder (NOS) Autoimmune endocrine disorder
Diabetes mellitus type I
Type 1 diabetes mellitus
Fulminant type 1 diabetes mellitus
 
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Event Category
Immune-Mediated Disorder
MedDRA PT
Polyglandular autoimmune syndrome
Polyglandular autoimmune syndrome type I
Polyglandular autoimmune syndrome type II
Polyglandular autoimmune syndrome type III
Autoimmune hypophysitis
Lymphocytic hypophysitis
Addison's disease
Addison's disease
Skin disorders
Psoriasis
Psoriasis
Vitiligo
Vitiligo
Erythema nodosum
Erythema nodosum
Alopecia areata
Alopecia areata
lichen planus
Lichen planus
Sweet’s syndrome
Acute febrile neutrophilic dermatosis
Autoimmune bullous skin diseases
Pemphigus
Pemphigoid
Dermatitis herpetiformis
Autoimmune dermatitis
Localised Scleroderma
Morphoea
Vasculitides
Vasculitis and vasculitides
Acute haemorrhagic oedema of infancy
Administration site vasculitis
Anti-neutrophil cytoplasmic antibody positive 
vasculitis
Aortitis
Application site vasculitis
Arteritis
Arteritis coronary
Behcet's syndrome
Capillaritis
Cerebral arteritis
Chronic pigmented purpura
Cutaneous vasculitis
Diffuse vasculitis
Eosinophilic granulomatosis with polyangiitis
Erythema induratum
Granulomatosis with polyangiitis
Haemorrhagic vasculitis
Henoch-Schonlein purpura
Henoch-Schonlein purpura nephritis
Hypersensitivity vasculitis 
Injection site vasculitis
Kawasaki's disease
Langerhans' cell histiocytosis
Lupus vasculitis
MAGIC syndrome
Microscopic polyangiitis
Nodular vasculitis
Ocular vasculitis
Optic ischaemic neuropathy
Optic neuropathy
Polyarteritis nodosa
Pulmonary vasculitis
Renal arteritis
Renal vasculitis
Retinal vasculitis
Rheumatoid vasculitis
Segmented hyalinising vasculitis
 
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Event Category
Immune-Mediated Disorder
MedDRA PT
Takayasu's arteritis
Temporal arteritis
Thromboangiitis obliterans
Urticarial vasculitis
Vaccination site vasculitis
Vascular purpura
Vasculitic rash
Vasculitic ulcer
Vasculitis
Vasculitis cerebral
Vasculitis gastrointestinal
Vasculitis necrotising
Other
Stevens-Johnson syndrome
Stevens-Johnson syndrome
Erythema multiforme
Toxic epidermal necrolysis
Blood autoimmune disoders
Autoimmune anaemia
Autoimmune haemolytic anaemia
Warm type haemolytic anaemia
Cold type haemolytic anaemia
Coombs positive haemolytic anaemia
Evans syndrome
Immune thrombocytopenic purpura 
Thrombocytopenic purpura
Thrombotic thrombocytopenic purpura
Autoimmune aplastic anaemia
Autoimmune neutropenia
Autoimmune pancytopenia
Antiphospholipid syndrome
Pernicious anaemia
Autoimmune glomerulonephritis
Glomerulonephritis rapidly progressive
IgA nephropathy
IgM nephropathy
Glomerulonephritis membranous
Glomerulonephritis membranoproliferative
Mesangioproliferative glomerulonephritis
Autoimmune nephritis
Chronic autoimmune glomerulonephritis
Tubulointerstitial nephritis and uveitis 
syndrome
Ocular autoimmune diseases
Uveitis
Ocular pemphigoid
Autoimmune retinopathy
Acute macular outer retinopathy
Autoimmune uveitis
Autoimmune heart disease
Autoimmune myocarditis
Autoimmune pericarditis
Sarcoidosis
Sarcoidosis
Pulmonary sarcoidosis
Neurosarcoidosis
Cutaneous sarcoidosis
Liver sarcoidosis
Muscular sarcoidosis
Ocular sarcoidosis
Sjögren’s syndrome
Sjogren's syndrome
 
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Event Category
Immune-Mediated Disorder
MedDRA PT
Idiopathic pulmonary fibrosis
Idiopathic pulmonary fibrosis
Idiopathic interstitial pneumonia
Interstitial lung disease
Pulmonary fibrosis
Goodpasture’s syndrome
Goodpasture’s syndrome
Raynaud's phenomenon
Raynaud's phenomenon
 
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GlaxoSmithKline Biologicals
Vaccines R&D
Protocol Administrative Change 1
eTrack study number 
and Abbreviated Title
207489 (NTHI MCAT-002)
IND number
16531
EudraCT number
2017-000880-34
Administrative Change 
Number: 
Administrative Change 1
Administrative Change
date:
15 December 2017
Co-ordinating Author:
, XPE Pharma & Science for GSK 
Biologicals
Rationale/Background for changes:
!
The inconsistency between the changed cut-off values for anti-PE, anti-PilA and 
anti-UspA2 ELISA assays in Amendment 1 and the cut-off values mentioned in 
Appendix A (laboratory assays) was corrected in this Administrative Change.
Text has been added in the following sections, as indicated with bold and italicized.:
APPENDIX A
LABORATORY ASSAYS
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 technical cut-off of the assay is 8 25 EU/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 technical cut-off of the assay is 7 16 EU/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 technical cut-off of the assay is 18 38 EU/mL. 
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GlaxoSmithKline Biologicals
Vaccines R&D
Protocol Amendment 2
eTrack study number 
and Abbreviated Title
207489 (NTHI MCAT-002)
IND number
16531
EudraCT number
2017-000880-34
Amendment Number: 
Amendment 2
Amendment date:
27 March 2019
Co-ordinating Author:
, XPE Pharma & Science for GSK 
Biologicals
Rationale/Background for changes:
!
The coordinating and contributing authors on (pages 1& 2) were updated to reflect 
the current team in this Amendment.
!
Copyright statement (page 2), date updated in this Amendment.
!
Glossary (pages 32 and 33), definitions were added for acquisition and apparition 
in this Amendment.
!
The text in Section 1.4.1 (page 42) related to spirometry was aligned with the 
wording used in the informed consent form (ICF) in this Amendment.
!
The text in Section 4.1.1 (page 50) was aligned with the wording used in the 
inclusion criteria in this Amendment.
!
The text in footnote c of Table 6 (page 61) was amended to clarify that pregnancy 
tests will be performed in on all females of childbearing potential in this 
Amendment. 
!
The text in Section 6.9.14 (page 67) was aligned with the changes made to 
Footnote c for Table 6 in this Amendment.
!
Clarification was provided in Section 6.9.21, Recording of AEs, SAEs, 
pregnancies and pIMDs (page 70) in this amendment (minor change to wording)
!
Table 10 (page 75) the new ELISA cut-offs were added in this Amendment as 
there are now qualified assays.
!
In Section 9.4.1 (page 100) text was added to clarify that AECOPD classified as 
SAE occurring within a defined time period should also be recorded in the eCRF 
as “AECOPD visit” or as “Missed AECOPD visit”
!
Synopsis (page 11) referring to Section 2.3 Tertiary objectives (page 44), and 
Synopsis (page 17) referring to Section 11.3 Tertiary endpoints (page 110) has 
been updated to include the analyses of acquisition and apparition of bacteria in 
culture and PCR.
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!
Clarification of the correct process to report pIMDs during the study was included 
in Section 9.4.5 Reporting of pIMDs to GSK Biologicals (page 102) in this 
Amendment.
!
Clarification was provided in Section 10.2.2 Subject (page 108) regarding the 
withdrawal procedure in this Amendment.
!
In Section 11.3 (Tertiary Endpoints, page 110), “acquisition and apparition” was 
added to the endpoints.
!
In Section 11.8, Analysis of Efficacy, Efficacy – Clinical (page 118) the text was 
modified to correct an inconsistency within the section, clarifying that all efficacy 
clinical endpoints will be computed with 95% confidence intervals with the 
exception of the primary clinical efficacy endpoint that will also be computed with 
87% confidence interval. There will be no change in the interpretation of the 
analysis compared to the previous version of the Protocol.
!
In Section 11.8, Analysis of Efficacy, Efficacy – Bacteriological Endpoint (PCR), 
(pages 119-120) text was added to clarify the timepoints for the analysis.
!
In Section 11.8, Analysis of Efficacy, Efficacy – Bacteriological Endpoint 
(culture), (page 120) text was added to clarify the timepoints for the analysis.
!
In Section 11.8 Analysis of Efficacy (page 120) a section was added regarding the 
definitions of acquisition and apparition and information regarding the analysis 
was added in this Amendment
!
Appendix A Laboratory Assays (page 136), the new ELISA cut-offs were added in 
this Amendment as there are now qualified assays.
!
Appendix B Clinical Laboratories, Table 26 (page 137) CEVAC and DDL added 
to the table of outsourced laboratories in this Amendment.
!
Minor corrections; e.g. correction of minor typographical and formatting errors 
were made for clarity in Section 4.1.1 (from eDiaries to eDiary), Section 6.7 (from 
SP to SPM), Section 9.1.3 (from eDiaries to eDiary), Section 11.4 (Table 23 and 
Table 24 [et al removed from footnote Keen et al. (2007) to Keen, 2007]), 
Sections 11.5.4 (Per protocol to per protocol), and 11.9.3 (from A descriptive 
statistics to Descriptive statistics).
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections:
Coordinating authors, page 1
!
(Amendment 2 onward) (XPE Pharma & Science 
for GSK Biologicals)
Contributing authors, page 2
!
(Senior Clinical Research & Development Lead)
(Amendment 2 onward) (Clinical Research & Development Lead)
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!
(Lead Statistician)
!
(Director Clinical Statistics)
!
(Amendment 2 onward) (Study Statistician)
!
(Amendment 2 onward) (Study 
Delivery Leads)
!
(CLS Clinical Read-out Team Leader)
!
(CLS Study manager)
!
(Amendment 2 onward) (Clinical Trials Supply 
Manager)
!
(Clinical Safety Representative)
!
(Oversight Data Manager)
!
(Study Data Manager)
!
(Amendment 2 onward)
(Regulatory Affairs Representatives)
Copyright statement, page 2
!
GSK Biologicals’ Protocol DS v 15.0 ©2017-2019 GSK group of companies or its 
licensor
Synopsis, page 11
!
To evaluate the effect of the investigational vaccine on the presence, 
acquisition/apparition and load of NTHi and/or Mcat at stable visits and AECOPD 
by PCR. 
!
To evaluate the effect of the investigational vaccine on the presence, 
acquisition/apparition and load of NTHi and/or Mcat at stable visits and AECOPD 
in a subset of sputum samples by culture. 
Synopsis, page 17
!
Occurrence (presence and absence), acquisition, apparition, and bacterial load 
measured by PCR of NTHi and/or Mcat in sputum before first vaccination and at 
Day 91, Day 181, Day 271, Day 361 and Day 451 and at each AECOPD visit. 
Sputum sample culture:
Occurrence (presence and absence), acquisition, apparition, and semi-quantitative 
bacterial load measured in a subset of sputum sample by culture of NTHi and/or Mcat in 
sputum before first vaccination and at Day 91, Day 181, Day 271, Day 361 and Day 451 
and at each AECOPD visit.
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Glossary, pages 32 and 33
The following definitions were added to the Glossary:
Acquisition:
The first time a bacterium is detected in the sputum of a 
patient over the course of the study visits (a positive 
status at the visit considered as baseline excludes a 
subject from this analysis). 
Apparition:
Detection of a bacterium in the sputum of a patient 
taken during a study visit which was not detected in the 
sputum taken during the previous visit.
Section 1.4.1, Data/rationale for risk, Spirometry, page 42
Spirometry can be in few cases In a few cases spirometry has been associated with 
dizziness. Strong exhalation can cause increased pressure in chest, eyes or stomach.
Occasionally after receiving the albuterol/salmeterol inhaler, a temporary sensation of 
"heart racing" and shakiness may be felt.
Section 2.3 Tertiary objectives, page 44

To evaluate the effect of the investigational vaccine on the presence, 
acquisition/apparition and load of NTHi and/or Mcat at stable visits and AECOPD 
by PCR. 

To evaluate the effect of the investigational vaccine on the presence, 
acquisition/apparition and load of NTHi and/or Mcat at stable visits and AECOPD 
in a subset of sputum samples by culture. 
Section 4.1.1, page 49
Per inclusion criteria, the subject should be a stable COPD patient (i.e. a subject for 
whom the last episode of AECOPD is resolved for at least 30 days at the time of first 
vaccination).
Table 6, Footnote c, page 61
Pregnancy tests will be performed on all females of childbearing potential at screening 
and prior to vaccination (Visit 1 and Visit 3). In case a chest X-ray will be performed 
(i.e. in subjects who do not have an X-ray / CT scan). The pregnancy test should be 
carried out prior to the chest X-ray and if a subject has a positive pregnancy test the chest 
X-ray should not be performed and the subject will be deemed not eligible for the study. 
Please also refer to Section 10.2.2. This pregnancy test should be repeated before 
vaccination at Visit 1 and Visit 3 (including those female subjects of childbearing 
potential who did not have a pregnancy test at screening because an X-ray/ CT scan was 
available within the last 3 months). 
 
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Section 6.9.14 Pregnancy, Page 67
Female subjects of childbearing potential are to have a pregnancy test at Screening and 
prior to vaccination (Visit 1 and Visit 3). The study vaccine may only be administered if 
the pregnancy test is negative.
Table 10: Humoral Immunity (Antibody determination) , page 74
System
Component
Method
Kit / 
Manufacturer
Unit*
Cut-off*
Laboratory
SERUM
anti-PD 
antibody
ELISA
In house
EU/ml
153
GSK Biologicals** 
or GSK designated 
laboratory
anti-PE 
antibody
25 16
anti-PilA 
antibody
16 8
anti-UspA2 
IgG antibody
38 28
Section 6.9.21, Recording of AEs, SAEs, pregnancies and pIMDs, page 70

At Screening visit, electronic Diary Cards will be distributed to the subject. The 
subject will be instructed to measure and record the oral or axillary body 
temperature, and any solicited local/general AEs (i.e. on the day of vaccination and 
during the next 6 days). Any solicited AE ongoing after Day 7 will be collected
followed in the eDiary until resolution (for a maximum of 30 days).
Section 9.4.1 Prompt reporting of serious adverse events, pregnancies, and other 
events to GSK Biologicals, page 100
The following text was added to the section: AECOPD (Section 4) hat meet the criteria 
of a SAE (Section 9.1.3) that occur in the time period defined in Section 9.3 should 
also be recorded in eCRF as “AECOPD visit” or as “Missed AECOPD visit”.
Section 9.4.5. Reporting of pIMDs to GSK Biologicals, page 102
Once a new onset of a pIMD or exacerbation of a pre-existing pIMD is diagnosed 
(serious or non-serious) in a study subject, …
Section 10.2.2. Subject withdrawal from study vaccines, page 108
A subject withdrawn from the study vaccines may not necessarily be withdrawn from the 
study as further study procedures or follow-up may be performed (safety or 
immunogenicity according to protocol procedure planned in the study protocol.
 
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Section 11.3 Tertiary endpoints, page 110
Sputum sample PC

Occurrence (presence and absence), acquisition, apparition, and bacterial load 
measured by PCR of NTHi and/or Mcat in sputum before first vaccination and at 
Day 91, Day 181, Day 271, Day 361 and Day 451 and at each AECOPD visit. 
Sputum sample culture:

Occurrence (presence and absence), acquisition, apparition, and semi-quantitative 
bacterial load measured in a subset of sputum sample by culture of NTHi and/or 
Mcat in sputum before first vaccination and at Day 91, Day 181, Day 271, Day 361 
and Day 451 and at each AECOPD visit. 
Section 11.8, Analysis of Efficacy, Efficacy – Clinical Endpoint, page 118
Efficacy – Clinical Endpoint
The following incidence rates of AECOPD (any type) occurring from enrolment up to 1 
month post-Dose 2 will be computed together with 87%95% CI, and incidence rates 
together with VE in the prevention of AECOPD (any type) will be computed over a 
period starting 1 month post-Dose 2 and lasting for 1 year, with 87%95% CI: 

All-cause moderate and severe AECOPD (primary endpoint).

All-cause, all-severity AECOPD.

All-cause AECOPD, by severity.
For the primary endpoint, the 95% CI will also be reported in order to evaluate the null 
hypothesis at 5% alpha level (2-side). For the primary endpoint, the 87% CI will also be 
reported in order to evaluate the null hypothesis at 13% alpha level (2-side). This 
objective will be considered a success if the lower limit of the 87% CI will be above 0%. 
Section 11.8, Analysis of Efficacy, Efficacy – Bacteriological Endpoint (PCR), pages
119-120
Incidence rates of AECOPD associated to NTHi and/or Mcat, and VE, together with 95% 
CI will be evaluated for all study period (starting from Day 1 until study completion) and 
at 3, 6, 9 and 12 months post-Dose 2 the following time periods:

At Month 3, 6, 9, 12, 15 from day 1 (cumulative)

At 6 months follow up period (from 1 month post-Dose 2)

At 3 months follow up period (from 1 month post-Dose 2) 
Section 11.8, Analysis of Efficacy, Efficacy – Bacteriological Endpoint (culture), 
page 120:
Incidence rates of AECOPD associated to NTHi and/or Mcat, and VE, together with 95% 
CI will be evaluated for all study period (starting from Day 1 until study completion) and 
at 3, 6, 9 and 12 months post-Dose 2 the following time periods:
 
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
At Month 3, 6, 9, 12, 15 from day 1 (cumulative)

At 6 months follow up period (from 1 month post-Dose 2)

At 3 months follow up period (from 1 month post-Dose 2) 
The model used will be the same as for the primary analysis. All above analyses will be 
performed in sputum samples using PCR. 
Section 11.8, Analysis of Efficacy, page 120 (the following text was added):
Acquisition and apparition
The following definitions will be used:

Acquisition: The first time a bacterium is detected in the sputum of a patient over 
the course of the study visits (a positive status at the visit considered as baseline 
excludes a subject from this analysis).

Apparition: Detection of a bacterium in the sputum of a patient taken during a 
study visit which was not detected in the sputum taken during the previous visit.
The following analyses will be performed for (NT)Hi (alone or with other bacteria), 
MCAT (alone or with other bacteria) and either Hi or MCAT:

Percentages of subjects with acquisition for each treatment group and risk ratio 
between groups, considering both Day 1 and Day 91 as baseline.

Percentages of subjects with apparition for each treatment group and risk ratio 
between groups, considering Day 1 as baseline.

Percentages of subjects with acquisition at AECOPD visit for each treatment 
group and risk ratio between groups, considering both Day 1 and Day 91 as 
baseline.

Percentages of subjects with apparition at AECOPD visit (when negative at 
previous stable visit) for each treatment group and risk ratio between groups, 
considering Day 1 as baseline

Frequency table for apparition (number of apparition for each subject from Day 
1), by treatment groups.
Appendix A Laboratory Assays, page 136
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 technical cut-off of the assay is 25 16 EU/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 technical cut-off of the assay is 16 8 EU/mL.
 
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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 technical cut-off of the assay is 38 28 EU/mL. 
Appendix B Clinical Laboratories, Table 26: Outsourced laboratories (page 137)
Laboratory
Address
CEVAC - University of Gent
De Pintelaan, 185 Gent, Belgium
DDL Diagnostic Laboratory B.V.
Visseringlaan 25, 2288 ER Rijswijk, The Netherlands
Q2 Solutions Clinical Trials (US)
27027 Tourney Road, Suite 2E
Valencia, CA 91355
USA
Q2 Solutions Clinical Trials (UK)
The Alba Campus Rosebank 
Livingston West Lothian, EH54 7EG Scotland, 
UK 
 
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