Occurrence of Potential Bacterial and Viral Pathogens in Stable Chronic Obstructive Pulmonary Disease (COPD) and During Acute Exacerbations of COPD (AECOPD), in Asia Pacific
Phase: NA
Conditions: Respiratory Disorders
Sponsor: GlaxoSmithKline

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
1
Study Protocol
Sponsor:
GlaxoSmithKline Biologicals
Rue de l’institut 89,
1330 Rixensart, Belgium
eTrack study number and 
Abbreviated Title
201112 (EPI-NTHI-001 BOD APA)
Date of protocol
Final Version 1: 02 March 2014
Date of protocol 
amendment
Amendment 1 Final: 13 February 2017
Amendment 2 Final: 20 October 2017
Amendment 3 Final: 19 October 2018
Title
Occurrence of potential bacterial and viral pathogens 
in stable chronic obstructive pulmonary disease 
(COPD) and during acute exacerbations of COPD 
(AECOPD), in Asia Pacific.
Detailed Title
A prospective, epidemiological, multi-country, cohort 
study to assess the occurrence of potential bacterial 
and viral pathogens in stable chronic obstructive 
pulmonary disease (COPD) and during acute 
exacerbations of COPD (AECOPD), in moderate to 
very severe COPD patients, in Asia Pacific.
Co-ordinating author
, Scientific Writer
Contributing authors
!
, Epidemiologist
!
, Clinical Research and 
Development Lead
!
, Clinical Research 
and Development Lead
!
 Senior Epidemiology Expert
!
, Vaccine Development Leader
!
 
 Biostatistician
!
 Lead 
statistician
!
 Project 
Delivery Lead
!
 Study Delivery Lead
!
 Study Delivery Manager, 
(External Consultant [Freelance∀for GSK 
Biologicals)
!
 Senior 
Manager, Oversight Data Management

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
1
19-OCT-2018
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
2
eTrack study number and 
Abbreviated Title
201112 (EPI-NTHI-001 BOD APA)
Detailed Title
A prospective, epidemiological, multi-country, cohort 
study to assess the occurrence of potential bacterial 
and viral pathogens in stable chronic obstructive 
pulmonary disease (COPD) and during acute 
exacerbations of COPD (AECOPD), in moderate to 
very severe COPD patients, in Asia Pacific.
Contributing authors
!
 Study Data Manager 
!
 Vaccine Supply 
Coordinator (CVO Europe, for GSK Biologicals)
!
 Clinical Readout Team 
Leader, Clinical Laboratory Sciences
!
 Study Manager, GVCL 
(Business & Decision Life sciences, for GSK 
Biologicals)/
 Study Manager, 
Clinical Laboratory Sciences
!
 Global 
Regulatory Lead and 
 Global 
Regulatory Affairs representative
!
 and 
 
 and
 
and 
 
Clinical Safety Representatives
!
 Expert Scientist, Clinical 
Laboratory Sciences
!
 Study Data Manager (Business & 
Decision Life Sciences, for GSK Biologicals)
!
Dr. 
, University of Sydney Head, 
Respiratory Trials, Contributing author from The 
George Institute for Global Health, Australia
GSK Biologicals’ Protocol DS v15.0
© 2014-2018 GSK group of companies or its licensor.

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
2
19-OCT-2018
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
3
Protocol Amendment 3 Sponsor Signatory Approval
eTrack study number and 
Abbreviated Title
201112 (EPI-NTHI-001 BOD APA)
Date of protocol amendment
Amendment 3 Final: 19 October 2018
Detailed Title
A prospective, epidemiological, multi-country, cohort 
study to assess the occurrence of potential bacterial 
and viral pathogens in stable chronic obstructive 
pulmonary disease (COPD) and during acute 
exacerbations of COPD (AECOPD), in moderate to 
very severe COPD patients, in Asia Pacific.
Sponsor signatory
Ashwani Kumar Arora
Clinical and Epidemiology Project Lead
Signature
Date
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
3
19-OCT-2018
For internal use only
- ----------------Checksum----------------!Ver.!Created On -  - 
75661ebdab2e949f7a1f1bc2071b9dec72aceccf 2.0 10/25/2018 6:16:52 PM -  - 
---------------------------------------------------------------------------- -

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
4
Protocol Amendment 3 Rationale
Amendment number:
Amendment 3
Rationale/background for changes:
The protocol has been amended to implement the following changes:

Removal of all STGG (Skim Milk-Tryptone-Glucose-Glycerol) wording
throughout the protocol. STGG product not being available, it has been decided to
replace it with cryobeads for storage of bacterial isolates. PCR testing on samples
stored in cryobeads was shown to be as efficient as for samples stored in STGG.
Besides, this decision has been taken for alignment with other COPD studies,
where STGG solutions are no longer used.

Clarification of technique used for target identification. For the primary endpoint,
various viral pathogens will be identified but not quantified. Along this line, the
wording “and by HRV quantitative RT-PCR” has been removed from primary
endpoint to avoid confusion as HRV viral load data will be reported as part of the
tertiary endpoints.

Clarification in exclusion criteria section (4.3). Administration of antibiotics
before study entry, where study entry is meant to be Visit 1.

Clarification in study procedure section (6.3) and in the section for recording
current medication (6.4.2.10) during scheduled visits, where it has been specified
that recording of any current medication is applicable for any disease not only
COPD-related. Moreover, a footnote referring to Table 10 “Reporting period for
SAE and AEs leading to withdrawal” has been added for further clarification, both
in Table 4 and 5.

Addition of a section (actual 6.4.2.6) for Pregnancy test for Visit 1, Visit 2 and
Visit 3. A Pregnancy test section for Screening Visit was included during Protocol
Amendment 1: to be consistent, same wording has been included for the
subsequent visits.

Clarification of reporting of severe AECOPDs. Two sentences have been added in
sections 7.1.1 and 7.2.2.1 for making clear that severe AECOPD events are not to
be reported as SAE as they are meant as disease-related outcomes.

Rewording in the table concerning reporting period for SAE and AEs leading to
withdrawal for better clarification (Table 10).

Addition of a new outsourced laboratory (DDL).

To correct some typographical errors.
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
4
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
5
Protocol Amendment 3 Investigator Agreement
I agree:

To conduct the study in compliance with this protocol, any mutually agreed future
protocol amendments or protocol administrative changes, with the terms of the study
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) or other
applicable guidelines and all applicable regulatory requirements.

To ensure that all persons assisting me with the study are adequately informed about
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 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 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, 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.
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
5
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
6
eTrack study number and 
Abbreviated Title
201112 (EPI-NTHI-001 BOD APA)
Date of protocol amendment
Amendment 3 Final: 19 October 2018
Detailed Title
A prospective, epidemiological, multi-country, cohort 
study to assess the occurrence of potential bacterial 
and viral pathogens in stable chronic obstructive 
pulmonary disease (COPD) and during acute 
exacerbations of COPD (AECOPD), in moderate to 
very severe COPD patients, in Asia Pacific.
Investigator name
Signature
Date
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
6
19-OCT-2018
For internal use only
- ----------------Checksum----------------!Ver.!Created On -  - 
75661ebdab2e949f7a1f1bc2071b9dec72aceccf 2.0 10/25/2018 6:16:52 PM -  - 
---------------------------------------------------------------------------- -

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
7
Sponsor Information
Sponsor
GlaxoSmithKline Biologicals
Rue de l’Institut 89
1330 Rixensart, Belgium
Sponsor Medical Expert for the Study
Refer to the local study contact information document.
Sponsor Study Monitor
Refer to the local study contact information document.
Study Contact for Reporting of a Serious Adverse Event (SAE)
GSK Biologicals Central Back-up Study Contact for Reporting SAEs: refer to protocol 
Section 7.3.2.
Study Contact for Reporting SAEs: refer to the local study contact information 
document.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
7
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
8
SYNOPSIS
Detailed Title
A prospective, epidemiological, multi-country, cohort study to 
assess the occurrence of potential bacterial and viral 
pathogens in stable chronic obstructive pulmonary disease 
(COPD) and during acute exacerbations of COPD 
(AECOPD), in moderate to very severe COPD patients, in 
Asia Pacific.
Objectives
Primary
To estimate the proportion of potential bacterial and viral 
pathogens (overall and by species) detected in sputum of 
stable COPD patients and during AECOPD, using 
respectively bacteriological methods and viral PCR, over the 
course of 1 year.
Secondary

To evaluate the concordance between PCR and 
bacteriological methods data in sputum for potential 
bacterial pathogens.

To estimate the proportion of potential bacterial and viral 
pathogens (overall and by species) detected in sputum of 
stable COPD patients, by GOLD grade.

To estimate the proportion of potential bacterial and viral 
pathogens (overall and by species) detected in sputum 
during AECOPD, by severity of AECOPD.

To estimate the incidence rate of all-cause AECOPD, 
overall and by GOLD grade.

To describe the severity and duration of all-cause 
AECOPD, overall and by GOLD grade.

To assess the impact of all-cause AECOPD on HRQOL.

To assess the impact of all-cause AECOPD on lung 
function.

To assess the impact of all-cause AECOPD on healthcare 
utilisation.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
8
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
9
Tertiary

To assess the use of EXACT-PRO for determining the 
end date of AECOPD.

To evaluate the load of bacterial and viral pathogens in 
stable COPD and during AECOPD.

To collect biological specimens for future respiratory 
disease-related testing:

Aliquots of sputum samples for assay development 
and microbiome analysis at stable visits and during 
exacerbation.

Blood sampling for potential 
identification/quantification of biomarkers at Visit 1 
and Visit 3.
Rationale for the 
study
Because the infectious aetiology of AECOPD has been 
suggested to vary according to geographical region, the 
primary purpose of this study (which will be conducted in 
several countries in Asia Pacific) is to evaluate the occurrence 
of potential bacterial and viral pathogens in the sputum of 
stable COPD patients and at the time of AECOPD. Given the 
increasing and projected burden of COPD in the Asia Pacific 
region, this study will also evaluate the frequency, severity 
and duration of AECOPD, as well as the impact of AECOPD 
on health-related quality of life (HRQOL), healthcare 
utilisation and lung function.
In addition, both PCR and bacteriological methods will be 
used for characterisation (quantification in some cases) of 
bacteria in sputum. To date, identification of bacteria and 
assessment of bacterial load is done in the vast majority of 
cases by culture. However, the few studies that have 
compared culture with PCR demonstrated that PCR is more 
discriminatory at detecting typical airway bacteria [Curran, 
2007; Singh 2014. Moreover, in a multi-centre study, PCR 
has the advantage that it can be performed on stored sputum 
samples, and can therefore be done centrally, whereas culture 
has to be performed on fresh sputum samples, which can lead 
to variable results due to variability in testing methods 
between laboratories.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
9
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
10
Study design

Type of design: Prospective, epidemiological, 
interventional, multi-country, cohort study.

Study population: A stable cohort of approximately 200 
moderate to very severe COPD patients with at least 1 
documented moderate or severe AECOPD in the year 
before enrolment.

Type of study: self-contained.

Data collection: Electronic Case Report Form (eCRF) 
and electronic diary cards.

Primary completion Date: Visit 3 (Month 12). Refer to 
glossary of terms for the definition of PCD.

End of Study (EoS): Last testing results released of 
samples collected at Visit 3.

Duration of the study: The study will last approximately 
1 year for each subject.

Note: Screening visit should ideally occur not more than 
6 weeks before visit 1.

Epoch 001: Prospective data collection starting at 
Screening Visit (Pre-Month 0) and ending at Visit 3 
(Month 12).
Synopsis Table 1
Study groups and epochs foreseen in the study
Study Groups
Number of 
subjects
Age (Min/Max)
Epoch
Epoch 001
Prospective
Approx 200
40 years
X
Discussion of study 
design
The primary objective of this study is to prospectively 
investigate the prevalence and distribution of bacteria and 
viruses isolated from sputum samples from moderate to very 
severe COPD patients and at the time of AECOPD, in Asian 
populations. In order to increase the chance that the patients 
will exacerbate during the study, only patients with a 
documented history of at least 1 moderate or severe AECOPD 
in the previous year will be recruited, as this is known to be 
the best predictor of AECOPD [Hurst, 2010. Therefore, this 
study will permit an estimation of incidence of AECOPD in a 
COPD population at increased risk of exacerbation. It will not 
provide a true population-based incidence of AECOPD. 
In order to study factors affecting disease progression in Asia 
Pacific, prospective data from a relatively large cohort of 
COPD patients is essential. The use of electronic Diary Cards 
to detect changes in the respiratory symptoms that define an 
AECOPD, the standardised questionnaires and spirometry 
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
10
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
11
assessments will allow robust conclusions to be drawn about 
the effects of exacerbations on decline in lung function and 
HRQOL. 
EXACT PRO will be used to assess breathlessness, cough and 
presence of sputum, chest symptoms, difficulty bringing up 
sputum, feeling tired or weak, sleep disturbance, and feeling 
scared or worried about their condition. Advantages to this 
approach include standardised data, reduced recall bias, and 
the potential to identify events and determine resolution based 
on a predefined scoring algorithm Leidy, 2011. Standardised 
questionnaires completed during study visits include the 
SGRQ-C and the CAT. The SGRQ-C is designed to assess 
HRQOL, current health and does not specify a recall period. 
The CAT is a simple, short, patient-completed instrument to 
assess HRQOL and symptom burden in patients with COPD. 
The CAT has good internal consistency and test-retest 
reliability, correlates strongly with the SGRQ-C, and is able to 
distinguish between stable patients and those undergoing an 
AECOPD Jones, 2012.
Number of subjects
The target is to enrol approximately 200 eligible moderate to 
very severe COPD patients.
Endpoints
Primary (Amended on 19 October 2018)

Occurrence of potential bacterial and viral pathogens in 
sputum of stable COPD patients and during AECOPD, 
over the course of 1 year:

Bacterial pathogens, as identified by bacteriological 
methods, including (but not necessarily limited to) H. 
influenzae, M. catarrhalis, S. pneumoniae, S. aureus, 
P. aeruginosa, K. pneumoniae and A. baumannii.

Viral pathogens, as identified by PCR, including (but 
not necessarily limited to) RSV, parainfluenza virus, 
enterovirus/ HRV, metapneumovirus, influenza 
virus, adenovirus, bocavirus and coronavirus.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
11
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
12
Secondary

Occurrence of potential bacterial pathogens in sputum of 
stable COPD patients and during AECOPD, as measured 
by real-time qualitative PCR/ quantitative PCR and 
compared to data from bacteriological methods, over the 
course of 1 year:

Including (but not necessarily limited to) 
H. influenzae, M. catarrhalis, S. pneumoniae, 
S. aureus and P. aeruginosa.

Occurrence of potential bacterial and viral pathogens 
(overall and by species) in sputum of stable COPD 
patients by GOLD grade, over the course of 1 year.

Occurrence of potential bacterial and viral pathogens 
(overall and by species) in sputum during AECOPD by 
severity of AECOPD, over the course of 1 year.

Incident rate (per subject per year) of AECOPD, overall 
and by GOLD grade, over the course of 1 year.

Severity of AECOPD, overall and by GOLD grade, over 
the course of 1 year.

Duration of AECOPD, overall and by AECOPD severity,
over the course of 1 year.

CAT score in stable COPD patients and during 
AECOPD, over the course of 1 year.

SGRQ-C score in stable COPD patients, over the course 
of 1 year.

FEV1% of predicted normal value in stable COPD 
patients, at Pre-Month 0 and Month 12.

Healthcare utilisation, over the course of 1 year.
Tertiary

EXACT-PRO scores in stable COPD patients and during 
AECOPD, over the course of 1 year.

Bacterial load measured by both culture and PCR in 
COPD and during AECOPD.

HRV load measured by PCR in COPD and during 
AECOPD.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
12
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
13
TABLE OF CONTENTS
PAGE
SPONSOR INFORMATION ............................................................................................7
SYNOPSIS......................................................................................................................8
LIST OF ABBREVIATIONS (AMENDED 19 OCTOBER 2018)......................................20
GLOSSARY OF TERMS ...............................................................................................22
TRADEMARKS .............................................................................................................26
1.
INTRODUCTION....................................................................................................27
1.1.
Background ................................................................................................27
1.2.
Rationale for the study................................................................................30
2.
OBJECTIVES.........................................................................................................30
2.1.
Primary objective ........................................................................................30
2.2.
Secondary objectives..................................................................................30
2.3.
Tertiary objective(s) ....................................................................................31
3.
STUDY DESIGN OVERVIEW ................................................................................32
3.1.
Discussion of study design..........................................................................34
3.1.1.
Detection of AECOPD..................................................................35
3.1.1.1.
Date of onset and end date of AECOPD.....................36
3.1.1.2.
Guideline for assessing AECOPD that increase 
in severity ...................................................................36
4.
STUDY POPULATION ...........................................................................................37
4.1.
Number of subjects/ centres .......................................................................37
4.1.1.
Recruitment of study centres .......................................................37
4.2.
Inclusion criteria for enrolment....................................................................37
4.3.
Exclusion criteria for enrolment (Amended 19 October 2018) .....................38
5.
CONDUCT OF THE STUDY ..................................................................................40
5.1.
Regulatory and ethical considerations, including the informed 
consent process..........................................................................................40
6.
DETAILED STUDY PROCEDURES (AMENDED 19 OCTOBER 2018)..................41
6.1.
Subject identification...................................................................................41
6.2.
General study aspects ................................................................................41
6.3.
Outline of study procedures ........................................................................41
6.4.
Detailed description of study procedures ....................................................44
6.4.1.
Procedures during the Screening Visit.........................................44
6.4.1.1.
Informed consent........................................................44
6.4.1.2.
Check inclusion and exclusion criteria ........................44
6.4.1.3.
Record demographic data ..........................................44
6.4.1.4.
Record medical history...............................................44
6.4.1.5.
Record AECOPD history within the previous 
year ............................................................................44
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
13
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
14
6.4.1.6.
Smoking exposure history (ATS-DLD-78A 
questionnaire)/biomass exposure history (At 
screening visit only)....................................................44
6.4.1.7.
Smoking status...........................................................45
6.4.1.8.
Physical examination..................................................45
6.4.1.9.
Pregnancy test ...........................................................45
6.4.1.10.
Measure/ record height and weight.............................45
6.4.1.11.
Pre- and post-bronchodilator spirometry.....................45
6.4.1.12.
Chest X-ray ................................................................46
6.4.1.13.
Train subjects on the use of electronic Diary 
Card and assign electronic Diary Card to 
subject........................................................................46
6.4.1.14.
Sputum sampling (Amended 19 October 2018)..........46
6.4.1.15.
Recording of AE/SAEs ...............................................47
6.4.1.16.
Screening conclusion .................................................47
6.4.2.
Procedures during Visit 1, Visit 2 and Visit 3................................47
6.4.2.1.
Check inclusion and exclusion criteria ........................47
6.4.2.2.
Record intercurrent comorbidities...............................47
6.4.2.3.
Vaccination History.....................................................47
6.4.2.4.
Smoking status...........................................................47
6.4.2.5.
Physical examination..................................................47
6.4.2.6.
Pregnancy test (Amended 19 October 2018)..............48
6.4.2.7.
Measure/ record height and weight.............................48
6.4.2.8.
Pre- and post-bronchodilator spirometry.....................48
6.4.2.9.
Record subject’s COPD status ...................................48
6.4.2.10.
Record current medication (Amended 19 
October 2018) ............................................................48
6.4.2.11.
Record healthcare resource utilisation........................48
6.4.2.12.
Additional treatments prescribed by primary 
and secondary care physician ....................................49
6.4.2.13.
Train subjects on the use of electronic Diary 
Card and assign electronic Diary Card to 
subject........................................................................49
6.4.2.14.
Return the electronic diary card..................................49
6.4.2.15.
Sputum sampling (Amended 19 October 2018)..........49
6.4.2.16.
Blood Sampling ..........................................................50
6.4.2.17.
HRQOL questionnaires ..............................................50
6.4.2.18.
Recording of AE/SAEs ...............................................50
6.4.2.19.
Study conclusion ........................................................50
6.4.3.
Procedures during AECOPD visit.................................................51
6.4.3.1.
Record date of visit.....................................................51
6.4.3.2.
Physical examination..................................................51
6.4.3.3.
Pregnancy Test ..........................................................51
6.4.3.4.
Chest X-rays/pneumonia confirmation........................51
6.4.3.5.
Confirm AECOPD and record start date .....................52
6.4.3.6.
Record current medication for AECOPD.....................52
6.4.3.7.
Record healthcare resource utilisation........................52
6.4.3.8.
Additional COPD treatments prescribed by 
primary and secondary care physician........................52
6.4.3.9.
Sputum sampling (Amended 19 October 2018)..........52
6.4.3.10.
HRQOL questionnaires ..............................................53
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
14
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
15
6.4.3.11.
Record AECOPD severity and AECOPD end 
date ............................................................................53
6.4.3.12.
Recording of AE/SAEs ...............................................53
6.4.4.
Sampling......................................................................................53
6.4.4.1.
Sputum Sampling .......................................................53
6.4.4.2.
Blood Sampling ..........................................................54
6.4.5.
Health Related Quality of Life questionnaires ..............................54
6.4.6.
Recording of AEs/SAEs...............................................................54
6.4.7.
Study conclusion..........................................................................54
6.5.
Biological sample handling and analysis.....................................................54
6.5.1.
Use of specified study materials ..................................................55
6.5.2.
Biological samples.......................................................................55
6.5.3.
Laboratory assays (Amended 19 October 2018)..........................56
7.
SAFETY.................................................................................................................59
7.1.
Safety definitions ........................................................................................59
7.1.1.
Definition of an adverse event (Amended 19 October 
2018) ...........................................................................................59
7.1.2.
Definition of a serious adverse event ...........................................59
7.1.3.
Clinical laboratory parameters and other abnormal 
assessments qualifying as AEs or SAEs......................................60
7.2.
Detecting and recording AEs, SAEs............................................................61
7.2.1.
Time periods for detecting and recording AEs and SAEs.............61
7.2.2.
Evaluation of SAEs (Amended 19 October 2018) ........................62
7.2.2.1.
Active questioning to detect SAEs..............................62
7.2.2.2.
Assessment of causality .............................................62
7.2.2.3.
Assessment of outcomes............................................63
7.3.
Reporting of SAEs ......................................................................................63
7.3.1.
Prompt reporting of SAEs related to study participation to 
GSK.............................................................................................63
7.3.2.
Contact information for reporting SAEs to GSK............................63
7.3.3.
Completion and transmission of SAEs reports related to 
study participation to GSK ...........................................................64
7.3.3.1.
Back-up system in case the electronic reporting 
system does not work.................................................64
7.3.4.
Updating of SAE after freezing of the subject’s eCRF..................64
7.3.5.
Regulatory reporting requirements for SAEs................................64
7.4.
Treatment of AEs........................................................................................65
8.
SUBJECT COMPLETION AND WITHDRAWAL.....................................................65
8.1.
Subject completion .....................................................................................65
8.2.
Subject withdrawal......................................................................................65
9.
STATISTICAL METHODS......................................................................................66
9.1.
Endpoints....................................................................................................66
9.1.1.
Primary endpoint (Amended 19 October 2018)............................66
9.1.2.
Secondary endpoints ...................................................................66
9.1.3.
Tertiary endpoints........................................................................67
9.2.
Determination of sample size......................................................................67
9.3.
Cohorts for Analyses...................................................................................68
9.3.1.
All screened Set...........................................................................68
9.3.2.
All Enrolled Set ............................................................................68
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
15
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
16
9.3.3.
Full Analysis Set ..........................................................................69
9.4.
Analysis of demographics ...........................................................................69
9.5.
Analysis of primary objective.......................................................................69
9.6.
Analysis of secondary objectives ................................................................70
9.7.
Analysis of tertiary objectives......................................................................71
9.8.
Conduct of analyses ...................................................................................71
9.8.1.
Sequence of analyses..................................................................71
9.8.2.
Statistical considerations for interim analyses..............................71
10. ADMINISTRATIVE MATTERS ...............................................................................72
10.1.
Electronic Case Report Form instructions...................................................72
10.2.
Study monitoring by GSK Biologicals..........................................................72
10.3.
Record retention .........................................................................................73
10.4.
Quality assurance.......................................................................................73
10.5.
Posting of information on publicly available registers and publication 
policy ..........................................................................................................74
10.6.
Provision of study results to investigators ...................................................74
10.7.
Data Sharing...............................................................................................74
11. COUNTRY SPECIFIC REQUIREMENTS...............................................................74
12. REFERENCES.......................................................................................................75
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
16
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
17
LIST OF TABLES
PAGE
Table 1
Classification of severity of airflow limitation in COPD (based on 
post-bronchodilator FEV1) ......................................................................27
Table 2
Classification of severity of AECOPD.....................................................29
Table 3
Study groups and epochs foreseen in the study.....................................33
Table 4
List of study procedures for scheduled visits ..........................................41
Table 5
List of study procedures for AECOPD visits ...........................................43
Table 6
Intervals between study visits.................................................................43
Table 7
Biological samples .................................................................................55
Table 8
Microbiology...........................................................................................57
Table 9
Planned assays on serological samples.................................................58
Table 10
Reporting period for SAE and AEs leading to withdrawal 
(Amended 19 October 2018)..................................................................61
Table 11
Timeframes for submitting SAEs related to study participation to 
GSK .......................................................................................................63
Table 12
Exact 95% confidence intervals of the percentage of occurrence 
of a specific bacterium from sputum collected during AECOPD .............67
Table 13
95% confidence intervals of AECOPD incidence rates with 
different overdispersion values...............................................................68
Table 14
GSK Biologicals’ laboratories .................................................................78
Table 15
Outsourced Laboratories........................................................................78
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
17
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
18
LIST OF FIGURES
PAGE
Figure 1
The refined ABCD assessment tool........................................................27
Figure 2
Study design overview ...........................................................................32
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
18
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
19
LIST OF APPENDICES
PAGE
APPENDIX A CLINICAL LABORATORIES (Amended 19 October 2018).....................78
APPENDIX B AMENDMENT TO THE PROTOCOL .....................................................79
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
19
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
20
LIST OF ABBREVIATIONS (Amended 19 October 2018)
A. baumannii
Acinetobacter baumannii
AE
Adverse Event
AECOPD
Acute exacerbation of COPD
ATS-DLD-78A
American Thoracic Society-Division of Lung Diseases-
78A
CAT
COPD assessment test
CI
Confidence Interval
CLS
Clinical Laboratory Sciences
COPD
Chronic Obstructive Pulmonary Disease
DTT
Dithiothreitol
eCRF
electronic Case Report Form
EoS
End of Study
ER
Emergency Room
EXACT-PRO
Exacerbations of Chronic Pulmonary Disease Tool -
Patient Reported Outcome
FAS
Full Analysis Set
FEV1
Forced expiratory volume in 1 second
FVC
Forced vital capacity
GCP
Good clinical practice
GOLD
Global Initiative for Chronic Obstructive Lung Disease
GP
General Practitioner
GSK
GlaxoSmithKline
H. influenzae
Haemophilus influenzae
HRQOL
Health-related quality of life
HRV
Human Rhinovirus
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
20
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
21
ICD
International Classification of Diseases
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
K. pneumoniae
Klebsiella pneumoniae
LAR
Legally Acceptable Representative
M. catarrhalis
Moraxella catarrhalis
OTC
Over-the-counter
P. aeruginosa
Pseudomonas aeruginosa
PCD
Primary Completion Date
PCR
Polymerase chain reaction
RSV
Respiratory syncytial virus
RT-PCR
Reverse transcription polymerase chain reaction
S. aureus
Staphylococcus aureus
S. pneumoniae
Streptococcus pneumoniae
SAE
Serious Adverse Event
SGRQ-C
St. George’s Respiratory Questionnaire for COPD 
patients
SPM
Study Procedures Manual
USA
United States of America
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
21
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
22
GLOSSARY OF TERMS
Adverse event:
Any untoward medical occurrence in a subject, 
temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal 
product, or temporally associated with a study procedure.
An adverse event (AE) can therefore be any unfavourable 
and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a medicinal product. 
For marketed medicinal products, this also includes 
failure to produce expected benefits (i.e., lack of 
efficacy), abuse or misuse.
Anonymised data:
Information about an individual that GSK or a third party 
cannot reasonably attribute to the individual, or could 
only attribute to the individual by expending a 
disproportionate amount of time, effort or expense (e.g. 
de-identified or aggregated information). For the purpose 
of this policy, Key-Coded personally identifiable 
information shall not be considered Anonymised 
Information
Current smoker
A person who is currently smoking or who stopped 
smoking within the past 6 months.
Cohort study:
A form of epidemiological study where subjects in a 
study population are classified according to their 
exposure status/disease and followed over time 
(prospective/ retrospective) to ascertain the outcome(s). 
Eligible:
Qualified for enrolment into the study based upon strict 
adherence to inclusion/exclusion criteria.
Epidemiological study:
An observational or interventional study without 
administration of medicinal product(s) as described in a 
research protocol.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
22
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
23
End of Study 
(Synonym of End of 
Trial)
For studies without collection of human biologicals 
samples or imaging data EoS is the Last Subject Last 
Visit (LSLV). 
For studies with collection of Human Biologicals 
Samples or imaging data, EoS is defined as the date of the 
last testing/reading released of the Human Biological 
Samples or imaging data, related to primary and 
secondary endpoints. EoS must be achieved no later than 
8 months after LSLV.
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 
immunogenicity follow-up, safety follow-up, ESFU, 
follow-up.
eTrack:
GSK Biologicals’ tracking tool for clinical/ 
epidemiological trials.
Evaluable:
Meeting all eligibility criteria, complying with the 
procedures defined in the protocol (see Section 9.3 for 
details on criteria for evaluability).
Former smoker
A person who stopped smoking for at least 6 months.
GOLD grade: 
(classification of severity 
of airflow limitation in 
COPD patients)
The spirometric classification of airflow limitation in 
COPD patients is based on post-bronchodilator FEV1 and 
can be divided into four GOLD grades [GOLD, 2013]:
GOLD grade
In patients with FEV1/ FVC < 0.70:
GOLD 1: Mild
FEV1 ≥ 80% predicted
GOLD 2: Moderate
50% ≤ FEV1 < 80% predicted
GOLD 3: Severe
30% ≤ FEV1 < 50% predicted
GOLD 4: Very Severe
FEV1 < 30% predicted
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
23
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
24
Interventional Human 
Subject Research:
Studies in which participants are administered medical 
care, medicinal products and/or medical/scientific 
procedures as described in a research protocol.
Non-interventional 
(observational) Human 
Subject Research:
Studies where medicinal products, should they be 
administered, are prescribed in normal (routine) medical 
practice. No medical care or medical/scientific procedures 
as required in a research protocol are administered to 
participants except as part of routine medical care.
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.
Research protocol:
A document that describes the objective(s), design, 
methodology, statistical considerations, and organisation 
of a study. The protocol usually also gives the 
background and rationale for the study, but these could be 
provided in other protocol referenced documents.
Prospective study:
A study in which the subjects/cases are identified and 
then followed forward in time in order to address one or 
more study objectives.
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.
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/ 
pharmaco-epidemiological study was concluded 
according to the pre-specified protocol or was terminated.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
24
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
25
Self-contained study:
Study with objectives not linked to the data of another 
study.
Site Monitor:
An individual assigned by the sponsor who is responsible 
for assuring the proper conduct of epidemiological studies 
at one or more investigational sites.
Study population:
Sample of population of interest.
Subject:
Term used throughout the protocol to denote an 
individual who has been contacted in order to participate 
or participates in the epidemiological study or a person 
about whom some medical information has been recorded 
in a database.
Subject number:
A unique number identifying a subject, assigned to each 
subject consenting to participate in the study.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
25
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
26
TRADEMARKS
The following trademarks are used in the present protocol.
Trademarks of the GSK group of 
companies
Generic description
COPD Assessment test (CAT)
Questionnaire to measure the impact of 
COPD on wellbeing and daily life
EXACT-PRO
Exacerbations of Chronic Pulmonary 
Disease Tool - Patient Reported Outcome
SGRQ-C
St. George’s Respiratory Questionnaire for 
COPD patients
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
26
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
27
1.
INTRODUCTION
1.1.
Background
Chronic Obstructive Pulmonary Disease (COPD) is a common preventable and treatable 
disease characterised by persistent airflow obstruction which is not fully reversible and 
which 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 GOLD grades as shown in 
Table 1 [GOLD, 2013]. In this study, additional parameters are going to be collected in 
order to allow for a combined assessment that could be used for future evaluation, as 
detailed in Figure 1 [GOLD, 2017].
Table 1
Classification of severity of airflow limitation in COPD (based on 
post-bronchodilator FEV1)
GOLD grade
In patients with FEV1/ FVC < 0.70:
GOLD 1: Mild
FEV1 ≥ 80% predicted
GOLD 2: Moderate
50% ≤ FEV1 < 80% predicted
GOLD 3: Severe
30% ≤ FEV1 < 50% predicted
GOLD 4: Very Severe
FEV1 < 30% predicted
GOLD = Global Initiative for Chronic Obstructive Lung Disease; FEV1 = forced expiratory volume in 1 second; 
FVC = forced vital capacity
Figure 1
The refined ABCD assessment tool
GOLD = Global Initiative for Chronic Obstructive Lung Disease; CAT = COPD assessment test; FEV1 = forced 
expiratory volume in 1 second; FVC = forced vital capacity; mMRC = Modified British Medical Research Council 
Questionnaire
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
27
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
28
In addition to the airflow limitation, number of exacerbation per year and 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 Typically GOLD 1 or GOLD 2 (Mild 
or Moderate airflow limitation); and/or 0-1 exacerbation per year and no 
hospitalization for exacerbation; and CAT score < 10 or mMRC grade 0-1

Patient Group B – Low Risk, More Symptoms Typically GOLD 1 or GOLD 2 (Mild 
or Moderate airflow limitation); and/or 0-1 exacerbation per year and no 
hospitalization for exacerbation; and CAT score ≥ 10 or mMRC grade ≥ 2

Patient Group C – High Risk, Less Symptoms Typically GOLD 3 or GOLD 4 
(Severe or Very Severe airflow limitation); 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 Typically GOLD 3 or GOLD 4 
(Severe or Very Severe airflow limitation); and/or ≥ 2 exacerbations per year or ≥ 1 
with hospitalization for exacerbation; and CAT score ≥ 10 or mMRC grade ≥ 2.
The airflow limitation in COPD is associated with an enhanced and chronic inflammatory 
response to noxious particles and gases in the airways and the lungs [Hogg, 2004]. The 
most important environmental risk factor for COPD is tobacco smoking. However, 
long-term exposure to traffic pollution and biomass smoke are also important 
contributors. Indoor air pollution (generated largely by inefficient and poorly ventilated 
stoves burning biomass fuels such as wood, crop waste and dung, or coal) for instance 
accounts for the high prevalence of COPD among non-smoking women in parts of the 
Middle East, Africa and Asia WHO, 2013.
COPD is the fifth leading cause of mortality worldwide, accounting for 6% of all deaths 
globally [WHO, 2015]. A recent study reported high overall morbidity and mortality rates 
due to COPD in the Asia Pacific region. The prevalence of moderate to severe COPD in 
adults aged 30 years or above was estimated to be 5.9% in South Korea, 5.4% in Taiwan, 
4.7% in Australia and 3.5% in Hong Kong [Tan, 2009]. The overall estimated prevalence 
COPD in Asia-Pacific was estimated to be 6.2% with 19.1% having severe COPD [Lim, 
2015]. The prevalence and burden of COPD are projected to continue to increase in the 
coming decades due to continued exposure to risk factors and the changing age structure 
of the world’s population [Mathers, 2006. In Asia, urbanisation is expected to play a 
major role in the increase of the number of prevalent cases of COPD between 2010 and 
2020 [Tan, 2009. In terms of the number of deaths, the burden of disease is higher in the 
Asia-Pacific region when compared to the industrialised western countries. It was 
estimated through mathematical modelling that 56.6 million people aged 30 years had 
moderate to severe COPD with a prevalence rate of 6.3% [Ko, 2008].
The morbidity and mortality of COPD is substantially contributed to by acute 
exacerbations of COPD (AECOPD). An AECOPD is defined as “a clinical diagnosis of 
exclusion, made when a patient with COPD experiences an acute worsening in 
respiratory symptoms (typically dyspnoea, cough, sputum quantity and/or sputum 
purulence), and in whom no alternative specific cause for that deterioration has been 
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
28
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
29
identified by clinical examination and/or corroborative testing. The worsening in 
respiratory symptoms may or may not warrant a change in underlying therapy and the 
symptoms will typically resolve over a period of days to weeks” [ERS/ATS Draft Task 
Force Recommendations, Major Symposium, ERS Scientific Congress Barcelona 2013. 
AECOPD are often associated with concurrent deteriorations in pulmonary function and 
increases in both local and systemic inflammation. 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 hospitalisation. Between 40 - 60% of medical 
expenditure for COPD is a direct consequence of AECOPD Cazzola, 2008. The severity 
of AECOPD can be graded according to the intensity of medical intervention required 
(see Table 2) [Wedzicha, 2007.
Table 2
Classification of severity of AECOPD
Grade
Intensity of medical intervention
Mild
Controlled with an increase in dosage of regular medications 
Moderate
Requires treatment with systemic corticosteroids and/ or antibiotics
Severe
Requires hospitalisation 
Bacteria, viruses and environmental pollution are also thought to be important causes of 
AECOPD [Sapey, 2006:

The lungs are not sterile and are known to be colonised with different strains of 
bacteria [Charlson, 2011; Erb-Downward, 2011; Monsó, 1995]. It has been 
suggested that the bronchial bacterial load increases during AECOPD [Miravitlles, 
2002; Wilkinson, 2006. Based on a recent literature review, the most frequent 
bacterial pathogens identified during AECOPD in European countries and in the 
USA were Haemophilus influenzae (H. influenzae), Streptococcus pneumoniae 
(S. pneumoniae), Moraxella catarrhalis (M. catarrhalis), Pseudomonas aeruginosa
(P. aeruginosa) and Staphylococcus aureus (S. aureus) [Mapi Research Trust-
literature review for GlaxoSmithKline (GSK) Biologicals. However, it has been 
suggested that the infectious aetiology of AECOPD can vary according to 
geographical region. In Asia, a rise in infections caused by P. aeruginosa and the 
Gram-negatives Klebsiella pneumoniae (K. pneumoniae) and Acinetobacter 
baumannii (A. baumannii) has been reported in several countries [Hui, 2011; Ye, 
2013]. In addition, the infectious aetiology of AECOPD has also been suggested to 
vary according to the severity of the illness, with P. aeruginosa being particularly 
common in patients with advanced disease Domenech, 2013; Ko, 2007.

The most commonly detected viruses during AECOPD are Human Rhinoviruses 
(HRV), RSV, coronaviruses, influenza, parainfluenza and adenoviruses [De Serres, 
2009; Sapey, 2006]. It has also been shown that viruses can be present in the airways 
of stable COPD patients, suggesting that some respiratory viruses may cause 
persistent low-grade infection contributing to the pathogenesis of disease [Mohan, 
2010].

Mixed bacterial and viral co-infections occur in 8-58% of exacerbations [De Serres, 
2009; Hutchinson, 2007; Papi, 2006; Perotin, 2013; Wilkinson, 2006]. 
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
29
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
30
AECOPD is sudden worsening of COPD symptoms. Many studies have attempted to 
measure the burden of bacterial or viral infections in patients with AECOPD, but very 
few have investigated the presence of mixed viral and bacterial infections both in stable 
COPD patients and during AECOPD.
1.2.
Rationale for the study
Because the infectious aetiology of AECOPD has been suggested to vary according to 
geographical region, the primary purpose of this study (which will be conducted in 
several countries in Asia Pacific) is to evaluate the occurrence of potential bacterial and 
viral pathogens in the sputum of stable COPD patients and at the time of AECOPD. 
Given the increasing and projected burden of COPD in the Asia Pacific region, this study 
will also evaluate the frequency, severity and duration of AECOPD, as well as the impact 
of AECOPD on health-related quality of life (HRQOL), healthcare utilisation and lung 
function.
In addition, both PCR and bacteriological methods will be used for characterisation and 
(quantification in some cases) of bacteria in sputum. To date, identification of bacteria 
and assessment of bacterial load is done in the vast majority of cases by culture. 
However, the few studies that have compared culture with PCR demonstrated that PCR is 
more discriminatory at detecting typical airway bacteria [Curran, 2007;Singh, 2014. 
Moreover, in a multi-centre study, PCR has the advantage that it can be performed on 
stored sputum samples, and can therefore be done centrally, whereas culture has to be 
performed on fresh sputum samples, which can lead to variable results due to variability 
in testing methods between laboratories.
2.
OBJECTIVES
2.1.
Primary objective

To estimate the proportion of potential bacterial and viral pathogens (overall and by 
species) detected in sputum of stable COPD patients and during AECOPD, using 
respectively bacteriological methods and viral PCR, over the course of 1 year.
Refer to Section 9.1.1 for the definition of the primary endpoint.
2.2.
Secondary objectives

To evaluate the concordance between PCR and bacteriological methods data in 
sputum for potential bacterial pathogens.

To estimate the proportion of potential bacterial and viral pathogens (overall and by 
species) detected in sputum of stable COPD patients, by GOLD grade.

To estimate the proportion of potential bacterial and viral pathogens (overall and by 
species) detected in sputum during AECOPD, by severity of AECOPD.

To estimate the incidence rate of all-cause AECOPD, overall and by GOLD grade.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
30
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
31

To describe the severity and duration of all-cause AECOPD, overall and by GOLD 
grade.

To assess the impact of all-cause AECOPD on HRQOL.

To assess the impact of all-cause AECOPD on lung function.

To assess the impact of all-cause AECOPD on healthcare utilisation.
Refer to Section 9.1.2 for the definition of the secondary endpoints.
2.3.
Tertiary objective(s)

To assess the use of EXACT-PRO for determining the end date of AECOPD.

To evaluate the load of bacterial and viral pathogen in stable COPD and during 
AECOPD.

To collect biological specimens for future respiratory disease-related testing:

Aliquots of sputum samples for assay development and microbiome analysis at 
stable visits and during exacerbation.

Blood sampling for potential identification/quantification of biomarkers at Visit 
1 and Visit 3.

Bacterial isolates for further strain characterisation.
Refer to Section 9.1.3 for the definition of the tertiary endpoints.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
31
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
32
3.
STUDY DESIGN OVERVIEW
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), are essential and 
required for study conduct.
Figure 2 presents an overview of the study design.
Figure 2
Study design overview
Type of design: Prospective, epidemiological, interventional, multi-country, cohort study.

Study population: A cohort of approximately 200 moderate to very severe COPD 
patients with at least 1 documented moderate or severe AECOPD in the year before 
enrolment.

Type of study: self-contained.

Data collection: Electronic Case Report Form (eCRF) and electronic diary cards.

Primary completion Date: Visit 3 (Month 12). Refer to glossary of terms for the 
definition of PCD.

End of Study (EoS): Last testing results released of samples collected at Visit 3.

Duration of the study: The study will last approximately 1 year for each subject from 
screening visit up to study conclusion.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
32
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
33
Note: Screening visit should ideally occur not more than 6 weeks before visit 1.

Epoch 001: Prospective data collection starting at Screening Visit (Pre-month 0) 
and ending at Visit 3 (Month 12).
Table 3
Study groups and epochs foreseen in the study
Study Groups
Number of 
subjects
Age
Epoch
Epoch 001
Prospective
Approx 200
40 years
X

Study visits/contacts:

Screening visit.

Three scheduled (stable) study visits occurring at 6 months intervals.

For each AECOPD: AECOPD visit (within 96 hours of the onset of the 
symptoms) and follow-up phone call(s) (at least every 2 weeks until the 
AECOPD has resolved). Follow-up phone contacts will define end of AECOPD.

COPD symptoms
Subjects will be asked to record their COPD symptoms in an electronic Diary Card 
on a daily basis:

Daily in the morning throughout the study: Morning symptoms questionnaire.

Daily at bedtime throughout the study: EXACT-PRO (EXAcerbations of Chronic 
Pulmonary Disease Tool - Patient Reported Outcome) questionnaire.

Biological samples:

Sputum samples collected at site (spontaneous or induced, as per investigator 
judgement) will be collected at each study visit at the site (scheduled stable
visits and AECOPD visits) if, in the opinion of the investigator, it is safe for the 
subject.
Or 

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. 
This is not allowed at scheduled visits when 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).

Blood samples for biomarker testing will be collected at Visit 1 (M0) and Visit 
3 (M12).
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
33
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
34

HRQOL assessments

Subjects will be asked to complete the COPD assessment Test (CAT) at each 
study visit (scheduled stablevisits and AECOPD visits).

Subjects will be asked to complete the St. George’s Respiratory Questionnaire 
for COPD patients (SGRQ-C) at each scheduled (stable) study visit (Visit 1 
Month 0, Visit 2 Month 6and at Visit 3 Month 12).

Pre- and post-bronchodilator spirometry assessments will be done for all subjects at 
Screening Visit (pre-Month 0) and at Visit 3 (Month 12).
3.1.
Discussion of study design
The primary objective of this study is to prospectively investigate the prevalence and 
distribution of bacteria and viruses isolated from sputum samples from moderate to very 
severe COPD patients and at the time of AECOPD, in Asian populations. In order to 
increase the chance that the patients will exacerbate during the study, only patients with a 
documented history of at least 1 moderate or severe AECOPD in the previous year will 
be recruited, as this is known to be the best predictor of AECOPD [Hurst, 2010. 
Therefore, this study will permit an estimation of incidence of AECOPD in a COPD 
population at increased risk of exacerbation. It will not provide a true population-based 
incidence of AECOPD. 
In order to study factors affecting disease progression in Asia Pacific, prospective data 
from a relatively large cohort of COPD patients is essential. The use of electronic Diary 
Cards to detect changes in the respiratory symptoms that define an AECOPD, the 
standardised questionnaires and spirometry assessments will allow robust conclusions to 
be drawn about the effects of exacerbations on decline in lung function and HRQOL. 
EXACT PRO will be used to assess breathlessness, cough and presence of sputum, chest 
symptoms, difficulty bringing up sputum, feeling tired or weak, sleep disturbance, and 
feeling scared or worried about their condition. Advantages to this approach include 
standardised data, reduced recall bias, and the potential to identify events and determine 
resolution based on a predefined scoring algorithm Leidy, 2011. Standardised 
questionnaires completed during study visits include the SGRQ-C and the CAT. The 
SGRQ-C is designed to assess HRQOL, current health and does not specify a recall 
period. The CAT is a simple, short, patient-completed instrument to assess HRQOL and 
symptom burden in patients with COPD. The CAT has good internal consistency and 
test-retest reliability, correlates strongly with the SGRQ-C, and is able to distinguish 
between stable patients and those undergoing an AECOPD Jones, 2012.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
34
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
35
3.1.1.
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, colds (nasal discharge 
and/or nasal congestion), fever (oral temperature 37.5°C) without other cause, 
increased cough, increased wheeze.
Note that: 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 or medically qualified individual contacts the subject to 
determine if the alert is an AECOPD or not, and if an AECOPD visit is warranted. 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 or medically qualified individual 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 or medically qualified individual concludes that the subject is not
experiencing an AECOPD, this should be documented/ reported in the electronic 
Diary website (StudyWorks). Please refer to study procedures manual (SPM) for 
more details on how to perform this.

If the investigator or medically qualified individual concludes that the subject may be 
experiencing an AECOPD, 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.

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.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
35
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
36
During the AECOPD visit, the investigator will 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/delegate 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 investigator/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 record should be obtained), or 
the subject is on holidays or not able to go the site.
3.1.1.1.
Date of onset and end date of AECOPD
The date of onset 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.
The end date should be based on when the investigator determines that the AECOPD 
symptoms have resolved. In determining this end date, consideration should be given to 
symptoms recorded in the electronic Diary Card and subject assessment during the phone 
calls.
Both start and end date of each confirmed AECOPD occurring from the screening visit to 
study conclusion will be recorded in the eCRF.
3.1.1.2.
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.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
36
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
37
4.
STUDY POPULATION
This will be a multi-country study to be conducted in Asia Pacific.
4.1.
Number of subjects/ centres
The target is to enrol approximately 200 eligible moderate to very severe COPD patients. 
Refer to Section 9.2 for a detailed description of the criteria used to estimate the sample 
size.
4.1.1.
Recruitment of study centres
Centres will be selected for study participation based on the following criteria:

Experience with patients with respiratory disorders.

Able to perform microbiology testing. Please refer to SPM for details on the 
requirements to be met for microbiology testing.

No limitations on the quantity of export of biological samples to GSK Biologicals or 
to designated laboratories.
4.2.
Inclusion criteria for enrolment
Deviations from inclusion criteria are not allowed because they can potentially jeopardise 
the scientific integrity of the study and 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., completion of electronic Diary Card, sputum 
sampling, pre- and post-bronchodilator spirometry, return for follow-up visits).

Written informed consent obtained from the subject.

Male or female aged 40 years or older at the time of enrolment.

Confirmed diagnosis of moderate to very severe COPD based on post-bronchodilator 
spirometry (i.e. forced expiratory volume in 1 second FEV1over forced vital 
capacity FVCratio FEV1/ FVC< 0.7 and FEV1 < 80% predicted GOLD grades 
2, 3 and 4.

Stable COPD patient* with documented history** (e.g. medical record verification) 
of at least 1 moderate or severe AECOPD within the 12 months before study entry.
* Patient for whom the last episode of AECOPD is resolved for at least 30 days at 
the time of study entry.
**Note: 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 
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
37
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
38
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 SPM for details on what is accepted as documented history of AECOPD. 
Refer to Table 2 for the definitions of moderate and severe AECOPD.

Current or former tobacco smoker (cigarette) with a smoking history of ≥ 10 pack-
years OR a subject exposed to biomass smoke for 20 years [Guoping Hu, 2010]
Refer to the glossary of terms for the definitions of pack-years, current and former 
smoker.

Able to provide a sputum sample at Screening Visit.
4.3.
Exclusion criteria for enrolment (Amended 19 October 2018)
Deviations from exclusion criteria are not allowed because they can potentially jeopardise 
the scientific integrity and 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:

Diagnosed with a respiratory disorder other than COPD (such as sarcoidosis, active 
tuberculosis or receiving tuberculosis treatment, clinically significant bronchiectasis, 
lung fibrosis, pulmonary embolism, pneumothorax, lung cancer diagnosed within the 
previous 5 years, current primary diagnosis of asthma in the opinion of the 
investigator), or chest X-ray 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.
* A chest X-ray must be taken at Screening Visit, if no chest X-ray taken within the 
previous 3 months is available.

Diagnosis of α-1 antitrypsin deficiency as the underlying cause of COPD.

Undergone or has had lung surgery 12 months before, or plans to have lung surgery 
12 months after, study entry.

Any confirmed or suspected immunosuppressive or immunodeficient condition, 
based on medical history and physical examination (no laboratory testing required).

Received chemotherapy within the 12 months before study entry.

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).
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
38
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
39

Administration of antibiotics within 1 month of study entry OR continuous 
administration of antibiotics (defined as more than 30 days in total) within 90 days 
before study entry*.
* Study entry is Visit 1. If this exclusion criteria is met during Screening Visit the 
patient can enter the study and this exclusion criteria will be reassessed during 
Visit 1.

Systemic administration of corticosteroids (PO/IV/IM) for more than 14 consecutive 
days within 90 days prior to informed consent.

Contraindication for spirometry testing (such as recent eye surgery, recent thoracic or 
abdominal surgery procedures, unstable cardiovascular status, recent myocardial 
infarction or pulmonary embolism).

Psychiatric illness or any other condition that interferes with the ability to understand 
the study procedures.

Pregnant female.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
39
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
40
5.
CONDUCT OF THE STUDY
5.1.
Regulatory and ethical considerations, including the 
informed consent process
The study will be conducted in accordance with the ICH Guideline for Good Clinical 
Practice (GCP) or other applicable guidelines, all applicable subject privacy requirements 
and the guiding principles of the Declaration of Helsinki.
GSK will obtain favourable opinion/approval to conduct the study prior to a site initiating 
the study in that country or will document that neither a favourable opinion nor an 
approval to conduct the study is needed.
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 Biologicals will provide full details of the above procedures to the investigator, 
either verbally, in writing, or both.
Freely given and written informed consent must be obtained from each subject, as 
appropriate, prior to participation in the study.
GSK Biologicals will prepare a model Informed Consent Form (ICF) which will embody 
the applicable ICH GCP or other applicable guidelines, and GSK Biologicals required 
elements. While it is strongly recommended that this model ICF 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.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
40
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
41
6.
DETAILED STUDY PROCEDURES (AMENDED 19
OCTOBER 2018)
6.1.
Subject identification
Subject numbers will be assigned sequentially to subjects consenting to participate, 
according to the range of subject numbers allocated to each study centre.
6.2.
General study aspects
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Procedures Manual (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.
6.3.
Outline of study procedures
Table 4 presents the study procedures involved during scheduled [stable] visits.
Table 4
List of study procedures for scheduled visits
Epoch
Epoch 001
Type of contact
Screening 
Visit
Visit 1
Visit 2
Visit 3
Time point
Pre-Month 0
Month 0
Month 6
Month 12
Informed consenta
●
Check inclusion/exclusion criteriaa
●
O
Record demographic dataa
●
Record medical history
●
Record history of AECOPD within the previous yearb
●
Record intercurrent comorbiditiesc
O
●
●
●
Record history of pneumococcal and influenza 
vaccination
O
●
●
●
Smoking exposure history (ATS-DLD-78A questionnaire)/ 
biomass exposure history (Biomass Exposure 
questionnaire)
O
Smoking status
●
●
●
●
Physical examination including vital signsh
●
O
O
O
Urine Pregnancy Test
●
●
●
●
Measure/ record height and weightd
●
●
Pre- and post-bronchodilator spirometrye
●
●
Chest X-rayf
●
Record subject’s COPD status (stable, recovered or not 
recovered)
●
●
●
Record current medication
●
●
●
Record healthcare resource utilisation
●
●
●
Record additional treatments prescribed by primary and 
secondary care physicians
●
●
●
Train subject on use of electronic Diary Card and assign 
electronic Diary Card to the subject
O
O
Return electronic Diary Card
O
Sputum samplingg
●
●
●
●
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
41
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
42
Epoch
Epoch 001
Type of contact
Screening 
Visit
Visit 1
Visit 2
Visit 3
Time point
Pre-Month 0
Month 0
Month 6
Month 12
Blood samples for biomarkers
●
●
Record Adverse Events (AEs)* ^
●
●
●
●
Record serious adverse events (SAEs) ^
●
●
●
●
Screening conclusion
●
Study conclusion
●
HRQOL questionnaires:
CAT
O
O
O
SGRQ-C
O
O
O
● is used to indicate a study procedure that requires documentation in the individual eCRF.
O is used to indicate a study procedure that does not require documentation in the individual eCRF.
a For non-eligible subjects, only informed consent, inclusion/ exclusion criteria, demographic data and SAEs related to 
study participation that occurred after signing the informed consent pages need to be completed in the subject’s eCRF. 
For other activities, ‘not done’ can be indicated. 
b Recordboth documented and self-reported, non-documented AECOPD. Subjects need documentation for at least 1 
moderate or severe AECOPD within the previous year to be eligible for study participation.
cSignificant comorbidities include weight loss, cardiovascular disease, hypertension, gastro-oesophageal reflux 
disease, osteoporosis/ osteopenia, skeletal muscle wasting and dysfunction, anxiety/ depression and diabetes.
dTo be recorded in the ‘Physical examination’ section of the eCRF.
eOnly study certified site staff can perform spirometry assessment.
fOnly if no chest X-ray is taken within the previous 3 months.
g Sputum can be collected spontaneously or can be induced, as per investigator judgement. Sputum sampling should 
only be done if, in the opinion of the investigator, it is safe for the subject.
* Non-serious AEs will be recorded in the eCRF and will not be entered into the safety database.
^ Refer to Table 10 for description of which AE/SAEs are collected in this study.
hPhysical examination (Visit1-3) should be done only if necessary by the investigator or delegate.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
42
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
43
Table 5 presents the list of study procedures for AECOPD visits.
Table 5
List of study procedures for AECOPD visits
Type of contact
AECOPD Visit
End of AECOPD phone call(s)
Time point
within 96 hours of onset 
symptoms
at least every 2 weeks as of 
AECOPD visit until AECOPD 
has resolvedi
Record date of visit
●
Physical examinationl
●
Urine Pregnancy Test
●
Chest X-rays/pneumonia confirmationj
●
Confirm AECOPD and record its start date
●
Record current medication for AECOPD
●
Record healthcare resource utilisation
●
Record additional COPD treatments prescribed by 
primary and secondary care physicians
●
Sputum samplingk
●
HRQOL questionnaire:
CAT
O
Record AECOPD severitym
●
●
Record AECOPD end date
●
Record Adverse Events (AEs)*^
●
●
Record serious adverse events (SAEs)^
●
●
● is used to indicate a study procedure that requires documentation in the individual eCRF.
iEnd of AECOPD phone calls/ visits should be scheduled at least every 2 weeks, until the AECOPD has resolved. Only 
the last phone call will be recorded in the eCRF as the end of the AECOPD phone call. All intermediate calls should be 
recorded on source documentation.
jOnly if clinically indicated to exclude another cause of worsening of symptoms (e.g. pneumonia). If a chest X-ray is 
clinically indicated but a chest X-ray/ CT scan has already been taken for that AECOPD as part of medical care before 
the study AECOPD visit takes places, the results of that chest X-ray/ CT scan can be used. All cases of pneumonia 
(including all signs and symptoms assessed to confirm pneumonia) should be documented in the eCRF.
kSputum can be collected spontaneously or can be induced, as per investigator judgement. Sputum sampling should 
only be done if, in the opinion of the investigator, it is safe for the subject.
l Physical examination should be done only if necessary by the investigator or delegate.
mAECOPD severity grading as indicated in Table 2.
*Non-serious AEs will be recorded in the eCRF and will not be entered into the safety database.
^ Refer to Table 10 for description of which AE/SAEs are collected in this study.
Table 6 presents the intervals between study visits.
Table 6
Intervals between study visits
Interval
Optimal length of interval
Allowed interval1
Screening Visit (pre-Month 0)Visit 1
14 days
42 days before Visit 1
Scheduled study visits
Visit 1 (Month 0) Visit 2 (Month 6)
182 days
175 - 203 days
Visit 2 (Month 6) Visit 3 (Month 12)
182 days
175 - 203 days
AECOPD-driven study visit(s) and/ or phone contacts
Onset AECOPD symptoms AECOPD Visit
-
max 96 hours2
1If an AECOPD occurs at the time one of the scheduled study visits is planned, 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 consultation with 
GSK, the concluding visit (Visit 3, Month 12) may however exceptionally be conducted outside of the allowed interval if 
necessary by the investigator.
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).
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
43
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
44
6.4.
Detailed description of study procedures
6.4.1.
Procedures during the Screening Visit
6.4.1.1.
Informed consent
The signed informed consent of the subject must be obtained before study participation 
during the screening visit. Refer to Section 5.1 for the requirements on how to obtain 
informed consent.
6.4.1.2.
Check inclusion and exclusion criteria
All applicable inclusion and exclusion criteria as described in Sections 4.2 and 4.3 will be 
checked before enrolment.
6.4.1.3.
Record demographic data
Demographic data such as date of birth, gender, geographic ancestry will be recorded in 
the subject’s eCRF.
6.4.1.4.
Record medical history
The subject’s medical history will be obtained by review of the subject’s medical records. 
Prior to study participation, any pre-existing conditions or signs and/or symptoms present 
in a subject will be recorded.
6.4.1.5.
Record AECOPD history within the previous year
Documented, self-reported and non-documented AECOPD should be recorded in the 
eCRF. However, for study participation the subject should have had at least one 
documented moderate or severe AECOPD episode within the previous year.
6.4.1.6.
Smoking exposure history (ATS-DLD-78A questionnaire)/biomass 
exposure history (At screening visit only)
The subject will be asked to complete the smoking history questionnaire (which is a 
shortened version of the American Thoracic Society-Division of Lung Diseases-78A 
[ATS-DLD-78A] questionnaire) by himself/herself. The subject will have to provide 
information about his/ her smoking history, including duration (number of years) and 
number of cigarettes smoked. Subject years exposed to biomass will be assessed from 
information obtained on indoor exposure to fuels such as wood, crop waste and dung, or 
coal.
From the information obtained via the questionnaire, calculation of the pack-years will be 
done for inclusion into the study. Please refer to the SPM for details on how to calculate 
pack years using this questionnaire and for guidance on administration of the exposure 
history questionnaire.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
44
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
45
6.4.1.7.
Smoking status
The subject’s smoking status (current or former smoker) will be recorded in the eCRF. 
Refer to the glossary of terms for the definitions of current and former smoker.
6.4.1.8.
Physical examination
At the screening visit, a complete physical examination of the subject will be performed 
which will include vital signs after at least 10 minutes of rest (systolic/ diastolic blood 
pressure, heart rate, respiratory rate). Collected information will be recorded in the eCRF.
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.
6.4.1.9.
Pregnancy test
Female subjects of childbearing potential are to have a urine pregnancy test prior to any 
study procedure. Note: The urine pregnancy test must be performed even if the subject is 
menstruating at the time of the study visit. The test should be carried out before 
performing chest x-ray. If the test is positive, the chest x- ray should not be performed 
and the subject should be withdrawn from the study.
6.4.1.10.
Measure/ record height and weight
The height and weight of the subject will be measured and recorded in the ‘Physical 
examination’ section of the eCRF.
6.4.1.11.
Pre- and post-bronchodilator spirometry
Pre- and post-bronchodilator spirometry should be performed during the screening visit. 
Only study-certified staff can perform spirometry assessment for this study. 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 during the Screening Visit a good quality spirometry was not obtained, the 
spirometry can be repeated, as per investigator’s medical judgement. If a repeat 
spirometry is elected, the site should make all possible efforts to repeat the spirometry 
preferably within 7 days of the previous spirometry. 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.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
45
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
46
6.4.1.12.
Chest X-ray
Screening - Baseline test
A posterior to anterior (PA) chest X-ray must be performed at the screening visit 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.
6.4.1.13.
Train subjects on the use of electronic Diary Card and assign electronic 
Diary Card to subject

From screening visit to visit 1, 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. 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.

The site staff will follow electronic Diary Card completion closely and should 
provide timely input/guidance to ensure that the subject correctly completes the 
eDiary Card both AM & PM as per protocol.
In addition, site staff will pro-actively monitor electronic Diary Card compliance 
throughout the study and provide the necessary input to maintain compliance.
6.4.1.14.
Sputum sampling (Amended 19 October 2018)

Sputum samples will be collected during the screening visit if, in the opinion of the 
investigator, it is safe for the subject. If it is not safe, the sputum sample will not be 
collected and the subject will not be included in the study.

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.

At home, sputum collection will not be permitted.

Collected sputum will be diluted in DTT, processed and cultured within 6hrs of 
collection for microbiology testing.

Remaining DTT-sputum will be aliquoted as such. These samples will be kept at       
-70/80°C until shipment to GSK or GSK designated lab for testing.
Refer to the SPM and the Central Laboratory Investigator Manual for more details and 
guidance on handling of sputum samples.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
46
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
47
6.4.1.15.
Recording of AE/SAEs

Recording of AE/SAEs

Refer to Section 7.2 for procedures for the investigator to record AE/SAEs. Refer to 
Section 7.3 for guidelines on how to submit SAE reports to GSK Biologicals.

The subjects will be instructed to contact the investigator immediately should they 
manifest any signs or symptoms they perceive as serious.
6.4.1.16.
Screening conclusion
The investigator will review all the data collected during the screening visit to ensure 
accuracy and completeness.
6.4.2.
Procedures during Visit 1, Visit 2 and Visit 3
6.4.2.1.
Check inclusion and exclusion criteria 
At visit 1, all applicable inclusion and exclusion criteria as described in Sections 4.2 and 
4.3 will be checked before enrolment.
6.4.2.2.
Record intercurrent comorbidities
Significant comorbidities include, but is not limited to, weight loss, cardiovascular 
disease, hypertension, gastro-oesophageal reflux disease, osteoporosis/ osteopenia, 
skeletal muscle wasting and dysfunction, anxiety/ depression and diabetes.
6.4.2.3.
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).
6.4.2.4.
Smoking status
The subject’s smoking status (current or former smoker) will be recorded in the eCRF. 
Refer to the glossary of terms for the definitions of current and former smoker.
6.4.2.5.
Physical examination
Physical examination at each study visit (Visit 1, Visit 2 and Visit 3) will be performed 
only if deemed necessary by the investigator or delegate.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
47
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
48
6.4.2.6.
Pregnancy test (Amended 19 October 2018)
Female subjects of childbearing potential are to have a urine pregnancy test prior to any 
study procedure. Note: The urine pregnancy test must be performed even if the subject is 
menstruating at the time of the study visit. 
6.4.2.7.
Measure/ record height and weight
The height and weight of the subject will be measured at Visit 3 and recorded in the 
‘Physical examination’ section of the eCRF.
6.4.2.8.
Pre- and post-bronchodilator spirometry
Pre- and post-bronchodilator spirometry should be performed during Visit 3 as detailed in
Table 4. Only study-certified staff can perform spirometry assessment for this study. 
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 during Visit 3 a good quality spirometry was not obtained, the spirometry can 
be repeated, as per investigator’s medical judgement. If a repeat spirometry is elected, the 
site should make all possible efforts to repeat the spirometry preferably within 7 days of 
the previous spirometry. 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.
6.4.2.9.
Record subject’s COPD status
The subject’s COPD status (stable/ recovered or not recovered) will be recorded in the 
eCRF.
6.4.2.10.
Record current medication (Amended 19 October 2018)

At each study visit/contact, the investigator should question the subject about any 
medications taken.

All medications administered will be recorded in the eCRF.
6.4.2.11.
Record healthcare resource utilisation
Healthcare use will be obtained through review of the subject’s medical record (aided by 
subject self-reporting). Healthcare 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 Card and reported in the 
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
48
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
49
eCRF at study visit. Refer to the SPM for more details and guidance on recording of 
healthcare use.
6.4.2.12.
Additional treatments prescribed by primary and secondary care 
physician
All treatments prescribed by the primary and secondary healthcare physician will be 
recorded in the eCRF.
6.4.2.13.
Train subjects on the use of electronic Diary Card and assign electronic 
Diary Card to subject

From screening visit to visit 1, 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. 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.

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.
6.4.2.14.
Return the electronic diary card
On the last visit (Visit 3), the site staff will pro-actively check with the subjects on 
whether he/she has returned the electronic Diary Card.
6.4.2.15.
Sputum sampling (Amended 19 October 2018)

Sputum samples will be collected during the scheduled visits, 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.

At home, sputum collection will not be permitted.

Collected sputum will be diluted in DTT, processed and cultured within 6hrs of 
collection for microbiology testing 

Remaining DTT-sputum will be aliquoted as such. These samples will be kept at       
-70/80°C until shipment to GSK or GSK designated lab for testing.
Refer to the SPM and the Central Laboratory Investigator Manual for more details and 
guidance on handling of sputum samples.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
49
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
50
6.4.2.16.
Blood Sampling

Blood samples for biomarker analysis will be taken at the scheduled visits; Visit 1 
(M0) and Visit 3 (M12), including:

Hematology profile, including differential cell counts
o
Approximately 2.0 mL of whole blood will be collected for hematology 
assessment. These samples should be kept at room temperature and shipped 
on the day of collection, ambient.

Specific biomarkers will include serum hsCRP, CXCL10 (IP-10) and plasma 
fibrinogen, may include other biomarkers based on results of ongoing disease 
understanding research.
o
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.
o
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.
o
Approximately 6.0 mL of whole blood (EDTA) will be collected and 
processed to plasma for other biomarker assessment. After processing, these 
samples should be kept at -70/-80°C until shipment.
Refer to the SPM and the Central Laboratory Investigator Manual for more details and 
guidance on the collection, handling, and processing of blood samples.
6.4.2.17.
HRQOL questionnaires 

The subject will be asked to complete the HRQOL questionnaires by himself/herself, 
during specified study visits directly in the electronic Diary Card as detailed in Table 
4 and Table 5.

Refer to the SPM for more details and guidance on the HRQOL questionnaires.
6.4.2.18.
Recording of AE/SAEs

Refer to Section 7.2 for procedures for the investigator to record AE/SAEs. Refer to 
Section 7.3 for guidelines on how to submit SAE reports to GSK Biologicals.

The subjects will be instructed to contact the investigator immediately should they 
manifest any signs or symptoms they perceive as serious.
6.4.2.19.
Study conclusion
The investigator will:

Review all the data collected to ensure accuracy and completeness 

Complete the Study Conclusion screen in the eCRF.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
50
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
51
6.4.3.
Procedures during AECOPD visit
6.4.3.1.
Record date of visit
If an AECOPD occurs at of the scheduled study visits, the date of visit should be 
document in the eCRF.
6.4.3.2.
Physical examination
Physical examination at the AECOPD visit will be performed only if deemed necessary 
by the investigator or delegate.
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.
6.4.3.3.
Pregnancy Test
Female subjects of childbearing potential are to have a urine pregnancy test prior to any 
study procedure. Note: The urine pregnancy test must be performed even if the subject is 
menstruating at the time of the study visit. The test should be carried out before 
performing chest x-ray. If the test is positive, the chest x- ray should not be performed 
and the subject should be withdrawn from the study.
6.4.3.4.
Chest X-rays/pneumonia confirmation
AECOPD visit test
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. new infiltrate for pneumonia 
cases).
All suspected pneumonias will require confirmation as defined by the presence of new 
infiltrate(s) on chest x-ray AND at least 2 of the following signs and symptoms: 

Increased cough,

Increased sputum purulence (colour) or production,

Auscultatory findings of adventitious sounds (e.g., egophony, bronchial breathing 
sounds, rales, etc),

Dyspnea or tachypnea,

Fever (oral temperature ≥37.5 °C),

Elevated WBC (>10,000/mm3 or >15% immature forms),

Hypoxemia (HbO2 saturation <88% or at least 2% lower than baseline value),
All incidences of pneumonia must be captured on the pneumonia page of the eCRF. 
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
51
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
52
The investigators and site staff should remain vigilant for the possible development of 
pneumonia in patients with COPD as the clinical features of such infections overlap with 
the symptoms of COPD exacerbations. For all suspected cases of pneumonia, 
investigators are strongly encouraged to confirm the diagnosis (this includes obtaining a 
chest x-ray) and to initiate appropriate therapy as promptly as possible.
Please refer to SPM for details on what should be considered for pneumonia 
confirmation. 
6.4.3.5.
Confirm AECOPD and record start date
The investigator should confirm the AECOPD based on his/her medical judgement. The 
date of onset of AECOPD will be determined as detailed in Section 3.1.1.1 and will be 
documented in the eCRF.
6.4.3.6.
Record current medication for AECOPD

At each study visit/contact, the investigator should question the subject about any 
medications administered for treatment of AECOPD.

All medications administered for treatment of AECOPD will be recorded in the 
eCRF.
6.4.3.7.
Record healthcare resource utilisation
Healthcare use will be obtained through review of the subject’s medical record (aided by 
subject self-reporting). Healthcare 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 the eDiary Card and reported in the 
eCRF at study visit. Refer to the SPM for more details and guidance on recording of 
healthcare use.
6.4.3.8.
Additional COPD treatments prescribed by primary and secondary care 
physician
All treatments prescribed by the primary and secondary healthcare physician will be 
recorded in the eCRF.
6.4.3.9.
Sputum sampling (Amended 19 October 2018)

Sputum samples during AECOPD should preferably be obtained before 
administration of the first dose of antibiotics to treat the AECOPD (if applicable). 
Sputum can be collected spontaneously or can be induced, as per investigator 
judgement. Sputum sampling should only be done if, in the opinion of the 
investigator, it is safe for the subject.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
52
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
53

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. This is not 
allowed at scheduled visits when subject should be in stable condition.

Collected sputum will be diluted in DTT, processed and cultured within 6hrs of 
collection for microbiology testing.

Remaining DTT-sputum will be aliquoted as such. These samples will be kept at       
-70/80°C until shipment to GSK or GSK designated lab for testing.
Refer to the SPM and the Central Laboratory Investigator Manual for more details and 
guidance on handling of sputum samples.
6.4.3.10.
HRQOL questionnaires 

The subject will be asked to complete the HRQOL questionnaire (CAT only) by 
himself/herself directly in the electronic Diary Card, during the AECOPD visit as 
detailed in Table 5.

Refer to the SPM for more details and guidance on the HRQOL questionnaires.
6.4.3.11.
Record AECOPD severity and AECOPD end date
The severity and end date of each confirmed AECOPD will be recorded in the eCRF. The 
AECOPD severity will be assessed using the AECOPD severity scale (refer Table 2) and 
the AECOPD end date will be determined as detailed in Section 3.1.1.1 and Section 
3.1.1.2.
6.4.3.12.
Recording of AE/SAEs

Refer to Section 7.2 for procedures for the investigator to record AE/SAEs. Refer to 
Section 7.3 for guidelines on how to submit SAE reports to GSK Biologicals.

The subjects will be instructed to contact the investigator immediately should they 
manifest any signs or symptoms they perceive as serious.
6.4.4.
Sampling
6.4.4.1.
Sputum Sampling

Sputum sampling: Refer to section 6.4 for description of the sampling procedure.
Full details for obtaining sputum samples are provided in the Module on Biospecimen 
Management in the SPM and in the Central Laboratory Investigator Manual
accompanying this protocol.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
53
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
54
6.4.4.2.
Blood Sampling
Blood sampling: Refer to section 6.4 for the description of sampling procedure. 
Full details for the collection, handling, and processing of blood samples are provided in 
the Module on Biospecimen Management in the SPM and in the Central Laboratory 
Investigator Manual accompanying this protocol.
6.4.5.
Health Related Quality of Life questionnaires 
Refer to section 6.4.2 for description of the Quality of Life (QoL) questionnaire. The 
subject will be asked to complete the HRQOL questionnaires by himself/herself, during 
specified study visits directly in the electronic Diary Card.
6.4.6.
Recording of AEs/SAEs

Refer sections 6.4.1.15, 6.4.2.18 and 6.4.3.12 for recording of AEs/SAEs.
6.4.7.
Study conclusion
Refer section 6.4.2.19 for study conclusion.
6.5.
Biological sample handling and analysis
Please refer to the SPM and the Central Laboratory Investigator Manual for details of 
biospecimen management (handling, storage and shipment).
Samples will not be labelled with information that directly identifies the subjects but will 
be coded with the identification number for the subject (subject number).

Collected samples will be used for protocol mandated research. In addition, these 
samples may be used to perform research related to the improvement, development 
and quality assurance of the laboratory tests described in this protocol. This may 
include the management of the quality of these tests, the maintenance or 
improvement of these tests, the development of new test methods, as well as making 
sure that new tests are comparable to previous methods and work reliably.

It is also possible that future findings may make it desirable to use the samples 
acquired in this study for future research, not described in this protocol. Therefore, 
all subjects in countries where this is allowed will be invited to give another specific 
consent to allow GSK or a contracted partner to use the samples for future research 
including development of tests and their quality assurance. 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.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
54
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
55
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/contact), 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.
6.5.1.
Use of specified study materials
When materials are provided by GSK Biologicals or the central laboratory, it is 
MANDATORY that all 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 analysis. The investigator must ensure that his/her personnel and the 
laboratory(ies) under his/her supervision comply with this requirement. However, when 
GSK Biologicals or the central laboratory does not provide material for collecting and 
storing samples, appropriate materials from the investigator’s site must be used. Refer to 
the Module on Clinical Trial Supplies in the SPM and Central Laboratory investigator 
manual.
6.5.2.
Biological samples
Table 7 present the biological samples that will be collected for this study.
Table 7
Biological samples
Sample type
Quantity
Unit
Timepoints
Sub-cohort
Fresh Sputum
Maximum possible
ml
Screening visit (Pre-Month 
0)
All screened 
subjects

Visit 1 (Month 0)

Visit 2 (Month 6)

Visit 3 (Month 12)
All enrolled 
subjects

AECOPD visit (within 
96 hours of onset of 
symptoms)
Blood for 
biomarkers
21
ml

Visit 1 (Month 0)

Visit 3 (Month 12)
All enrolled 
subjects
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
55
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
56
6.5.3.
Laboratory assays (Amended 19 October 2018)
Please refer to APPENDIX A for the address of the clinical laboratories used for sample 
analysis.
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.
Standard bacteriological methods (and semi-quantitative counts) will be performed on 
fresh sputum samples at the investigator’s institution and/or at a laboratory designated by 
GSK Biologicals. Identification of potential bacterial pathogens will be performed 
according to agreed identification methods (potential pathogens including, but not 
necessarily limited to, H. influenzae, S. pneumoniae, M. catarrhalis, S. aureus, 
P. aeruginosa, K. pneumoniae and A. baumannii). All results should be entered in the 
eCRF.
Further bacterial characterization for H. influenzae isolates: Identified H. influenzae
isolates should be collected and stored in the investigator’s institution and will undergo 
further species confirmation (i.e. confirmed H. influenzae) and when possible, further 
differentiation (i.e., Hi/NTHi) at GSK Biologicals' laboratory or at a laboratory 
designated by GSK Biologicals using molecular techniques such as PCR. Identified 
H. influenzae isolates might undergo further testing at GSK Biologicals' laboratory or at a 
laboratory designated by GSK Biologicals’ using other molecular techniques such as 
PCR and sequencing.
Identified M. catarrhalis isolates should be collected and stored in the investigator’s 
institution and might undergo further species confirmation (and when possible, further 
differentiation) at GSK Biologicals' laboratory or at a laboratory designated by GSK 
Biologicals using molecular techniques such as PCR and sequencing.
Identified P. aeruginosa isolates should be collected and stored in the investigator’s 
institution and might potentially undergo further testing at GSK Biologicals' laboratory or 
at a laboratory designated by GSK Biologicals.
Further bacterial pathogens identification (including, but not necessarily limited to, H. 
influenzae, S. pneumoniae, M. catarrhalis, S. pyogenes, S. aureus and P. aeruginosa) and
quantification (for H. influenzae, S. pneumoniae, M. catarrhalis) on stored sputum 
samples will be performed at GSK Biologicals' laboratory or a laboratory designated by 
GSK Biologicals using qualitative PCR and/or quantitative PCR.
Viral pathogens identification (including, but not necessarily limited to, RSV, 
parainfluenza virus, enterovirus/ HRV, metapneumovirus, influenza virus, adenovirus, 
bocavirus and coronavirus) on stored sputum samples will be performed at GSK 
Biologicals' laboratory or a laboratory designated by GSK Biologicals using multiplex
reverse transcription polymerase chain reaction (RT-PCR).
In addition, some respiratory viral pathogens (such as HRV) will be quantified in stored 
sputum samples (or subset) using RT-PCR at GSK Biologicals' laboratory or at a 
laboratory designated by GSK Biologicals.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
56
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
57
Table 8 present the methods that will be used for identification of bacterial and viral 
pathogens.
Table 8
Microbiology
System
Component
Method
Scale
Laboratory
Quality assessment
Fresh sputum
Please refer to SPM and/or 
Central Laboratory Manual 
for components tested
Gram staining
Qualitative/ 
semi-
quantitative
Investigator institution or 
GSK designated 
laboratory
Bacterial pathogen identification
Fresh sputum
Respiratory bacterial 
pathogens
(including H. influenzae,
S. pneumoniae, 
M. catarrhalis, S. aureus,
P. aeruginosa, 
K. pneumoniae and A. 
baumannii)
Standard 
bacteriological 
culture and 
standard 
identification 
methods including 
semi-quantitative 
culture
Qualitative 
Investigator’s institution 
and/or at a laboratory 
designated by GSK 
Biologicals
Semi-
quantitative
H. influenzae 
isolates of positive 
H. influenzae culture 
plates
H. influenzae species 
confirmation and when 
possible Hi/NTHi 
differentiation
Sample collection for 
potential further 
characterisation
Molecular 
techniques such 
as differentiation 
PCR
Qualitative
GSK Biologicals 
laboratory* or designated 
laboratory
Stored sputum
Respiratory bacterial 
pathogens
(including H. influenzae,
S. pneumoniae, 
M. catarrhalis, S. aureus and
P. aeruginosa, 
Streptococcus pyogenes))
Multiplex PCR
Qualitative 
and/ or quant
itative
GSK Biologicals 
laboratory * or 
designated laboratory
Viral pathogen identification
Stored sputum
Respiratory viral pathogens 
(including RSV, 
parainfluenza virus, 
enterovirus/ HRV, 
metapneumovirus, influenza 
virus, adenovirus, bocavirus 
and coronavirus)
Multiplex-PCR
Qualitative
GSK Biologicals 
laboratory * or 
designated laboratory
Respiratory viral pathogens 
(such as HRV)
RT-PCR
Quantitative
GSK Biologicals 
laboratory* or designated 
laboratory
* GSK Biologicals laboratory refers to the Clinical Laboratory Sciences (CLS) in Wavre, Belgium; Rixensart, Belgium; 
Marburg, Germany.
Stored frozen sputum samples (in dithiothreitol [DTT]) might be used for assay 
development, such as assays for diagnostic purpose or for microbiome analysis and/or for 
assay validation/characterization purpose and/or quality control.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
57
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
58
Additional testing on stored sputum samples (such as, but not limited to, K. pneumoniae 
and A. baumannii PCR detection, quantitative PCR for other bacterial and/or viral 
pathogens, further characterisation of virus such as rhinovirus typing, pathogen 
genome/gene sequencing, pathogen quantitative/qualitative serotype-specific PCR, 
multilocus sequence typing, microarray typing, 16sRNA analysis) or on H. influenzae, M. 
catarrhalis and P. aeruginosa bacterial isolates (such as agglutination assays, further 
strain characterisation using new molecular biology tools) 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 respiratory diseases and/ or should such 
test(s) become available at GSK Biologicals’ laboratory or a laboratory designated by 
GSK.
Table 9 present the planned assays on serological samples.
Table 9
Planned assays on serological samples
Sample type
Component
Method
Scale
Laboratory
Plasma
Fibrinogen 
Per contract laboratory’s 
procedures
Quantitative
GSK 
Biologicals
or GSK 
designated 
lab
Serum
hsCRP
Per contract laboratory’s 
procedures
Quantitative
Serum
CXCL10 (IP-10)
Per contract laboratory’s 
procedures
Quantitative
Whole blood
Leukocytes (White 
Blood Cells) 
Per contract laboratory’s 
procedures
Quantitative 
Neutrophils *
Per contract laboratory’s 
procedures
Quantitative
Lymphocytes *
Per contract laboratory’s 
procedures
Quantitative
Eosinophils *
Per contract laboratory’s 
procedures
Quantitative
Basophils *
Per contract laboratory’s 
procedures
Quantitative
Monocytes *
Per contract laboratory’s 
procedures
Quantitative
Erythrocyte (Red 
Blood Cells) 
Per contract laboratory’s 
procedures
Quantitative
Haemoglobin 
Per contract laboratory’s 
procedures
Quantitative
Platelets
Per contract laboratory’s 
procedures
Quantitative
*For white blood cell differential counts
Additional testing for biomarkers on stored serum/plasma 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 respiratory diseases available at GSK 
Biologicals’ laboratory or a laboratory designated by GSK.
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.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
58
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
59
7.
SAFETY
The investigator or site staff is/are responsible during the study for the detection and 
documentation of events meeting the criteria and definition of an 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.
7.1.
Safety definitions
7.1.1.
Definition of an adverse event (Amended 19 October 2018)
An AE is any untoward medical occurrence in a subject, temporally associated with the 
use of a medicinal product, whether or not considered related to the medicinal product, or 
temporally associated with a study procedure.
Examples of an AE include 

Signs, symptoms, or the clinical sequelae of a suspected interaction.
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.

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.

Occurrence of a severe AECOPD, unless in the opinion of the Investigator this is 
related to study procedure.
7.1.2.
Definition of a serious adverse event
An 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.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
59
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
60
c.
Requires hospitalisation or prolongation of an 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 SAE.
d.
Results in disability/incapacity, 
Note: The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhoea, influenza like illness, and accidental trauma (e.g., sprained 
ankle) which may interfere or prevent everyday life functions but do not constitute a 
substantial disruption.
or
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.
7.1.3.
Clinical laboratory parameters and other abnormal assessments 
qualifying as AEs or SAEs
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 AEs or SAEs if they meet the 
definition of an AE or an SAE (refer to Sections 7.1.1 and 7.1.2). Clinically significant 
abnormal laboratory findings or other abnormal assessments that are present at baseline 
and significantly worsen following the start of the study will also be reported as AEs or 
SAEs. However, clinically significant abnormal laboratory findings or other abnormal 
assessments that are associated with the disease being studied, unless judged by the 
investigator as more severe than expected for the subject’s condition, or that are present 
or detected at the start of the study and do not worsen, will not be reported as AEs or 
SAEs.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
60
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
61
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.
7.2.
Detecting and recording AEs, SAEs
7.2.1.
Time periods for detecting and recording AEs and SAEs
AEs and SAEs related to study participation will be collected and recorded from the time 
of the first study visit until the subject is discharged from the study.
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) will be collected and recorded from the time the subject consents to participate 
in the study/study start until she/he is discharged from the study.
AEs leading to withdrawal from the study, will be collected and recorded from the time 
of the first study visit until the subject is discharged from the study.
An overview of the protocol-required reporting periods for SAEs and AEs leading to 
withdrawal is given in Table 10.
Table 10
Reporting period for SAE and AEs leading to withdrawal (Amended 
19 October 2018)
Study activity
Screening 
Visit
Visit 1
Visit 2
Visit 3
AECOPD
Visit
Study 
Conclusion
Pre-Month 
0
M 0
M 6
M 12
Within 96 
hours of 
onset 
symptoms
AEs/SAEs 
related to 
study 
participation*
AEs/SAEs
leading to 
withdrawal 
from the 
study
*Study participation: Specific procedures required by study participation.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
61
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
62
7.2.2.
Evaluation of SAEs (Amended 19 October 2018)
7.2.2.1.
Active questioning to detect SAEs
Each subject/ will be instructed to contact the investigator immediately should the subject 
manifest any signs and symptoms (s)he perceives/ they perceive as serious. However, an 
occurrence of severe AECOPD is not defined as an SAE and therefore does not need to 
be reported as such, unless in the opinion of the Investigator this is related to a study 
procedure.
All SAEs either observed by the investigator or his/ her staff or reported by the subject 
spontaneously or in response to a direct question will be evaluated by the investigator. 
The nature of each event, date and time of onset, outcome, intensity and possible 
relationship to the study procedures should be established.
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 the 
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.
7.2.2.2.
Assessment of causality
The investigator should assess the causality of each SAE. The investigator will use 
clinical judgement to determine the relationship between the SAEs and study 
participation. Alternative causes, such as natural history of the underlying diseases, other 
concomitant therapy and other risk factors will be considered and investigated.
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 SAE 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. 
If an event meets the criteria to be considered as ‘serious’ (see section 7.1.2), additional 
examinations/tests will be performed by the investigator in order to determine ALL 
possibly contributing factors to each SAE.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
62
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
63
Possibly contributing factors include:
!
Medical history.
!
Concomitant medication.
!
Protocol required procedure.
!
Other procedure not required by the protocol.
7.2.2.3.
Assessment of outcomes
The investigator will assess the outcome of all 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).
7.3.
Reporting of SAEs
7.3.1.
Prompt reporting of SAEs related to study participation to GSK
SAEs that occur in the time period defined in Section 7.2.1 will be reported promptly to 
GSK within the timeframes described in Table 11 once the investigator determines that 
the event meets the protocol definition of an SAE.
Table 11
Timeframes for submitting SAEs related to study participation to 
GSK
Type of event
Initial reports
Follow-up of relevant information
on a previous report
Timeframe
Documents
Timeframe
Documents
SAEs related to study 
participation
24 hours*
Electronic/
Expedited Adverse 
Event Report
24 hours*
Electronic/
Expedited Adverse Event Report
* Timeframe allowed after receipt or awareness of the information.
7.3.2.
Contact information for reporting SAEs to GSK 
Back-up Study Contact for Reporting SAEs
24/24 hour and 7/7 day availability:
GSK Biologicals Clinical Safety & Pharmacovigilance
Fax: 
 or 

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
63
19-OCT-2018
PPD
PPD

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
64
7.3.3.
Completion and transmission of SAEs reports related to study 
participation to GSK
Once an investigator becomes aware that an SAE has occurred in a study subject, the 
investigator (or designee) must complete the information in the electronic Expedited 
Adverse Event 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 an SAE, the report should still be completed within 24 
hours. Once additional 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.
7.3.3.1.
Back-up system in case the electronic reporting system does not work
If the electronic reporting system does not work, the investigator (or designee) must 
complete, then date and sign a paper Expedited Adverse Event Report and fax it to the 
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 designee) must complete the electronic Expedited Adverse 
Event Report within 24 hours. The final valid information for regulatory reporting will be 
the information reported through the electronic reporting system.
7.3.4.
Updating of SAE after freezing of the subject’s eCRF
When SAE information is received after freezing of the subject’s eCRF, new or updated 
information should be recorded on a paper Expedited Adverse Event Report, with all 
changes signed and dated by the investigator. The updated report should be faxed to the 
GSK Biologicals Clinical Safety and Pharmacovigilance department or to the Study 
Contact for Reporting SAEs (see the Sponsor Information) within the designated 
reporting time frames specified in Table 11.
Note: For studies using INFORM, freezing of the subject’s eCRF would mean removal of 
write access in the subject’s eCRF.
7.3.5.
Regulatory reporting requirements for SAEs
The investigator will promptly report all SAEs to GSK Biologicals in accordance with the 
procedures detailed in Section 7.3.1. GSK Biologicals has a legal responsibility to 
promptly notify, as appropriate, both the local regulatory authority and other regulatory 
agencies about the safety of a product under epidemiological 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.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
64
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
65
7.4.
Treatment of AEs
Treatment of any AE is at the sole discretion of the investigator and according to current 
good medical practice. Any medication administered for the treatment of a SAE (that are 
required to be reported as per protocol should be recorded in the Expedited Adverse 
Event Report of the subject’s eCRF.
8.
SUBJECT COMPLETION AND WITHDRAWAL
8.1.
Subject completion
A subject who returns for the concluding visit foreseen in the protocol is considered to 
have completed the study.
8.2.
Subject withdrawal
Subjects who are withdrawn because of AEs or SAEs related to study participation must 
be clearly distinguished from subjects who are withdrawn for other reasons.
From an analysis perspective, a ‘withdrawal’ from the study refers to any subject who did 
not come back for the concluding contact foreseen in the protocol.
All data collected until the date of withdrawal/last contact of the subject will be used for 
the analysis.
A subject is considered a ‘withdrawal’ from the study when no study procedure has 
occurred, no follow-up has been performed and no further information has been collected 
for this subject from the date of withdrawal/last contact.
Investigators will make an attempt to contact those subjects who do not return for 
scheduled visits or follow-up. The mode of contact will be by telephone. Three phone 
contacts will be made with an interval of one week between each phone call.
Information relative to the withdrawal will be documented in the eCRF. The investigator 
will document whether the decision to withdraw a subject from the study was made by 
the subject himself/herself or by the investigator, as well as which of the following 
possible reasons was responsible for withdrawal:

SAE.

Non-serious AE.

Protocol violation (specify).

Consent withdrawal, not due to an AE*.

Moved from the study area.

Lost to follow-up.

Other (specify).
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
65
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
66
*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.
9.
STATISTICAL METHODS
9.1.
Endpoints
9.1.1.
Primary endpoint (Amended 19 October 2018)

Occurrence of potential bacterial and viral pathogens in sputum of stable COPD 
patients and during AECOPD, over the course of 1 year:

Bacterial pathogens, as identified by bacteriological methods, including (but not 
necessarily limited to) H. influenzae, M. catarrhalis, S. pneumoniae, S. aureus, 
P. aeruginosa, K. pneumoniae and A. baumannii.

Viral pathogens, as identified by PCR, including (but not necessarily limited to) 
RSV, parainfluenza virus, enterovirus/ HRV, metapneumovirus, influenza virus, 
adenovirus, bocavirus and coronavirus.
9.1.2.
Secondary endpoints

Occurrence of potential bacterial pathogens in sputum of stable COPD patients and
during AECOPD, as measured by real-time qualitative PCR/ quantitative PCR and 
compared to data from bacteriological methods, over the course of 1 year:

Including (but not necessarily limited to) H. influenzae, M. catarrhalis, S. 
pneumoniae, S. aureus and P. aeruginosa.

Occurrence of potential bacterial and viral pathogens (overall and by species) in 
sputum of stable COPD patients by GOLD grade, over the course of 1 year.

Occurrence of potential bacterial and viral pathogens (overall and by species) in
sputum during AECOPD by severity of AECOPD, over the course of 1 year.

Incident rate (per subject per year) of AECOPD, overall and by GOLD grade, over 
the course of 1 year.

Severity of AECOPD, overall and by GOLD grade, over the course of 1 year.

Duration of AECOPD, overall and by AECOPD severity, over the course of 1 year.

CAT score in stable COPD patients and during AECOPD, over the course of 1 year.

SGRQ-C score in stable COPD patients, over the course of 1 year.

FEV1% of predicted normal value in stable COPD patients, at Pre-Month 0 and 
Month 12.

Healthcare utilisation, over the course of 1 year.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
66
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
67
9.1.3.
Tertiary endpoints

EXACT-PRO scores in stable COPD patients and during AECOPD, over the course 
of 1 year.

Bacterial load measured by both culture and PCR in COPD and during AECOPD.

HRV load measured by PCR in COPD and during AECOPD.
9.2.
Determination of sample size
The primary objective of this study is to describe the proportion of bacterial and viral 
pathogens (overall and by species) detected in sputum in stable COPD and during 
AECOPD.
Assuming around 90% of the All Enrolled Set participated in the study, on average 1 
AECOPD visit and 80% of the above population set can provide an evaluable sputum 
sample at AECOPD, for 240, 200, 160, and 50 enrolled subjects, one may expect around 
180, 140, 120, 40 sputum samples, respectively. Assuming that results from these sputum 
samples are independent and that the between country variability is much smaller than the 
within country variability, we would have the following 95% exact confidence interval 
for different incidences in sputum samples from exacerbations (see Table 12).
Table 12
Exact 95% confidence intervals of the percentage of occurrence of a 
specific bacterium from sputum collected during AECOPD
%
Number of evaluable sputum samples during AECOPD
N=180
N=140
N=120
N=40
5
[
2.3
;
9.3
]
[
2.0
;
10.0
]
[
1.9
;
10.6
]
[
0.6
;
16.9
]
10
[
6.0
;
15.3
]
[
5.6
;
16.2
]
[
5.3
;
16.8
]
[
2.8
;
23.7
]
20
[
14.4
;
26.6
]
[
13.7
;
27.6
]
[
13.3
;
28.3
]
[
9.1
;
35.6
]
30
[
23.4
;
37.3
]
[
22.6
;
38.3
]
[
22.0
;
39.0
]
[
16.6
;
46.5
]
40
[
32.8
;
47.6
]
[
31.8
;
48.6
]
[
31.2
;
49.3
]
[
24.9
;
56.7
]
50
[
42.5
;
57.5
]
[
41.4
;
58.6
]
[
40.7
;
59.3
]
[
33.8
;
66.2
]
N = total number of evaluable sputum samples during AECOPD.
One of the secondary objectives is to estimate the incidence rate of all-cause AECOPDs 
in the study population.
Assuming around 80% of the all enrolled set completed the study, for 240, 200, 160 and 
50 subjects enrolled, one would have at least 190, 160, 130 and 40 subjects evaluable 
respectively. Assuming further that around 80% of the subjects can provide an evaluable 
sputum sample at AECOPD, this would lead to around 150, 130, 100, 30 subjects (see 
Table 13).
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
67
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
68
Table 13
95% confidence intervals of AECOPD incidence rates with different 
overdispersion values
Φ = 1
Φ =1.5
Φ =2
0.2 AECOPD/ subject/ year
95% CI*
95% CI*
95% CI*
T
n
Value (n/T)
LL
UL
LL
UL
LL
UL
30
6
0.20
0.04
0.36
0.00
0.40
-0.03
0.43
100
20
0.20
0.11
0.29
0.09
0.31
0.08
0.32
130
26
0.20
0.12
0.28
0.11
0.29
0.09
0.31
150
30
0.20
0.13
0.27
0.11
0.29
0.10
0.30
1 AECOPD/ subject/ year
95% CI*
95% CI*
95% CI*
T
n
Value (n/T)
LL
UL
LL
UL
LL
UL
40
40
1.00
0.69
1.31
0.62
1.38
0.56
1.44
130
130
1.00
0.83
1.17
0.79
1.21
0.76
1.24
160
160
1.00
0.85
1.15
0.81
1.19
0.78
1.22
190
190
1.00
0.86
1.14
0.83
1.17
0.80
1.20
2 AECOPD/ subject/ year
95% CI*
95% CI*
95% CI*
T
n
Value (n/T)
LL
UL
LL
UL
LL
UL
40
80
2.00
1.56
2.44
1.46
2.54
1.38
2.62
130
260
2.00
1.76
2.24
1.70
2.30
1.66
2.34
160
320
2.00
1.78
2.22
1.73
2.27
1.69
2.31
190
380
2.00
1.80
2.20
1.75
2.25
1.72
2.28
3 AECOPD/ subject/ year
95% CI*
95% CI*
95% CI*
T
n
Value (n/T)
LL
UL
LL
UL
LL
UL
40
120
3.00
2.46
3.54
2.34
3.66
2.24
3.76
130
390
3.00
2.70
3.30
2.64
3.36
2.58
3.42
160
480
3.00
2.73
3.27
2.67
3.33
2.62
3.38
190
570
3.00
2.75
3.25
2.70
3.30
2.65
3.35
* Normal approximation with variance = Φ n/T2, where Φ is the overdispersion factor for a Poisson distribution 
(calculations performed in Microsoft Excel).
T = Total number of evaluable subjects; n =Total number of exacerbations; CI = confidence interval; LL = lower limit; 
UL = upper limit.
9.3.
Cohorts for Analyses
The following study cohorts will be evaluated.
9.3.1.
All screened Set
The all screened set will include all screened patients.
9.3.2.
All Enrolled Set
The all enrolled set will include all successfully screened subjects in the study.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
68
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
69
9.3.3.
Full Analysis Set
The Full Analysis Set (FAS) will include all enrolled patients except for those who 
discontinued the study during Visit 1.
Study objectives will be assessed on the FAS. The population set for each analysis will 
change according to the subjects evaluable for the specific endpoint.
Note: Subjects using antibiotics on a continual basis (defined as more than 1 month in 
total) will be allowed to continue study participation, but may be eliminated from the 
analyses.
9.4.
Analysis of demographics
Demographic characteristics (age at enrolment, gender and geographical ancestry) and 
cohort description will be summarised using descriptive statistics:

Frequency tables will be generated for categorical variable such as geographical 
ancestry.

Mean, median, standard deviation, minimum and maximum will be provided for 
continuous data such as age.
The distribution of subjects enrolled among the study sites will be tabulated.
Withdrawal status will be summarised according to the reason for withdrawal. The 
number of withdrawn patients will be tabulated by study visit and overall.
All tables will also be generated by country.
9.5.
Analysis of primary objective
The proportion of sputum samples obtained at each visit (confirmed stable visits* and 
AECOPD visits and positive for specific bacterial/ viral pathogens by bacteriological 
methods and PCR, respectively (overall and by bacterial/viral species) will be computed 
with 95% confidence intervals.
* A confirmed stable visit will be defined as a scheduled study visit for which the 
investigator confirms in the eCRF that the subject is stable/ has recovered from a 
previous exacerbation.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
69
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
70
9.6.
Analysis of secondary objectives
The proportion of sputum samples obtained at each visit (confirmed stable visits* and 
AECOPD visits [any severity, mild, moderate and severe) and positive for specific 
bacterial pathogens by both bacteriological methods and PCR (overall and by bacterial 
species) will be computed with 95% confidence intervals.
* A confirmed stable visit will be defined as a scheduled study visit for which the 
investigator confirms in the eCRF that the subject is stable / has recovered from a 
previous exacerbation.
The proportion of sputum samples obtained at each stable visit and positive for specific
bacterial/viral pathogens by bacteriological methods and PCR, respectively (overall and 
by bacterial/ viral species) will be computed with 95% confidence intervals, by GOLD 
grade at enrolment.
The proportion of sputum samples obtained at each AECOPD visits and positive for 
specific bacterial/ viral pathogens by bacteriological methods and PCR, respectively 
(overall and by bacterial/viral species) will be computed with 95% confidence intervals, 
by AECOPD severity.
The proportion of sputum samples obtained at each confirmed stable/AECOPD visit with 
previous administration of antibiotics or not and positive for specific bacterial/ viral 
pathogens by bacteriological culture and PCR, respectively (overall and by bacterial/viral 
species) will be computed with 95% confidence intervals.
The following incidence rates will be computed, with 95% confidence intervals (CI):

All-cause AECOPD.

AECOPD having sputum containing bacterial pathogens found by PCR or by 
bacteriological methods or by both methods (overall and by, but not limited to, the 
following bacterial species: H. influenzae, M. catarrhalis, S. pneumoniae, S. aureus, 
and P. aeruginosa).
The 95% CI of the incidence rate will be computed using a model which accounts for 
repeated events. The Generalised linear model assuming the Negative Binomial 
distribution for the response variable with logarithm as link function, and the logarithm of 
time for follow-up as an offset variable will be used. The incidence rates described above 
will also be computed for mild, moderate severe AECOPD and by GOLD grade at 
enrolment and will be estimated by country.
The number of subjects that report at least 1 AECOPD will be tabulated and descriptive 
statistics (median, mean, range, standard deviation, first and third quartiles) on the 
number of days of AECOPD episodes will be presented, for any, mild, moderate and 
severe AECOPD.
Descriptive statistics (median, mean, range, standard deviation, first and third quartiles) 
on the CAT and SGRQ-C scores will be tabulated at each respective visit.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
70
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
71
Summary statistics (mean, median, standard deviation, maximum and minimum) on 
post-bronchodilator FEV1% of predicted normal value will be tabulated at each 
respective visit. 
Descriptive summaries on healthcare use will be provided.
9.7.
Analysis of tertiary objectives
Descriptive statistics (median, mean, range, standard deviation, first and third quartiles) 
on the end date of AECOPD as provided by the investigator or estimated by 
EXACT-PRO (via a specific algorithm which will be detailed in the Statistical Analysis 
Plan) will be presented.
Descriptive summaries of the quantity of specific bacteria at each scheduled [stable] and 
exacerbation visit will be provided for both culture and PCR analysis.
Descriptive summaries of the quantity of specific viruses at each scheduled [stable] and 
exacerbation visit will be provided for PCR analysis.
A conditional logistic model will be fitted to estimate the odds ratio of being in a stable 
state vs. an exacerbation state given the presence or not of several bacterial pathogens 
found by bacteriological culture and by country. The same model will also be performed 
for bacterial and viral pathogens found by PCR.
9.8.
Conduct of analyses
Any deviation(s) or change(s) from the original statistical plan outlined in this protocol 
will be described and justified in the final study report.
9.8.1.
Sequence of analyses

An interim analysis of the bacterial primary objective will be performed when at 
least 40 AECOPD sputum samples are available. The rate of positive samples will be 
computed for Hi, NTHi and Mcat together and per pathogen. No study report will be 
written at this stage.

A final analysis of all objectives will be performed after the last subject last visit of 
the entire study. A final study report will be written at this stage.
9.8.2.
Statistical considerations for interim analyses
All analyses are exploratory and will be conducted on final data and therefore no 
statistical adjustment for interim analyses is required.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
71
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
72
10.
ADMINISTRATIVE MATTERS
To comply with ICH GCP or other applicable guidelines, administrative obligations 
relating to data collection, monitoring, archiving data, audits, confidentiality, ownership, 
public disclosure requirements and publications must be met.
10.1.
Electronic Case Report Form instructions
A validated GSK defined electronic data collection tool will be used as the method for 
data collection.
In all cases, subject initials will not be collected nor transmitted to GSK. Subject data 
necessary for analysis and reporting will be entered/transmitted into a validated database 
or data system. Clinical data management will be performed in accordance with 
applicable GSK standards and data cleaning procedures.
While completed eCRFs are reviewed by a GSK Biologicals’ Site Monitor at the study 
site, omissions or inconsistencies detected by subsequent eCRF review may necessitate 
clarification or correction of omissions or inconsistencies with documentation and 
approval by the investigator or appropriately qualified designee. In all cases, the 
investigator remains accountable for the study data. 
Once the database is archived and the clinical study report is complete and approved by 
all parties, each participating investigator will be provided with a CD-ROM of the final 
version of the data generated at his/her investigational site.
10.2.
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 a eCRF review and a Source Document 
Verification (SDV). By SDV we understand verifying eCRF entries by comparing them 
with the source data that will be made available by the investigator for this purpose. 
The Source Documentation Agreement Form describes the source data for the different 
data in the eCRF. This document should be completed and signed by the site monitor and 
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
72
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
73
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.
10.3.
Record retention
Following closure of the study, the investigator must maintain all site study records 
(except for those required by local regulations to be maintained elsewhere) in a safe and 
secure location. The records must be easily accessible, when needed (e.g., audit or 
inspection), and must be available for review in conjunction with assessment of the 
facility, supporting systems, and staff. Where permitted by applicable laws/regulations or 
institutional policy, some or all of these records can be maintained in a validated format 
other than hard copy (e.g., microfiche, scanned, electronic); however, caution needs to be 
exercised before such action is taken. The investigator must ensure that all reproductions 
are legible and are a true and accurate copy of the original and meet accessibility and 
retrieval standards, including re-generating a hard copy, if required. Furthermore, the 
investigator must ensure that an acceptable back-up of the reproductions exists and that 
there is an acceptable quality control procedure in place for making these reproductions.
GSK will inform the investigator/institution of the time period for retaining these records 
to comply with all applicable regulatory requirements. The minimum retention time will 
meet the strictest standard applicable to a particular site, as dictated by ICH GCP or other 
applicable guidelines, any institutional requirements or 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 and transfer of 
ownership of the records in the event the investigator leaves the site. 
10.4.
Quality assurance
To ensure compliance with GCP or other applicable guidelines 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.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
73
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
74
10.5.
Posting of information on publicly available 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.
Studies that do not evaluate vaccines/products are progressed for publication in the 
scientific literature when the results provide important scientific or medical knowledge or 
are relevant for patient care, and will be considered for disclosure on the GSK website 
and in publicly accessible regulatory registry(ies).
10.6.
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 Biologicals site or other 
mutually-agreed 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.
10.7.
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.
11.
COUNTRY SPECIFIC REQUIREMENTS
Not applicable.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
74
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
75
12.
REFERENCES
Anthonisen NR, Manfreda J, Warren CP et al. Antibiotic therapy in exacerbations of 
chronic obstructive pulmonary disease. Ann Intern Med. 1987; 106: 196-204.
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.
Charlson ES, Bittinger K, Haas AR et al. Topographical continuity of bacterial 
populations in the healthy human respiratory tract. Am J Respir Crit Care Med. 2011; 
184: 957-63.
Curran T, Coyle PV, McManus TE et al. Evaluation of real-time PCR for the detection 
and quantification of bacteria in chronic obstructive pulmonary disease. FEMS Immunol 
Med Microbiol. 2007; 50: 112-8.
De Serres G, Lampron N, La Forge J et al. Importance of viral and bacterial infections in 
chronic obstructive pulmonary disease exacerbations. J Clin Virol. 2009; 46: 129-33.
Domenech A, Puig C, Martí S et al. Infectious etiology of acute exacerbations in severe 
COPD patients. J Infect. 2013; 67: 516-23.
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.
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
Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the 
diagnosis, management, and prevention of Chronic Obstructive Pulmonary Disease, 
updated 2017. Available from: 
http://goldcopd.org/gold-2017-global-strategy-diagnosis-management-prevention-copd/
Guoping Hu, MD, PhD; Yumin Zhou, MD et al. Risk of COPD from Exposure to 
Biomass Smoke: A Metaanalysis. CHEST. 2010; 138(1):20–31
Hogg JC, Chu F, Utokaparch S et al. The nature of small-airway obstruction in chronic 
obstructive pulmonary disease. N Engl J Med. 2004; 350: 2645-53.
Hui DS, Ip M, Ling T et al. A multicentre surveillance study on the characteristics, 
bacterial aetiologies and in vitro antibiotic susceptibilities in patients with acute 
exacerbations of chronic bronchitis. Respirology. 2011; 16: 532-9.
Hurst JR, Vestbo J, Anzueto A et al. Susceptibility to exacerbation in chronic obstructive 
pulmonary disease. N Engl J Med. 2010; 363: 1128-38.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
75
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
76
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.
Jones P, Miravitlles M, van der Molen T et al. Beyond FEV₁ in COPD: a review of 
patient-reported outcomes and their measurement. Int J Chron Obstruct Pulmon Dis.
2012; 7: 697-709.
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.
Ko FWS, Hui DSC, Lai CKW et al. Worldwide burden of COPD in high- and low-
income countries. Part III. Asia-Pacific studies. Int J Tuberc Lung Dis. 2008;12(7):713–
717.
Leidy NK, Wilcox TK, Jones PW et al. Standardizing measurement of chronic 
obstructive pulmonary disease exacerbations. Reliability and validity of a patient-
reported diary. Am J Respir Crit Care Med. 2011; 183: 323-9.
Lim Sam, Lam Chi-Leung David et al. Impact of chronic obstructive pulmonary disease 
(COPD) in the Asia-Pacific region: the EPIC Asia population-based survey. Asia Pacific 
Family Medicine. 2015; 14:4
Mathers CD and Loncar D. Projections of global mortality and burden of disease from 
2002 to 2030. PLoS Med. 2006; 3: e442.
Miravitlles M. Exacerbations of chronic obstructive pulmonary disease: when are bacteria 
important? Eur Respir J Suppl. 2002; 36: 9s-19s.
Mohan A, Chandra S, Agarwal D et al. Prevalence of viral infection detected by PCR and 
RT-PCR in patients with acute exacerbation of COPD: A systematic review. Respirology. 
2010;15(5):536.42.
Monsó E, Ruiz J, Rosell A et al. Bacterial infection in chronic obstructive pulmonary 
disease. A study of stable and exacerbated outpatients using the protected specimen 
brush. Am J Respir Crit Care Med. 1995; 152: 1316-20.
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.
Perotin JM, Dury S, Renois F et al. Detection of multiple viral and bacterial infections in 
acute exacerbation of chronic obstructive pulmonary disease: a pilot prospective study. J 
Med Virol. 2013; 85: 866-73.
Singh Richa, Mackay AJ et al. Inflammatory thresholds and the species-specific effects 
of colonising bacteria in stable chronic obstructive pulmonary disease. Respiratory 
Research. 2014; 15: 114.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
76
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
77
Sapey E, Stockley RA. COPD exacerbations 2: aetiology. Thorax. 2006; 61: 250-8.
Tan WC, Seale P, Ip M et al. Trends in COPD mortality and hospitalizations in countries 
and regions of Asia-Pacific. Respirology. 2009; 14: 90-7.
Wedzicha JA and Seemungal TA. COPD exacerbations: defining their cause and 
prevention. Lancet. 2007; 370: 786-96.
World Health Organization (WHO). Priority environment and health risks. 2013. 
Available from: http://www.who.int/heli/risks/indoorair/indoorair/en/#. Accessed: 27 July 
2016.
World Health Organization (WHO). Chronic obstructive pulmonary disease (COPD) Fact 
Sheet. 2015. Available from: http://www.who.int/mediacentre/factsheets/fs315/en/. 
Accessed: 20 October 2017.
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.
Ye F, He LX, Cai BQ et al. Spectrum and antimicrobial resistance of common pathogenic 
bacteria isolated from patients with acute exacerbation of chronic obstructive pulmonary 
disease in mainland of China. Chin Med J (Engl). 2013; 126: 2207-14.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
77
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
78
APPENDIX A
CLINICAL LABORATORIES (Amended 19
October 2018)
Table 14
GSK Biologicals’ laboratories
Laboratory
Address
GSK Biologicals Clinical 
Laboratory Sciences (CLS) 
Rixensart
Biospecimen Reception - B7/44
Rue de l'Institut, 89 - B-1330 Rixensart -
Belgium
GSK Biologicals Clinical 
Laboratory Sciences (CLS) 
Wavre-Nord Noir Epine
Avenue Fleming, 20 - B-1300 Wavre - Belgium
Table 15
Outsourced Laboratories
Laboratory
Address
Q² Solutions Clinical Trials (US)
27027 Tourney Road, Suite 2E
Valencia, CA 91355
USA
Q² Solutions (Singapore)
Tan Tock Seng Hospital
Dept of Laboratory Medicine
Level 2, Podium Block
Tan Tock Seng Hospital
11 Jalan Tan Tock Seng
Singapore 308433
DDL Diagnostic Laboratory B.V.
Fonteijnenburghlaan 7
Voorburg
Netherland
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
78
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
79
APPENDIX B
AMENDMENT TO THE PROTOCOL
GlaxoSmithKline Biologicals
Vaccine Value & Health Science (VVHS)
Protocol Amendment 1
eTrack study number 
and Abbreviated Title
201112 (EPI-NTHI-001 BOD APA)
Amendment number:
Amendment 1
Amendment date:
13 February 2017
Co-ordinating author:
 Scientific Writer
Rationale/background for changes: 
The protocol amendment has been issued to implement the following changes:
!
Alignment of the protocol to the updated GOLD consensus report of 2017 and the 
COPD fact sheet.
!
Alignment of the study endpoints to the study objectives.
!
Overall update based on the scientific and operational experience gained from the 
current COPD studies.
!
To update the new literature references.
!
To reflect the upgrade to new version for CRF, ICF, protocol, SPM and overall 
changes in the functions due to reorganization.
!
To correct some typographical errors.
!
Update of the GSK laboratory’s name.
Amended text has been included in bold italics and deleted text in strikethrough in the 
following sections:
Title page:
Title
Occurrence of potential bacterial and viral pathogens 
in stable chronic obstructive pulmonary disease 
(COPD) and during acute exacerbations of COPD 
(AECOPD), in Asia Pacific.

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
79
19-OCT-2018
PPD

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
80
Detailed Title
A prospective, epidemiological, multi-country, cohort 
study to assess the occurrence of potential bacterial 
and viral pathogens in stable chronic obstructive 
pulmonary disease (COPD) and during acute 
exacerbations of COPD (AECOPD), in moderate to 
very severe COPD patients, in Asia Pacific.
Contributing authors
!
 Epidemiologist
!
 Clinical Research
Development and Research Development Lead
!
 Clinical 
Research Development and Research
Development Lead
!
 
 Biostatistician
!
 Lead 
statistician
!
 Project
Delivery Lead
!
 Study Delivery Lead
!
 Study Delivery Manager, 
(External Consultant [Freelance∀for GSK 
Biologicals)
!
Study Data 
Manager (Business & Decision Life Sciences for 
GSK Biologicals) Senior Manager, Oversight 
Data Management
!
 Study Data Manager
!
 Vaccine Supply 
Coordinator (CVO Europe, for GSK Biologicals)
!
 Project Manager, GVCL
Clinical Readout Team Leader, Clinical 
Laboratory Sciences
!
 Study Manager, GVCL 
(Business & Decision Life sciences, for GSK 
Biologicals)/
 Study Manager, 
Clinical Laboratory Sciences
!
Global 
Regulatory Lead and
 Technical
Global Regulatory Affairs representative

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
80
19-OCT-2018
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
81
!
 and 
 
 and 
 
and 
 Clinical Safety 
Representatives
!
 Expert Scientist, Clinical 
Laboratory Sciences
!
 Study Data Manager (Business 
& Decision Life Sciences, for GSK Biologicals)
!
Dr. 
, University of Sydney Head, 
Respiratory Trials, Contributing author from The 
George Institute for Global Health, Australia
Contributing author from The George Institute for Global Health, Australia
!
Dr. 
, University of Sydney Head, Respiratory Trials
Trademarks
Trademarks of the GlaxoSmithKline 
group of companies
Generic description
EXACT-PRO®
Exacerbations of Chronic Pulmonary 
Disease Tool - Patient Reported Outcome
SGRQ-C
St. George’s Respiratory Questionnaire 
for COPD patients
Background
Chronic Obstructive Pulmonary Disease (COPD) is a common preventable and treatable
disease characterised by persistent airflow obstruction which is not fully reversible and 
which is usually progressive in the long term. The classification of COPD is done based 
on the patient’s spirometric classification according to GOLD, 2013. The airflow 
limitation in COPD patients can be classified into GOLD grades as shown in Table 1 
[GOLD, 2013]. In this study, additional parameters are going to be collected in order to 
allow for a combined assessment that could be used for future evaluation, as detailed 
in Figure 1 [GOLD, 2017]. 

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
81
19-OCT-2018
P
P
D
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
82
Figure 1 The refined ABCD assessment tool
GOLD = Global Initiative for Chronic Obstructive Lung Disease; CAT = COPD assessment test; FEV1 = forced 
expiratory volume in 1 second; FVC = forced vital capacity; mMRC = Modified British Medical Research 
Council Questionnaire
The classification of severity of airflow limitation in COPD patients is provided 
according to GOLD, 2017 as follows,

Patient Group A – Low Risk, Less Symptoms Typically GOLD 1 or GOLD 2 (Mild 
or Moderate airflow limitation); and/or 0-1 exacerbation per year and no 
hospitalization for exacerbation; and CAT score < 10 or mMRC grade 0-1

Patient Group B – Low Risk, More Symptoms Typically GOLD 1 or GOLD 2 (Mild 
or Moderate airflow limitation); and/or 0-1 exacerbation per year and no 
hospitalization for exacerbation; and CAT score ≥ 10 or mMRC grade ≥ 2

Patient Group C – High Risk, Less Symptoms Typically GOLD 3 or GOLD 4 
(Severe or Very Severe airflow limitation); 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 Typically GOLD 3 or GOLD 4 
(Severe or Very Severe airflow limitation); and/or ≥ 2 exacerbations per year or ≥ 
1 with hospitalization for exacerbation; and CAT score ≥ 10 or mMRC grade ≥ 2.
COPD is the fifth leading cause of mortality worldwide, accounting for 6% of all 
deaths globally [WHO 2015]. A recent study reported high overall morbidity and 
mortality rates due to COPD in the Asia Pacific region. The prevalence of moderate to 
severe COPD in adults aged 30 years or above was estimated to be 5.9% in South Korea, 
5.4% in Taiwan, 4.7% in Australia and 3.5% in Hong Kong [Tan, 2009]. The overall 
estimated prevalence COPD in Asia-Pacific was estimated to be 6.2% with 19.1% 
having severe COPD [Lim, 2015]. The prevalence and burden of COPD are projected to 
continue to increase in the coming decades due to continued exposure to risk factors and 
the changing age structure of the world’s population [Mathers, 2006. In Asia, 
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
82
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
83
urbanisation is expected to play a major role in the increase of the number of prevalent 
cases of COPD between 2010 and 2020 [Tan, 2009. In terms of the number of deaths, 
the burden of disease is higher in the Asia-Pacific region when compared to the 
industrialised western countries. It was estimated through mathematical modelling that 
56.6 million people aged 30 years had moderate to severe COPD with a prevalence rate 
of 6.3% [Ko, 2008].
Synopsis and Section 1.2 Rationale for the study
Because the infectious aetiology of AECOPD has been suggested to vary according to 
geographical region, the primary purpose of this study (which will be conducted in 
several countries in Asia Pacific) is to evaluate the occurrence of bacterial and viral 
pathogens in the sputum of stable COPD patients and at the time of AECOPD. Given the 
increasing and projected burden of COPD in the Asia Pacific region, this study will also 
evaluate the frequency, severity and duration of AECOPD, as well as the impact of 
AECOPD on health-related quality of life (HRQOL), healthcare utilisation, and lung 
functionand on exercise capacity.
In addition, both PCR and bacteriological methods will be used for characterisation and 
(quantification in some cases) of bacteria in sputum. To date, identification of bacteria 
and assessment of bacterial load is done in the vast majority of cases by culture. 
However, the few studies that have compared culture with PCR demonstrated that PCR is 
more discriminatory at detecting typical airway bacteria [Curran, 2007; Singh, 2014. 
Moreover, in a multi-centre study, PCR has the advantage that it can be performed on 
stored sputum samples, and can therefore be done centrally, whereas culture has to be 
performed on fresh sputum samples, which can lead to variable results in case of due to
variability in testing methods between laboratories.
Synopsis and Section 2 Objectives
Primary objective 

To estimate the proportion of bacterial and viral pathogens (overall and by species) 
detected in sputum of stable COPD patients and during AECOPD. To estimate the 
proportion of potential bacterial and viral pathogens (overall and by species) 
detected in sputum of stable COPD patients and during AECOPD, using 
respectively bacteriological methods and viral PCR, over the course of 1 year.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
83
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
84
Secondary objectives

To evaluate the concordance between PCR and bacteriological methods 
databacteriological culture with respect to their ability to characterise and (quantify 
in some cases) bacterial pathogens in sputum in sputum for potential bacterial 
pathogens.

To estimate the proportion of potential bacterial and viral pathogens (overall and by 
species) detected in sputum of stable COPD patients, by GOLD grade.

To estimate the proportion of potential bacterial and viral pathogens (overall and by 
species) detected in sputum during AECOPD, by severity of AECOPD.

To assess the impact of all-cause AECOPD on exercise capacity.
Tertiary objectives

To estimate the difference in the presence of bacterial pathogens in sputum between 
stable state and AECOPD.

To evaluate the load of bacterial and viral pathogen in stable COPD and during 
AECOPD.

To collect biological specimens for future respiratory disease-related testing:

Aliquots of sputum samples for assay development and microbiome analysis at 
stable visits and during exacerbation.

Blood sampling for potential biomarkers for identification/quantification of 
biomarkers.

Bacterial isolates for further strain characterisation.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
84
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
85
Section 3 Study design overview
Note: Screening visit should ideally occur not more than be longer than 6 weeks before 
visit 1 .Study visits/contacts:

Screening visit.

6-monthly Three scheduled (stable) study visits occurring at 6 month intervals.

For each AECOPD: AECOPD visit (within 96 hours of the onset of the 
symptoms) and follow-up phone call(s) (at least every 2 weeks until the 
AECOPD has resolved). Follow-up phone contacts will define end of AECOPD.

Biological samples:

Blood samples for biomarker testing will be collected at Visit 1 (M0), Visit 3 
(M12).
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
85
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
86
Synopsis and Section 3.1 Discussion of study design
The primary objective of this study is to prospectively investigate the prevalence and 
distribution of bacteria and viruses isolated from sputum samples from moderate to very 
severe stable COPD patients (with moderate-very severe COPD ) and at the time of 
AECOPD, in Asian populations. In order to increase the chance that the patients will 
exacerbate during the study, only patients with a documented history of at least 1 
moderate or severe AECOPD in the previous year will be recruited, as this is known to be 
the best predictor of AECOPD [Hurst, 2010. Therefore, this study will permit an 
estimation of incidence of AECOPD in a COPD population at increased risk of 
exacerbation. It will not provide a true population-based incidence of AECOPD.
In order to study factors affecting disease progression in Asia Pacific, prospective data 
from a relatively large cohort of COPD patients is essential. The use of electronic Diary 
Cards to detect changes in the respiratory symptoms that define an AECOPD, the 
standardised questionnaires and spirometry assessments, and exercise capacity tests will 
allow robust conclusions to be drawn about the effects of exacerbations on decline in 
lung function and HRQOL. Furthermore, the completeness of vital status information will 
allow to determine the effects of exacerbations and hospitalizations on mortality to be 
examined with confidence.
EXACT PRO will be used to assess breathlessness, cough and presence of sputum, chest 
symptoms, difficulty bringing up sputum, feeling tired or weak, sleep disturbance, and 
feeling scared or worried about their condition. Advantages to this approach include 
standardised data, reduced recall bias, and the potential to identify events and determine 
resolution based on a predefined scoring algorithm Leidy, 2011. Standardised 
questionnaires completed during study visits include the SGRQ-C and the CAT. The 
SGRQ-C is designed to assess HRQOL, current health and does not specify a recall 
period. The CAT is a simple, short, patient-completed instrument to assess HRQOL and 
symptom burden in patients with COPD. The CAT has good internal consistency and test-
retest reliability, correlates strongly with the SGRQ-C, and is able to distinguish between 
stable patients and those undergoing an AECOPD Jones, 2012.
Section 3.1.1 Detection of AECOPD
Note that:

Any symptom occurring on at least 5 consecutive days prior to a potential 
exacerbation will not be taken into account to define an exacerbation.
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 site staff contacts the subject to determine if the alert is an AECOPD or 
not, and if check whether an AECOPD visit is warranted. In addition, the site should 
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
86
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
87
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 site 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 site concludes that the subject is not experiencing an AECOPD, this should be 
documented/ reported in the eCRF. Please refer to study procedures manual (SPM) 
for more details on how to perform this.

If the site concludes that the subject may be experiencing an AECOPD, 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 CRF in medical records section and obtain all relevant information 
regarding the AECOPD(hospital record, medical record etc) and record this in 
the eCRF.
During the AECOPD visit, the investigator will 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/delegate 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. However, in exceptional cases, in consultation with 
GSK Biologicals, the concluding visit (Visit 3, Month 12) may be exceptionally
conducted outside of the allowed interval, if deemed necessary by the investigator. The 
reason for this should be documented in the eCRF.
The investigator/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 record should be 
obtained), or the subject is on holidays or not able to go the site.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
87
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
88
Section 3.1.1.1 Date of onset and end date of AECOPD
The date of onset 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.
The end date should be based on when the investigator determines that the AECOPD 
symptoms have resolved. In determining this end date, consideration should be given to 
symptoms recorded in the electronic Diary Card and subject assessment during the 
phone calls.
Section 4.1 Number of subjects/centres
The target is to enrol approximately 200 eligible moderate to very severe COPD patients. 
All subjects should be recruited within the period of 1 year.
Section 4.2 Inclusion criteria for enrolment

Confirmed diagnosis of moderate to very severe COPD based on post-bronchodilator 
spirometry (i.e. forced expiratory volume in 1 second FEV1over forced vital 
capacity FVCratio FEV1/ FVC< 0.7 AND and FEV1 < 80% predicted GOLD 
grades 2, 3 and 4.

Stable COPD patient* with documented history** (e.g. medical record verification) 
of at least 1 moderate or severe AECOPD within the 12 months before study entry.
* Patient for whom the last episode of AECOPD is resolved for at least 30 days at 
the time of study entry.**Note: 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.

Current or former tobacco smoker (cigarette) with a smoking history of ≥ 10 pack-
years OR a subject exposed to biomass smoke for 20 years. [Guoping Hu 2010]
Section 4.3 Exclusion criteria for enrolment

Undergone or planning lung surgery within 12 months from study entry. Undergone 
or has had lung surgery 12 months before, or plans to have lung surgery 12 
months after, study entry.

Administration of antibiotics within 1 month of study entry OR continuous 
administration of antibiotics (defined as more than 1 month 30 days in total) within 
the three months 90 days before study entry.

Systemic administration of corticosteroids (PO/IV/IM) for more than 14 
consecutive days within 90 days prior to informed consent.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
88
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
89

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).

Mentally impaired patients.Psychiatric illness or any other condition that interferes 
with the ability to understand the study procedures.

Pregnant female with COPD.
Section 6.3 Outline of study procedures
Table 4
List of study procedures for scheduled [stable] visits
Epoch
Epoch 001
Type of contact
Screening 
Visit
Visit 1
Visit 2
Visit 3
Time point
Pre-Month 0
Month 0
Month 6
Month 12
Smoking exposure history (ATS-DLD-78A questionnaire)/ 
biomass exposure history
●O
Urine Pregnancy test
●
Physical examination including vital signs
●
O
O
O
Record healthcare resource utilisation for COPD
Blood samples for biomarkers and haematology
●
●
HRQOL questionnaires:
CAT
O
O
O
SGRQ-C
O
O
O
6MWT
●
●
● is used to indicate a study procedure that requires documentation in the individual eCRF.
O is used to indicate a study procedure that does not require documentation in the individual eCRF.
a For non-eligible subjects, only informed consent, inclusion/ exclusion criteria, demographic data and SAEs related to 
study participation that occurred after signing the informed consent pages need to be completed in the subject’s eCRF. 
For other activities, ‘not done’ can be indicated. 
b Recordboth documented and self-reported, non-documented AECOPD. Subjects need documentation for at least 1 
moderate or severe AECOPD within the previous year to be eligible for study participation.
c Significant comorbidities include weight loss, cardiovascular disease, hypertension, gastro-oesophageal reflux 
disease, osteoporosis/ osteopenia, skeletal muscle wasting and dysfunction, anxiety/ depression and diabetes.
d To be recorded in the ‘Physical examination’ section of the eCRF.
e Only study certified site staff can perform spirometry assessment.
f Only if no chest X-ray is taken within the previous 3 months.
g Sputum can be collected spontaneously or can be induced, as per investigator judgement. Sputum sampling should 
only be done if, in the opinion of the investigator, it is safe for the subject.
* Non-serious AEs will be recorded in the eCRF and will not be entered into the safety database.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
89
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
90
Table 5
List of study procedures for AECOPD visit
Type of contact
AECOPD Visit
End of AECOPD phone call(s)
Time point
within 96 hours of onset 
symptoms
at least every 2 weeks as of 
AECOPD visit until AECOPD 
has resolvedh
Record date of visit
●
Physical examination
●
Urine Pregnancy Test
● 
Chest X-rays/pneumonia confirmationi
●
Confirm AECOPD and record its start date
●
Record current medication for COPD
●
Record healthcare resource utilisation
●
Record additional COPD treatments prescribed by 
primary and secondary care physicians
●
Sputum samplingj
●
HRQOL questionnaire:
CAT
O
Record AECOPD severityk
●
●
Record AECOPD end date
●
Record Adverse Events (AEs) related to study 
participation*
●
●
Record serious adverse events (SAEs)
●
●
● 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.
h End of AECOPD phone calls/ visits should be scheduled at least every 2 weeks, until the AECOPD has resolved. 
i Only the last phone call will be recorded in the eCRF as the end of the AECOPD phone call. All intermediate calls 
should be recorded on source documentation.
j j Physical examination should be done only if necessary.
i Only if clinically indicated to exclude another cause of worsening of symptoms (e.g. pneumonia). If a chest X-ray is 
clinically indicated but a chest X-ray/ CT scan has already been taken for that AECOPD as part of medical care before 
the study AECOPD visit takes places, the results of that chest X-ray/ CT scan can be used. All cases of pneumonia 
(including all signs and symptoms assessed to confirm pneumonia) should be documented in the eCRF.
j Sputum can be collected spontaneously or can be induced, as per investigator judgement. Sputum sampling should 
only be done if, in the opinion of the investigator, it is safe for the subject.
kAECOPD severity grading as indicated in Table 1.
* Non-serious AEs will be recorded in the eCRF and will not be entered into the safety database.
Table 6
Intervals between study visits
Interval
Optimal length of interval
Allowed interval1
Screening Visit
Screening Visit (pre-Month 0)Visit 1 
14 days
42 days before Visit 1
Scheduled study visits
Visit 1 (Month 0) Visit 2 (Month 6)
182 days 
175 - 203 days
Visit 2 (Month 6) Visit 3 (Month 12)
182 days 
175 - 203 days
AECOPD-driven study visit(s) and/ or phone contacts
Onset AECOPD symptoms AECOPD Visit
-
max 96 hours2
1If an AECOPD occurs at the time one of the scheduled [stable] study visits is planned, 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 consultation with 
GSK, the concluding visit (Visit 3, Month 12) may however exceptionally be conducted outside of the allowed interval if 
necessary by the investigator.
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).
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
90
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
91
Section 6.4.1.5 Record AECOPD history within the previous year
Documented, self-reported and non-documented AECOPD should be recorded in the 
eCRF. However, for study participation the subject should have had at least one 
documented moderate or severe AECOPD episode within the previous year.
Section 6.4.1.6 Smoking exposure history (ATS-DLD-78A questionnaire)/biomass 
exposure history (At Screening screening visit ONLY only)
The subject will be asked to complete the smoking history questionnaire (which is a 
shortened version of the American Thoracic Society-Division of Lung Diseases-78A 
[ATS-DLD-78A] questionnaire) by himself/herself. This questionnaire will be provided 
in paper. The subject will have to provide information about his/ her smoking history, 
including duration (number of years) and number of cigarettes smoked. Subject years 
exposed to biomass will be assessed from information obtained on indoor exposure to 
fuels such as wood, crop waste and dung, or coal.
Section 6.4.1.9 Pregnancy test
Female subjects of childbearing potential are to have a urine pregnancy test prior to 
any study procedure. Note: The urine pregnancy test must be performed even if the 
subject is menstruating at the time of the study visit. The test should be carried out 
before performing chest x-ray. If the test is positive, the chest x- ray should not be 
performed and the subject should be withdrawn from the study.
Section 6.4.1.13 Train subjects on the use of electronic Diary Card and assign 
electronic dairy card to subject

The site staff will follow electronic Diary Card completion closely and should 
provide timely input/guidance to ensure that the subject correctly completes the 
eDiary Card both AM & PM as per protocol reaches the targeted learning curve.
Section 6.4.1.14 Sputum sampling

Sputum sample collected at subject’s home (spontaneous):At home, sputum 
collection will not be permitted. However, Sself-collection of the sputum sample 
will be allowed only in specific cases, where the first dose of antibiotics absolutely 
needs to be taken before an AECOPD visit can take place.

Collected sputum will be diluted in DTT, processed and cultured within 6hrs of 
collection for microbiology testing 

Remaining DTT-sputum will be aliquoted as such and/or further diluted in STGG . 
These samples will be kept at -70/80°C until shipment to GSK or GSK designated 
lab for testing.
Refer to the SPM and the Central Laboratory Investigator Manual for more details and 
guidance on handling of sputum samples.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
91
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
92
Section 6.4.2.1 Check inclusion and exclusion criteria
At visit 1, all applicable inclusion and exclusion criteria as described in Sections 4.2
and 4.3 will be checked before enrolment.
Section 6.4.2.10 Record healthcare utilisation for COPD
Healthcare use for each COPD patient will be obtained through review of the subject’s 
medical record (aided by subject self-reporting). Healthcare utilisation includes primary, 
secondary and tertiary care settings such as self-care with over-the-counter [OTC] drugs, 
general practitioner (GP) visits, emergency room (ER) visits, and hospital visits.
Healthcare utilisation includes all unscheduled visits to a physician office, visits to 
urgent care, visits to emergency department, and hospitalizations. Healthcare use for the 
COPD should be entered in the eCRF. Refer to the SPM for more details and guidance on 
recording of healthcare use.
Section 6.4.2.14 Sputum Sampling

Sputum samples will be collected during the scheduled stable visits, if in the opinion 
of the investigator, it is safe for the subject.

Collected sputum will be diluted in DTT, processed and cultured within 6hrs of 
collection for microbiology testing.

Remaining DTT-sputum will be aliquoted as such and/or further diluted in STGG . 
These samples will be kept at -70/80°C until shipment to GSK or GSK designated 
lab for testing.
Refer to the SPM and the Central Laboratory Investigator Manual for more details and 
guidance on handling of sputum samples.
Section 6.4.2.15 Blood Sampling

Blood samples for biomarker analysis will be taken at the scheduled visits; Visit 
1(M0) and Visit 3 (M12), including:

Hematology profile, including differential cell counts
o
Approximately 2.0 mL of whole blood will be collected for hematology 
assessment. These samples should be kept at room temperature and 
shipped on the day of collection, ambient.

Specific biomarkers will include serum hsCRP, CXCL10 (IP-10) and plasma 
fibrinogen, may include other biomarkers based on results of ongoing disease 
understanding research.
o
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.
o
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.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
92
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
93
o
Approximately 6.0 mL of whole blood (EDTA) will be collected and 
processed to plasma for other biomarker assessment. After processing, 
these samples should be kept at -70/-80°C until shipment.
Refer to the SPM and the Central Laboratory Investigator Manual for more details and 
guidance on the collection, handling, and processing of blood samples.
Sections 6.4.2.16MWT

The subject should perform the supervised, standardised 6MWT at Visit 1 and Visit 
3 as presented in Table 4. The result of the test will be recorded in the eCRF.

Refer to the SPM for more details and guidance on the 6MWT.
Sections 6.4.3.3 Pregnancy Test
Female subjects of childbearing potential are to have a urine pregnancy test prior to 
any study procedure. Note: The urine pregnancy test must be performed even if the 
subject is menstruating at the time of the study visit. The test should be carried out 
before performing chest x-ray. If the test is positive, the chest x- ray should not be 
performed and the subject should be withdrawn from the study.
Section 6.4.3.7 Record healthcare utilisation for AECOPD
Healthcare use for each AECOPD will be obtained through review of the subject’s 
medical record (aided by subject self-reporting). Healthcare utilisation includes primary, 
secondary and tertiary care settings such as self-care with over-the-counter [OTC] drugs, 
general practitioner (GP) visits, emergency room (ER) visits, and hospital visits. all 
unscheduled visits to a physician office, visits to urgent care, visits to emergency 
department, and hospitalizations. Healthcare use for the AECOPD should be entered in 
the eCRF. Refer to the SPM for more details and guidance on recording of healthcare use.
Section 6.4.3.9 Sputum sampling

Collected sputum will be diluted in DTT, processed and cultured within 6hrs of 
collection for microbiology testing 

Remaining DTT-sputum will be aliquoted as such and/or further diluted in STGG . 
These samples will be kept at -70/80°C until shipment to GSK or GSK designated 
lab for testing.
Refer to the SPM and the Central Laboratory Investigator Manual for more details and 
guidance on handling of sputum samples.
Section 6.4.4.1 Sputum sampling
Full details for obtaining sputum samples are provided in the Module on Biospecimen 
Management in the SPM and in the Central Laboratory Investigator Manual 
accompanying this protocol.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
93
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
94
Section 6.5 Biological sample handling and analysis
Please refer to the SPM and the Central Laboratory Investigator Manual for details of 
biospecimen management (handling, storage and shipment).
Section 6.5.1 Use of specified study materials
When materials are provided by GSK Biologicals or the central laboratory, it is 
MANDATORY that all 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 PP analysis (See Section 9.3 for the definition of study cohorts/data sets 
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 or the central laboratory does not provide material for collecting and 
storing samples, appropriate materials from the investigator’s site must be used. Refer to 
the Module on Clinical Trial Supplies in the SPM and Central Laboratory investigator 
manual.
Section 6.5.2 Biological samples
Table 7 Biological Samples
Sample type
Quantity
Unit
Time point
Screening 
Visit
Visit 1
Visit 2
Visit 3
AECOPD
Visit
Fresh/stored
sputum
Maximum 
possible
mL
Pre-Month 0
Month 0
Month 6
Month 12
Within 96 hours 
of onset of 
symptoms
Blood for 
biomarkers 
21
mL
Month 0
Month 12
Section 6.5.3 Laboratory assays
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.
Standard bacteriological methodsculture (and semi-quantitative counts) will be 
performed on fresh sputum samples at the investigator’s institution and/or at a 
laboratory designated by GSK Biologicals. Identification of potential bacterial pathogens 
will be performed according to agreed identification methods (potential pathogens 
including, but not necessarily limited to, H. influenzae, S. pneumoniae, M. catarrhalis, S. 
aureus, P. aeruginosa, K. pneumoniae and and A. baumannii). All results should be 
entered in the eCRF.
Further bacterial characterization for H. influenzae isolates:Identified H. influenzae
isolates should be collected and stored in the investigator’s institution and will undergo 
further species confirmation ((i.e. H. influenzae/ H. haemolyticus and when possible, 
further differentiation (i.e., Hi/NTHi) at GSK Biologicals' laboratory or at a laboratory 
designated by GSK Biologicals using molecular techniques such as H. influenzae/ 
Haemophilus haemolyticus (H. haemolyticus) differentiation PCR. Identified H. 
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
94
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
95
influenzae isolates might undergo further testing at GSK Biologicals' laboratory or at a 
laboratory designated by GSK Biologicals’ using molecular techniques such as PCR 
and sequencing.
Identified M. catarrhalis isolates should be collected and stored in the investigator’s 
institution and might undergo further species confirmation (and when possible, further 
differentiation) at GSK Biologicals' laboratory or at a laboratory designated by GSK 
Biologicals using molecular techniques such as PCR and sequencing.
Identified P. aeruginosa isolates should be collected and stored in the investigator’s 
institution for future testing at GSK Biologicals' laboratory or at a laboratory 
designated by GSK Biologicals.
Further bacterial pathogen identification (including, but not necessarily limited to, H. 
influenzae, S. pneumoniae, M. catarrhalis, S. pyogenes, S. aureus and P. aeruginosa) and 
quantification (for H. influenzae, S. pneumoniae, M. catarrhalis) on stored sputum 
samples will be performed at GSK Biologicals' laboratory or a laboratory designated by 
GSK Biologicals using multiplex qualitative PCR and/or quantitative PCR.
Viral pathogen identification (including, but not necessarily limited to, RSV, 
parainfluenza virus, enterovirus/ rhinovirus, metapneumovirus, influenza virus, 
adenovirus, bocavirus and coronavirus) on stored sputum samples will be performed at 
GSK Biologicals' laboratory or a laboratory designated by GSK Biologicals using 
multiplex reverse transcription polymerase chain reaction (RT-PCR).
In addition, some respiratory viral pathogens (such as rhinovirus) may be quantified in 
stored sputum samples using RT-PCR at GSK Biologicals' laboratory or at a laboratory 
designated by GSK Biologicals.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
95
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
96
Table 8
Microbiology
System
Component
Method
Scale
Laboratory
Quality assessment
Fresh sputum
Please refer to SPM and/or 
Central Laboratory Manual 
for components tested
Gram staining
Qualitative/ 
semi-
quantitative
Investigator institution 
or GSK designated 
laboratory
Bacterial pathogen identification
Fresh sputum
Respiratory bacterial 
pathogens
(including H. influenzae,
S. pneumoniae, 
M. catarrhalis, S. aureus,
P. aeruginosa, 
K. pneumoniae and A. 
baumannii)
Standard 
bacteriological 
culture and 
standard 
identification 
methods including 
semi-quantitative 
culture
Qualitative 
Investigator’s institution 
and/or at a laboratory
designated by GSK 
Biologicals
Semi-
quantitative
H. influenzae
isolates of positive 
H. influenzae culture 
plates
H. influenzae/ 
H.haemolyticus 
differentiation
Molecular 
techniques such 
as differentiation 
PCR
Qualitative
GSK Biologicals 
laboratory* or designated 
laboratory
M. catarrhalis 
isolates of positive 
M. catarrhalis 
culture plates
Sample collection for 
isolate characterisation
Molecular 
techniques 
Qualitative
GSK Biologicals 
laboratory* or 
designated laboratory
P. aeruginosa 
isolates of positive 
P. aeruginosa 
culture plates
Sample collection for 
isolate characterisation
Molecular 
techniques 
Qualitative
GSK Biologicals 
laboratory* or 
designated laboratory
Stored sputum
Respiratory bacterial 
pathogens
(including H. influenzae,
S. pneumoniae, 
M. catarrhalis, S. aureus and
P. aeruginosa, 
Streptococcus pyogenes)
Multiplex 
qualitative PCR 
and/ or 
quantitative PCR
Qualitative 
and/ or 
quantitative
GSK Biologicals 
laboratory * or designated 
laboratory
Viral pathogen identification
Stored sputum
Respiratory viral pathogens 
(including RSV, 
parainfluenza virus, 
enterovirus/ rhinovirus, 
metapneumovirus, influenza 
virus, adenovirus, bocavirus 
and coronavirus)
Multiplex PCR
Qualitative 
and/or 
quantitative
GSK Biologicals 
laboratory * or designated 
laboratory
Respiratory viral 
pathogens (such as 
rhinovirus)
RT-PCR
Quantitative
GSK Biologicals 
laboratory* or 
designated laboratory
* GSK Biologicals laboratory refers to the Clinical Laboratory Sciences (CLS) Global Vaccines Clinical Laboratories 
(GVCL) in Wavre, Belgium; Rixensart, Belgium.
Stored frozen sputum samples (either in dithiothreitol [DTT] and/or in DTT 
supplemented with skim milk, tryptone, glucose, and glycerine [STGG] medium) might 
be used for assay development, such as assays for diagnostic purpose or for microbiome 
analysis and/or for assay validation/characterization purpose and/or quality control.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
96
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
97
Additional testing on stored sputum samples (such as, but not limited to, K. pneumoniae 
and A. baumannii PCR detection, quantitative PCR for other bacterial and/or viral 
pathogens, further characterisation of virus such as rhinovirus typing, pathogen 
genome/gene sequencing, quantitative/qualitative serotype-specific PCR, multilocus 
sequence typing, microarray typing, 16sRNA analysis) or on H. influenzae, M. 
catarrhalis and P. aeruginosa H. influenzae isolates (such as further strain 
characterisation using new molecular biology tools) 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 respiratory diseases COPD and/ or should such 
test(s) become available at GSK Biologicals’ laboratory or a laboratory designated by 
GSK.
Table 9
Planned assays on serological samples
Sample type
Component
Method
Scale
Laboratory
Plasma
Fibrinogen 
Per contract laboratory’s 
procedures
Quantitative
GSK 
Biologicals
or GSK 
designated 
lab
Serum
hsCRP
Per contract laboratory’s 
procedures
Quantitative
Serum
CXCL10 (IP-10)
Per contract laboratory’s 
procedures
Quantitative
Whole blood
Leukocytes (White 
Blood Cells) 
Per contract laboratory’s 
procedures
Quantitative 
Neutrophils *
Per contract laboratory’s 
procedures
Quantitative
Lymphocytes *
Per contract laboratory’s 
procedures
Quantitative
Eosinophils *
Per contract laboratory’s 
procedures
Quantitative
Basophils *
Per contract laboratory’s 
procedures
Quantitative
Monocytes *
Per contract laboratory’s 
procedures
Quantitative
Erythrocyte (Red 
Blood Cells) 
Per contract laboratory’s 
procedures
Quantitative
Haemoglobin 
Per contract laboratory’s 
procedures
Quantitative
Platelets
Per contract laboratory’s 
procedures
Quantitative
*For white blood cell differential counts
Additional testing for biomarkers on stored serum/plasma 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 respiratory 
diseases available at GSK Biologicals’ laboratory or a laboratory designated by GSK.
Section 7.2.1 Time periods for detecting and recording AEs and SAEs 
AEs and SAEs related to study participation will be collected and recorded from the time 
of the first study visit until the subject is discharged from the study.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
97
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
98
AEs leading to withdrawal from the study will be collected and recorded from the time 
of the first study visit until the subject is discharged from the study.
An overview of the protocol-required reporting periods for SAEs and AEs leading to
withdrawal is given in Table 9.
Table 10
Reporting period for SAE 
Study activity
Screening 
Visit
Visit 1
Visit 2
Visit 3
AECOPD
Visit
Study 
Conclusion
Pre-Month 
0
M 0
M 6
M 12
Within 96 
hours of 
onset 
symptoms
AEs/SAEs
leading to 
withdrawal 
from the 
study
Synopsis and Section 9 Statistical endpoints
Primary endpoint

Occurrence of potential bacterial and viral pathogens in sputum of stable COPD 
patients and during AECOPD, over the course of 1 year:

Bacterial pathogens, as identified by bacteriological culture methods, including 
(but not necessarily limited to) H. influenzae, M. catarrhalis, S. pneumoniae, S. 
aureus, P. aeruginosa, K. pneumoniae and A. baumannii.

Viral pathogens, as identified by multiplex RT PCR, including (but not 
necessarily limited to) RSV, parainfluenza virus, enterovirus/ rhinovirus, 
metapneumovirus, influenza virus, adenovirus, bocavirus and coronavirus and 
by rhinovirus quantitative RT-PCR.
Secondary endpoints

Occurrence of potential bacterial pathogens in sputum of stable COPD patients and 
during AECOPD, as measured by multiplex real-time qualitative PCR/ quantitative 
PCR and compared to data from bacteriological methods, over the course of 1 year:

Including (but not necessarily limited to) H. influenzae, M. catarrhalis, S. 
pneumoniae, S. aureus and P. aeruginosa.

Occurrence of potential bacterial and viral pathogens (overall and by species) in 
sputum of stable COPD patients by GOLD grade, over the course of 1 year.

Occurrence of potential bacterial and viral pathogens (overall and by species) in 
sputum during AECOPD by severity of AECOPD, over the course of 1 year.

Number Incident rate (per subject per year) of AECOPD, overall and by GOLD 
grade, over the course of 1 year.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
98
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
99

Severity of AECOPD, overall and by GOLD grade, over the course of 1 year.

Duration of AECOPD, overall and by AECOPD severity, over the course of 1 year.

FEV1% of predicted normal value in stable COPD patients, at Pre-Month 0 and 
Month 12.

Healthcare utilisation for COPD, over the course of 1 year.

Tertiary endpoints

Bacterial load measured by both culture and PCR in COPD and during AECOPD.

Viral load measured by PCR in COPD and during AECOPD.
Section 9.5 Analysis of primary objective
The proportion of sputum samples obtained at each visit (confirmed stable visits* and 
AECOPD visits [any severity, mild, moderate and severe) and positive for specific 
bacterial/ viral pathogens by bacteriological culture methods and PCR, respectively 
(overall and by bacterial/viral species) will be computed with 95% confidence intervals.
* A confirmed stable visit will be defined as a scheduled stablestudy visit for which 
the investigator confirms in the eCRF that the subject is stable/ has recovered from a 
previous exacerbation.
Section 9.6 Analysis of secondary objectives
The proportion of sputum samples obtained at each visit (confirmed stable visits* and 
AECOPD visits [any severity, mild, moderate and severe) and positive for specific 
bacterial pathogens by both bacteriological methods and PCR (overall and by bacterial 
species) will be computed with 95% confidence intervals.
* A confirmed stable visit will be defined as a scheduled stablestudy visit for which 
the investigator confirms in the eCRF that the subject is stable / has recovered from 
a previous exacerbation.
The proportion of sputum samples obtained at each stable visit and positive for specific 
bacterial/viral pathogens by bacteriological methods and PCR, respectively (overall and 
by bacterial/ viral species) will be computed with 95% confidence intervals, by GOLD 
grade at enrolment.
The proportion of sputum samples obtained at each AECOPD visits and positive for 
specific bacterial/ viral pathogens by bacteriological methods and PCR, respectively 
(overall and by bacterial/viral species) will be computed with 95% confidence intervals, 
by AECOPD severity.
These proportions will be also presented by GOLD grade at enrolment.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
99
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
100
The following incidence rates will be computed, with 95% confidence intervals (CI):

All-cause AECOPD.

AECOPD having sputum containing bacterial pathogens found by PCR and or by 
bacteriological methods or by both methods overall and by, but not limited to, the 
following bacterial species: H. influenzae, M. catarrhalis, S. pneumoniae, S. aureus, 
and P. aeruginosa).
The 95% CI of the incidence rate will be computed using a model which accounts for 
repeated events. The Generalised linear model assuming the Negative Binomial 
distribution for the response variable with logarithm as link function, and the logarithm of 
time for follow-up as an offset variable will be used. The incidence rates described above 
will also be computed for mild, moderate AECOPD and for severe AECOPD and by 
GOLD grade at enrolment and will be estimated by country.
Descriptive statistics (median, mean, range, standard deviation, first and third quartiles) 
on the CAT and SGRQ-C scores will be tabulated at each respective visit.
Descriptive summaries on healthcare use for COPD will be provided.
Section 9.6 Analysis of tertiary objectives
Descriptive summaries of the quantity of specific bacteria at each scheduled [stable] 
and exacerbation visit will be provided for both culture and PCR analysis.
Descriptive summaries of the quantity of specific viruses at each scheduled [stable] and 
exacerbation visit will be provided for PCR analysis.
Section 9.8.1 Sequence of analyses

An interim analysis of the bacterial primary objective will be performed when by the 
time of country allocation for the Phase 2 vaccine trial (provided that at least 4050
AECOPD sputum samples are available). The rate of positive samples will be 
computed for Hi, NTHi and Mcat together and per pathogen. No study report will 
be written at this stage.

A final analysis of all objectives will be performed after the last subject last visit of 
the entire study. A final study report will be written at this stage.
Section 12 References
Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for 
the diagnosis, management, and prevention of Chronic Obstructive Pulmonary 
Disease, updated 2017. Available from: 
http://goldcopd.org/gold-2017-global-strategy-diagnosis-management-prevention-copd/
Guoping Hu, MD, PhD; Yumin Zhou, MD et al. Risk of COPD from Exposure to 
Biomass Smoke: A Metaanalysis. CHEST. 2010; 138(1):20–31
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
100
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
101
Lim Sam, Lam Chi-Leung David et al. Impact of chronic obstructive pulmonary 
disease (COPD) in the Asia-Pacific region: the EPIC Asia population-based survey. 
Asia Pacific Family Medicine. 2015; 14:4
Singh Richa, Mackay AJ et al. Inflammatory thresholds and the species-specific effects 
of colonising bacteria in stable chronic obstructive pulmonary disease. Respiratory 
Research. 2014; 15: 114
World Health Organization (WHO). Chronic obstructive pulmonary disease (COPD) 
Fact Sheet. 2015. Available from: http://www.who.int/mediacentre/factsheets/fs315/en/. 
Accessed: 13 February 2017
Appendix A Clinical Laboratories
Table 14
GSK Biologicals’ laboratories
Laboratory
Address
GSK Biologicals Clinical 
Laboratory Sciences (CLS), 
Global Vaccine Clinical Laboratory, 
Rixensart
Biospecimen Reception - B7/44
Rue de l'Institut, 89 - B-1330 Rixensart - Belgium
GSK Biologicals Clinical 
Laboratory Sciences (CLS), 
Global Vaccine Clinical Laboratory, 
Wavre-Nord Noir Epine
Avenue Fleming, 20 - B-1300 Wavre - Belgium
Table 15
Outsourced Laboratories
Laboratory
Address
Q² Solutions Clinical Trials (US)
27027 Tourney Road, Suite 2E
Valencia, CA 91355
USA
Q² Solutions (Singapore)
Tan Tock Seng Hospital
Dept of Laboratory Medicine
Level 2, Podium Block
Tan Tock Seng Hospital
11 Jalan Tan Tock Seng
Singapore 308433
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
101
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
102
GlaxoSmithKline Biologicals
Vaccine Value & Health Science (VVHS)
Protocol Amendment 2
eTrack study number 
and Abbreviated Title
201112 (EPI-NTHI-001 BOD APA)
Amendment number:
Amendment 2
Amendment date:
20 October 2017
Co-ordinating author:
 Scientific Writer
Rationale/background for changes: 
The protocol has been amended to implement the following changes:
!
The study procedure with respect to pre- and post-bronchodilator spirometry 
during the screening visit has been amended in order to clarify that if a good 
quality spirometry was not obtained, the test can be repeated (preferably within 7 
days of the previous spirometry) as per investigator’s medical judgement.
!
Update of the laboratory section to better clarify that:
#
The PCR on H. influenzae isolate samples allows discrimination of Hi from 
non-Hi & identification of NTHi. Furthermore, reference to H. haemolyticus
has been deleted from the protocol as the PCR that will be performed on 
bacterial Hi isolates is designed to identify H. influenzae and not 
H. haemolyticus.
!
The cohorts for analyses have been updated as the PP analysis is not applicable to 
this specific study design, as all patients will be included in the analysis. 
Furthermore, according to ICH E9 recommendation a Full Analysis Set (FAS), 
All Screened set and All Enrolled Set have been added.
!
To correct some typographical errors.
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.
Amended text has been included in bold italics and deleted text in strikethrough in the 
following sections:
Contributing authors
!
 and 
 
 and 
 
and 
, 
Clinical Safety Representatives

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
102
19-OCT-2018
PPD
PPD
PPD
PPD
PPD
PPD
PPD

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
103
© [2017] GSK group of companies or its licensor. Copyright 2014-2017 of the GlaxoSmithKline 
group of companies. All rights reserved. Unauthorised copying or use of this information is 
prohibited.
List of Abbreviations
FAS
Full Analysis Set
DTT
Dithiothreitol
HRV
Human Rhinovirus
STGG
Skim Milk-Tryptone-Glucose-Glycerol
H. haemolyticus
Haemophilus haemolyticus 
PP
Per Protocol
Glossary of terms
Evaluable:
Meeting all eligibility criteria, complying with the 
procedures defined in the protocol, and, therefore, 
included in the per protocol (PP) analysis (see Section 9.3
for details on criteria or evaluability).
Trademarks
Note: In the body of the protocol (including the synopsis), the names of the products 
will be written without the superscript symbol ™ or ® and in italics.
Trademarks of the GlaxoSmithKline GSK 
group of companies
Generic description
COPD Assessment test™(CAT)
Questionnaire to measure the impact of 
COPD on wellbeing and daily life
EXACT-PRO®
Exacerbations of Chronic Pulmonary 
Disease Tool - Patient Reported Outcome
SGRQ-C
St. George’s Respiratory Questionnaire for 
COPD patients
Synopsis and Section 1.2 Rationale for the study
Because the infectious aetiology of AECOPD has been suggested to vary according to 
geographical region, the primary purpose of this study (which will be conducted in 
several countries in Asia Pacific) is to evaluate the occurrence of potential bacterial and 
viral pathogens in the sputum of stable COPD patients and at the time of AECOPD. 
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
103
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
104
Given the increasing and projected burden of COPD in the Asia Pacific region, this study 
will also evaluate the frequency, severity and duration of AECOPD, as well as the impact 
of AECOPD on health-related quality of life (HRQOL), healthcare utilisation and lung 
function.
Synopsis and Section 3 Study design overview

COPD symptoms
Subjects will be asked to record their COPD symptoms in an electronic Diary Card 
on a daily basis:

Daily in the morning throughout the study: Morning symptoms questionnaire.

Daily at bedtime throughout the study: EXACT-PRO (EXAcerbations of Chronic 
Pulmonary Disease Tool - Patient Reported Outcome) questionnaire.

Biological samples:

Sputum samples collected at site (spontaneous or induced, as per investigator 
judgement) will be collected at each study visit at the site (scheduled stable
visits and AECOPD visits) if, in the opinion of the investigator, it is safe for the 
subject.
Synopsis and Section 2.3 Tertiary objectives
Blood sampling for potential biomarkers for identification/quantification of biomarkers at 
Visit 1 and Visit 3.
Section 3.1.1 Detection of AECOPD
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 site staff investigator or medically qualified individual contacts the 
subject to determine if the alert is an AECOPD or not, and if an AECOPD visit is 
warranted. 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 site investigator or medically qualified 
individual 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 or medically qualified individual site concludes that the subject is 
not experiencing an AECOPD, this should be documented/ reported in the eCRF in 
the electronic Diary website (StudyWorks). Please refer to study procedures manual 
(SPM) for more details on how to perform this.

If the investigator or medically qualified individual site concludes that the subject 
may be experiencing an AECOPD, 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.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
104
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
105
Section 5.1 Regulatory and ethical considerations, including the informed consent 
process
Freely given and written or witnessed, thumb-printed informed consent must be obtained 
from each subject, as appropriate, prior to participation in the study.
Section 6.3 Outline of study procedures
Table 16
List of study procedures for scheduled visits
Epoch
Epoch 001
Type of contact
Screening 
Visit
Visit 1
Visit 2
Visit 3
Time point
Pre-Month 0
Month 0
Month 6
Month 12
Smoking exposure history (ATS-DLD-78A questionnaire)/ 
biomass exposure history (Biomass Exposure 
questionnaire)
O
Record additional COPD treatments prescribed by 
primary and secondary care physicians
●
●
●
Record Adverse Events (AEs) related to study 
participation*
●
●
●
●
Record serious adverse events (SAEs) related to study 
participation
●
●
●
●
hPhysical examination should be done only if necessary by the investigator or delegate.
Table 5 List of study procedures for AECOPD visits
Type of contact
AECOPD Visit
End of AECOPD phone call(s)
Time point
within 96 hours of onset 
symptoms
at least every 2 weeks as of 
AECOPD visit until AECOPD 
has resolvedi
Record date of visit
●
Physical examinationl
●
Urine Pregnancy Test
●
l Physical examination should be done only if necessary by the investigator or delegate.
Section 6.4.1.1 Informed consent
The signed/thumb printed informed consent of the subject must be obtained before study 
participation during the screening visit. Refer to Section 5.1 for the requirements on how 
to obtain informed consent and assent, as appropriate.
Section 6.4.1.11 Pre and post-bronchodilator spirometry
Pre- and post-bronchodilator spirometry should be performed during the screening visit. 
Only study-certified staff can perform spirometry assessment for this study. Spirometry 
will be performed using following the eResearchTechnology (ERT) instructions for use 
FlowScreen manual techniques that meet published standards [ATS/ERS, 2005and 
following all safety requirements. 
A good quality spirometry should be obtained, and will be confirmed by the spirometry 
provider. If during the Screening Visit a good quality spirometry was not obtained, the 
spirometry can be repeated, as per investigator’s medical judgement. If a repeat 
spirometry is elected, the site should make all possible efforts to repeat the spirometry 
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
105
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
106
preferably within 7 days of the previous spirometry. The data will be directly transferred 
from the provider to GSK Biologicals.
Section 6.4.1.14 Sputum sampling
Sputum samples will be collected during the screening visit if, in the opinion of the 
investigator, it is safe for the subject. If it is not safe, the sputum sample will not be 
collected and the subject will not be included in the study.

At home, sputum collection will not be permitted. However, self-collection of the 
sputum sample will be allowed only in specific cases, where the first dose of 
antibiotics absolutely needs to be taken before an AECOPD visit can take place.
Section 6.4.2.7 Pre- and post-bronchodilator spirometry
Pre- and post-bronchodilator spirometry should be performed during Visit 3 as detailed in 
Table 4. Only study-certified staff can perform spirometry assessment for this study. 
Spirometry will be performed using techniques that meet published standards 
[ATS/ERS, 2005] following the eResearchTechnology (ERT) instructions for use 
FlowScreen manual and following all safety requirements. The data will be directly 
transferred from the provider to GSK Biologicals.
Section 6.4.2.7 Pre- and post-bronchodilator spirometry
Pre- and post-bronchodilator spirometry should be performed during Visit 3 as detailed in 
Table 4. Only study-certified staff can perform spirometry assessment for this study. 
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 during Visit 3 a good quality spirometry was not obtained, the spirometry 
can be repeated, as per investigator’s medical judgement. If a repeat spirometry is 
elected, the site should make all possible efforts to repeat the spirometry preferably 
within 7 days of the previous spirometry. The data will be directly transferred from the 
provider to GSK Biologicals.
Section 6.4.2.10 Record healthcare resource utilisation
Healthcare use will be obtained through review of the subject’s medical record (aided by 
subject self-reporting). Healthcare 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 Card and reported in the 
eCRF at study visit entered in the eCRF. Refer to the SPM for more details and guidance 
on recording of healthcare use.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
106
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
107
Section 6.4.2.11 Additional COPD treatments prescribed by primary and secondary 
care physician
Section 6.4.2.14 Sputum sampling

At home, sputum collection will not be permitted.

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. This is not 
allowed at scheduled visits when subject should be in stable condition.

Remaining DTT-sputum will be aliquoted as such and/or when possible further 
diluted in STGG. These samples will be kept at -70/80°C until shipment to GSK or 
GSK designated lab for testing.
Section 6.4.2.16 HRQOL questionnaires

The subject will be asked to complete the questionnaires on HRQOL questionnaires 
by himself/herself, during specified study visits directly in the electronic Diary Card
as detailed in Table 4 and Table 5.
Section 6.4.3.4 Chest X-rays/pneumonia confirmation

Fever (oral temperature ≥> 37.5 °C),
All incidences of pneumonia must be captured on the pneumonia page of the eCRF. 
All pneumonias must be captured on the AE/SAE page of the eCRF and on the 
pneumonia page of the eCRF.
The investigators and site staff should remain vigilant for the possible development of 
pneumonia in patients with COPD as the clinical features of such infections overlap with 
the symptoms of COPD exacerbations. For all suspected cases of pneumonia, 
investigators are strongly encouraged to confirm the diagnosis (this includes obtaining a 
chest x-ray) and to initiate appropriate therapy as promptly as possible. All diagnoses of 
pneumonia (radiographically confirmed or unconfirmed) must be reported as an AE or 
SAE (if applicable) as detailed in Section 7.2 and Section 7.3.
Section 6.4.3.7 Record healthcare resource utilisation
Healthcare use will be obtained through review of the subject’s medical record (aided by 
subject self-reporting). Healthcare 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 the eDiary Card and reported in 
the eCRF at study visit entered in the eCRF. Refer to the SPM for more details and 
guidance on recording of healthcare use.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
107
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
108
Section 6.4.3.10 HRQOL questionnaires

The subject will be asked to complete the HRQOL questionnaire (CAT only) by 
himself/herself directly in the electronic Diary Card, during the AECOPD visit as 
detailed in Table 5.
Section 6.4.5 Health related quality of life questionnaires
Refer to section 6.4.2 for description of the Quality of Life (QoL) questionnaire. The 
subject will be asked to complete the HRQOL questionnaires by himself/herself, during 
specified study visits directly in the electronic Diary Card.
The investigator will provide the Quality of Life (QoL) questionnaire to the subject to 
record his/her condition until the next visit. The subjects will be instructed to return the 
completed QoL questionnaire to the investigator at the next visit/contact.
Collection and verification of the completed diary card/QoL questionnaire will take place 
during discussion with the subject at the subsequent visit. Any unreturned diary 
cards/QoL questionnaires will be solicited from the subjects through telephone call(s) or 
any other convenient procedure. The investigator will transcribe the collected information 
into the eCRF in English.
Section 6.5.1 Use of specified study materials
When materials are provided by GSK Biologicals or the central laboratory, it is 
MANDATORY that all 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 9.3 for the definition of study 
cohorts/data sets 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 or the central laboratory does not provide material for collecting 
and storing samples, appropriate materials from the investigator’s site must be used. 
Refer to the Module on Clinical Trial Supplies in the SPM and Central Laboratory 
investigator manual.
Section 6.5.3 Laboratory assays
Further bacterial characterization for H. influenzae isolates: Identified H. influenzae
isolates should be collected and stored in the investigator’s institution and will undergo 
further species confirmation (i.e. confirmed H. influenzae/ H. haemolyticus) and when 
possible, further differentiation (i.e., Hi/NTHi) at GSK Biologicals' laboratory or at a 
laboratory designated by GSK Biologicals using molecular techniques such as 
H. influenzae/ Haemophilus haemolyticus (H. haemolyticus) differentiation PCR. 
Identified H. influenzae isolates might undergo further testing at GSK Biologicals' 
laboratory or at a laboratory designated by GSK Biologicals’ using other molecular 
techniques such as PCR and sequencing.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
108
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
109
Identified P. aeruginosa isolates should be collected and stored in the investigator’s 
institution and might potentially undergo further for future testing at GSK Biologicals' 
laboratory or at a laboratory designated by GSK Biologicals.
In addition, some respiratory viral pathogens (such as HRVrhinovirus) may will be 
quantified in stored sputum samples (or subset) using RT-PCR at GSK Biologicals' 
laboratory or at a laboratory designated by GSK Biologicals.
Table 8 Microbiology
System
Component
Method
Scale
Laboratory
Quality assessment
Fresh sputum
Please refer to SPM and/or 
Central Laboratory Manual 
for components tested
Gram staining
Qualitative/ 
semi-
quantitative
Investigator institution or 
GSK designated 
laboratory
Bacterial pathogen identification
Fresh sputum
Respiratory bacterial 
pathogens
(including H. influenzae,
S. pneumoniae, 
M. catarrhalis, S. aureus,
P. aeruginosa, 
K. pneumoniae and A. 
baumannii)
Standard 
bacteriological 
culture and 
standard 
identification 
methods including 
semi-quantitative
culture
Qualitative 
Investigator’s institution 
and/or at a laboratory 
designated by GSK 
Biologicals
Semi-
quantitative
H. influenzae isolates 
of positive 
H. influenzae culture 
plates
H. influenzae species 
confirmation and when 
possible Hi/NTHi 
differentiation
Sample collection for 
potential further 
characterisation
H. influenzae/ 
H.haemolyticus 
differentiation
Molecular 
techniques such 
as differentiation 
PCR
Qualitative
GSK Biologicals 
laboratory* or designated 
laboratory
M. catarrhalis 
isolates of positive
M. catarrhalis 
culture plates
Sample collection for isolate 
characterisation
Molecular 
techniques 
Qualitative
GSK Biologicals 
laboratory* or 
designated laboratory
P. aeruginosa 
isolates of positive 
Paeruginosa culture 
plates
Sample collection for isolate 
characterisation
Molecular 
techniques 
Qualitative
GSK Biologicals 
laboratory* or 
designated laboratory
Viral pathogen identification
Stored sputum
Respiratory viral pathogens 
(including RSV, 
parainfluenza virus, 
enterovirus/ HRVrhinovirus, 
metapneumovirus, influenza 
virus, adenovirus, bocavirus 
and coronavirus)
Multiplex-PCR
Qualitative 
and/or 
quantitative
GSK Biologicals 
laboratory * or designated 
laboratory
* GSK Biologicals laboratory refers to the Clinical Laboratory Sciences (CLS) in Wavre, Belgium; Rixensart, Belgium; 
Marburg, Germany.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
109
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
110
Stored frozen sputum samples (either in dithiothreitol [DTT] and/or in DTT 
supplemented with skim milk, tryptone, glucose, and glycerine [STGG] medium) might 
be used for assay development, such as assays for diagnostic purpose or for microbiome 
analysis and/or for assay validation/characterization purpose and/or quality control.
Stored frozen sputum samples (in DTT supplemented with skim milk, tryptone, glucose, 
and glycerine [STGG] medium) might be collected when possible for potential assay 
development/validation purpose.
Additional testing on stored sputum samples (such as, but not limited to, K. pneumoniae 
and A. baumannii PCR detection, quantitative PCR for other bacterial and/or viral 
pathogens, further characterisation of virus such as rhinovirus typing, pathogen 
genome/gene sequencing, pathogen quantitative/qualitative serotype-specific PCR, 
multilocus sequence typing, microarray typing, 16sRNA analysis) or on H. influenzae, M. 
catarrhalis and P. aeruginosa bacterial isolates (such as agglutination assays, further 
strain characterisation using new molecular biology tools) 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 respiratory diseases and/ or should such 
test(s) become available at GSK Biologicals’ laboratory or a laboratory designated by 
GSK.
Section 7.2.1 Time periods for detecting and recording AEs and SAEs
Table 10 Reporting period for SAE and AEs leading to withdrawal
Study activity
Screening 
Visit
Visit 1
Visit 2
Visit 3
AECOPD
Visit
Study 
Conclusion
Pre-Month 0
M 0
M 6
M 12
Within 96 
hours of 
onset 
symptoms
AEs/SAEs 
related to 
study 
participation*
AEs leading to 
withdrawal 
from the study
*Study participation: Specific procedures required by study participation.
Synopsis and Section 9.1.3

Human Rhinovirus (HRV) Viral load measured by PCR in COPD and during 
AECOPD.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
110
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
111
Section 9.2 Determination of sample size
Assuming around 90% of the All Enrolled Set participated in the study population is in 
the PP cohort, on average 1 AECOPD visit per subject and 80% of the above population 
setsubjects in the PP cohort can provide an evaluable sputum sample at AECOPD, for 
240, 200, 160, and 50 enrolled subjects, one may expect around 180, 140, 120, 40 sputum 
samples in the exacerbation category of the PP analysis, respectively. Assuming that 
results from these sputum samples are independent and that the between country 
variability is much smaller than the within country variability, we would have the 
following 95% exact confidence interval for different incidences in sputum samples from 
exacerbations (see Table 12).
Assuming around 8090% of the all enrolled set population is in the PP cohort, from 
which around 90% of the subjects completed the study the one year follow up, for 240, 
200, 160 and 50 subjects enrolled, one would have at least 190, 160, 130 and 40 subjects 
evaluable respectively. Assuming further that around 80% of the subjects can provide an 
evaluable sputum sample at AECOPD, this would lead to around 150, 130, 100, 30 
subjects (see Table 13).
Section 9.3.1 All screened set
The all screened set will include all screened patients.
Section 9.3.2 Total All Enrolled cohort Set
The all enrolled set will include all successfully screened subjects in the study The total 
enrolled cohort will include all subjects enrolled in the study.
Section 9.3.3 Full Analysis Set
The Full Analysis Set (FAS) will include all enrolled patients except for those who 
discontinued the study during Visit 1.
Study objectives will be assessed on the FAS. The population set for each analysis will 
change according to the subjects evaluable for the specific endpoint.
The PP cohort will include all evaluable subjects (i.e. those meeting all eligibility criteria 
and complying with procedures described in the protocol) who did not receive a 
concomitant medication/ vaccination leading to elimination from the PP cohort.
Missed study visits and intervals between study visits will not be considered as criteria 
for exclusion from the PP cohort.
Note: Subjects using antibiotics on a continual basis (defined as more than 1 month in 
total) will be allowed to continue study participation, but may be eliminated from the per 
protocol (PP) cohort analyses.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
111
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
112
Section 9.4 Analysis of demographics
Withdrawal status will be summarised according to the reason for withdrawal. The 
number of withdrawn patients will be tabulated by study visit and overall.
Withdrawal status will be summarised 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 PP analyses will be tabulated.
Section 12 References
M.R. Miller, J. Hankinson, V. Brusasco et al. Standardisation of spirometry. Eur Respir 
J. 2005;26:319-38. Series ‘‘ATS/ERS task force: standardisation of lung function 
testing’’.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
112
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
113
GlaxoSmithKline Biologicals
Vaccine Value & Health Science (VVHS)
Protocol Amendment 3
eTrack study number 
and Abbreviated Title
201112 (EPI-NTHI-001 BOD APA)
Amendment number:
Amendment 3
Amendment date:
19 October 2018
Co-ordinating author:
 Scientific Writer
Rationale/background for changes: 
!
Removal of all STGG (Skim Milk-Tryptone-Glucose-Glycerol) wording 
throughout the protocol. STGG product not being available, it has been decided 
to replace it with cryobeads for storage of bacterial isolates. PCR testing on 
samples stored in cryobeads was shown to be as efficient as for samples stored in 
STGG. Besides, this decision has been taken for alignment with other COPD 
studies, where STGG solutions are no longer used.
!
Clarification of technique used for target identification. For the primary endpoint, 
various viral pathogens will be identified but not quantified. Along this line, the 
wording “and by HRV quantitative RT-PCR” has been removed from primary 
endpoint to avoid confusion as HRV viral load data will be reported as part of the 
tertiary endpoints.
!
Clarification in exclusion criteria section (4.3). Administration of antibiotics 
before study entry, where study entry is meant to be Visit 1.
!
Clarification in study procedure section (6.3) and in the section for recording 
current medication (6.4.2.10) during scheduled visits, where it has been specified 
that recording of any current medication is applicable for any disease not only 
COPD-related. Moreover, a footnote referring to Table 10 “Reporting period for 
SAE and AEs leading to withdrawal” has been added for further clarification, 
both in Table 4 and 5.
!
Addition of a section (actual 6.4.2.6) for Pregnancy test for Visit 1, Visit 2 and 
Visit 3. A Pregnancy test section for Screening Visit was included during 
Protocol Amendment 1: to be consistent, same wording has been included for the 
subsequent visits.

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
113
19-OCT-2018
PPD

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
114

Clarification of reporting of severe AECOPDs. Two sentences have been added 
in sections 7.1.1 and 7.2.2.1 for making clear that severe AECOPD events are not 
to be reported as SAE as they are meant as disease-related outcomes.

Rewording in the table concerning reporting period for SAE and AEs leading to 
withdrawal for better clarification (Table 10).

Addition of a new outsourced laboratory (DDL).

To correct some typographical errors.
Amended text has been included in bold italics and deleted text in strikethrough in the 
following sections:
List of Abbreviations
STGG
Skim Milk-Tryptone-Glucose-Glycerol
Section 4.3 Exclusion criteria for enrolment

Administration of antibiotics within 1 month of study entry OR continuous 
administration of antibiotics (defined as more than 30 days in total) within 90 days 
before study entry. 
* Study entry is Visit 1. If this exclusion criteria is met during Screening Visit the 
patient can enter the study and this exclusion criteria will be reassessed during Visit 
1.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
114
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
115
Section 6.3 Outline of study procedures
Table 4 List of study procedures for scheduled visits
Epoch
Epoch 001
Type of contact
Screening 
Visit
Visit 1
Visit 2
Visit 3
Time point
Pre-Month 0
Month 0
Month 6
Month 12
Informed consenta
●
Check inclusion/exclusion criteriaa
●
O
Record demographic dataa
●
Record medical history
●
Record history of AECOPD within the previous yearb
●
Record intercurrent comorbiditiesc
O
●
●
●
Record history of pneumococcal and influenza 
vaccination 
O
●
●
●
Smoking exposure history (ATS-DLD-78A questionnaire)/ 
biomass exposure history (Biomass Exposure 
questionnaire)
O
Smoking status
●
●
●
●
Physical examination including vital signsh
●
O
O
O
Urine Pregnancy Test
●
●
●
●
Measure/ record height and weightd
●
●
Pre- and post-bronchodilator spirometrye
●
●
Chest X-rayf
●
Record subject’s COPD status (stable, recovered or not 
recovered)
●
●
●
Record current medication for COPD
●
●
●
Record healthcare resource utilisation
●
●
●
Record additional treatments prescribed by primary and 
secondary care physicians
●
●
●
Train subject on use of electronic Diary Card and assign 
electronic Diary Card to the subject
O
O
Return electronic Diary Card
O
Sputum samplingg
●
●
●
●
Blood samples for biomarkers
●
● 
Record Adverse Events (AEs)*^ related to study 
participation
●
●
●
●
Record serious adverse events (SAEs)^ related to study 
participation
●
●
●
●
Screening conclusion
●
Study conclusion
●
HRQOL questionnaires:
CAT
O
O
O
SGRQ-C
O
O
O
^ Refer to Table 10 for description of which AE/SAEs are collected in this study.
h Physical examination (Visit1-3) should be done only if necessary by the investigator or delegate.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
115
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
116
Table 5 List of study procedures for AECOPD visits
Type of contact
AECOPD Visit
End of AECOPD phone call(s)
Time point
within 96 hours of onset 
symptoms
at least every 2 weeks as of 
AECOPD visit until AECOPD 
has resolvedi
Record date of visit
●
Physical examinationl
●
Urine Pregnancy Test
●
Chest X-rays/pneumonia confirmationj
●
Confirm AECOPD and record its start date
●
Record current medication for AECOPD
●
Record healthcare resource utilisation
●
Record additional COPD treatments prescribed by 
primary and secondary care physicians
●
Sputum samplingk
●
HRQOL questionnaire:
CAT
O
Record AECOPD severitym
●
●
Record AECOPD end date
●
Record Adverse Events (AEs)*^ related to study 
participation
●
●
Record serious adverse events (SAEs)^ related to 
study participation
●
●
^ Refer to Table 10 for description of which AE/SAEs are collected in this study.
Section 6.4 Detailed description of study procedure
Sputucm sampling at sub-sections 6.4.1.14 – 6.4.2.15 – 6.4.3.9:
Remaining DTT-sputum will be aliquoted as such and/or further diluted in STGG. These 
samples will be kept at -70/80°C until shipment to GSK or GSK designated lab for 
testing.
Section 6.4.2.6 Pregnancy test
Female subjects of childbearing potential are to have a urine pregnancy test prior to 
any study procedure. Note: The urine pregnancy test must be performed even if the 
subject is menstruating at the time of the study visit. 
Section 6.4.2.10 Record current medication for COPD

At each study visit/contact, the investigator should question the subject about any 
medications taken. administered for treatment of COPD.

All medications administered for treatment of COPD will be recorded in the eCRF.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
116
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
117
Section 6.5.3 Laboratory assays
Table 8 Microbiology 
Further bacterial pathogens identification  
Viral pathogens identification
System
Component
Method
Scale
Laboratory
Quality assessment
Fresh sputum
Please refer to SPM and/or 
Central Laboratory Manual 
for components tested
Gram staining
Qualitative/ 
semi-
quantitative
Investigator institution or 
GSK designated 
laboratory
Bacterial pathogen identification
Fresh sputum
Respiratory bacterial 
pathogens
(including H. influenzae,
S. pneumoniae, 
M. catarrhalis, S. aureus,
P. aeruginosa, 
K. pneumoniae and A. 
baumannii)
Standard 
bacteriological 
culture and 
standard 
identification 
methods including 
semi-quantitative 
culture
Qualitative 
Investigator’s institution 
and/or at a laboratory 
designated by GSK 
Biologicals
Semi-
quantitative
H. influenzae 
isolates of positive 
H. influenzae culture 
plates
H. influenzae species 
confirmation and when 
possible Hi/NTHi 
differentiation
Sample collection for 
potential further 
characterisation
Molecular 
techniques such 
as differentiation 
PCR
Qualitative
GSK Biologicals 
laboratory* or designated 
laboratory
Stored sputum
Respiratory bacterial 
pathogens
(including H. influenzae,
S. pneumoniae, 
M. catarrhalis, S. aureus and
P. aeruginosa, 
Streptococcus pyogenes))
Multiplex PCR
Qualitative 
and/ or quant
itative
GSK Biologicals 
laboratory * or 
designated laboratory
Viral pathogen identification
Stored sputum
Respiratory viral pathogens 
(including RSV, 
parainfluenza virus, 
enterovirus/ HRV, 
metapneumovirus, influenza 
virus, adenovirus, bocavirus 
and coronavirus)
Multiplex-PCR
Qualitative
GSK Biologicals 
laboratory * or 
designated laboratory
Respiratory viral pathogens 
(such as HRV)
RT-PCR
Quantitative
GSK Biologicals 
laboratory* or designated 
laboratory
Stored frozen sputum samples (in DTT supplemented with skim milk, tryptone, glucose, 
and glycerine [STGG] medium) might be collected when possible for potential assay 
development/validation purpose.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
117
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
118
Synopsis Primary endpoints and Section 9.1.1 Primary endpoint

Occurrence of potential bacterial and viral pathogens in sputum of stable COPD 
patients and during AECOPD, over the course of 1 year:

Bacterial pathogens, as identified by bacteriological methods, including (but not 
necessarily limited to) H. influenzae, M. catarrhalis, S. pneumoniae, S. aureus, 
P. aeruginosa, K. pneumoniae and A. baumannii.

Viral pathogens, as identified by RT PCR, including (but not necessarily limited 
to) RSV, parainfluenza virus, enterovirus/ Human Rhinovirus (HRV), 
metapneumovirus, influenza virus, adenovirus, bocavirus and coronavirus and 
by HRV quantitative RT-PCR.
Section 7.1.1 Definition of an adverse event
An AE is any untoward medical occurrence in a subject, temporally associated with the 
use of a medicinal product, whether or not considered related to the medicinal product, or 
temporally associated with a study procedure.
Examples of an AE include 

Signs, symptoms, or the clinical sequelae of a suspected interaction.
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.

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.

Occurrence of a severe AECOPD, unless in the opinion of the Investigator this is 
related to study procedure.
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
118
19-OCT-2018

CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
19-OCT-2018
119
Section 7.2.1 Time periods for detecting and recording AEs and SAEs – Table 10
Study activity
Screening 
Visit
Visit 1
Visit 2
Visit 3
AECOPD
Visit
Study 
Conclusion
Pre-Month 
0
M 0
M 6
M 12
Within 96 
hours of 
onset 
symptoms
AEs/SAEs 
related to 
study 
participation*
AEs/SAEs
leading to 
withdrawal 
from the 
study
Section 7.2.2.1 Active questioning to detect SAEs
Each subject/ will be instructed to contact the investigator immediately should the subject 
manifest any signs and symptoms (s)he perceives/ they perceive as serious. However, an 
occurrence of severe AECOPD is not defined as an SAE and therefore does not need to 
be reported as such, unless in the opinion of the Investigator this is related to a study 
procedure.
Appendix A
Table 15 Outsourced Laboratories
Laboratory
Address
Q² Solutions Clinical Trials (US)
27027 Tourney Road, Suite 2E
Valencia, CA 91355
USA
Q² Solutions (Singapore)
Tan Tock Seng Hospital
Dept of Laboratory Medicine
Level 2, Podium Block
Tan Tock Seng Hospital
11 Jalan Tan Tock Seng
Singapore 308433
DDL Diagnostic Laboratory B.V.
Fonteijnenburghlaan 7
Voorburg
Netherland
 
CONFIDENTIAL
201112 (EPI-NTHI-001 BOD APA)
Protocol Amendment 3 Final
75661ebdab2e949f7a1f1bc2071b9dec72aceccf
119
19-OCT-2018